The Red Book ELSO 5th Edition [PDF]

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Extracorporeal Life Support: The ELSO Red Book

5th Edition

Thomas V. Brogan, M.D. Laurance Lequier, M.D. Roberto Lorusso, M.D., Ph.D. Graeme MacLaren, M.D. Giles Peek, M.D.

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Senior Editor: Thomas V. Brogan Editors: Laurance Lequier, Roberto Lorusso, Graeme MacLaren, Giles Peek Manuscript Editor: Cindy Cooke Cover Design: Madeleine Eiche Back Cover: Photo of Dr. Bartlett and former ECLS patient, 2009 Layout: Peter Rycus

©2017 Extracorporeal Life Support Organization, Ann Arbor, Michigan Previous editions 1996, 2000, 2005, 2012 Printed in the United States of America ISBN 978-0-9656756-5-9

Dedication The editors would like to dedicate the 5th Edition of the Red Book to Peter Rycus. For many in the ECMO community, Peter Rycus is ELSO, having worked tirelessly for over two decades. He maintains the ELSO data registry, helps to edit the Red Book and ELSO guidelines, and organizes the website, conferences, and training courses. His is often the first face many of us see when arriving at a meeting. He has published more than 70 studies using ELSO data and provided data to researchers throughout the world that have been used in many more studies. Additionally, Peter has been instrumental in the establishment of the global ELSO chapters and has flown all over the world to insure their success. He represents ELSO with unending cheer, boundless enthusiasm, and unmatched organizational skills. Akin to Radar on “Mash,” he usually seems to know what you want before you do. Members of the ECMO community owe Peter a debt of gratitude for his work. As the editors of this Red Book, we take this opportunity to express our appreciation.

We would also like to dedicate this edition to the individual ELSO centers who provide the clinical care needed to provide patients and families with hope and the opportunity to live beyond hospital discharge. Nurses, ECMO specialists, perfusionists, respiratory therapists, physicians, surgeons, researchers, and managers create advances in clinical care and research. ELSO centers provide the data to the Registry that permits benchmarking, quality improvement, and research. Individuals at ELSO centers unselfishly advise clinicians at other centers under the difficult circumstances we have all experienced. In recognition of the immense amount of effort and commitment that you, the people who use ECMO, devote to your patients, we the editors dedicate this Red Book to you. Please continue your amazing work!

ELSO Member Centers 2017

List of Contributors

Erik E. Abel, PharmD, BCPS Cardiothoracic Surgery and Mechanical Circulatory Support The Ohio State University Wexner Medical Center, Columbus Darryl Abrams, MD Division of Pulmonary, Allergy, Critical Care Columbia University College of Physicians and Surgeons New York-Presbyterian Hospital, New York

Rubia Baldassarri, MD Azienda Ospedaliero Universitaria Pisana, Pisa Ryan Barbaro, MD Division of Pediatric Critical Care University of Michigan, Ann Arbor Robert H. Bartlett, MD, FELSO Professor of Surgery, Emeritus University of Michigan, Ann Arbor

Peta M. A. Alexander, MBBS Cardiac Intensive Care Unit Boston Children’s Hospital, Boston

Patricia Bastero, MD Texas Children’s Hospital Baylor College of Medicine, Houston

Gail M. Annich, MD The Hospital for Sick Children University of Toronto

John Beca, MD Paediatric Intensive Care Unit Starship Children’s Hospital, Auckland

Veronica Armijo-Garcia, MD The University of Texas Health Science Center at San Antonio

Dorothy M. Beke, RN, MS, CPNP-PC/AC Cardiac Intensive Care Unit Boston Children’s Hospital, Boston

Matthew Bacchetta, MD Division of Thoracic Surgery Columbia University College of Physicians and Surgeons New York-Presbyterian Hospital, New York

Jan Bělohlávek, MD, PhD General Teaching Hospital Charles University of Prague

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Contributors

Mirko Belliato, MD IRCCS Policlinico San Matteo Foundation, Pavia Melania Bembea, MD, PhD Charlotte R. Bloomberg Children’s Center Johns Hopkins University, Baltimore Derek Best, RN, RSCN, BN Royal Children’s Hospital Melbourne, Victoria Shazia Bhombal, MD Division of Neonatal & Developmental Medicine Stanford University School of Medicine, Palo Alto James M. Blum, MD, FCCM Chief, Critical Care, Department of Anesthesiology Department of Biomedical Informatics Emory University Hospital, Atlanta Stephen J. Bottrell, CCP Royal Children’s Hospital Melbourne, Victoria Susan L. Bratton, MD, MPH Division of Pediatric Critical Care Medicine University of Utah Department of Pediatrics, Salt Lake City Nicolas Bréchot, MD, PhD Groupe Hôpital de la Pitié Salpetrière Assistance Publique-Hôpitaux de Paris Université Pierre et Marie Curie, Paris Steve Brediger, RRT-NPS Department of Respiratory Care Boston Children’s Hospital, Boston Brian C. Bridges, MD, FAAP Division of Pediatric Critical Care Medicine Vanderbilt University School of Medicine, Nashville

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Daniel Brodie, MD Division of Pulmonary, Allergy, Critical Care Columbia University College of Physicians and Surgeons New York-Presbyterian Hospital, New York Thomas V. Brogan, MD Seattle Children’s Hospital University of Washington School of Medicine, Seattle Kate L. Brown MD, MPH, MRCP Pediatric Cardiac Intensive Care Great Ormond Street Hospital for Children, London Hergen Buscher, MD, FCICM, EDIC, DEAA Intensive Care Medicine St. Vincent’s Hospital, Darlinghurst Warwick Butt MBBS, FRACP, FCICM, FELSO Royal Children’s Hospital University of Melbourne Jonathan W. Byrnes, MD The Heart Institute Cincinnati Children’s Hospital Medical Center University of Cincinnati School of Medicine Daniele Camboni, MD Department of Cardiothoracic Surgery University Medical Center, Regensburg Luis Caneo, MD, PhD Heart Institute University of Sao Paulo Medical School Gerry Capatos, MBBCh, FCP Arwyp Private Hospital Johannesburg Titus Chan, MD, MS, MPP Pediatric Cardiac Critical Care Medicine Seattle Children’s Hospital, Seattle

Contributors

Yih-Sharng Chen, MD, PhD Chief, Cardiovascular Surgery National Taiwan University Hospital, Taipei

Carl F. Davis, MB, MCH, FRCS Department of Paediatric Surgery Royal Hospital for Children, Glasgow

Roberto Chiletti MD, FCICM Department of Paediatric Intensive Care Unit The Royal Children’s Hospital, Melbourne

Joseph A. Dearani, MD Departments of Cardiovascular Surgery Mayo Clinic, Rochester

Jonna Clark, MD Pediatric Critical Care Medicine Department of Bioethics and Humanities Seattle Children’s Hospital, Seattle

Lorenzo Del Sorbo, MD Interdepartmental Division of Critical Care Medicine University of Toronto

Alain Combes, MD, PhD Groupe Hôpital de la Pitié Salpetrière Assistance Publique-Hôpitaux de Paris Université Pierre et Marie Curie, Paris

Matteo Di Nardo, MD Department of Pediatric Anesthesia and Intensive Care Children’s Hospital Bambino Gesù, Rome

Steven A. Conrad, MD PhD, MCCM Muslow Endowed Chair of Clinical Informatics Professor of Medicine, Pediatrics and Emergency Medicine Louisiana State University Health Sciences Center, Shreveport

Rodrigo Diaz, MD, MEd Unidad ECMO Clinica Las Condes, Santiago

David S. Cooper, MD, MPH The Heart Institute Cincinnati Children’s Hospital Medical Center University of Cincinnati School of Medicine Timothy Cornell, MD Department of Surgery University of Michigan, Ann Arbor Heidi J. Dalton MD, MCCM Director, Adult and Pediatric ECLS INOVA Fairfax Hospital, Fairfax Cosimo D’Alessandro, MD Hôpital de la Pitié Salpetrière Assistance Publique-Hôpitaux de Paris Université Pierre et Marie Curie, Paris

Yves d’Udekem, MD, PhD, FRACS Royal Children’s Hospital Murdoch Children’s Institute University of Melbourne Amy L. Dzierba, PharmD, BCPS, BCCCP, FCCM New York-Presbyterian Hospital Columbia University Medical Center, New York Aly El-Banayosy, MD Professor of Surgery and Medicine INTEGRIS Baptist Medical Center, Oklahoma City Eddy Fan, MD, PhD Interdepartmental Division of Critical Care Medicine, University of Toronto Gail M. Faulkner, RGN, RSCN Womens & Childrens CMG Glenfield Hospital, Leicester

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Contributors

Richard T. Fiser, MD University of Arkansas for Medical Science College of Medicine Arkansas Children’s Hospital, Little Rock

Matthew T. Harting, MD, MS Children’s Memorial Hermann Hospital University of Texas McGovern Medical School, Houston

Francis Fynn-Thompson MD Department of Cardiac Surgery Boston Children’s Hospital, Boston

Silvia M. Hartmann, MD Pediatric Critical Care Medicine Seattle Children’s Hospital, Seattle

James D. Fortenberry, MD Pediatrician-in-Chief Emory University, Atlanta

Chris Harvey, MB, ChB, MRCS Heartlink ECMO Centre Glenfield Hospital, Leicester

Björn Frenckner, MD, PhD Professor of Pediatric Surgery Karolinska University Hospital, Stockholm

Micheal L. Heard, RN Children’s Healthcare of Atlanta

Curt D. Froehlich, MD Nemours Alfred I duPont Hospital for Children Wilmington, Delaware

Jenna Heichel, MSN, APRN, CPNP-AC Division of Cardiac Critical Care Children’s National Health System Washington, DC

Samir K. Gadepalli, MD Division of Pediatric Surgery University of Michigan, Ann Arbor

Maggie M. Hickey, RGN, RSCN Deputy ECMO Coordinator University Hospitals of Leicester

Antonella Galeone, MD, PhD Hôpital de la Pitié Salpetrière Assistance Publique-Hôpitaux de Paris Université Pierre et Marie Curie, Paris

Ronald B. Hirschl, MD Division of Pediatric Surgery University of Michigan, Ann Arbor

Sandro Gelsomino, MD, PhD Cardio-Thoracic Surgery Department Maastricht University Medical Centre, Maastricht Fabio Guarracino, MD Azienda Ospedaliero Universitaria Pisana, Pisa Isaac Hammond, PA-C Pediatric Cardiothoracic Surgery Children’s Hospital at Montefiore, Bronx

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Stephen B. Horton PhD, CCP, CCP, FACBS Royal Children’s Hospital The University of Melbourne Aparna Hoskote, MBBS, MD, MRCP Consultant Pediatric Cardiac Intensive Care Great Ormond Street Hospital for Children, London Syed Hussain, MD Department of Thoracic and Cardiovascular Surgery The Cleveland Clinic, Cleveland

Contributors

Hanneke IJsselstijn, MD, PhD Departments of Pediatric Surgery and Intensive Care Erasmus Medical Center – Sophia Children’s Hospital, Rotterdam William Alex Jakobleff, Jr., MD Montefiore Medical Center Albert Einstein College of Medicine, Bronx Marcus D. Jarboe, MD Division of Pediatric Surgery University of Michigan, Ann Arbor Melissa B. Jones, MSN, APRN, CPNP-AC Division of Cardiac Critical Care Children’s National Health System Washington DC Hussein D. Kanji, MD, MSc, MPH, FRCP Critical Care Medicine University of British Columbia, Vancouver Javier Kattan, MD School of Medicine Pontificia Universidad Católica de Chile, Santiago Shaf Keshavjee, MD Toronto General Hospital University of Toronto Christa Jefferis Kirk, PharmD Seattle Children’s Hospital Roxanne Kirsch, MD, MBE, FRCPC, FAAP The Hospital for Sick Children University of Toronto School of Medicine, Toronto Kevin P. Lally, MD, MS University of Texas McGovern Medical School The Fetal Center at Children’s Memorial Hermann Hospital, Houston

Stephanie Larsen, BS RRT-NPS Department of Respiratory Care Boston Children’s Hospital, Boston Charles Larson MDCM, FRCPC Department of Paediatric Intensive Care Unit The Royal Children’s Hospital, Melbourne Guillaume Lebreton, MD Hôpital de la Pitié Salpetrière Assistance Publique-Hôpitaux de Paris Université Pierre et Marie Curie, Paris Philippe Léger, MD Hôpital de la Pitié Salpetrière Assistance Publique-Hôpitaux de Paris Université Pierre et Marie Curie, Paris Pascal Leprince, MD, PhD Hôpital de la Pitié Salpetrière Assistance Publique-Hôpitaux de Paris Université Pierre et Marie Curie, Paris Laurance L. Lequier, MD Medical Director, PICU Stollery Children’s Hospital, Edmonton Roberto Lorusso, MD, PhD Cardio-Thoracic Surgery Department Maastricht University Medical Centre Maastricht William R. Lynch, MD Thoracic Surgery, Department of Surgery University of Michigan, Ann Arbor Graeme MacLaren, MBBS, FRACP, FRCP, FCICM, FCCM National University Health System, Singapore Royal Children’s Hospital, Melbourne Marlous J Madderom, PhD Dept. of Pediatric Surgery and Intensive Care Erasmus Medical Center – Sophia Children’s Hospital, Rotterdam xi

Contributors

Jos Maessen, MD, PhD Cardio-Thoracic Surgery Department Maastricht University Medical Centre Maastricht Patti Massicotte, MD Stollery Children’s Hospital Edmonton Ciro Mastroianni, MD, PhD Hôpital de la Pitié Salpetrière Assistance Publique-Hôpitaux de Paris Université Pierre et Marie Curie, Paris Wesley A. McKamie, RRT CCP Cardiac Perfusionist Baptist Medical Center, Little Rock D. Michael McMullan, MD, FACS Cardiothoracic Surgery Seattle Children’s Hospital University of Washington Medical School, Seattle Giulio Melisurgo, MD San Raffaele Hospital Vita-Salute University, Milan Malaika Mendonca, MD Division Chief, Pediatric Cardiac Critical Care Sheikh Khalifa Medical City Elizabeth A. Moore, MBA, RN, BSN University of Iowa Hospitals, Iowa City Naoto Morimura, MD, PhD Department of Emergency Medicine Yokohama City University Graduate School of Medicine, Yokohama Tracy Morrison, MSQA, BSN, RN Premier Health Miami Valley Hospital, Dayton

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Chirine Mossadegh, RN Hôpital Pitié-Salpêtrière Assistance Publique-Hôpitaux de Paris Justin Muir, PharmD Clinical Pharmacy Manager New York-Presbyterian Hospital Columbia University Medical Center, New York Priya Nair, MBBS St. Vincent’s Health Network University of New South Wales, Sydney Jose Navia, MD Department of Thoracic & Cardiovascular Surgery The Cleveland Clinic, Cleveland Roy Ochiai, MD, PhD Department of Anesthesiology TohoUniversity School of Medicine, Tokyo Mark T. Ogino, MD FAAP Nemours Alfred I duPont Hospital for Children Wilmington Matthew L. Paden, MD Division of Pediatric Critical Care Emory University, Atlanta Federico Pappalardo, MD San Raffaele Hospital Vita-Salute University, Milan Bhavesh M. Patel, MD, FRCP, RDMS Department of Critical Care Medicine Mayo Clinic Hospital, Phoenix Meral Patel, MD Division of Pediatric Critical Care Emory University, Atlanta

Contributors

Giles J. Peek, MD, FRCS, CTh, FFICM, FELSO Chief, Pediatric Cardiothoracic Surgery, ECMO Director Children’s Hospital at Montefiore, New York Vincent Pellegrino MBBS, FRACP, CICM Alfred Intensive Care Unit Alfred Hospital, Melbourne Antonio Pesenti, MD, FELSO Università di Milano Fondazione Cà Granda Ospedale Maggiore Policlinico, Milan Suneel Pooboni, MBBS, MD, DCH, FRCP, FRCPCH, FCCP University Hospitals of Leicester Leicester, United Kingdom Richard Porter, MBChB, FRCA, FFICM, EDIC, PGCert Heartlink ECMO Centre Glenfield Hospital University Hospitals of Leicester NHS Trust

Melissa Reynolds, PhD Colorado State University Fort Collins, Colorado Simon G. Robinson, BM, BS Glenfield, Leicester Children’s Hospital University Hospitals of Leicester NHS Trust Peter P. Roeleveld, MD Consultant Pediatric Intensivist ECMO Director Leiden University Medical Center Juan J. Ronco, MD, FRCPC Vancouver General Hospital University of British Columbia Vancouver Peter Rycus, MPH, FELSO Extracorporeal Life Support Organization (ELSO) Ann Arbor, MI Lindsay M. Ryerson, MD Department of Pediatrics Stollery Children’s Hospital, Edmonton

Thomas Pranikoff, MD, FACS Surgeon-in-Chief Brenner Children’s Hospital, Winston-Salem

Sameh M. Said, MD Departments of Cardiovascular Surgery Mayo Clinic, Rochester

Parthak Prodhan, MD, FAAP, FCCM University of Arkansas for Medical Sciences Arkansas Children’s Hospital, Little Rock

Caroline Sampson, MBBS, BMedSci, FRCA, FFICM, EDIC Heartlink ECMO Centre Glenfield Hospital University Hospitals of Leicester NHS Trust

Lakshmi Raman, MD Department of Pediatrics University of Texas Southwestern Medical Center, Dallas. Marco Ranucci, MD Department of Cardiothoracic and Vascular Anesthesia and ICU IRCCS Policlinico San Donato, Milan,

Gregory J. Schears, MD Departments of Anesthesiology Mayo Clinic, Rochester, MN Christof Schmid, MD Department of Internal Medicine University Medical Center Regensburg

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Contributors

Matthieu Schmidt, MD, PhD Hôpital de la Pitié Salpetrière Assistance Publique-Hôpitaux de Paris Université Pierre et Marie Curie, Paris Jamie McElrath Schwartz, MD Charlotte R. Bloomberg Children’s Center Johns Hopkins University School of Medicine, Baltimore Steven M Schwartz, MD, FRCPC The Hospital for Sick Children The University of Toronto School of Medicine, Toronto Arlene Sheehan, RN, MS, NNP  Neonatal ECMO Program Lucile Packard Children’s Hospital Stanford, Palo Alto Ayan Sen, MD, MSc, FACEP, FCCP Mayo Clinic College of Medicine Mayo Clinic Hospital, Phoenix Lara Shekerdemian, MB ChB, MD, MHA, FRACP Chief of Critical Care Texas Children’s Hospital Baylor College of Medicine, Houston Jayne Sheldrake, RN Intensive Care Unit The Alfred Hospital, Melbourne Billie L. Short, MD, FELSO Children’s National Health System The George Washington University School of Medicine, Washington, DC Dr Farah Siddiqui, MBChB University Hospitals of Leicester Glenfield General Hospital, Leicester

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Rachel Sirignano, MD Division of Pediatric Critical Care Emory University, Atlanta Jon H Smith, MBChB, MRCP, FRCA Freeman Hospital Newcastle upon Tyne Lamia Soghier, MD Children’s National Health System The George Washington University School of Medicine, Washington, DC Thomas Staudinger, MD Vienna General Hospital Medical University of Vienna Denise M. Suttner, MD Rady Children’s Hospital San Diego, CA Justyna Swol, MD Intensive Care and Emergency Medicine HELIOS Frankenwaldklinik, Kronach Ravi R. Thiagarajan, MBBS, MPH Children’s Hospital Boston Harvard Medical School, Boston John M. Toomasian, MS, CCP, FELSO Extracorporeal Life Support Laboratory University of Michigan School of Medicine, Ann Arbor Sebastian Tume, MD Baylor College of Medicine Texas Children’s Hospital, Houston Shirley Vallance, MPH Intensive Care Unit The Alfred Hospital, Melbourne

Contributors

Krisa Van Meurs, MD Rosemarie Hess Professor of Neonatal and Developmental Medicine Stanford University School of Medicine Lucile Packard Children’s Hospital, Palo Alto Leen Vercaemst, B.CP, ECCP, RN, RM Perfusionist, ECMO Coordinator, Coordinator Perfusion School Leuven Gasthuisberg Campus, UZ Leuven Gregor Walker, MB, MD, FRCS Department of Paediatric Surger Royal Hospital for Children, Glasgow Patrick Weerwind, PhD Cardiovascular Research Institute Maastricht (CARIM) Maastricht University Medical Centre Maastricht Anne Marie Winkler, MD Director of Medical Affairs Instrumentation Laboratory, Bedford Jennifer Workman, MD Division of Pediatric Critical Care Medicine University of Utah Department of Pediatrics, Salt Lake City Yu Xia, MD, MS Department of Cardiothoracic and Vascular Surgery Montefiore Medical Center, Bronx

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Preface to the 5th Edition

Since the publication of the 4th edition of the Red Book, significant evolution has occurred in the application of extracorporeal life support (ECLS). The technology has been improved, making circuits simpler, smaller, and safer. At the same time, a number of studies have examined ECLS in adults and children, deepening our understanding of when and how it is used. As a consequence, the number of ELSO centers had expanded to 465 at the end of 2016, and the only continent that has yet to see substantial growth in the presence of ECLS centers is Antarctica. To reflect the rapid expansion of ECLS application, we have altered the structure of this, the 5th Edition of the ELSO Red Book. However, like the 4th Edition, the content closely follows the ECLS guidelines published by ELSO. The book has been divided into large sections covering issues related to specific patient populations, including detailed discussion of indications and provision of mechanical support for these patient groups. These sections are preceded by ECLS principles that relate to all or nearly all patients receiving mechanical support. The final section covers more particular applications of ECLS, other forms of mechanical support, and organizational issues. Throughout this edition the terms extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS) are used interchangeably. Despite advances in the technology and new applications of this support mode, the older and less inclusive term ECMO has proven to have undying character. As such we have chosen to keep ECMO along with the newer and broader term ECLS. As with previous editions, and in the spirit of academic collaboration, any figure, table, or text not previously bound by copyright may be reproduced in scientific publications without further permission, conditional on the source being referenced. We would like to express our sincere gratitude to the experts from the ECLS community who have enthusiastically contributed to this edition of the Red Book and have advanced the science of ECLS. Also, we wish to thank Cindy Cooke, our manuscript editor and Peter Rycus, the layout editor. Thomas V. Brogan Laurance Lequier Roberto Lorusso Graeme MacLaren Giles Peek

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Table of Contents

Dedication............................................................................................................................v Preface to the 5th Edition............................................................................................... xvii I. Extracorporeal Life Support: General Principles 1. The History and Development of Extracorporeal Support.......................................1 Extracorporeal Support: Earliest Beginnings..........................................................1 Global Spread of ECMO.........................................................................................6 Perseverance: Experience and Growing Indications in Adult ECMO.................... 9 References..............................................................................................................12 2. The History of ECMO: First Hand Accounts...........................................................17 The History of ECMO: First Hand Accounts.........................................................17 A Conversation with Dr. Robert H. Bartlett...........................................................17 A Conversation with Dr. Jay Zwischenberger........................................................22 3. Evolution and History of Global ELSO................................................................... 25 EuroELSO..............................................................................................................25 Asia-Pacific ELSO.................................................................................................26 Latin American ELSO...........................................................................................27 South and West Asian ELSO ............................................................................... 28 References............................................................................................................. 29 4. The Physiology of Extracorporeal Life Support......................................................31 Cardiopulmonary Physiology................................................................................31 Cardiopulmonary Pathophysiology.......................................................................33 Cardiopulmonary Pathophysiology during ECMO...............................................33 The ECMO Circuit............................................................................................... 34 Modes of Vascular Access and Perfusion..............................................................36 CO2 Removal.........................................................................................................45 ECMO Management when the Native Lung is Recovering..................................46 Summary................................................................................................................47 5. The Circuit.................................................................................................................. 49 Introduction........................................................................................................... 49 Historical Background.......................................................................................... 49 General Principles of Circuit Design.................................................................... 50 Blood Tubing Plasticizers......................................................................................51 ECLS Circuit Components....................................................................................52 Blood Pumps..........................................................................................................52 Pulsatility...............................................................................................................52 Roller Pumps..........................................................................................................53 Roller Pump Servo Regulation............................................................................. 54 Centrifugal Blood Pumps..................................................................................... 54 Centrifugal Pump Inlet Pressure Monitoring Techniques......................................55 Blood Pump Performance......................................................................................56 Regulatory Status...................................................................................................56 Pump Related Complications.................................................................................57 xix

Table of Contents

Commercial Centrifugal Pumps........................................................................... 60 Gas Exchange Devices..........................................................................................63 Commercial Gas Exchange Devices......................................................................65 Gas Exchanger Related Complications................................................................ 70 Heat Exchange and Heat Regulation.....................................................................71 Heat Exchanger Related Complications................................................................72 Circuit Priming......................................................................................................73 Circuit Monitoring.................................................................................................73 Summary................................................................................................................75 References..............................................................................................................76 6. Adverse Effects of ECLS: The Blood Biomaterial Interaction...............................81 Introduction............................................................................................................81 Normal Hemostasis ..............................................................................................82 Activation of the Coagulation Pathway.................................................................82 Activation of the Fibrinolytic Pathway..................................................................83 Developmental Hemostasis....................................................................................83 Coagulation Pathway Activation and Inflammatory Response............................ 84 Activation of the Coagulation System during ECLS.............................................87 Activation of the Innate Immune System...............................................................87 Endothelial Function in Hemostasis and Circuit Modifications........................... 88 References............................................................................................................. 90 7. Anticoagulation and Disorders of Hemostasis......................................................... 93 Introduction............................................................................................................93 Anticoagulation......................................................................................................93 Anticoagulation Monitoring...................................................................................95 Anticoagulation Laboratory Schedule and Blood Product Replacement.............. 98 Hemorrhagic and Thrombotic Complications...................................................... 99 Conclusions........................................................................................................... 99 References........................................................................................................... 100 8. Transfusion Management during Extracorporeal Support................................. 105 Blood Product Transfusion during Extracorporeal Support................................105 Use of Coagulation Factor Replacement............................................................. 111 References............................................................................................................117 II. Extracorporeal Life Support: Neonatal Respiratory Disease 9. Neonatal Respiratory Diseases............................................................................... 123 Introduction..........................................................................................................123 Congenital Diaphragmatic Hernia (CDH)...........................................................123 Meconium Aspiration Syndrome (MAS).............................................................123 Persistent Pulmonary Hypertension of the Newborn...........................................126 Pneumonia/Sepsis................................................................................................127 Surfactant Deficiency – Hyaline Membrane Disease......................................... 128 Surfactant Deficiency – Term Infants in Respiratory Failure............................. 129 References........................................................................................................... 130 xx

Table of Contents

10. Congenital Diaphragmatic Hernia and ECMO................................................... 133 Introduction..........................................................................................................133 Diagnosis.............................................................................................................133 Management........................................................................................................ 134 Mechanical Ventilation....................................................................................... 134 Inhaled Nitric Oxide............................................................................................135 Sildenafil..............................................................................................................135 Fetal Interventions...............................................................................................136 Management Adjuncts.........................................................................................137 ECMO..................................................................................................................137 Summary..............................................................................................................143 References........................................................................................................... 144 11. Indications and Contraindications in Neonates with Respiratory Failure.........151 Introduction..........................................................................................................151 Patient Selection Criteria.....................................................................................151 Indications............................................................................................................151 Contraindications.................................................................................................152 Weight 70%. When the native heart function is adequate, conduct a trial off bypass. When heart function is satisfactory, decannulate the patient.

Figure 4-13. VV-ECMO for respiratory support. 2-Cannula access.

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Venovenous ECMO In venovenous ECMO (VV), the perfusate blood is returned to the venous circulation and mixes with venous blood coming from the systemic organs, raising the oxygen content and lowering CO2 content in the right atrial blood. This mixed blood, now higher in oxygen content, passes into the right ventricle, the lungs, and into the systemic circulation. VV access is achieved by draining venous blood from the IVC via the femoral vein and reinfusing into the RA via the jugular (Figure 4-13), or by draining from the IVC and SVC and reinfusing into the RA via a separate lumen in a double lumen cannula (Figure 4-14). Hemodynamics during VV access are not affected by the circuit. Since the volume of blood removed is exactly equal to the volume of blood reinfused; there is no net effect on central venous volume or pressure, right or left ventricle filling, or hemodynamics. The content of oxygen and CO2 in the patient’s arterial blood represents that of right ventricle blood modified by any pulmonary function that might exist. The systemic blood flow is the native cardiac output and is unrelated to the extracorporeal flow.

Figure 4-14. VV-ECMO with a double lumen cannula.

The Physiology of Extracorporeal Life Support

Gas Exchange in VV-ECMO In VV-ECMO, some of the systemic venous return is drained into the ECMO system, oxygenated, and returned to the right atrium. Some of the systemic venous return goes directly to the right atrium where it mixes with the ECMO perfusate blood. The mixed blood passes through the right ventricle, native lungs, left heart and into the systemic circulation. In severe respiratory failure, the native lungs contribute little or none to gas exchange, so the arterial oxygen and CO2 levels are the result of mixing the oxygenated ECMO blood with the deoxygenated native venous blood. As a result, the arterial saturation ranges from 60% to 90%, depending on the relative amount of ECMO flow, native venous flow, lung function, and cardiac output. The desaturated arterial blood results in normal systemic oxygen delivery as long as the cardiac output and hemoglobin concentration (oxygen content) are adequate. These relationships are often confusing to ICU staff, because the usual goal of management is to keep the arterial saturation over 90%.

outlet minus inlet O2 content. Because the outlet blood is typically 100% saturated and PO2 is over 500 mmHg the dissolved oxygen can be as much as 10% of the oxygen content. Blood flow is limited by the resistance to flow in the drainage cannula, the suction produced by the pump or siphon, and the geometry of the cannulated vessel (usually the vena cava or right atrium). Typical maximum flow at 100 cm/H2O suction for common sizes of venous cannulas is 4-5 liters per minute. Relation of Extracorporeal Oxygenation to Systemic Oxygen Delivery Assuming that there is no native lung function, the systemic arterial content, saturation, and PO2 will result from mixing the flow of oxygenated blood from the membrane lung with the flow of venous blood which passes into the right ventricle, not into the ECMO drainage cannula, (hereafter referred to as the native venous flow). The amount of oxygen in systemic arterial blood is the result of the mixture of these two flows (Figure 4-15).

Oxygenation To illustrate the principles, the discussion begins with the assumption that there is no native lung gas exchange (which is often the case in ECMO patients). In a membrane lung (as in the native lung) oxygenation is a much greater problem than CO2 removal, so the initial focus is on oxygenation. The circuit and blood flow are planned for total oxygen supply (VO2) at rest or during moderate exercise. For adults this is 120 cc/min/m2 (3 cc/kg/min), or 250300 cc of oxygen/min for average adults. The membrane lung must be large enough to transfer this amount of oxygen. All devices currently on the market can achieve this (see “rated flow”). The oxygen supply from the membrane lung is dependent on the blood flow, the hemoglobin concentration, and the difference between the

Figure 4-15. Mixing of perfusate with native venous flow during VV-ECMO.

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Chapter 4

Calculations Related to Mixing Two Flows

Systemic Arterial PO2, Saturation, and Content During VV ECMO

When two blood flows of different oxygen contents mix, the resultant oxygen content is the average of the amount of oxygen in each of the two flows (not the average of the partial pressures). The amount of oxygen contributed by each flow is the oxygen content (in cc/dL) in the blood times the flow rate (in dL/min). The equation summarizing these events is in Figure 4-16. The same calculation can be done using saturation rather than oxygen content. This calculation using saturation is done for simplicity and is not an exact representation of the amount of oxygen content but is useful at the bedside (Figure 4-17). The combinations of flow and oxygen (expressed as saturation) variations are shown in Figure 4-18. Of the variables in the equation, all are known except the flow of venous blood which does not go through the extracorporeal circuit (the native venous flow). The native venous flow can be back calculated from the systemic arterial oxygen content or saturation. The total venous return (cardiac output) is the sum of the native venous and circuit flow.

Use of these equations in VV patient physiology are shown in Figure 4-18. In these examples, one variable is changed while others are held constant to illustrate the principles. Clinically, all these variables may change simultaneously and at different rates. For simplicity of the examples, we assume no native lung function, and approximate the points on the graphs. We do not account for dissolved oxygen in calculation of O2 content, although it can be significant when the PO2 is over 300. Example 1: Typical VV physiology. Suppose the extracorporeal flow for an adult with no lung function is 4 l/min and the systemic PO2 is 50 mmHg, saturation 88%, O2 content 12.3 cc/ dl. The Hb is 10.5 gm/dl and the venous blood saturation is 64%. The patient’s oxygen consumption is 200 cc/min. The oxygen content of blood leaving the membrane lung is determined primarily by the concentration of hemoglobin. At hemoglobin concentration of 10.5 gm/dl and 64% saturation, the drainage (inlet) O2 content is 9 cc/dl and the outlet content at 100% satura-

Figure 4-16. The relationship among flow and O2 content are shown in the equation. During ECMO all the variables are known except native venous flow (F2) and total flow (cardiac output). Native venous flow can be calculated. Cardiac output is F2 plus F1. This assumes no lung function and no recirculation.

Figure 4-17. The relationships among flow and O2 content using the data in Example 1. The same calculations are shown using saturation rather than content.

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The Physiology of Extracorporeal Life Support

tion is 14 cc/dl. The amount of oxygen supplied is lower. The systemic oxygen delivery is 920 to the patient is the outlet minus inlet content cc/min. The DO2/VO2 is 4.6. There has been (which is 5 cc/dl), times the flow (40 dl/min) a gain in systemic oxygen delivery because of equals 200 cc oxygen supplied per minute. The the higher cardiac output, despite a decrease in native venous flow is calculated at 2 L/min (per arterial saturation and content. If the patient’s equation in Figure 4-17) so the cardiac output is systemic oxygen consumption is 200 cc/min, 6 L/min (native plus circuit venous flow). DO2 systemic oxygen delivery is perfectly adequate is the arterial content (12.3 cc/dl) x 60 dl/min = and full aerobic metabolism is supported, even 738 cc/O2/min. DO2/VO2 ratio is 3.64. The O2 though the arterial PO2 is 45 mmHg and artecontent of native venous blood is the same as rial saturation is 84%. No changes are required the drainage content (9 cc/dl). The final com- but the ICU staff need to understand that the plete equation is 40 dl/min x 14 c/dl divided by hypoxemia does not require intervention. Un60 dl/min, plus 20 dl/min x 9 dl divided by 60 derstanding this concept can be difficult when dl/min=12.3 cc/O2/dl (corresponding to a PO2 the plan is to keep the arterial saturation over of approximately 50 mm/Hg). The calculation 90%. (Point B, Figure 4-18) Example 3: Anemia. The patient in Exusing saturation is 4 L/min x 100% + 2 L/min x 70% ÷ 6 L/min which yields a systemic arterial ample 1 is moderately anemic (Hb 10, 5 gm%) but stable. Suppose the hemoglobin suddenly saturation of 88% (Point A, Figure 4-18) Example 2: Increased cardiac output at drops to 8 gm%. The venous drainage is fixed fixed ECMO flow. If, in the same patient, the at 4 L/min by the resistance of the drainage cardiac output (venous return) increases to 8 L/ cannula, and cardiac output is 6 L/min. The min and the circuit flow is fixed at 4 L/min there outlet content at 100% sat is 10.7. The amount will more native venous return at 64% sat mix- of oxygen supplied by the membrane lung is ing with the fully saturated ECMO flow. The 10.7 minus 9 which is 1.7 cc/dl, so the memsystemic arterial content will decrease to 11.5 brane lung is supplying only 68 cc/min. The and the saturation will decrease to 84% corre- native venous flow is 20 dl/min and content is sponding to PO2 of 45 mmHg. The total amount 9 cc/dl. The arterial content has gone from 11.5 of oxygen going to the patient is the same (200 to 9.8, the arterial sat to 80% and the DO2 has cc/min), but the systemic saturation and PO2 gone from 738 cc/min to 588. This results in a DO2/VO2 ratio of 2.9 (assuming no difference in metabolic rate). However, since only 68 cc of oxygen is being added per minute, and the oxygen consumption is 200 cc/min, venous (inlet) content and saturation decrease quickly. When the inlet content falls to 5.7 (saturation 50%) the membrane lung O-I difference is 5 cc/ dl and the oxygen supplied is 200 cc/min. The mixture of the fully saturated blood at 40 dl/ min and the 50% saturated native venous flow results in arterial saturation of 75% and arterial content 9 cc/dl. The systemic oxygen delivery is 540 cc/min and the VO2/DO2 ratio is 2.7. The patient can remain in steady state with arterial saturation 75% and venous saturation 50%, but Figure 4-18. Mixing of flows in VV-ECMO. any further decrease in hemoglobin or increase Data from Examples 1-4 are shown. 43

Chapter 4

in metabolic rate will result in supply depen- flow from 4 to 5 L/min (maintaining Hb 10.5). dency and lactic acidosis (Point C, Figure 4-18). The DO2 increases to 792 cc/min, and the DO2/ Example 4: Increased metabolic rate. VO2 is 3.9. The third alternative for example 4 is Suppose the patient in Example 1 becomes to paralyze and cool the patient, decreasing the hypermetabolic (VO2=250 cc/min). The size of VO2 back to 200 cc/min. A fourth consideration the venous cannula determines that the circuit is to add another membrane lung to increase flow is at maximum at 4 L/min so the circuit the gas exchange surface, but O2 supply is still oxygen delivery is limited to 200 cc/min. The limited by the blood flow, so this will not help. cardiac output is 6 L/min. Going through the The tradeoff between extracorporeal flow same arithmetic, the patient will fall behind and hemoglobin is demonstrated in Figure 4-19. at the rate of 50 cc of oxygen per minute and This example shows a 80 kg man with oxygen venous content and saturation will steadily de- requirement of 240 cc/min, but the relationships crease (70% to 45%, for example). As venous remain the same for any size patient. Under saturation and content decrease, the oxygenator most circumstances, the risks of increasing will still increase the outlet saturation to 100% extracorporeal flow are greater than the risks and oxygen content to 14 cc/dl, so the circuit of transfusion. outlet minus inlet oxygen difference (oxygen supply) will go up as the venous saturation Oxygenation in VV-ECMO goes down (from 5 to 6 for example). Systemic saturation will decrease because the saturation The combination of venous access cannula, and content of the native venous blood going membrane lung size, and hemoglobin concenthrough the heart and lungs will decrease. At tration should be planned to match or exceed venous content 7.5 the O-I content difference resting VO2 (120 cc/m2/min for adults). The is 6.5 and the oxygen supplied is 260 cc/min. membrane lung will supply the most oxygen Steady state is reached with arterial saturation at at a normal hemoglobin (15 gm/dl). All the about 75% and PaO2 35 mmHg. The DO2/VO2 important variables related to blood flow and is 2.1 and any increase in activity will lead to oxygenation can be measured or calculated. It anaerobic metabolism which will produce lac- is essential to know the patient’s oxygen contate rather than CO2, and lactic acidosis results. In time, this will lead to multiple organ failure and death (Point D, Figure 4-18). How can systemic oxygen delivery be increased in Examples 3 and 4? Turning up the ventilator FiO2 or airway pressure will not help. Furthermore, the whole objective is to avoid increasing FiO2 and pressure from the mechanical ventilator. There are four alternatives. The first is to increase the hemoglobin concentration to normal. When hemoglobin goes from 10.5 to 15, systemic oxygen delivery goes to 930 cc/ min, arterial saturation returns to 95%, venous saturation goes to 80%, and the patient is stable Figure 4-19. The tradeoff between hemoand well supported. The DO2/VO2 is 4.6. The globin and flow. The relationships to deliver second alternative is to increase the suction or 240 cc O2 per minute are shown, but the same add another cannula and increase the circuit calculations can be done for any oxygen supply. 44

The Physiology of Extracorporeal Life Support

sumption and systemic oxygen delivery to decide the best way to manage the extracorporeal circuit. Hypoxemia (PaO2 40-60, SaO2 70-90) always occurs with venovenous support and is adequate to maintain normal oxygen delivery. If systemic oxygen delivery falls to a critical level (near twice consumption), circuit oxygen supply must be increased by: 1) transfusing to a higher hemoglobin or; 2) adding additional venous drainage access to increase the flow. There is a tradeoff of risk between transfusion and increasing circuit flow which favors transfusion of RBCs. Membrane lungs function optimally at a normal hematocrit. Recirculation during VV-ECMO Since VV-ECMO reinfuses blood drained from the vena cavae or right atrium back into the central venous system, the potential exists for some of the returned blood to be drained by the circuit before it mixes with the native venous flow. Recirculation reduces the effective extracorporeal flow by the recirculated amount. For example, if total circuit flow is 5 L/min and recirculation is 20% (1 L/min), then only 4 L/min of oxygenated blood is available to the patient. Determinants of recirculation include the type and placement of cannulas, and the extracorporeal flow in relation to cardiac output and vena caval native blood flow. Two-site single lumen cannulation is always associated with some recirculation, since the vena caval flow is less than the circuit drainage, necessitating blood from the atrium containing oxygenated blood from the circuit being drained as well. Three-site single lumen cannulation, in which both vena cavae are drained, reduces recirculation. Similarly, the dual lumen bicaval cannula provides drainage from both vena cavae, and is associated with low recirculation. Recirculation fraction is also related to overall circuit flow relative to cardiac output. As cardiac output decreases, the fraction in-

creases, and becomes markedly elevated when cardiac output drops below extracorporeal flow. Increases in recirculation during extracorporeal support can result from dislodgement of cannulas, such as closer approximation of singlelumen cannulas from inadvertent advancement, or accidental withdrawal or advancement of a dual lumen cannula, in which the distal drainage port moves into the right atrium, or the reinfusion port advances into the inferior vena cava, respectively. Hemodynamics during VV-ECMO Unlike venoarterial support, VV-ECMO does not provide any direct hemodynamic support since there is no reinfusion of blood into the arterial system. Venous return and pulsatility are unaffected since drainage and reinfusion are in equilibrium. Despite the lack of direct support, however, myocardial function and cardiac output typically improve during VV support. Reduction in mechanical ventilatory support that is allowed from improved gas exchange reduces right ventricular afterload and improves RV function. Improved oxygenation of the pulmonary vascular bed can mitigate hypoxic vasoconstriction. Higher oxygen saturation of left ventricular blood results in improved myocardial oxygenation and reversal of hypoxia-induced myocardial depression. Reduction in acidosis from correction of hypercarbia and reversal of anaerobic metabolism also contribute to improved myocardial function. This indirect support is usually sufficient to reduce or eliminate requirements for cardiovascular pharmacologic agents. Improved organ perfusion can help reverse renal, hepatic, and other organ failure. CO2 Removal CO2 production is equal to O2 consumption (when the Respiratory Quotient is 1), so the 45

Chapter 4

amount of CO2 exchanged per minute is essen- of gas exchange in the placenta and fetus. Betially the same as the amount of oxygen (120 cause of the blood flow requirements for gas cc/min/m2 for adults). Because CO2 is much exchange support, the arteriovenous route is not more soluble and diffusible in blood than O2, a reasonable approach to total extracorporeal CO2 clearance will exceed oxygenation in any respiratory support, except when the patient can circumstance, so all the circuit management is tolerate a large arteriovenous shunt and increase based on oxygenation. If CO2 clearance is the in cardiac output (such as a premature infant). only or the major goal, much lower blood flow However, AV flow through a membrane lung can be used and hemoglobin concentration is can provide significant CO2 removal, decreasing not important. The amount of CO2 elimination the need for mechanical ventilation. is a function of the membrane lung surface area and the gradient between the inlet PCO2 ECMO Management when the Native Lung (typically 50 mmHg) and the sweep gas (0). The is Recovering systemic PCO2 is the result of mixing circuit All the preceding discussion describes a outlet blood (PCO2 typically 30 mmHg) with native flow (typically 45 mmHg). Like oxygen- situation when there is no native lung function. ation, the actual amount of CO2 removed by the As the native lung begins to recover, some oxymembrane lung is the inlet CO2 content minus gen and CO2 exchange will occur. The effect the outlet content times the flow. However, CO2 will be to improve systemic arterial oxygenation content is difficult to measure or calculate, so and PaCO2 with no change in the extracorporeal actual CO2 removal is measured as the % CO2 flow rate and hemoglobin. It is tempting to in the exhaust gas times the gas flow. Unlike increase ventilator settings and FiO2 in order to oxygenation, measuring or calculating the ac- take advantage of this recovery, but this may add tual amount of CO2 exchanged by the circuit is to lung injury and delay lung recovery. ECMO not critical; the sweep gas is simply adjusted to is continued during rest ventilator settings, and maintain the desired systemic PCO2 (typically when arterial PCO2 drops below 40 the sweep 40 mmHg). gas to the membrane lung can be proportionally One phenomenon unique to ECMO is the decreased. When the systemic arterial saturaeffect of water accumulation on the gas side tion exceeds 95%, the extracorporeal flow can of the membrane lung. This is the only cir- be gradually decreased (changing the ratio of cumstance in which CO2 clearance is less than circuit to native venous flow). When the exoxygenation. Understanding the reason is a tracorporeal support has decreased from total good exercise in understanding how membrane support to approximately 50%, extracorporeal lungs work. support can be briefly discontinued (at moderate ventilator settings) to test native lung function. Arteriovenous CO2 Removal When native lung function is sufficient for total patient support, ECMO can be discontinued. Arteriovenous (AV) extracorporeal circula- Because reestablishing vascular access in tion is commonly used for hemodialysis but not ECMO can be difficult, it is wise to continue for cardiac or pulmonary support. The AV route ECMO support for a day or two beyond this can be used for gas exchange provided the arte- point to allow more lung recovery, unless there rial blood is desaturated, and the cardiovascular is a pressing reason to take the patient ECMO system can tolerate the arteriovenous fistula (systemic bleeding or CNS complications). with a large enough flow to achieve adequate gas exchange. This is, after all, the mechanism 46

The Physiology of Extracorporeal Life Support

Managing VV-ECMO Based on These Principles In VV access, the parameters described in Figures 4-13-15 are monitored and VO2, DO2 are calculated from these measurements. That information is used to adjust the ECMO variables and the patient variables to maintain DO2/ VO2 at 3:1 or higher. 1. As in VA access, plan the circuit based on the best estimation of the metabolic rate (adults, 3-4 cc/kg/min for both O2 and CO2) and the drainage flow which can be achieved from the largest drainage cannula (or cannulas) which can be placed. Plan for total support, realizing that there may be some native lung function and total support may not be necessary. For a septic 80kg adult you will need 5 L/min flow, and an oxygenator with rated flow over 5 L/min to supply 300 cc O2/min. 2. On ECMO go to the highest flow to determine the maximum drainage capacity, then turn down the ventilator to rest settings (FiO2 0.3, CPAP 10-15 cm H2O) and wean off the vasoactive drugs. The hypermetabolism will decrease to baseline. The lungs may go to total consolidation. Adjust the sweep gas to keep the PaCO2 40 mm Hg. 3. When the patient is stable (usually 6-12 hours) determine the variables of O2 kinetics, using the formulas described above. If oxygen supply is adequate (DO2:VO2 over 3) no changes are necessary. If oxygen supply is inadequate (DO2:VO2 under 3) and the patient is anemic, transfuse to a higher hemoglobin (12-14 gm/dl). If DO2 is still inadequate, change the drainage cannula to a larger size and increase flow. 4. Manage the patient based on continuous venous and arterial saturation monitoring. Plot the position on Figure 4-4 frequently. Calculate the variables if oxygen supply seems excessive or inadequate.

5. When the native lung begins to recover (the arterial saturation is >95%) turn down the flow, keeping the venous saturation >70%, and the sweep flow, keeping the PaCO2 at 40. When native lung function is adequate, trial off ECMO then decannulate. Summary Managing a patient on ECMO requires a thorough understanding of normal and abnormal cardiopulmonary physiology, and a thorough understanding of the ECMO circuit. Based on this understanding, the ECMO system is used to replace part or all of heart and lung function, maintaining normal systemic physiology while the damaged organs can recover or be replaced.

47

5 The Circuit John M. Toomasian, MS, CCP, Leen Vercaemst, RN, ECCP, Stephen Bottrell, CCP, Stephen B. Horton, PhD, CCP, FACBS

Introduction The extracorporeal life support (ECLS) circuit consists of the set of artificial organs and equipment that provides mechanical support of the failing heart and/or lungs for days, weeks, or months. A proper circuit design provides a footprint to meet the expected metabolic demands of the patient including adequate oxygen (O2) delivery and carbon dioxide (CO2) removal. The circuit may also provide access for additional therapeutic modalities such as hemofiltration, continuous renal replacement therapy, and cardiovascular intervention. The circuit requires management by trained specialists who are readily available to respond and troubleshoot any circuit related irregularity. This chapter describes the fundamental components of an ECLS circuit, based on the ELSO Guidelines that served as an update from the material from Chapter 8 of the 4th edition of the Redbook.1 Historical Background ECLS involves several mechanical platforms developed to support the circulation, allowing time for the affected organ system to recover. The traditional circuit was adapted from devices and techniques used during standard cardiopulmonary bypass (CPB). Unlike traditional CPB that used a direct contact gas-

blood contact gas exchange device with an open venous cardiotomy reservoir for return of shed blood from the operative field, the ECLS circuit required a closed circuit with a gas exchange device that had no direct air-blood contact. A “true” membrane-type gas exchange device would function for days, weeks, or months. Several membrane lungs were used during the early clinical history of ECLS including the Landé-Edwards and Bramson membrane lungs.2, 3 However, the gas exchanger that allowed for routine use was the spiral wound reinforced silicone rubber membrane lung developed by Theodor Kolobow in the 1960s.4 This device had a long blood path which resulted in a high resistance to blood flow, often generating a 200300 mmHg device pressure gradient. Priming was complex and required a carbon dioxide flush and the use of a vacuum. The membrane was made from silicone rubber, a highly gas permeable barrier. Gas transfer occurred by simple molecular diffusion. The device was manufactured in several sizes based on effective surface area by SciMed, Avecor, and Medtronic. Some devices had an integrated heat exchanger. The device was used for 50 years, until production was discontinued in 2012. Despite its few shortcomings, the Kolobow membrane lung had an outstanding and reliable performance record that was the gold standard for gas exchangers.

49

Chapter 5

The earliest circuits used roller pumps, as for short-term intraoperative use for CPB (not centrifugal pumps were only design concepts. to exceed 6 hours). Many CPB components are The classic roller pump was described by many used in an “off-label” application for extended but was often credited to Debakey.5 Roller use at the discretion of the treating physician, pumps used for ECLS were produced in many in a manner that may be outside the indication sizes and manufactured by various compa- for use. Experience with off-label use has been nies including: American Optical, Travenol, applied to select patient groups for extended Polystan, Stockërt, Cobe, Rhone Poulenc, and periods of time. Governmental restrictions for Sarns. Roller pumps were driven by either belt device use vary by country. For instance, the or direct drive and presented a unique set of European CE Mark may have different labelled challenges, especially related to management clearance criteria than the identical device used of the circuit pressure. A catastrophic blowout in the U.S. The descriptions in this chapter do occurred if the positive pressure (outlet) side not reflect any specific manufacturer’s recomwas clamped or occluded. If the pump inlet mendations. pressure became excessive (negative), air could enter. Regulating the blood inflow to the circuit General Principles of Circuit Design became significant. Prior to any servo control mechanisms, the venous return could only be The ECLS circuit is made from biomaterials gauged visually and pump speed adjusted manu- and plastics commonly used in traditional CPB. ally. This was tedious, dangerous, and impracti- The patient and the circuit are typically anticocal for use outside the operating room. When agulated to prevent thrombosis. Each circuit can the roller pump flow exceeded the venous return, vary in sophistication and complexity; however, the positive blood displacement characteristics each new level of complexity requires the of the roller pump would easily entrain air into knowledge to troubleshoot and rectify problems the circuit. To minimize this risk, a small com- that may result. The ECLS circuit may contain pliant silicone rubber chamber was inserted into a number of access sites that can measure or the circuit proximal to the pump. If the chamber monitor specific patient parameters such as was full, blood flow was not impaired and the extracorporeal blood flow(s), circuit pressures, pump would operate at its set speed. However, oxygen saturation(s), hemoglobin or inline when pump flow exceeded drainage (ie, kinked blood gases, and other metabolic parameters. venous drainage line, cannula malposition, or Variations of this design exist and depend on hypovolemia), the chamber would empty and patient size, physiologic needs, and institutional partially collapse, tripping a micro-switch that philosophy. When designing the circuit, a goal stopped or slowed the roller pump.6 As ECLS would be to minimize or eliminate additional expanded and grew in the 1980s, this design blood components in the prime solution. The was described, copied, and modified throughout tubing that connects the patient to the essential the world. This system has been the historic circuit components should not be lengthy, but template for newer ECLS circuit configurations adequate in length to allow for patient movethat have been used since the mid 2000s and has ment and transport. Resistance to flow increases been eloquently described in earlier editions of as tubing length increases.10 Larger volume circuits expose the blood to additional foreign the Redbook.7-9 In the United States, all medical devices surface areas that may promote greater inflamare “cleared” for use by the U.S. Food and Drug matory response and chance of thrombosis.11 Administration (FDA) for specific indications. Circuits that contain longer than required tubing The majority of components are manufactured lengths with an excessive number of stopcocks, 50

The Circuit

connectors, and access sites risk more circuit Blood Tubing Plasticizers related complications. Each connector causes The majority of conduit tubing is made turbulent blood flow, potential blood element damage, and creates an area of stagnation that from a formulation of polyvinylchloride (PVC) can induce clot formation. The “ring thrombus” mixed with a plasticizer. The amount of plastiis commonly observed at a tubing-connector cizer determines the tubing durometer or flexjunction. Luer lock connections have a potential ibility. Known as Di-2(ethyl hexyl) phthalate to entrain air or leak blood. The access port of (DEHP), DEHP is used to make PVC flexible. any Luer connector should be positioned point- However, in recent years, concerns have been ing upwards to avoid thrombus formation that expressed regarding the release of DEHP into often occurs if the connector is positioned at a the circulation. The FDA has previously islower place, allowing blood cells to collect and sued a public notification regarding exposure clot. Double luer connectors increase access and to DEHP.14 The lipid content, temperature, and can be considered when multiple access sites the duration of exposure all affect the leaching are required. Luer connectors can be used at the of DEHP. Adverse effects have been reported patient “bridge” site, eliminating the need for in laboratory animals, with the greatest conY-connectors used with a bridge or “diamond” cern being its effects on the male reproductive configurations. This also eliminates stagnant system.15 The FDA concluded that health risks from DEHP exposure exist and non–DEHP areas that are subject to potential thrombosis. With simple design objectives, gas ex- containing substitute products should be used change devices have been developed that in male neonates, pregnant women, and peripumaximize exterior hollow fiber technology with bertal boys when available. Leaching of DEHP modern compressed surface polymers such as does occur in ECMO circuits, although coated polymethylpentene (PMP) or polyolefin (PO). circuits decrease or eliminate DEHP leaching These materials exchange gas as efficiently as from pre-primed circuits.16 The European Commission on Food and their predecessors and can be designed to have less surface area resulting in a lower device Health also published opinions on DEHP in pressure gradient. The new generation centrifu- 2002, 2008, and 2014. Opinions in 2008 and gal pumps are much more efficient than their 2014 stated “there is no conclusive evidence predecessors and when used in conjunction that DEHP exposure via medical treatments has with the new lower resistance gas exchange harmful effects in humans.” However, “the new devices provide support without the problems information indicates that there is still a reason of hemolysis and mechanical failure commonly for some concern for prematurely born male observed by their predecessors.12 More sophis- neonates, because of the high human exposure ticated computer controlled servo-regulated during certain medical procedures.”17 Male systems exist and when used in conjunction neonates treated in intensive care units are with newer thin wall cannula designs (including considered at a higher risk of DEHP exposure double lumen catheters), many of the problems during medical procedures “due to their physiobserved with older ECLS systems have been cal conditions, the immaturity of many systems significantly reduced. Integrated component and organs, as well as their small size.” The systems have continued the trend towards sim- 2014 opinion statement also mentioned that plicity, with a smaller footprint. Biocompatible “DEHP-containing plasticized PVC devices circuits also continue to make slow progress to are important for many treatments and justified reduce some of the deleterious effects of the because of the benefits of these procedures.” circuit surfaces on blood elements.13 51

Chapter 5

There are active efforts to find safe and suitable alternatives to DEHP in medical devices. ECLS Circuit Components The circuit consists of three primary components: blood pump, gas exchange device, and heat exchanger. The components are connected by standard medical grade tubing. The circuit also includes catheters for vascular access, access sites, monitors, and safety devices. With each additional component added, such as an isolated heat exchanger, circuit shunts (ie, bridges, recirculation lines), connector based oxygen saturation measurement systems, monitors, bubble detectors, and alarms, the circuit becomes more complex. Added complexity may require additional training and limit operation to a trained circuit specialist. The tubing length and diameter will contribute to the resistance to blood flow. Achieving the desired flow is determined by the vascular access site(s), drainage tubing diameter, cannula size(s), resistance, and pump properties. Tubing size is chosen to allow free venous drainage with minimal resistance. The blood flow through one meter of tubing at 100 mmHg pressure gradient for common internal diameter tubing (inches) is: 3/16”: 1.2 L/min; ¼”: 2.5 L/min; 3/8”: 5L/min; ½”:10L/ min.18 A small caliber tubing connection or “bridge” that joins the drainage and reinfusion lines may be incorporated into the circuit at a position close to the patient. A bridge may be constructed from tubing or high flow stopcocks and small caliber tubing (such as 1/8”-1/4” according to circuit size). As a stagnant area the bridge can contribute to thrombosis when clamped for prolonged periods. The bridge allows for the patient to be separated from the circuit in situations such as trial periods off support, weaning, or an emergency. Periodically the bridge is opened and “flashed” allowing blood to shunt through the connection to reduce clot formation. Several studies have demonstrated the adverse effects of this practice.19-21 As a 52

result of these potential adverse effects, a number of modifications to the bridge have been employed, including an open bridge (regulating flow with a thumb clamp), placing a clamp on the bridge to occlude flow totally, and a bridge that is closed with stopcocks that can be opened when needed. 22 A bridge is usually not required during VV support. Blood Pumps The ECLS blood pump controls the required blood flow for the patient. They differ in design, capacity, hemocompatibility, durability, availability, and hardware features. The choice of a pump depends on many factors including local expertise and experience, console and hardware features, regulatory issues, economics, and availability. Pumps belong to two basic subgroups: occlusive (positive displacement) that include modified roller pumps with inlet pressure control and nonocclusive (rotary) that are centrifugal, diagonal, and axial with inlet pressure control, or peristaltic. Rotary pumps require preload and afterload adjustment; whereas positive displacement pumps displace volume as a function of pump speed regardless of preload or afterload conditions. Figure 5-1 shows the international trend in blood pump usage from 2005-2015 from the ELSO Registry data that includes transition from roller pumps to centrifugal pumps, currently the predominat pump type except in neonates. The chart shows the percent breakdown of pump type use per year and the number of cases in each patient subgroup (neonatal, pediatric, and adult). Pulsatility Traditional blood pumps used for ECLS support deliver blood flow in a continuous, nonpulsatile mode. Though not typically used, in theory pulsatile flow has advantages. Pulsatile perfusion modes have been used to support patients on CPB undergoing primary surgical

The Circuit

procedures or long-term ventricular support. The greatest limitation to pulsatile support is the capability to generate a mechanical physiologic pulse wave. The debate over pulsatile vs. nonpulsatile flow continues with no clearly demonstrated superiority of either type. The use of a pulsatile extracorporeal membrane oxygenation platform (PECMO) has shown an increase in coronary blood flow when using R-wave triggered pulse (at a 1 to 2 ratio) in an experimental porcine model.23 Some reported benefits include improved microcirculation and therefore better end organ function resulting in improved myocardial, cerebral, renal, and splanchnic perfusion.24-26 Mechanical challenges include energy loss from circuit components, synchronicity, and hematological effects. Energy losses can occur from both the oxygenator and circuit, supporting the importance of proper circuit selection.27

Figure 5-1. Extracorporeal Life Support Organization Registry data showing the trend in international gas exchange device use from 2005-2015. The number of cases is reported by neonatal, pediatric and adult subgroups and the total number of cases. Pump usage is based on the percentage of the total number reported per year. The trend shows a transition from roller pumps to centrifugal pumps in all subgroups except for neonates.

Roller Pumps Prior to the advent of modern centrifugal pumps, the roller pump was commonly used for ECLS. The venous drainage inlet to the roller pump required gravity drainage, which resulted in a siphon to the pump. To create this siphon effect, the pump had to be in a dependent position, relative to the patient separated typically by 100-150 cm. The roller pump was servo regulated, so the gravity siphon did not cause an extreme in pressure negative enough to produce cavitation and red cell trauma. As a positive displacement pump, the roller pump generates forward flow as a function of the tubing size and pump speed. They often become advantageous with lower flows and blood flow management requires rates in the 10-25 mL range. If standard PVC tubing is used in the raceway, it can usually withstand a 48-hour period of support without failure when properly occluded. Rupture resistant PVC tubing has been used to extend the longevity of the pump raceway conduit. By altering the plasticizer content, raceway tubing is made more durable and can tolerate the repetitive compression caused by the occlusive roller pump. Rupture resistant PVC, or polyurethane tubing, can extend performance for several weeks; however, the risk of a raceway rupture always remains a concern.28, 29 Roller pumps work remarkably well, but require constant monitoring and troubleshooting.30, 31 Roller pumps may be operated for extended periods and are considered hemocompatible depending on the occlusive settings within the housing. Apart from potential blood damage from improper or over-occlusion, the compression of the pump rollers against the tubing could potentially release substances or particulate emboli into the circuit. The process of advancing a new tubing segment into the raceway or “walking” the raceway tubing minimizes this potential complication.

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Chapter 5

Roller Pump Servo Regulation Roller pumps must be servo regulated to prevent excessive levels of negative inlet pressure that may result in air being entrained into the circuit. This requires the incorporation of a reservoir (“bladder”) or pressure buffer between the patient drainage line and the pump to avoid excessive negative pressure when the pump flow exceeds the return. Blood flow is modulated downward or stopped, based on a set pressure parameter.32 The drainage line should be of sufficient diameter and length to optimize a passive gravity siphon, which can be enhanced by elevating the patient. The desired blood flow rate, when using a roller pump is a function of the size of tubing selected and rotations per minute (rpm). Tubing selection is often based on expected maximum flow rates. For flows ranging up to 1.5-2.0 LPM, 1/4” size tubing is often selected. For flows up to 3.0 LPM, 3/8” size tubing can be used in the roller pump housing. For flows exceeding 4.0 LPM, 1/2” size tubing is commonly used. Centrifugal Blood Pumps Pumps are classified as either axial (Impella), diagonal (Medos DP3), or centrifugal (CentriMag, Rotaflow, Revolution). Centrifugal pumps generate a higher pressure, but use relatively lower rpm compared to axial pumps. The blade design includes characteristics of blade thickness, pitch/angle number, and distance from the pump housing that all effect performance characterization.33-37 Performance characteristics of axial, diagonal, and centrifugal pumps are diagramed in Figure 5-2. Greater motion and pressure per rpm (hydraulic power) is generated as the device changes design (movement from axial to radial design) while the operational rpm increases as the size of the device decreases. Axial pumps operate at relatively higher rpm to provide adequate

54

outlet pressures to achieve flow. A flow meter measures the blood flow rate exiting the pump. Centrifugal pumps generate flow by a spinning rotor which applies suction to the blood inlet and then propels the blood outward from the pump housing by generating a positive pressure. This occurs without any tubing compression and allows for longer continuous pump operation without replacement, as well the ability to clamp or occlude the circuit tubing without violating the circuit’s integrity. The first centrifugal pump used for ECLS was the Bio-medicus constrained vortex pump. The pumphead consisted of a series of concentric cones that created a centrifugal force which directed blood forward to a dedicated outlet. A fixed shaft anchored the cones and a seal was incorporated within the blood path resulting in a stagnant blood zone at the pumphead base. A consequence of this design was localized heat generation that was poorly dissipated and at high rpm. The use of early centrifugal blood pumps in conjunction with high resistance gas exchange devices required high rpm to generate forward flow. High levels of plasma free hemoglobin due to heat generation, sheer stress, and resultant hemolysis were observed in some patients.38-42 Hemolysis is one major factor considered in pump design, for hemolysis is thought to be caused, in part, by

Figure 5-2. Performance characteristics of axial, diagonal and centrifugal pumps. Greater motion and pressure per rpm (hydraulic power) is generated as the device changes design (movement from axial to radial design) while the operational revolutions increase as the size of the device decreases.

The Circuit

the shear and the time exposed to shear forces. The disposable pumphead has a magnetic rotor that couples directly to a shaft or bearing. The blood is contained within the disposable pumphead. When connected, the pumphead couples to the motor with magnets. As the motor spins, the pumphead spins to the rpm generated by the pump motor. Localized heat is generated around the seal and if there is sufficient washout around the seal, heat induced thrombosis is minimized. Newer centrifugal designs are more efficient primarily due to a key design feature described by Mendler.43 This design features a hole located adjacent to the impeller that allows blood to continually wash the area around the rotor, reducing or eliminating any stagnant areas. This design decreases the mechanically induced hemolysis observed in earlier centrifugal pump designs. However, when used outside a safe flow high pressure head window, these devices become less hemocompatible. Use of high flow centrifugal pumps in neonates and children requires downsizing of the tubing to fit the 1/4” circuit adding more shear stress and turbulence contributing to blood cell damage and local thrombus formation. Free hemoglobin should be monitored and the pumphead replaced if

Figure 5-3. Pivot bearing centrifugal pump. The pump eliminates a central shaft and seal by using a blood flushed bearing, thereby avoiding stagnant zones, and reducing areas of high shear and turbulence. (Figure courtesy of Piyumi Fernando)

hemolysis becomes excessive or thrombosis is suspected. Many of the problems related to localized heat generation and hemolysis have subsided with proper understanding and use of these pumps. Pivot bearing (Figure 5-3) and bearing free magnetic levitation designs (Figure 5-4) along with the incorporation of low resistance, short blood path gas exchange devices, have allowed for safer use in more recent years.44 Centrifugal Pump Inlet Pressure Monitoring Techniques The circuit can become more streamlined with shorter line lengths to reduce the forces generated by the centrifugal pump. Shorter line lengths may enable better blood drainage. One method of measuring the negative pressure in the drainage line incorporates a compliance-like chamber/bladder into the line. The Better Bladder™ (Circulatory Technology, Inc., Oyster Bay, NY) is a safety device made from PVC with a flexible balloon within a rigid chamber. The pressure between the bladder and rigid chamber can be measured and reflects the negative pressure in the drainage tubing.45,46 The

Figure 5-4. Cross sectional view of a magnetically levitated pump. Bearing less design allows for no contact with the pump impeller as the impeller is suspended in a magnetic field. (Figure courtesy of Piyumi Fernando)

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Chapter 5

device is positioned between the patient and the pump inlet and requires a pressure transducer to monitor the pre-pump pressure. The BetterBladder™ provides compliance in the venous line to reduce large negative pressure spikes at the pump inlet and allows for noninvasive pressure measurements while removing the risk of accidental air entrapment. Abrupt cessation of venous flow can cause a large negative pressure spike at the inlet and outlet of the centrifugal pump. Measurement of the inlet pressure allows time for a pressure regulated centrifugal pump to be adjusted downward, reducing the steady state negative pressure, especially if it is excessive and collapses the vasculature around the drainage cannula. Lowering the negative pressure in the drainage line would be reflected at the cannula site and cause less potential intima damage. A large negative pressure spike at the outlet of the centrifugal pump will also result in negative pressures inside the oxygenator, allowing retrograde flow from the patient, or air entry in the oxygenator if used in combination with porous or ruptured membrane fibers. Blood Pump Performance The desired blood flow rate in centrifugal blood pumps relates primarily to two categories of expected maximum flow rates: high flow range and low flow range. High flow range pumps traditionally provide flow from 1-8 LPM (although some pumps can generate up to 10 LPM). Centrifugal pumps with 3/8” inlet and outlet connections are considered high flow range pumps, meaning they have a low hemolysis index for a high range of flow with a physiological pressure head. These pumps can be used safely at lower flow rates as the pressure head will lower in relation to the decrease in the flow rate. However, these pumps lose their optimal performance characteristics when their optimal flow/pressure head window changes when high rpm are required for lower flows, such as neonatal or pediatric support. Higher 56

resistance can be observed with smaller cannulas and circuits resulting in similar or higher pressure heads as with higher flow systems. Hence, blood cell contact time within the pump increases substantially and the red blood cells may be damaged at a much faster rate. Low flow range pumps typically provide flows up to 2 LPM. They can be considered in low flow/ high pressure situations, such as neonatal/pediatric support or extracorporeal CO2 removal settings. These pumps are available with 1/4” inlet and outlet connections. Currently there are two lower range flow pumps available: the first generation Medtronic Bio-medicus BP50, and the PediVAS magnetic levitated pump. They are recommended for use up to 1.5 LPM and 1.7 LPM, respectively. Use in neonates can cause more blood damage compared to use in adults and compared to roller pumps.47,48 The newer lower flow pump designs, such as the PediVAS seem to ameliorate this complication. Regulatory Status The regulatory status of centrifugal pump technology varies by country. Many circuit components, including centrifugal pumps, are used off label from their designated indications. In the U.S. all centrifugal blood pumps are cleared by the FDA for use in CPB for up to 6 hours. Use for extended support is conducted entirely off label. The CentriMag is cleared for 30-day use as a VAD but not in an ECLS setting, when a gas exchange device is included inline. In contrast, CE (Conformité Européene) marking offers longer periods of validated use in the ECLS setting, which is mostly based upon manufacture recommendations. Newer generation centrifugal pump designs have initially been used outside the U.S. The recommended use of many devices is much longer in Europe compared to the U.S. For example: Medos DP3 (7 days), Maquet Cardiohelp (30 days), Lifebox (28 days, with the Livanova Revolution centrifugal pump).

The Circuit

Pump Related Complications Hemolysis Hemolysis is defined in the ELSO Registry as the appearance of free hemoglobin in the blood plasma in concentrations exceeding 50 mg/dL. The plasma hemoglobin should be 50 mg/dL should be investigated for cause. Elevated free hemoglobin may relate to intermittent venous line chattering, extremes in negative pressure generated by the centrifugal pump, air-blood interface related to cardiac surgery (if the patient is immediately on ECLS postcardiotomy), partial circuit or component thrombosis, as well as high shear stresses related to turbulent flow. Hemolysis can also be a consequence of water and blood mixing if the integrity of the heat exchanger membrane has been violated. Subclinical hemolysis does not necessarily indicate RBCs are undamaged, because normally the constituents of red cells are removed by efficient elimination mechanisms. When the rate of destruction exceeds the rate of elimination, free hemoglobin levels increase. Free circulating hemoglobin causes nephrotoxicity and binds rapidly and irreversibly to endogenous NO, inducing a range of potential unfavorable side effects, such as increased vascular resistance, increased thrombin generation, platelet dysfunction, and clotting disorders. Shear forces may also contribute to hemolysis. When exposed to a shear stress environment of below the threshold cell rupture, erythrocytes can be sublethally damaged, which is a reversible phenomenon, depending on the duration and intensity of exposure to subatmospheric pressure and/or blood/air interface. The RBC does not lyse, but stiffens and becomes rigid, making it more difficult to enter the microcirculation and exchange or release oxygen in the lungs and end organs. Erythrocytes resist shear stress better than other blood cells. Leucocytes, platelets, and von Willebrand proteins are much

more fragile and the clinical relevance of their destruction is being increasingly investigated and recognized.50 Blood cell damage by centrifugal blood pumps depends on the design of the pump, the rotational speed, suction pressure, the pressure head and presence of air and/or clots. The comparison of hemolysis and blood handling related to centrifugal and conventional roller pumps has showed centrifugal pumps may not be as hemolytic as roller pumps when used properly.51,52 In order to investigate a new centrifugal pump design, three pumps were compared: Rotaflow, Bio-medicus BP50, and a conventional roller pump. The Bio-medicus and Rotaflow pumps showed similar results until 24 hours when the Bio-medicus became more hemolytic. The difference became significant at day 6 (p 300 mmHg can cause damaging turbulence and shear force which will result in hemolysis.63 Commercial Centrifugal Pumps There are a number of commercial centrifugal pumps that have been used for extended ECLS whose characteristics are summarized in Figure 5-6. Individual device availability and regulatory status varies from country to country and by certifying agency. Indications for use may also vary by country. The regulatory status of each device described is not listed due to the wide variation and changing status of each device.

Figure 5-6. Characterization and performance parameters of commercial centrifugal blood pumps.

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The Circuit

Maquet Rotaflow The Rotaflow centrifugal pump (Maquet Cardiopulmonary AG, Hirrlingen, Germany) (Figure 5-7) was introduced in 1995. This pump was able to reduce heat generation from the bearing and seal and improved hydraulic efficiency with minimal blood damage. In testing, the Rotaflow pump showed strong hydraulic efficiency compared to other devices.45 The disposable pumphead features a low friction one-point pivot bearing that supports a multifinned impeller. The pumphead is controlled by a remote drive motor tethered to a control console. An ECLS ICU console incorporates additional safety features that minimize inadvertent manipulation of the speed control or power switch. The unit is manually controlled and not servo regulated. The pumphead is compact with a priming volume of 32 mL and has an outer diameter of 85.5 mm, a height of 48 mm, and a weight of 60 gm. It is constructed to exploit the potential of the radial magnetic drive in eliminating a central shaft and seal using a blood flushed bearing, avoiding stagnant zones, and reducing areas of high shear and turbulence. The drive magnets are embedded in a shrouded impeller with four blood channels. A single pivot bearing supports the impeller at its bottom, in which the sapphire ball bearing is held in the center of the completely open rotor

Figure 5-7. Rotaflow centrifugal pumphead (Maquet Cardiopulmonary, Hirrlingen, Germany).

by a 1 mm steel strut (Figure 5-3). The blood gap between the impeller and housing is conical on either side. The outflow exits into a circular recuperator and a spiral volume chamber. All blood contacting parts are made of acrylic and polycarbonate resins. Livanova Revolution Centrifugal Pump The Revolution centrifugal pump (Livanova, Arvada, CO) features a sealless, low friction bearing (Figure 5-8). The pumphead is controlled by the Livanova Centrifugal Pump (SCP) System that can be integrated with the safety devices of the S5™ and C5™ systems. When certain conditions are detected (low level, bubble, or retrograde flow), this feature allows for some servo-regulatory controls that are unavailable with other centrifugal pump technologies. The Revolution 5 version that has been qualified for 5 days of use is available in some countries. Medtronic BPX-80 and BP-50 The Medtronic BPX pump design (Medtronic, Minneapolis, MN) features a patented vertical outlet and a smooth vortex cone design that provides superior micro air retention. This pump has been used widely during clinical open heart surgery, but is associated with higher hemolysis

Figure 5-8. Revolution centrifugal pumphead (Livanova, Arvada, CO, USA).

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Chapter 5

with extended use.41 The current BPX80 has 3/8” inlet and size outlet connectors and has a priming volume of 80 ml with a recommended blood flow up to 8 LPM. The BP50 has 1/4” inlet and outlet connectors and has a priming volume of 48 mL with a recommended blood flow up to 1.5 LPM. Both pumphead versions are available with Carmeda heparin coating and may be used with any Biomedicus pump console. Medtronic Affinity Centrifugal Pump The Medtronic Affinity centrifugal pump (Medtronic, Minneapolis, MN) has a smooth cone and low profile fins enabling blood flow to 10 LPM with a ceramic heat resistant pivot shaft. The pumphead has a 40 mL priming volume and interfaces with the Medtronic Biomedicus console. The external motor driver rotates in the opposite direction than the traditional Biomedicus pumphead. The Affinity pumphead is offered with two surface coatings: Carmeda heparin coating and the nonheparin Balance Biosurface (UK) (Figure 5-9).

Figure 5-9. Medtronic Affinity centrifugal pumphead (Medtronic, Minneapolis, MN).

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CentriMag Magnetic Levitated Pump The CentriMag pump technology (St. Jude Medical, St. Paul, MN) is based on the principles of magnetic levitation. The CentriMag features bearingless technology which contains no seals. The pump rotor is levitated within the disposable pumphead housing by a magnetic field so that when the motor is powered up, the resultant magnetic field aligns and maintains the rotor in a position in which no direct contact to any other part of the pumphead housing occurs. When the pump is engaged the magnetic field fluctuates allowing the rotor to spin at the rate set by the control console. The risk of thrombus formation is reduced by uniform unidirectional flow and less stagnation, while reduced shear stress attenuates hemolysis. The CentriMag adult unit can produce flows up to 10 LPM. The pediatric version, referred to as the PediVAS (PediMag U.S.) can produce flows up to 1.5 LPM. Both pumpheads are operated by the same console and hardware. These pumps require flow probes to enable the system. The pumphead cannot be manually hand cranked, so a backup system is required (Figure 5-10).

Figure 5-10. CentriMag™ Maglev System (St. Jude Medical, St. Paul, MN).

The Circuit

Medos Delta Stream

flow mode controls the pump speed to avoid inadvertent retrograde flow. The system cannot be manually hand cranked.

The Medos Deltastream DP3 pump (Medos Medizintechnik AG, Stolberg, Germany) (Figure 5-11) is a hybrid of centrifugal and Gas Exchange Devices axial technologies that utilizes higher rpm but shorter transit time to generate blood flow. The Rated Flow DP3 has 3/8” inlet and outlet connectors for adult use (a design with 1/4” size connectors for The gas exchange device is designed to add pediatric use is pending). The pumphead prim- oxygen and remove CO2. The device must be of ing volume is 16 mL and generates a flow range adequate size to provide for the total anticipated of 0-8 LPM at a pump speed from 100-10000 metabolic requirements of the patient. The gas rpm. The pumphead incorporates a ceramic exchange device should be able to transfer bearing and magnetic coupling with an optional the amount of oxygen being consumed by the pulsatility mode (rate 40-90 beats/min). The patient, as well as the amount of CO2 being MDC console is portable, lightweight (10 kg), produced by the patient. The surface area and and contains two batteries (90-minute power/ blood path mixing determine the maximum battery) that allow the pump to be operated oxygenation capacity of any gas exchanger. independently from the driving console. The A standard referred to as “rated flow” allows detachable touch screen monitor can display op- for direct comparisons of all gas exchange deerational parameters such as flow, rpm, pressure, vices. The rated flow is the blood flow rate at and temperature. The controlling hardware has which venous blood, with a saturation of 75% three integrated pressure channels with nega- and hemoglobin of 12 gm/dL will exit the gas tive pressure regulation, zero flow mode, and exchange device with a saturation of 95%.64 air bubble detection, as well as a display of the charging condition of both batteries. The zero Oxygen Delivery

Figure 5-11. Medos Deltastream pump system ((Medos Medizintechnik AG, Stolberg, Germany).

Patient metabolic needs determine the amount of oxygen delivery required. The maximal oxygen delivery of a gas exchange device is the amount of oxygen delivered per minute when running at rated flow. This is determined by calculating the difference in oxygen content between the outlet blood and the inlet blood to the gas exchanger. This difference is typically 4-5 cc O2/dL. Multiplying this by blood flow rate through the gas exchanger yields the oxygen delivered by the gas exchanger in cc O2/min. A gas exchange device with a rated flow of 2.0 L/min will offer a maximal oxygen delivery of 100 cc O2/min. A device with a rated flow of 4.0 L/min will offer a maximal oxygen delivery of 200 cc O2/min. Based on the anticipated oxygen delivery requirements, the appropriate size gas exchange device can be chosen. 63

Chapter 5

Sweep Gas

Pressure Gradients

Early generation gas exchange devices The gas ventilated through the gas exchange device is referred to as the sweep gas. For most were characterized by a long blood path and applications, sweep gas will be 100% oxygen. a high pressure gradient. These early designs There are occasions during cardiac support or included flat sheet silicone rubber membranes by institutional preference when the sweep gas and the “blood inside” hollow fiber bundle will be a mixture of oxygen and compressed configurations. Design modifications lead room air, thus requiring an oxygen-air blender. to a hollow fiber concept with “gas inside” In some instances, when the pCO2 must be main- and blood circulating outside the fibers. This tained, carbogen gas (5% CO2, 95% O2) or 100% configuration resulted in significantly lower CO2 gas (in small amounts) may be titrated into pressure gradients in the blood path.65 This dethe sweep gas. In some institutions, a gas flow sign has been applied to all subsequent device rate equal to the blood flow rate (1:1) is used designs regardless of hollow fiber material. The to begin support. The gas to blood flow ratio is first widely used biomaterial was microporous then adjusted to maintain the systemic pCO2 at polypropylene. Although this material could a desired range (ie, 36-44 mmHg). Increasing be manufactured as a flat sheet, fiber technolsweep gas flow rate increases CO2 clearance ogy provided more effective surface area and but does not affect oxygenation. Decreasing was relatively inexpensive to manufacture. the sweep gas flow rate elevates the pCO2, but Engineering designs to maximize secondary usually does not affect oxygenation. Water va- flows and mixing in the blood path, optimizing por can condense within the gas compartment gas exchange, and lowering the device presof the membrane lung and may be cleared by sure gradient have improved performance and intermittently increasing sweep gas flow to a allowed for smaller sized devices. The lower higher rate. If there is excessive water that has resistance made these newer generation gas exnot been purged, the pCO2 may rise. ECLS can change devices more practical for long duration be used for CO2 removal in addition to full meta- use. Microporous polypropylene hollow fiber bolic support. In most gas exchange devices, gas exchange devices are limited in longevity the amount of oxygen added and CO2 removed because over time, plasma will leak across the is the same at a gas to blood flow ratio of 1:1. fiber eventually causing device failure.66,67 Gas Since membrane gas exchangers clear CO2 more transfer normally occurs across a protein layer efficiently than adding oxygen, CO2 can be re- covering the fibers micropores. Over time, exmoved with blood flows as low as 0.75 L/min/ posure to phospholipids in the blood causes the m2. In cases when CO2 regulation is required, surface tension at the blood/gas interface in the the gas exchange device size can be smaller than micropores to decrease. As the surface tension the device required for full support. Ventilation decreases, plasma begins to weep through the to maximize CO2 removal is typically greater micropores into the gas side of the membrane. than 4:1 on the gas to blood flow ratio rate. It As a result, gas exchange efficiency falls.68 This must be noted that some manufacturers limit the membrane failure has limited the widespread recommended gas to blood flow ratios in their use of polypropylene devices for extended use. instructions for use. Polymethylpentene (PMP) fibers that became available in the early 2000s showed promise as a plasma leakage resistant fiber. Polymethylpentene is a chemical cousin to polypropylene fibers that when the outer surface 64

The Circuit

is compressed it displays a more leak resistant the sweep gas pressure exceeds the blood path property than the microporous polypropylene. pressure. This may occur if the device blood Although PMP has been described as more of a path pressure becomes negative, which can “solid” membrane, in fact PMP is microporous. occur with an unregulated centrifugal pump. During manufacture, the fibers are compressed Air can also be pulled across the membrane to form an outer surface or “skin” with proper- surface when blood flow ceases and the device ties similar to that of a solid membrane. Even is positioned above the level of the patient’s though the PMP membranes are “solid-like,” heart. In this circumstance, blood within the gas gas can still be entrained across the PMP ma- exchange device can drain by gravity into the terial into the blood path if a large negative dependent blood tubing, subsequently pulling pressure is applied. Therefore, it is important air across the fibers and “de-priming” the device. to maintain positive pressure on the blood path To minimize the risk of air embolization through side. The PMP fibers, produced by Membrana the gas exchanger blood path, pressures must GmbH (Wuppertal, Germany), have similar be maintained higher than the gas side presgas exchange characteristics as polypropylene sure.70 Pressure pop off valves may be placed but it is more challenging to handle, so PMP is in the gas supply line to insure the gas pressure typically matted and either wound or stacked remains low. Sweep gas pressures may be servo in relatively short blood path configurations. regulated and the gas exchange device should Current PMP hollow fiber devices have low be kept below the patient’s heart to minimize pressure gradients and the fibers mimic a “solid air embolism risk. As newer generation gas hollow-fiber” technology with minimal plasma exchange devices and centrifugal pumps have leakage.69 Polymethylpentene devices were allowed the transport of patients within and first described in two pilot clinical studies. The between hospitals, the gas exchange device may device was reported as showing feasibility and inadvertently be repositioned above the level longevity in long-term ECLS support. The Me- of the heart while venous drainage pressures dos HiLite LT was used in six patients in whose are subatmospheric. If blood flow were stops transfusion rates were significantly lower and by either a line kink, patient cough, or clot plasma leakage was not observed.12 Similarly, formation within gas exchange device, risk of no plasma leakage occurred in 23 patients with air embolism exists. Maquet diffusion membrane device that was used for up to 46 days in conjunction with a Commercial Gas Exchange Devices centrifugal pump.69 However, plasma leakage Figure 5-12 shows the utilization of memhas been observed in clinical application. The initial experience with PMP devices demon- brane lung types from 2005-2015, based on data strated promise in durability, inflammatory submitted to the Extracorporeal Life Support response attenuation, and decreased transfu- Organization Registry. The data incorporates sion requirements making these gas exchange all patient groups and is expressed as a perdevices well suited for long-term ECLS use. centage of the total number of cases reported Since their introduction, other PMP devices per year. The trend shows the growth in PMP of varying sizes have entered the marketplace. gas exchanger use and the gradual phase out of the silicone rubber units worldwide. Many commercial membrane lungs are available Gas Exchanger Induced Air Embolism for clinical use and some are described in the Gas bubbles can pass across the gas ex- sections below. The regulatory status for each change device membrane into the blood path if individual device varies from country to country 65

Chapter 5

and by certifying agency. In the U.S., most gas exchange devices are cleared for up to 6 hours of use. In Europe, CE marking may be extended to days or weeks. The regulatory status of each device is not listed, due to that wide variation and changing status of each device. There are several commercial gas exchange devices used for extended ECLS whose technical characteristics are summarized in Figure 5-13.

PMP hollow fibers and contains an integrated heat exchanger. The design effectively prevents formation of microbubbles and protects against bacterial contamination from the gas side. The Quadrox iD has a low pressure drop across the fiber bundle. The designs for bundling the fibers within the oxygenator and the flow pattern through the device are key factors in decreasing the priming volume.71

Maquet Quadrox- iD

Medos Hilite LT

The Maquet Quadrox- iD diffusion membrane device (Maquet Cardiopulmonary AG, Hirrlingen, Germany) comes in adult and infant/pediatric sizes (Figure 5-14). The device is constructed of plasma resistant hydrophobic

The Medos Hilite LT (Medos Medizintechnik AG, Stolberg, Germany) is produced in three sizes with an integrated heat exchanger. The device is characterized by a low pressure differential between blood inlet and outlet and

Figure 5-12. Data from the Extracorporeal Life Support Organization showing the trend in international gas exchange device use from 2005-2015. The number of cases is reported by neonatal, pediatric and adult subgroups and the total number of cases . Gas exchanger use is based on the percentage of the total number reported per year. The trend shows a transition from silicone rubber devices towards polymethylpentene devices in all subgroups.

66

The Circuit

Figure 5-13. Performance characteristics of commercial membrane lungs.

Figure 5-14. Maquet Quadrox iD Adult and ID Pediatric membrane lungs. (Maquet Cardiopulmonary, Hirrlingen, Germany).

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Chapter 5

a smaller priming volume than the QuadroxiD. The HiLite LT devices are suitable for use with all pump types. The Medos LT device is illustrated in Figure 5-15 and is available with or without a surface coating. Novalung Lung Assist Device The iLA Activve and iLA platforms (Novalung GmbH, Heilbronn, Germany) consist of multiple versions of different gas exchange devices for support of respiratory failure. The Novalung Membrane Ventilator, a low resistance temporary artificial lung that can provide CO2 transfer across its membrane fibers with or without the use of a blood pump, is designed primarily for extracorporeal CO 2 removal. Total CO2 management can be achieved allowing for protective mechanical ventilation lung management strategies. Clinical use has shown benefits and good feasibility in a wide number of etiologies including ARDS and COPD.72, 73

Figure 5-15. Medos HiLite LT membrane lung (Medos Medizintechnik AG, Stolberg, Germany).

68

It has also served as an artificial lung to bridge patients to lung transplant with or without a blood pump.74, 75 The iLA Activve system is used in conjunction with a blood pump and comes in three sizes. The individual platforms support a range of metabolic conditions from isolated CO2 removal to full metabolic support. Livanova EOS ECMO Livanova (London, UK) produces two sizes of extended use gas exchangers. The Lilliput 2 ECMO gas exchanger is a pediatric unit made with PMP fibers.66 The device has a phosphorylcholine surface coating and has been validated for up to 5 days of extended support. The device requires the use of a blood pump. The D 905 EOS ECMO unit (Figure 5-16) is a larger adult sized device that is phosphorylcholine coated. The device has been validated for 5 days of use outside U.S.

Figure 5-16. Livanova EOS ECMO membrane lung. (Livanova, London, UK).

The Circuit

Nipro Biocube Nipro Corporation, (Osaka, Japan) produces three sizes of plasma tight hollow fiber membrane gas exchange devices with or without an integrated heat exchanger. The membrane material is a polyolefin. The device utilizes a biocompatible heparin based coating with an ionic coupling to promote durability and antithrombogenic properties (Figure 5-17). Eurosets Oxygenators Eurosets (Medolia, Italy) manufacture three sizes of PMP oxygenators (Figure 5-18) that have been validated for 14 days of use (Europe only). The gas exchanger is coated with a lipid based phosphorylcholine coating and contains an integral heat exchanger. Paragon Oxygenators The Paragon oxygenator series (Chalice Medical, Nottinghamshire, UK) is a standalone unit constructed with PMP fibers, specifically designed for long-term applications (Figure 5-19). The Paragon device has a vent

at top of the unit to assist in priming and gross air removal. The device is coated with a proprietary synthetic albumin surface coating called Rheopax. The Paragon series comes in six sizes with different flow ratings and an intended use for up to 15 days (Europe only). Integrated Pump/Oxygenator Systems The incorporation of a pump and gas exchanger into a single unit optimizes portability. The Maquet Cardiohelp HLS module integrates three major ECLS circuit components (gas exchanger, pump, and heat exchanger) into a single product (Figure 5-20). The product has integrated sensors to detect inlet saturation, hemoglobin/hematocrit, and temperature. Three pressure parameters can be measured. The HLS module comes in two sizes: HLS Module Advanced 5.0 (blood flows up to 5.0 LPM) and HLS Module Advanced 7.0 (blood flows up to 7.0 LPM). The system is coated with the Maquet Bioline thromboresistant surface and

Figure 5-18. Eurosets membrane lung series. (Eurosets, Medolia, Italy).

Figure 5-17. Nipro 6000P membrane lung. (Nipro Corporation, Osaka, Japan).

Figure 5-19. Paragon membrane lung series. (Chalice Medical, Nottinghamshire, UK).

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Chapter 5

has different regulatory clearances depending on country. The module can be positioned on a portable cart and may be used for patient transport. The system can be operated with a minimal number of controls. These systems may be able to provide more feedback servo regulation of essential parameters (ie, venous inlet pressure, venous saturation, CO2 exhaust gas, sweep rate, and pressure gradient monitoring). The benefits of simplicity must be weighed against cost in an integrated system. Any integrated system should be potentially easy to set up, prime, and initiate, as well as allow for patient transport. This type of system would simplify the use for multiple patients in a large volume center. Such a system should be easier to implement in an emergent setting (ie, ECPR, catheterization lab rescue) and allow for support while the patient was assessed for the best treatment options.

Figure 5-20. Maquet Cardiohelp. (Maquet Cardiopulmonary, Hirrlingen, Germany).

70

Gas Exchanger Related Complications Plasma Leakage Plasma leakage has been a problem in microporous polypropylene hollow fiber devices which lose their hydrophobic character over time during long-term applications. The advent of PMP fibers has greatly diminished this problem, although it can still occur. Polymethylpentene fibers are hybrid in nature and microporous and layered by a true membrane, preventing plasma from leaking through the pores. Most PMP devices are made from plasma leak resistant fibers. These fibers have been developed not to avoid but to improve plasma leakage as this is in function of the thickness of the nonporous fiber skin, which again needs to be limited in favor of gas transfer capacities.67 There have been a few reports from plasma leakage in PMP devices.76 The fibers can be overstretched due to winding on spools for shipment, causing microtears through which plasma leakage can occur. One report explains that PMP fibers become less permeable to gas and plasma as soon as an albumin layer forms on this membrane, sealing the fibers. This explains why the fibers are more porous to gas when dry primed with crystalloid solution as opposed to blood. If the albumin coating over the PMP micropore is inadequate, which in part may be due to an altered protein composition in certain patients, plasma leak may occur after some time.77 It is important to recall that PMP is a microporous material even though the presence of the dense skin largely prevents air entry in the blood and the plasma breakthrough times are much longer in respect to the common microporous fibers.78 Additionally, transfer of volatile anesthetic gas, such as Isoflurane, is impaired in PMP membrane devices.79

The Circuit

Device Thrombosis

Heat Exchange and Heat Regulation

Despite anticoagulation strategies and the theoretic benefits of passivated bio-surfaces, oxygenator thrombosis occurs nonetheless. The ELSO Registry reports (2015) an average of 10% oxygenator clots in cardiac ECMO with a higher incidence in neonates (13%) as opposed to adults (10%). In respiratory support, a higher incidence from 17% in neonates to 14% in adults has been observed. 80 Oxygenator clots can be detected by a variety of parameters, such as increasing transmembrane pressures, rising D-dimers, decreased gas transfer, hemolysis, and direct observation. If these parameters are monitored regularly, then the device may be replaced in a controlled setting instead of an emergent change out when the device suddenly fails. Although sudden thrombosis does not usually occur, there should be protocols for urgent oxygenator change-out.81

ECLS constantly exposed the blood to the ambient temperature of the environment. The circuit should be capable of maintaining the patient at normothermia (37o C). The oxygen in the sweep gas comes from a cold liquid oxygen source and the evaporative vapor-losses across the membrane dissipate heat, also cooling the patient. Therefore, a heat exchanger may be integrated into the gas exchange device, but can be a standalone component. ECLS patients, especially infants and small children may require active warming to maintain normal body temperature with a heater cooler device. Warming the gas source or employing topical warming methods in small patients (ie, warm air blanket) may also prove effective. For larger patients, direct blood warming may be implemented, but is often not required and is discontinued if temperature autoregulation is maintained. While the heat exchanger is typically used to maintain temperature, it can also cool for neuroprotection, to decrease patient metabolic demands, or to treat fevers. Heat exchangers require an external recirculating water bath which circulates water through a coil or network of fibers in the blood path. The coil, or fiber network, is often integrated within the shell of the gas exchange device. The temperature of the circulating water bath is regulated to control the patient or blood path temperature. In general, the temperature of the water is maintained between 36 to 0.5 < 0.4 0.4 – 0.6 0.4 – 0.6 > 0.6 < 0.5 0.5 – 0.7 0.5 – 0.7 > 0.7

96

UNFH Rate Change ↑10 – 20% No Change ↓10 – 20% ↑10 – 20% No Change ↓10 – 20% ↑10 – 20% No Change ↓10 – 20%

ACT Goal Range (seconds) ↑10 – 20 seconds No Change ↓10 – 20 seconds ↑10 – 20 seconds No Change ↓10 – 20 seconds ↑10 – 20 seconds No Change ↓10 – 20 seconds

Anticoagulation and Disorders of Hemostasis

for this use is mixed. A retrospective study of neonatal and pediatric ECLS patients revealed increased in AT levels with AT concentrate administration, but no other clinically significant changes, including UNFH infusion rate, ACTs, chest tube output, or packed red blood cell (PRBC) transfusion volume.48 In another single center pediatric ECLS study, supplementation Antithrombin Level with AT concentrate for activity levels of 10 min (low clotting factors) or CT (extem) >100 sec

Approach Administer FFP or prothrombin complex concentrate

MA 30% (consider higher goal for neonates and children with cyanotic congenital heart disease or lower goal for stable, adult patients) >50%-80% (>0.5-0.8 u/mL), consider AT replacement if on maximum dose of UNFH and unable to obtain therapeutic anti-factor Xa assay

Anticoagulation and Disorders of Hemostasis

and underlying pathophysiology should dictate adjustments of laboratory determinations and blood product administration. Laboratory testing can be decreased and blood product transfusion reduced in patients who have reached a stable clinical status. Blood product transfusion carries with it infectious and non-infectious risks and will be covered in Chapter 8

Conclusions

The number and complexity of patients supported with ECLS continues to increase. With this growth comes an even greater need for improved surfaces for blood-circuit interaction, safer anticoagulation, and enhanced anticoagulation monitoring. Consultation with hematology specialists and laboratory medicine should Hemorrhagic and Thrombotic Complica- be considered for managing complex issues regarding anticoagulation for ECLS or for any tions ECLS patient with unexplained hemorrhagic or Hemorrhagic complications produce sig- thrombotic complications. nificant morbidity and mortality among ECLS patients. Their prevention requires correcting coagulopathy and thrombocytopenia, careful titration of anticoagulation therapy, and repair of surgical sources of bleeding. The ELSO Registry defines a significant clotting complication as requiring a change in a portion of the circuit or entire circuit. In the July 2015 ELSO International Registry Report across all age groups and indications, circuit clots have been reported in nearly 40% of all ECLS runs, with the oxygenator being the site with the greatest number of reported clots.52 Inadequate anticoagulation, low flow states, and patient hypercoagulability lead to increased risk of thrombosis. Areas of stasis or turbulence in the ECLS circuit are prone to clot formation. Even when thrombotic complications are not evident during an ECLS run, thrombosis is commonly observed during postmortem examinations of ECLS patients. A single center report of postmortem examinations of pediatric ECLS patients revealed significant thrombosis in 69% of patients overall and 85% of patients with a history of congenital heart disease.53 In a report of autopsy findings of postcardiotomy adult ECLS patients, over 70% had previously unrecognized thromboembolic complications.54

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References 1. Verstraete M. Heparin and thrombosis: a seventy year long story. Haemostasis. 1990;20 Suppl 1:4-11. 2. Verstraete M. Pharmacotherapeutic aspects of unfractionated and low molecular weight heparins. Drugs. 1990;40(4):498-530. 3. Sinauridze EI, Panteleev MA, Ataullakhanov FI. Anticoagulant therapy: basic principles, classic approaches and recent developments. Blood Coagul Fibrinolysis. 2012;23(6):482-493. 4. Newall F, Johnston L, Ignjatovic V, Monagle P. Unfractionated heparin therapy in infants and children. Pediatrics. 2009;123(3):e510518. 5. Pratt CW, Church FC. Antithrombin: structure and function. Semin Hematol. 1991;28(1):3-9. 6. Finley A, Greenberg C. Review article: heparin sensitivity and resistance: management during cardiopulmonary bypass. Anesth Analg. 2013;116(6):1210-1222. 7. Sandset PM, Bendz B, Hansen JB. Physiological function of tissue factor pathway inhibitor and interaction with heparins. Haemostasis. 2000;30 Suppl 2:48-56. 8. Warkentin TE, Greinacher A. Heparininduced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):311S-337S. 9. Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol. 2003;121(4):535-555. 10. Jang IK, Hursting MJ. When heparins promote thrombosis: review of heparininduced thrombocytopenia. Circulation. 2005;111(20):2671-2683. 11. Martel N, Lee J, Wells PS. Risk for heparininduced thrombocytopenia with unfractionated and low-molecular-weight heparin

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thromboprophylaxis: a meta-analysis. Blood. 2005;106(8):2710-2715. 12. Warkentin TE, Sheppard JA, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood. 2000;96(5):1703-1708. 13. Avila ML, Shah V, Brandao LR. Systematic review on heparin-induced thrombocytopenia in children: a call to action. J Thromb Haemost. 2013;11(4):660-669. 14. Obeng EA, Harney KM, Moniz T, Arnold A, Neufeld EJ, Trenor CC, 3rd. Pediatric heparin-induced thrombocytopenia: prevalence, thrombotic risk, and application of the 4Ts scoring system. The Journal of pediatrics. 2015;166(1):144-150. 15. Warkentin TE. Heparin-induced thrombocytopenia. Curr Opin Crit Care. 2015;21(6):576-585. 16. Hirsh J, O’Donnell M, Weitz JI. New anticoagulants. Blood. 2005;105(2):453-463. 17. Gladwell TD. Bivalirudin: a direct thrombin inhibitor. Clin Ther. 2002;24(1):38-58. 18. Jyoti A, Maheshwari A, Daniel E, Motihar A, Bhathiwal RS, Sharma D. Bivalirudin in venovenous extracorporeal membrane oxygenation. J Extra Corpor Technol. 2014;46(1):94-97. 19. Nagle EL, Dager WE, Duby JJ, et al. Bivalirudin in pediatric patients maintained on extracorporeal life support. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2013;14(4):e182-188. 20. Pieri M, Agracheva N, Bonaveglio E, et al. Bivalirudin versus heparin as an anticoagulant during extracorporeal membrane oxygenation: a case-control study. J Cardiothorac Vasc Anesth. 2013;27(1):30-34. 21. Ranucci M, Ballotta A, Kandil H, et al. Bivalirudin-based versus conventional heparin anticoagulation for postcardiotomy

Anticoagulation and Disorders of Hemostasis

extracorporeal membrane oxygenation. Critical care. 2011;15(6):R275. 22. Koster A, Weng Y, Bottcher W, Gromann T, Kuppe H, Hetzer R. Successful use of bivalirudin as anticoagulant for ECMO in a patient with acute HIT. The Annals of thoracic surgery. 2007;83(5):1865-1867. 23. Ranucci M. Bivalirudin and post-cardiotomy ECMO: a word of caution. Critical care. 2012;16(3):427. 24. Phillips MR, Khoury AI, Ashton RF, Cairns BA, Charles AG. The dosing and monitoring of argatroban for heparin-induced thrombocytopenia during extracorporeal membrane oxygenation: a word of caution. Anaesthesia and intensive care. 2014;42(1):97-98. 25. Dolch ME, Frey L, Hatz R, et al. Extracorporeal membrane oxygenation bridging to lung transplant complicated by heparininduced thrombocytopenia. Exp Clin Transplant. 2010;8(4):329-332. 26. Beiderlinden M, Treschan T, Gorlinger K, Peters J. Argatroban in extracorporeal membrane oxygenation. Artificial organs. 2007;31(6):461-465. 27. Scott LK, Grier LR, Conrad SA. Heparininduced thrombocytopenia in a pediatric patient receiving extracorporeal membrane oxygenation managed with argatroban. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2006;7(5):473475. 28. Young G, Yonekawa KE, Nakagawa P, Nugent DJ. Argatroban as an alternative to heparin in extracorporeal membrane oxygenation circuits. Perfusion. 2004;19(5):283-288. 29. Mejak B, Giacomuzzi C, Heller E, et al. Argatroban usage for anticoagulation for ECMO on a post-cardiac patient with heparin-induced thrombocytopenia. J Extra Corpor Technol. 2004;36(2):178-181.

30. Johnston N, Wait M, Huber L. Argatroban in adult extracorporeal membrane oxygenation. J Extra Corpor Technol. 2002;34(4):281-284. 31. Bembea MM, Annich G, Rycus P, Oldenburg G, Berkowitz I, Pronovost P. Variability in anticoagulation management of patients on extracorporeal membrane oxygenation: an international survey. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2013;14(2):e77-84. 32. Uden DL, Payne NR, Kriesmer P, Cipolle RJ. Procedural variables which affect activated clotting time test results during extracorporeal membrane oxygenation therapy. Critical care medicine. 1989;17(10):10481051. 33. Seay RE, Uden DL, Kriesmer PJ, Payne NR. Predictive performance of three methods of activated clotting time measurement in neonatal ECMO patients. ASAIO journal. 1993;39(1):39-42. 34. Bosch YP, Ganushchak YM, de Jong DS. Comparison of ACT point-of-care measurements: repeatability and agreement. Perfusion. 2006;21(1):27-31. 35. Maul TM, Wolff EL, Kuch BA, Rosendorff A, Morell VO, Wearden PD. Activated partial thromboplastin time is a better trending tool in pediatric extracorporeal membrane oxygenation. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2012;13(6):e363-371. 36. Chan AK, Black L, Ing C, Brandao LR, Williams S. Utility of aPTT in monitoring unfractionated heparin in children. Thrombosis research. 2008;122(1):135-136. 37. Ignjatovic V, Furmedge J, Newall F, et al. Age-related differences in heparin response. Thrombosis research. 2006;118(6):741-745.

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38. Khaja WA, Bilen O, Lukner RB, Edwards R, Teruya J. Evaluation of heparin assay for coagulation management in newborns undergoing ECMO. American journal of clinical pathology. 2010;134(6):950-954. 39. Liveris A, Bello RA, Friedmann P, et al. Anti-factor Xa assay is a superior correlate of heparin dose than activated partial thromboplastin time or activated clotting time in pediatric extracorporeal membrane oxygenation*. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2014;15(2):e72-79. 40. Bembea MM, Schwartz JM, Shah N, et al. Anticoagulation monitoring during pediatric extracorporeal membrane oxygenation. ASAIO journal. 2013;59(1):63-68. 41. Teruya J. Coagulation Tests Affected by Acute Phase Reactants Such as CRP and Factor VIII. Paper presented at: International Conference on Hematology and Blood Disorders; September 23 - 25, 2013; Research Triangle Park, NC USA. 42. Irby K, Swearingen C, Byrnes J, Bryant J, Prodhan P, Fiser R. Unfractionated heparin activity measured by anti-factor Xa levels is associated with the need for extracorporeal membrane oxygenation circuit/membrane oxygenator change: a retrospective pediatric study. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2014;15(4):e175-182. 43. Northrop MS, Sidonio RF, Phillips SE, et al. The Use of an Extracorporeal Membrane Oxygenation Anticoagulation Laboratory Protocol Is Associated With Decreased Blood Product Use, Decreased Hemorrhagic Complications, and Increased Circuit Life. Pediatric critical care medicine : a journal of the Society of Critical Care Medi-

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cine and the World Federation of Pediatric Intensive and Critical Care Societies. 2014. 44. Kostousov V, Nguyen K, Hundalani SG, Teruya J. The influence of free hemoglobin and bilirubin on heparin monitoring by activated partial thromboplastin time and anti-Xa assay. Archives of pathology & laboratory medicine. 2014;138(11):15031506. 45. Alexander DC, Butt WW, Best JD, Donath SM, Monagle PT, Shekerdemian LS. Correlation of thromboelastography with standard tests of anticoagulation in paediatric patients receiving extracorporeal life support. Thrombosis research. 2010;125(5):387-392. 46. Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant. The American journal of pediatric hematology/oncology. 1990;12(1):95-104. 47. Wong TE, Huang YS, Weiser J, Brogan TV, Shah SS, Witmer CM. Antithrombin concentrate use in children: a multicenter cohort study. The Journal of pediatrics. 2013;163(5):1329-1334.e1321. 48. Niebler RA, Christensen M, Berens R, Wellner H, Mikhailov T, Tweddell JS. Antithrombin replacement during extracorporeal membrane oxygenation. Artificial organs. 2011;35(11):1024-1028. 49. Byrnes JW, Swearingen CJ, Prodhan P, Fiser R, Dyamenahalli U. Antithrombin III supplementation on extracorporeal membrane oxygenation: impact on heparin dose and circuit life. ASAIO journal. 2014;60(1):5762. 50. Ryerson LM, Bruce AK, Lequier L, Kuhle S, Massicotte MP, Bauman ME. Administration of Antithrombin Concentrate in Infants and Children on ECLS Improves Anticoagulation Efficacy. ASAIO journal. 2014. 51. Mintz PD, Blatt PM, Kuhns WJ, Roberts HR. Antithrombin III in fresh frozen plasma,

Anticoagulation and Disorders of Hemostasis

cryoprecipitate, and cryoprecipitate-depleted plasma. Transfusion. 1979;19(5):597598. 52. Extracorporeal Life Support Organization. Registry Report. Ann Arbor: University of Michigan; July 2015. 53. Reed RC, Rutledge JC. Laboratory and clinical predictors of thrombosis and hemorrhage in 29 pediatric extracorporeal membrane oxygenation nonsurvivors. Pediatr Dev Pathol. 2010;13(5):385-392. 54. Rastan AJ, Lachmann N, Walther T, et al. Autopsy findings in patients on postcardiotomy extracorporeal membrane oxygenation (ECMO). Int J Artif Organs. 2006;29(12):1121-1131.

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8 Transfusion Management during Extracorporeal Support Anne Marie Winkler, MD

Blood Product Transfusion during Extracorporeal Support Blood transfusion during extracorporeal support typically occurs for several reasons, including circuit priming, restoration of oxygen carrying capacity, maintenance of a hemostatic balance, and treatment of hemorrhagic complications. The variability of blood products included in the circuit prime was captured in a recent international cross-sectional survey with 119 of 121 ELSO-reporting centers responding.1 Of those centers, 92% of circuit primes included packed red blood cells (RBC), 50% fresh frozen plasma (FFP), one center whole blood, and another center including platelets, in addition to other solutions. As a result, the majority of patients are exposed to at least one blood product during extracorporeal support. Additionally, 91 of 117 (78%) respondents from the same survey had an institutional protocol for blood product management with transfusion thresholds differing for pediatric only programs as compared to adult only or mixed adult/pediatric programs. Of the 81 pediatric only program respondents, the median hematocrit threshold reported for RBC transfusion for a typical ECMO patient was 35% (range 25-40%) compared to 30% (range 20-40%) for adult and mixed adult/ pediatric programs (p5.0 kg and can be used with either roller or centrifugal pumps. The authors use a 16F cannula in babies weighing >3.4 kg. Until recently, dual lumen cannulae were unsuitable for centrifugal systems as they were not reinforced to cope with the negative pressures generated by the centrifugal system (roller pumps depend on passive drainage by gravity). OriGen still supplies a 15F polyurethane, non-reinforced dual lumen VV cannula that is suitable for use with roller pumps only. Covidien (now Medtronic Inc., Dublin, Ireland) also makes a non-reinforced 14F dual lumen catheter. Only reinforced cannulae are suitable for use with centrifugal pump systems. Bicaval cannulae are unsuitable for neonates as the 13F Avalon Elite Bicaval (Maquet Cardiovascular, LLC., Wayne NJ) dual lumen

ECLS Cannulation for Neonates with Respiratory failure

cannula was withdrawn because of a high incidence of complications.5 Although the 16F version is available, it should be reserved for older children. There is no role for cephalad cannulae in neonatal VV-ECMO.6 Cannulation Technique Patient Position and Preparation As a rule, neonatal cannulation is undertaken in the NICU on an open bassinette. The patient is paralyzed, sedated, and given suitable analgesia. The patient is placed with their head towards the surgeon, with a small roll under the shoulders to extend the neck and with the head turned to the left to maximally expose the right side. A small amount of Trendelenburg (head down) position is recommended until the vessels are cannulated. Care must be taken to ensure adequate vascular access and a well secured endotracheal. Resuscitation drugs should be prepared and available. In open cannulations, atropine should be available as irritation of the vagus nerve can cause bradycardia. Also, lidocaine can be used topically to relax vessels that go into spasm if handled. A diathermy (Bovie) pad should be placed on the patient. Echocardiography should be available, particularly for VVDL-ECMO, as it is essential to visualize the cannula in the heart to confirm good position and direction of the return jet (Figure 12-2). For VA cannulation, confirmation of cannula position following cannulation is best practice and essential if any difficulty achieving full and consistent ECMO flows ensue. The arterial cannula can be viewed proximal to the aortic arch, and care should be taken to avoid a lower position as this can cause aortic valve malfunction. In CDH patients, it is particularly useful to see the venous cannula enter the right atrium to avoid malplacement.4

Figure 12-2. Top: Echocardiographic views of a VVDL cannula is a good position. Note the Eustachian valve is just beyond the catheter and can cause problems with venous drainage if the cannula is too low. Middle: Demonstrating optimal direction of the return jet towards the tricuspid valve. Bottom: Pseudo-long-axis view. The jet is directed appropriately to the tricuspid valve. In this patient, the TV is not open, which is why the jet splays.

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VVDL Percutaneous Technique Steps 1. Prepare and position patient as described above. 2. After a standard prep and drape, portable ultrasound is used to locate the RIJV. A Seldinger technique is used with a small (22-gauge) needle and a fine (0.018”) guidewire to access the vein with the aid of US guidance. Most VVDL cannulae come with an insertion kit although, for initial access, the authors favor the 4F access system produced by Merit Medical (Prelude® Sheath Introducer). The presence of the guidewire in the right atrium, demonstrated by echocardiography, confirms correct venous placement. 3. The 0.018” guidewire should be upsized to the more robust 0.035” guidewire before advancing dilators/cannulae. 4. Make a small incision in the neck around the guidewire to facilitate dilator/cannulae introduction. 5. Depending on the cannula size, one or two introducer/dilators are used to dilate the skin, subcutaneous tissue and venotomy. 6. As each dilator is withdrawn, some gentle pressure on the neck by an assistant will stop any bleeding. 7. When exchanging dilators, ask for confirmation that the tip of the guidewire has not changed to avoid the guidewire being inadvertently withdrawn, or advanced into the right ventricle (or through the atrial wall). 8. Prepare the cannula by placing the appropriate introducer down the venous limb of the cannula. Ensure the arterial (return) limb of the VVDL cannula is capped. 9. A heparin bolus of 50-100 U/kg is given at this stage (if ECMO flows are not established within 20 minutes, another bolus should be given).

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10. The authors’ practice is to advance the introducer about 5 cm beyond the cannula tip, and to grip this as the introducer/ cannula are advanced over the guidewire into the right internal jugular vein. It is essential to ensure that the ECMO cannula does not slip forward or backwards on the introducer until the 5 cm of the introducer has been inserted into the right internal jugular vein. During this process it is also essential to keep a firm grip on the guidewire to ensure this is held steady and not also introduced further. 11. With the introducer held steady, the cannula is gently slid forward on the static introducer with a slight left-right wrist rotation action (“wiggling”) to facilitate advancement. It is imperative that the introducer not be advanced beyond 5 cm to avoid atrial injury and possible cardiac tamponade. 12. When the cannula is in the right atrium (as seen on echocardiography), the introducer and guidewire are simultaneously removed, backflow of blood is confirmed and the venous tubing is clamped with a tubing clamp. A finger over the connector prevents blood loss prior to clamping. 13. A second tubing clamp is used for the “arterial” tubing and the cap is removed. If the patient has low intravascular volume, a small amount of pressure on the liver will bring blood up into the tubing. 14. The authors recommend clamping the venous tubing from the right and the “arterial” tubing from the left as best practice. 15. The cannula needs to be orientated such that the “arterial” tubing is anteromedial and the venous tubing posterolateral. 16. Ensure the tubing is free of air bubbles, particularly at the junctions of the connectors. 17. The ECMO circuit is connected. The authors always connect the return tubing

ECLS Cannulation for Neonates with Respiratory failure

to the “arterial” limb first, ensuring this tubing comes from the oxygenator. 18. Good position of the cannula is confirmed on echocardiography at optimal ECMO flow to ensure the return jet is directed at the tricuspid valve. 19. The cannula is fixed firmly in place with 2.0 Ethibond or silk sutures. An occlusive dressing is applied. VVDL Semi-open Technique 1. Positioning and prepare as above. 2. A transverse 2 cm incision over the right sternomastoid muscle about 1 cm above the clavicle is used. 3. The sternomastoid fibres are separated using retractors just enough to visualise the anterior surface of the IJV. No deeper dissection is undertaken to preserve the natural tissue support for the internal jugular vein. 4. The 24-gauge catheter is introduced through the skin a few centimetres above the incision and inserted into the IJV under direct vision. The 0.035” guidewire is introduced through the needle and advanced into the right atrium under echocardiographic control. 5. The remainder of the cannulation follows the guidelines for the percutaneous technique above apart from the need for formal closure of the wound. Rarely, the percutaneous (and semi-open) technique is unsuccessful, particularly if there is a large haematoma around the vein. In these cases, a formal neck exploration and isolation of the RIJV is required. Follow the steps noted below for insertion and securing of the venous cannula.

VA Open Technique 1. Prepare and position patient as recommended above. 2. Either make a 2-3 cm transverse incision as described above or an oblique incision parallel with sternomastoid can be used (the former has a better cosmetic appearance). 3. The sternomastoid muscle is separated and retracted to display the carotid sheath, which is opened. 4. It is best to isolate the RCCA initially, leaving the RIJV undisturbed. It is found medial and deep to the internal jugular vein, and once identified, it should be slung with two 2-0 silk loops. Ensure the vagus nerve is identified and untouched to avoid bradycardia. 5. Without occluding the RCCA, a heparin bolus 50-100 U/kg is given (if ECMO flows are not established within 20 minutes, another bolus should be given) 6. Ligate the RCCA cephalad with 2-0 silk over a short silicone bootie. The ends are left long and clipped as they form a useful method of retracting the vessel and will be used later for final cannula fixation. 7. A bulldog clip is placed on the artery as centrally (low) as possible and an arteriotomy formed with an 11 blade. This is best done by lifting the anterior surface of the artery with nontoothed forceps and by incising the artery with a scalpel angled 45 degrees towards the operator. 8. The lubricated cannula with introducer in place is gently inserted into the arteriotomy, taking care not to damage the intima (vessel dilators may help). The bulldog clamp is released by the assistant as the cannula is advanced. Expect a small amount of bleeding at this point but this will stop as the cannula is advanced. It is helpful to pull up on the cephalad tie to straighten and ensure correct tension 163

Chapter 12

on the artery as the cannula is inserted and advanced. 9. Advance the cannula gently. Usually, 3 cm is an adequate length for the intravascular component of the arterial cannula. Be careful not to advance the cannula too far as it may injure the aortic valve. (1/3 distance between insertion site and xiphisternum is a reasonable initial guess). 10. Remove the introducer and place a finger immediately on the end to prevent blood loss before a tubing clamp is applied. 11. Tie the second silk loop down onto the artery and cannula over another silicone bootie. The authors’ practice is to place a second silk tie around the vessel/bootie/ cannula for reassurance. 12. Next, the IJV is isolated with two silk ties and ligated cephalad in similar fashion to the artery. 13. A bulldog clip is placed onto the vein close to the clavicle. 14. A venotomy is made in the same fashion as the artery. 15. Gently place the introducer and venous cannula into the venotomy, holding the venotomy open with nontoothed forceps. Take care with the vein, as it is more fragile than the artery and can tear. Gentle cephalad traction is helpful. 16. Once the tip of the introducer/cannula is in place, the bulldog is released by the assistant and the cannula advanced. 17. The venous cannula has a number of side holes and there will be bleeding from these until they are all in the vein lumen. Until all the side holes are in place, air embolism remains a risk. Head-down position and full paralysis helps prevent this complication. 18. Great care must be taken to ensure the vein is not damaged as the cannula is advanced, especially as it passes behind the clavicle. Do not attempt to force it in; it must “glide” in. The cannula should be 164

advanced to achieve a low atrial position; aiming for the level of the nipple is a reasonable landmark, although accurate positioning with echocardiography is good practice. (2/3 distance between insertion site and xiphisternum is a reasonable initial guess). 19. The introducer is removed and tubing clamp applied as above. Some pressure of the liver may be required to fill the cannula with blood. 20. The venous cannula is tied in place as described for the arterial cannula above. The authors prefer to use different coloured silicone booties for artery and vein. 21. Final fixation is achieved by tying the ends of the cephalad ties (artery and vein) around the appropriate cannulae. Then, one of the ends is tied to one of the 4 long ends of the ties around the cannula centrally. This helps to ensure the cannulae cannot be displaced accidentally. 22. The ECMO circuit is connected to the cannula tubing using a bubble-free technique. It is the authors’ practice to always attach the arterial/return cannula to the ECMO circuit first. Either way, the surgeon must visually trace the tubing (arterial in this case) handed to him/her back to the oxygenator to ensure that it is correctly orientated. This reduces the risk of inadvertently connecting the ECMO circuit in reverse configuration. 23. Once optimal flow is achieved, the wound is closed in layers after ensuring hemostasis. 24. The cannulae are fixed firmly to the skin with 2-0 Ethibond sutures and the wound is dressed. The surgeon and team should not leave until ECMO flow is adequate and the patient has been positioned with the head being brought back to a more central position to facilitate venous drainage on the contralateral side.

ECLS Cannulation for Neonates with Respiratory failure

Post Cannulation Imaging For all the above methods, a plain chest radiograph should be obtained following the procedure to determine catheter position (Figures 12-3 through 12-5). The following should be considered when inspecting the CXR: • The perforated distal plastic section of the Biomedicus venous cannula (size 8-14F) is radiolucent but the tip has a metal “dot” that is opaque on x-ray and should be sited 1 cm above the diaphragm. • The entire intracorporeal section of the Biomedicus arterial cannula is radiopaque, and the tip should be sited approximately 1 cm below the clavicle. • Some of the older reinforced OriGen cannulae are only partially radiopaque but the tip is about 5 cm beyond the visible component on x-ray. • Recent reinforced OriGen cannulae are radiopaque to the tip.

Figure 12-3. Optimal position of Bio-Medicus venous and arterial cannulae. Note the radiopaque “dot” at the distal end of the venous cannula

Figure 12-4. Top: Nonreinforced Origen VVDL cannula in good position. Bottom: Reinforced OriGen VVDL cannula with radiopaque reinforcement of the cannula.

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Decannulation

breath-hold in a paralyzed (or sedated) patient. Pressure is applied to the exit site and, while still Decannulation (see Chapter 16), after per- applying pressure, a single absorbable suture is cutaneous and semi-open VVDL cannulation is used to close the skin. This is an important step straightforward; simply requiring the cannula to stop bleeding from the site (and will shorten to be withdrawn after discontinuing ECMO and greatly the time needed to apply pressure!). clamping the tubes. Again, care must be taken Decannulation after VA-ECMO requires a to avoid air embolism, so it is advisable to have formal operation with paralysis, sedation, and the patient in a head-down position and a short analgesia. The wound is reopened. The site of vessel cannulation is exposed to achieve vascular control proximally and distally with 2-0 silk loops around the vessels. The previously placed silicone booties protect the vessels when incising the silk ties with a scalpel and this facilitates vessel repair. The highest risk of air embolus is during venous cannula removal due to the numerous side holes; so the authors recommend removing this cannula first to allow rapid reinstitution of ECMO support in the case of air embolus. While removing the venous cannula the medical team should give a ventilator “inspiratory hold” to minimize the chance of venous air embolism. A Satinsky vascular clamp is used to occlude the central vein as the cannula is removed. Once the venous cannula has been removed +/- repaired, the arterial cannula is removed in identical fashion. It is the authors’ practice to repair the vessels (especially the RCCA) in all but the longest runs. Bulldog clamps are placed cephalad and centrally on the vessels to gain control. The arteriotomy (and venotomy where appropriate) is closed with 6-0 or 7-0 polypropylene. Ensure the lumen of the vessel is filled with heparinized saline and remove the cephalad clamp, allow the artery to fill with blood before the central clamp is removed. If the vessels are in poor condition (usually after long runs) they should be tied off with nonabsorbable ties. The neck wound is closed in layers with absorbable sutures according to personal preference. Figure 12-5. Top: Biomedicus venous and arterial cannulae in a patient with left CDH. Bottom: OriGen VVDL cannula in a patient with left CDH.

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References 1. Haynes AB, Weisner TG, Berry WR et al. A surgical safety checklist to reduce morbidity and mortality in a global population. N Eng J Med 2009;360:491-499. 2. Roberts N, Westrope C, Pooboni SK et al. Venovenous extracorporeal membrane oxygenation for respiratory failure in inotrope dependent neonates. ASAIO J 2003;49(5):558-571. 3. Frenckner B, Palmar K, Linden V. Neonates with congenital diaphragmatic hernia have smaller neck veins than other neonates – an alternative route for cannulation. J Pediatr Surg 2002;37(6):906-908. 4. Fisher JC, Jefferson RA, Kuenzler KA, Stolar CJ, Arkovitz MS. Challenges to cannulation for extracorporeal support in neonates with right-sided congenital diaphragmatic hernia. J Pediatr Surg 2007;42(12):21232128, 2007 5. Speggiorin S, Robinson SG, Harvey C, et al. Experience with the Avalon bicaval double-lumen veno-venous cannula for neonatal respiratory support. Perfusion 2015;30(3):250-254. 6. Skarsgard ED,Salt DR,Lee SK. Extracorporeal Life Support Organization Registry. Venovenous extracorporeal membrane oxygenation in neonatal respiratory failure: does routine, cephalad jugular drainage improve outcome? J Pediatr Surgery 2004;39(5):672-676.

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13 Congenital Comorbidities among Neonatal Extracorporeal Life Support (ECLS) Patients with Respiratory Failure Javier Kattan, MD, Mark T. Ogino, MD

Background

Congenital Anomalies

With the evolution in the past few decades of neonatal intensive care treatments and extracorporeal life support (ECLS), more complex and severe cases have been selected to receive ECLS with the consequent increase in mortality and morbidity rates in newborns who receive ECLS suffering from hypoxic respiratory failure (HRF) and persistent pulmonary hypertension of the newborn (PPHN). Special attention to neonatal comorbidities during ECLS will help clinicians anticipate complications, improve survival, and decrease short and long-term morbidities. An understanding of comorbidities is essential to improve selection criteria for ECLS for complex newborn cases. A review of the ELSO Registry by Zabrocki et al. reported the impact of comorbidities in the Pediatric ECLS cohort’s survival statistics.1 Comorbidities related to ECLS in neonatal HRF and/or PPHN can be congenital or acquired in origin. The congenital comorbidities will be the primary focus of this chapter and the acquired comorbidities will be discussed in chapters specific to the organ system.

Pulmonary Disease categories for pulmonary comorbidities can be grouped as: surfactant protein deficiencies, alveolar capillary dysplasia, anomalies of airways and lung parenchyma, thoracic dystrophies, and disorders of the diaphragm (Figure 13-1 and 13-2). These and other pulmonary anomalies are reviewed in Chapter 9 and 10. Chronic Lung Disease/Bronchopulmonary Dysplasia. No systematic studies of neonates with CLS/BPD exist but case reports of successful support with ECLS have been reported. In a review of the ELSO Registry, Smith et al. showed that survival to discharge in neonates who are cannulated after day 7 of life was significantly lower (61% vs. 83%) than in neonates cannulated at 1 week of age or less.2 However the older neonates had a lower rate of intracranial hemorrhage than the younger group. Cardiac The most common cardiac diagnoses within the ELSO Registry include myocarditis, cardiomyopathy, intractable arrhythmias with hemodynamic compromise, pulmonary hypertension, and unique ventricular circulation.3 Respiratory 169

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ECLS support can be complicated by difficult patients. Neonatal cardiac patients placed on to diagnose cardiac or vascular comorbidities ECLS were reviewed by Grist et al. to deterin neonates that may present as severe PPHN. mine the first adjusted anion gap (AGc), the Poor outcome in these patients relates to the first venoarterial carbon dioxide (CO2) gradihigh incidence of cardiovascular collapse and ent (p[v-a]CO2), and the first Viability Index end-organ dysfunction; therefore, early echo- (AGc + p[v-a]CO2 = VI) on ECLS.6 Some key cardiography is recommended for neonates clinical indicators were identified for increased with presumed PPHN. Ten percent of ECLS mortality: an AGc ≥ 23 mEq/L, a p[v-a]CO2 ≥ referrals, all with presumed PPHN, were found 16 mmHg, and a VI ≥ 28. An elevated AGc and to have congenital heart disease (CHD).4 The VI correlated with a significantly higher risk most common diagnoses being transposition of for mortality, with survival to discharge being the great arteries, total anomalous pulmonary 20% or less.6 venous return, then left-sided heart obstructive lesions.4 Computed tomographic angiography Gastrointestinal and cardiac catheterization can be used in CHD patients receiving ECLS to define extra and Abdominal wall defects are related to PPHN intracardiac anatomy in the chest (see Chapter or lung hypoplasia and have sufficient severity 10).5 Mortality in the CHD group diagnosed to develop HRF and hemodynamic instability.7 while on ECLS was 50%, compared with 11% Although omphalocele and gastroschisis may for correctly identified CHD patients.4 This produce HRF due to PPHN the use of ECMO observation reaffirms the importance of basing to support these patients seems rare.8 neonatal ECLS support in centers with cardiac Abdominal compartment syndrome (ACS), surgical services.4 an acquired comorbidity associated with abECLS intervention prior to severe organ dominal wall defect repair or other abdominal failure may improve survival in neonatal cardiac surgeries, can lead to compromise in venous

Figure 13-1. VA-ECLS in a newborn with PPHN, finally diagnosed as an alveolar capillary dysplasia by a biopsy. A) X-ray on ECLS; B) & C) histology showing vascular and capillary misalignment.

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blood return ECLS support.9 This ACS occurs especially in patients with massive capillary leak and post abdominal surgery patients with an increasing abdominal distension. Timely placement of a peritoneal dialysis catheter and drainage of peritoneal fluid can improve venous return and improve oxygen delivery by improving ECMO flows.10,11 Renal Disease Acute kidney injury (AKI) frequently complicates neonatal critical illness resulting especially in newborns with HRF and PPHN on ECLS (approximately 50%), significantly increasing ECMO duration and mortality rate.12,13 Renal replacement therapy due to acute kidney injury while on ECLS is independently associated with neonatal mortality12,13 (see Chapter 62). Oligohydramnios often occurs in association with congenital renal disease (CRD) and may result in the development of HRF from pulmonary hypoplasia, delayed lung maturation,

or PPHN.14 Frequent causes of CRD include urinary obstruction (eg, posterior urethral valves), renal dysplasia, and vesicoureteral reflux. In the past, the prognosis in these high-risk cases was extremely poor, although successful support with ECLS in neonates with CRD has been reported.14,15 Factors associated with successful long-term outcome include renal disease amenable to surgical correction, aggressive nutritional support, and a reliable social support system.14,15 Wightman et al. recently investigated the prevalence and survival to discharge of neonates with underlying kidney disease who received ECLS from 1989 to 2012. They analyzed the 28,755 neonates from the ELSO Registry and reported that survival was lower in neonates with kidney disease (49% vs. 82% pulmonary failure without CDH, 25% vs. 51% pulmonary with CDH, 21% vs. 41% cardiac diagnosis), suggesting that kidney disease be considered when evaluating ECLS candidacy.16

Figure 13-2. Multivariate analysis of factors associated with ECMO or death. (Pediatr Crit Care Med. 2013 Nov;14(9):876-883)

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An extensive discussion on treatment options for congenital renal disease extends beyond the scope of this chapter. The use of RRT and other renal failure treatment modalities is discussed in chapter 62. Hematologic

poorly understood. Wu et al. reported the risk factors and radiologic features of sinovenous thrombosis in neonates of greater than 36 weeks’ gestational age occurring over an 11year period.17 Of 29 patients, 29% received ECLS treatment, and 23% had CHD. Genetic thrombophilias were present in four of the seven infants tested. Eighteen neonates had multiple maternal, neonatal, perinatal, or prothrombotic complications. Venous sinus thrombosis was often accompanied by infarction (50%) or intraventricular hemorrhage (33%).17,18

Family history of blood dyscrasias should alert the clinician of possible hemostatic problems; however, diagnostic confirmation in the neonatal period often proves difficult to establish due to the dynamic nature of coagulation factors associated with postmenstrual age and Immunodeficiency impact of stress on neonatal factor levels. ECLS masks hematologic disorders even further due Primary immunodeficiency disorders to consumption and replacement of coagula- (PID) are rare with an estimated incidence of tion factors during the ECLS course. Suspicion 1 in 1200 live births in the United States,19,20,21 of a congenital hematologic disorder requires making the probability of encountering such a monitoring and testing after decannulation condition extremely rare in potential neonatal and recovery from primary condition leading ECLS candidates. Recognizing PID in the critically ill neonate is difficult in the absence to ECLS. Diagnostic categories to consider are of physical findings suggestive of immunodehemorrhagic and thromboembolic. Neonatal ficiency syndromes. These syndromes include 22q11.2 deletion syndrome, Wiskott-Aldrich diagnoses include: syndrome, and X-linked ectodermal dysplasia.19 • Hereditary Hemorrhage Disorders: Hemo- Newborn screening can detect T-cell PID21 and philia A/B, Von Willebrand disease may alert the clinician to an early recognition of • Hereditary Thromboembolic Disorders: these disorders. Disorders of innate immunity, Prothrombotic disorders, Activated Protein complement deficiencies, humoral and cellular C resistance, Factor V Leiden mutation, immunity may be a causative factor in recurProthrombin gene mutation, AT3 deficiency, rent infections or infections by nosocomial Protein C deficiency, Protein S deficiency organisms and need to be considered if the Disseminated Intravascular Coagulation patient survives ECLS support. Identifying a (DIC). Patients may experience coagulopathy PID also has important implications for other or disseminated intravascular coagulation prior family members.

to cannulation. Every attempt should be made to correct existing coagulation abnormalities before cannulation as the addition of heparin or other anticoagulants will exacerbate these defects. Few data exist to predict the impact of such complications on outcomes (see Chapters 7 and 8). Venous sinus thrombosis. The etiology of neonatal venous sinus thrombosis remains 172

Malignancies The peak cancer incidence in children is the first year of life, and 13% of these cases are diagnosed in the neonatal period.22 The most common neonatal malignancies include neuroblastoma (54%), leukemia (13%), renal tumors (13%), and sarcoma (11%).22

Congenital Comorbidities among Neonatal ECLS Patients with Respiratory Failure

Hereditary conditions are associated with tumors, but only Wilms tumor, retinoblastoma, and hepatoblastoma present in the neonatal period. Genetic conditions, such as Trisomy 21, are associated with neoplasms including leukemia.23 Survival rates generally are lower for malignancies presenting in the neonatal period; however, newer drug therapies and interventions have resulted in a wide variation in survival rates and detailed evaluation of the malignancy is required for prognostication and should be considered to determine a neonate’s candidacy for ECLS.

infectious agents become clinically significant pathogens in this population.26 Some bacterial, fungal, and viral agents are described below. Bacterial

Bacterial infections continue to be an important cause of mortality in the neonate around the world, with an incidence of 1 to 10 in 1,000 livebirths.27,28 The most common agents of early onset sepsis are: Streptococcus group B, Escherichia coli, Listeria monocytogenes, Streptococcus pneumoniae, Haemophilus, Streptococcus group A, and Staphylococcus aureus. Listeria monocytogenes. In an ELSO Infections Registry report of patients between 1975 and In neonates with septic shock unrespon- 1991, nine neonates received ECLS for severe sive to conventional medical management, HRF associated with Listeria monocytogenes ECLS serves as a viable treatment option. In infection.29 The ECLS duration for patients 1990, McCune et al. reported on 100 neonates with Listeria infection (median, 210 hours) was treated with VA-ECLS of which 10% were prolonged compared to neonates with other didue to septic shock.24 The survival rate for the agnoses, a result likely associated with severe 10 neonates was 100%. Neonates with sepsis necrotizing pneumonia. Six of the nine infants required greater ventilatory support after ECLS (67%) recovered completely.29 Legionella. Moscatelli et al. reported and had a higher incidence of chronic lung disease (30% vs. 12%) than neonates receiv- the first neonatal case of hospital-acquired ing ECLS for meconium aspiration syndrome Legionella pneumonia in a newborn with unor respiratory distress syndrome. The study diagnosed tracheoesophageal fistula and HRF showed that neonates with sepsis also suffered requiring VV-ECLS support before fistula repair. higher rates of intracranial hemorrhage than Standardized multiplex PCR assay allowed others supported with ECLS (40% vs. 26%).24 early diagnosis.30 Neonatal and pediatric patients with sepsis have Bordetella pertussis. Pertussis carries a been successfully supported with venovenous high risk of mortality in very young infants.31 support (see Chapter 56). Skinner et al. dem- The mechanism of refractory cardiorespiratory onstrated that survival in septic patients was failure is complex and not clearly delineated. higher in the VV-ECLS group (79%) than in Mean age of patients with pertussis placed on the VA-ECLS group (64%).25 VA-ECLS had ECLS is approximately 90 days (range: 1 day increased mortality risk after adjustment for to 3 years). Overall mortality is approximately age, use of vasoactive agents, and advanced 70%.32 Surgical sepsis. ECLS can aid resolution respiratory support. The authors suggest that when technically feasible, VV-ECLS can be of not only PPHN, but also cardiopulmonary considered as the first therapeutic choice in this distress due to neonatal sepsis. Surgical sepsis, such as in cases of gastric rupture, is one of the patient population.25 Due to the relative immunocompromised most serious causes of surgical sepsis in the status of a neonate, common and uncommon 173

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neonatal period and is reported to be successfully treated on ECLS support.33 Staphylococcus epidermidis and Staphylococcus aureus. Secondary nosocomial infections in the neonatal period, frequently due to Staphylococcus epidermidis and Staphylococcus aureus, have been reported to cause severe recurrent PPHN, requiring iNO or ECLS.34 Fungal Fungal infection before or during ECLS increases the odds of mortality, and the magnitude of this effect depends upon the age group and timing of infection.35 For patients with fungal infections before ECLS, 82%-89% demonstrated presumed clearance during support. Although the risk of mortality increased with fungal infections, ongoing infection does not appear to be a contraindication to initiation or continuation of support.35 Aspergillus. Infection/colonization is associated with a 22% overall survival-to-discharge rate among children supported on ECLS, including neonates. The ELSO Registry data confirm that Aspergillus infection can occur among ECLS patients without known immunodeficiencies.36 A high level of suspicion for Aspergillus infection should be maintained when lung disease in patients on ECLS does not improve.36 Candida species. Neonatal invasive candidiasis is associated with preterm infants and carries significant morbidity and mortality.37 Pre-ECMO Candida species infection is associated with increased risk of mortality; however, Pluim et al. reviewed the ELSO Registry but did not differentiate nosocomial versus invasive congenital disease.35 Viral Viral infection can cause severe HRF in neonates. Acute respiratory infections in infants are caused most frequently by respiratory syncytial virus (RSV), influenza, parainfluenza, 174

adenovirus, and metapneumovirus.38 Below we will review some especial viral infection requiring ECLS in neonates. Adenovirus. In 1994, Kinney et al. reported on two infants with fulminant early onset sepsis syndrome and HRF secondary to congenital adenovirus infection successfully treated with ECLS.39 However, ELSO Registry data showed survival of only 11% among neonates infected with adenovirus. Neonatal presentation, acidosis, sepsis, and increased peak inspiratory pressure (PIP) are important pre-ECLS factors associated with in-hospital mortality when considering a trial of ECLS; pneumothorax and brain hemorrhage were ECLS-related complications associated with mortality.40 Cytomegalovirus (CMV). In 1992, Tierney et al. reported on disseminated CMV infection after ECLS. In parts of the world where CMV-negative blood remains unavailable, CMV infection has been described post ECLS. Leukoreduction of blood products is a possible solution in these cases; however, clear benefits have not yet been demonstrated.41 Herpes simplex infection (HSV). In a study by Prodham et al. neonates with HSV infection supported on ECLS demonstrated low hospital survival rates (25%).42 Clinical presentation with septic shock was associated with higher mortality for the HSV group and mortality rates have remained unchanged over the last 35 years.42 Human Immunodeficiency Virus (HIV). The only reported cases of HIV infected patients on ECLS have been in the adult population.43 Infants born to a mother with HIV infection have a lower risk of viral transmission with interventions to prevent transmission, which includes antiretroviral agent treatment.44 The diagnostic evaluation for HIV infection is typically delayed until 2 weeks of age; however, DNA PCR testing can be performed on the neonate as early as the first day of life for a preliminary diagnosis.44 Neonates suspected of HIV infection and who

Congenital Comorbidities among Neonatal ECLS Patients with Respiratory Failure

would benefit from ECLS should be considered as candidates with the improved survival rates. Miscellaneous viral pathogens. Human parvovirus B19 infection is one of the leading causes of nonimmune hydrops. ECLS support for Parvovirus infection has only been reported for myocarditis in the pediatric age group.45 RSV is a nosocomial infection that has led to nursery outbreaks.46 Neonates with bronchopulmonary dysplasia are at risk for severe HRF that requires ECLS support.47 Other viral pathogens that lead to infections of the fetus and neonate include varicella, rubella, enterovirus, and viral hepatitis. The agents are known biologic teratogens with the common target organs being neurologic, ophthalmologic, dermatologic, and gastrointestinal.48 Primary pulmonary infection, as well as cardiac anomalies that require immediate medical intervention, are rare.48

Intraventricular Hemorrhage (IVH) Although neonates with grade 1 IVH are generally considered candidates for cannulation for ECMO there is more concern about newborns with grade II or III bleeds. A survey of neonatologists found that most would offer ECLS for a newborn with grade II but not grade III IVH.53 Few data exist to guide management decision on these complicated patients. Myopathies

Neurologic

In 1994 Sandler et al. reported two unrelated infants with low Apgar scores, pneumothoraces, and severe PPHN who were treated with ECLS while receiving chemical sedation and neuromuscular paralysis.54 After decannulation from ECLS, hypotonia and hypoventilation persisted. Neurologic evaluation confirmed that both infants had a congenital myopathy.54

Neonatal Encephalopathy

Vascular Variants

Common origin of the carotid arteries Newborns with acute hypoxic/ischemic events resulting in cerebral injury after a peri- (COCA) is a normal anatomic variant reported natal event are at risk for developing HRF from to occur in approximately 11% to 15% of the meconium aspiration syndrome, idiopathic general population, presuming that patients are pulmonary hypertension, or pneumonia.49 De- at higher risk for adverse neurologic sequelae spite evidence to support the continued use of owing to potential occlusion of both carotid arECLS in these defined groups of neonates, rates teries by the arterial cannula. However, Lamers of impairment among survivors remain high.49 et al. demonstrated that COCA has no predictive Therapeutic hypothermia provides neuropro- value in determining PDI and MDI outcomes tection in mature infants exposed to perinatal and no significance in predicting an increased asphyxia, although in newborn infants treated risk of adverse neurologic sequelae.55 Therefore, by ECMO/ECLS, the use of mild hypothermia although a common aortic arch variant, COCA for the first 48 to 72 hours did not result in im- does not appear to increase the risk of neuroproved outcomes up to 2 years of age in a recent logic injury in infants undergoing VA ECLS.55 randomized trial in the United Kingdom.50 Data upon neonates with moderate to severe hypox- Arteriovenous Fistula emic ischemic encephalopathy (HIE) supported ECLS can sustain severely ill neonates with with ECMO remain limited but relatively positive.51,52 Consequently neonates with potential high output heart failure secondary to intracraniHIE should be considered for ECMO when al arteriovenous fistula (AVF). In 2004, Burry et al. described the first successful novel approach other contraindications do not exist. 175

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to the management of high output heart failure secondary to an intracranial high-flow dural arteriovenous fistula (DAVF), performing an embolization (coils and liquid embolic agents) in conjunction with the use of an ECMO/ECLS circuit. This report also documents the first use of an ECLS cannula for intraarterial cerebral angiography.56 Inborn Errors of Metabolism Acute signs of an inborn error of metabolism leading to clinical decomposition can present in a newborn as severe metabolic acidosis, cardiovascular failure, and respiratory failure.57,58 Organic acidurias, urea cycle disorders, maple syrup urine disease, and fatty acid oxidation disorders can present with life threatening conditions. ECMO can provide cardiac and respiratory support while metabolic imbalances are corrected and can support hemodialysis to rescue newborns with metabolic defects (eg, urea cycle defects with life threatening hyperammonemia and HRF).57,58 A neonate with medium chain acyl-coenzyme A dehydrogenase deficiency (MCAD) was placed on ECMO after a cardiac arrest from ventricular tachycardia and fibrillation and survived to discharge .59 Genetic Abnormalities

Trisomy 21 The incidence of PPHN is higher in neonatal patients with trisomy 21 when compared with the general neonatal population (1.2% vs. 0.1%).61 Patients with a cardiac indication for ECLS have higher mortality compared with those supported for respiratory indications. Despite differences in indications for ECLS, patients with Down syndrome (DS) have similar hospital survival rates as those without DS; thus, by itself, the diagnosis should not be considered a risk factor for in-hospital mortality for ECLS. Recently, Gupta et al. evaluated morbidity and mortality associated with ECLS in infants with DS and heart disease. The most common cardiac defects in this group included common AV canal (63%) and tetralogy of Fallot (40%). The mortality rate was lower in those with DS than in controls (44 vs. 56 %).62 Cashen et al. also recently reported on 30 years of data from the ELSO Registry including 623 patients with DS and 46,239 control patients. The prevalence of DS was 13.5/1000 patients who received ECLS. There was no significant difference in survival between patients with or without DS (63% vs. 57%). In DS patients, independent risk factors for mortality before cannulation included cardiac indication and milrinone use. Multivariable risk factors for mortality while receiving ECLS included hemorrhagic, neurologic, renal, and pulmonary complications.63

ECLS has been used in children with genetic syndromes with good results including high survival and few complications. Uppu et Trisomy 13 and Trisomy 18 al. conducted a retrospective review of children These genetic disorders have characteriswith CHD and genetic syndromes who received ECLS and showed that ECMO/ECLS duration, tic physical features which alert clinicians to hospital LOS, and mortality were similar in consider a genetic evaluation. Cardiovascular patients with and without underlying genetic and abdominal wall defects and other organ abnormality. Among genetically abnormal pa- anomalies are commonly associated with these tients, renal insufficiency and need for dialysis syndromes, also known as Patau syndrome were associated with mortality. However, only (Trisomy 13) and Edwards Syndrome (Trisomy 56% were discharged home, and the survivors 18), respectively. In the December 2013 ELSO Neonatal Respiratory Failure Supplement to the had a high late mortality of 42%.60 ELSO General Guidelines, both of these diagno176

Congenital Comorbidities among Neonatal ECLS Patients with Respiratory Failure

ses were listed as “lethal chromosome disorders” and contraindications to neonatal respiratory failure.64 Nelson et al. in a 2016 article reviewed the survival and surgical interventions for these diagnoses and found that 19.8% of those with trisomy 13 and 12.6% of infants with trisomy 18 died in the first year of life, but 10 year survival was higher than previously reported (12.9% and 9.8%, respectively).65 A survey of ELSO Neonatal ECMO centers reported some centers would consider ECLS support for this population of patients.53 Chylothorax and Genetics Congenital chylothorax occurs rarely in neonate but carries major morbidity and mortality. The majority of such infants have associated chromosomal anomalies, malformations (80%), and comorbidities that require prolonged intensive care and sometimes ECLS support, associated to hypoxic respiratory failure. In a retrospective series of 10 cases of congenital chylothorax, 8 infants were diagnosed antenatally, and 3 of these infants had antenatal pleural drainage. Postnatal management for chylothorax includes drainage of fluid, ventilation, albumin, octreotide, and dietary modification with medium-chain triglyceride-enriched formula. Noonan syndrome and trisomy 21 are the most common underlying genetic diagnosis for chylothorax.66 Prematurity Current guidelines for ECLS in neonates continue to list prematurity (less than and equal to 32 weeks gestation) and birth weight (less than 2 kg) as relative contraindications.64 These recommendations derive from a 1987 study that documented decreased survival and an increase in intraventricular hemorrhage (IVH) in this cohort of newborns.67 Smith et al. demonstrated recently that neonates cannulated for ECLS after the first week of life had greater mortal-

ity despite lower rates of CNS hemorrhage than neonates who received ECLS earlier.2 Premature infants cannulated after 1 week had fewer CNS hemorrhages than premature infants treated with ECLS starting within the first week of life.2 Hardart et al. in 2004 made a similar conclusion based upon a retrospective study of the ELSO Registry between the years of 1992 and 2000 but found that postconceptual age of ≤32 weeks was the best age predictor of ECMO related intracranial bleeds.68 Rozmiarek et al. reviewed the ELSO Registry and concluded that ECLS cannulation for infants less than 2 kg may be safe with a IVH incidence of 5.5%, which is lower than previously reported.69 A data collection survey study of neonatal respiratory center directors reported that 65% of the respondents would consider neonates with a gestational age of less than 2 kg as potential ECMO candidates, and 58.1% setting 35 weeks or greater as the lowest gestational age.53 The limits continue to be challenged with the placement of low birth weight and premature infants with complex congenital heart disease on postcardiotomy and perioperative venoarterial ECMO.70,71 Careful anticoagulation management in this group of patients is essential to minimize the risk of an intracranial accident. Conclusion Neonates considered for ECLS can have multiple comorbidities but many of these complications may remain undiagnosed at birth. However, the longest standing and greatest experience for the use of ECLS exists in this population. The outcomes of ECLS in neonates with respiratory failure remain excellent. With careful evaluation of underlying comorbidities and adherence to appropriate ECLS guidelines, neonatal patients will continue to have excellent outcomes.

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References 1. Zabrocki LA, Brogan TV, Statler KD, et al. Extracorporeal membrane oxygenation for pediatric respiratory failure: Survival and predictors of mortality. Crit Care Med. 2011; 39(2):364–370. 2. Smith KM, McMullan DM, Bratton SL, et al. Is age at initiation of extracorporeal life support associated with mortality and intraventricular hemorrhage in neonates with respiratory failure. J Perinatol. 2014;34(5):386-391. 3. Paden ML, Rycus PT, Thiagarajan RR; ELSO Registry. Update and outcomes in extracorporeal life support. Semin Perinatol. 2014;38(2):65-70. 4. Brown KL, Miles F, Sullivan ID, et al. Outcome In neonates with congenital heart disease referred for respiratory extracorporeal membrane oxygenation. Acta Paediatr. 2005;94(9):1280-1284. 5. Friedman BA, Schoepf UJ, Bastarrika GA, Hlavacek AM. Computed tomographic angiography of infants with congenital heart disease receiving Extracorporeal Membrane Oxygenation. Pediatr Cardiol. 2009;30(8):1154-1156. 6. Grist G, Whittaker C, Merrigan K, et al. Identifying neonatal and pediatric cardiac and congenital diaphragmatic hernia extracorporeal membrane oxygenation patients at increased mortality risk. Extra Corpor Technol. 2010;42(3):183-190. 7. Partridge EA, Hanna BD, Panitch HB, et al. Pulmonary hypertension in giant omphalocele infants. J Pediatr Surg. 2014 Dec;49(12):1767-1770. 8. Lalani A, Benson Ham P, Wise LJ, et al. Management of patients with gastroschisis requiring extracorporeal membrane oxygenation for concurrent respiratory failure. Am Surg. 2016;82(9):768-772. 9. Rollins MD, Deamorim-Filho J, Scaife ER, Hubbard A, Barnhart DC. Decompressive 178

laparotomy for abdominal compartment syndrome in children on ECMO: effect on support and survival. J Pediatr Surg. 2013;48(7):1509-1513. 10. Prodhan P, Imamura M, Garcia X, et al. Abdominal compartment syndrome in newborns and children supported on extracorporeal membrane oxygenation. Asaio J. 2012;58(2):143-7. 11. Wu ET, Huang SC, Chiu IS, Ko WJ. Abdominal compartment syndrome caused failure of venous return in a neonate during extracorporeal membrane oxygenation support. Pediatr Crit Care Med. 2006;7(4):400401. 12. Fleming GM, Sahay R, Zappitelli M, et al. The incidence of acute kidney injury and its effect on neonatal and pediatric extracorporeal membrane oxygenation outcomes: A multicenter report from the kidney intervention during extracorporeal membrane oxygenation study group. Pediatr Crit Care Med. 2016;Epub ahead of print. 13. Askenazi DJ, Ambalavanan N, Hamilton K, et al. Acute kidney injury and renal replacement therapy independently predict mortality in neonatal and pediatric noncardiac patients on extracorporeal membrane oxygenation. Pediatr Crit Care Med. 2011;12(1):e1-e6. 14. Caesar RE, Packer MG, Kaplan GW, et al. Extracorporeal membrane oxygenation in the neonate with congenital renal disease and pulmonary hypoplasia. J Pediatr Surg. 1995;30:1560-1563. 15. Gibbons MD, Horan KK, Djeter SW Jr, et al. Extracorporeal membrane oxygenation: An adjunct in the management of the neonate with the neonate with severe respiratory distress and congenital urinary tract anomalies. J Urol. 1993;150 (2 Pt 1):434-437. 16 Wightman A, Bradford MC, Symons J, Brogan TV. Impact of kidney disease on survival in neonatal extracorporeal life support. Pediatr Crit Care Med. 2915;16(6):576-582

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17. Wu YM, Hamrick SE, Miller SP, et al. Intraventricular hemorrhage in term neonates caused by sinovenous thrombosis. Ann Neurol. 2003;54(1):123-126. 18. Wu YW, Miller SP, Chin K, et al. Multiple risk factors in neonatal sinovenous thrombosis. Neurology. 2002;59(3):438-40. 19. Walkovich K, Connelly JA. Primary immunodeficiency in the neonate: Early diagnosis and management. Semin Fetal Neonatal Med. 2016;21(1):35-43. 20. Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol. 2007;27(5):497-502. 21. Barbaro M, Ohlsson A, Borte S, et al. Newborn screening for severe primary immunodeficiency diseases in Sweden- a 2-year pilot TREC and KREC screening study. J Clin Immunol. 2016; Epub ahead of print. 22. Linabery AM, Ross JA. Trends in childhood cancer incidence in the U.S. (1992-2004). Cancer. 2008;112(2):416-432. 23. Bhatnagar N, Nizery L, Tunstall O, Vyas P, Roberts I. Transient abnormal myelopoiesis and AML in Down Syndrome: an Update. Curr Hematol Malig Rep. 2016;11(5):333341 24. McCune S, Short BL, Miller MK, Lotze A, Anderson KD. Extracorporeal membrane oxygenation therapy in neonates with septic shock. J Pediatr Surg. 25(5):479-482. 25. Skinner SC, Iocono JA, Ballard HO, et al. Improved survival in venovenous vs venoarterial extracorporeal membrane oxygenation for pediatric noncardiac sepsis pateints: a study of the Extracorporeal Life Support Organization registry. J Pediatr Surg. 2012;47(1):63-67. 26. Kumar SK, Bhat BV. Distinct mechanisms of the newborn innate immunity. Immunol Lett. 2016 May;173:42-54. 27. Bedford Russell AR, Kumar R. Early onset neonatal sepsis: diagnostic dilemmas and

practical management. Arch Dis Child Fetal Neonatal Ed. 2015;100(4):F350-354. 28. Dong Y, Speer CP. Late-onset neonatal sepsis: recent developments. Arch Dis Child Fetal Neonatal Ed. 2015;100(3):F257-263. 29. Hirschl RB, Butler M, Coburn CE, Bartlett RH, Baumgart S. Listeria monocytogenes and severe newborn respiratory failure supported with extracorporeal membrane oxygenation. Arch Pediatr Adolesc Med. 1994;148(5):513-517. 30. Moscatelli A, Buratti S, Castagnola E, Mesini A, Tuo P. Severe neonatal Legionella pneumonia: full recovery after extracorporeal life support. Pediatrics. 2015;136(4):e1043-e1046. 31. Straney L, Schibler A, Ganeshalingham A et al; Australian and New Zealand Intensive Care Society Centre for Outcomes and Resource Evaluation and the Australian and New Zealand Intensive Care Society Paediatric Study Group. Burden and outcome of severe pertussis infection in critically ill infants. Pediatr Crit Care Med. 2016;17(8):735-742. 32. Halasa NB, Barr FE, Johnson JE, Edwards KM. Fatal Pulmonary Hypertension Associated With Pertussis In Infants: Does Extracorporeal Membrane Oxygenation Have A Role? Pediatrics. 2003;112:12741278. 33. Nagaya M, Kato J, Nimi N, Tanaka S. Extracorporeal membrane oxygenation for newborns with gastric rupture. Pediatr Surg Int. 2001;17(1):35-38. 34. Hintz SR, Benitz WE, Halamek LP, Van Meurs KP, Rhine WD. Secondary infection presenting as recurrent pulmonary hypertension. J Perinatol. 2000;20(4):262-4. 35. Pluim T, Halasa N, Phillips SE, Fleming G. The morbidity and mortality of patients with fungal infections before and during extracorporeal membrane oxygenation support. Pediatr Crit Care. 2012;13(5):e288-e293.

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36. Garcia X, Mian A, Mendiratta P, et al. Aspergillus infection and extracorporeal membrane oxygenation support. J Intensive Care Med. 2013;28:178-184. 37. Aliaga S, Clark RH, Laughon M, et al. Changes in the Incidence of Candidiasis in Neonatal Intensive Care Units. Pediatrics. 2014;133(2):236-242. 38. Pavia AT. Viral infections of the lower respiratory tract: old viruses, new viruses, and the role of diagnosis. Clin Infect Dis. 2011;52(4):S284-289. 39. Kinney JS, Hierholzer JC, Thibeault DW. Neonatal pulmonary insufficiency caused by adenovirus infection successfully treated with extracorporeal membrane oxygenation. J Pediatr. 1994;125(1):110-112. 40. Prodhan P, Bhutta AT, Gossett JM, et al. Extracorporeal membrane oxygenation support among children with adenovirus infection: a review of the extracorporeal life support organization registry. Asaio J. 2014;60(1):4956. 41. Tierney AJ, Higa TE, Finer NN. Disseminated cytomegalovirus infection after extracorporeal membrane oxygenation. Pediatr Infect Dis J. 1992;11(3):241-243. 42. Prodhan P, Wilkes R, Ross A, et al. Neonatal herpes virus infection and extracorporeal life support. Pediatr Crit Care Med. 2010;11(5):599-602. 43. Cawcutt K, Gallo De Moraes A, Lee SJ, et al. The use of ECMO in HIV/AIDS with Pneumocystis jirovecii pneumonia: a case report and review of the literature. ASAIO J. 2014;60(5):606-608. 44. American Academy of Pediatrics. Human immunodeficiency virus infection. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book®: 2015 Report of the committee on infectious diseases. American Academy of Pediatrics; 2015; 453-476. 45. Vigneswaran TV, Brown JR, Breuer J, Burch M. Parvovirus B19 myocarditis in children:

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an observational study. Arch Dis Child. 2016;101(2):177-180. 46. Valenti WM, Clarke TA, Hall CB, Menegus MA, Shapiro DL. Concurrent outbreaks of rhinovirus and respiratory syncytial virus in an intensive care nursery: epidemiology and associated risk factors. J Pediatr. 1982;100(5):722-726. 47. Flamant, C., Hallalel, F., Nolent, P. et al. Severe respiratory syncytial virus bronchiolitis in children: from short mechanical ventilation to extracorporeal membrane oxygenation. Eur J Pediatr. 2005;164(2):93-98. 48. Seaver LH. Adverse environmental exposures in pregnancy: teratology in adolescent medicine practice. Adolesc Med. 2002;13(2):269-291. 49. McNally H, Bennett CC, Elbourne D, Field DJ; UK Collaborative ECMO Trial Group. United Kingdom collaborative randomized trial of neonatal extracorporeal membrane oxygenation: follow-up to age 7 years. Pediatrics. 2006;117(5):e845-e854. 50. Field D, Juszczak E, Linsell L, et al. Neonatal ECMO Study of Temperature (NEST): a randomized controlled trial. Pediatrics. 2013;132(5):e1247-e1256. 51. Hirakawa E, Ibara S, Tokuhisa T, et al. Single-center experience of extracorporeal membrane oxygenation in 61 neonates. Pediatr Int. 2016, epub ahead of print. 52. Massaro A, Rais-Bahrami K, Chang T, et al. Therapeutic hypothermia for neonatal encephalopathy and extracorporeal membrane oxygenation. J Pediatr. 2010;157(3):499-501. 53. Chapman RL, Peterec SM, Bizzarro MJ, Mercurio MR. Patient selection for neonatal extracorporeal membrane oxygenation: beyond severity of illness. J Perinatol. 2009;29(9):606-611. 54. Sandler DL, Burchfield DJ, Mccarthy JA, Rojiani AM, Drummond WH. Early-onset respiratory failure caused by severe congenital neuromuscular disease. J Pediatr. 1994;124(4):636-638.

Congenital Comorbidities among Neonatal ECLS Patients with Respiratory Failure

55. Lamers LJ, Rowland DG, Seguin JH, Rosenberg EM, Reber KM. The effect of common origin of the carotid arteries in neurologic outcome after neonatal ECMO. J Pediatr Surg. 2004;39(4):532-536. 56 Burry M, Reig AS, Beierle EA, Chen MK, Mericle RA. Extracorporeal membrane oxygenation combined with endovascular embolization for management of neonatal high-output cardiac failure secondary to intracranial arteriovenous fistula. Case report. J Neurosurg. 2004;100(2):197-200 57. Wen JX, Feldenberg LR, Abraham E, et al. Continuous venovenous hemodialysis via extracorporeal membrane oxygenation pump for treatment of hyperammonemia secondary to propionic acidemia in monochorionic diamniotic twin boys. J Pediatr. 2016;175:231-232. 58. Summar M, Pietsch J, Deshpande J, Schulman G. Effective hemodialysis and hemofiltration driven by an extracorporeal membrane oxygenation pump in infants with hyperammonemia. J Pediatr. 1996;128(3):379382. 59. Kumar G, Mattke AC, Bowling F, et al. Resuscitation of a neonate with medium chain acyl-coenzyme a dehydrogenase deficiency using extracorporeal life support. World J Pediatr Congenit Heart Surg. 2014;5(1):118120. 60. Uppu SC, Goyal S, Gossett JM, et al. Extracorporeal membrane oxygenation in children with heart disease and genetic syndromes. Asaio J. 2013;59(1):52-56. 61. Cua CL, Blankenship A, North AL, Hayes J, Nelin LD. Increased incidence of idiopathic persistent pulmonary hypertension in Down Syndrome neonates. Pediatr Cardiol. 2007;28(4):250-254. 62. Gupta P, Gossett JM, Rycus PT, Prodhan P. Extracorporeal membrane oxygenation in children with heart disease and down syndrome: a multicenter analysis. Pediatr Cardiol. 2014;35(8):1421-1428.

63. Cashen K, Thiagarajan RR, Collins JW Jr, et al. Extracorporeal membrane oxygenation in pediatric trisomy 21: 30 years of experience from the Extracorporeal Life Support Organization Registry. J Pediatr. 2015;167(2):403-408. 64. Extracorporeal Life Support Organization. In: ELSO Neonatal respiratory failure supplement to the ELSO general guidelines, version 1.3 December 2013. Page 3; www. elso.org 65. Nelson KE, Rosella LC, Mahant S, Guttmann A. Survival and surgical interventions for children with trisomy 13 and 18. JAMA. 2016;316(4):420-428. 66. Downie L, Sasi A, Malhotra A. Congenital chylothorax: associations and neonatal outcomes. J Paediatr Child Health. 2014;50(3):234-238. 67. Cilley RE, Zwischenberger JB, Andrews AF, et al. Intracranial hemorrhage during extracorporeal membrane oxygenation in neonate. Pediatrics. 1986;78(4):699-704. 68. Hardart GE, Hardart MK, Arnold JH. Intracranial hemorrhage in premature neonates treated with extracorporeal membrane oxygenation correlates with conceptional age. J Pediatr. 2004;145(2):184-189. 69. Rozmiarek AJ, Qureshi FG, Cassidy L, et al. How low can you go? Effectiveness and safety of extracorporeal membrane oxygenation in low-birth-weight neonates. J Pediatr Surg. 2004;39(6):845-847. 70. Rhee YJ, Han SJ, Chong YY, et al. Extracorporeal membrane oxygenation in a 1,360-g premature neonate after repairing total anomalous pulmonary venous return. Korean J Thorac Cardiovasc Surg. 2016;49(5):379-382. 71. Azakie A, Johnson NC, Anagnostopoulos PV, Egrie GD, Lavrsen MJ, Sapru A. Cardiac surgery in low birth weight infants: current outcomes. Interact Cardiovasc Thorac Surg. 2011;12(3):409-413.

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14 Medical Management of the Neonate with Respiratory Failure on ECLS Shazia Bhombal, MD, Arlene M. Sheehan, RN, NNP, Krisa P. Van Meurs, MD

Fluids, Electrolytes, and Nutrition Initial daily fluid intake on ECMO is usually limited to 60-100 ml/kg/day as the usual neonatal ECMO patient is edematous due to substantial fluid overload prior to cannulation. In addition to the usual fluid requirements, fluid loss occurs from the oxygenator. Studies of insensible fluid loss from the Quadrox D found loss to be 48.0±2.1 ml per liter of sweep flow.1 Sepsis or hypoxic-ischemic injury may also cause significant capillary leak. Transient renal dysfunction with oliguria is common but usually spontaneously resolves over the first 48-72 hours. A natural diuresis phase occurs as cardiac output improves, capillary leak resolves, and fluid mobilization takes place. Renal function and fluid balance in newborns with severe cardiorespiratory failure managed with venovenous (VV) ECMO was compared to neonates managed without ECMO.2 VV-ECMO was associated with positive fluid balance, lower urine output, and higher BUN and creatinine values in the first 96 hours of bypass without any differences in blood pressure or diuretic use. These changes are likely due to activation of cytokines by the ECMO circuit. Most of the positive fluid balance was related to packed red blood cells and platelet transfusions. Diuretics are commonly used following ECMO initiation. If urine output does not improve, hypoxia and

hypotension may have resulted in acute tubular necrosis. Continuous renal replacement therapy (CRRT) is indicated to accomplish fluid and solute removal. Historically, neonates on ECMO were not fed enterally due to concerns regarding intestinal perfusion prior to ECMO, intestinal ischemia, and the risk of necrotizing enterocolitis. Gut barrier function and intestinal distension due to obstruction are other concerns. A single center study over a 5-year period demonstrated that neonates on ECMO tolerated enteral feedings well without any serious adverse effects.3 Infants with congenital diaphragmatic hernia (CDH) were excluded; however, a notable finding is that 80% of newborns fed enterally were receiving inotropic support. Over the duration of the study the use of enteral feedings increased from 71% to 94%, and the time to initiation of feeds dropped from 67 to 37 hours. A recent survey of enteral nutrition practices in ECMO centers found that the vast majority of respondents reported providing enteral feeding to neonatal ECMO patients; however, significant variability with regard to diagnostic and clinical parameters was used to guide decision-making.4 The American Society for Parenteral and Enteral Nutrition (ASPEN) published clinical guidelines for nutritional support in neonates supported with ECMO in 2010 that recommended

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starting enteral feedings once the newborn had dium content of blood products. Both sodium stabilized clinically.5 and potassium requirements may be increased Caloric intake is optimized through the among patients receiving routine diuretics. Caluse of total parenteral nutrition (TPN). Protein cium and magnesium requirements may also be in the form of amino acids is added, although higher than usual. Metabolic alkalosis may berenal protein preparations such as Aminosyn RF come evident due to exposure to large amounts may be necessary if the blood urea nitrogen is of blood products containing the anticoagulant elevated.6 ASPEN guidelines recommend that citrate-phosphate-dextran. nutritional support be initiated expeditiously as optimal weight gain is difficult to achieve Respiratory in ECMO neonates given their illness, fluid restriction, and high protein catabolic rates.5 Demographics Recommended goals are 100-120 kcal/kg/day and up to 4 grams/kg/day of protein. Excess ECMO for neonatal respiratory failure is calories are not helpful as they do not decrease utilized for a variety of diagnoses, including protein catabolism, but can result in increased meconium aspiration syndrome (MAS), CDH, carbon dioxide production. Many centers use persistent pulmonary hypertension of the lipid emulsions as part of the TPN regimen, al- neonate (PPHN), respiratory distress syndrome though some centers limit lipid infusions during (RDS), sepsis, viral or bacterial pneumonia, and the early days of treatment due to concern about air leak syndrome. Neonates with respiratory their use in the context of severe respiratory dis- failure, specifically meconium aspiration, had ease7,8 and clot formation in the extracorporeal previously comprised the largest ECMO uticircuit.9 Ranitidine is usually added prophy- lization group in the ELSO Registry, peaking lactically to TPN at a dose of 2 mg/kg/day to in 1992 at approximately 1500 cases, falling attempt to limit the significant complication of steadily in the mid 1990s with introduction of gastritis-associated gastric bleeding exacerbated inhaled nitric oxide (iNO), surfactant, and high by anticoagulation.10 frequency ventilation, and stabilizing at apSerum electrolytes are monitored at least proximately 800 cases per year (Figure 14-1).11 daily, and glucose every 12 hours. Serum A review of the ELSO Registry database from sodium levels may be high due to the high so- 1988-1998 by Roy et al. to evaluate effect of

Figure 14-1. Neonatal ECLS diagnosis by year.11

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changes in management found that while there ECMO management. Rest settings on VV are was little variation in the demographics such as usually higher than those used on VA. Typical mean gestational age, gender, or age at time of VA settings are PIP (cm H20) 15-20, PEEP 5, ECMO cannulation, there was a change in the Rate 15-20, FiO2 0.21, and typical VV settings proportion of patients with specific diagnoses.12 are PIP 15-25, PEEP 5-10, Rate 20-30, and FiO2 CDH increased from 18% in 1988 to 26% in 0.30-0.50.16 Some advocate for higher PEEP to 1998 of the neonatal respiratory population, prevent alveolar collapse without compromiswhile RDS decreased from 15% to 4%. The ing venous return. An older multicenter study reported use of high frequency ventilation, found that high PEEP of 12-14 cm H2O vs. low surfactant, and iNO increased from 0% for all PEEP of 3-5 cm H2O facilitated lung recovery three treatment modalities in 1988 to 46%, 36%, and resulted in shorter ECMO runs.17 Continued and 24% respectively by 1997. As treatment for use of surfactant while on ECMO in the setting MAS evolved, CDH became the leading indica- of neonatal respiratory failure has demonstrated tion for neonatal ECMO.13,14 ECMO survival is benefit. One small single center study adminis94% in the MAS population and 50% in patients tered surfactant or placebo at hours 2, 8, 20, and with CDH (Table 14-1).11 A review of the ELSO 32 and found significantly decreased duration of Registry between 2000-2010 found that patients ECMO, improved pulmonary mechanics, and with irreversible pulmonary dysplasia, such as reduced complications when compared with a alveolar capillary dysplasia, surfactant protein placebo group.18 deficiency, and pulmonary lymphangiectasia, Patient arterial blood gases, along with were placed on ECMO at an older chronologic circuit pre and post oxygenator blood gases, age and for longer duration than typical patients are obtained every 6-12 hours. Daily chest rawith PPHN.15 The authors concluded that these diographs are obtained to confirm line, catheter, patients are often difficult to distinguish from and tube position; assess lung volume changes those with PPHN. Suspicion of irreversible following significant atelectasis or collapse; pulmonary dysplasia and potential lung biopsy and to evaluate free air. Air leaks can be manshould be considered in patients placed on aged with lower ventilator settings including ECMO at ≥ 5 days of life and on ECMO for >10 low CPAP settings, decreasing until no further days. Survival to discharge for this subgroup is air leaks are present, with gentle reexpanding only 3% compared to survival of 81% in PPHN. of lung over longer period of time. A large or tension pneumothorax, particularly if obstructVentilation Strategies ing venous return, requires placement of a chest tube (see Chapter 61). Radiograph findings While on ECMO, the lungs are allowed combined with frequent or continuous tidal to rest and recover from the underlying lung volume measurements and blood gases provide disease and from barotrauma caused by pre- the ECMO practitioner with the data needed to formulate a weaning plan. Routine pulmonary clearance is essential Table 14-1. Neonatal Respiratory ECMO while on ECMO. Endotracheal suctioning is statistics by diagnosis (1990-2014).11 recommended every 4-6 hours. Changes in secretions should be noted, including watching Diagnosis TotalR Avg Run Longest Run Survival uns Time (Hrs) Time (Hrs) for blood tinged secretions. Pulmonary hemorCDH 6784 266 2549 50% MAS 7352 138 1327 94% rhage was reported in 4.5% of neonatal patients PPHN 4388 160 1908 76% undergoing ECMO.11 Treatment of pulmonary RDS 998 151 1093 83% Sepsis 2450 152 1200 68% hemorrhage varies with the severity of the event Other 2941 191 1843 61% 185

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and includes limitation of suctioning, increasing PEEP, decreasing anticoagulation parameters, increasing platelet count target, and instillation of dilute epinephrine. Extubation on ECMO Extubation while on ECMO has been utilized in the adult population and in children. A single center experience with extubation on ECMO reported a decreased need for sedation as well as possibly faster resolution of pulmonary inflammation.19 In this small series, 16 of 511 ECMO patients were extubated for at least 24 hours during their ECMO run. Five of the 16 patients were newborns. No complications were seen; however, the authors emphasize that emergency procedures need to be modified to allow for emergent reintubation. A case report described a neonate on ECMO for biventricular myocardial hypertrophy extubated to high flow nasal cannula (Vapotherm) on day 7 until heart transplant on day 59 of ECMO.20

choscopy in patients with persistent atelectasis including removal of secretions and identifying infectious etiology.22,23 One institution reported their experience in patients on ECMO for cardiac failure with 15% of patients undergoing bronchoscopy for continued atelectasis despite ventilator changes and only found minor complications including bleeding in 6% of bronchoscopies performed.23 Bronchoscopy was useful in a majority of the cases, with benefits including subsequent improvement in aeration and new diagnosis of infection. In neonatal patients with CDH on ECMO, 8 out of 17 patients received a therapeutic bronchoscopy on ECMO, of which the majority demonstrated radiologic improvement following bronchoscopy.24 Overall the procedure was well tolerated with only minimal complications of bleeding, similar to other studies. Cardiovascular Hemodynamic Support

Neonates with respiratory failure being considered for ECMO often require inotropic Prone positioning should be considered or pressor support. Patients with decreased in patients on prolonged ECMO support, with cardiac function may still be considered for benefits including reducing the risk of develop- VV-ECMO. Studies have found that use of ment of pressure ulcers as well as improving inotropes substantially decrease both in patients aeration to posterior portions of the lungs and in with VV- and VA-ECMO.25,26 Some centers alveolar ventilation-perfusion matching. While continue low-dose dopamine during VA-ECMO positioning requires significant coordination, to improve renal perfusion, though there is no overall it was well tolerated in a center that clear evidence this practice improves outcomes. reported placing approximately 60% of their One institution evaluated cardiac function in 15 pediatric ECMO patients prone at some point infants on VV-ECMO and found borderline or during their bypass course.21 The most com- normal cardiac indices prior to ECMO, with mon complication was bleeding. There were normalization of function on ECMO.27 The auno reports of decannulation or endotracheal thors concluded that VV-ECMO did not worsen cardiac function, potentially due to avoidance tube dislodgement. of an increase in LV afterload as seen with VAECMO, as well as increased oxygen content Bronchoscopy provided to coronary arteries with VV-ECMO. Importantly, echocardiography demonStudies in the pediatric population on ECMO have illustrated the usefulness of bron- strates that institution of VA-ECMO can lead Prone Position

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initially to increased myocardial dysfunction.28 PA systolic pressure, and arterial blood pressure Higher flow rates on VA-ECMO increase after- during the ECMO course.28 In general, cardiac load, which may account for decreased myo- function initially decreases, and then improves cardial contractility. In extreme cases, patients over 48-72 hours. PA pressures can also be can develop myocardial stun as evidenced by followed with echocardiography on ECMO, dampening of the arterial waveform, and patient demonstrating changes in shunt flow when PaO2 similar to post oxygenator PO2. Usually pulmonary hypertension improves. transient, cardiac stun often results from arterial Echocardiography also can play a role flow directing towards the aortic arch, as well as during ECMO weaning, though more so in decreased coronary oxygenation compared with the setting of VA-ECMO with assessment in VV-ECMO. When the arterial cannula flows pressures and function, rather than VV-ECMO, down the ascending aorta, improvement in car- which relies on assessment of improvements diac function usually occurs following cannula in oxygenation and pulmonary compliance. adjustment. Myocardial stun by echocardiogra- In a single center prospective study, authors phy was reported in 4.5% of neonatal respiratory utilized echocardiography while weaning from ECMO patients in the ELSO Registry.11 VA-ECMO and found that increased morbidity and mortality could be predicted by failure to increase velocity time integral (VTI), a surroHypertension gate for cardiac output.31 Similarly, increases in Hypertension occurs commonly on ECMO; OI predicted poor outcomes. 12% of neonatal ECMO patients had systolic hypertension requiring vasodilators (2015 Infection ELSO Registry).11 One institution noted systemic hypertension in 93% of their neonatal Infections acquired during ECMO are ECMO population, with an associated increase not uncommon and can significantly increase in intracranial hemorrhage and plasma renin ECMO duration and decrease survival. A reactivity.29 Prior to a protocol that medically view of ELSO data from 1998-2008 found managed systemic hypertension on ECMO, that the overall infection rate for neonates was 50% of neonates at the institution had clinically 7.6% with the incidence increasing with longer significant intracranial bleeds, compared with runs and in VA-ECMO patients.32 Coagulase9% after initiation of the protocol. The authors negative Staphylococci were the most comfound captopril to be the most effective in low- mon organisms, followed by Candida. The commonly identified organisms had associaering blood pressure. tions with invasive support (eg, central lines, endotracheal tubes, and urinary catheters). Echocardiography Thus, continuing strategies to prevent line and Echocardiography may be a useful tool ventilator-associated infections should decrease throughout the ECMO course. Prior to cannula- the nosocomial infection rate of these neonates. tion echocardiography may unmask underlying Although reducing infections on ECMO is imcardiac pathology, including total anomalous portant, the benefit of prophylactic antibiotics pulmonary venous return. It has been utilized remains unclear, although a review of 11 studduring or after cannulation to evaluate cannula ies showed no difference in infection rates.33 A position.30 Echocardiography has demonstrated survey of ELSO centers demonstrated a varying changes in cardiac performance while on VA- use of antibiotic prophylaxis on ECMO, reflectECMO, including changes in cardiac function, ing this uncertainty.34 At this time, no strong 187

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evidence shows that routine prophylactic antibiotics decrease nosocomial infections on ECMO. ECMO Circuit Considerations in the Neonatal Patient Cannulation Cannulation of the neonate poses several challenges, largely because of small neck vessel size, and is covered in Chapter 12. Pump Selection A survey of neonatal ECMO centers revealed a shift from roller head to centrifugal pumps in the past decade.35 Prior to this time roller pumps were used in almost all neonatal ECMO programs. In 2002, a small number of centers surveyed reported routine use of centrifugal pumps for neonates, while in a 2011 survey found that nearly 50% of centers surveyed reported using centrifugal blood pumps for neonatal ECMO.35 Centrifugal pumping systems have the benefit of smaller circuit size, less blood-prosthetic surface area and inherent protection against cavitation and overpressurization of the circuit. They do not require gravity drainage and can be placed closer to the patient. In contrast, roller pumps are less expensive (no disposable centrifugal cone) and simpler in design but have the rare complication of raceway rupture. Hemolysis occurs commonly with centrifugal pumps, especially with small cannula, due to the shearing force on blood components created by the vortex in the pump head. Hemolysis with resulting elevations in plasma free hemoglobin (pfHb) can cause vasoconstriction and acute kidney injury. Newer generation centrifugal pumps have been designed to have less stagnation in the pump head with decreased hemolysis. Despite design improvements there remain recent reports of patients supported on centrifugal pumps exhibiting hemolysis during 188

ECMO as evidenced by spikes in pfHB to over 100 mg/dl.36 pfHB levels decrease after change out of the pump head. Patients supported with centrifugal pumps should have routine screening of pfHB. If the level exceeds 50 mg/dl, the cause should be investigated.37 A small study compared neonatal respiratory patients treated with roller pumps to those treated with new generation centrifugal pumps and a Quadrox oxygenator. The study found increased hemolysis, increased need for component change, and a higher mortality in the centrifugal group.38 The authors concluded that neonates are at a greater risk of hemolysis than older patients due to differences in flow and pressure dynamics specific to neonatal centrifugal systems. In a larger study using the ELSO Registry, Barrett et al. compared outcomes of neonates supported with centrifugal or roller pumps.39 The centrifugal pump group had higher rates of hemolysis, hyperbilirubinemia, hypertension, and acute renal failure than the roller pump group. They separated the centrifugal group into older vs. newer generation pumps and found the same morbidities, but at a lower rate with the newer pumps. They recommended avoidance of high flow rates (unspecified) in neonates on centrifugal pumps, and careful monitoring for hemolysis. Loss of pump flow is another issue reported with centrifugal pumping systems. Centrifugal pumps are nonocclusive and flow dependent. When patient arterial pressure exceeds pump arterial pressure, loss of forward pump flow and the potential for retrograde flow from the patient arterial circulation back through the circuit, into the patient venous system can occur. Retrograde flow is more likely to occur at lower pump speeds such as during initiation or weaning and with increases in patient arterial resistance such as hypertension. Small children and neonates are at increased risk of retrograde flow because of lower pump flow rates than adults. A study comparing three centrifugal pumps showed that the Bio-Medicus was the

Medical Management of the Neonate with Respiratory Failure on ECLS

least likely to demonstrate retrograde flow at prime blood is not introduced slowly into the low speeds, followed by the Rotaflow and Cen- systemic circulation. On VA bypass, flow is troMag.40 Centers that use centrifugal pumps adequate when the venous saturation is greater to support children or neonates must educate than 70% and the patient is not acidotic or specialists to monitor circuit venous pressures hypotensive after pressors have been weaned. closely and to maintain a patient arterial pres- Ventilator support should be decreased to rest sure greater than pump arterial pressure. settings. On VV-ECMO, support is adequate if Additionally, shear forces generated by arterial saturation is in an acceptable range on ECMO pumps activate platelets causing release low ventilator settings and any hypotension or of platelet derived micro particles (PMPs). Mi- acidosis resolves. Pump flow can range from cro particles are small cell-derived vesicles that 80-150 ml/kg/min. In the event that pump flow is inadequate promote thrombosis by exposure of membrane phosphatidylserine. In a study comparing roller after commencing bypass, cannula position and centrifugal pumps using simulated circuits should be evaluated by chest radiograph or ulprimed with swine blood, the generation of trasound. Once cannula position is optimized, PMPs was 2.5 times greater in the latter sys- suboptimal ECMO support can be addressed tems.41 This may be of particular importance with a second, cephalad cannula in the jugular in the neonatal cardiac ECMO population who vein to augment venous drainage. An 8 or 10 Fr have a high rate of thrombotic complications.11 arterial cannula is used for this technique (not a venous cannula) as it does not have side ports. If the infant on VV bypass remains hypoCircuit Prime tensive or hypoxic, inotrope/pressors can be For neonatal ECMO the circuit is primed continued and ventilator pressures and FiO2 with packed red blood cells (PRBCs) and fresh increased to supplement ECMO support. Infrozen plasma (FFP) to a hematocrit of 35-45%. jurious ventilator settings should be avoided. The blood prime is heparinized, and then cal- Conversion to VA-ECMO should be considered, cium added to correct the hypocalcemia caused although it is a challenging procedure. Cannulaby citrate anticoagulation. Acidosis is corrected tion of the artery can be done on bypass but the with bicarbonate. The blood prime is warmed infant will need to be supported off-bypass for to 37 degrees centigrade unless the infant is replacement of the venous catheter. Alternaundergoing hypothermia therapy. In that case, tively, the VV catheter can be left in place and the blood should be warmed to a temperature both lumens used for drainage but commonly, the arterial lumen clots of 34 degrees C. Pump Flow

Sweep Gas Flow

Once ECMO is initiated, pump flow should be increased over a period of several minutes in order to determine the maximal flow that can be achieved. Subsequently, pump flow is decreased to meet patient demand. When initiating VV bypass it is important to increase pump flow slowly, as prime blood may have elevated potassium levels that can cause myocardial dysfunction and even asystole if the

Sweep gas flow is initiated in a 1:1 ratio of blood flow to gas flow. If pump flow is 300 ml/min then sweep flow is 0.3 L/min. Sweep flow is adjusted to target an arterial pCO2 of 40-45 mmHg unless there is significant precannulation hypercarbia. If significant hypercarbia is present prior to cannulation, the pCO2 should be slowly brought into the target range of 45-50. FiO2 of the sweep gas is started at 189

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60-100% then titrated as needed to keep the Hematologic post oxygenator PaO2 between 150 and 400 mmHg. Carbon dioxide may be added to the Coagulation Abnormalities sweep gas or sweep flow can be decreased, once Many newborns that are candidates for minimal sweep flow for a particular oxygenator ECMO present with coagulation derangements is reached, to prevent hypocarbia. When initiating ECMO support it is critical secondary to sepsis or hypoxia. Whenever to correct hypercapnia slowly. Hypocapnia in possible, factor depletion, thrombocytopenia, the newborn is associated with cerebral va- and hypofibrinogenemia should be corrected soconstriction and an increased incidence of (see Chapter 8). It is also important to verify periventricular leukomalacia, intraventricular that the infant received Vitamin K at birth. Daily monitoring of coagulation fachemorrhage, cerebral palsy, and poor neurodevelopmental outcome. Rapid changes in blood tors, platelet count, and hematocrit are done gas carbon dioxide levels may also lead to an every 8-12 hours and deficiencies corrected increase in neonatal brain injury.42 In-line blood (see Chapter 7). ECMO goals include maintaingas system is an important adjunct to monitor ing a platelet count greater than 80,000, hemacircuit carbon dioxide and blood pH levels. tocrit greater than 35-40%, fibrinogen greater Near-infrared spectroscopy may be useful than 150 mg/dl, and normal PT and INR. for monitoring cerebral saturation in neonatal Anticoagulation ECMO patients. Weaning Weaning from VA- and VV-ECMO support is indicated with improvement of chest radiograph, tidal volumes, patient venous saturation, and patient arterial blood gases. ECMO pump flow is decreased by 10-20 ml/hour as long as venous saturation is >65% and arterial saturation is >90%, until 50% bypass is achieved. Sweep FiO2 can also be weaned. At that point ventilator rate may be increased. At 30% bypass, ventilator FiO2 should be increased and ECMO pump flow weaned until a flow rate of 20 ml/ kg/min (10% bypass) is reached, where the patient is considered to be “idling” on ECMO. If blood gases are adequate, decannulation should be scheduled. If blood gases are marginal, a trial off bypass support should be considered. In patients who have had a long bypass run or have serious complications such as intracranial hemorrhage, it may be necessary to use high frequency ventilation, surfactant replacement, inotropes or steroids, or iNO to wean off. This is discussed further in Chapter 16. 190

Anticoagulation of the neonate on ECMO is challenging due to immaturity of the coagulation system and the propensity for intracranial hemorrhage in the neonate. Anticoagulation practices are covered in Chapter 7. Surface coating with heparin or coating with other polymers may decrease the incidence of bleeding or thrombotic complications. A new generation of anticoagulants, direct thrombin inhibitors (DTIs), has been FDA approved in the U.S. since 2000. As yet, there are no retrospective studies of efficacy or safety of DTIs in children or infants. Baird et al. performed a retrospective review of 604 pediatric respiratory and cardiac ECMO patients in a single institution and looked at the impact of ACT and heparin dose on survival.43 Increased heparin dose was predictive of survival, independent of all other variables. ACT level was not a predictor of survival. It was suggested that a potential explanation for improved survival was fewer thromboembolic complications in the patients that received higher doses of heparin. These provocative findings have not

Medical Management of the Neonate with Respiratory Failure on ECLS

been reproduced. Figure 14-2 shows the probability of survival increasing with increased heparin administration up to 70 units/kg, then a decline with higher doses. The probability of survival based on ACT remains the same (58%) across all ranges of ACT (150-500 seconds).43

Neuromonitoring on Neonatal ECMO

Current techniques for neuromonitoring of the neonatal ECMO patient include neurologic exam, head ultrasound, EEG, amplitude integrated EEG (aEEG), and near-infrared spectroscopy (NIRS). Close and frequent monitoring Neurologic System of the neurologic exam is warranted on ECMO. Clinical identification of intracranial injury (eg, Neonatal ECMO patients have high risk hemorrhage) is unusual and complicated by of brain injury with resulting adverse neuro- sedation. Routine pain level scoring should be developmental outcome. Potential injury can implemented and appropriate response evalube attributed to the underlying disease process ated throughout the ECMO course. leading to ECMO as well as to accompanying Intracranial hemorrhage (ICH), the most hypoxia, hypotension, and hypocarbia. Can- significant complications in neonates on ECMO, nulation produces further alterations in cerebral occurs in 7.5%, and the incidence of cerebral blood flow related to ligation of the right jugular infarction is also noteworthy at 6.9%.11 In an vein and the right carotid artery, resulting in analysis of the ELSO Registry, gestational age cerebral ischemia, reperfusion injury, and loss was the strongest predictor of ICH in neonates of cerebral autoregulation. Neonatal ECMO on ECMO but pre-ECMO factors included survivors have a significant incidence of neuro- acidosis, primary diagnosis of sepsis, coaguimaging abnormalities and neurodevelopmental lopathy, and treatment with epinephrine.44 The disability (see Chapter 17). Thus, regular as- prevalence of intracranial lesions was found sessment of the neurologic exam, daily head in another large study to be lower in neonates ultrasound, and consideration of other neuro- receiving VV-ECMO (12.7% versus 17.4%, diagnostic modalities are advisable. Prompt p=0.1).45 The strongest predictor of disability recognition of potentially treatable conditions in ECMO survivors is the extent and severity is important to optimize outcome. of abnormality on post-ECMO neuroimaging.46 Head ultrasound (HUS) studies should be performed prior to the initiation of ECMO, with serial daily HUS commencing 12-24 hours after cannulation. Khan et al. have reported that over 90% of intracranial hemorrhages occur in the first 5 days of ECMO therapy.47 Some ECMO centers perform HUS less frequently after day 5 or perform daily HUS only in high risk infants or infants with abnormal HUS pre-ECMO or immediately following cannulation.47-49 Aminocaproic acid (Amicar), an inhibitor of fibrinolysis, has been used to lower ICH in high risk newborns. A study by Wilson in 1993 using historical controls found a significant reduction in ICH in a group of neonates treated with Amicar and a low rate Figure 14-2. Relationship between heparin dose and the predicted probability of survival.50 of thrombotic complications.50 A later study of 191

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Amicar use in the same institution concluded that Amicar did not alter the rate of ICH when compared to ELSO Registry data; however, it did lower the rate of surgical site bleeding.51 New intracranial hemorrhage or extension of ICH on ECMO can be promptly recognized on HUS. Treatment options are limited. Lowering anticoagulation targets and increasing platelet count are not often successful and discontinuing ECMO support is usually necessary. Earlier detection of neurologic injury permits therapeutic intervention and potentially can improve outcomes. Conventional EEG is not routinely used in the neonatal ECMO population unless seizure activity is suspected. The ELSO Registry reports clinical seizures in 8.8% of neonates.11 Abnormalities in serial EEGs during ECMO are helpful in predicting mortality and neurologic morbidity.52-53 Conversely, the combination of normal serial HUS and EEG without significant abnormalities appears to be highly predictive of normal post-ECMO neuroimaging.54 Amplitude integrated EEG (aEEG) is being used with increasing frequency in the NICU. This device displays both a limited channel EEG recording as well as a compressed aEEG trace allowing evaluation of the brain’s background activity, change in that activity over time, and screening for seizures. aEEG has the advantage of easy and early clinical use with minimal impact on patient care. Studies comparing standard EEG and aEEG in neonates have found good agreement between the two modalities. Pappas et al. performed serial aEEG recordings at a variety of time points prior to ECMO, after cannulation and prior to discharge.55 Abnormal aEEG predicted death or moderate to severe intracranial injury with sensitivity of 1.0, specificity of 0.75, positive predictive value to 0.86 and negative predictive value of 1.0. Interestingly, infants with adverse outcome had abnormal tracings before or within the first 24 hours on ECMO but no significant alteration in aEEG background or lateralizing 192

effects following cannulation, suggesting that adverse outcomes in ECMO survivors were due to underlying illness and accompanying hypoxia and hypoperfusion. Near-infrared spectroscopy (NIRS) has emerged as an effective, noninvasive technique for neuromonitoring in a variety of intensive care settings. Oxy-hemoglobin (HbO2) and deoxy-hemoglobin (HHb) have different nearinfrared absorption spectra, and so regional tissue oxygen saturation (rSO2) can be calculated: rSO2=HbO2/(HbO2 + HHb). The rSO2 reflects a regional balance between oxygen supply and demand of the underlying tissue, similar to a mixed venous oxygen saturation. Interpretation of NIRS values must be made in the context of other factors that influence cerebral blood flow and oxygenation such as mean arterial blood pressure, carbon dioxide tension, anemia, glucose levels, metabolic rate, and drug administration. While an absolute value of rSO2 associated with neurologic injury has not been determined, a cerebral rSO2 40 is used to indicate the severity of respiratory distress and is used as one referral indicator for ECMO.4 However, the calculation does not account for neonates receiving nitric oxide (NO) or differences in OI due to high frequency oscillatory ventilation (HFOV). In recent years, neonates are usually referred for ECMO when the IO exceeds 25. Neonates cannulated onto VV or VAECMO do not rely on their lungs for gaseous exchange. Mechanical ventilation is weaned to ‘rest settings.’ Typical rest settings for a neonate are: PIP 20 cm H2O, PEEP 10 cm H2O, ventilation rate of 10 bpm, and FiO2 0.3/0.4. The ECMO Specialist must measure blood gases/continuous oxygen saturations via pulse oximetry to ensure the neonate is well supported

Nursing Management of the Neonate with Respiratory Failure on Extracorporeal Life Support

and must meet set parameters as prescribed by susceptible to pressure sores on the shoulders. the ECMO team directly managing the patient. This risk can be alleviated by raising the head Endotracheal tube (ETT) position must be of the bed, evenly distributing pressure across reviewed on the latest chest radiograph to assure the shoulders, neck, and head. Elevation of the appropriate positioning. Patency and security of arm in front of the face (in the free style posithe ETT aid in the neonate’s recovery process. tion) can also relieve pressure on the shoulder Failure to secure ETT fixation adequately is the and neck. Care should be taken that the neonate most common reason for unplanned extuba- does not slide down the cot, forcing tension on tion.6 There is a potential risk of trauma due to the ECMO cannulae and potential inadvertent reintubation. Tube insertion should be carried decannulation. This risk can be further enout by an experienced practitioner. Nasal bleed- hanced by the patient making subtle wriggle ing due to instrumentation can be severe and movements due to under sedation, so optimal difficult to manage.11 ET suctioning should be sedation is essential. guided by the neonate’s condition and disease process.7 Deep suction beyond the end of the Ventilator-Associated Pneumonia (VAP) ETT should be measured and recorded, eliminating trauma or perforation of the carina. The VAP develops more than 48 hours posuse of a ‘yanker’ sucker and suction catheters tintubation.11 Clinical guidelines/protocols and for nasal suction should be avoided to prevent education aid in preventing VAP and include trauma to soft tissue. The use of saline for ET implementation of standard infection and lavage is contentious. Puchalski8 found that control practice: excellent hand hygiene; use saline does not aid the removal of secretions, and appropriate disposal of personal protective but may increase the bacterial colonization of equipment eg, gloves, aprons, goggles/masks; alcohol rub in place at every bed space for use the lower airways. by all members of the multidisciplinary team (and parents). Prevention of aspiration is also Prone Positioning on ECMO vital–the neonate must be nursed in the semiAnother strategy employed for the man- recumbent position with elevation of the head agement of severe respiratory failure is prone of the bed to 30-45°, unless contraindicated. positioning. Prone positioning can improve Gastric distension should be avoided in entergas exchange. Guérin et al.9 describe how their ally fed neonates to prevent VAP. The ventilator trial showed that patients with severe ARDS/ circuit should only be changed if soiled or damsevere hypoxemia (Pa02:Fi02 ratio of 0.6, and a PEEP of 5 cm H20) can Equipment must be single use only. benefit from prone treatment when used early and in relatively long sessions. This is a strategy Sedation that is used routinely on/off ECMO to improve Sedatives and analgesia are frequently used gas exchange in Leicester. When used in combination with VV-ECMO, in the care of the neonate on ECMO to facili18 hours of prone positioning improves both tate tolerance of ECMO, protect cannula, and oxygenation and respiratory system compli- promote patient comfort. Although inadvertent ance.10 Gravity has its greatest effect in the decannulation or dislodgement of the cannula prone position, pressing the shoulders into the is potentially fatal Wildschut et al.12 found that mattress, particularly if the pelvis is elevated interruption of sedatives and analgesics can with a roll under the hips, making the neonate occur in neonates on ECMO without increased 203

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risk of complications. The use of a sedation assessment tool Comfort B scale aids in ensuring patient comfort and achieving optimum sedation. A bedside neurological assessment can be made on sick neonates by practicing a daily sedation hold; sedation can then be recommenced following a satisfactory assessment. Neuromuscular blocking agents (NMBA) are used in neonates and infants, despite a lack of guidelines and professional standards.13 NMBA are most often used at ECMO cannulation, or for other procedures but are becoming less commonly used via continuous infusion over long periods due to the complications associated with their use. Cardiovascular

vascular resistance, vasopressor support may be beneficial. The ECMO Specialist must consider maintaining cardiovascular stability and evaluate on a continual basis. One measure to ensure appropriate drug delivery and optimal patient management is to administer all vasoactive infusions into the patient’s central line access rather than the ECMO circuit. In the event of a circuit emergency the neonate continues to receive vasoactive drugs/infusions. Echocardiography is required on admission, periodically during the ECMO run, and prior to trial off. Echo confirms cannula placement, evaluates pulmonary artery pressures, and provides insight in response to ECMO support and trial off support.

Neurological The nursing care involves continuous monitoring of the patient’s heart rate, oxygen saturaAt referral the baseline assessment criteria tions, blood pressure, mixed venous saturations, must include review of head ultrasound scan and temperature (core/peripheral). Circulatory before ECMO. Neonates with severe respiraassessments include warmth of extremities, tory failure are usually heavily sedated and pulses (may be absent on VA support at high paralyzed prior to commencement of ECMO. flow), blood volume, colour of extremities, After cannulation, paralysis is discontinued but urine output, presence/absence of edema, and sedation (eg, morphine/midazolam infusions) capillary refill time. The ECMO Specialist is continued. Daily neurological examinations must administer vasoactive infusions via central are required. Routine pain level scoring must venous access or ECMO circuit, maintain ad- be part of the evaluation of the neonate and apequate blood volume, and position the neonate propriate response evaluated and documented to promote optimal perfusion of extremities and throughout the patient’s treatment. minimize edema. Close monitoring of neurological status is Neonates with severe respiratory failure essential due to the potential for brain injury commonly receive inotropic agents. Usually caused by pre-ECMO hypoxia, acidosis and following ECMO initiation, inotropic drugs hypo-perfusion. Reducing sedation may prove are weaned rapidly. In the majority of neo- challenging to the neonate, team members, and natal respiratory cases, inotropes are weaned family. The ECMO Specialist must ensure because systemic perfusion is supported with patient safety and ongoing pump flow at all VA-ECMO or cardiac performance is improved times, as well as maintaining good position and with increased myocardial oxygen delivery. patency of the cannulas. The pupillary response Concern that neonates on VV-ECMO require and fontanel size and fullness are evaluated for greater inotropic support has been dispelled by evidence of increased intracranial pressure. The studies that revealed they tolerate weaning of neonate is continuously monitored for evidence such support as well as VA-ECMO patients after of any seizure activity. Movement of extremicannulation.14 If the neonate has low systemic ties, tone, and visual tracking are also essential 204

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parts of the neurological assessment15 made are also essential. Intracranial hemorrhage (ICH) commonly complicates neonatal ECMO. Head ultrasounds are recommended and performed to monitor function. Khan et al.16 found over 90% of ICH cases occur in the first 5 days of ECMO. Electroencephalography (EEG) Cerebral Function Analysing Monitoring (CFAM) are also invaluable in predicting mortality/neurological morbidity.17,18 The combination of active medical and nursing assessment, head ultrasound, and EEG appears to be highly predictive of postECMO outcome as measured by neuroimaging (MRI/CT).19 Meticulous nursing care can help to prevent further neurological compromise. Anticoagulation increases the risk of ICH and the ECMO Specialist must be vigilant in maintaining ACT parameters. team. Over heparinization must be avoided and compliance with prescribed ACT management parameters must be followed. Cannulation of the jugular vein can interfere with venous return, so elevating the head of the bed and keeping the neonate’s head midline may help minimize this risk. Neurological recovery may be enhanced by minimal handling, ensuring all cares are performed together, and periods of designated rest and quiet are preserved. Fluid Balance–Renal/Elimination Renal dysfunction in the neonatal ECMO patient is linked to pre-ECMO hypoxia and hypotension. Fluid overload occurs commonly before ECMO and increased volume requirements on ECMO may continue due to capillary leak. Diuresis is advised once hemodynamic lability subsides. With insufficient urine output, CVVH can aid fluid management. CVVH is connected directly to the ECMO circuit via pigtails post pump/pre oxygenator (see Chapter 62). Basic nursing care and patient positioning help prevent skin breakdown especially with significant oedema. The ECMO Specialist records all in-

take and output measures and closely monitors electrolytes.20 Other basic interventions include maintenance of the urinary catheter daily weight and assessment of intravascular volume, . Gastrointestinal (GI) Concerns and Nutrition Neonates in the NICU need a nutritional care plan to meet their metabolic demand to assure repair and growth. A dietetics referral ensures appropriate nutritional intake. Neonates who are cannulated onto ECMO will have had some degree of hypoxia, acidosis, low cardiac output requiring inotropes, paralysis and sedation which are all contributing factors in the risk of developing gastrointestinal related problems. Common GI complications include bleeding, distension, and dysmotility. Instability prior to initiation of ECMO can place the neonate at risk of bowel ischemia. The ECMO Specialist must continually monitor the nature and quantity of gastric aspirates, and assess bowel sounds, distension, and tenderness. Decompression of the stomach is aided by the use of a nasogastric tube. However, in some centers jejunal feeding is preferred to reduce stomach dysfunction and emesis. Naso/orogastric tubes must be assessed due to the risks of bleeding from the mucous membranes of the nasopharynx/oropharynx. Careful management of enteral feeding and bowel elimination is a vital part of the assessment process. Neonates need a nutritional care plan to help reduce the risk associated with the introduction of milk. Breast milk is the preferred diet and should be encouraged. A high risk regime where small amounts of ‘gut priming’ or trophic feeds are given may avert unwanted complications. An example of a high risk regime would be commencing at 0.5 mls per kg and increasing 0.5 mls per kg 12 hourly as tolerated. Monitoring tolerance by aspiration of the nasogastric tube 4 hourly, documenting the amount, and describing the content guides the rate at which feeds are increased or decreased.21 When feeds 205

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are not tolerated or when gastric feeds cannot be given, total parental nutrition (TPN) can be administered directly into central access or ECMO circuit. Assessment of administering TPN includes close monitoring of blood sugars. Therefore, minimizing non-nutritional fluid administration will help to maximize provision of carbohydrate, fat, and protein.20

tidisciplinary team. Three basic principles underpin the management of bleeding: optimization of anticoagulation, drug therapy, and survival intervention. The ECMO Specialist must maintain adequate levels of anticoagulation, as prescribed, to prevent clotting of the circuit, avoid over heparinization and bleeding. The causes of bleeding on ECMO are usually related to preexisting coagulopathy, circuit reHematological Management/Bleeding lated platelet and factor consumption, and the use of heparin. The ECMO Specialist must be Unconjugated bilirubin accounts for most vigilant in inspecting the ECMO cannula, IV cases of jaundice in neonates and approximately lines, and chest drain sites for bleeding or clot60% of term neonates develop jaundice. 22 ting. Changes to the circuit or patient should Jaundice is often exacerbated hemolysis in the be communicated to the ECMO team. Minor ECMO circuit caused by ‘drag’ on the venous bleeding can be controlled by correcting any drainage as a result of hypovolemia and high coagulopathy and reducing the ACT range. Control of massive bleeding usually involves pump rotor flow rates. Visual progression of jaundice may indicate surgical intervention and discontinuation of the level of bilirubin. However, it should not the heparin infusion temporarily. Lowering the replace actual bilirubin measurement. A chart ACT places a greater risk of circuit thrombosis is used to plot the bilirubin level and is used as and may lead to component/circuit change. Prevention is key to reducing bleeding on a guide for ongoing monitoring and treatment. Phototherapy is most commonly used in the ECMO. Avoidance of discontinuing IV lines or treatment of unconjugated hyperbilirubine- tubes and reducing the IV access attempts after mia. It converts bilirubin to a water soluble cannulation. Subcutaneous and intramuscular cis-form, increasing excretion.23 Maximum injections must be avoided. Sampling of blood skin exposure is the key to success and often must always occur via the ECMO circuit or IV/ neonates are nursed naked, with the exception arterial access. Extra care is taken on placement of a small nappy. Care must be taken to prevent of nasogastric/orogastric tubes, mouth care, and retinal damage. Eyes can be shielded with soft suctioning as once bleeding starts it can be difopaque ‘goggles,’ which must be tight enough ficult to cease on ECMO support. to prevent them from slipping off the eyes, but loose enough to prevent restricted blood flow or Hygiene and Skin Care potential skin damage. These ‘goggles’ should A complete assessment of the skin is perbe removed at intervals to assess the eyes for formed on admission and at regular intervals abrasion, dryness, and signs of infection. during hygiene needs. This includes assessment Bleeding and Anticoagulation Management of cannulation site, dressing changes and IV sites, and particular attention to the back of the Complications of bleeding and thrombosis head, sacrum, and heels. Ultimately identifying remain a challenge to the ECMO team and patients at risk is part of the ECMO Specialist’s represent the most important complication responsibility when assessing patient’s needs. Frequent repositioning of the neonate proof ECMO. Successful management requires vigilance and skill of all members of the mul- motes prevention of skin damage. Reposition206

Nursing Management of the Neonate with Respiratory Failure on Extracorporeal Life Support

ing is advised 3-4 hourly. Pressure relieving mattresses are used to reduce the incidence of pressure sores. Dressings to the neck and IV sites are changed as necessary, not on a routine basis. Nutritional status and maintenance of adequate tissue perfusion are essential for improving patient outcome. Family Support

education with regards to the technology, so if the neonate develops a complication they may have some preparation, aiding them to make difficult decisions regarding withdrawal of care. When faced with futility, the parents must never be made to feel that the decision to stop treatment depends on them. This decision belongs to the multidisciplinary team and the inevitable outcome clarified for the parents, to avoid the lingering belief that their baby will survive and recover.29 The ECMO team then supports the family through end of life care, often a difficult skill to acquire. Providing some control in the situation, despite the unavoidable outcome, such as with creating a memory box can provide such control. Other activities include, taking photographs, making handprints and footprints, and cutting locks of hair. The parents will be encouraged to take turns holding their baby while on ECMO. The care givers themselves also require support through this process. Other healthcare professionals with skills in end of life care include pastoral care, social work team, and liaison nurses. These teams provide invaluable resources to aid the ECMO Specialist/multidisciplinary team members, parents and family members throughout this experience. The ECMO Specialist continually evaluate the needs of the neonate and parent. They must inquire about specific care needs, be aware of religious practices and beliefs, and ensure that parents take regular breaks in order to aid sleep, eat, and rest.

Interventions when caring for a neonate on ECMO must focus on family centered care. The nurse and specialist care not only for the patient, but for the family as well.24 The family must be included in all aspects of patient care beginning with the referral process, and throughout the stay in the NICU. Because the environment is foreign and the parents separated from their baby, the team should try to make the entire family feel they can actively participate in direct care.25,26,27,28 The team needs to respond to the needs of each family. Families commonly feel in crisis, finding it extremely difficult to process information. Nursing interventions, where possible, should promote positive psychosocial care to decrease these feelings of stress, anxiety, and loss of control. The ECMO team has to cope with parental distress, suffering, and feelings of powerlessness. The ECMO Specialist and team members must support parents and develop strategies and interventions to minimize parental stress. They should encourage parents to develop a relationship with their baby despite the complex care. If parents require interpreters, the team Conclusion members must access this support, so the parThe role of the ECMO Specialist is possibly ents can ask questions and feel fully informed, thereby reducing stress and anxiety. ECMO one of the most rewarding roles in intensive team members should encourage parents to care, requiring a holistic approach to nursing discuss their feelings, anxieties, and experience the critically ill neonate and family members. in the NICU. Honesty in discussion is essential. As technology has advanced, the ECMO SpeIn the event of patient deterioration, hope of cialist undertakes the nursing and technical role, recovery must be balanced with the prospect leading to complete care of the neonate. The of a negative outcome. This allows families to nurse–patient and nurse–family relationship find coping strategies. Parents need to receive are crucial to supporting parents through this 207

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traumatic time while their baby is in the NICU. Providing emotional support, clear, honest information, and communicating effectively enables parents to feel safe, involved, and confident during this time. The ECMO Specialist role is ever changing and will continue to evolve over time. Continuing education and development of specialist skills are essential for continuation of safe, expert care.

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References 1. Faulkner G, Killer H. Job profile. ECMO Specialist. Job description from UHL. UK 2000. 2. Chadwell L, Keene S. Ethical concerns that arise when working with Extracorporeal Membrane Oxygenation in the NICU: a nursing perspective. Internet J Law, Healthcare Ethics. 2008;6(1):2. 3. Merriam-Webster Dictionary online. Wikipedia April 26 2012. 4. UK Collaborative ECMO Trial Group. UK collaborative randomised trial of neonatal Extracorporeal Membrane Oxygenation. Lancet 1996;348(9020):75-82. 5. McNally H, Bennett CC, Elbourne D, Field DJ; UK Collaborative randomised trial of neonatal Extracorporeal Membrane Oxygenation ECMO Trial Group: follow-up to age 7 years. Pediatrics 2006;117(5):e845854. 6. Merkel L, Beers K, Lewis M. M, Stauffer J, Mujsce D. J, Kresch M. J (2014). Reducing unplanned extubation in the NICU. J. Pediatrics 2014;133(5):1-8. 7. Clifton-Koeppel R. Endotracheal tube suctioning in the newborn: a review of the literature. Newborn Inf Nurs Review 2006;6(2):94-99. 8. Puchalski M. L. Should saline be used when suctioning the endotracheal tube of the neonate? Available at http://www. medscape.com/viewarticle/552862 (2007). 9. Guerin C, Reignier J, Richard C et al. Prone positioning in severe acute respiratory distress syndrome. NEJM 2013;368:21592168. 10. Kimmoun A, Roche S, Bridey C, et al. Prolonged prone positioning under VV ECMO is safe and improves oxygenation and respiratory compliance. Ann Intensive Care. 2015;5(1):35. 11. SARI Working Group. A strategy for the control of antimicrobial resistance in Ire-

land. SARI Working Group 2011: 1-31. Available on line at www.hpsc.ie/A-Z/MicrobiologyAntimicrobialResistance/InfectionControlandHAI/ Guidelines/File,12530,en.pdf 12. Wildschut E. D, Hanekamp M. N, Vet N. Jet al. Feasibility of sedation and analgesia interruption following cannulation in neonates on Extracorporeal Membrane Oxygenation. Intensive Care Med 2010;36(9):1587-1591. 13. Honsel M, Giugni C, Brierley J. Limited professional guidance and literature are available to guide the safe use of neuromuscular block in infants. Acta Paediatr. 2014;103(9):e370-e373. 14. Knight GR, Dudell GG, Evans ML, Grimm PS. A comparison of venovenous and venoarterial Extracorporeal Membrane Oxygenation in the treatment of neonatal respiratory failure. Crit Care Med 1996;24(10):16781683. 15. Voepel-Lewis T, Merkel S, Tait AR, Trzcinka A, Malviya S. The reliability and validity of the Face, Legs, Activity, Cry, Consolability observational tool as a measure of pain in children with cognitive impairment. Anaes Analg 2002;95:1224-1229. 16. Khan AM, Shabarek FM, Zwishenberger JB et al. Utility of daily head ultrasonography for infants on Extracorporeal Membrane Oxygenation. J Paediat Surg 1998;33(8):1229-1232. 17. Korinthenberg R, Kachel W, Koelfen W, Schultze C, Varnholt V. Neurological findings in newborn infants after Extracorporeal Membrane Oxygenation, with specific reference to the EEG. Dev Med Child Neurol. 1993;35(3):249-257. 18. Graziani LJ, Streletez LJ, Baumgart S, Cullen J, McKee LM. Predictive value of neonatal electroencephalograms before and during Extracorporeal Membrane Oxygenation. J Paediatr 1994;125(6 PT 1):969-975. 209

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19. Gannon CM, Kornhauser MS, Gross GW et al. When combined, early bedside head ultrasound and electroencephalography predict abnormal computerised tomography or magnetic resonance brain images obtained after ECMO treatment. J. Perinatol 2001;21(7):451-455. 20. Remenapp R. T, Winklerprins A, Mossberg I. Chapter 41. ECMO Extracorporeal Cardiopulmonary Support In Critical Care 3rd edition chapter 41: 602. 21. Patole SK, de Klerk N. Impact of standardised feeding regimes on incidence of neonatal necrotizing enterocolitis: a systemic review and meta-analysis of observational studies. Arch Disease Child Fetal Neonatal Ed 2005;90(2):F147-151. 22. Evans D. Neonatal Jaundice. BMJ Clin Evid 2007;12:319 1-12. 23. Vreman HJ, Wong RJ, Stevenson DK. Phototherapy: current methods and future directions. Semin Perinatol 2004;28(5):326-333. 24. Callery P. Caring for parents of hospitalised children: a hidden area of nursing work. J Adv Nurs 1997;26(5):992-998. 25. Feldman R, Weller A, Leckman FJ, Kuint J, Edelman IA. The nature of mother’s tie to her infant: Maternal bonding under conditions of proximity, separation and potential loss. J Child Psychol Psychiatry 1999;40(6):929-939. 26. Hall EO. Being in an alien world: Danish parents’ lived experiences when a newborn or small child is critically ill. Scand J Caring Sci. 2005;19(3):179-185. 27. Hall EO. Danish parents’ experiences when their newborn or critically ill small child is transferred to the PICU. Nurs Crit Care. 2005;10(2):90-97. 28. Söderström I, Benzein E, Saveman B. Nurses’ experiences of interactions with family members in intensive care units. Scand J Caring Sci 2003;17(2):185-192. 29. Curley MA, Meyer EC. Parental experience of highly technical therapy: survivors and 210

non-survivors of Extracorporeal Membrane Oxygenation support. Pediatr Crit Care Med 2003;4(2):214-219.

16 Weaning and Decannulation of Neonates with Respiratory Failure on ECLS Chris Harvey, MB, ChB, MRCS

Weaning Neonatal respiratory extracorporeal life support (ECLS) provides the shortest run time and the best survival (84% to separation from ECMO and 74% to discharge or transfer) of any of the groups in the Extracorporeal Life Support Organization (ELSO) Registry.1 Traditionally, as respiratory function improves the ECLS flow and sweep are slowly weaned until the patient achieves good arterial gases on minimal ECLS support, while remaining on a lung protective ventilation strategy. Exactly what constitutes minimal depends upon the circuit configuration used and the individual components within the circuit, especially the oxygenator. Flows from 30-50 ml/kg/min are often quoted as expectable minimal levels.2 Once stable at minimal ECLS support the patient may be trailed off ECLS. The downside in slowly weaning the ECLS flow is the increased likelihood of circuit related thrombotic complications. To counter this problem there may be a need to maintain circuit anticoagulation at a slightly higher level with an increased risk of hemorrhagic complications. An alternative approach maintains the ECLS flow at approximately 100 ml/kg/min and to decide on the appropriateness of a trial off ECLS by evaluating other clinical parameters. Maintaining flow at higher levels reduces the

risk of circuit related thrombotic complications. Knowing the diagnosis and the natural history of the underlying condition helps in determining the appropriateness of a trial off (eg, simple meconium aspiration usually reaches the point of weaning before a neonate with confirmed sepsis or congenital diaphragmatic hernia). Serial chest radiographs should show clearing of the lung parenchyma with corresponding improvement in lung compliance (Figure 16-1). Echocardiography confirms that the pulmonary arterial pressure has decreased to below 2/3 systemic pressures. Inotropes often commenced pre-ECLS in attempt to reduce shunting by increasing the systemic pressure should have been substantially weaned and any pneumothorax or active air leak should have resolved. If cannulated for VV-ECMO the readiness for a trial off ECMO can be assessed simply by increasing the

Figure 16-1. CXR postcannulation and at trial off showing improvement in lung fields.

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FiO2 to 1 on the ventilator, a rapid rise of >5% in peripheral saturations indicates likely success. Special Circumstances Occasionally the decision to progress to decannulation is not related to clinical improvement. In such circumstances the most common reason is bleeding, especially intracranially where a desire to decannulate to prevent further bleeding overrides the need for a lung protective ventilatory strategy. The other scenario in which an alternative approach may be considered is the “one way wean.” This would apply to patient in whom ECLS may not be contributing to a positive clinical outcome but the patient is not sufficiently moribund or the outlook with conventional critical care not sufficiently bleak for all treatment to be fully withdrawn. The patient is ventilated and decannulated irrespective of the ventilation or cardiovascular support required in the hope that continuing conventional treatment may yet still yield a positive outcome.

to approximately 100 ml/kg/min to reduce the risk of circuit thrombosis. If the arterial blood gases prove unacceptable, reconnection of the sweep gas reestablishes ECLS. As flow through the entire circuit is maintained long trial offs (6-24 hrs) are possible, especially if arterial blood gases are borderline. The routine use of inhaled nitric oxide should be avoided and held in reserve should the respiratory function decrease following decannulation. A PaO 2 >60 mmHg (8 kPa) with a FiO2 of 70% are common goals, although arterial saturations 10 Paralysis ↓Temperature HFO/NO/PGI2

Pre Oxygenator SaO2 high (>80) (Recirculation) Consider: Changing cannulae positions to reduce recirculation

Figure 22-2. Venovenous clinical pathway. (Adapted with permission from Alfred Hospital, Melbourne, AU: INOVA Fairfax Hospital, June 30, 2016)

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Management of the Pediatric Respiratory Failure Patient on ECMO

output from baroreceptors in the myocardium or vasculature sensing an “underfilled” atrium. Tachycardia and hypertension can result. Also, the nonpulsatile flow of VA-ECMO may cause increases in renin and angiotensin from the kidneys detecting inadequate flow (even though flow may be normal). Thus, common medications to treat hypertension during VA-ECMO include angiotensin converting enzyme inhibitors or beta-blockers such as esmolol. Nitroprusside, or other vasodilators can also be used, although caution should be taken as they may reduce venous return and limit ECMO flow. They may also cause a further decrease in cardiac filling pressures, which may exacerbate the normal reaction of the heart and cause more tachycardia and increased cardiac output. Hypertension that occurs with VV-ECMO is less likely due to these mechanisms and may reflect volume overload or other factors that increase systemic vascular resistance or cardiac output such as agitation, pain, etc. Hypotension in VA-supported patients can be treated with increased flow from the ECMO circuit, administration of fluids (if hypovolemic), or may require inotropic support, especially in patients with vasodilatory shock or sepsis. Patients on VV support are dependent on adequate native cardiac function and the need for vasoactive support should be based on cardiac performance and hemodynamics. Hypoxia and Related Complications Hypoxia and related complications in VAsupported patients can be reversed by increasing flow into the ECMO circuit. Limitation of venous outflow needed to support oxygenation and hemodynamics in VA support may require placement of additional venous drainage cannulas if simpler measures such as volume loading or optimizing cannula placement prove ineffective. Femoral VA-ECMO can result in upper body hypoxemia (differential cyanosis) if the patient has severe respiratory failure and native

cardiac ejection preferentially supports the heart and brain (upper body). In this circumstance, a cannula may be placed into the right internal jugular (IJ) vein or right atrium and return from the ECMO circuit incorporated into this cannula by means of a Y connector. (Commonly called venoarteriovenous [VAV] ECMO.) This approach directs oxygenated blood from ECMO into the right heart and improves upper body saturation. Care should be taken to monitor flow both in this cannula and the femoral arterial site, as adequate flow into both cannulas is needed to prevent clotting (the right atrial cannula is usually larger and gets more flow). Flow restriction with a Hoffman clamp is often used to balance blood flow. Patients on VV-ECMO with hypoxia to a level that is causing clinical harm at a tissue level can also have trials of increased ECMO flow, although at higher flow the risk of recirculation increases. In patients with 2-site cannulation, draining from the femoral venous cannula and reinfusing into the right atrial site may limit recirculation. Learning to accept low oxygen saturations (even to 70-80%), which are often well tolerated in some patients, and monitoring for adequacy of perfusion in terms of lactate measurements, cerebral oximetry, and clinical status (eg, adequate urine output) are important aspects of care. While increased inspired oxygen to the ventilator circuit or escalation of ventilator settings may also improve systemic gas exchange, maintaining nontoxic ventilator support to optimize the milieu for lung recovery is important and hence not an adoptable strategy if it can be avoided. Red blood cell transfusion to increase oxygen delivery is sometimes helpful in hypoxic patients, although controversy over goal hemoglobin levels exists. Most centers maintain a hemoglobin of 8-12 g/dL. If transfusion is ineffective, then reducing oxygen consumption by sedation and/or lowering temperature may be helpful. Decreasing cardiac output will 271

Chapter 22

increase the proportion of saturated blood from the ECMO circuit traversing the native cardiac/ pulmonary circuit and may improve saturation, although adverse effects of low cardiac output on tissue perfusion must be avoided. Another venous cannula to provide increased additional drainage can also be added. In 2-site cannulation, a 3rd cannula can be added to the femoral site and both lower body cannulas used for drainage. The right IJ or right atrial cannula can then be used in a similar fashion, a venous (or arterial) cannula can be introduced which is then Y’ed into the oxygenated return limb of the ECMO circuit. Limitation of venous flow may require additional cannula placement. Hypothermia can be an adopted strategy to reduce cardiac output and the metabolic demand of the body. If inadequate oxygenation on VV-ECMO and/or patient factors leads to hemodynamic failure, the patient may require conversion to VA support Infection There are no indications for prophylactic antibiotics in patients on ECMO. Markers of blood stream infections, such as temperature lability and inflammatory markers, may not be reliable. The need for multiple manipulations to maintain temperature in the desired range may be a clue to fever, but patients are not “allowed” to mount a febrile response since the ECMO circuit can control temperature fairly easily. White blood cell counts may change as a response to initiation of ECMO, although the function of white blood cells is thought to return to normal within a few days. Biomarkers such as procalcitonin or CRP may be useful, especially as trending studies. Cultures for suspected infection and appropriate treatment should be instituted as needed. Routine circuit cultures, however, are not currently recommended.

272

Renal Renal failure is associated with increased mortality. In a recent metaanalysis, 55.6% of ECMO patients had acute kidney injury with 35% of them requiring renal replacement therapy (RRT).6 While there is a current trend to maintain strict fluid balance and avoid overload, especially by the third day of ECMO, care must be taken to not cause hypovolemia or impaired perfusion. Almost all patients receive diuretics, either in intermittent dosing or constant infusion. Following intake and output of fluids and concentrating medications are important aspects of care. Continuous renal replacement therapies (CRRT) are used to maintain fluid balance, support failing kidneys, and potentially clear proinflammatory cytokines from the blood (see Chapter 62). To better define the efficacy of RRT for patients on ECMO in this recent metaanalysis, the total ECMO mortality rate was compared to the use of RRT. If the use of RRT was less than 30%, mortality rates were lower. However, increasing the use of RRT from 30% to 50% decreased mortality, suggesting that use of renal replacement therapy on ECMO may actually decrease mortality. Furthermore, based on the metaanalysis, the risk ratio of mortality increased if RRT was delayed.7,8 Another recent study of 86 children on ECMO compared those who received hemofiltration to those who did not. The main indication for hemofiltration was fluid overload in 67%, renal failure in 21%, and electrolyte abnormalities in 11.6%. Patients receiving hemofiltration had longer duration of ECMO support (127 hours vs. 121 hours, p=0.05) and received more platelet transfusions. There was no difference in the proportion of patients decannulated or who survived to hospital discharge (49% in hemofiltration compared to 63% in controls, p=0.19).9 Data from the ELSO Registry shows that about 30% of pediatric and adult patients undergoing ECMO undergo renal replacement either by hemofiltration or dialysis, although

Management of the Pediatric Respiratory Failure Patient on ECMO

elevations of creatinine greater than 1.5 mg/dl were reported in only 15% of pediatric patients. Other adjunct extracorporeal therapies such as plasmapheresis/plasma exchange or liver support systems have been used successfully during ECMO. Nutrition

membrane lungs affect pharmacokinetics and dynamics is under investigation. Therapeutic drug level measurements should be done, when available, to demonstrate adequate dosing (see Chapter 71). Sedation

Maintaining patient comfort, safety of the ECMO circuit, and minimizing the adverse effects of narcotics, benzodiazepines, and other medications is the goal. Opioids such as fentanyl and morphine are often already in place at the time of ECMO initiation and continue as first line drugs. Tachyphylaxis to fentanyl (and morphine) can occur over time and rapid escalation of these medications can occur. The impact of newer tubing material, coatings, and membrane lung composition may also affect circulating levels of sedatives, although data on current circuitry and pharmacodynamics and kinetics is just beginning to appear. Benzodiazepines such as midazolam are also frequent during ECMO. Given the longer duration of ECMO that many patients currently incur, the dosage of sedative medication can become extremely large. Further, weaning sedation in ECMO survivors often lengthens hospital stay due to withdrawal complications.11,12 Despite its cost, dexmedetomidine can be helpful in limiting the need for other medications while still providing patient comfort. The need for multiple medications, often at high dose, to maintain patients “asleep and quiet” is another reason why allowing them to be more awake is valuable. In an international survey of sedation Pharmacology practice, fentanyl and morphine were the most commonly used opioids while midazolam and Many circulating drug levels may be re- lorazepam were common benzodiazepines.13 duced from hemodilution or adherence to the Answers to queries asked in the survey are ECMO circuit. With the newer circuit coatings, shown in Table 22-2. shorter tubing lengths, and oxygenator materials currently in use, much of the prior research in this area is likely to be invalid. Many new investigations are underway. How newer circuits and Adequate nutrition is essential for healing; provided by total parenteral nutrition, enteral feeding, or a combination of both. Enteral feeding has been shown safe and effective during ECMO in all groups of patients and may limit the need for total parenteral nutrition and its associated complications. With the current trend to maintain patients awake, extubated, or with a tracheostomy, oral feeding can also be established in some patients. In patients unable to tolerate nasogastric (NG) or oral feeding, nasojejunal (NJ) placement early in the course is useful. Such placement can be done safely even with anticoagulation on board. If unable to place blindly, consider early fluoroscopic help to avoid delay in feeding initiation. Caloric goals should be similar to those of critically ill patients and time-to-goal calories should be reached as soon as possible.10A. One reason often quoted for use of CRRT is to control volume overload related to feedings, although this remains controversial. It is agreed, however, that TPN including use of intralipid should be limited and enteral nutrition remain the goal. Lipid infusion with newer PMP membranes has not been associated with oxygenator failure.

273

Chapter 22 Table 22-2. Sedation Practices Questions (Adapted with permission from Buscher H, Vaidiyanathan S, Al-Soufi S, et al. Sedation practice in venovenous extracorporeal membrane oxygenation: an international survey. ASAIO J. 2013;59(6):636-641) Total (n = 102) What level of sedation do you most often achieve when your patient is on full ECMO support? Cooperative and tranquil Response to commands only Brisk response to light glabellar tap or loud auditory stimulus Sluggish response to glabellar tap or loud auditory stimulus No response to glabellar tap or loud auditory stimulus

Nonexpert (n = 84)

Expert (n = 18)

34 (33) 18 (18) 8 (8) 27 (26) 15 (15)

27 (32) 15 (18) 7 (8) 23 (27) 12 (14)

7 (39) 3 (17) 1 (6) 4 (22) 3 (17)

Compared with other patients in your intensive care unit with similar target sedation levels: What do you think is the dose requirement in ECMO patients? Generally much more Generally more Similar Generally less Generally much less

21 (21 38 (37) 31 (30) 10 (10) 2 (2)

14 (17) 35 (42) 26 (31) 7 (8) 2 (2)

7 (39) 3 (17) 5 (28) 3 (17) 0

Do you use a sedation score to prescribe and/or monitor sedation? Yes No Sometimes

50 (49) 34 (33) 18 (18)

41 (49) 25 (30) 18 (21)

9 (50) 9 (50) 0

Do you reduce/stop sedation daily to assess the patients’ neurology? Yes No Sometimes

44 (43) 22 (22) 36 (35)

36 (43) 18 (21) 30 (36)

8 (44) 4 (22) 6 (33)

0.109

Referring to adult patients on veno-venous ECMO: What benzodiazepine do you use most frequently? Midazolam Lorazepam Other

81 (79) 18 (18) 3 (3)

63 (75) 18 (21) 3 (4)

18 (100) 0 0

Referring to adult patients on veno-venous ECMO: What opioid do you use most frequently? Morphine Fentanyl Sufentanil Remifentanil

44 (43) 46 (45) 10 (10) 2 (2)

35 (42) 41 (49) 8 (10) 0

9 (50) 5 (28) 2 (11) 2 (11)

Do you use Propofol routinely? Yes No Sometimes

36 (35) 65 (64) 1 (1)

28 (33) 55 (65) 1 (1)

8 (44) 10 (56) 0

What other cosedatives do you use in ECMO patients (more than one answer possible)? Ketamine Clonidine Dexmedetomidine Barbiturate Other None

29 (28) 26 (25) 42 (41) 6 (6) 5 (5) 30 (29)

23 (27) 16 (19) 37 (44) 5 (6 ) 4 (95) 26 (31)

6 (33) 10 (56) 5 (28) 1 (6) 1 (6) 4 (22)

What proportion of you ECMO patients will be on muscle relaxants for longer than 24 hrs at one point during ECMO? 10–14 days of venti57% in 1993 to 72% in 2007. This suggests that lation. It was not until >14 days that the estiamong children with ARF, any survival benefits mated probability of survival decreased to 50%. gained from improved ECMO technology and Similar trends were noted for other diagnostic experience are likely being tempered by the subsets as well. These data suggest that children increased complexity of patients supported with up to 14 days of pre-ECMO ventilation on ECMO. The presence of certain comorbid should be considered as viable candidates for conditions adversely impacts survival. Renal ECMO support and for those who receive >14 failure and liver failure are associated with days of pre-ECMO ventilation consideration a 33% and 16% survival rate, respectively. for ECMO support should be made on a caseSimilarly, patients with hematopoietic stem cell by-case basis. transplant, solid organ transplant, and primary Temporal trends assessing ECMO canimmunodeficiency also have low survival rates nulation strategy indicate a steady increase in (5%,39%,and 34% respectively).6,9,10 Among venovenous (VV) ECMO and double-lumen patients with cardiac disease requiring ECMO VV cannulation compared with venoarterial for ARF, survival for cardiomyopathy/myocar- (VA) ECMO cannulation. From 1993 to 2007, ditis was 43% and for cardiac arrest prior to VV-ECMO cannulation increased from 35% to ECMO support was 38%. Surprisingly, survival 46%, and the use of double-lumen VV catheters was much higher in those with congenital heart increased from 1% to 19%.6 In contrast to eardisease with two ventricles (52%), one ventricle lier studies,14 hospital survival with VA-ECMO (60%), or chronic lung disease (59%).6,11 support was lower (51%) compared to those Another factor which has clearly emerged with two-catheter VV support (66%) or doubleto affect survival is the duration of pre-ECMO lumen VV catheter support (70%). Similar to mechanical ventilation.12,13 Despite wide ac- patients initially treated with VA-ECMO, those ceptance and practice of low tidal volume transitioned from VV- to VA-ECMO had 49% ventilation strategies to limit ventilator-induced survival. Improved survival in patients receivlung injury, a longer duration of pre-ECMO me- ing VV-ECMO cannulation may reflect patient chanical ventilation lowers survival. Due to this selection because VV-ECMO offers no direct fact, an accepted pediatric criterion for patient cardiac support and more critically ill patients selection in the early part of the ECMO experi- are often placed on VA-ECMO. ence typically included pre-ECMO mechanical Among children with ARF supported on ventilation of 52 days on ECMO. These ences are noted within patient subsets as well. survival rates are significantly lower than surFor example, in a child with viral pneumonia the vival for children supported for 20 mmHg), • Low cardiac index (< 2 L/min/m2), reduces tricuspid regurgitation by realignment 5 • Rising lactates with evidence of end organ of the ventricular septum. If this is the mechainvolvement, nism of morphologic RV failure, then tricuspid • Failure to respond to optimized vasoactive regurgitation and RV failure can be expected to support, occur after conventional repair. • Neurologically intact with reasonable likelihood of either reversibility or qualification Role of Ischemia for either long term mechanical support or transplantation. The RV working as a systemic ventricle at systemic pressures with the resultant hyFor postcardiotomy patients, ECMO should pertrophy of the myocardium may not receive be considered with failure to wean from carsufficient coronary blood flow. This results in diopulmonary bypass despite high inotropic ischemia of the RV myocardium, which, in support with or without IABP placement. 333

Chapter 28

Contraindications to ECMO Support in ACHD Among patients with multisystem organ failure ECMO is not usually associated with good outcome, most likely due to the severe end-organ damage that occurred prior to its initiation. Therefore, it is best to consider earlier ECMO prior to irreversible organ damage occurs. In patients with sepsis (see Chapter 56) ECMO management may prove difficult due to the associated systemic vasoplegia and inability to maintain circuit flows that sustain satisfactory mean arterial pressure. Other contraindications include irreversible neurological damage or other prohibitions for transplantation with no hope of myocardial recovery. Finally, severe aortic valvular regurgitation, and unwitnessed cardiac arrest or prolonged cardiorespiratory resuscitation (>60 minutes) represent additional contraindications. ECMO should be considered as a bridge to conventional operation or postcardiotomy recovery, and patients with ACHD should be considered for ECMO support if myocardial recovery is expected with or without surgery. Management Strategies

Chapter 7). We routinely obtain thromboelastography (TEG) with and without heparinase to judge intrinsic coagulation and the heparin effect. For postcardiotomy patients, we usually wait until chest tube drainage is low (2.0) in the setting of supraventricular tachycardia induced cardiomyopathy have increased risk for receiving MCS to prevent circulatory collapse and facilitate pharmacologic control of rhythm abnormalities.23 ECLS is also occasionally used to provide support for patients who experience cardiovascular collapse due to accidental or intentional poisoning26 and for patients who experience life-threatening systemic low cardiac output state due to acute right heart failure related to pulmonary hypertensive crisis.27 The use of MCS in the management of end-stage heart failure has dramatically evolved during the past two decades. Short-term extracorporeal devices and durable implantable ventricular assist devices are now standard heart failure therapies in adults and late adolescent children. Technologic advances in highly efficient implantable centrifugal and axial flow pumps have proven difficult to miniaturize for use in small children, infants, and neonates. Consequentially, ECLS remains an important component of mechanical heart failure therapy in some patient populations. Bridge to Transplantation Optimal timing and indications for MCS as a bridge to transplantation have not been clearly established in the highly heterogeneous pediatric patient population. Waiting list mortality is

significantly higher for children who require ECMO as a bridge to transplant (Hazard Ratio 3.1) than those who receive mechanical ventilator support or no invasive support.28 When used as a short-term bridge to transplantation, ECLS survival to transplantation approximates 45%.29 However, approximately one third of patients who are successfully transplanted die prior to hospital discharge. Patients with singleventricle forms of congenital heart disease and those who require prolonged pretransplant ECLS (>14 days) are at greatest risk of dying. Survival is much higher in patients with severe primary or secondary cardiomyopathy bridged to transplantation with ECLS.30,31 Data from a large, propensity score-matched study showed that overall survival rates are significantly higher in pediatric patients who are bridged to transplantation with a ventricular assist device (VAD) than ECMO.32 However, patients with complex forms of congenital heart disease were excluded from the primary analysis, largely limiting general applicability of the observed survival advantage to patients with predominately cardiomyopathic and inflammatory forms of heart failure. Although VADs appear to provide a superior form of bridge to transplantation in older children and in children with nonstructural heart disease, survival rates in patients with functional single ventricle heart disease who require VAD support remain poor. This is especially true for neonates and patients with shunted sources of pulmonary blood flow.33 In addition, the apparently encouraging survival rate in patients who are bridged with the VAD is tempered by the fact that 29% of patients experienced a stroke and 97% experienced some form of serous adverse event during support. In addition to worse pretransplant outcomes, pediatric patients who are bridged to transplantation with ECMO also experience significantly worse short-term and long-term posttransplant survival compared to patients who do not require MCS prior to transplantation and those who are bridged to transplantation with a VAD.34 341

Chapter 29

There is general agreement that ECMO serves successfully as a bridge-to-decision and as a bridge-to-bridge (bridge-to-VAD).35 When used in the setting of acute hemodynamic decompensation, including ECPR, ECMO provides a readily available and rapidly initiated form of MCS. In most cases, the degree of myocardial recovery, if any, is unknown at time of initiation. During this period of clinical uncertainty, ECMO is useful as a bridge to decision regarding transplant candidacy as neurologic function and end-organ recovery are assessed. Consideration should be given to transitioning potential transplantation candidates to VAD support (bridge-to-bridge) if myocardial recovery does not occur within 7-14 days. While this approach is associated with improved survival in most patients, it is less clear whether VAD support is better than ECMO for supporting infants with single ventricle heart disease to transplantation. Posttransplantation Support Early posttransplant dysfunction may prevent separation from CPB at transplantation or lead to life-threatening low cardiac output state during the early posttransplant period. ECMO can provide mechanical support for these patients in whom survival reaches approximately 50%.1 Neonates appear to have greater risk for death than older children. Irreversible graft dysfunction is the most common reason for discontinuing support in this patient population. The use of ECMO to as a bridge to recovery for patients who experience severe acute rejection remote from transplantation is less successful and many patients will ultimately require retransplantation.36 Procedural Support Catheter based interventional and diagnostic procedures can be safely performed on patients receiving ECMO support.37 The 342

most common indications for cardiac catheterization on ECMO include assessment of operative results and percutaneous left heart decompression. Early detection and correction of residual cardiac lesions appears to shorten ECMO duration and improve survival so the use of catheter based diagnostic procedures should be considered when noninvasive diagnostic studies fail to identify a reason for inability to separate from ECMO.38,39 ECMO is also useful for providing cardiopulmonary support during high-risk catheter based interventions beyond the perioperative period and has proven to be a safe alternative to CPB during complex airway surgery and repair of pulmonary artery sling.40 ECPR Clinical outcomes tend to be better in children who receive extracorporeal cardiopulmonary resuscitation (ECPR, see Chapter 27) for underlying cardiac disease than those who have a noncardiac etiology of acute cardiopulmonary failure.41 Patients with underlying cardiac disease are typically being monitored in an intensive care setting and have adequate vascular access. These patients tend to be younger, less likely to have preexisting organ dysfunction, and more likely to experience ventricular dysrhythmia than asystole prior to cardiac arrest.42,43 Potential benefits of ECPR include improved myocardial oxygen delivery, reduced myocardial workload, reduced vasopressor and inotropic therapy, reduced pulmonary barotrauma and intrathoracic pressure, improved end-organ perfusion and oxygen delivery, reversal of acidosis, and targeted temperature control. Current resuscitation guidelines from the American Heart Association support the use of ECPR in pediatric patients with a cardiac diagnosis who experience in-hospital cardiac arrest in a center with ECLS expertise.44

Indications and Contraindications for ECLS in Children with Cardiovascular Disease

Respiratory Support

rate following ECPR approaches 30% in preterm babies and is as high as 21% in neonates Some children with underlying cardiac 12 years

400

Anthropometry • • •

Physical examination MRI Brain if any new neurological deficit Age-appropriate neurodevelopmental screen

•

Dietician referral and input Focused care with input from specialist nurses and liaison with community Structured followup

•

Dietician referral and input

• •

Neurology/neonatologist/Pediatrician/ Community pediatrician referral and support (depending on local practice) Physiotherapist

• •

Hearing

Hearing tests

•

Audiology assessment and input

Vision

Vision tests

•

Ophthalmology/Optometrist referral

Growth

Anthropometry

•

Dietician referral and input

Mental and motor development, vision

•

• •

Pediatrician/Community pediatrician (depending on local practice) Physiotherapist

• •

4-5 years

Anthropometry Neuro-imaging if any acute neurological event Baseline age-appropriate neurodevelopmental screen

Intervention

Formal assessment tool –as per local practice Age-appropriate parent filled questionnaires Vision Tests

Hearing

Hearing tests

•

Audiology assessment and input

Language

Speech and Language assessment

•

Speech and Language input

Growth, mental and motor development, speech and language, behavior

•

Formal assessment tool as per local practice Age-appropriate parent filled questionnaires Child Behavior Checklist

•

Pediatrician/Community pediatrician (depending on local practice) Physiotherapist Speech and Language Therapist

Growth, mental and motor development, speech and language, behavior, memory

•

Formal assessment tool as per local practice Age-appropriate parent filled questionnaires Child Behavior Checklist

•

Self-esteem

Quality of life score

• •

• •

Growth, • neuropsychological tests, intelligence, motor, • behavior, memory • Quality of life/Selfesteem

Formal assessment tool as per local practice Age-appropriate parent filled questionnaires Child Behavior Checklist

Quality of Life Score

• •

• • • •

Pediatrician/Community pediatrician (depending on local practice) Physiotherapist Speech and Language Therapist Cognitive rehabilitation Additional help at school

•

Psychology referral

• • • • •

Pediatrician/Community pediatrician (depending on local practice) Physiotherapist Speech and Language Therapist Cognitive rehabilitation Additional help at school

•

Psychology referral

Outcomes, Complications, and Followup of Neonates and Children with Cardiovascular Disease

References 1. ELSO. Registry of the Extracorporeal Life Support Organisation. Michigan: Ann Arbor;2015. 2. Mascio CE, Austin EH, 3rd, Jacobs JP, et al. Perioperative mechanical circulatory support in children: an analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. J Thorac Cardiovasc Surg. Feb 2014;147(2):658-664: discussion 664-655. 3. Simmonds J, Dominguez T, Longman J, et al. Predictors and Outcome of Extracorporeal Life Support After Pediatric Heart Transplantation. Ann Thorac Surg. Jun 2015;99(6):2166-2172. 4. Kane DA, Thiagarajan RR, Wypij D, et al. Rapid-response extracorporeal membrane oxygenation to support cardiopulmonary resuscitation in children with cardiac disease. Circulation. Sep 14 2010;122(11 Suppl):S241-248. 5. Brown KL, Ridout DA, Shaw M, et al. Healthcare-associated infection in pediatric patients on extracorporeal life support: The role of multidisciplinary surveillance. Pediatr Crit Care Med. Nov 2006;7(6):546-550. 6. Dalton HJ, Garcia-Filion P, Holubkov R, et al. Association of bleeding and thrombosis with outcome in extracorporeal life support. Pediatr Crit Care Med. Feb 2015;16(2):167174. 7. Gupta P, Beam B, Schmitz ML. Outcomes associated with the use of renal replacement therapy in children receiving extracorporeal membrane oxygenation after heart surgery: a multi-institutional analysis. Pediatr Nephrol. Jun 2015;30(6):1019-1026. 8. Polito A, Barrett CS, Rycus PT, Favia I, Cogo PE, Thiagarajan RR. Neurologic injury in neonates with congenital heart disease during extracorporeal membrane oxygenation: an analysis of extracorpo-

real life support organization registry data. ASAIO J. Jan-Feb 2015;61(1):43-48. 9. Marino BS, Lipkin PH, Newburger JW, et al. Neurodevelopmental Outcomes in Children With Congenital Heart Disease: Evaluation and Management: A Scientific Statement From the American Heart Association. Circulation. Aug 28 2012;126(9):1143-1172. 10. Chaturvedi RR, Macrae D, Brown KL, et al. Cardiac ECMO for biventricular hearts after paediatric open heart surgery. Heart. May 2004;90(5):545-551. 11. Morris MC, Ittenbach RF, Godinez RI, et al. Risk factors for mortality in 137 pediatric cardiac intensive care unit patients managed with extracorporeal membrane oxygenation. Crit Care Med. Apr 2004;32(4):1061-1069. 12. Thourani VH, Kirshbom PM, Kanter KR, et al. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) in pediatric cardiac support. Ann Thorac Surg. Jul 2006;82(1):138-144; discussion 144-135. 13. Freeman CL, Bennett TD, Casper TC, et al. Pediatric and neonatal extracorporeal membrane oxygenation: does center volume impact mortality?*. Crit Care Med. Mar 2014;42(3):512-519. 14. Ravishankar C, Gaynor JW. Mechanical support of the functionally single ventricle. Cardiol Young. Feb 2006;16 Suppl 1:55-60. 15. Allan CK, Thiagarajan RR, del Nido PJ, Roth SJ, Almodovar MC, Laussen PC. Indication for initiation of mechanical circulatory support impacts survival of infants with shunted single-ventricle circulation supported with extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg. Mar 2007;133(3):660-667. 16. Hoskote A, Bohn D, Gruenwald C, et al. Extracorporeal life support after staged palliation of a functional single ventricle: subsequent morbidity and survival. J Thorac Cardiovasc Surg. May 2006;131(5):11141121.

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Chapter 35

17. Jaggers JJ, Forbess JM, Shah AS, et al. Extracorporeal membrane oxygenation for infant postcardiotomy support: significance of shunt management. Ann Thorac Surg. May 2000;69(5):1476-1483. 18. Booth KL, Roth SJ, Thiagarajan RR, Almodovar MC, del Nido PJ, Laussen PC. Extracorporeal membrane oxygenation support of the Fontan and bidirectional Glenn circulations. Ann Thorac Surg. Apr 2004;77(4):1341-1348. 19. Rood KL, Teele SA, Barrett CS, et al. Extracorporeal membrane oxygenation support after the Fontan operation. J Thorac Cardiovasc Surg. Sep 2011;142(3):504-510. 20. Jolley M, Thiagarajan RR, Barrett CS, et al. Extracorporeal membrane oxygenation in patients undergoing superior cavopulmonary anastomosis. J Thorac Cardiovasc Surg. Oct 2014;148(4):1512-1518. 21. Rajagopal SK, Almond CS, Laussen PC, Rycus PT, Wypij D, Thiagarajan RR. Extracorporeal membrane oxygenation for the support of infants, children, and young adults with acute myocarditis: a review of the Extracorporeal Life Support Organization registry. Crit Care Med. Feb 2010;38(2):382-387. 22. Duncan BW, Bohn DJ, Atz AM, French JW, Laussen PC, Wessel DL. Mechanical circulatory support for the treatment of children with acute fulminant myocarditis. J Thorac Cardiovasc Surg. Sep 2001;122(3):440-448. 23. Madden K, Thiagarajan RR, Rycus PT, Rajagopal SK. Survival of neonates with enteroviral myocarditis requiring extracorporeal membrane oxygenation. Pediatr Crit Care Med. Jul 9 2010. 24. Fraser CD, Jr., Jaquiss RD, Rosenthal DN, et al. Prospective trial of a pediatric ventricular assist device. N Engl J Med. Aug 9 2012;367(6):532-541. 25. Almond CS, Singh TP, Gauvreau K, et al. Extracorporeal membrane oxygenation for bridge to heart transplantation among chil402

dren in the United States: analysis of data from the Organ Procurement and Transplant Network and Extracorporeal Life Support Organization Registry. Circulation. Jun 28 2011;123(25):2975-2984. 26. Gajarski RJ, Mosca RS, Ohye RG, et al. Use of extracorporeal life support as a bridge to pediatric cardiac transplantation. J Heart Lung Transplant. Jan 2003;22(1):28-34. 27. Levi D, Marelli D, Plunkett M, et al. Use of assist devices and ECMO to bridge pediatric patients with cardiomyopathy to transplantation. J Heart Lung Transplant. Jul 2002;21(7):760-770. 28. Dipchand AI, Mahle WT, Tresler M, et al. Extracorporeal Membrane Oxygenation as a Bridge to Pediatric Heart Transplantation: Effect on Post-Listing and Post-Transplantation Outcomes. Circulation. Heart failure. Sep 2015;8(5):960-969. 29. Kaushal S, Matthews KL, Garcia X, et al. A multicenter study of primary graft failure after infant heart transplantation: impact of extracorporeal membrane oxygenation on outcomes. Pediatr Transplant. Feb 2014;18(1):72-78. 30. Ibrahim AE, Duncan BW, Blume ED, Jonas RA. Long-term follow-up of pediatric cardiac patients requiring mechanical circulatory support. Ann Thorac Surg. Jan 2000;69(1):186-192. 31. Hamrick SE, Gremmels DB, Keet CA, et al. Neurodevelopmental outcome of infants supported with extracorporeal membrane oxygenation after cardiac surgery. Pediatrics. Jun 2003;111(6 Pt 1):e671-675. 32. Chow G, Koirala B, Armstrong D, et al. Predictors of mortality and neurological morbidity in children undergoing extracorporeal life support for cardiac disease. Eur J Cardiothorac Surg. Jul 2004;26(1):38-43. 33. Mahle WT, Forbess JM, Kirshbom PM, Cuadrado AR, Simsic JM, Kanter KR. Cost-utility analysis of salvage cardiac extracorporeal membrane oxygenation in

Outcomes, Complications, and Followup of Neonates and Children with Cardiovascular Disease

children. J Thorac Cardiovasc Surg. May 2005;129(5):1084-1090. 34. Lequier L, Joffe AR, Robertson CM, et al. Two-year survival, mental, and motor outcomes after cardiac extracorporeal life support at less than five years of age. J Thorac Cardiovasc Surg. Oct 2008;136(4):976-983 e973. 35. Iguchi A, Ridout DA, Galan S, et al. Longterm survival outcomes and causes of late death in neonates, infants, and children treated with extracorporeal life support. Pediatr Crit Care Med. Jul 2013;14(6):580586. 36. Friedland-Little JM, Aiyagari R, Yu S, Donohue JE, Hirsch-Romano JC. Survival through staged palliation: fate of infants supported by extracorporeal membrane oxygenation after the Norwood operation. Ann Thorac Surg. Feb 2014;97(2):659-665. 37. Cengiz P, Seidel K, Rycus PT, Brogan TV, Roberts JS. Central nervous system complications during pediatric extracorporeal life support: incidence and risk factors. Crit Care Med. Dec 2005;33(12):2817-2824. 38. Barrett CS, Bratton SL, Salvin JW, Laussen PC, Rycus PT, Thiagarajan RR. Neurological injury after extracorporeal membrane oxygenation use to aid pediatric cardiopulmonary resuscitation. Pediatr Crit Care Med. Jul 2009;10(4):445-451. 39. Wagner K, Risnes I, Berntsen T, et al. Clinical and psychosocial follow-up study of children treated with extracorporeal membrane oxygenation. Ann Thorac Surg. Oct 2007;84(4):1349-1355. 40. Marino BS, Shera D, Wernovsky G, et al. The development of the pediatric cardiac quality of life inventory: a quality of life measure for children and adolescents with heart disease. Qual Life Res. May 2008;17(4):613-626. 41. Taylor AK, Cousins R, Butt WW. The long-term outcome of children managed with extracorporeal life support: an insti-

tutional experience. Crit Care Resusc. Jun 2007;9(2):172-177. 42. Chrysostomou C, Maul T, Callahan PM, et al. Neurodevelopmental Outcomes after Pediatric Cardiac ECMO Support. Frontiers in pediatrics. 2013;1:47. 43. Ryerson LM, Guerra GG, Joffe AR, et al. Survival and neurocognitive outcomes after cardiac extracorporeal life support in children less than 5 years of age: a tenyear cohort. Circulation. Heart failure. Mar 2015;8(2):312-321. 44. Costello JM, O’Brien M, Wypij D, et al. Quality of life of pediatric cardiac patients who previously required extracorporeal membrane oxygenation. Pediatr Crit Care Med. Nov 3 2011. 45. Wray J, Lunnon-Wood T, Smith L, et al. Perceived quality of life of children after successful bridging to heart transplantation. J Heart Lung Transplant. Apr 2012;31(4):381-386. 46. Garcia Guerra G, Robertson CM, Alton GY, et al. Health-related quality of life in pediatric cardiac extracorporeal life support survivors. Pediatr Crit Care Med. Oct 2014;15(8):720-727

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36 Adult Respiratory Diseases Predisposing to ECLS Hussein D. Kanji, MD, MSc, MPH, FRCPC, Juan J. Ronco, MD, FRCPC

Introduction

Initial Diagnostic and Management Approaches to Respiratory Disease

Over the course of three decades we have struggled to improve the outcome of patients Severe hypoxic respiratory failure has sigwith acute respiratory distress syndrome nificant mortality.1 Elucidating the etiology may (ARDS). Only recently we have begun to make require multiple data points, including history progress in the management of these complex and physical examination, to confirm the diagcases resulting in decreased mortality. The nosis and its chronicity. Whether the current principal paradigm related to the observed out- illness represents progression of an underlying come is to achieve lung rest and abate ongoing condition, an acute exacerbation of an existing inflammation and tissue damage after primary disease, or a novel acute respiratory ailment, the or secondary lung insult. In this context ECLS current illness will guide management decisions has resurfaced as perhaps the ultimate strategy and inform prognostication. Acute exacerbation to achieve this therapeutic goal. In addition, the may be caused by reversible infectious, environdecrease in iatrogenic lung injury, along with a mental, or inflammatory conditions. Therefore systematic improvement in the delivery of care early recognition and appropriate treatment is in ICU have played a major role in decreasing necessary. The history can provide important mortality, although it remains difficult to quan- diagnostic data such as an infectious prodrome, tify which components of care contribute most travel, purulent or bloody secretion, and conto the observed improved outcomes. Similar to stitutional symptoms. Assessment of the host the progress made in critical care, the iatrogenic immune status will inform consideration of complications of ECLS are better managed due opportunistic infections (see section on Immuto progress in cannulation techniques, circuits, nocompromised host). History should guide pumps, anticoagulation strategies, and efficient diagnostic testing and form the basis for the system delivery. While there are volumes of pretest probability for diagnostic evaluations. text characterizing ARDS, in this chapter we All patients with severe respiratory disease take a dynamic approach to respiratory condi- and impaired gas exchange should have a chest tions producing hypoxemic respiratory failure radiograph and CT scan,2 cultures (bacterial, to allow clinicians to diagnose and intervene fungal, and mycobacterial), and viral studies to rule out infectious causes. Management expeditiously. decisions should be based upon findings from 405

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these investigations. If a diagnostic conundrum still exists, the expected course deviates from predicted, or there is a paucity of diagnostic data, an open lung biopsy may be considered. These elements will be discussed in greater detail subsequently. Imaging and Acute Respiratory Distress Syndrome (ARDS) Radiography, computed tomography (CT), and ultrasonography have pivotal roles both in the diagnosis and management of ARDS, providing insight into the extension and severity of respiratory illnesses while functionally assessing the lung volume and response to recruitment interventions such as PEEP.3-6 In addition, CT has been instrumental to comprehend the pathophysiology of lung disease and abnormal gas exchange.7 For example, contrast CT of the chest demonstrating flow into consolidated lung provides visual inference to anatomical shunt or significant V/Q mismatch as well as impaired pulmonary hypoxic vasoconstriction (HPV). When obtaining chest CT in patients with ARDS the lung must be fully inflated to appreciate both the histological-architectural array features and the distribution of lung disease. This may occur with large pleural effusions, atelectasis, or inadequate recruitment maneuvers. In contrast to CT, chest radiography has low sensitivity and specificity for the diagnosis of ARDS.8 Sensitivity is lower for focal compared to diffuse disease distribution limiting the value of bedside radiography due to under recognition of this syndrome. Gas Exchange Hypoxemia is a defining feature of respiratory diseases, but the initial degree of hypoxemia is a poor predictor of outcome unless quite severe (PaO2/FiO2 20% hemosiderin laden macrophages) Cytology (lymphocyte predominance) Cytology, flow cytometry

Table 36-3. Mimickers of ARDS. Mimicker Acute exacerbation forms of usual interstitial pneumonitis (UIP) or nonspecific interstitial pneumonitis (NSIP) Vasculitides (including pulmonary renal syndromes) Alveolar hemorrhagic syndromes* Hypersensitivity pneumonitis Acute eosinophilic pneumonia Connective tissue diseases Malignancy (intravascular lymphoma, lymphangitis carcinomatosis) Acute interstitial pneumonitis (AIP) *Including alveolar filling with RBCs, without septal inflammation, resulting from anticoagulants, thrombolytic therapy, and/or thrombocytopenia (bland pulmonary hemorrhage). Not in order of frequency or importance.

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Open Lung Biopsy The pathology underlying the clinical and radiological presentation descriptive of ARDS results from diffuse parenchymal injury, which in turn invokes a stereotypic inflammatory response in the lungs followed by repair.39 Many factors contribute to lung injury, namely the acuity, severity, duration, and type of the injury will influence the cellular composition of the tissue response. Observed changes in histopathology depend greatly on biopsy timing relative to the onset of the insult. Inflammatory processes tend to overlap with regard to clinical, radiological, physiological, and histopathological features, adding to the complexity and heterogeneity in “defining” the syndrome. Acute lung injury (interstitial edema, intraalveolar fibrin and reactive type II cells) is the histopathological pattern associated with acute clinical lung disease.39 Several subtypes of acute lung injury are recognized histopathologically (diffuse alveolar damage [DAD], acute eosinophilic pneumonia, acute fibrinous and organizing pneumonia [OP], diffuse alveolar hemorrhage). When specific findings are incomplete (ie, no hyaline membranes), the generic term “acute lung injury” is appropriate. When intraalveolar hyaline membranes are present it is termed “diffuse alveolar damage (DAD).” DAD is a common histopathological pattern of injury in acute diffuse lung disease, particularly in ARDS patients and those who are immunosuppressed. Conditions associated with DAD include acute idiopathic interstitial pneumonia (AIP), infections, toxic inhalants and aspiration, drug reactions, shock, connective tissue diseases, acute radiation reactions, acute hypersensitivity pneumonitis, and alveolar hemorrhage. DAD can also occur in patients with idiopathic pulmonary fibrosis and other chronic ILDs, possibly as a natural component of the disease evolution and following an acute exacerbation. In addition to acute lung injury with hyaline membranes (DAD), the presence 410

of tissue necrosis, eosinophils, diffuse alveolar hemorrhage, and/or a background of fibrosis (acute on chronic fibrosis) point to a specific cause of the syndrome. An alveolar filling pattern where alveoli are filled with cells (immature fibroblasts, macrophages, neutrophils, and or siderophages) or noncellular proteinaceous material, points toward organizing pneumonia in any of the above settings for DAD. Though the standard definition of ARDS attempts to capture the pathological diagnosis of diffuse alveolar damage, both autopsy and open lung biopsy results demonstrate that the two are not synonymous. Specifically, DAD can have other causes such as connective tissue diseases that are not considered classic risk factors for ARDS.40 We have seen patients with ARDS in whom biopsies revealed minimal histopathological changes. Baring sampling error, this situation suggests a biopsy perfromed early in illness progression, and/or the presence of cardiogenic pulmonary edema. Clinical history and CT results should be reviewed for further insights into the diagnosis. In addition, the history of the illness leading to ARDS, patient immunological status, and high resolution chest CT provides gross anatomical-pathological information that combined with histopathology often aids diagnosis. We suggest that similar to the management of interstitial lung disease, an approach incorporating input from clinicians, thoracic surgeons, chest radiologists, and lung pathologist in the form of a multidisciplinary conference, should be conducted in each individualized case where an open lung biopsy is considered. The indication and optimal timing of open lung biopsy in respiratory conditions leading to hypoxic respiratory failure remains a source of controversy. Clinicians must weigh the risk of this intervention with the likelihood of diagnosis when BAL is noncontributory and/or reveals process(es) responsive to steroids or antiinflammatory therapy. Confronted with a lack of evidence-based guidelines, the intensivist

Adult Respiratory Diseases Predisposing to ECLS

must apply intelligent-based medicine instead and personalize the indication of an open lung biopsy on a case-by-case basis. The practice of blind steroid administration in the setting of ARDS is fraught with potential side effects including immunosuppression. Furthermore, without a tissue diagnosis the appropriate duration of therapy is unclear.41 Complications of open lung biopsy in nonresolving ARDS have been demonstrated to be quite low. Limited data describe complications of lung biopsy on ECLS.42 Evidence suggests that lung biopsies influence decisionmaking in the majority of cases of ARDS, and when contributory, significant associated survival benefit accrues.43,44 We recommend lung biopsy when the diagnosis remains unclear or the disease trajectory deviates from the presumed clinical course in the context of disease timing and radiographic findings. Summary Respiratory disease and acute hypoxic respiratory failure represent a voluminous topic and this chapter serves simply as an introduction. The approach to such patients must remain dynamic, concomitantly instituting investigation and management. Specifically, the objective must continue to abate iatrogenic injury, optimize oxygenation, and hemodynamics, whilst considering multiple etiologies, mimics, and host immune response. ECLS effectively improves oxygenation and allows “lung rest.” However, successful therapy is built upon recognition and treatment of the inciting insult. ECLS can provide the time for diagnosis, treatment, and recovery while minimizing further lung injury. In summary, a concise, goal oriented approach such as the one suggested herein, can serve as a roadmap for clinicians to achieve stabilization, elucidation of the pathology, and optimize individualized therapy.

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References 1. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA, 2012; 59: 2526-2533. 2. Goodman LR, Gattinoni L. Multidetector CT Evaluation of Acute Respiratory Distress Syndrome. Multidetector-Row CT of the Thorax; 2006:121-130. 3. Malbouisson LM, Muller JC, Constantin JM, Lu Q, Puybasset L, Rouby JJ. Computed Tomography Assessment of Positive End-expiratory Pressure-induced Alveolar Recruitment in Patients with Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med, 2001;163(6):1444-50 4. Chiumello D, Froio S, Bouhemad BD, Camporota L, Coppola S. Clinical review: Lung imaging in acute respiratory distress syndrome patients - an update. Crit Care. 2013; 17(6): 243 5. Rouby J-J, Puybasset L, Nieszkowska A, Lu Q. Acute respiratory distress syndrome: Lessons from computed tomography of the whole lung. Critical Care Med, 2003;31(Supplement):S285-S295. 6. Pesenti A, Tagliabue P, Patroniti N, Fumagalli R. Computerised tomography scan imaging in acute respiratory distress syndrome. Intensive Care Med. 2001;27(4):631-639. 7. Gattinoni L, Caironi P, Pelosi P, Goodman LR. What has computed tomography taught us about the acute respiratory distress syndrome? Am J Respir Crit Care Med. 2001;164(9):1701-1711. 8. Figueroa-Casas JB, Brunner N, Dwivedi AK, Ayyappan AP. Accuracy of the chest radiograph to identify bilateral pulmonary infiltrates consistent with the diagnosis of acute respiratory distress syndrome using computed tomography as reference standard. J Critical Care. 2013;28(4):352-357. 9. Villar J, Fernández RL, Ambrós A, et al. A Clinical Classification of the Acute Respi412

ratory Distress Syndrome for Predicting Outcome and Guiding Medical Therapy. Crit Care Med. November 2015;43(2):34653. 10. Villar JS, Kacmarek RM, P rez-M ndez L, Aguirre-Jaime A. A high positive endexpiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: A randomized, controlled trial. Crit Care Med. 2006;34(5):1311-1318. 11. Goligher EC, Kavanagh BP, Rubenfeld GD, et al. Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. A secondary analysis of the LOVS and ExPress trials. Am J Respir Crit Care Med. 2014;190(1):70-76. 12. Gattinoni L, Carlesso E, Brazzi L, Caironi P. Positive end-expiratory pressure. Current Opinion in Critical Care. 2010;16(1):39-44. 13. Vieillard-Baron A, Price LC, Matthay MA. Acute cor pulmonale in ARDS. Intensive Care Med. 2013;39(10):1836-1838. 14. Luecke T, Pelosi P. Clinical review: Positive end-expiratory pressure and cardiac output. Crit Care. 2005;9(6):607-621. 15. Mekontso Dessap A, Boissier F, Leon R, Carreira S, Campo FR, Lemaire F. Prevalence and prognosis of shunting across patent foramen ovale during acute respiratory distress syndrome. Crit Care Med. 2010;38(9):1786-1792. 16. Patroniti N, Isgrò S, Zanella A. Clinical management of severely hypoxemic patients. Current Opinion in Critical Care. 2011;17(1):50-56. 17. Ronco JJ, Belzberg A, Phang PT, Walley KR, Dodek PM, Russell JA. No differences in hemodynamics, ventricular function, and oxygen delivery in septic and nonseptic patients with the adult respiratory distress syndrome. Crit Care Med. 1994;22(5):777782.

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18. Vieillard-Baron A. Septic cardiomyopathy. Ann Intensive Care. 2011;1(1):6. 19. MacLaren G, Butt W, Best D, Donath S, Taylor A. Extracorporeal membrane oxygenation for refractory septic shock in children: One institutionʼs experience. Pedia Crit Care Med. 2007;8(5):447-451. 20. MacLaren G, Butt W, Best D, Donath S. Central extracorporeal membrane oxygenation for refractory pediatric septic shock. Pedia Crit Care Med. 2011;12(2):133-136. 21. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, et al. Comparison of two fluid-management strategies in acute lung injury. New Engl J Med. 2006;354(24):2564-2575. 22. Kanji HD, McCallum J, Sirounis D, MacRedmond R, Moss R, Boyd JH. Limited echocardiography-guided therapy in subacute shock is associated with change in management and improved outcomes. J Crit Care. 2014;29(5):700-705. 23. Sarkar S, Rasheed HF Clinical review: Respiratory failure in HIV-infected patients - a changing picture. Crit Care. 2013; 17:228. 24. Azoulay E, Schlemmer B. Diagnostic strategy in cancer patients with acute respiratory failure. Intensive Care Med. 2006;32(6):808-822. 25. Azoulay E, Mokart D, Pene F, Lambert J, Kouatchet A, Mayaux J et al. Outcomes of Critically Ill Patients With Hematologic Malignancies: Prospective Multicenter Data From France and Belgium--A Groupe de Recherche Respiratoire en Reanimation Onco-Hematologique Study. J Clin Onc. 2013;31(22):2810-2818. 26. Sanchez JF, Ghamande SA, Midturi JK, Arroliga AC. Invasive Diagnostic Strategies in Immunosuppressed Patients with Acute Respiratory Distress Syndrome. Clinics in Chest Medicine. 2014;35(4):697-712.

27. Shorr AF, Susla GM, O’Grady NP. Pulmonary infiltrates in the non-HIV-infected immunocompromised patient: etiologies, diagnostic strategies, and outcomes. Chest. 2004;125(1):260-271. 28. Harris B, Lowy FD, Stover DE, Arcasoy SM. Diagnostic Bronchoscopy in SolidOrgan and Hematopoietic Stem Cell Transplantation. Ann ATS. 2013;10(1):39-49. 29. Simon H. Invariants Of Human Behavior. Annual Review of Psychology. 1990;41(1):1-19. 30. Gibelin A, Parrot A, Maitre B, et al. Acute respiratory distress syndrome mimickers lacking common risk factors of the Berlin definition. Intensive Care Med. 2016;42(2):164-172. 31. Churg A, Müller NL, Silva CIS, Wright JL. Acute exacerbation (acute lung injury of unknown cause) in UIP and other forms of fibrotic interstitial pneumonias. Am J Surg Path. 2007;31(2):277-284. 32. Zafrani L, Lemiale V, Lapidus N, Lorillon G, Schlemmer B, Azoulay E. Acute Respiratory Failure in Critically Ill Patients with Interstitial Lung Disease. Assassi S, ed. PLoS ONE. 2014;9(8):e104897 33. Nizami IY, Kissner DG, Visscher DW, Dubaybo BA. Idiopathic bronchiolitis obliterans with organizing pneumonia. Chest. 1995;108(1):271-7. 34. Janz DR, O’Neal HR Jr, Ely EW. Acute eosinophilic pneumonia: A case report and review of the literature. Crit Care Med. 2009;37(4):1470-1474. 35. Mukhopadhyay S, Parambil J. Acute Interstitial Pneumonia (AIP): Relationship to Hamman-Rich Syndrome, Diffuse Alveolar Damage (DAD), and Acute Respiratory Distress Syndrome (ARDS). Semin Respir Crit Care Med. 2012;33(05):476-485. 36. Philit F, Etienne-Mastroïanni B, Parrot A, Guérin C, Robert D, Cordier J-F. Idiopathic Acute Eosinophilic Pneumonia. Am

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J Respir Crit Care Med. 2002;166(9):12351239. 37. Schwarz MI, Albert RK. “Imitators” of the ARDS: Implications for Diagnosis and Treatment. Chest. 2004;125(4):1530-1535. 38. Guérin C, Thompson T, Brower R. The ten diseases that look like ARDS. Inten Care Med. 2014;41(6):1099-1102.. 39. Leslie KO. My approach to interstitial lung disease using clinical, radiological and histopathological patterns. J Clin Path. 2009;62(5):387-401. 40. Palakshappa JA, Meyer NJ. Which Patients With ARDS Benefit From Lung Biopsy? Chest. 2015;148(4):1073-1082. 41. Donati SY, Papazian L. Role of open-lung biopsy in acute respiratory distress syndrome. Current Opinion in Critical Care. 2008;14(1):75-79. 42. Guérin C, Bayle F, Leray V, et al. Open lung biopsy in nonresolving ARDS frequently identifies diffuse alveolar damage regardless of the severity stage and may have implications for patient management. Intensive Care Med. 2014;41(2):222-230. 43. Papazian L, Doddoli C, Chetaille B, et al. A contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients. Crit Care Med. 2007;35(3):755-762. 44. Libby JL, Gelbman BD, Altroki NK, Christos PJ, Libby DM. Surgical Lung Biopsy in Adult Respiratory Distress Syndrome: A Meta-Analysis. Ann Thora Surg. 2014; 98(4):1254-60.

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37 Indications and Contraindications for ECLS in Adults with Respiratory Failure Lorenzo Del Sorbo, MD, Eddy Fan, MD, PhD

Introduction In 1972, the first successful application of extracorporeal life support (ECLS) in an adult with respiratory failure was reported.1 In this case, venoarterial extracorporeal membrane oxygenation (VA-ECMO) was initiated as a rescue measure in a 24-year old patient who developed trauma-related acute respiratory distress syndrome (ARDS) refractory to the conventional treatment of that era: tidal volume 1 liter, positive end-expiratory pressure (PEEP) 8 cmH2O, fraction of inspired oxygen (FiO2) 100%. After 75 hours, ECMO support was discontinued and the patient recovered. Today, with the exception of clinical trials, ECLS is still considered in patients with respiratory failure as a potential rescue intervention.2 Both remarkable improvements in technology3 and several clinical investigations4 have contributed to the diffusion of ECLS in different contexts and with different indications.5-8 While large randomized controlled trials demonstrating the efficacy of ECLS in improving patientimportant outcomes are lacking,9 the decision to use ECLS is typically based on the balance of potential risks and benefits in each individual case.2 However, the principles guiding the selection of candidates with respiratory failure for ECLS include: 1) a high risk of death despite optimization of conventional treatment; 2) the

diagnosis of a potentially reversible disease; and 3) the absence of contraindications.2,7,10-12 With these principles in mind, we will discuss the criteria used by experienced ECLS centers to optimize benefits and minimize risks of ECLS in patients with respiratory failure. ECLS Considerations in Patients with High Risk of Death Despite Optimization of Conventional Management Mechanical ventilation (MV), the standard therapy to support gas exchange and improve survival in patients with respiratory failure, may not suffice in the worst cases or may potentiate and worsen lung injury (ventilator-induced lung injury [VILI]) by producing induces alveolar overdistension and cyclic tidal recruitment.13,14 The most severe patients experience increased mortality.13,14 In patients with respiratory failure, ECLS is a support mode based on solid physiological rationale. ECLS effectively maintains adequate gas exchange, replacing the respiratory function through an artificial lung, thereby unloading the respiratory system, allowing recovery.3,4,8,10,15 However, ECLS carries significant risks and evidence-based thresholds to guide initiation of ECLS have not been established. Therefore, outside of clinical trials, it is typically considered as rescue treatment only when patients are at high 415

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risk of death despite conventional therapy.2,16 Since the main goal of ECLS in patients with respiratory failure is to improve ventilation and oxygenation, it can be utilized with the following major objectives (Figure 37-1): 1) as rescue from refractory hypoxemia; 2) as rescue from refractory hypercapnia; or 3) as rescue from injurious mechanical ventilation. ECLS for Rescue from Refractory Hypoxemia Common causes of respiratory failure with refractory hypoxemia requiring ECLS include acute respiratory distress syndrome (ARDS), primary graft dysfunction following lung transplantation, acute pulmonary embolism, acute eosinophilic pneumonia, alveolar hemorrhage, and large bronchopleural fistula. Among these causes, ARDS has been the focus of most studies in ECLS in patients with respiratory failure. High extracorporeal blood flow is crucial in achieving oxygenation during ECLS, venovenous ECMO (VV-ECMO) is the configuration most often applied in patients with refractory

hypoxemia. If vasodilatory shock complicates respiratory failure, VV-ECMO might remain the mode of choice while vasopressors would be administrated to manage low systemic vascular resistance (see Chapter 56). In addition, with right ventricular dysfunction secondary to respiratory failure, function may improve with the rapid reversal of hypoxemic vasoconstriction with VV-ECMO. However, if concomitant left ventricular or biventricular failure complicates respiratory failure resulting in end organ hypoperfusion, VA-ECMO, or a hybrid configuration (eg, venoarterial-venous ECMO (VAV-ECMO) would be more appropriate (Figure 37-1). Ideally, ECLS for refractory hypoxemia should be initiated in patients, whose predicted hypoxemia-related morbidity and mortality outweigh the risk of ECLS-related complications. Early referral for ECLS is crucial, allowing for proper assessment and timely cannulation of the patient. However, there is a paucity of data and the exact timing remains unclear.9 In particular, none of the three randomized clinical trials convincingly demonstrated the efficacy of the

Figure 37-1. Scheme of possible configurations based on the main pathophysiological indications for ECLS.

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Indications and Contraindications for ECLS in Adults with Respiratory Failure

routine application of ECLS in patients with ARDS as compared to conventional therapy.17-19 Therefore, several professional organizations have released different recommendations characterized by distinctive definition of refractory hypoxemia and thresholds for ECLS initiation (Table 37-1). In the Extracorporeal Life Support Organization (ELSO) guidelines,2 ECLS is indicated in patients with a mortality risk >80%, identified by a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) 90% and a Murray score of 3-4. However, ECLS could also be considered in less severely ill hypoxemic pa-

tients with a mortality risk >50%, identified by a PaO2:FiO2 90% and a Murray score of 2-3 (Figure 37-2).20 In the Conventional ventilatory support versus Extracorporeal membrane oxygenation for Severe Adult Respiratory failure (CESAR) randomized controlled trial,17 eligibility criteria included severe but potentially reversible respiratory failure, a Murray score ≥3.0, or uncompensated hypercapnia with a pH 80%: -P/F < 80 with FiO2 > 0.90 -Murray score of 3-4

-OI > 30 -P/F < 70 with PEEP ≥ 15 cmH2O for patients in an ECMO center -pH < 7.25 X > 2 hrs -Hemodynamic instability

-Potentially reversible respiratory failure -Murray Score ≥ 3.0 -pH < 7.20 despite optimum conventional treatment

EOLIA NCT01470703 -P/F < 50 with FiO2 >0.8 X >3 hrs, -P/F 0.8 for >6 hrs, -pH6 hrs (RR increased to 35/min) with MV settings adjusted to keep Pplat P/F < 100 with PEEP ≥ Murray score ≥2.5 50%: 10 cmH2O for patients -P/F < 150 with awaiting transfer to an FiO2 > 0.90 ECMO center -Murray score of 2-3 -Intracranial bleeding -Peak inspiratory -MV ≥ 7 days Contraindications to -Conditions incompatible with -Other contraindication pressure >30 cmH2O -Age < 18 years ECMO normal life to anticoagulation -FiO2 >0.8 -Pregnancy -Preexisting -Previous severe -BMI > 45 kg/m² -Ventilation for > 7 conditions affecting disability -Chronic respiratory days quality of life (CNS -Poor prognosis of -Intracranial bleeding insufficiency treated with status, end stage underlying disease long duration oxygen or -Contraindication to malignancy, risk of -Mechanical ventilation anticoagulation respiratory assistance systemic bleeding > 7 days. -Previous history of HIT -Contraindication to with -Malignancy with fatal continuation of anticoagulation) prognosis within 5 years active treatment -Age -Patient moribund -SAPS II > 90 -Futility: patients -Non drug-induced coma who are too sick following cardiac arrest (e.g., -Irreversible neurological immunosuppression) pathology , have been on -ECMO cannulation not conventional therapy possible too long (MV >7 days) BMI=body mass index; Cesar=Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure; CNS=central nervous system; ECMOnet=Italian ECMO network; EOLIA=Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome; HFO=high frequency oscillation; MV=mechanical ventilation; NO=nitric oxide; PaO2/FiO2: arterial partial pressure of oxygen to fraction of inspired oxygen ratio; PEEP=positive end expiratory pressure; RR=respiratory rate Consideration for ECMO

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According to the Italian ECMO network (ECMOnet),21 indications for ECMO in ARDS patients with suspected H1N1 infection comprised one of the following: oxygenation index (FiO 2:PaO 2 x mean airway pressure) >30; PaO2:FiO2 55 mmHg and pH 0.8, pre-ECMO MV >7 days, intracranial bleeding, contraindication to limited anticoagulation, and contraindication to continuation of active treatment.17 Moreover, in the ongoing EOLIA trial, the following exclusion criteria have been established: pre-ECMO MV >7 days; weight greater than 1 kg/cm; body mass index greater than 45 422

kg/m²; chronic respiratory insufficiency treated with oxygen therapy of long duration and/ or long-term respiratory assistance; previous history of heparin-induced thrombocytopenia (HIT); malignancy with fatal prognosis within 5 years; moribund patient; SAPS II greater than 90; non drug-induced coma following cardiac arrest; irreversible CNS pathology; decision to limit therapeutic interventions; lack of vascular access. The lack of adequate vascular access may not be acknowledged as a contraindication, but needs to be carefully evaluated, being a critical limitation to the ECLS feasibility and efficacy.4 Investigators have tried to identify clinical parameters independently associated with a poor prognosis for ECLS patients with refractory respiratory failure, primarily ARDS.49-52 Although these investigations do not address the issue of the identifying contraindications to ECLS, they may help in decision making to define risks and benefits of extracorporeal respiratory support. The largest of these investigations examined 2355 adult patients from the ELSO Registry with acute respiratory failure supported with ECLS.52 Factors present at ECLS institution including older age, cardiac arrest before ECLS, CNS dysfunction, renal dysfunction immunocompromised status, associated nonpulmonary infection, iNO use, bicarbonate infusion, longer duration of pre-ECLS MV, higher PaCO2, and higher PIP were independent risk factors associated with hospital mortality. Bacterial pneumonia, viral pneumonia, aspiration pneumonia, asthma, trauma and burn, and the use of neuromuscular blocking agents were protective factors. Finally, recent expert opinion reported the most common clinical situations where ECLS application is unlikely to be successful.37 Among these, it is worth highlighting two important issues. The first includes ECLS volume, as centers with high ECLS volumes demonstrate lower mortality.35, 54 The second is the diagnosis of refractory septic shock with

Indications and Contraindications for ECLS in Adults with Respiratory Failure

preserved cardiac function (see Chapter 56). In this setting, even ECLS at high flow may insufficient to reestablish adequate oxygen delivery and match the high metabolic demand due to increased cardiac output. In a recent series of 32 patients treated with ECLS for refractory septic shock, the hospital mortality rate reached 78%. Interestingly, the presence of severe myocardial injury based on elevated troponin was associated with a lower risk of hospital mortality.55 Data support the application of VA-ECMO in patients with severe septic-induced cardiogenic shock refractory to high doses of vasopressors.56 However, more robust evidence is needed to define the role of ECLS in septic patients. Conclusions Despite the lack of evidence-based criteria, ECLS application in patients with respiratory failure is expanding due to the increasing simplicity and safety of its management. However, since ECLS remains complex, high risk, and resource intensive, it should be used in centers with sufficient experience and expertise. Additionally, rigorous clinical trials are needed to further define the indications and contraindications of this technology.

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References 1. Hill JD, O’Brien TG, Murray JJ, et al. Prolonged extracorporeal oxygenation for acute post-traumatic respiratory failure (shock-lung syndrome). Use of the Bramson membrane lung. N Engl J Med. 1972;286:629-634. 2. (ELSO) ELSO. Extracorporeal Life Support Organization (ELSO) Guidelines for Adult Respiratory Failure. 2013. 3. MacLaren G, Combes A, Bartlett RH. Contemporary extracorporeal membrane oxygenation for adult respiratory failure: life support in the new era. Intensive Care Med. 2012;38:210-220. 4. Del Sorbo L, Cypel M, Fan E. Extracorporeal life support for adults with severe acute respiratory failure. Lancet Respir Med. 2014;2:154-164. 5. Paden ML, Conrad SA, Rycus PT, et al. Extracorporeal Life Support Organization Registry Report 2012. ASAIO J. 2013;59:202-210. 6. Abrams D, Brodie D. Emerging indications for extracorporeal membrane oxygenation in adults with respiratory failure. Ann Am Thorac Soc. 2013;10:371-377. 7. Agerstrand CL, Bacchetta MD, Brodie D. ECMO for adult respiratory failure: current use and evolving applications. ASAIO J. 2014;60:255-262. 8. Abrams D, Combes A, Brodie D. Extracorporeal membrane oxygenation in cardiopulmonary disease in adults. J Am Coll Cardiol. 2014;63:2769-2778. 9. Munshi L, Telesnicki T, Walkey A, et al. Extracorporeal life support for acute respiratory failure. A systematic review and metaanalysis. Ann Am Thorac Soc. 2014;11:802-810. 10. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med. 2011;365:1905-1914.

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11. Sidebotham D, McGeorge A, McGuinness S, et al. Extracorporeal membrane oxygenation for treating severe cardiac and respiratory disease in adults: Part 1--overview of extracorporeal membrane oxygenation. J Cardiothorac Vasc Anesth. 2009;23:886892. 12. Richard C, Argaud L, Blet A, et al. Extracorporeal life support for patients with acute respiratory distress syndrome: report of a Consensus Conference. Ann Intensive Care. 2014;4:15. 13. O’Gara B, Fan E, Talmor DS. Controversies in the Management of Severe ARDS: Optimal Ventilator Management and Use of Rescue Therapies. Semin Respir Crit Care Med. 2015;36:823-834. 14. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. 2013;369:21262136. 15. Gattinoni L, Carlesso E, Langer T. Clinical review: Extracorporeal membrane oxygenation. Crit Care. 2011;15:243. 16. (ELSO) ELSO. Extracorporeal Life Support Organization (ELSO) General Guidelines for all ECLS Cases. 2013. 17. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374:1351-1363. 18. Morris AH, Wallace CJ, Menlove RL, et al. Randomized clinical trial of pressurecontrolled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med. 1994;149:295-305. 19. Zapol WM, Snider MT, Hill JD, et al. Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA. 1979;242:21932196.

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20. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis. 1988;138:720–723. 21. Patroniti N, Zangrillo A, Pappalardo F, et al. The Italian ECMO network experience during the 2009 influenza A(H1N1) pandemic: preparation for severe respiratory emergency outbreaks. Intensive Care Med. 2011;37:1447-1457. 22. Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet. 2004;364:709-721. 23. McFadden ER, Jr. Acute severe asthma. Am J Respir Crit Care Med. 2003;168:740-759. 24. Laghi F, Goyal A. Auto-PEEP in respiratory failure. Minerva Anestesiol. 2012;78:201221. 25. Crotti S, Lissoni A, Tubiolo D, et al. Artificial lung as an alternative to mechanical ventilation in COPD exacerbation. Eur Respir J. 2012;39:212-215. 26. Lund LW, Federspiel WJ. Removing extra CO2 in COPD patients. Curr Respir Care Rep. 2013;2:131-138. 27. Lindenauer PK, Stefan MS, Shieh MS, et al. Outcomes associated with invasive and noninvasive ventilation among patients hospitalized with exacerbations of chronic obstructive pulmonary disease. JAMA Intern Med. 2014;174:1982-1993. 28. Del Sorbo L, Pisani L, Filippini C, et al. Extracorporeal CO2 removal in hypercapnic patients at risk of noninvasive ventilation failure: a matched cohort study with historical control. Crit Care Med 2015;43:120-127. 29. Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372:747-755. 30. Terragni PP, Rosboch G, Tealdi A, et al. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2007;175:160-166.

31. Gattinoni L, Pesenti A, Mascheroni D, et al. Low-frequency positive-pressure ventilation with extracorporeal CO2 removal in severe acute respiratory failure. JAMA. 1986;256:881-886. 32. Cove ME, MacLaren G, Federspiel WJ, et al. Bench to bedside review: Extracorporeal carbon dioxide removal, past present and future. Crit Care. 2012;16:232. 33. Fitzgerald M, Millar J, Blackwood B, et al. Extracorporeal carbon dioxide removal for patients with acute respiratory failure secondary to the acute respiratory distress syndrome: a systematic review. Crit Care. 2014;18(3):222. 34. Bein T, Weber-Carstens S, Goldmann A, et al. Lower tidal volume strategy ( approximately 3 ml/kg) combined with extracorporeal CO2 removal versus ‘conventional’ protective ventilation (6 ml/kg) in severe ARDS : The prospective randomized Xtravent-study. Intensive Care Med. 2013;39(5):847-856. 35. Combes A, Brodie D, Bartlett R, et al. Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients. Am J Respir Crit Care Med. 2014;190:488496. 36. Ventetuolo CE, Muratore CS. Extracorporeal life support in critically ill adults. Am J Respir Crit Care Med. 2014;190:497-508. 37. Schmidt M, Brechot N, Combes A. Ten situations in which ECMO is unlikely to be successful. Intensive Care Med. 2016;42(5):750-752. 38. Cypel M, Keshavjee S. Extracorporeal life support as a bridge to lung transplantation. Clin Chest Med. 2011;32:245-251. 39. Chiumello D, Coppola S, Froio S, Colombo A Del Sorbo L. Extracorporeal life support as bridge to lung transplantation: a systematic review. Crit Care. 2015;19:19.

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40. Strueber M. Bridges to lung transplantation. Curr Opin Organ Transplant 2011;16:458461. 41. Diaz-Guzman E, Hoopes CW, Zwischenberger JB. The evolution of extracorporeal life support as a bridge to lung transplantation. ASAIO J. 2013;59:3-10. 42. Wang CH, Chou CC, Ko WJ, et al. Rescue a drowning patient by prolonged extracorporeal membrane oxygenation support for 117 days. Am J Emerg Med. 2010;28(6):750 e5-7. 43. Mauri T, Foti G, Zanella A, et al. Long-term extracorporeal membrane oxygenation with minimal ventilatory support: a new paradigm for severe ARDS? Minerva Anestesiol. 2012;78(3):385-389. 44. Akkanti B, Hussain R, Nathan S, et al. Prolonged Veno-Venous Extracorporeal Membrane Oxygenation in a Patient with Acute Respiratory Distress Syndrome. ASAIO J. 2016;62(2):e13-14. 45. Arlt M, Philipp A, Voelkel S, et al. Extracorporeal membrane oxygenation in severe trauma patients with bleeding shock. Resuscitation. 2010;81:804-809. 46. Wu SC, Chen WT, Lin HH, et al. Use of extracorporeal membrane oxygenation in severe traumatic lung injury with respiratory failure. Am J Emerg Med. 2015;33:658-662. 47. Abrams D, Agerstrand CL, Biscotti M, et al. Extracorporeal membrane oxygenation in the management of diffuse alveolar hemorrhage. ASAIO J. 2015;61:216-218. 48. Sharma NS, Wille KM, Bellot SC, et al. Modern use of extracorporeal life support in pregnancy and postpartum. ASAIO J. 2015;61:110-114. 49. Hwang GJ, Sheen SH, Kim HS, et al. Extracorporeal membrane oxygenation for acute life-threatening neurogenic pulmonary edema following rupture of an intracranial aneurysm. J Korean Med Sci 2013;28:962964.

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50. Chiu LC, Tsai FC, Hu HC, et al. Survival predictors in acute respiratory distress syndrome with extracorporeal membrane oxygenation. Ann Thorac Surg. 2015;99:24350. 51. Pappalardo F, Pieri M, Greco T, et al. Predicting mortality risk in patients undergoing venovenous ECMO for ARDS due to influenza A (H1N1) pneumonia: the ECMOnet score. Intensive Care Med. 2013;39(2):275281. 52. Schmidt M, Zogheib E, Roze H, et al. The PRESERVE mortality risk score and analysis of long-term outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. Intensive Care Med. 2013;39:1704-1713. 53. Schmidt M, Bailey M, Sheldrake J, et al. Predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score. Am J Respir Crit Care Med. 2014;189:1374-1382. 54. Barbaro RP, Odetola FO, Kidwell KM, et al. Association of hospital-level volume of extracorporeal membrane oxygenation cases and mortality. Analysis of the extracorporeal life support organization registry. Am J Respir Crit Care Med. 2015;191:894901. 55. Park TK, Yang JH, Jeon K, et al. Extracorporeal membrane oxygenation for refractory septic shock in adults. Eur J Cardiothorac Surg. 2015;47:e68-74. 56. Brechot N, Luyt CE, Schmidt M, et al. Venoarterial extracorporeal membrane oxygenation support for refractory cardiovascular dysfunction during severe bacterial septic shock. Crit Care Med. 2013;41:161626. 57. Gattinoni L, Agostoni A, Pesenti A, et al. Treatment of acute respiratory failure with low-frequency positive-pressure ventilation

Indications and Contraindications for ECLS in Adults with Respiratory Failure

and extracorporeal removal of CO2. Lancet. 1980;2(8189):292-294. 58. Zimmermann M, Bein T, Arlt M, et al. Pumpless extracorporeal interventional lung assist in patients with acute respiratory distress syndrome: a prospective pilot study. Crit Care. 2009;13(1):R10. 59. Terragni PP, Del Sorbo L, Mascia L, et al. Tidal volume lower than 6 ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal. Anesthesiology. 2009;111(4):826-835. 60. MacDonnell KF, Moon HS, Sekar TS, Ahluwalia MP. Extracorporeal membrane oxygenator support in a case of severe status asthmaticus. Ann Thorac Surg. 1981;31(2):171-175. 61. Hebbar KB, Petrillo-Albarano T, CotoPuckett W, Heard M, Rycus PT, Fortenberry. Experience with use of extracorporeal life support for severe refractory status asthmaticus in children. Crit Care. 2009;13(2):R29. 62. Mikkelsen ME, Woo YJ, Sager JS, et al. Outcomes using extracorporeal life support for adult respiratory failure due to status asthmaticus. ASAIO J. 2009;55:47-52. 63. Brenner K, Abrams DC, Agerstrand CL, et al. Extracorporeal carbon dioxide removal for refractory status asthmaticus: experience in distinct exacerbation phenotypes. Perfusion. 2014;29:26-28. 64. Pesenti A, Rossi GP, Pelosi P, et al. Percutaneous extracorporeal CO2 removal in a patient with bullous emphysema with recurrent bilateral pneumothoraces and respiratory failure. Anesthesiology. 1990;72:571573. 65. Abrams DC, Brenner K, Burkart KM, et al. Pilot study of extracorporeal carbon dioxide removal to facilitate extubation and ambulation in exacerbations of chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2013;10:307-314. 66. Burki NK, Mani RK, Herth FJ, et al. A novel extracorporeal CO(2) removal sys-

tem: results of a pilot study of hypercapnic respiratory failure in patients with COPD. Chest. 2013;143:678-686. 67. Karagiannidis C, Strassmann S, Philipp A, et al. Venovenous extracorporeal CO2 removal improves pulmonary hypertension in acute exacerbation of severe COPD. Intensive Care Med. 2015;41:1509-1510.

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38 ECLS Cannulation for Adults with Respiratory Failure William Lynch, MD

Introduction

dual lumen cannula placed with fluoroscopy guidance. This single site cannulation strategy This chapter focuses on issues related to makes ambulatory ECLS possible and practical. cannulating an adult in respiratory failure for VA-ECLS in adults typically requires femoral VV-ECLS. Cannulation techniques (percuta- artery cannulation with venous drainage being neous, open, semi-open), preferred routes of from the femoral vein, right internal jugular vein, access (arterial and venous, venous only, single or both. Femoral artery cannulation commonly site cannulation, multiple sites) and cannula requires distal arterial reperfusion to protect the selection are described. Primary respiratory leg from ischemia. The axillary artery is also failure (pneumonia, aspiration) and secondary an option with the advantage of keeping canrespiratory failure (trauma, postoperative) are nulas out of the groin, again making ambulation considered together as either hypoxic respirato- practical and safe. Axillary artery cannulation ry failure or pure hypercarbic respiratory failure. requires open surgical technique. Arterial canA section is dedicated to respiratory failure in nulation of the femoral arteries can be done the setting of severe sepsis. This chapter mirrors percutaneously but often is done with open the outline of the ELSO Guidelines for Adult surgical technique. Decannulation of arteries Respiratory Failure.1 commonly requires surgical repair of the artery. Respiratory failure can produce hypoxia, Femoral artery and/or vein cannulation makes hypercarbia, or a combination of the two. ECLS ambulation impractical and arguably unsafe. for hypoxic failure requires flows similar to Consider the following scenario describnative cardiac output, sometimes referred to ing an adult with ARDS. Hypoxic respiratory as “high flow” ECLS, while support for hyper- failure is initially supported with mechanical carbia requires flows of about 10-20% of the ventilation. As support is escalated, uncomfortcardiac output, or relatively “low flow” ECLS. able modes of ventilation are used and sedation Hypoxia is typically supported with VV-ECLS is necessary. Patients commonly require volume when cardiac function is adequate. If cardiac resuscitation and sometimes paralysis. Vasoacfunction is compromised, VA-ECLS providing tive infusions are added to maintain adequate biventricular support and pulmonary support, is cardiac output. Sometimes permissive hyperan option. VV-ECLS can be offered with single capnia is allowed. The patient remains hypoxic site cannulation. This typically is right internal and hypercarbic. As a consequence, pulmonary jugular, percutaneous cannulation, using bicaval vascular resistance is high and the right ventricle 429

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struggles. High intrathoracic pressures, second- VV-ECLS does not offer cardiac support, it may ary to the ventilator, diminish cardiac return and reverse many of the disturbed hemodynamics further disturb hemodynamics. that are a consequence of hypoxia and hyperThis patient is now hemodynamically un- carbia, as well as mechanical ventilation which stable with marginally supported hypoxic and causes increased intrathoracic pressure and hypercarbic respiratory failure. What do you do associated need for sedation. next? The ECLS strategy you choose is based on the pathophysiology of the disease threaten- Cannulation Decision Making for Adult ing the patient. Is this just hypoxia? If so, “high Respiratory Failure flow” VV-ECLS may be indicated. Does the patient suffer primarily from hypercarbia? In Respiratory failure is multifactorial. The this case, “low flow” VV-ECLS only may be clinical picture will be your guide in making required. Could this be sepsis, in which case decisions about mode of support, size of canVA-ECLS potentially requiring very high flows nulas, and anatomic placement of the cannulas. may be needed. Is this a pulmonary embolus Decisionmaking begins with recognizing the necessitating use of VA-ECLS? Essentially you pathophysiology of the disease and then choosare trying to decide if this patient has sufficient ing the appropriate mode of ECLS. These are cardiac function to be supported with VV-ECLS, the real decisions and once made, cannula type, realizing that VV-ECLS will not directly sup- size, and site of insertion is determined. Then port cardiac function. For this particular patient, cannulating is a technical exercise and ECLS the ECHO shows a dilated RV and inotropic and initiation is only logistics.2-5 vasopressor infusions are needed to support a Patient conditions that will drive cannulamarginal blood pressure. This hemodynamically tion decisionmaking are described below. fragile patient seems to require VA-ECLS. This patient, while critical and questionably Hemodynamically Supportable Respiratory unstable, tolerates a move to the operating room Failure where fluoroscopy is used to guide placement of a bicaval cannula via the right internal jugular VV-ECLS is the preferred mode of extravein. VV-ECLS is initiated. Bright red oxygen- corporeal support, for adult respiratory failure ated blood is instilled into the right ventricle and when cardiac function is adequate or moderately is ejected through the pulmonary vasculature. depressed. A typical patient will be on signifiThe pulmonary hypoxic vasoconstriction is cant ventilator support; 80-100% FiO2; 10-20 reversed; the pulmonary vasculature relaxes; cmH2O PEEP; peak airway pressure of 30-40 right ventricular strain is relieved and hemody- cmH20; respiratory rate of up to 40 breaths per namics improves. Systemic oxygenation climbs. minute. Sedation is necessary, perhaps even Coronaries deliver blood with increased oxygen paralytics. Some vasoactive infusions might be capacity to struggling myocytes. Ventricular used to augment cardiac output and maintain function responds and hemodynamics further blood pressure. If the patient seems stable, VVimprove. Oxygen delivery and CO2 clearance ECLS support is an appropriate place to start. are accomplished by VV-ECLS and dependence Ideally, a dual lumen cannula should be placed on mechanical ventilation wanes. Ventilation in the right internal jugular but this requires pressure and rate can be lowered, decreasing transporting the patient to a room capable of intrathoracic pressure, allowing cardiac venous fluoroscopy. Transporting these patients can be return to rise. All of this results in improved he- challenging and often times the safest strategy is modynamic function. In this example, although to travel using the ICU ventilator. Transitioning 430

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to a transport ventilator can interrupt the airway, release the PEEP, de-recruit the lung and result in an unrecoverable condition. Clamping the endotracheal tube is wise when making any break in the circuit. Echocardiography guidance is acceptable for placing the dual lumen cannula, however critical aspects of cannulae positioning can be missed by echo.6-9 Real time fluoroscopy allows visualizing the wire and the entire length of the cannula during cannulation. Even with the wire appropriately positioned below the diaphragm in the inferior vena cava, the cannula can still enter the right ventricle, the coronary sinus, or the hepatic veins. Any of these cannulation misadventures can be unrecognized on echo, leading to an unrecoverable complication. If the patient is stable enough to move, it is advantageous to go to a fluoroscopic capable suite for dual lumen cannula placement. A fluoroscopy capable operating room offers advantages if it becomes necessary to convert to an open surgical cannulation. Otherwise, a catheterization lab or interventional radiology suite will be adequate. Those new to cannulating should only use fluoroscopy when placing the current generation of adult dual lumen VV cannulas.10 Figures 38-1 and 38-2 show a chest x-ray of a patient after placement of the bicaval cannula.

Figure 38-1. Chest x-ray after placement of 31 Fr Avalon Elite dual lumen bi-caval cannula

Unstable Respiratory Failure with Supportable Hemodynamics Some respiratory failure patients are precarious and unstable. Some patients are so fragile that they will not tolerate changes in bed positioning. These patients cannot be safely transported to a fluoroscopy suite, so a bedside cannulation is indicated. If VV-ECLS is the indicated mode, two-site VV-ECLS cannulation is the safest option. In this clinical scenario, it can be more challenging to attempt a bedside echocardiography guided dual lumen cannula. The typical strategy would include the right internal jugular vein and one or both femoral veins. Echocardiography is helpful to position long cannulas placed in the femoral veins, designed to have the tip near the right atrium.

Figure 38-2. Anatomical landmarks labeled. 31 French Avalon Elite bi-caval cannula. The cannula is straight and the tip is below the diaphragm. If the tip bowed to the left or the right, there would be concern for placement into a hepatic vein. The reinfusion port is 10 cm proximal to the tip and is where the cannula tapers. The SVC drainage is about 14.5 cm; about 4.5 cm from the taper. This adult is 5’9” (175 cm). The carina is at the level of the 6th thoracic vertebral body (T6). The tricuspid valve should be level with the 8th thoracic vertebral body (T8). This cannula is designed to have reinfusion jet directed towards, and across, the tricuspid valve.

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Venous drainage from the femoral cannula with return to the internal jugular vein cannula is the most common technique. Successful support can also be offered with venous drainage from the internal jugular vein as well, returning oxygenated blood to the femoral cannula.11 Figures 38-3 and 38-4 show a chest x-ray of a patient with two venous cannulas. Unstable Respiratory Failure with Unstable Hemodynamics In this presentation, it will be important to decide if the clinical status is due to isolated respiratory failure, sepsis, a pulmonary embolus, perhaps there is a tension pneumothorax. Respiratory failure that has progressed to hemodynamic instability and malperfusion is unlikely to be isolated respiratory failure. If it is, perhaps the decision to move to ECLS has taken too long. Ideally, the initiation of ECLS for isolated respiratory failure should never be an emergency. VA-ECLS is the indicated mode when significant hemodynamic support is required. The

Figure 38-3. Venovenous ECLS using two cannulas. A 23 Fr long drainage cannula is placed in the right femoral vein. A short 21 Fr cannula is placed in the right internal jugular vein.

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most common approach is the femoral artery and vein. The internal jugular vein is also an acceptable site for venous drainage. Femoral arterial cannulas can cause lower extremity malperfusion, by obstructing distal arterial perfusion, causing ischemia, compartment syndrome, and loss of leg. Distal perfusion can be supported by placing an 8-12 Fr cannula in the femoral artery, and directing flow in an antegrade fashion to the leg. An alternative approach can be retrograde perfusion of the leg, accomplished by placing a 4-8 Fr cannula in the posterior tibial artery.12 Flow of 100-150 cc/min is sufficient to perfuse the leg. Hypercarbia without Hypoxia Hypercarbia is a consequence of under ventilation and is more frequently being managed with extracorporeal techniques. Clearance of CO2 can be efficiently and quickly achieved with extracorporeal techniques, requiring about 25% of blood flow necessary for VV-ECLS used to support hypoxia. There are two approaches. One is venovenous, using a dual lumen cannula,

Figure 38-4. The long venous drainage cannula has the tip in the hepatic cava, near the atrial caval junction. The reinfusion cannula is near the confluence of the right internal jugular vein, the innominate vein and the right atrium.

ECLS Cannulation for Adults with Respiratory Failure

a pump and a membrane gas exchange device. The other approach is utilizing an arteriovenous shunt, a pair of cannulas and a membrane gas exchange device. This is commonly referred to AVCO2R removal. Groin vessels are most commonly used and awake ambulation is impractical.13 Respiratory Failure and Sepsis Hypoxia, hypercarbia, metabolic and/ or mixed acidosis, hypotension, and cardiac dysfunction are seen in sepsis. VA-ECLS can offer gas exchange, biventricular support and augment blood pressure. VA-ECLS for malperfusion in sepsis seems rationale, but remains controversial, as it is not always certain if improving tissue perfusion is always possible. VA-ECLS has been reported as effective in children and continues to appear in the literature related to adult sepsis.14-16 Sepsis physiology represents a spectrum and there is little guidance to help identify generalizable indications and contraindications. Large studies would help guide clinical thinking; however, studies of this nature are impractical and not on the horizon. VA-ECLS for severe refractory sepsis is a complicated undertaking and should be considered by experienced ECLS programs.17-20 Technical Aspects of Cannulation for Adult Respiratory Failure The decision to cannulate has been made. The necessary mode is based on the patient’s pathophysiology. Technical considerations of the various modes are described below. VV-ECLS Cannulation-Single Site, Dual Lumen Dual lumen cannulation via the right internal jugular vein, guided with fluoroscopy, is preferred. The Avalon Elite® dual lumen bicaval cannula is currently available and in four sizes

appropriate for adult support (20 Fr, 23 Fr, 27 Fr, 31 Fr). These larger diameter cannulas are the same length, 31 cm, and offer flows limited by the diameter. Most adults have a right internal jugular vein large enough to accommodate the 27 Fr and 31 Fr sizes. ECLS flow will always be limited by venous drainage, when the cannula is appropriately positioned. Percutaneous Seldinger technique should be the primary approach. The Avalon Elite has a separate dilator and wire kit appropriate for these 31 cm length cannulas. The wire is 210 cm and is relatively flimsy. Stiffer wires of the same length can be helpful and these are available in most fluoroscopy suites. Ultrasound should be used to identify the internal jugular and initiate access. The jugular diameter can be measured, helping to choose ideal cannulae size. Fluoroscopy is used to assure wire placement is in the hepatic cava, as opposed to the right ventricle, coronary sinus, or hepatic veins. Fluoroscopy is used as dilations take place and as the cannula is inserted. While the wire might be in the appropriate position, the stiffer cannula can still pass into the ventricle, coronary sinus, and hepatic veins, carrying the wire along in its path. Injury to these structures can be a life threatening complication. The skin incision should be slightly smaller than the diameter of the cannula, so that the final placement will be closely approximated to the edge of the skin incision, minimizing bleeding at the insertion site. Serial dilations are necessary to create a tract, from skin to vein, to receive the cannula. Gentle steady pressure is required. The cannula has a tendency to buckle if the tract is too tight. Creating the tract takes patience and can be accomplished in a controlled, slow fashion. Creating the tract will be a distraction from proper wire positioning. It is common that while focusing on the dilations, the wire will either pull back or loop in the ventricle. Once satisfied with the dilation, review wire positioning with fluoroscopy. It remains common practice to systemically 433

Chapter 38

anticoagulate the patient prior to cannula insertion. 50-100 units/kg of unfractionated heparin is a typical dose and is about 1/3 the dose used for cardiopulmonary bypass. Waiting for the heparin to circulate makes sense. Checking baseline coagulation parameters prior to cannulating should be done. Multiple strategies of anticoagulation exist (see Chapter 8) and will not be discussed in this chapter. The cannula is designed to have the distal drainage tip in the hepatic cava. The reinfusion jet is designed to be oriented towards, and at the level of the tricuspid valve. The cannula tip is easier to see radiographically, after the introducer is removed. However, once the introducer is removed, it is difficult, and unsafe, to advance the cannula. The most common reason for advancement of the cannula is that the tip is in the right ventricle. The introducer should be replaced and the tip advanced under fluoroscopy. A cannula placed too deep can be easily pulled back without having to replace the introducer. Figure 38-1 is a chest x-ray documenting appropriate cannula position. Figure 38-2 identifies anatomic landmarks of a typical adult patient and the cannula. Daily chest x-rays can help identify changes in cannula positioning. Taking a picture of the cannula site at the skin can be used as an additional tool for nurses to monitor changes in cannula position. Activity on ECLS is encouraged and cannula position changes are possible. Once the cannula is appropriately positioned, VV-ECLS support can be initiated. Flow should be slowly established (0.5 -1.0 L liter/min) in order to minimize hemodynamic instability. Once oxygenated blood is being infused via the cannula, flow can be increased. Flow should be increased to identify the maximum flow achievable. Adult support typically requires 60-80 cc/kg/min (3-6 liters/min) supporting metabolic needs of about 3 cc O2/kg/ min, when hemoglobin is close to normal. At the time of cannulation, if you are not able to achieve the anticipated flow rate for the cannula 434

chosen, there is likely a positioning problem. This should be identified at the time of cannulation not upon return to the ICU. Open surgical approaches are possible for adult cannulation but few clinical scenarios would require this strategy. VV-ECLS Cannulation-Two Site, or Multiple Multiple site VV cannulation is possible and practical but should be reserved for patients who are not candidates for single site dual lumen approach. This can be safely done at the bedside without any visualization techniques; however, ultrasound is usually helpful. Previously placed central lines can be used and exchanged over a wire. Venous access typically is the right internal jugular vein and a femoral vein. A common approach is placing a long 23-28 Fr cannula for venous drainage from the patient in a femoral vein with arterialized return going to the right internal jugular cannula. Since the vena cava is a right-sided structure, the right femoral vein is preferred for placement of the long cannulas but the left femoral vein is a reasonable and safe alternative. The right internal jugular vein cannula can be relatively small (17-23 Fr), realizing that the pressure generated by the pump will overcome the resistance of a small diameter cannula. Short cannulas should be used in the internal jugular position. These cannulas should be placed using ultrasound guided Seldinger techniques. Surface or transesophageal echocardiography can be used to optimize the position of the long venous drainage cannula, ideally with the tip outside the right ventricle. This two-cannula approach can be hindered by recirculation. Recirculation can be identified by falling arterial saturations with increasing pump flows. Supporting a diagnosis of recirculation will be an associated increase in “mixed venous” saturations, commonly estimated by measuring the saturation of the venous drainage blood, not the true mixed venous, which is measured distal to the pulmonic valve. Recir-

ECLS Cannulation for Adults with Respiratory Failure

culation is only an issue if the ECMO support is felt to be marginal (patient arterial saturation 30

Risk Prediction Model (Y/N) Yes

CNS dysfunction(3) Renal dysfunction(3) Cardiac dysfunction(3)

Brogan

1986-2006

1473

Enger

2008-2013

304

Schmid

2007-2010

176

Schmidt (PRESERVE score)

2008-2012

Roch

Aubron

(1)

ELSO Adult Respiratory database University Medical Center Regensburg

Age Weight

No

Age Immunocompromised(4)

Yes

University Medical Center Regensburg 3 French Centers

Age

No

140

Age BMI Immunocompromised(4) Charlson Score(5) McCabe and Jackson Score(5)

Yes

2009-2013

85

Marseille, France

Age BMI Comorbidities(7)

Yes

2005-2011

52

Melbourne, Australia

Age Chronic respiratory failure +Cystic Fibrosis Immunocompromised

No

Effect of advanced age or co-morbidity on mortality (Weighting) Age 18-49 (Score 0)(2) Age 50-59 (Score -2)(2) Age ≥60 (Score -3)(2) Immunocompromised (Score -2)(2) BMI >30 not associated with hospital mortality CNS dysfunction (Score -7) (3) Renal dysfunction: independently associated hospital mortality Odds Ratio 0.77 (but not included in the score) Cardiac dysfunction not associated with hospital mortality Age: Highly significantly associated with mortality across early and late cohorts Age (per 5 years) Odds ratio hospital mortality 1.193 (CI 1.1 - 1.2) Immunocompromised Odds ratio 2.6 (CI 1.3 – 5.2) Age Age 55 (score 3) (6) BMI >30 (score -2) (6) associated with increased survival Immunocompromised (score 2) (6) Co-morbidity scores were strongly associated with outcome in the univarate analysis, but were not found to be independently associated with outcome in this study population Age 45 (Score 1)(8) BMI (and BMI>30) not associated with mortality Comorbidities: no effect on outcome Age not found to be associated with mortality Chronic respiratory illnesses not found to be associated with mortality Immunocompromised state not found to be associated with mortality

2355 with complete data on first ECMO run Greater negative scores associated with increased mortality. Total score range -22 to 15 with a total score of 0 indicating a 50% risk of hospital mortality Includes both acute and chronic illnesses (4) Immunocompromised state included is similar to ELSO category (does not include cirrhosis) and does include high-dose or long-term corticosteroids or other immunosuppressive therapy (5) Summary score of 21 common Comorbidities. Each condition allocated a point score of 1-6 points. Metastatic solid tumor = 6 points (max) (6) Higher score indicates greater risk of death at 6 months post ICU discharge (Total score range 0 – 14) with scores of -1 and -2 converted to 0 (7) 8 separate Comorbidities were listed: Chronic lung disease, diabetes, transplantation, malignancy, immunocompromised, HIV, drug addiction (8) Greater positive scores associated with increased mortality. Total score range 0-4 (2) (3)

441

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with ECLS. The presence of neurological assign risk to patients presenting to hospital dysfunction appears highly associated with with CAP.13,14 Comorbidities included in this poor survival.3 score were: age, neoplastic disease, chronic • Many degenerative comorbidities such as liver disease, congestive heart failure, cerechronic lung, heart, kidney, and liver failure brovascular disease, and chronic renal failure. and those due to vascular disease are not All comorbidities were associated with higher routinely captured in ECLS case series or mortality and rates of ICU and hospital admisthe ELSO database but likely contribute sion. Neoplastic diseases and liver disease had to clinical outcomes. Validated summary the highest weightings for increased mortality. scores of comorbidities such as the Charl- Although less well validated, specific risk preson and McCabe Scores best represent the diction tools for mortality prediction for CAP burden of these illnesses.10-12 Only one patients in intensive care, which incorporate ECLS study (140 patients) has used such chronic health variables have demonstrated the an approach to measure the independent presence of advanced age, chronic respiratory relationship between common comorbidi- disease, immunosuppression, and a comorbidity ties and outcome in a multicenter study and classified by the McCabe Classification likely leading to death within five years, as strong failed to find an independent association.7 independent predictors of hospital mortality.15,16 In ARDS, risk prediction most commonly Ideally, scoring systems to capture comorbidity burden of patients considered for rests only on oxygenation indices.17 Where other ECLS would have simple and accurate data risk prediction variables have been incorporated capture from hospital records and be updated into risk prediction models they have incorpoand revalidated over time. Linking such data to rated APACHE chronic health states and do not ECLS use across many centers and including it directly measure the effect of comorbidities.18,19 in large databases such as ELSO may greatly A recent ICU mortality risk prediction for improve risk prediction by incorporating effects Australasia, which includes APACHE chronic of comorbidities. health variables, has measured the contribution of age and chronic health conditions for all Impact of Comorbidities on Outcome in ICU patients as almost 25%.20 These studies Non-ECLS Adults with Severe Respiratory support the strong negative effect of comorbidiFailure ties on survival and health resource utilization. To some extent these finding would apply to Of all patients with severe respiratory patients receiving ECLS support for similar failure, patients receiving ECLS make up a underling conditions. small proportion. Research into the association between the presence of comorbidities and pa- Specific Common Comorbidities and Their tient outcome from common causes of severe Interaction with ECLS respiratory failure such as community acquired pneumonia (CAP) and ARDS in non-ECLS Obesity populations have used either a ubiquitous ICU scoring system such as APACHE (Acute PhysiThe proportion of obese adults (BMI >30) ology and Chronic Health Evaluation) or other is increasing in many countries and this trend scoring systems discussed below. is expected to continue. In the first wave of the The pneumonia severity index (PSI) is a 2009 H1N1 influenza pandemic, morbid obesity widely cited and validated scoring system to (BMI>40) increased the hospitalization rate, 442

Comorbidities among ECLS Patients with Respiratory Failure

receipt of invasive mechanical ventilation, and, along with immunosuppression and chronic lung disease, acted as a risk factor for severe disease.21-26 Crude mortality rates from acute respiratory failure with invasive mechanical ventilation is lower for morbidly obese patients than nonobese patients and being underweight is associated with higher mortality.21,27 Morbidly obese patients have been noted to be younger with fewer accompanying comorbidities. After adjusting for age and other confounders, mortality does not differ significantly for obese and morbidly obese patients with severe respiratory failure supported with invasive mechanical ventilation or ECLS compared to nonobese adults.21,28,29 In addition, morbid obesity provides challenges to the provision of ECLS for severe respiratory failure in adults.30 Ultrasound guidance for cannulation of femoral vessels may be impossible or difficult and double-lumen jugular cannulation is more common in these patents.28 Although achieving adequate ECLS blood flow to meet oxygenation targets in morbidly obese patients often proves difficult, it was not associated with reduced survival.28 Morbid obesity was also associated with higher rates of renal failure in H1N1 cases and altered inflammatory mediator profile.31 Morbid obesity may also impact patient transport platforms used for interhospital transport of ECLS cases. Malignancy The presence and treatment of malignancy create many forms of severe respiratory failure for which mechanical ventilation may provide limited benefit. Younger patients with these conditions, but without other comorbidities, are often considered for ECLS support.32 Reports on ECLS outcomes remain few, some centers have for decades provided ECLS to younger patients with respiratory failure associated with hematological malignancy and reported survival rates much lower than other cohorts

receiving ECLS for respiratory failure, except some patients with renal failure.33,34 Some health providers advocate for aggressive treatment in this cohort despite high mortality. Chronic Renal Failure There are no reports of patient outcome with advanced renal failure in adult ECLS case series of respiratory failure. The number of patients with endstage renal failure (ESRF) and chronic kidney disease (CKD) is increasing due to rising incidences of diabetes and hypertension and these patients have a higher incidence of developing critical illness.35 Chronic renal failure patients have a higher mortality following ICU admission but this appears due to a much higher number of comorbidities associated with ESRF rather than an effect of renal failure per se. A systematic review found that survival of patients with ESRF admitted to ICU with respiratory failure was less than in those patients developing acute renal failure during their ICU admission, but that long-term survival was reduced following ICU admission and that cardiac failure and infections remain the commonest causes of death.36 As such, the presence of advanced renal disease would be expected to be associated with reduced hospital survival following ECLS support for reversible causes of severe respiratory failure and elevated mortality rates following ICU admission and increase the risk of secondary infection. Chronic Liver Disease Reporting of ECLS support for patients with advanced forms of chronic liver disease (CLD) remains rare and many centers would exclude such patients from ECLS support other than in the early post liver transplant setting.37,38 Early and long-term survival rates reported in severe CLD admitted to ICU, without the use of ECLS, strongly suggest that in the cases of refractory respiratory failure, enduring pa443

Chapter 39

tient benefit would be unlikely with the use of ECLS.39,40 In carefully selected cases of refractory respiratory failure with lesser forms of CLD, ECLS could be considered but it would be presumed to impose higher risks of sepsis and bleeding complications. Summary Degenerative processes associated with advancing age including arterial vascular disease and chronic failure of the lungs, kidney, and liver are poorly captured in descriptive ECLS case series. Estimates of their negative effect on outcome can be made from broader studies examining their effect on outcome from critical illness not involving ECLS. While in all cases the presence of advanced forms of these comorbidities would have an adverse effect on survival and recovery, their presence alone would not necessarily contraindicate ECLS support, but would have to be considered in conjunction with other factors. Of these conditions, advanced forms of chronic liver disease would appear be the strongest deterrent to the use of ECLS for severe respiratory failure. The adverse effects of immunosuppressive conditions and malignancies on patient outcome are commonly captured in ECLS and severe respiratory failure case-series; however, definitions of immunosuppressive conditions vary slightly and incorporate a broad range of conditions of ranging severity. Selection and subsequent management of such patients supported with ECLS is extremely challenging and should be the domain of highly specialized ECLS centers. Obesity does not seem to have a negative effect on outcome from severe respiratory failure with or without ECLS particularly with single organ failure. Finally, the effect of comorbidities on outcome from severe respiratory failure is likely to interact with other factors known to effect outcome such as age, acute illness severity, 444

timeliness and adequacy of ECLS support, as well as complications from ECLS. The ability to make better-informed clinical decisions in the future will require risk prediction models incorporating improved patient data collection including past medical problems. Comorbidities and age contribute heavily to mortality risk prediction in critically ill populations but are currently not incorporated into such models for ECLS patients.

Comorbidities among ECLS Patients with Respiratory Failure

References 1. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009;374:1351-63. 2. Williamson EJ, Forbes A. Introduction to propensity scores. Respirology 2014;19:625-35. 3. Schmidt M, Bailey M, Sheldrake J, et al. Predicting Survival after Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Failure. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) Score. Am J Respir Crit Care Med 2014;189:1374-82. 4. Brogan TV, Thiagarajan RR, Rycus PT, Bartlett RH, Bratton SL. Extracorporeal membrane oxygenation in adults with severe respiratory failure: a multi-center database. Intensive Care Med 2009. 5. Enger T, Philipp A, Videm V, et al. Prediction of mortality in adult patients with severe acute lung failure receiving venovenous extracorporeal membrane oxygenation: a prospective observational study. Crit Care 2014;18:R67. 6. Schmid C, Philipp A, Hilker M, et al. Venovenous extracorporeal membrane oxygenation for acute lung failure in adults. J Heart Lung Transplant 2012;31:9-15. 7. Schmidt M, Zogheib E, Roze H, et al. The PRESERVE mortality risk score and analysis of long-term outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. Intensive Care Med 2013;39:1704-13. 8. Roch A, Hraiech S, Masson E, et al. Outcome of acute respiratory distress syndrome patients treated with extracorporeal membrane oxygenation and brought to a referral center. Intensive Care Med 2014;40:74-83.

9. Aubron C, Cheng AC, Pilcher D, et al. Factors associated with outcomes of patients on extracorporeal membrane oxygenation support: a 5-year cohort study. Crit Care 2013;17:R73. 10. Needham DM, Scales DC, Laupacis A, Pronovost PJ. A systematic review of the Charlson comorbidity index using Canadian administrative databases: a perspective on risk adjustment in critical care research. J Crit Care 2005;20:12-9. 11. D’Hoore W, Sicotte C, Tilquin C. Risk adjustment in outcome assessment: the Charlson comorbidity index. Methods Inf Med 1993;32:382-7. 12. Fernandez R, Baigorri F, Navarro G, Artigas A. A modified McCabe score for stratification of patients after intensive care unit discharge: the Sabadell score. Crit Care 2006;10:R179. 13. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336:243-50. 14. Kwok CS, Loke YK, Woo K, Myint PK. Risk prediction models for mortality in community-acquired pneumonia: a systematic review. BioMed research international 2013;2013:504136. 15. Leroy O, Georges H, Beuscart C, et al. Severe community-acquired pneumonia in ICUs: prospective validation of a prognostic score. Intensive Care Med 1996;22:130714. 16. Rello J, Rodriguez A, Lisboa T, Gallego M, Lujan M, Wunderink R. PIRO score for community-acquired pneumonia: a new prediction rule for assessment of severity in intensive care unit patients with community-acquired pneumonia. Crit Care Med 2009;37:456-62. 17. Dechert RE, Park PK, Bartlett RH. Evaluation of the oxygenation index in adult respiratory failure. The journal of trauma and acute care surgery 2014;76:469-73. 445

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18. Brown LM, Calfee CS, Matthay MA, et al. A simple classification model for hospital mortality in patients with acute lung injury managed with lung protective ventilation. Crit Care Med 2011;39:2645-51. 19. Cooke CR, Shah CV, Gallop R, et al. A simple clinical predictive index for objective estimates of mortality in acute lung injury. Crit Care Med 2009;37:1913-20. 20. Pilcher D, Paul E, Bailey M, Huckson S. The Australian and New Zealand Risk of Death (ANZROD) model: getting mortality prediction right for intensive care units. Crit Care Resusc 2014;16:3-4. 21. Kumar G, Majumdar T, Jacobs ER, et al. Outcomes of morbidly obese patients receiving invasive mechanical ventilation: a nationwide analysis. Chest 2013;144:48-54. 22. Davies A, Jones D, Bailey M, et al. Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome. JAMA 2009;302:1888-95. 23. Webb SA, Pettila V, Seppelt I, et al. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. N Engl J Med 2009;361:1925-34. 24. Pham T, Combes A, Roze H, et al. Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)-induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis. Am J Respir Crit Care Med 2013;187:276-85. 25. Noah MA, Peek GJ, Finney SJ, et al. Referral to an extracorporeal membrane oxygenation center and mortality among patients with severe 2009 influenza A(H1N1). JAMA 2011;306:1659-68. 26. Patroniti N, Zangrillo A, Pappalardo F, et al. The Italian ECMO network experience during the 2009 influenza A(H1N1) pandemic: preparation for severe respiratory emergency outbreaks. Intensive Care Med 2011;37:1447-57. 27. O’Brien JM, Jr., Phillips GS, Ali NA, Lucarelli M, Marsh CB, Lemeshow S. Body 446

mass index is independently associated with hospital mortality in mechanically ventilated adults with acute lung injury. Crit Care Med 2006;34:738-44. 28. Al-Soufi S, Buscher H, Nguyen ND, Rycus P, Nair P. Lack of association between body weight and mortality in patients on venovenous extracorporeal membrane oxygenation. Intensive Care Med 2013;39:19952002. 29. Singanayagam A, Singanayagam A, Chalmers JD. Obesity is associated with improved survival in community-acquired pneumonia. Eur Respir J 2013;42:180-7. 30. Swol J, Buchwald D, Dudda M, Strauch J, Schildhauer TA. Veno-venous extracorporeal membrane oxygenation in obese surgical patients with hypercapnic lung failure. Acta Anaesthesiol Scand 2014;58:534-8. 31. Cruz-Lagunas A, Jimenez-Alvarez L, Ramirez G, et al. Obesity and pro-inflammatory mediators are associated with acute kidney injury in patients with A/H1N1 influenza and acute respiratory distress syndrome. Experimental and molecular pathology 2014;97:453-7. 32. Wohlfarth P, Ullrich R, Staudinger T, et al. Extracorporeal membrane oxygenation in adult patients with hematologic malignancies and severe acute respiratory failure. Crit Care 2014;18:R20. 33. Gow KW, Heiss KF, Wulkan ML, et al. Extracorporeal life support for support of children with malignancy and respiratory or cardiac failure: The extracorporeal life support experience. Crit Care Med 2009;37:1308-16. 34. Gow KW, Wulkan ML, Heiss KF, et al. Extracorporeal membrane oxygenation for support of children after hematopoietic stem cell transplantation: the Extracorporeal Life Support Organization experience. J Pediatr Surg 2006;41:662-7. 35. Hotchkiss JR, Palevsky PM. Care of the critically ill patient with advanced chronic

Comorbidities among ECLS Patients with Respiratory Failure

kidney disease or end-stage renal disease. Curr Opin Crit Care 2012;18:599-606. 36. Arulkumaran N, Annear NM, Singer M. Patients with end-stage renal disease admitted to the intensive care unit: systematic review. Br J Anaesth 2013;110:13-20. 37. Choi NK, Hwang S, Kim KW, et al. Intensive pulmonary support using extracorporeal membrane oxygenation in adult patients undergoing liver transplantation. Hepato-gastroenterology 2012;59:1189-93. 38. Auzinger G, Willars C, Loveridge R, et al. Extracorporeal membrane oxygenation for refractory hypoxemia after liver transplantation in severe hepatopulmonary syndrome: a solution with pitfalls. Liver Transpl 2014;20:1141-4. 39. Levesque E, Saliba F, Ichai P, Samuel D. Outcome of patients with cirrhosis requiring mechanical ventilation in ICU. J Hepatol 2014;60:570-8. 40. Juneja D, Gopal PB, Kapoor D, Raya R, Sathyanarayanan M. Profile and outcome of patients with liver cirrhosis requiring mechanical ventilation. J Intensive Care Med 2012;27:373-8.

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40 Medical Management of the Adult with Respiratory Failure on ECLS Caroline Sampson, MBBS, Richard Porter, MBChB

Introduction The medical management of the patient with severe respiratory failure receiving VV extracorporeal support is complex and can be very challenging. Ideally, the patient with severe respiratory impairment, not the ECLS circuit, should be the center of attention. ECLS specific treatment should incorporate routine intensive care unit (ICU) management, alter treatment strategies, and avoid complications. Optimal care of VV-ECLS patients requires teamwork, attention to detail, and enhanced clinical experience. Ventilatory Support During institution of extracorporeal respiratory support, mechanical ventilation settings often exceed the guidelines of lung protective ventilation in an attempt to achieve acceptable arterial oxygen saturations. Therefore, it is imperative that all patients should be ventilated within lung protective parameters; aiming for a tidal volume of ≤6 ml/kg ideal body weight with plateau airway pressures ≤30 cmH20 to avoid any further ventilator initiated lung injury (VILI). This has demonstrated, in numerous trials, to confer a mortality benefit in ARDS.1-3 Extracorporeal respiratory support temporarily replaces the native pulmonary function allow-

ing time for recovery and reduction of further damage to the lung secondary to aggressive ventilator strategies (ventilator induced lung injury). A large systematic review confirmed that potentially injurious mechanical ventilation parameters were reduced with the initiation of ECLS. That mortality was lower in groups of patients who had a lower intensity of applied ventilation following ECLS initiation.4 A multicenter retrospective study also demonstrated that not only were protective mechanical ventilation strategies routinely employed following ECLS initiation, but that higher levels of PEEP were independently associated with improved survival.5 Further prospective trials defining optimal targets for tidal volume, plateau pressure, PEEP, and FiO2 are warranted. In practice at our institution, the default initial “rest ventilatory” settings for ECLS patients include using a bilevel airway pressure mode with an inspired pressure of 20-25 cmH20 and a positive end expiratory pressure (PEEP) of 10 cmH20, with a rate of 10-12 breaths per minute. Parameters will vary depending on the underlying reason for ECLS support, such as prolonging expiratory times in patients with acute bronchospasm and using higher levels of PEEP in obese patients. We aim to reduce FiO2 to 30% accepting PaO2 ≥45 mmHg. In some patients, particularly with higher body mass indexes or high cardiac output states, a partial 449

Chapter 40

ventilatory strategy is necessary using inspira- Bronchoscopy tory pressures up to 30 cmH20 and PEEP up to Bronchoscopic examination and lung la14 cmH20. We also keep FiO2 10 secs 3. If no response move -2 Light sedation Awakens and briefly sustains eye contact and opening to stage 3. for < 10 secs -3 Moderate sedation Any movement in response to voice but no eye contact 3. Physical stimulation by shoulder shake or sternal rub (if safe) Assess response to -4 Deep sedation Movement or eye opening to physical stimulation physical stimulus. -5 Unrousable No response to physical stimulation

452

Medical Management of the Adult with Respiratory Failure on ECLS

more awake patient. At our center, we adjust sedation to target the more awake patient as per Figure 40-1. Delirium We use the Confusion Assessment Method for the ICU (CAM-ICU) to assess for delirium.16 This requires a sedation level greater than -3 by RASS scoring (responsive to verbal commands). To be positive there must be evidence of a change in mental function from baseline or fluctuation of mental status, including inattention and either disorganized thinking or an altered level of consciousness. We use haloperidol as the first line for delirium. Alpha 2 agonists,

Initial 48 hours Following 48 hours Difficult Agitation

including clonidine or dexmedetomidine, and antipsychotics such as olanzapine and risperidone, can also be used. Rivastigmine, however, should be avoided as it is associated with a higher mortality.17 Dangerous agitation, which may cause ECLS circuit compromise, requires urgent management. We would routinely give propofol boluses to gain control and adjust the underlying sedation management. Intracerebral Hemorrhage Intracerebral hemorrhage is a relatively rare but often fatal complication of ECLS therapy. Deterioration in neurological function should instigate an urgent CT scan of the brain. The

•Morphine and midazolam – as intravenous infusions •May require paralysis – agent of choice is atracurium as infusion •Aim for spontaneous breathing and resposnsive to voice (RASS 0 to -1)if clinically feasible by end of 48 hours period •This is achieved by stopping paralysis ASAP and actively reducing morphine and midazolam

•If ongoing sedation requirements still present use: •Remifentanil infusion •Propofol infusion if hypnotic agent required (ideally boluses to control dangerous agitation) •If ongoing agitation or delirium use haloperidol regularly •Aim to stop propofol and remifentanil over 48 hours – if needed clonidine can be used to facilitate this

•Dexemeditomidine if above techniques have failed to achieve awake and spontaneously breathing patient - by consultant initiation only

Figure 40-1. Management of sedation.

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presence of intracerebral hemorrhage should be discussed with neurosurgical specialists; however, in our experience, treatment is often not possible and the outlook poor. Heparin infusion should be stopped immediately if intracranial hemorrhage is suspected. Renal Support Although no difference occurred in mortality between liberal vs. conservative fluid management in the FACCT study, lower duration of mechanical ventilation and length of ICU stay were seen.18 We target negative fluid balance in patients as soon as feasible, based upon cardiovascular stability. Our initial approach includes the use of diuretics, (eg, furosemide). We favor continuous infusion to reduce the ‘swings’ in fluid status, permitting a more controlled diuresis. If patients do not respond adequately to diuretics, continuous renal replacement therapy (CRRT) can be initiated via connection to the ECLS circuit or separately inserted vascular access catheters. Insertion of central venous access risks complications in anticoagulated patients, so we use the circuit if such devices are not already in situ prior to commencement of VV-ECLS. Nutrition

prophylaxis for stress ulcers with ranitidine or proton pump inhibitors if previously received. First line treatment for minor upper GI bleeds is an omeprazole infusion with gastroscopy if bleeding is significant or ongoing. Endocrine Support Routine measurement of cortisol levels is no longer undertaken.13 We commence hydrocortisone in the event of significant vasoplegic shock as described above. We target glucose levels of less than 10 mmol per liter using insulin infusion if required. Tight glucose control is no longer indicated.21 Hematological Abnormalities In the event of persistent abnormalities in the blood count or suspected immunosuppression, we perform a blood film. Consideration for bone marrow aspiration should be given as we have identified unknown leukemias in patients failing to improve on VV-ECLS. Persistent thrombocytopenia raises the possibility of heparin-induced thrombocytopenia. Chapter 7 covers this heparin complication. Infection as the Indication for Respiratory ECLS Support

The most common indication for respiraThe aim is to commence full enteral nutrition as early as possible. A number of studies tory ECLS support is primary lung infection have shown that enteral nutrition is well toler- (bacterial, fungal or viral) or ARDS as part of ated by most patients on ECLS, albeit with a systemic sepsis spectrum. During 2014-2015, frequent interruptions and slightly less delivery 72% of the patients in our center had infection of calories and protein than desired.19,20 The as their initial diagnosis. Initial antibiotic covermajority of patients with feeding intolerance age should be broad spectrum to cover all likely are managed with pro-kinetics if required. As organisms in collaboration with local microbia second line, additional metoclopramide fol- ology guidelines, and knowledge of antibiotic lowed by erythromycin may be used. In the resistance patterns from the referring hospital. event enteral nutrition cannot be achieved A macrolide antibiotic is usually added to cover within a timeframe of 5-7 days, we then com- atypical organisms. In peak influenza season, mence total parenteral nutrition (TPN) via a we treat all patients with antiviral medications dedicated lumen or line. All patients receive active against the current circulating viral strains 454

Medical Management of the Adult with Respiratory Failure on ECLS

until investigations prove them to be influenza negative. It is imperative to maintain dialogues with referring centers so that any positive or negative microbiological results reported after transfer are communicated to the ECLS center in a timely fashion. ECLS patients should have daily input from local microbiological teams. On admission, all patients in our center have a full septic screen comprising: • Blood, urine, and sputum specimens for microscopy, cultures, and sensitivity • Serum for atypical pneumonia screen (mycoplasma, chlamydia, Coxiella) • Urine for legionella antigen detection • Full blood born virus screen (HIV and hepatitis B and C) • Throat swab for respiratory viral PCR (including influenza A&B, respiratory syncytial virus and parainfluenzae strains) • Methicillin Resistant Staphylococcus Aureus (MRSA) screen • Any other investigations dictated by the patient’s condition, including wound swabs, stool or blood cultures from existing indwelling vascular access catheters, sputum for acid-alkali fast bacilli etc. We do not take routine surveillance blood cultures from ECLS circuits unless indicated by clinical or radiological signs of new infection, nor do we use prophylactic antibiotics, other than preprocedure antibiotics. Likewise, we do not routinely change vascular access devices without suspicion of line sepsis to minimize risks from undertaking central and arterial access in anticoagulated patients. Experienced operators, with meticulous attention to aseptic technique, must undertake any attempts at vascular access in ECLS patients. Measures to reduce the incidence of VAP should be strictly adhered to, including selective oral decontamination with chlorhexidine, nursing the patient 30⁰ head up, and the use of endotracheal and tracheostomy tubes with supraglottic suction devices.

Infection Complicating ECLS Support Exposure of whole blood to an extracorporeal circuit induces the systemic inflammatory response syndrome (SIRS) with activation of the complement cascade and release of proinflammatory cytokines namely interleukin 6, 8 (IL-6, IL-8) and tumour necrosis factor (TNF-α) (See Chapter 6). This is most marked at the initiation of ECLS support or following circuit changes. Much of the adult ECLS data has been extrapolated from animal, neonatal, or cardiopulmonary bypass data with the latter having confounding variables such as ischemiareperfusion injury and nonpulsatile flow.22-24 Infection surveillance therefore remains challenging as many normal parameters, including temperature and inflammatory markers, are unreliable in the context of circuit induced-SIRS reaction and heater-cooler control of patient temperature. Evidence in adult VA-ECLS patients suggests that CRP and procalcitonin levels can differentiate infectious vs. noninfectious inflammation with cut off values of 98 mg/L and 1.89 ng/ml respectively particularly if the two are combined, but this conflicts with data from the pediatric ECLS population.25,26 Following the initial SIRS response, ECLS induces a relative immune-paresis, increasing the risk of further septic episodes. We maintain a high index of suspicion for new infection in our ECLS patients. A full septic screen is sent, including bronchioalveolar lavage specimens for microbiological examination. The choice of antibiotic coverage with suspected new episodes of sepsis should cover unusual and resistant organisms, again guided by local patterns of pathogens and resistance. Fungal infections are common and we have a low threshold for adding an antifungal agent with suspected new or unresolving infection. Aggressive source control in imperative and CT scanning may be required to rule out empyemas, abdominal, or pelvic collections. Systemic anticoagulation should not delay urgent radiological or surgical 455

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drainage of collections and heparin is usually discontinued peri-procedure. Conclusion Meticulous attention to the daily medical management of VV-ECLS patients is vital to obtain the best possible outcomes for these complex, resource intensive patients, but this exercise is rewarding and worthy of these efforts.

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References 1. Network TARDS. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342(18):1301–8. 2. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351(4):327–36. 3. Sakr Y, Vincent J-L, Reinhart K, et al. High tidal volume and positive fluid balance are associated with worse outcome in acute lung injury. Chest 2005;128(5):3098–108. 4. Marhong J, Munshi L, Detsky M, Telesnicki T, Fan E. Mechanical ventilation during extracorporeal life support (ECLS): a systematic review. Intensive Care Med. 2015 Jun;41(6):994-1003 5. Schmidt M, Stewart C, Bailey M, et al. Mechanical Ventilation Management During Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome: A retrospective International Multicenter Study. Crit Care Med. 2014;43(3):654-664. 6. Santos C, Ferrer M, Roca J, Torres A, Hernández C, Rodriguez-Roisin R. Pulmonary gas exchange response to oxygen breathing in acute lung injury. Am J Respira Crit Care Med 2000;161(1):26–31. 7. Young D, Lamb SE, Shah S, et al. Highfrequency oscillation for acute respiratory distress syndrome. N Engl J Med 2013;368(9):806–13. 8. Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med 2013;368(9):795–805. 9. Guérin C, Reignier J, Richard J-C, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368(23):2159–68.

10. Kimmoun A, Guerci P, Bridey C, Ducrocq N, Vanhuyse F, Levy B: Prone positioning use to hasten veno-venous ECMO weaning in ARDS. Intensive Care Med (2013) 39:1877–1879 11. Braune S, Kienast S, Hadem J, Wiesner O, Wichmann D, Nierhaus A, Simon M, Welte T, Kluge S. Safety of percutaneous dilatational tracheostomy in patients on extracorporeal lung support. Intensive Care Med. 2013; 39:1792–1799 12. Schmid C, Philipp A, Hilker M, Rupprecht L, Arlt M, Keyser A, Lubnow M, Müller T: Venovenous extracorporeal membrane oxygenation for acute lung failure in adults. J Heart Lung Transpl. 13. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358(2):111–24. 14. Riker RR, Fraser GL. Altering intensive care sedation paradigms to improve patient outcomes. Anesthesiology Clinics 2011;29(4):663–74. 15. Sessler CN. The Richmond Agitation-Sedation Scale: Validity and Reliability in Adult Intensive Care Unit Patients. Am J Respira Crit Care Med 2002;166(10):1338–44. 16. Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med 1999;27(7):1325–9. 17. van Eijk MMJ, Roes KCB, Honing MLH, et al. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial. Lancet 2010;376(9755):1829–37. 18. Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354(24):2564–75. 19. Ferrie S, Herkes R, Forrest P. Nutrition support during extracorporeal membrane oxygenation (ECMO) in adults: a retrospec457

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tive audit of 86 patients. Intensive Care Med. 2013;39(11):1989-1994. 20. Ridley EJ, Davies AR, Robins EJ, et al. Nutrition therapy in adult patients receiving extracorporeal membrane oxygenation: a prospective, multicentre, observational study. Crit Care Resusc. 2015;17(3):183189. 21. Finfer S, Chittock DR, Su SY-S, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360(13):1283–97. 22. Warltier DC, Laffey JG, Boylan JF, Cheng DCH. The Systemic Inflammatory Response to Cardiac Surgery. Anesthesiology 2002;97(1):215–52. 23. Day JRS, Taylor KM. The systemic inflammatory response syndrome and cardiopulmonary bypass. Internat J Surg 2005;3(2):129–40. 24. McILwain RB, Timpa JG, Kurundkar AR, et al. Plasma concentrations of inflammatory cytokines rise rapidly during ECMO-related SIRS due to the release of preformed stores in the intestine. Lab Invest 2009;90(1):128–39. 25. Pieri M, Greco T, De Bonis M, et al. Diagnosis of infection in patients undergoing extracorporeal membrane oxygenation: A casecontrol study. The Journal of Thoracic and Cardiovascular Surg 2012;143(6):1411–1. 26. Rungatscher A, Merlini A, De Rita F, et al. Diagnosis of infection in paediatric venoarterial cardiac extracorporeal membrane oxygenation: role of procalcitonin and Creactive protein. Eur J Cardiothorac Surg 2013;43(5):1043–9.

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41 Nursing Care of the Adult Respiratory ECLS Patient Jayne Sheldrake, RN, Shirley Vallance, MPH

Introduction Over the last decade, many adult ECLS centers have progressively incorporated respiratory ECLS care into the scope of practice of specially trained ICU medical and nursing staff and moved away from having dedicated noncritical care staff overseeing care by the bedside. The incorporation of circuit monitoring and care into the nursing scope of practice in particular, has facilitated the growth in ECLS for respiratory failure in the critical care environment and is expected to grow further with the increasing interest in partial ECLS support of respiratory failure.1 Bedside nursing management of ECLS patients plays an essential role in patient outcomes. The nurse role demands continual vigilance to identify and respond to changes in the patient and circuit function, but also performs an essential role in the prevention of complications. The bedside nurse is often the primary responder and care coordinator and often the first to identify complications in any or indeed all of these areas. Standard nursing care practices should be implemented for these patients with several areas requiring additional focus/assessment and checks while the patient is on ECMO support.2 This chapter covers the delivery of daily nursing care of the adult patient receiving ECLS for severe respiratory failure for critical care

trained nurses having received specific education and training including ongoing assessments and competency evaluations. ECLS Specific Nursing Care ECLS patients require the same initial assessment and scrutiny as other ICU patients. This thorough assessment is an essential component of the daily routine. Patients on ECLS require additional initial assessments/checks carried out by the nurse when commencing care for the patient each shift. The additional patient checks include circuit and equipment checks and neurological and vascular assessment and observations.3 Circuit checks include taking blood samples for hemolysis screening alongside other patient pathology tests. Checks of the circuit and review of circuit integrity are a vital component of preventative management and initial and ongoing review by the primary caregiver, the bedside nurse. Checklists and Preventative Care A circuit and equipment checklist, which includes checks for power source and battery function, gas delivery, cannula dressing positions and security, circuit settings, and availability of spare and emergency equipment, should be completed at the beginning of each shift. 459

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Completing checks with the outgoing nurse is best practice. Any identified problems should be managed in a timely manner to minimize risk or further complications. Backup equipment and knowledge of how to access and use these supports are imperative. A backup console should be available. Alternatives sources for power and oxygen delivery should be part of the checklist. Knowledge of personnel available and how to contact them is also an important strategy for preventative management. Cannula Care The key initial assessment of the circuit and cannula ensures patient safety. Pulses distal to any cannula should be checked initially and hourly thereafter. The cannula assessment includes visual assessment of cannula sites and securing devices. The positioning of the cannula should be measured and documented. The dressing integrity should also be reviewed. ECLS Circuit Observations and Monitoring of Circuit Function Preventative management to identify any complications early is essential. Regular blood tests for bleeding, hemolysis, and fibrinolysis screening in addition to anticoagulation monitoring should be carried out according to local practice. The initial circuit assessment/ observations should be completed at the start of the shift and then at least hourly. Correct management of circuit function depends greatly on regular sampling and reviewing of the blood tests and results. Console Settings, Safety, and Responses Nurses should review and document the console settings and alarms. As the primary caregiver, the nurse can identify early, any changes in the console settings and alarms. This monitoring requires an understanding of 460

and ability to set alarms appropriately as well as trouble shooting the system. Hourly checks should include mode of ECMO support, documentation of patient parameters such as blood flow, venous blood oxygenation, circuit pressures, fresh gas flow, and fraction of oxygen delivered. Timely circuit interventions include adjusting alarm limits, pump speed settings, and alterations of gas flow in response to patient changes. Adjustments to circuit settings require specific training and physiological understanding of the circuit and patient gas exchange. Changes in circuit/membrane pressures are often the first sign of circuit dysfunction that could potentially result in suboptimal ECLS support, as well as minor or catastrophic complications. Maintenance of the console power source and backup blood pumping options are vital. The bedside nurse plays a crucial role in the detection of pump/console failure and the rapid commencement of emergency support. Patient position, room size, the presence of additional equipment, such as a continuous renal replacement (CRRT) machine, and connection of the circuit to a heater can make disengaging and moving the pump head challenging. Nursing staff play a crucial role in cubicle layout and must maintain sufficient access to the circuit to allow timely emergency interventions. Renal Replacement Continuous renal replacement (CRRT) provides a stable mode of renal support for adults with respiratory failure and allows excellent control of fluid balance.4,5 Connection and disconnection of the CRRT machine to the circuit has been incorporated into the scope of practice of the bedside nurse. Accessing the CRRT machine from the ECLS circuit increases the longevity of the hemofiltration life and optimizes fluid CRRT management.6 Connections of the CRRT machine onto the positive pressure region of the ECLS circuit and returning CRRT blood to a pre-oxygenator side of the oxygenator

Nursing Care of the Adult Respiratory ECLS Patient

risk of the patient pulling or compromising lines and circuit integrity. References to the management of awake or ambulating patients on VV-ECLS support have Emergency Responses increased in the literature. Different strategies As the first responder the bedside nurse are needed for the awake or sedated patient. A should receive training in emergency response. substantial number of VV-ECLS patients VVConsole failure, circuit rupture, accidental ECLS are not suitable for ‘awake’ ECLS or decannulation and massive bleeding need im- participation in their own care. Reasons may mediate response while calling for medical include hypoxemia despite VV-ECLS, and/or assistance. Emergency procedure training of the need for neuromuscular blockade or deep the bedside nurse must include appropriate sedation due to the severity of their lung injury.7 clamping and unclamping of the circuit, disen- A sedated ECLS patient requires the same care gaging the pump head and initiating the backup focus as other ICU patients in a sedated state. system, establishing alternative gas supplies The bedside nurse spends a great deal and adjustments of pump speed in the event of of time with the ‘awake’ ECLS patient and access insufficiency (inadequate venous return their families. Literature suggests that patient to the circuit resulting in unstable circuit flows). participation aids recovery and is influenced Competencies should incorporate emergency by the level of sedation.8 Other benefits of paresponses and regular training with wet lab tient participation include increased transplant simulation training if available. recovery and decreased postoperative hospital length of stay.9 An additional focus needs to General Nursing Care of the ECLS Patient be on psychological support for the patient and their families. By requiring additional checks, ECLS extends the timeframe required to carry out hourly Patient Moves and Pressure Area Care observations and documentation, a primary nursing duty. As a result, time management is an A necessary, thorough patient assessment essential strength for the nurse to competently requires additional resources and staffing to care for the patient prioritizing needs and asking ensure safe implementation of interventions. for additional resources when required. An individual, often called a ‘spotter,’ allocated solely for handling the ECLS circuit, can be Neurological Assessment and Sedation used. An “ECLS only” area, where the ECLS Practice (and Awake ECLS) circuit rests off the bed can decrease risk of pulling or entanglement. Removing any items (ie, ECLS carries an increased risk of neu- urinary catheter, other drains) that could potenrological insult and poor outcome therefore tially compromise the ECLS circuit decreases neurological assessment is imperative.3 This the risk of the ECLS circuit tubing compromise. risk increases partly due to the anticoagulation Notifying the medical team that the patient is required to assist smooth running of the ECLS being turned or moved maintains patient safety therapy. Pupil assessment becomes critical and and ensures assistance is availability of assisneeds to be carried out regularly. Sedation aims tance if required, often including a member of should be discussed and agreed upon during the medical team caring for the patient. the multidisciplinary ward round to allow the Prevention strategies should be applied bedside nurse to provide safe care with minimal to specific areas identified as high risk of skin decreases the risk of patient complications such as air emboli.

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breakdown.10 Dressings placed between patient skin and circuit tubing prophylactically can decrease the development of pressure injury. Repositioning the circuit tubing hourly also decreases risk. A small adjustment of the circuit on the lower limbs, particularly if edematous, can help prevent pressure injury. A nonadhesive dressing to cushion the circuit tubing on the patient will also assist. Rotating the bed, if possible, can also relieve pressure. Placement of a heel wedge elevates vulnerable skin areas prone to breakdown, decreasing risk of injury. These pressure prevention strategies can be incorporated into the hourly assessment of the ECLS cannula and circuit. Prevention of Bleeding Anticoagulation puts the ECLS patient at risk of bleeding from any intervention. Prevention of bleeding complications, no matter how minor, aids positive outcomes. Only an ECLS trained individual should carry out necessary procedures. Common procedures such as NG tube placement, urinary catheterization, peripheral venous cannulation, and similar interventions usually performed by the nurse should be assisted by ECLS medical staff. Ensuring blood products remain available with a current group (or type) and are saved is an essential component of the bedside nursing role. Checking the coagulation screen and identifying areas for review aids in prevention of bleeding. The timely administration of blood products, which depends on severity and site(s), may require additional staff assistance. A dressing impregnated with a procoagulant may be placed on the bleeding site. Sighting of the cannula remains a priority, but often difficult when bleeding occurs. Manual pressure is a useful tool to minimize bleeding but both the limb and the cannula site need frequent observation, at 15 minute intervals, to identify complications that may require more aggressive management.

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Hygiene and Infection Prevention Interventions for patient hygiene need to be adapted to suit the ECLS population and decrease risk of bleeding/complications. Shaving should be performed with a clipper or dry shaver only. Brushing teeth can cause significant trauma and bleeding. If a toothbrush is used it should be a small soft brush head. Mouthwash and oral suctioning should be minimal and as clinically indicated. Care should be taken to minimize bleeding. Brushing should be stopped if bleeding occurs. Oral swabs can also be used. Washing solutions with any alcohol content, such as Chlorhexidine, can be detrimental to ECLS circuit integrity. Hygiene interventions often require additional staffing and should be carried out as part of the clustered care alongside patient assessment and pressure area care. Nutrition Nutrition assessment, goals and plan, and delivery of care follow standard practice for other ICU patients. There is no difference in glucose management, electrolyte control, and stress ulcer prevention from any other ICU patient.11 Little published literature clearly defines the nutritional needs in the adult ECLS population. One study found adults on ECLS received 55% of their nutritional requirements compared to 71% once decannulated. This study was not limited to VV-ECLS, but reviewed all adult ECLS groups.12 Ensuring adequate enteral nutrition can be difficult due to the stoppage of feeding for procedures, poor absorption confounded by sedation and other medications, late onset of enteral support, and increased metabolism related to the stress response. Still, performing nutritional assessment to define nutritional goals can also be quite a challenge. Accurate weights performed regularly and other assessment methods such as a metabolic cart, may prove difficult and time consuming, often requiring additional resources. The nurse and dietician

Nursing Care of the Adult Respiratory ECLS Patient

should collaborate to facilitate safe and accurate assessment and delivery of nutritional needs. Bowel Management Bowel management is crucial but challenging as the critically ill have increased risk of ileus, bowel obstruction, or fecal incontinence, which can hinder skin integrity and promote infection. Application of topical skin barriers optimizes skin integrity but frequent cleaning for incontinence decreases their effect.10 Fecal management systems may minimize these risks but their introduction has its own risks. The risks of these devices should be reviewed prior to insertion. Signs of or history of bleeding, clotting, and coagulation profile are also reviewed and optimized prior to insertion. A rectal bag is less invasive and may decrease complications and may prove a better choice in some cases. Review and assessment for the most appropriate bowel management system can be carried out on the skin pressure care assessment when additional resources to reposition the patient are already being utilized. Staff Support

for this patient group and with outside psychological support should be essential components of any ECLS program. Role Allocation Role allocation is instrumental when commencing any procedure identified as complex or high risk. The low volume of ECLS patients decreases familiarity, often enhancing stress associated with these complex patients. A team leader allocates roles for any high risk procedure. Each individual should fully understand their role allocation and place in the team approach. The roles should be allocated with individual strengths and limitations in mind.13 Interhospital transports should only be embarked upon if essential for diagnosis and treatment decisions (see Chapter 55). Adequate staffing and role allocation optimize safety in such a complex procedure.14 ECLS patients are unique in a few areas. Only in these areas, should the clinical nursing management differ. The benefits and risks have to be carefully considered prior to any intervention no matter how small.

The nurses caring for this patient group are highly skilled and experienced in critical care but often represent a small group within a larger team. This can result in those nurses caring almost exclusively for ECLS patients with little break from acute and high intensity workload. As discussed, ECLS patients are physically demanding, exposing the nurse to high physical demands for most of the shift. CRRT and other adjuncts increase this physical burden. The family dynamics of the patient with a complex admission can also increase the nursing workload. Awake ECLS patients add further challenges. Many support personnel, such as social workers and psychologists, can help minimize these additional work stressors. Providing these nurses with breaks from caring 463

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References

Ostomy Continence Nursing, 2007. 44(2): p. 163-175. 1. Leligdowicz A, Current Opinion in Critical 11. Compton R, Straub M, Frey J, Zidek W, Care. Critical Care Medicine, 2015. 21(1): Schafer JH. Pressure ulcer predictors in p. 13-19. ICU patients: nursing skin assessment 2. Gay, Critical care challenges in the adult versus objective parameters. J Wound Care ECMO patient. Dimensions of Critical Care 2008. 1017(10): p. 417-424. Nursing 2005. 24(4): p. 157-162. 12. G, L., Nutritional support in adult patients 3. Risnes I, Nome T, Sundet K, et al. Cerebral receiving extracorporeal membrane oxyOutcomes In Adult Patients treated with genation. Critical Care and Resusitation, extracorporeal membrane oxygenation. . 2010. 12(4): p. 230. AnnThorac Surg 2006. 81: p. 1401-6. 13. Stubs D, Pellegrino V, Smith K, et al. Re4. Yap HJ, Fang JC, Huang CC. Combination fractory cardiac arrest treated with mechaniof continuous renal replacement therapies cal CPR, hypothermia, ECMO and early (CRRT) and extracorporeal membrane reperfusion (the CHEER trial). Resuscitaoxygenation (ECMO) for advanced cardiac tion, 2015. 86(Jan ): p. 88-94. patients. Renal Failure, 2015. 25(2): p. 183- 14. Shields J, Krau S. Nurses’ knowledge of 193. Intra-hospital Transfer. Resuscitation, 2015. 5. Chen H, Yin NN, Zhou ZX. Combination 50(2): p. 293-314. of extracorporeal membrane oxygenation and continuous renal replacement therapy in critically ill patients: a systematic review. Critical Care Epub 2014. 18(6): p. 675. 6. Crosswell AB, Matthew J, Roodenburg O. Vascular access site influences circuit life in continuous renal replacement therapy. Critical Care and Resusitation, 2014. 16(2): p. 127-130. 7. Needham D. Early physical medicine and rehabilitation for patients with acute respiratory failure: a quality improvement project. Arch Phys Med Rehab, 2010. 91(4): p. 536-542. 8. Javidfar J. Current Opinion Organ transplantation, 2012. 17(5): p. 496-502. 9. Fuehner T, Hadem J, Wiesner O, et al. Extracorporeal Membrane Oxygenation in Awake Patients as Bridge to Lung Transplantation. Am J Respir Crit Care Med, 2012. 185(7): p. 763-768. 10. Benoit RA. The effect of a pressure ulcer prevention program and the bowel management system in reducing pressure ulcer prevalence in an ICU setting. J Wound

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42 Weaning and Decannulation of Adults with Respiratory Failure on ECLS Hergen Buscher, MD, FCICM, EDIC, DEAA

Introduction As with mechanical ventilation, the aim of extracorporeal life support (ECLS) should be to minimize support to the lowest level needed to achieve the therapeutic goal. ECLS treatment goals may change from providing oxygenation, to clearing carbon dioxide, to allowing for lung protective ventilation, or even extubation, during support. In this regard the weaning process starts at the time of cannulation and should be separated from the process of liberation where the aim is decannulation, only after certain criteria have been achieved. Unlike in mechanical ventilation, where over the last number of years criteria for relative safe and lung protective ventilation have been introduced, the optimal level of ECLS remains still unknown. VV-ECLS Physiology The preferred mode for respiratory support is VV-ECLS.1 The main adjustments are blood flow, sweep gas flow, and gas composition. The indications include severe hypoxia (oxygenation failure), hypercarbia (ventilation failure), or most commonly a combination of the two. To treat oxygenation failure most of venous to right ventricle needs to pass through the oxygenator when the lungs provide no significant contribution to gas exchange. Blood flow is limited by

venous return, drainage cannula size, and position which require optimizing by augmenting native cardiac output, cannula size, and position. In addition, the recirculation fraction should be minimized. In the absence of significant lung capacity to oxygenate blood subphysiologic arterial oxygen saturations (often measured in the range of 85-90%) are expected. An attempt to increase blood flow to improve this situation may increase recirculation, hemolysis, and fluid overload, add to venous drainage problems, or require additional cannulae. Importantly a single liter per minute of oxygen exceeds the average oxygen consumption of an adult and is theoretically enough to fully saturate the blood passing through an ECLS circuit.2,3 Most adult ECLS centers use pure oxygen as gas. Air-oxygen mixture should saturate blood to 100% in well-functioning oxygenators and therefore an increase in oxygen concentration does not contribute to an increase in oxygen delivery. It remains unclear if this ‘safety margin’ increases the risk of oxygen toxicity to the pulmonary system. There is insufficient evidence to recommend a specific oxygen concentration in VV-ECLS as long as the blood leaving the oxygenator is fully oxygenated.1 In contrast, clearing venous carbon dioxide (CO2) does not significantly depend on blood flow but mainly is a function of gas flow. Approximately 90% of CO2 is transported in the 465

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blood as bicarbonate.4 For that reason, less than 500 ml of blood contains all CO2 produced per minute and very little blood flow is needed to clear that amount. The gas flow should be adjusted to achieve a normal pH rather than a normal pCO2 since many patients may have a chronic respiratory acidosis with metabolic compensation. A slight increase in gas flow beyond this may aid a patient suffering from tachypnea and respiratory distress. Initiation of VV-ECLS After cannulation, a significant amount of blood volume will be drained from the patient toward the extracorporeal circuit and will be replaced by the priming fluid of the circuit. This most often consists of a crystalloid solution, which will lead to hemodilution of the blood volume. Often patients experience hemodynamic compromise as a result of severe hypoxia and consequently may suffer from brief but significant hypotension. It is important to insure that hemodynamic support with vasopressors or a fluid bolus can be delivered. Preexisting intravascular hypovolemia may be exacerbated by ECLS and optimal pump function may be compromised by poor venous drainage. If the drainage cannula is confirmed to be in an optimal position further fluid boluses may be needed. Once instituted, ECLS support delivers oxygenated blood to the patient and often resulting in improved hemodynamic function. Changes in ventilatory settings allowing lung protective or even ultra-lung protective ventilation result in reduction in intrathoracic pressure with improved preload and RV afterload. Unloading of the RV by a combination of reduced ventilator pressure and reduced pulmonary resistance secondary to the correction of hypoxia and hypercarbia may play the main role in this observation. ECLS also very effectively corrects severe respiratory acidosis. Rapid reversal or over correction of respiratory acidosis may be detri466

mental in some settings such as spontaneously breathing patients or suspected brain injury. A stepwise increase in gas flow in association with a reduction in minute ventilation may be necessary. Since bolus heparin doses are often administered during cannulation the bleeding risk may be increased at this point. Maintaining VV-ECLS The most common problem during ECLS is poor venous drainage. Venous drainage depends on the size and position of the cannula, venous filling (depending on venous return and preload), and ECLS pump speed. Any of these parameters can cause suboptimal drainage. If we ensure that the VV-ECLS cannula is optimally positioned, adding an additional drainage cannula may be needed to address poor venous drainage but this extra cannula often results only in moderate increases in blood flow (see Chapter 38). Increasing ECLS pump speed will increase blood flow but may increase recirculation and hemolysis, although this is less likely with optimal venous drainage.5 Of course, this strategy relies on adequate venous return. Once this critical volume is reached the drained vein may collapse leading to a sudden drop of blood flow to zero. The acute hypoxia will be substantial and only a reduction in pump speed will free up the drainage cannula. Figure 42-1 illustrates the importance of not increasing ECLS pump flow beyond a sustainable drainage (area A). Plateauing of the relationship (area B) may not be observed since venous filling is a dynamic process and can change quickly, for example secondary to increased intrathoracic pressures (eg, coughing). Increasing venous filling by administration of fluid boluses is a common reflex when blood flow is deemed to be inappropriate. However, this benefit is usually temporary and ultimately can lead to fluid overload. A restrictive approach to fluid management in ARDS improves survival and therefore the

Weaning and Decannulation of Adults with Respiratory Failure on ECLS

same strategy needs to be applied during ECLS. post oxygenator PaO2 or need for increases in Trying to maintain high levels of blood flow sweep gas flows. There is no single marker or by fluid administration ultimately reduces the score for device failure and it remains a matter chance of organ recovery. Reducing the blood of clinical judgement to determine if an exflow targets or improving venous drainage by change is needed, keeping in mind that patients additional cannulation are preferred options. who are completely dependent on ECLS should ECLS circuit failure occurs rarely in adults undergo an elective exchange rather than an but early signs need to be addressed to avoid urgent procedure which usually results in severe a catastrophic event. Modern oxygenator and respiratory and/or hemodynamic instability. pumps can last for weeks or in some cases months without exchange and signs of failure Recirculation often develop slowly so that elective changes can be planned for (see Chapter 5). A sudden Recirculation of already oxygenated blood loss of function should be an uncommon prob- into the drainage cannula complicates VVlem in modern adult ECLS practice. ECLS. Again, higher ECLS pump speed and Risk factors for component failure include blood flow may increase this problem. As a conprothrombotic conditions including low or sequence, oxygen delivery does not increase in no anticoagulation, trauma, or underlying proportion to flow while complications includthrombophilic disease. Routine care includes ing hemolysis and poor drainage occur more regular monitoring and documentation of clot commonly. No simple bedside test measures the formation and of changes in biochemical mark- recirculation fraction nor can it be completely ers of hemolysis and thrombosis such as free avoided during VV-ECLS. Optimal placement hemoglobin, d-dimers, fibrinogen, and platelets. of drainage and return cannula, in a two-site Thrombin fragment and thrombin-anti-thrombin VV-ECLS configuration, and proper positioncomplexes may increase while factor XIII may ing of bicaval dual-lumen VV-ECLS cannula, drop, but these are not part of standard monitor- are both essential to minimize recirculation.7 ing in most centers.6 Failing oxygenators may The most frequent clinical sign associated with gradually loose function noted by a decrease in recirculation is desaturation, which can be acute and life threatening. An experienced team of nurses, ECLS specialists, respiratory therapists, and medical staff at the bedside is essential to deal with this swiftly to avoid poor outcome. Addressing drainage problems, circuit failure, and recirculation early will avoid the majority of these episodes. Additionally, in the absence of oxygenation by the lungs desaturation always occurs when native cardiac output significantly exceeds ECLS blood flow. Clinical situations where this may be accelerated include pain, delirium, and sepsis. These syndromes are Figure 42-1. Function of blood flow to pump not always easy to diagnose during ECLS and it speed. Area A - linear increase of blood flow with pump speed. Area B - Ineffective increase takes experience to address them expeditiously in pump speed secondary to poor venous filling. (see Chapter 40). Area C - acute drop in blood flow secondary to venous collapse. Not to scale.

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Weaning VV-ECLS A successful stepwise weaning of sweep gas flow may therefore indicate the recovery of the ventilator function (CO2 clearance) but not necessarily the recovery of oxygenation. Over prolonged ECLS support the ability of an oxygenator to clear CO2 can decline and increasing amounts of gas flow become necessary. When this change is observed in association with other indicators of oxygenator failure a system change may be indicated. For VV-ECLS the following procedure should be followed: once the level of ventilator support is deemed to be appropriate and safe, the extracorporeal gas flow can be reduced in a stepwise fashion to zero with close monitoring of arterial oxygenation and CO2 levels. It usually becomes necessary to increase the respiratory rate and FiO2 settings used to rest the lungs while on full ECLS support. Some centers wean extracorporeal blood flow parallel to the gas flow, to a set minimum flow; however, no changes in blood flow are absolutely necessary, since during the provision of VV-ECLS without gas flow, the drained venous blood will return to the venous system without any change in oxygen content. Protocols that include weaning of extracorporeal blood flow may add the risk of thromboembolic complications at a time when anticoagulation may also be reduced in preparation for decannulation. Over the following hours, sometimes extending to days, the patient needs to be closely monitored for signs of weaning failure. Some extracorporeal devices have a built in mixed venous saturation monitor. A steep drop in saturation may indicate weaning failure. When a pulmonary artery catheter is present, the same phenomenon can be observed as well as signs of acute cor-pulmonale. Echocardiography may also be helpful. Signs of poor tissue oxygenation such as lacticemia or new organ impairment may indicate that further extracorporeal support is needed. Once a patient has stable hemodynamic parameters and adequate oxygen delivery 468

with no gas flow on VV-ECLS, decannulation can be attempted. Liberation and Decannulation The weaning of mechanical ventilation drives the timing for liberation from extracorporeal support. The targeted level of ventilator support deemed appropriate to allow for the removal of the extracorporeal system varies from patient to patient. However, the majority will be ventilated at the time of liberation, well within lung protective ventilation with a PaO2/FiO2 ratio above 100 mmHg without extracorporeal support. It should also be possible to achieve almost normal CO2 clearance (pH >7.3). Factors which may have negative impact on the respiratory function including infections or other organ failure should be well controlled before decannulation, since reinstitution of ECLS often proves more complex. In some situations, continuing with ECLS to the point of liberating a patient from mechanical ventilation first is appropriate. Little evidence exists in which group of patients, perhaps with the exception of patients waiting for lung transplantation, would benefit from this strategy and more trials on this subject are desperately needed. An elevated aPTT is a risk factor for post decannulation complications.8 Heparin free ECLS in adult patients on modern extracorporeal devices has been reported for up to 25 days and many centers routinely stop anticoagulation before decannulation.9 Percutaneously placed cannula can be removed after clamping the circuit with the help of local compression for 20 to 60 minutes. The use of a pursestring suture is often recommended. After prolonged ECLS runs and in patients with minimal subcutaneous tissue or signs of tissue infections at the cannula site surgical consultation may be needed. Clot formations around venous cannula have been described and risk for thromboembolic complications during decannulation exists.10 In case of a sudden hemodynamic deterioration the possibility of a pulmonary embolism

Weaning and Decannulation of Adults with Respiratory Failure on ECLS

must be considered and venous ultrasound postremoval is indicated in any case. If a cannula was placed with an open approach or an arterial cannula is in place the decannulation strategy should be discussed with the team who performed the procedure as an open repair may be indicated. Patients on VA support and respiratory failure need to follow the VA weaning protocol with special consideration for systemic oxygenation and differential hypoxia (see Chapter 51). Other Modes of Support In the recent past low flow extracorporeal systems have been introduced for extracorporeal CO2 removal, (ECCOR, see Chapter 63).11 These systems are either pump driven venovenous or pumpless arteriovenous in configuration. During weaning and liberation no change in blood flow is needed. Reduction in gas flow leads to less effective CO2 removal and ceasing it altogether mimics decannulation. The relation between CO2 removal and gas flow is not linear and attention needs to be taken to monitor native CO2 clearance during weaning. The Patient Who Cannot be Weaned According to the 2015 ELSO report, respiratory support averaged approximately 12 days, which exceeds that needed for cardiac support. Much longer support times of over 100 days have been reported and indeed according to a recent analysis of the database, duration of support alone does not predict futility.12 Full lung recovery has been demonstrated after many weeks on support.13 However, complications related to intensive care and extracorporeal support itself can accumulate and can make prolonged runs very difficult. ELSO reports suggest that about 2/3 of all adult runs wean successfully. In the CESAR trial only 9% of all patients died of persistent respiratory failure while the majority of deceased patients developed extrapulmonary organ failure.4

A small proportion of patients may qualify for lung transplantation and early contact with the appropriate transplant center is indicated (see Chapter 58). In a recent review of the international lung transplantation database ~4% of all transplants received ECLS first.14 Two scenarios are common. Patients with chronic disease who have already been placed on the transplant waiting list may have an acute deterioration and need ECLS support. These patients are unlikely to be weaned from ECLS successfully and ventilator weaning and extubation may be desirable once it has been confirmed that transplantation remains an option. On the other hand, patients on extracorporeal support with the intention to bridge to recovery may fail to show significant improvement. No clear cutoff time exists after which a referral for lung transplantation should be considered. The appropriateness of this option depends on the patient’s condition, age, and premorbid state as well as on local availability of lung transplantation and wait times. Since full recovery after prolonged ECLS runs has been observed and long-term survival times after transplantation may be shorter the decision for transplantation can only be made on an individual basis in discussion with the local transplant center.13 Conclusion Since up to a third of adult patients on respiratory support may not be able to be weaned, the appropriateness of ECLS should be reviewed regularly and similar to other invasive life support including mechanical ventilation or renal replacement therapy, should be continued only if a reasonable chance of a positive outcome exists. The withdrawal of extracorporeal life support for futility needs to follow local ethical guidelines with ongoing discussions with family and/ or patient. Organ donation post withdrawal of extracorporeal life support should be considered.

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References 1. ELSO Guidelines for respiratory support Vers 1.3 (searched January 2016) https:// www.elso.org/Resources/Guidelines.aspx 2. Schmid C, Philipp A, Hilker M, et al. Venovenous extracorporeal membrane oxygenation for acute lung failure in adults. J Heart Lung Transplant. 2012;31(1):9-15. 3. Javidfar J, Brodie D, Iribarne A, et al. Extracorporeal membrane oxygenation as a bridge to lung transplantation and recovery. J Thorac Cardiovasc Surg2012;144(3):71621. 4. Peek GJ, Mugford M, Tiruvoipati R et al. Efficacy and economic assessment of conventional ventilator support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374(9698):1351–63. 5. Toomasian JM, Bartlett RH. Hemolysis and ECMO pumps in the 21st Century. Perfusion. 2011; 26(1):5-6. 6. Protti A, L’Acqua C, Panigada M. The delicate balance between pro-(risk of thrombosis) and anti- (risk of bleeding) coagulation during extracorporeal membrane oxygenation. Ann Transl Med. 2016;10.210-37. 7. Abrams D, Bacchetta M, Brodie D. Recirculation in venovenous extracorporeal membrane oxygenation. ASAIO. 2015;61(2): 115-21. 8. Yeo HJ, Kim HJ, Jang JH, Kang LH, Cho WH, Kim D: Vascular Complications Arising from Hemostasis with Manual Compression Following Extracorporeal Membrane Oxygenation Decannulation. 2016;31(2):123-6. 9. Herbert DG, Buscher H, Nair P. Prolonged venovenous extracorporeal membrane oxygenation without anticoagulation: a case of Goodpasture syndrome-related pulmonary haemorrhage. Critical Care and Resuscitation: Journal of the Australasian Academy 470

of Critical Care Medicine. 2014;16 (1):6972. 10. Kalem V, Buchwald D, Strauch J, et al. Surgical extraction after thrombosis around the Avalon dual lumen cannula. Ann R Coll Surg Engl. 2014;96(1):106-8E. 11. Abrams D, Brenner K, Burkart K, et al. Pilot Study of extracorporeal carbon dioxide removal to facilitate extubation and ambulation in exacerbations of chronic obstructive pulmonary disease. AnnalsATS. 2013;10(4):307-14. 12. Lacono A, Groves S, Garcia J, Griffith B. Lung transplantation following 107 days of extracorporeal membrane oxygenation. European Journal of Cardio-thoracic Surgery. 2010; 37:969-71. 13. Muller G, Guillon A, Garot D, Mercier E, Perrotin D. Strategies for the withdrawal of extracorporeal membrane oxygenation for severe acute respiratory failure support: a new challenge? Anaesthesia and Intensive Care. 2012;40(2):359. 14. Gulack BC, Hirji SA, Hartwig MG. Bridge to lung transplantation and rescue posttransplant: the expanding role of extracorporeal membrane oxygenation. J Thorac Dis. 2014;6(8):1070-9.

43 Outcomes and Complications of Adult Respiratory ECLS Matthieu Schmidt, MD, PhD

Short-term Outcome of ARDS Patients on VV-ECLS Outcomes of patients with severe ARDS treated with the latest extracorporeal life support (ECLS) technology, which includes a centrifugal pump, a polymethylpentene membrane oxygenator, and tubing with biocompatible surface treatment show mortality rates ranging from 36 to 56 %. The first large international multicenter database, using 20-year data from the ESLO Registry on 1,473 patients with a median age of 34 years, reported an all-cause mortality rate of 50%.1 Risk factors associated with a poorer outcome were advanced age, days on mechanical ventilation prior to ECLS, and decreased patient weight. More recently, the randomized controlled trial CESAR of patients with severe, potentially reversible ARDS reported 63% of survival without severe disability at six months in the ECMO group.2 Patients had a mean age of 40 years and a mean APACHE II score of 20. Sixty percent had a primary diagnosis of pneumonia. In 2009, the positive results of the CESAR trial and the A(H1N1) influenza pandemic led to an exponential increase in ECLS use in severe ARDS. The short-term outcome of patients with A(H1N1) influenza-related ARDS treated with ECLS appeared positive (ie, 71% ICU survival) considering the severity at cannulation characterized by a median low-

est PaO2/FiO2 ratio of 56 mmHg, a lowest pH of 7.2, and a modified acute lung injury score of 3.8.3 However, other studies have reported better outcomes of A(H1N1) influenza-related ARDS compared to other ARDS etiologies.4,5 Lastly, similar short-term outcome has been reported in two recent cohorts by Schmidt et al. In the first cohort, the PRESERVE cohort,5 in which 140 patients from three French ICUs were studied retrospectively, Schmidt et al. report a 64% survival rate at ICU discharge and 60% survival at 6 months. This cohort includes 95% of VV-ECLS with a median time between intubation and ECLS cannulation of 5 (1–11) days for bacterial pneumonia (45%) and A(H1N1) influenza-related ARDS (26%). Interestingly, 68% patients were transported via a mobile ECLS team and their prognosis was comparable to those who received VV-ECLS support in their initial center hospital. In the second cohort, 2,355 patients from the international ELSO Registry were analyzed,4 57% of whom survived to hospital discharge after a median of 170 hours on ECLS with VV mode used for 82%. ECLS therapy was initiated after a median of 57 hours of mechanical ventilation with high positive end-expiratory pressure level, neuromuscular blocker agents (49%), inhaled nitric oxide (20%), and high-frequency oscillatory ventilation (10%).

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Long-term Outcomes after ECLS for Severe ARDS ECLS patients often experience prolonged ICU and hospital length of stay (LOS), often exceeding 1 month.1,6 Thus, evaluation of the impact of this therapy on long-term pulmonary function, quality of life (QoL), and psychological status appears crucial in the decisional process to use ECLS in ARDS patients. To date, the long-term prognosis after ECLS for ARDS remains underreported. Frenckner et al. described long-term outcome in 21 patients for the first time,7 most of whom had limited fibrosis lesions on CT scan and pulmonary function tests (PFTs) within normal limits. Similarly, patients in the ECLS arm of the CESAR trial2 exhibited comparable or better health related QoL scores (measured by the SF 36 questionnaire) than those reported by patients in the conventional arm.8,9 Exertional dyspnea was reported by 50% and 40 % of 12 influenza A (H1N1) ECMO patients and 25 controls, respectively.10 Anxiety and depressive symptoms were reported by 28% and 56% of patients respectively, whereas 40% were at risk of posttraumatic stress syndrome (PTSD).10 However, the one-year QoL in ECLS patients was poorer than a sex and age-matched general population.10 Lastly, the largest study published to date was reported by Schmidt et al.6 on a population of 84 6-month survivors. In that series, 36% of the patients reported exertional dyspnea, whereas 30% were still receiving pulmonary treatments after a median of 17-month followup. Health related quality of life (HRQL) evaluation in 80% of the 6-month survivors revealed satisfactory mental health but persistent physical and emotional related difficulties. Main ECLS Related Complications and Their Impact on Outcome Based on cohort series previously described, overall in-ICU or in-hospital mortality of 472

ARDS patients supported with ECLS remains unacceptably high. Indeed, ECLS support can cause severe and potentially life-threatening complications. Bleeding Complications Bleeding remains a major ECLS complication, with intracerebral bleeding being the most dreaded, and still widely impacts short-term outcome and the overall cost. The main mechanisms involved include anticoagulation, thrombocytopenia, and consumption of coagulation factors. In addition, impaired platelet function11 and acquired von Willebrand syndrome increase the risk of bleeding for ECLS patients.12 In a review of ECLS complications among 1763 patients, serious bleeding occurred in 33%.13 Similarly, bleeding occurred in 29% of patients on ECLS during the A-(H1N1) influenza pandemic.3 Lastly, the incidence of intracerebral bleeding for adult patients on VV-ECLS in the last ELSO database reports was 3.8%. Aubron et al. reported that red blood cells transfusion reached approximately 1 unit per day and 17% of patients underwent surgery for bleeding issues.14 However, a restrictive transfusion policy on ECLS seems possible with implementation of a lower objective for systemic anticoagulation, a fixed transfusion threshold of 7 g/dL, and an auto-transfusion during decannulation.15 Thromboembolic Events Given the significant morbidity and mortality attributed to bleeding, anticoagulation targets have generally declined over the last 5–10 years, which may increase the risk of thromboembolic events. In 2006, Rastan et al. reported autopsy results performed on 78 out of 154 patients, who died after postcardiotomy ECLS, describing major discrepancies between clinical and postmortem examination. The true incidence of thromboembolic events, which approached 50%, was highly underestimated by

Outcomes and Complications of Adult Respiratory ECLS

clinical evaluation.16 The risk of such events ARDS, a total of 146 ECMO procedures were increased with the ECLS duration, especially performed on 139 patients. Thirty-six patients beyond 6 days and was still frequent despite had a total of 46 infections (30.1 infectious systemic anticoagulation. Presently, ECLS is episodes per 1,000 days of ECLS).21 Catheter-related, cannula, and bloodstream predominantly provided using miniaturized centrifugal pumps, low resistance oxygenators, and infections, as well as ventilator associate pneuheparin-bonded circuit components. All have monia (VAP) prevalence were all collected in contributed to lower anticoagulation require- recent studies. Although the frequency varied ments. The prevalence of post-decannulation between studies, the most commonly infected deep vein thrombosis (DVT) in the cannulated site was the lung. Indeed, the frequency of VAP vessel in adults who received VV-ECLS for se- among ECLS patients was higher in the recent vere respiratory failure has been highlighted.17,18 study of Schmidt et al. (55% of all patients) Of 127 patients requiring ECLS for ARDS, underlying the discrepancies of the surveillance 9.5% reported partial vein thrombosis of the system between ECLS centers and the controcannulated vessels.18 More recently, the preva- versial use of antibiotics prophylaxis to prevent lence of DVT in cannulated vessels following NIs with ECLS patients. Lastly, from a clinical ECLS was estimated at 8.1/1,000 cannula days point of view, the time to NI occurrence is imin a cohort of 81 survivors. Routine venous portant. For instance, mean time to the first NI, Doppler ultrasound following decannulation is first VAP, and infection of the femoral cannula insertion site were 8±11, 7±12, and 12±6 days, warranted in this population. respectively.20 NI occurrence during ECLS Infectious Complications was consistently independently associated with death in ICU. Also the risk of NIs increases The high incidence of nosocomial infec- with patient severity at ICU admission and with tions (NIs) during ECLS contributes to poor longer duration of ECLS support.20,21 To date, outcomes. Altered immunity, cannulation of specific strategies for the prevention of ECLSgreat vessels, and insertion of invasive devices associated infections have not been rigorously (endotracheal tube, central venous catheter, studied. Research on preventive strategies on urinary catheter) increase the risk of develop- ECLS such as antibiotic prophylaxis, routine ing NIs. Few studies have reported infections surveillance cultures, or the use of chlorhexicomplications in adults receiving ECLS and in dine gluconate-impregnated sponges in cannula most of them, indication for ECLS was both dressing is warranted. respiratory and cardiac failure. A recent report based on the ELSO Registry showed that the Hemolysis adult infection rate was higher than newborns (30.6 vs. 10.1 per 1000 ECLS day), especially Minor hemolysis commonly occurs during for patients requiring ECLS for cardiogenic VV-ECLS. A study of 207 pediatric patients shock (37 per 1000 ECLS day).19 Schmidt et with ECLS reported at least one episode of al. reported a total of 142 (64%) NIs (75.5 per hemolysis in 66% patients.22 Hemolysis was 1000 ECLS day) among 220 patients who un- classified as mild (48 hours ECLS support for refractory 1.0 g/L) or severe (50 mg/dL, occurred in 3.9% of survivors and 15.9 % of non-survivors (p=0.002) and a Cox proportional hazard analysis identified hemolysis as an independent predictor of mortality (OR=3.4, 95% confidence interval: 1.3-8.8, p=0.01).23 Further study to investigate causes of hemolysis on ECLS and to confirm its influence on morbidity and mortality are warranted.

while maintaining Plateau pressure 30 cmH20 and inability to increase pre-ECMO PEEP above 10 cmH20 474

Outcomes and Complications of Adult Respiratory ECLS

Conclusion Although the use of ECLS for severe refractory ARDS has markedly increased since 2009, the hospital mortality of these patients remains high (from 35 to 45%). In addition, despite major technological improvement of the devices, this technology remains marred by numerous complications, which might occur during long ECLS runs. This specific management reinforces the need to perform ECLS in high volume and expert referral centers. In addition, greater knowledge of the impact of such complex therapy on long-term pulmonary function, quality of life, and psychological status is warranted.

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References 1. Brogan TV, Thiagarajan RR, Rycus PT, Bartlett RH, Bratton SL. Extracorporeal membrane oxygenation in adults with severe respiratory failure: a multicenter database. Intensive Care Med. 2009;35(12):2105-2114. 2. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374(9698):1351-1363. 3. Davies A, Jones D, Bailey M, et al. Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome. JAMA. 2009;302(17):1888-1895. 4. Schmidt M, Bailey M, Sheldrake J, et al. Predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score. Am. J. Respir. Crit. Care Med. 2014;189(11):1374-1382. 5. Schmidt M, Combes A. Influence of ventilatory strategy on the PRESERVE mortality risk score: response to Camporota et al. Intensive Care Med. 2014;40(6):916. 6. Schmidt M, Zogheib E, Roze H, et al. The PRESERVE mortality risk score and analysis of long-term outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. Intensive Care Med. 2013;39(10):17041713. 7. Frenckner B, Palmer P, Linden V. Extracorporeal respiratory support and minimally invasive ventilation in severe ARDS. Minerva Anestesiol. 2002;68(5):381-386. 8. Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of the

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acute respiratory distress syndrome. N Engl J Med. 2003;348(8):683-693. 9. Schelling G, Stoll C, Haller M, et al. Healthrelated quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome. Crit Care Med. 1998;26(4):651-659. 10. Luyt CE, Combes A, Becquemin MH, et al. Long-term outcomes of pandemic 2009 influenza A(H1N1)-associated severe ARDS. Chest. 2012;142(3):583-592. 11. Cheung PY, Sawicki G, Salas E, Etches PC, Schulz R, Radomski MW. The mechanisms of platelet dysfunction during extracorporeal membrane oxygenation in critically ill neonates. Crit. Care Med. 2000;28(7):25842590. 12. Heilmann C, Geisen U, Beyersdorf F, et al. Acquired von Willebrand syndrome in patients with extracorporeal life support (ECLS). Intensive Care Med. 2012;38(1):62-68. 13. Zangrillo A, Landoni G, Biondi-Zoccai G, et al. A meta-analysis of complications and mortality of extracorporeal membrane oxygenation. Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine. 2013;15(3):172178. 14. Aubron C, Cheng AC, Pilcher D, et al. Factors associated with outcomes of patients on extracorporeal membrane oxygenation support: a 5-year cohort study. Crit Care. 2013;17(2):R73. 15. Agerstrand CL, Burkart KM, Abrams DC, Bacchetta MD, Brodie D. Blood conservation in extracorporeal membrane oxygenation for acute respiratory distress syndrome. Ann. Thorac. Surg. 2015;99(2):590595. 16. Rastan AJ, Lachmann N, Walther T, et al. Autopsy findings in patients on postcardiotomy extracorporeal membrane oxygenation (ECMO). Int. J. Artif. Organs. 2006;29(12):1121-1131.

Outcomes and Complications of Adult Respiratory ECLS

17. Cooper E, Burns J, Retter A, et al. Prevalence of Venous Thrombosis Following Venovenous Extracorporeal Membrane Oxygenation in Patients With Severe Respiratory Failure. Crit. Care Med. 2015;43(12):e581-584. 18. Camboni D, Philipp A, Lubnow M, et al. Support time-dependent outcome analysis for veno-venous extracorporeal membrane oxygenation. Eur. J. Cardiothorac. Surg. 2011;40(6):1341-1346;discussion 13461347. 19. Bizzarro MJ, Conrad SA, Kaufman DA, Rycus P. Infections acquired during extracorporeal membrane oxygenation in neonates, children, and adults. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2011;12(3):277-281. 20. Schmidt M, Brechot N, Hariri S, et al. Nosocomial infections in adult cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation. Clin. Infect. Dis. 2012;55(12):1633-1641. 21. Aubron C, Cheng AC, Pilcher D, et al. Infections acquired by adults who receive extracorporeal membrane oxygenation: risk factors and outcome. Infect. Control Hosp. Epidemiol. 2013;34(1):24-30. 22. Lou S, Maclaren G, Best D, Delzoppo C, Butt W. Hemolysis in pediatric patients receiving centrifugal-pump extracorporeal membrane oxygenation: prevalence, risk factors, and outcomes*. Crit. Care Med. 2014;42(5):1213-1220. 23. Omar HR, Mirsaedi M, Socias S, et al. Plasma Free Hemoglobin is an Independent Predictor of Mortality among Patients on ECMO Support. PLOS 2015 24. Hodgson CL, Hayes K, Everard T, et al. Long-term quality of life in patients with acute respiratory distress syndrome requiring extracorporeal membrane oxygenation

for refractory hypoxaemia. Crit Care. Oct 19 2012;16(5):R202. 25. Hemmila MR, Rowe SA, Boules TN, et al. Extracorporeal life support for severe acute respiratory distress syndrome in adults. Ann. Surg. 2004;240(4):595-605; discussion 605-597. 26. Schmidt M, Bailey M, Sheldrake J, et al. Predicting Survival after ECMO for Severe Acute Respiratory Failure: the Respiratory ECMO Survival Prediction (RESP)-Score. Am J Respir Crit Care Med. 2014;189(11):1374-1382. 27. Roch A, Hraiech S, Masson E, et al. Outcome of acute respiratory distress syndrome patients treated with extracorporeal membrane oxygenation and brought to a referral center. Intensive Care Med. 2014;40(1):7483. 28. Enger TB, Philipp A, Videm V, et al. Prediction of mortality in adult patients with severe acute lung failure receiving venovenous extracorporeal membrane oxygenation: a prospective observational study. Crit Care. 2014;18(2):R67. 29. Pappalardo F, Pieri M, Greco T, et al. Predicting mortality risk in patients undergoing venovenous ECMO for ARDS due to influenza A (H1N1) pneumonia: the ECMOnet score. Intensive Care Med. 2013;39(2):275281. 30. Campbell BT, Braun TM, Schumacher RE, Bartlett RH, Hirschl RB. Impact of ECMO on neonatal mortality in Michigan (19801999). J Pediatr Surg. 2003;38(3):290-295; discussion 290-295. 31. Jen HC, Shew SB. Hospital readmissions and survival after nonneonatal pediatric ECMO. Pediatrics. 2010;125(6):1217-1223. 32. Karamlou T, Vafaeezadeh M, Parrish AM, et al. Increased extracorporeal membrane oxygenation center case volume is associated with improved extracorporeal membrane oxygenation survival among

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pediatric patients. J. Thorac. Cardiovasc. Surg. 2013;145(2):470-475. 33. NHS NICE GUIDANCE, last accessed March 14th 2014, http://www.nice.org.uk/ guidance/IPG391/. 34. ECMOnet, last accessed March 14th 2014, http://www.ecmonet.org/. 35. NSW Critical Care Tertiary Referral Networks and Transfer of Care (ADULTS), last accessed March 14th 2014, http://www0. health.nsw.gov.au/policies/pd/2010/pdf/ PD2010_021.pdf. 36. Combes A, Brodie D, Bartlett R, et al. Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients. Am. J. Respir. Crit. Care Med. 2014;190(5):488-496. 37. Beurtheret S, Mordant P, Paoletti X, et al. Emergency circulatory support in refractory cardiogenic shock patients in remote institutions: a pilot study (the cardiac-RESCUE program). Eur Heart J. 2013;34(2):112-120. 38. Forrest P, Ratchford J, Burns B, et al. Retrieval of critically ill adults using extracorporeal membrane oxygenation: an Australian experience. Intensive Care Med. 2011;37(5):824-830. 39. Linden V, Palmer K, Reinhard J, et al. High survival in adult patients with acute respiratory distress syndrome treated by extracorporeal membrane oxygenation, minimal sedation, and pressure supported ventilation. Intensive Care Med. 2000;26(11):16301637.

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44 Adult Cardiovascular Defects, Diseases, and Procedures that Predispose to ECLS Roberto Lorusso, MD, PhD, Mirko Belliato, MD, Patrick Weerwind, PhD, Sandro Gelsomino, MD, PhD, Jos Maessen, MD, PhD

Acute Myocardial Infarction Currently, the optimal therapy for acute myocardial infarction (AMI) is primary percutaneous coronary intervention (PCI), and despite early revascularization, 6% to 10% of patients with AMI with ST-segment elevation present refractory cardiogenic shock (RCS). The mortality rate in this clinical scenario ranges from 40% to 80%, and with a rather constant incidence over time.1-6 RCS is usually defined as systolic blood pressure 4 mml/L,52 and incomplete sternal closure are factors which seem to increase mortality if ECMO is applied after surgery (Table 44-1). Interestingly, the relation between age and the use of ECMO in the postcardiotomy setting was investigated by several groups, and contradictory findings have been reported.1,38-46 It seems, however, that although a higher mortality rate can be expected,53,54 there are no contraindications to the application of such temporary support in older patients.45 Furthermore, although mid- and long-term followup has been poorly investigated, it has been shown that hospital survivors from ECMO implant, regardless of their age, have rather satisfactory mid- and long-term outcomes, with cumulative survival rates higher than 50% at five years.11,38,39 Postcardiac transplant graft failure deserves a short commentary. It has been shown that posttransplant cardiac graft failure occurs in 2% to 26% of transplanted patients,47-50 with a clear benefit from an early implant with regard to patient survival.51 ECMO weaning may achieve very satisfactory results, with more than 80% of

Adult Cardiovascular Defects, Diseases, and Procedures that Predispose to ECLS

the patients weaned, and with relatively short ECMO duration.47 LV unloading, in this setting, appears to be critical, and, although careful attention based on the extreme susceptibility of the transplanted graft to any kind of ischemia47

is certainly warranted, more liberal application of LV venting still remains a controversial issue and its actual benefits are yet to be demonstrated conclusively.

Table 44-1. Published series of extracorporeal membrane oxygenation implanted in postcardiotomy patients. Author

Ref

Pts (nr.)

Prevalence° (%)

Ko

1

76

2.6%

Smedira

38

97

0.48%

ECMO Duration (mean±SD, hrs if available) 132±139^^ 118±57§§ 99±33# 48-72¶

Weaning (%)

Survival to Hospital Discharge (%)

46,7%

26.3%**

Acute renal failure requiring dialysis on ECMO

39.2%¶¶

35%

na

Predictors of Hospital Mortality

Age>70 years, Diabetes, Obesity, Preop chronic renal failure, Operative Rastan 39 517 1.2% 78,7±68.4 63.3% 24.8% lactate >4 mmol/L, Logistic Euroscore >20 Older age, Higher preoperative albumin, Diabetes Elsharkawy 40 239 0.58% na na 36% history, CABG surgery, Longer CPB time Age >60 yrs,CVVH, Total Bilirubin>6 Wu 42 110 2.6% 143±112 60.9% 43.6% mg/dl, ECMO duration >110hrs Preop atrial fibrillation, Chronic renal failure, Lactic Saxena 43 45* na 103±74.3 53.3% 24.4% acidosis on ECMO, Persistent coagulopathy on ECMO Age >65 years, 85±12.5^ Fiser 44 51 0.9% 31% 16% LVEF< 30% after 64.7±9.2§ 48 hours on ECMO CK-MB relative Zhang 45 32 na 64.8±40.8 43.7% 25% index as the ratio of CK-MB to total CK Incomplete sternal Unosawa 46 47 na na 61.7% 29.7% closure, ECMO support >48 hours Pts=patients; °=In relation to global cardiac surgery activity; ¶=Institute strategy implies to keep ECMO for 48-72 hours and then switch to VAD or heart transplant; ¶¶=18 patients underwent heart transplant; *=this publication deals with elderly patients (>70 years of age) only; CVVH=continous venovenous hemofiltration; CABG=coronary artery bypass surgery; CPB=cardiopulmonary bypass; ^=heart transplant patients; §=non-heart transplant patients; ^^=died on ECMO; §§=weaned from ECMO, but died in hospital; #=survivors to hospital discharge; **=Other patients were bridged to VAD or heart transplant

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Acute Myocarditis Acute myocarditis (AM) frequently has a benign course with rather rapid cardiac recovery and favourable early and midterm outcome.55 Rarely, however, a more malignant course, namely acute fulminant myocarditis (AFM), might occur with rapidly refractory hemodynamic compromise ultimately leading to patient death if no mechanical cardiocirculatory support is promptly instituted.56-71 The etiology of acute myocarditis is often undefined, but viral or other infective agents apparently represent the most frequent cause.55-59,70 Endomyocardial biopsy is considered the gold standard in the diagnostic workup, although this procedure remains largely underutilized and has shown low negative predictive value.55-58,69,71 Markers of myocardial damage provide relevant information about the extent of ongoing cardiac compromise and chance of recovery.72,73 High troponin-I levels have been shown to be associated with a more malignant form of AM (less than one month duration) suggesting that myocardial necrosis is an early event requiring a prompt diagnosis and aggressive treatment to limit such an overwhelming process.72 McCarthy and colleagues have interestingly linked AFM to a more favourable outcome as compared to nonfulminant pattern of AM.74 In their experience only two patients needed mechanical circulatory support indicating a more benign form of AFM in that patient cohort.74 Generally speaking, a lethal outcome, unless aggressively and rapidly treated primarily with cardiocirculatory assistance, is likely in AFM. Indeed, severe dysfunction of both cardiac ventricular chambers is almost invariably present.60,61,64,66,69,71,75 The efficacy of VA-ECMO in such cases has been consistently proven and is advisable based on the ease and speed of implantation, on the immediate biventricular as well as respiratory assistance, and on a limited resource consumption as compared to other assist devices.59-71 ECMO is an invaluable tool 484

in these patients since cardiac recovery is expected in the majority of the affected patients within a relatively short time.59-71,75 In AM and particularly in AFM, careful daily monitoring of cardiac function and related aspects is warranted. Significant stasis of blood in the left atrium or left ventricle may occur due to extremely poor contractility, making appropriate peripheral perfusion almost entirely dependent on ECMO flow, a condition which often leads to permanent aortic valve closure or reduced blood flow across the mitral valve due to high intraventricular pressure. Left chamber venting may, therefore, be warranted more often than in other ECMO settings.71,76 Complications are frequent, as in all ECMO settings, and may have a significant negative impact on in-hospital outcome.59-72 The use of associated immunosuppressive therapy on ECMO is still controversial,77 although a benefit of such a complementary treatment in case of poor response to cardiocirculatory support has been reported.78 Despite severe myocardial involvement cardiac recovery in AM usually takes place within 7 to 10 days,59-71,75 although this period may be longer. Published VA-ECMO weaning rates after cardiac recovery in AFM range from 66% to 100% with survival to hospital discharge ranging from 60% to 100% (Table 44-2). The extent of end-organ and myocardial compromise, as previously measured by the amount of cardiac-related enzyme release or lactate levels at the time of ECMO implantation, and the time-to-normalization of end-organ perfusion as expressed by a significant reduction of lactate levels, have been directly related to the probability of cardiac improvement, ECMO weaning, and in-hospital survival.68,71,73 Recently data from 147 patients included in the ELSO Registry have been reported, showing a hospital discharge of 61%, with pre-ECMO arrest, need for higher ECMO flows at 4 hours postimplant, central nervous system injury, renal failure, arrhythmia, and hyperbilirubinemia

Adult Cardiovascular Defects, Diseases, and Procedures that Predispose to ECLS

being independent predictors of in-hospital death at multivariable analysis.62 In a small proportion of patients, a switch to more durable and sophisticated devices or to heart transplant is mandatory due to lack of cardiac recovery (Table 44-2). The overall outcome of patients transplanted in these circumstances is still less than optimal,71,75 probably because patients requiring such surgical treatment are often in suboptimal clinical condition with end-organ failure and are usually exposed

to prolonged ECMO support and therefore have higher complication rates.60,71,75 However, favourable early and midterm outcomes in patients supported with VAD or with heart transplantation have also been reported.68 Following heart recovery and hospital discharge, AM recurrence is uncommon and can effectively be treated with medical therapy.68,70,71 Mid and long-term results of patients submitted to VA-ECMO for AM or AFM are good, unless temporary myocardial disease resulted in per-

Table 44-2. Published series of extracorporeal membrane oxygenation in acute fulminant myocarditis.

Author

Ref Pts

ECMO Weaning Pts (%)

ECMO Duration (mean±SD, hrs, if available)

Pts Switched to LVAD or Heart Transplant

Survival to Hospital Postop Survival Discharge (%)(mean followup) Pts (%)

Aoyama 61

52

42 (80.7%)

186±134

na

31 (59.6%) na

Diddle

62

147

101 (69%)

138

9^

90 (61%)

na

Pages

63

6

5 (83%)

312±96

1*

5 (83%)

80% (1 year)

Chen

65

15

14 (93%)

129±50

2*

11 (73%)

na

Hsu

66

51

na

171.5±121 (incl 6* - 3^ (incl 31 (61%) pediatric pts) pediatric pts)

na

Ishida

67

20

12 (60%)

na

0

12 (60%)

100% (2.6±2.1 years)

Mirabel

68

35

na

240

4^

24 (69%)

100% (1.5 years)

Asaumi

69

6

4 (67%)

130

1*

4 (67%)

na

Maejima 70

8

na

na

0

6 (75%)

100% (range 1.4 - 5.9 years)

Lorusso

71

57

43 (75.5%)

237±456

2* - 3^

41 (71.9%)

65.9% (5 years)

Su

75

14

9

131 (txp pts excluded)

2^

10 (71,4%)

100% (4 years)

(64.2%)

Pts=patients; LVAD=left ventricular assist device; SD=Standard Deviation;*=pts switched to LVAD; ^=pts swtiched to heart transplant

485

Chapter 44

manent LV dysfunction. In these cases, a less favourable prognosis, similar to other chronic heart failure conditions, is expected following hospital discharge.71 In summary, ECMO for AM in its most malignant form represents an extremely effective tool to counteract or limit the life-threatening progression of ongoing myocardial damage and dysfunction, and despite a rather high rate of complications, myocardial recovery can be expected in a relatively short time, with very few patients requiring more aggressive therapies. The long-term outcome is also favourable, although it remains less defined in patients switched to VAD or heart transplant as well as in those showing persistent LV dysfunction at hospital discharge.

combination with coronary ischemia. Because of ventricular interdependence, RV dilatation in acute severe PE leads to paradoxical interventricular septal shift that deforms the LV cavity and results in diastolic LV function impairment and compromised LV filling leading to reduction of LV output, systemic hypotension, and ultimately to severe haemodynamic instability.84 Respiratory insufficiency in PE is mainly caused by circulatory imbalance.85 Low cardiac output results in ventilation-perfusion mismatch, leading to hypoxemia. The ventilation of lung units with absent or reduced perfusion induces increased dead space ventilation with the resultant increase of the end-tidal to arterial CO2 gradient, and finally hypercapnia. The therapeutic options according to the American Heart Association80 include thromboAcute Pulmonary Embolism lytic therapy. This is a reasonable choice with an acceptable risk of bleeding complications Pulmonary embolism (PE) is one of the for MAPE, and may be considered also for less most undiagnosed conditions in hospitalized pa- massive PE with clinical evidence of an adverse tients, with an overall mortality rate up to 15%.79 prognosis, with severe right ventricular (RV) Rapid, efficient strategies of investigation and dysfunction and hemodynamic instability or management are necessary. When massive acute increasing respiratory failure. Surgical embopulmonary embolism (MAPE) occurs, acute lectomy and catheter-based techniques should right ventricular failure and cardiogenic shock be considered in patients with contraindications often result in early death. The American Heart to systemic thrombolysis or continued instabilAssociation and the European Society of Car- ity after thrombolysis, and may be mandatory diology guidelines define massive PE as acute for less massive PE with worsening respiratory PE with sustained hypotension (systolic blood failure or severe RV dysfunction. pressure 40 mmHg for at least 15 minutes or requiring should always be made on the basis of local inotropic support).80,81 hospital expertise and experience with a patientBoth circulation and gas exchange are centered approach. compromised during acute PE. Pulmonary The use of ECMO is a potentially lifesavarterial obstruction of more than 30–50% of ing therapeutic option that can provide clinical the total cross-sectional area of the pulmonary stability allowing definitive treatment if the arterial bed82 and subsequent release of vaso- patient is critically ill due to severe cardiogenic active substance (serotonin, thromboxane A2) shock, previous cardiac arrest, severe acidosis, lead to acute pulmonary hypertension.83 Such a or untreatable hypoxemia. ECMO can be used hemodynamic state causes a pressure overload as standalone treatment without any further and an increase in right ventricle (RV) afterload definitive therapy, and some cases of successcausing RV failure, which is considered to be ful use of ECMO as standalone treatment have the primary cause of death in severe PE, often in been recently reported.85,86 486

Adult Cardiovascular Defects, Diseases, and Procedures that Predispose to ECLS

The rationale of ECMO as a support for RV failure in MAPE, in a venoarterial configuration, is to divert the blood from right to left circulation bypassing the pulmonary bed which relieves the RV pressure overload, does not cause further elevation of the pulmonary pressures, and increases left-sided pressures.87 VA-ECMO allows the unloading of the acutely overloaded right atrium and ventricle, thereby improving LV output due to ventricular interdependence.88 Beside stabilizing the hemodynamic status, VA-ECMO relieves hypoxemia, which ensures adequate organ oxygenation and allows therapeutic anticoagulation until clot dissolution. Patients requiring ECMO have extensive pulmonary thromboemboli, and therefore the aggressive use of catheter-based intervention appears to have beneficial effects in case of MAPE, making quick weaning of the patient from the extracorporeal support possible.89 The most used approach for VA-ECMO, in up to 80% of the patients, is femoral cannulation. This technique allows rapid cannulation at the bedside so the correction of the abnormal physiological status can start immediately, thereby preventing severe organ failure by providing full cardiorespiratory support until clot dissolution occurs with systemic heparinization or by the definitive therapy. Venovenous ECMO can only be used if the patient does not have any severe hemodynamic impairment but only major hypoxia and this strategy needs to take into account the possible presence of residual thrombus in the deep vein (femoral or jugular) or in the right atrium. An interesting solution could be venoarterial-venous ECMO (VAV-ECMO) that can support circulation and oxygenation. This technique can totally solve the Harlequin Syndrome when the patient’s heart still has a residual ejection function. VAV-ECMO is not simple to configure and it needs extensive monitoring of the blood flow in both inlet branches and outlet pressure (to avoid arteriovenous shunting between the two outlet cannulas).

The successful use of standalone ECMO in some cases, without any other definitive therapy, can possibly be explained by the effect of continuous and effective systemic heparinization. It has been shown that autolysis of the thrombus, allowing RV recovery, is possible within five days in the absence of hypercoagulable disorders such as factor V Leiden disease, antiphospholipid syndrome, and malignancy states.90 ECMO for selected patients with massive PE is associated with favourable outcomes. Indeed, the ELSO Registry reports the survival of patients supported by ECMO for respiratory and cardiac failure to discharge or transfer back to the referring hospital to be 56% and 30%, respectively.91 Patients presenting in cardiac arrest have worse outcomes (survival 29%),92 but other data93 suggests that patients with massive PE presenting in cardiac arrest are more likely to survive with good neurological outcomes (survival 51%) with a measured cerebral performance in category 1 or 2. Maggio and collaborators89 developed an algorithm for the management of suspected PE with impending or existing RV failure. The most interesting part of that algorithm is the placement of inferior vena cava filters, preferably before the patients could be weaned from ECMO but before decannulation. For this the use of a drainage cannula placed in the internal jugular vein is necessary. ECMO use in the context of massive PE should be considered, balancing possible benefits and the chance of recovery without significant neurological sequelae on one hand and the potential risks on the other hand. The major complication of ECMO use in PE is massive bleeding and this occurs as a result of systemic thrombolysis, of persistent changes in the coagulation due to the hepatic shock, or of uncontrolled fibrinolysis that induces a disseminated intravascular coagulopathy.94 In conclusion a rapidly implanted ECMO support system can be a lifesaving treatment in the setting of massive MAPE and the risks of 487

Chapter 44

this therapeutic strategy are well justified by the good results in the category of patients with a very high risk for morbidity and mortality. Cardiogenic Shock in Other (Rare) Non Surgery-Related Etiologies

Other challenging and life-threatening conditions are represented by malignant arrhythmias or electrical storms which may be sometimes refractory to aggressive pharmacological agents or to repeated electrical shocks, which are used for hemodynamic stabilization and recovery of normal cardiac electrical activity.102,103 Although uncommon, these experiences suggest that ECMO might be considered a valuable option to counteract cardiocirculatory dysfunction due to variable etiologies which are refractory to medical therapy, as well as for treating acute circulatory impairment which can be the consequence of poisoning.

In patients with life-threatening hemodynamic instability, VA-ECMO can be considered when shock persists despite volume administration, the use of inotropes and vasoconstrictors, and IABP implantation. There are several rare, but life-threatening conditions which are characterized by refractory cardiocirculatory impairment which might benefit from prompt and temporary assistance of the circulation. A series of 12 patients affected by endo- Cardiocirculatory Support or Bailout crine-related cardiogenic shock have been Assistance During Interventional Cardiology reported by Chao and collaborators.95 In this Interventional cardiology is certainly an series, endocrine emergencies included cardiocirculatory crisis secondary to pheocromo- emerging setting for ECMO application.104,105 cytoma (4 patients), thyroid storm (5 patients), Indeed, temporary cardiocirculatory support has and diabetic ketoacidosis (3 patients). The been used for various indications, ranging from clinical features were different depending on prophylactic support in high-risk PCI or transthe underlying endocrine disorder, but were catheter procedures, to bailout approach in case equally compromising the cardiocirculatory of cardiac arrest or shock during or following system with severe and RCS. In all patients, cardiological interventions. Arlt and colleagues the cardiac function and the general conditions have reported the use of ECMO in ten patients showed a fast recovery, whereby only a short in cardiac arrest which occurred during PCI or period of ECMO support was necessary.95 The transcatheter aortic valve implantation (TAVI) use of ECMO to successfully counteract RCS with a percutaneous approach.106 All patients in a pheochromocytoma crisis has been reported had heart activity rapidly restored, and two in other cases.96-98 TAVI patients were converted to surgical aortic ECMO has been shown to be life-saving valve replacement while on ECMO, whereas in and highly effective also in the presence of all PCI cases ECMO allowed the completion of Takotsubo-like or related syndromes.99-100 This the coronary intervention during cardiocirculawell known stress-induced and related myocar- tory assistance. In this series of patients with a dial dysfunction is associated with disparate mean age of 73 years the survival to hospital conditions, ranging from intraoperative to discharge was 50%, with one patient eventually pregnancy or pharmacologycally solicited hy- undergoing heart transplantation. Causes of perreactive myocardial response.99-101 Duration death were multiorgan failure in 3 cases (43%), of ECMO support may also vary remarkably bowel ischemia in 2 (28%), and nonreversible in these circumstances from a few hours to a cardiac failure in 2 (28%). The Regensburg few days.99-101 group has published a series of eight patients undergoing TAVI who were submitted to ECMO 488

Adult Cardiovascular Defects, Diseases, and Procedures that Predispose to ECLS

because of complications, and nine patients high. These conditions may be perioperative had TAVI while on prophylactic ECMO. They refractory hypoxemia, severe acidosis with showed that ECMO may also be valuable in profound cardiovascular impairment, ongoing bail-out cases, but the mortality remains high severe cardiac damage or left and right severe in these circumstances.107 ventricular dysfunction which might further Interestingly, ECMO might be used also as be exacerbated by the myocardial ischemia a temporary support to improve different trans- inevitably generated by open heart surgery. A catheter procedures in case the patients require short period of hemodynamic and metabolic emergent cardiac defect correction, but have stabilization and compensation prior to the concurrent multi-organ failure which cannot be surgical procedure might be beneficial in these treated surgically. Temporary ECMO support circumstances, bring the patient in a better cliniduring Mitraclip (MitraClip®, Abbott Labora- cal and metabolic condition to undergo surgery, tories, Abbott Park, Illinois, U.S.) application and reduce or prevent intra or perioperative has been shown to be feasible and effective.108 complications. Short-term mechanical assistance was also There are several case reports about the shown to be beneficial in the presence of inces- use of prophylactic ECMO in the presence of sant ventricular fibrillation.109 In these cases, post acute myocardial infarction ventricular ECMO might act as cardiocirculatory support septal defect.110-113 It is of note that delaying the during electrophysiological procedures, and surgical correction might improve the chance with a special circuit configuration (Y-connector of a successful surgical repair because of better in the arterial cannula to allow passage of the tissue strength, but this delay could increase the ablation catherer, and keeping higher ECMO right and left ventricular dysfunction which can flows during the interventional procedure) be associated with the intracardiac defect. Rohn might be effectively applied even in these criti- and Hobbs have independently reported about the use of ECMO as a preoperative bridge to cal circumstances. These experiences are anecdotal and, as definitive surgical repair of postinfarction vensuch, do not represent evidenced-based indica- tricular septal defect (VSD),110-115 and Tsai and tions, but offer a new perspective in handling colleagues have used ECMO support as a bridge a compromised circulation in an emergency to definitive surgery in a patient with recurrent situation when a cardiac intervention is neces- VSD following initial surgical repair.114 sary to interrupt a vicious cycle and a surgical A bridge to cardiac surgery with ECMO procedure cannot be performed because of a might be applied also in other surgery related prohibitive risk. conditions like acute mitral insufficiency due to papillary muscle rupture,115 or left ventricular Preoperative Support (postinfarct ventricular free wall rupture.116,117 ECMO can be used also septal defect, papillary muscle or left free as a stand alone support to allow recovery of left ventricular free wall rupture without surgiwall rupture, acute endocarditis) cal repair118. Acute endocarditis may be the cause of Other potential scenarios of ECMO use in cardiovascular medicine are represented by acute severe cardiocirculatory compromise eiacute cardiac defects with severe RCS with or ther due to valve insufficiency and cardiac dyswithout respiratory impairment which might function leading to hemodynamic deterioration benefit from surgical correction, but the risk or to a refractory septic state. ECMO, besides for operative or perioperative complications septic shock, may have a role as prompt supand a fatal outcome is considered to be too port in case of cardiopulmonary deterioration 489

Chapter 44

(also in septic shock) and bridge the patients to the surgical correction of the endocarditisrelated valve abnormalities.119,120 ECMO may be particularly valuable in those patients who present with biventricular dysfunction, often with multivalvular infectious involvement. In such circumstances ECMO may provide pre and perioperative support, particularly for the dysfunctional right ventricle which often is the cause of the unfavourable outcome. Despite effective cardiocirculatory assistance the removal of the source of the infection and the correction of concurrent valve dysfunction must be promptly addressed and carried out since the persistence of such conditions and maintaining a conservative approach usually leads to intractable septic shock and ultimately to the death of the patient121. Acutely Decompensated Chronic Cardiomyopathy The term chronic cardiomyopathy (CCM) refers to a number of diseases that affect the heart by compromising the cell and the related interstitium, ultimately leading to severe contractile impairment characterized by a rather long-lasting course. Cardiomyopathy can have different causes: it can be genetic; it can occur as result of metabolic or nutritional disorders; be secondary to long-term hypertension, coronary disease, or cardiac valve dysfunction; and even be pregnancy related. Sometimes, however, cardiomyopathy occurs with no discernible cause, and is than called idiopathic cardiomyopathy. There are three main types of cardiomyopathy: hypertrophic, dilated, and restrictive. This section will deal only with dilated CCM, either ischemic or idiopathic, as this is the most common for potential ECMO use. Dilated CCM is a severe myocardial disease characterized by dilatation and impaired function of the left or both ventricles, which affects >36.5 individuals per 100,000.122 Although this type can affect people of all ages, it occurs more 490

often in the middle-aged population and is more likely to affect men. It has a considerable annual mortality rate, ranging from to 5% to 10%.122 Sudden death accounts for up to 50% of all deaths and is most often due to rapid ventricular tachycardia or ventricular fibrillation and less often due to bradyarrhythmias or asystole.123 Patients affected by CCM may progress through a variable time-related asymptomatic phase of cardiac dysfunction, which can usually be well controlled by medical therapy, but after a certain amount of time they may develop episodes of acute heart failure, or the heart evolves toward an end stage cardiac dysfunction.122 These patients are at a higher risk for death as compared to other patients with acute RCS since this situation is usually associated with exhausted cardiac reserve and long-lasting dysfunction of other organs, namely liver, kidney, and gut. Furthermore, long-lasting aggressive pharmacological therapy make these patients also poor or nonresponders to maximal medical therapy in the presence of acute decompensation. Cardiogenic shock remains a life-threatening emergency with a overall mortality rate ranging from 50% to 80%.124 The treatment of RCS in the presence of CCM is more challenging than in the situation of primary acute heart failure. Mechanical circulatory support is, in most of these circumstances, the only form of therapy that may be lifesaving. Patients can be in preshock condition due to long-lasting cardiac and endorgan hypoperfusion. VA-ECMO definitely represents a valuable and immediate support to improve hemodynamics, gas exchange, and consequently organ perfusion. It has been demonstrated that VA-ECMO implantation quickly restores hemodynamic function. Lactate, creatinine, and transaminases serum levels will be reduced, leading to less need for vasopressor and inotropic agents; in this way the perfusion of the organs is improved and the myocardial oxygen consumption is reduced.125 Tarzia and colleagues have recently shown that patients

Adult Cardiovascular Defects, Diseases, and Procedures that Predispose to ECLS

treated with VA-ECMO for acutely decom- should be optimized to improve the bridge-topensated CCM had a higher rate of end-organ bridge function to more aggressive therapies dysfunction, needed more frequently inotropes like VAD or heart transplant.129,130 VA-ECMO and also higher doses, had more renal failure may also help to ascertain the suitability of (67% vs. 38%), and hepatic failure (48% VAD implantation and cardiac transplant, and vs. 19%), and needed higher ECMO flow to to obtain clinical stability prior to considering achieve good organ perfusion, as compared to VAD insertion as “destination therapy,” and the group of patient with acute primary RCS.126 reduce mortality and morbidity following VAD Furthermore, recovery was achieved only in the or cardiac transplant procedures.126,127,129,130 Maracute group. They suggested that patients with asco and colleagues have compared 23 patients an acute failure of CCM need an early ECMO who received VA-ECMO prior to VAD with implantation and, probably, multiorgan support 35 patients who had VAD without previous if the low cardiac out state is already established circulatory support, and have shown how the at the start of ECMO. These authors showed ECMO-related group had more comorbidities that in the CCM group (27 patients), 85% of and end-organ dysfunction prior to VAD imthe patients were switched to VAD (52%) or plant, but the final outcome was comparable to to heart transplant (33%), as compared to the the other group. This indicates that ECMO may patients with acute heart failure of which 8% lead to clinical improvement prior to the subseunderwent a heart transplant, 24% had a bridge- quent procedure and improve the final outcome to-bridge procedure and 49% recovered.126 by reducing the expected higher morbidity and Furthermore, the long-term survival of the two mortality130. groups did not differ (77% at one month, 56% The use of ECMO allows survival to be at six months, and 51% at one year in the acute maximized in patients who are otherwise heart failure group, and 71%, 56%, and 55% untreatable and face an extremely severe progin the CCM group, respectively).126 These data nosis in CCM, regardless of the etiology of the are in contrast with the series of Bermudez and cardiomyopathy. In the context of chronic procollaborators, who showed a comparable early gressive cardiac failure, ECMO may represent outcome, but a remarkably less favorable results the ultimate rescue strategy, and could save at midterm in the CCM group as compared to the patient’s life by functioning as a bridge-topatients supported for a primary acute failure bridge tool, or bridge to transplant. If the patient (64%, 48% and 48% at 30 days, one year and is not a candidate for one of these two options, two years in the acute group, versus 56%, 11% the caregiver’s team should carefully reconsider and 11%, in the CCM group, respectively).127 the indication for implantation of ECMO supThe most common and safe cannulation port. This is to avoid the indiscriminate use of approach is peripheral implantation as a bifemo- this highly technological tool and encourage ral VA-ECMO. Central cannulation is still an instead its use at the right time and in the right option, but has a higher rate of complications, patients so they can have a chance for survival due to the prolonged cardiac support and a and a longer life.131 higher risk for limb ischemia. The use of axillary artery cannulation for blood return might Conclusions be considered and could, in these cases, give It has become increasingly evident that better access.128 As mentioned, myocardial recovery in pa- ECMO represents a valuable tool in the prestients with CCM is rather unlikely and, therefore, ence of severe cardiac compromise, with or VA-ECMO and associated medical therapies without concomitant respiratory dysfunction, 491

Chapter 44

in adult patients. Beside traditional settings like AMI, postcardiotomy, and acute or decompensated chronic cardiac diseases, other clinical conditions represent potential and promising scenarios for ECMO use, including prophylactic or preoperative ECMO support to allow the safe performance of various procedures, bailout cardiocirculatory assistance during catheterbased interventional cardiology, or temporary support during acute heart failure of variable etiologies. Refinement of patient selection and management, timing of implantation and duration of support, and a team approach, together with ongoing technological and pharmaceutical (see alternatives to heparin) improvement, will provide further development and new applications of these systems. This will lead to better ECMO use outcomes in adult patients who need hemodynamic support in conventional or novel clinical settings of cardiovascular medicine.

492

Adult Cardiovascular Defects, Diseases, and Procedures that Predispose to ECLS

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department: a retrospective study. J Cardiothorac Surg. 2015 Feb 24;10:23. 18. O’Neill WW, Schreiber T, Wohns DH, et al. The current use of Impella 2.5 in acute myocardial infarction complicated by cardiogenic shock: Results from the US Impella Registry. J Interv Cardiol. 2014;27:1–11. 19. Dagmar MO, Josè PS E. Percutaneous cardiac support devices for cardiogenic shock: current indications and recommendations. Heart. 2012; 98: 1246-54. 20. Aoyama N, Imai H, Kurosawa T, et al. Therapeutic strategy using extracorporeal life support, including appropriate indication, management, limitation and timing of switch to ventricular assist device in patient with acute myocardial infarction. J Artif Organs. 2014;17:33-41. 21. Rhee I, Kwon SU, Sung K, et al. Experience with emergency percutaneous cardiopulmonary support in in-hospital cardiac arrest o cardiogenic shock due to the ischemic heart disease. Korean J Thorac Cardiovasc Surg. 2006;39:201-7 22. Chen YS, Lin JW, Yu HY, et al. Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis. Lancet. 2008 Aug 16;372(9638):554-61. 23. Wang J, Han J, Jia Y, Zeng W, Shi J, Hou X, Meng X. Early and intermediate results of rescue extracorporeal membrane oxygenation in adult cardiogenic shock. Ann Thorac Surg. 2009;88:1897-903 24. Yeh CF, Wang CH, Tsai PR, Wu CK, Lin YH, Chen YS. Use of ECMO to rescue patients with refractory ventricular arrhythmia in acute myocardial infarction. Medicine. 2015;94:e1241 25. Unai S, Tanaka D, Ruggiero N, Hirose H, Cavarocchi NC. Acute myocardial infarction complicated by cardiogenic shock: an algorithm-based ECMO program can 494

improve clinical outcomes. Artif Organs 2015, Jul 6. doi: 10.1111 26. Negi S, Sokolovic M, Koifman E, et al. Contemporary use of veno-arterial ECMO for refractory cardiogenic shock in acute coronary syndrome. J Invasive Cardiol. 2015 Dec 15. pii: JIC20151215-2. 27. Yeh CF, Wang CH, Tsai PR, Wu CK, Lin YH, Chen YS. Use of ECMO to rescue patients with refractory ventricular arrhythmia in acute myocardial infarction. Medicine. 2015;94:e1241 28. Vainer J, van Ommen V, Maessen J, Geskes G, Lamerichs L, Waltenberger J. Elective high risk percutaneous coronary intervention supported by extracorporeal life support. Am J Cardiol. 2007;99:771-3 29. Narotsky DL, Mosca MS, Mochari-Greenberger H, et al. Short-term and longer-term survival after veno-arterial extracorporeal membrane oxygenation in an adult patient population: does older age matter? Perfusion. 2015 Oct 5. pii: 0267659115609092 30. Madershahian N, Wippermann J, Liakopoulos O, et al. The acute effect of IABPinduced pulsatility on coronary vascular resistance and graft flow in critical ill patients during ECMO. J Cardiovasc Surg. 2011;52:411-8 31. Sauren LD, Reesink KD, Selder JL, Beghi C, van der Veen FH, Maessen JG. The acute effect of intra-aortic balloon counterpulsation during extracorporeal life support: an experimental study. J Artif Organs. 2007;31:31-8 32. Kawashima D, Gojo S, Nishimura T, et al. Left ventricular mechanical support with Impella provides more ventricular unloading in heart failure than extracorporeal membrane oxygenation. ASAIO J. 2011;57:169–76. 33. Koeckert MS, Jorde UP, Naka Y, Moses JW, Takayama H. Impella LP 2.5 for left ventricular unloading during venoarterial

Adult Cardiovascular Defects, Diseases, and Procedures that Predispose to ECLS

extracorporeal membrane oxygenation support. J Card Surg. 2011;26:666–8. 34. Eudailey KW, Yi SY, Mongero LB, Wagener G, Guarrera JV, George I. Transdiaphragmatic left ventricular venting during peripheral venous-arterial extracorporeal membrane oxygenation. Perfusion. 2015;30:701-3 35. Hoefer D, Ruttmann E, Poelzl G, et al. Outcome evaluation of the bridge-to-bridge concept in patients with cardiogenic shock. Ann Thorac Surg. 2006;82:28-33. 36. Kouraki K, Schneider S, Uebis R, et al. Characteristics and clinical outcome of 458 patients with acute myocardial infarction requiring mechanical ventilation. Results of the BEAT registry of the ALKK-study group. Clin Res Cardiol. 2011;100:235–9. 37. Alozie A, Kische S, Birken T, et al. Awake ECMO as bridge to recovery after left main coronary artery occlusion: a promising concept of haemodynamic support in cardiogenic shock. Heart Lung Circ. 2014;23:e217-21 38. Smedira NG, Blackstone EH. Postcardiotomy mechanical support: risk factors and outcome. Ann Thorac Surg .2001;71:S60S66 39. Rastan AJ, Dege A, Mohr M, et al. Early and late outcome of 517 consecutive patients treated with extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock. J Thorac Cardiovasc Surg. 2010;139:302-11 40. Elsharkawi HA, Li L, Sakr Esa WA, Sessler DI, Bashour CA. Outcome in patients who require venoarterial extracorporeal membrane oxygenation support after cardiac surgery. J Cardio-Thorac Vasc Anesth. 2010;24:946-51 41. Rastan AJ, Lachman N, Walther T, et al. Autopsy findings in patients on postcardiotomy ECMO. Int J Artif Organs. 2006;29:1-11 42. Wu MY, Lin PJ, Lee MY, et al. Using extracorporeal life support to resuscitate

adult postcardiotomy cardiogenic shock: treatment strategies and predictors of shortterm and midterm survival. Resuscitation. 2010;81:1111-6 43. Saxena P, Neal J, Joyce LD, et al. Extracorporeal membrane oxygenation support in postcardiotomy elderly patients: the Mayo Clinic experience. Ann Thorac Surg. 2015;99:2053-60 44. Fiser SM, Tribble CG, Kaza AK, et al. When to discontinue extracorporeal membrane oxygenation for postcardiotomy support. Ann Thorac Surg. 2001;71:210-4 45. Zhang R, Kofidis T, Kamiya H, et al. Creatin kinase isoenzyme MB relative index as a predictor of mortality on extracorporeal membrane oxygenation support for postcardiotomy cardiogenic shock in adult patients. Eur J Cardio-Thorac Surg. 2006;30:617-20 46. Unosawa S, Sezai A, Hata M, et al. Longterm outcomes of patients undergoing ECMO for refractory postcardiotomy cardiogeni shock. Surg Today. 2013;43:264-70 47. Borges Lima E, da Cunha CR, Barzilai VS, et al. Experience of ECMO in primary graft dysfunction after orthotopic heart transplantation. Arq Bras Cardiol. 2015;105:285-91 48. D’Alessandro C, Aubert S, Golmard JL, et al. ECMO temporary support for early graft failure after cardiac transplantation. Eur J Cardio-Thorac Surg. 2010;37:343-9 49. Kittleson MM, Patel J, Moriguchi J, Kawano M, et al. Heart transplant recipients supported with ECMO: outcomes from a single-centre experience. J Heart Lung Transplant 2011;30:1250-6 50. Listijono D, Watson A, Pye R, et al. Usefulness of ECMO for early cardiac allograft dysfunction. J Herat Lung Tranplant. 2011;30:783-9 51. Saed D, Stosik H, Islamovic M, et al. Femoro-femoral versus atrio-aortic ECMO: selecting the ideal cannulation technique. Artif Organ. 2014;38:549-55

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52. Li CL, Wang H, Jia L, Ma N, Meng X, Hou XT. The early dynamic behaviour of lactate is linked to mortality in postcardiotomy patients with extracorporeal membrane oxygenation support: a retrospective observational study. J Thorac Cardiovasc Surg. 2015;149:1445-50 53. Hernandez AF, Grab JD, Gammie JS, et al. A decade of short-term outcomes in postcardiac surgery ventricular assist device implantation. Circulation. 2007;116:606-12 54. Hiesinger W, Boyd JH, Woo YJ. Ventricular assist device implantation in the elderly. Ann Cardio-Thorac Surg. 2014;3:570-2 55. Caforio AL, Pankuweit S, Arbustini E, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34:2636-48 56. Gupta S, Markham DW, Drazner MH, Mammen PPA. Fulminant myocarditis. Nat Clin Proc Cardiovasc Med. 2008;11:693706 57. Ginsberg F, Parrillo JE. Fulminant myocarditis. Crit Care Clin. 2013;29:465-83 58. Maisch B, Ruppert V, Pankuweit S. Management of fulminant myocarditis: a diagnosis in search of its etiology but with therapeutic options. Curr Heart Fail Rep. 2014;11:166-77 59. Acker MA. Mechanical circulatory support for patients with acute fulminant myocarditis. Ann Thorac Surg. 2001;71:S73-6 60. Cheng R, Hachamovitch R, Kittleson M, et al. Clinical outcome in fulminant myocarditis requiring extracorporeal membrane oxygenation: a weighted meta-analysis of 170 patients. J Card Fail. 2014;1-7 61. Aoyama N, Izumi T, Hiramori K, et al. National survey of fulminant myocarditis in Japan. Circ J. 2002;66:133-44 62. Diddle JW, Almodovar MC, Rajagopal SK, Rycus PT, Thiagarajan RR. Extracorporeal 496

membrane oxygenation for the support of adults with acute myocarditis. Crit Care Med. 2015;43:1016-25 63. Pages ON, Aubert S, Combes A, et al. Paracorporeal pulsatile biventricular assist device versus extracorporeal membrane oxygenation: extracorporeal life support in adult fulminant myocarditis. J Thorac Cardiovasc Surg. 2009;137:194-7 64. Mody KP, Takayama H, Landes E, et al. Acute mechanical circulatory support for fulminant myocarditis complicated by cardiogenic shock. J Cardiovasc Trans Res. 2014;7:156-64 65. Chen YS, Yu HS, Huang SC, et al. Experience and results of extracorporeal membrane oxygenation in treating fulminant myocarditis with shock: what mechanical support should be considered first? J Heart Lung Transplantat. 2005;24:81-7 66. Hsu KH, Chi NH, Yu HY, et al. Extracorporeal membranous oxygenation support for acute fulminant myocarditis: analysis of a single center’s experience. Eur J CardioThorac Surg. 2011;40:682-8 67. Ishida K, Wada H, Sakakura K, et al. Long-term follow-up on cardiac function following fulminant myocarditis requiring percutaneous extracorporeal cardiopulmonary support. Heart Vessels. 2013;23:86-90 68. Mirabel M, Luyt CE, Leprince P, et al. Outcomes, long-term quality of life, and psychological assessment of fulminant myocarditis patients rescued by mechanical circulatory support. Crit Care Med. 2011;39:1029-35 69. Asaumi Y, Yasuda S, Morii I, et al. Favourable clinical outcome in patients with cardiogenic shock due to fulminant myocarditis supported by percutaneous extracorporeal membrane oxygenation. Eur Heart J. 2005;26:2185-92 70. Maejima Y, Yasu T, Kubo N, et al. Longterm prognosis of fulminant myocarditis

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rescued by percutaneous cardiopulmonary support device. Circ J. 2004;68:829-33 71. Lorusso R, Centofanti P, Gelsomino S, et al for the GIROC Investigators. Ann Thorac Surg. 2015, in press 72. Smith SC, Ladenson JH, Mason JW, Jaffe AS. Elevations of cardiac troponin I associated with myocarditis. Experimental and clinical correlates. Circulation. 1997;95:163-8 73. Luyt CE, Landivier A, Leprince P, et al. Usefulness of cardiac biomarkers to predict recovery in patients on extracorporeal membrane oxygenation support for refractory cardiogenic shock. J Crit Care. 2012;27:7-14 74. McCarthy III RE, Boehmer JP, Hruban RH, et al. Long-term outcome of fulminant myocarditis as compared to acute (nonfulminant) myocarditis. N Engl J Med. 2000;342:690-5 75. Su TW, Tseng YH, Wu TI, Lin PJ, Wu MY. Extracorporeal life support in adults with hemodynamic collapse from fulminant cardiomyopathies: the chance of bridging to recovery. ASAIO J. 2014:60:664-9 76. Hacking DF, Best D, d’Udekem Y, et al. Elective decompression of the left ventricle in pediatric patients may reduce the duration of venoarterial extracorporeal membrane oxygenation. Artif Organs. 2015;39:319-26 77. Mason JW, O’Connel JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. New Engl J Med. 1995;333:269-75 78. Nakashima H, Umeyama Y, Minami K. Successive immunosuppressive treatment of fulminant myocarditis that is refractory to mechanical circulatory support. Am J Case Rep. 2013;14:116-9 79. Janata K, Holzer M, Domanovits H, et al. Mortality of patients with pulmonary embolism. Wien Klin Wochenschr. 2002;114:766-72.

80. Jaff MR, McMurtry MS, Archer SL, et al. American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology. Management of massive and submassive pulmonary embolism, ilio-femoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123:1788-830 81. Konstantinides SV, Torbicki A, Agnelli G, et al; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35:3033-80 82. McIntyre KM, Sasahara AA. The hemodynamic response to pulmonary embolism in patients without prior cardiopulmonary disease. Am J Cardiol. 1971;28:288-94. 83. Smulders YM. Pathophysiology and treatment of haemodynamic instability in acute pulmonary embolism: the pivotal role of pulmonary vasoconstriction. Cardiovasc Res. 2000;48:23-33 84. Goldhaber SZ, Elliott CG. Acute pulmonary embolism: part I: epidemiology, pathophysiology, and diagnosis. Circulation. 2003;108:2726-9 85. Burrowes KS, Clark AR, Tawhai MH. Blood flow redistribution and ventilation-perfusion mismatch during embolic pulmonary arterial occlusion. Pulm Circ. 2011;1:365-76 86. Leacche M, Unic D, Goldhaber SZ, et al. Modern surgical treatment of massive pulmonary embolism: results in 47 consecutive patients after rapid diagnosis and aggressive surgical approach. J Thorac Cardiovasc Surg. 2005;129:1018–23 497

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87. Wan S1, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of randomised control trials. Circulation. 2004;110:744–9 88. Belohlavek J, Rohn V, Jansa P, et al. Venoarterial ECMO in severe acute right ventricular failure with pulmonary obstructive hemodynamic pattern. J Invasive Cardiol. 2010;22:365-9 89. Maggio P, Hemmila M, Haft J, Bartlett R. Extracorporeal life support for massive pulmonary embolism. J Trauma. 2007;62:570– 6 90. Kawahito K, Murata S, Adachi H, Ino T, Fuse K. Resuscitation and circulatory support using extracorporeal membrane oxygenation for fulminant pulmonary embolism. Artif Organs. 2000;24:427-30 91. Munakata R, Yamamoto T, Hosokawa Y, et al. Massive pulmonary embolism requiring extracorporeal life support treated with catheter-based interventions. Int Heart J. 2012;53:370-4 92. Extracorporeal Life Support Organization: Extracorporeal Life Support (ECLS) Registry Report International Summary. Ann Arbor, MI: Extracorporeal Life Support Organization; 2014 93. Deakin CD, Nolan JP, Soar J, et al. European Resuscitation Council Guidelines for Resuscitation 2010. Section 4. Adult Advanced Life Support. Resuscitation. 2010;81:1305–52 94. Yusuff HO, Zochios V, Vuylsteke A. Extracorporeal membrane oxygenation in acute massive pulmonary embolism: a systematic review. Perfusion. 2015;30:611-6 95. Chao A, Wang CH, You HC, et al. Highlighting indications of ECMO in endocrine emergencies. Sci Rep. 2015;5:13361 96. Banfi C, Juthier F, Ennezat PV, et al. Central extracorporeal life support in pheochromocytoma crisis. Ann Thorac Surg. 2012;93:1303-5 498

97. Ritter S, Guertler T, Meier CA, Genoni M. Cardiogenic shock due to pheochromocytoma rescued by ECMO. Interact Cardiovasc Thorac Surg. 2011;13:112-3 98. Sojod G, Diana M, Wall J, D’Agostino J, Mutter D, Marescaux J. Successful ECMO treatment for pheochromocytoma-induced acute cardiac failure. Am J Emerg Med. 2012;30:1017.e1-3 99. Li S, Koerner MM, El Banayosy A, soleimani B, Pae WE, Leuenberger UA. Takotsubo’s syndrome after mitral valve repair and rescue with extracorporeal membrane oxygenation. Ann Thorac Surg. 2014;97:1777-8 100. Esnault P, Nèe L, Signouret T, Jaussaud N, Kerbaul F. Reverse Takotsubo cardiomyopathy after iatrogenic epinephrine injection requiring percutaneous extracorporeal membrane oxygenation. Can J Anaesth. 2014;61:1093-7 101. Flam B, Broomè M, Frenckner B, Branstrom R, Bell M. Pheocromocytoma-induced Takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation. J Intensive Care Med. 2015;30:365-72 102. Hu W, Chen L, Liu C, et al. Three cases of electrical storm in fulminant myocarditis treated with ECMO. Am J Emerg Med. 2015;33:606.e3-8 103. Pagel PS, Lilly RE, Nicolosi AC. Use of ECMO to temporize circulatory instability during severe Brugada electrical storm. Ann Thorac Surg. 2009;88:982-3 104. Tomasello SD, Boukhris M, Ganyukov V, et al. Outcome of extracoproreal membrane oxygenation support for complex high-risk elective percutaneous coronary interventions: a single-centre experience. Heart & Lung. 2015;44:309-13 105. Seco M, Forrest P, Jackson SA, et al. Extracorporeal membrane oxygenation for very high-risk transcatheter aortic

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valve implantation. Heart Lung & Circul. 2014;23:957-62 106. Artl M, Phillip A, Voelkel S, et al. Early experiences with miniaturized extracorporeal life-support in the catheterization laboratory. Eur J Cardio-Thorac Surg. 2012;42:858-63 107. Husser O, Holzamer A, Philipp A, et al. Emergency and prophylactic use of miniaturized veno-arterial extracorporeal membrane oxygenation in transcatheter aortic valve implantation. Cath Cardiovasc Interv. 2013;82:E542-E551 108. Staudacher DL, Bode C, Wengenmayer T. Severe mitral regurgitation requiring ECMO therapy treated by interventional valve reconstruction using the MitraClip. Catheter Cardiovasc Interv. 2015;85:170-5 109. Ucer E, Fredersdorf S, Jungbauer C, et al. A unique acces for the ablation catheter to treat elecrical storm in a patient with extracorporeal life support. Europace. 2014;16:299-302 110. Komminemi M, Lang RM, Russo MJ, Shah AP. Percutaneous closure of infacrt related ventricular septal defects assisted with portable miniaturized extracorporeal membrane oxygenation: a case-series. Cardiovasc Revasc Med. 2013;14:241-5 111. Rohn V, Spacek M, Belohlavek J, Tososki J. Cardiogenic shock in a patient with posterior postinfarction ventricular septal rupture: successful treatment with extracorporeal membrane oxygenation (ECMO) as ventricular assist device. J Card Surg. 2009;24:435-6 112. Gregoric ID, Mesar T, Kar B, et al. Percutaneous ventricular assist device and extracorporeal membrane oxygenation support in a patient with postinfarction ventricular septal defect and free wall rupture. Heart Surg Forum. 2013;16:150-1 113. Hobbs R, Korutla V, Suzuki Y, Acker M, Vallabhajosyula P. Mechanical circulatory support as a bridge to definitive surgical repair after post-myocardial infarct

ventricular septal defect. J Card Surg. 2015;30:535-40 114. Tsai MT, Wu HY, Chan SH, Luo CY. Extracorporeal membrane oxygenation as a bridge to definite surgery in recurrent postinfarction ventricular septal defect. ASAIO J. 2012;58:88-9 115. Obadia B, Theron A, Gariboldi V, Collart F. Extracorporeal membrane oxygenation as a bridge to surgery for ischemic papillary muscle rupture. J Thorac Cardiovasc Surg. 2014;147:82-4 116. Anastasiadis K, Antonitsis P, Hadjimiltiades S, et al. Management of left ventricular free wall rupture under extracorporeal membrane oxygenation. Int J Artif Organs. 2009;32:756-8 117. Formica F, Corti F, Avalli L, Paolini G. ECMO support for the treatment of cardiogenic shock due to left ventricular free wall rupture. Interact Cardiovasc Thorac Surg. 2005;4:30-32 118. Abedi-Valugerdi G, Gabrielsen A, Fux T, Hillebrant CG, Lund LH, Corbascio M. Management of left ventricular rupture after myocardial infarction solely with ECMO. Circul Heart Fail. 2012;5:e65-e67 119. Noyes AM, Ramu B, Parker MW, Underhill D, Gluck JA. Extracorporeal membrane oxygenation as a bridge. Tex Heart Inst J. 2015;42:471-3 120. Vohra HA, Jones C, Vola N, Haw MP. Use of extracorporeal membrane oxygenation in the management of sepsis secondary to an infected right ventricle-to-pulmonary artery Contegra conduit in an adult patient. Interact Thorac Cardiovasc Surg. 2009;8:272-4 121. Santhosh JG, Preethi W, Sanghetaa M, Bijn T. Outcome of patients with infective endocarditis who were treated with extracorporeal membrane oxygenation and continuous renal replacement therapy. Clinics Pract. 2014;4:66-70 122. Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: 499

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a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2008;29:270–6 123. The MERIT-HF study group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001–7 124. Hollenberg SM, Kavinsky CJ, Parrillo JE. Cardiogenic shock. Ann Intern Med. 1999; 131:47–59 125. Demondion P, Fournel L, Golmard JL, Niculescu M, Pavie A, Leprince P. Predictors of 30-day mortality and outcome in cases of myocardial infarction with cardiogenic shock treated by extracorporeal life support. Eur J Cardiothorac Surg. 2014;45:47-54. 126. Tarzia V, Bortolussi G, Bianco R, et al. Extracorporeal life support in cardiogenic shock: impact of acute versus chronic etiology on outcome. J Thorac Cardiovasc Surg. 2015;150:333-40 127. Bermudez CA, Rocha RV, Toyoda Y, et al. ECMO for advanced refractory shock in acute and chronic cardiomyopathy. Ann Thorac Surg. 2011;92:2125-31 128. Biscotti M, Bacchetta M. The “Sport model”: ECMO using the subclavian artery. Ann Thorac Surg. 2014;98:1487-9 129. Hoefer D, Ruttmann E, Poelzl G, et al. Outcome evaluation of the bridge-to-bridge concept in patients with cardiogenic shock. Ann Thorac Surg. 2006;82:28–33 130. Marasco SF, Lo C, Murphy D, et al. Extracorporeal life support bridge to ventricular assist device: the double bridge strategy. ASAIO J. 2016;40:100-6. 131. Abrams D, Combes A, Brodie D. What’s new in extracorporeal membrane oxygenation for cardiac failure and cardiac arrest in adults? Intensive Care Med. 2014;40:60912

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45 Extracorporeal Cardiopulmonary Resuscitation in Adults Jan Bělohlávek, MD, PhD, Yih-Sharng Chen, MD, PhD, Naoto Morimura, MD, PhD

Introduction Survival after cardiac arrest (CA) remains poor. Worldwide, neurologically favorable survival in patients resuscitated by emergency services for out-of-hospital cardiac arrest (OHCA) is only 2-11%, eventually 12-19% in patients with initially shockable rhythms1 and slightly better for in-hospital cardiac arrest (IHCA) of 22%.2 Still, in certain subgroups of patients with witnessed cardiac arrest, shockable rhythms, high quality post cardiopulmonary resuscitation (CPR) care, including targeted temperature management, early coronary reperfusion, treatment of electrolyte disorders, seizures, and pneumonia, neurologically favorable outcome as high as 25-30% can be reached. 1 Moreover, other interventions including reduction in no-flow time by early bystander CPR, telephone assisted bystander CPR, early defibrillations using automated external defibillators (AEDs), adequate compression depth and rate of CPR, compression to ventilation ratios, appropriate oxygenation, use of targeted temperature management, catecholamines to improve cardiac output, thrombolysis and early percutaneous coronary intervention (PCI) have been adopted into routine care and tested with an aim of improving cardiac arrest outcomes.3 Large studies have employed mechanical chest compression devices.4,5 The main aim of resus-

citation, however, remains the early return of spontaneous circulation (ROSC). Prolonged CA and CA without ROSC bears dismal prognoses.6 In patients without ROSC, the chance of survival when transport to the hospital occurs during CPR falls below 4%.7,8 Therefore, substituting failed ROSC by an extracorporeal device presents an attractive approach in refractory CA. The concept of using an extracorporeal pump for artificial circulation is old9 and has been tested initially in moribund patients with challenging survival. Fifteen longterm survivors out of 39 patients urgently cannulated for ECLS at the bedside within 15 minutes of CA were reported by Mattox in 1976.10 Fiftyfour studies with 675 patients in CA treated by percutaneous cardiopulmonary bypass between 1966 and 2005 reported survival to discharge of 42% (IQR 15.4%, 75%).11 However, most probably these results underreported poor outcomes. 11 These initial reports and crucial advances in technology, availability of miniaturized simple ECLS devices useful for transporting patients, compatible extracorporeal circuits, novel percutaneous cannulas suitable for rapid implantation, and ongoing efforts to improve outcome of CA became the prerequisites for the implementation of extracorporeal mechanical support technique to CPR, ie, development of extracorporeal cardiopulmonary resuscitation (ECPR). ECPR has been recognized in European Resuscitation 501

Chapter 45

Guidelines 2015 as a rescue therapy for those patients in whom initial advanced life support measures are unsuccessful or to facilitate specific interventions (eg, coronary angiography and PCI or pulmonary thrombectomy for massive pulmonary embolism).12 The American Heart Association (AHA) guidelines are more cautious regarding the recommendation for ECPR because of the ongoing paucity of available data.13 A recent metaanalysis compared ECPR to conventional CPR and showed a favorable effect on 3-6 month survival with good neurological outcome in ECPR subjects. However, the effect of ECPR on survival to discharge in OHCA has not been clearly shown indicating the need for strict criteria for implementation of ECPR in such a setting.14 This chapter aims to provide an overview on the current role of ECPR in clinical practice, serving as a practical guide for performing ECPR. Definition of ECPR ECPR applies ECLS in patients who remain in CA despite conventional CPR, or when intermittent ROSC occurs, but repetitive CA reoccurs. In other words, ECPR is used in refractory CA, when chances of obtaining and sustaining ROSC are poor. Unfortunately, definitions of refractory CA vary from 10 to 30 minutes of CPR without ROSC.15,16 The optimal duration of refractory CA prior to ECPR remains unknown, but both for IHCA and OHCA, maximal time of approximately 15 minutes of CPR seems to be reasonable.17,18 Cannulation to ECPR ensures complete mechanical support suitable to provide temporary circulation and gas exchange. Cannulation usually occurs via the femoro-femoral venoarterial route, because of easy accessibility, (Figures 45-1 and 45-2). Alternative approaches include the femoro-subclavian, jugulo-subclavian or jugulo-femoral routes. The term ECPR is used to describe an intention to treat a CA 502

patient with venoarterial ECMO. Alternatively, for ECMO or ECLS, other terms including percutaneous or emergency CPB and eventually portable or percutaneous cardiopulmonary support, are used interchangeably. Organizational Issues Related to ECPR Implementation ECPR usually occurs in tertiary care institutions provided by a dedicated ECMO team. The ECMO team consists of professionals from intensive care, cardiology, cardiac surgery, and other specializations collaborating with specialized nurses and perfusionists. In-hospital coordination between the ECMO and CPR teams must include rules to activate the ECPR team in a 24/7 coverage model. ECMO team members must be well trained in venoarterial cannulation, circuit management, and early postresuscitation care (see Chapter 67). An ECLS-trained physician and perfusionist or specialist provides 24-hour coverage for ECLS patients. Physicians trained in vascular ultrasound for the insertion, maintenance, and surveillance of ECMO cannulae and distal perfusion cannula should also be available. Intensive care unit (ICU) care

Figure 45-1. A typical scheme of a femorofemoral VAl ECMO circuit setting including distal perfusion cannula for prevention of limb ischemia used for ECPR. IVC=inferior vena cava; RA=right atrium; arrows depict blood flow direction.

Extracorporeal Cardiopulmonary Resuscitation

must be adjusted to ECMO use, ie, intensive care unit nurses should be specifically trained in ECLS and circuit management. The nurse-topatient ratio during the postresuscitation phase should be 1:1, depending on the local regulations or resource availability. The ECLS team should be self sufficient and able to set up the ECLS circuit quickly. The specialist team may also be responsible for managing equipment and supplies, regular service administration, troubleshooting, daily rounds, education, patient database administration, quality control,17 and coordination of neurological, psychiatric, psychological and rehabilitation care. Adjustments may be implemented depending on the site where ECPR is provided. ECPR for IHCA is usually provided in the ICU or operating room. Experiences mainly from France and Germany show tha for OHCA, ECPR occurs primarily in the cathlab or emergency departments.18-23 Accordingly, the ECMO team has to be prepared both for in-hospital and inter-hospital transport of ECLS patients. Facilities and Equipment Appropriate for ECPR Complex intensive care serves as a prerequisite to provide ECPR service and involves the

cardiology, cardiac surgery, general intensive care, and emergency departments. Supportive departments necessary for ECPR patients comprise: biochemistry with emergently available common laboratory tests (arterial blood gases, lactate, hemoglobin, glucose often available also bedside); radiology including vascular ultrasound, vascular embolizations, CT imaging used to adopt adjustments specific for ECMO patients;24 blood bank, pharmacy, coronary angiography and PCI service. Essential equipment readily available for use at the site of ECPR (or on the “ECPR trolley“) should consist of ECMO cannulation sets, ECMO cannulas (15 to 21 Fr for arterial and 19 to 29 Fr for venous access), 150 cm catheterization wires including stiff wires for adequate support, catheterization sheats 5 to 8 Fr for vessel access establishment, eventually useful for distal perfusion, stopcocks, basic surgical instruments required for open access to femoral vessels and other routine material used for invasive procedures including sterile dressing, drapes, etc. A preassembled dry-primed or wet-primed ECLS machine should remain available 24/7, with regularly checked technical and battery status. ECLS machine can be situated at the ICU, cathlab, emergency department, or within operating room areas. The team should be trained to deploy the device for full use within 5-10 minutes from decision to proceed with ECPR. An overview of essential prerequisites to perform ECPR is summarized in Table 45-1. The Ideal ECPR Patient

Figure 45-2. An ECPR patient on the ICU. The patient had severe aortic stenosis and coronary artery disease leading to ECPR for refractory OHCA.

Patients who might be excellent candidates for ECPR consideration (Table 45-2) have a CA with initially shockable rhythm, a witnessed arrest with immediate CPR with no sustained ROSC within 10-15 minutes of advanced life support by an emergency medical service/CPR team, and age less than 75 years.25,26 The final decision on whether to proceed with ECPR falls to the ECMO team and is based on estab503

Chapter 45

lished criteria. Within an ongoing randomized trial, a strict protocol and inclusion/exclusion criteria both for enrollment of the patient into the “ECPR” study itself and also for a final decision whether to connect an ECLS is used (Tables 45-3 and 45-4).18 An age limit in ECPR remains controversial. The ELSO Registry analysis, with its inherent reporting biases, has an acceptable hospital discharge rate of 22% in the elderly; however, indication for ECPR in older patients must be considered Table 45-1. Essential prerequisites to perform ECPR. ECPR For IHCA For OHCA Resuscitation team for hospital Resuscitation team at the site 24/7 where OHCA is referred to 24/7 Early alert system to notify Early alert system to notify ECMO team leader about IHCA cardiac center/emergency department coordinator about OHCA Coordinated collaboration with Coordinated collaboration with CPR team leader EMS crew/dispatcher during transport with ongoing CPR (mechanical chest compressions) ECMO team ready within 15 minutes at the site of ECPR 24/7 available preassembled ECLS device and perfusionist/specialist Ability to transport a patients Ability to admit patients with with ongoing CPR in the hospital ongoing CPR via mechanical chest compressions (mechanical chest compressions used) Ability to cannulate and perform invasive procedures (coronary angiography) under ongoing CPR (includes technical skills and equipment) Readily available: echocardiography, vascular ultrasound, basic laboratory examinations, optional monitoring of cerebral tissue saturation Trained ICU team available at the site of ECPR

on a case-by-case basis.27 The short time for such a decision renders the complex decision that encompasses ethical, social, financial, and logistical even more challenging. Definitely, inappropriate ECLS cannulation may produce serious consequencies28 while potential organ donation has been used as an indication to proceed with ECPR.29 ECPR Cannulation Technique During ECPR, the ECMO team leader assesses patient suitability for cannulation (Table 45-4), the quality of CPR (position and effects of mechanical chest compression deTable 45-2. Criteria of patients suitable for ECPR consideration. Criteria Witnessed sudden arrest (public place, EMS crew, emergency department, ICU, cathlab, operating theatre) Assumption of cardiac etiology and reversible cause (acute coronary syndrome, pulmonary embolism, myocarditis, shockable rhythm, etc.) High-quality CPR started immediately after the collapse Intermittent ROSC No major comorbidities Age under 70 years (individual, case by case consideration)

Table 45-3. Inclusion and exclusion criteria for a randomized study of ECPR.18 Inclusion Criteria Age ≥18 and ≤ 65 years Witnessed OHCA of presumed cardiac cause Minimum of 5 minutes of ACLS performed by emergency medical service team without sustained ROSC Unconsciousnessa ECLS team and ICU bed capacity in cardiac center available

Exclusion Criteria OHCA of presumed noncardiac cause Unwitnessed collapse Suspected or confirmed pregnancy ROSC within 5 minutes of ACLS performed by EMS team Conscious patient Known bleeding diathesis or suspected or confirmed acute or recent intracranial bleeding Suspected or confirmed acute stroke Known severe chronic organ dysfunction or other limitations to therapy “Do not resuscitate” order or other circumstances that make 180 day survival unlikely Known pre-arrest cerebral performance category CPC ≥ 3

OHCA=out-of-hospital cardiac arrest; ACLS=advanced cardiac life support; ROSC=return of spontaneous circulation; EMS=emergency medical service; CPC=cerebral performance category. a Defined as no response to verbal or painful stimuli during ACLS

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vice), and neurological status. Small pupils are considered to be a favorable prognostic factor,30 similarly lactate values below 5 mmoL/L,31 however, lactate values are usually higher in ECPR patients. Alternatively, some reports indicate brain near infrared spectroscopy (NIRS) can be a potentially valuable tool in assessing patients under CPR.32 When care includes EPCR, a perfusionist or specialist primes the ECLS pump, femoral vessels are visualized by ultrasound, and the patient is draped in a sterile fashion to begin cannulation. Generally, cannulation during ongoing CPR is challenging, puncture of the vessels may not be easy, and advancement of the wire must be done cautiously but rapidly. Occasionally, it may be difficult to distinguish between the artery and the vein, therefore cannulation under fluoroscopy may be required. The direction the wires advances helps assess whether artery or vein has been punctured. Another alternative includes inserting a regular catheterization sheath to perform brief angiography, which not only distinguishes artery from vein but helps to choose the cannula diameter and excludes possible peripheral arterial disease (Figure 45-3). Position of the venous cannula can be confirmed under fluoroscopy or by echocardiography. Later positional changes without an inserted wire should be avoided. After cannulas are safely inserted and retrograde flow from the cannulas is brisk (an easy aid to confirm correct intraluminal position), the exTable 45-4. Inclusion and exclusion criteria for initiation of ECLS in a randomized study on ECPR.18 Inclusion Criteria No ROSC or ROSC with ongoing shock (defined as sustained hypotension less than 90 mmHg of systolic pressure or the need for bolus doses of vasopressors to maintain circulation) Admission to catheterization lab not more than 60 minutes after the collapse/initial call to EMSa Consensus of ECMO team members on ECLS initiation

Exclusion Criteria Signs of death or irreversible organ damage

Known bleeding diathesis Inadequate arterial and/or venous access for femoro-femoral cannulation

ROSC=return of spontaneous circulation a If the exact collapse time was not known, an initial call to EMS was considered

Panel A:

Panel B:

Figure 45-3. ECPR patient: previously healthy 55-year old man with ongoing CPR for OHCA from ventricle fibrillation resulting in CPR. Panel A: femoral artery cannulation, with two sheaths accidentally inserted into the same artery (arrows). One was subsequently removed, the other one exchanged for arterial ECLS cannula. No bleeding occurred. Panel B: angiography of the left coronary artery after institution of ECLS flow, non-beating heart, proximal LAD occlusion (upper arrow), significant atherosclerotic lesion on distal circumflex artery (lower arrowhead).

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tracorporeal circuit is attached. Patient receives full anticoagulation, unless contraindicated (suspicion of bleeding), usually with a bolus of unfractionated heparin of 75-100 IU/kg followed by continuous infusion to keep activated clotting time close to 200 seconds, or an aPTT at 50-70 seconds (see Chapter 7). In some centers or instances, ECPR with surgical cutdown and exposure of the femoral vessels is used, and might be preferrable in case of difficult echo visualization or lack of fluoroscopy imaging. Optimal Cannula Diameter Choosing cannula diameter size can prove difficult but important because changing them after cannulation is stressful and potentially dangerous. When considering the appropriate cannula diameter, an important factor is the presence of peripheral arterial disease. A smaller diameter cannula to prevent damage or tearing of the femoral or iliac artery can prevent this potentially fatal complication. Consequently, smaller cannula may not need a distal perfusion to prevent cannulated limb ischemia and some centers, including the Regensburg group, prefer this approach.33 Target ECLS flows relate to cannula diameter. For a targeted flow of 3.5-4 L/min an arterial cannula of 15-17 Fr should suffice. For higher flows, larger cannulas are needed. The authors prefer larger cannulas to reach a flow of more than 60-70 mL/kg/min, 5 L/min or more in larger patients, however no firm data support any single approach. Reperfusion Technique and Initial ECLS Flow Setting The ECLS circuit, unless wet primed beforehand, is usually primed with cold crystalloid for a cold flush reperfusion technique,34-36 although evidence is scarce and based on experimental settings. Intravenous cold fluid boluses during ECLS initiation may help correct hypovolemia to assure ECLS flow and 506

institute target hypothermia quickly. However, this intervention is not based on established evidence. Starting with a lower sweep gas oxygen concentration is based on studies suggesting the harmful effects of hyperoxia after ROSC.37,38 Titration to target peripheral saturation of 9095% seems reasonable, bearing in mind that in a majority of ECPR patients pulse oximetry may be inaccurate. Thus brain tissue regional saturations by NIRS provide better in-line (sampling every 6 seconds or similar depending on device used) control with target values around 60-70%. Beginning with inspired oxygen of 50-60% and later increases based on above monitoring appears reasonable. Blood flow is usually set to 4 L/min and eventually increased gradually. Thiagarajan et al. analyzed the ELSO Registry for ECPR and found an initial pump flow of 3 L/min in both survivors and nonsurvivors and it remained constant after 24 hours.39 Sweep flow initially matches that of the blood flow. Complications during Implantation and Initial Launching Several serious complications may occur during percutanous cannulation. Unsuccesful cannulation itself occurs with usually fatal consequencies due to refractory CA. Surgical exploration of the groin, as mentioned, serves as an alternative; however, severe atherosclerotic femoral/iliac artery disease may preclude even a surgical approach. Alternative approaches usually for arerial cannulation should be immediately tried if femoral cannulation is unfeasible. The axillary approach with a 15 Fr cannula is probably best and if succesful, allows enough reperfusion into the ascending aorta but may need later conversion to a different site. Prolonged cannulation over 30 minutes usually means an overall time of CPR over 60 minutes, often associated with poor neurological outcome or death. Vessel injury or rupture must be avoided by a careful technique during all stages of cannulation, espcially during wire insertion.

Extracorporeal Cardiopulmonary Resuscitation

The guiding principle is to be perfectly sure that the wire is properly inserted in the vessel lumen. Simultaneous distal cannulation of the same vessel (Figure 45-3) may happen and usually does not cause signficant problems. One sheath/ wire is either removed when a large cannula is inserted into the vessel, or better left in situ for later safe removal. Despite proper arterial cannulation, arterial wall dissection may occur, causing vessel narrowing or obstruction after removal of the cannula. This must be detected early and corrected. If not, it may cause severe limb ischemia. Venous cannulation is easier but improper position (not enough deep or too deep) may cause cannula dysfunction or inappropriate ECLS flow. Generally, if the ECLS flow proves adequate despite suboptimal cannula position, change of the cannula position is not recommended. Cannula insertion of the same vessel (usually the vein) may prove fatal if not immediately recognized and corrected. The telltale

Figure 45-4. Accidental double cannulation of the femoral vein during ECPR. A 44-years old male with primary pulmonary arterial hypertension with cardiac arrest cannulated on ICU. The arterial cannula was erroneously inserted into the femoral vein, complication was immediately identified by a presence of recirculation (bright red blood in venous limb) and corrected by insertion of a cannula into the femoral artery. Two cannulas in the femoral vein were left in situ, attached by Y-connector and used for simultaneous drainage of inferior vena cava.

sign is highly oxygenated blood in the venous cannula due to complete recirculation. A new cannula must be inserted into an appropriate vessel (Figure 45-4). Rhythm Analysis, Conversion of Ventricle Fibrillation (VF) and Further Investigation ECPR patients on ECLS may present a variety of heart rhythms. In patients with refractory ventricular fibrillation (VF) as a cause of CA, ventricle arrhythmia usually persists. It remains unclear when another trial of conversion to sinus rhythm should be performed. However, if the anticipated cause of refractory VF is an acute coronary occlusion or chronic severe coronary artery disease, PCI on ECLS should preceed defibrillation (pH and potasium correction should also be performed). Other malignant rhythms or other causes of refractory CA should be identified as soon as possible. The causes of refractory CA differ from causes of usual CA and, unfortunately, may often be irreversible (aortic rupture, other severe bleeding, intracranial hemorage). It is straightfoward to continue with coronary angiography following institution of ECLS. If the cause is not established with pulmonary angiography or aortography, and other causes including pericardial tamponade have been excluded by bedside echocardiography, then CT scan of the brain and chest/abdominal exams should be performed. Frequent laboratory examination is of paramount importance in ECPR. Initial examination should exclude severe electrolyte imbalances, assess organ functions, and allow thorough monitoring, mainly by means of lactate, blood gases, and hemoglobin levels. Not only at ECLS start, but also the trend in blood levels of lactate values and base excess40 and other variables (hemoglobin) may correlate with outcome in ECPR. Blood gas monitoring every 15 to 30 minutes after cannulation helps manage the dynamic changes that can occur.

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Postresuscitation Care Monitoring

Studies on ECPR in IHCA

Monitoring during venoarterial ECMO differs from that of other ICU patients. Blood pressure must be monitored invasively, due to nonpulsatility. Pulsatility is defined as a pulse pressure over 15 mmHg.41 Right radial artery for blood pressure monitoring and blood gases examination is mandatory. In any interpretation of monitored data, it must be kept in mind that the final result comes from a combination of spontaneous and extracorporeal circuits and is influenced by the ratio of those two flows. Therefore, cerebral and peripheral tissue NIRS may help monitor not only the brain and peripheral perfusion, but also overall hemodynamic status and further identify deteriorations requiring hemodynamic interventions or other investigations.42,43 Patients with nonpulsatile flow or with severely impaired left ventricle function may develop pulmonary edema or left ventricle thrombosis which may require left ventricle venting or intraaortic balloon counterpulsation, (see Chapters 48 and 64).44 Target temperature and protective ventilator management on ECLS is also a part of routine care.

Multiple observational studies (Table 45-5) report encouraging results of ECPR in IHCA with neurologically favorable survival in up to 35% of cases.45-49 In an analysis of 135 IHCA cases (50), average CPR duration lasted 56 minutes, 56% received subsequent intervention to treat the underlying etiology, weaning rate was 59% and 34% patients survived to discharge with 89% having acceptable neurologic status.50 Patients were resuscitated in the ICU (61%), cath lab (16%), and emergency room (19%). Importatnly, this study also demonstrated a declining chance of survival with prolonged duration of CPR. The probability of survival was approximately 50%, 30%, and 10% when CPR lasted 30, 60, or 90 minutes, respectively. Similar results of increased short-term and long-term survival benefit over conventional CPR in patients with in-hospital cardiac arrest of cardiac origin treated by ECPR have been confirmed in a propensity analysis.51 Therefore, based on available studies, ECLS for in-hospital CA has become a standard of care in many tertiary institutions, despite the fact that no randomized study confirmed its effectivity.

Table 45-5. Characteristics and outcomes of selected ECPR studies in IHCA. Study, Citation Country Chen et al. (2008)46 Taiwan

Lin et al. (2010)69 Taiwan Shin et al. (2011)48 Taiwan Chou et al. (2014)70 Taiwan Zhao et al. (2015)47 China Blumenstein et al. (2016)49 Germany

508

Design

N

Prospective

59

Prospective

59

Retrospective

85

Retrospective

43

Retrospective

24

Retrospective

52

Age (yrs) Male (%) 18-75

Time to ECLS (min) 60

59 85% 60 62% 61 93% 59 79% 72 54%

40

Neurologically Favorable Survival 42% 30% 30% 18% (33% overall) 24%

42

28%

60

35%

36

33%

33

21%

Extracorporeal Cardiopulmonary Resuscitation

Studies on ECPR in OHCA Use of ECPR in OHCA may appear even more attractive than in IHCA. OHCA patients are generally younger, previously healthy, and the cause of CA is usually of cardiac origin. Sudden CA is often caused by a single reversible condition in contrast to polymorbid in-hospital patients suffering IHCA. On the other hand, prehospital logistics in the care for OHCA victims plays a major role in selecting suitable patients for ECPR. Trials assessing ECPR in OHCA are listed in Table 45-6. These trials were observational, not randomized, and performed mainly

in Japan, Korea, Taiwan, France, Germany, and Italy. Currently, two randomized trials of ECPR in OHCA are ongoing in Prague and Vienna (NCT01511666 and NCT01605409).52,53 Most studies suffered a high risk of confounding bias due to the observational design.29 Nonetheless, patients included were usually under 75 years of age, no-flow times were below 5 minutes and low-flow periods were variable ranging up to 140 minutes, mainly close to 60 minutes. Prognostically favorable indicators included witnessed arrests, shockable rhythms, and reversible causes of CA. Treatments provided in addition to ECLS included PCI, targeted tem-

Table 45-6. Characteristics and outcomes of selected ECPR studies in OHCA. Study, Citation Design N Age (yrs) Time to Neurologically Country Male (%) ECLS (min) Favorable Survival 71 Nagao et al. (2000) 54 Prospective 36 25%a Japan (70) 61 Nagao et al (2010)72 57-62 Prospective 171 66 12% Japan (83-91)b 16 Le Guen et al (2011) 42 Prospective 51 120 4% France (90) 73 Megarbane et al (2011) 46 Prospective 47 155 2% France (77) Avalli et al (2012)74 46 Retrospective 18 78 5% Italy (94) 75 70 Haneya et al (2012) 48 Retrospective 26 15% Germany (65) 76 Fagnoul et al (2013) 48 Prospective 14 22% Belgium (58) 58c Leick et al (2013)54 Retrospective 28 MR 29% Germany 30 Maekawa et al (2013) 54 Prospective 53 49 15% Japan (83) 77 Tazarourte et al (2013) 39 d Retrospective 27 140 4% France (56) Kim et al (2014)56 53 Prospective 55 69 14% Korea (75) Mochizuki et al 51 Retrospective 32 84 16% (2014)79 (78) Japan 57 Sakamoto et al, (2014) 56.3 12% Prospective 260 Japan (90) Stub et al (2014) Prospective 11 20e 27% Australia 78 Wang et al (2014) Prospective 50.7 31 68 26% Taiwan observational (75) 58 Choi et al. (2016) 56 Retrospective 320 44 9% Republic of Korea (81) N=number of patients in study a outcome combined with hypothermia treatment in non-ECLS patients b reported in quartiles related to hypothermia therapy c time from cardiac arrest to ECLS separately for OHCA not reported d mixed population of ECPR patients: resuscitative ECLS and organ preservation e Cannulation time

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perature management, and intraaortic baloon counterpulsation. Outcomes in studies varied substantially with neurologically favorable survival ranging from 4% to 29%, mainly around 15-25%.16,54 Recent systematic review of studies on ECPR in OHCA states overall survival in 833 patients in 20 studies of 22% including 13% with good neurological recovery.29 However, ECPR in OHCA remains challenging with many unresolved issues including optimal patient populations, variables associated with a favorable neurological outcome, cost-benefit analysis of this resource demanding strategy, etc. Different approaches to minimize no-flow and low-flow states include prehospital mobile ECPR deployment55 compared to early transport under high-quality ongoing CPR (ie, mechanical) with ECPR commencement after hospital admission.18 Hopefully, ongoing randomized trials will help to define the future role of ECPR in OHCA.Efforts to increase survival in refractory OHCA should outweigh the risk of neurologically impaired survivors.56-58 Of note, organ donation is an important issue in ECPR for OHCA and should be acknowledged as a relevant outcome in ECPR studies.29 Studies on ECPR in the Pediatric Population In children, the survival rate after CA ranges from 9 to 47% for in-hospital events and 0%–29% for events outside the hospital. The survival rate for pediatric ECPR was reported to be 33-51%, which was higher than for conventional CPR (see Chapter 27).59-62 ECPR as a Stepwise Approach to Refractory CA ECPR itself does not assure favorable outcome in refractory CA. Connecting a patient to ECLS must follow a protocolized approach during CPR, therefore several centers have developed policies encompassing mechanical CPR, targeted temperature control, and early 510

reperfusion: the CHEER trial,63 Prague OHCA study.18 Weaning from ECLS after ECPR Weaning follows a similar path of all venoarterial ECMO (see Chapter 51); however, close neurological monitoring and prognostication must occur. Patients after prolonged CPR may suffer irreversible cardiac damage and favorable neurological outcome may strenghten the efforts to proceed with more advanced mechanical circulatory support or heart transplantation. Thus, early extubation of an ECPR patient still dependent on ECLS may be very helpful in this regard.64,65 In the ELSO Registry, ECMO duration in these patients has been reported to range up to 60-70 hours.39 Ethical Issues in ECPR ECPR is associated with potential harm to patients and/or their relatives. Although recovery of the heart often occurs, a coma or vegetative state could result.57 It has earned the title of a “bridge to nowhere“ in which the patient awakens, but has no cardiac function and is not a transplant or destination therapy candidate.66 ECPR can prolong the time to death in patients with unfavorable outcome, potentially harming patients and their relatives. Moreover, ECLS dependency may lead to the decision to turn off the device, which is stressfull for both the team and family members. ECPR is definitely considered an important advance in the treatment of cardiac arrest. Currently, it seems ethically appropriate to use ECPR when a likelihood of clinical benefit exists, clinicians have adequate training and expertise, and institutions can provide subsequent care.28

Extracorporeal Cardiopulmonary Resuscitation

Future Extracorporeal CPR does not yet represent the standard of care. Ongoing randomized studies have to elucidate whether ECPR is worth implementing into routine practice. Moreover, technological advances should enable improved end-organ support. Miniaturization may enhance the use of wearable/implantable devices. In emergency preservation and resuscitation, investigators may go beyond ECPR and overcome the current drawbacks of this approach.67,68

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(ECMO). Insights Imaging. 2014;5(6):731742. 25. Reynolds JC, Frisch A, Rittenberger JC, Callaway CW. Duration of resuscitation efforts and functional outcome after outof-hospital cardiac arrest: when should we change to novel therapies? Circulation. 2013;128:2488-2494. 26. Bossaert LL, Perkins GD, Askitopoulou H, et al. European Resuscitation Council Guidelines for Resuscitation 2015: section 11. The ethics of resuscitation and end-oflife decisions. Resuscitation. 2015;95:301– 310. 27. Mendiratta P1, Wei JY, Gomez A, et al. Cardiopulmonary resuscitation requiring extracorporeal membrane oxygenation in the elderly: a review of the Extracorporeal Life Support Organization registry. ASAIO J. 2013;59(3):211-215. 28. Riggs KR, Becker LB, Sugarman J. Ethics in the use of extracorporeal cardiopulmonary resuscitation in adults. Resuscitation. 2015;91:73-75. 29. Ortega-Deballon I, Hornby L, Shemie SD, Bhanji F, Guadagno E. Extracorporeal resuscitation for refractory out-of-hospital cardiac arrest in adults: A systematic review of international practices and outcomes. Resuscitation. 2016 Feb 1. pii: S03009572(16)00044-7. 30. Maekawa K, Tanno K, Hase M, Mori K, Asai Y. Extracorporeal cardiopulmonary resuscitation for patients with out-ofhospital cardiac arrest of cardiac origin: a propensity-matched study and predictor analysis. Crit Care Med. 2013;41(5):11861196. 31. Jung C, Janssen K, Kaluza M, et al. Outcome predictors in cardiopulmonary resuscitation facilitated by extracorporeal membrane oxygenation. Clin Res Cardiol. 2016;105(3):196-205. 32. Ito N, Nishiyama K, Callaway CW, et al. Noninvasive regional cerebral oxygen satu513

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ration for neurological prognostication of patients with out-of-hospital cardiac arrest: A prospective multicenter observational study. Resuscitation. 85(6):778–784 33. Ganslmeier P, Philipp A, Rupprecht L, et al. Percutaneous cannulation for extracorporeal life support. Thorac Cardiovasc Surg 2011; 59:103-107. 34. Kagawa E. Extracorporeal cardiopulmonary resuscitation for adult cardiac arrest patients. World J Crit Care Med. 2012;1(2):46-49. 35. Janata A, Weihs W, Schratter A, et al. Cold aortic flush and chest compressions enable good neurologic outcome after 15 mins of ventricular fibrillation in cardiac arrest in pigs. Crit Care Med. 2010;38(8):1637-1643 36. Boller M, Jung SK, Odegaard S, Muehlmatt A, Katz JM, Becker LB. A combination of metabolic strategies plus cardiopulmonary bypass improves short-term resuscitation from prolonged lethal cardiac arrest. Resuscitation. 2011;82(Suppl 2):S27-34. 37. Wang CH, Chang WT, Huang CH, et al. The effect of hyperoxia on survival following adult cardiac arrest: a systematic review and meta-analysis of observational studies. Resuscitation. 2014;85(9):1142-1148. 38. Dell‘Anna AM, Lamanna I, Vincent JL, Taccone FS. How much oxygen in adult cardiac arrest? Crit Care. 2014;18(5):555. 39. Thiagarajan RR, Brogan TV, Scheurer MA, Laussen PC, Rycus PT, Bratton SL. Extracorporeal membrane oxygenation to support cardiopulmonary resuscitation in adults. Ann Thorac Surg. 2009;87(3):778785. 40. Jouffroy R, Lamhaut L, Guyard A, et al. Base excess and lactate as prognostic indicators for patients treated by extra corporeal life support after out hospital cardiac arrest due to acute coronary syndrome. Resuscitation. 2014;85(12):1764-8 41. Undar A, Frazier OH, Fraser CD, Jr. Defining pulsatile perfusion: quantification in

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terms of energy equivalent pressure. Artif Organs 1999;23(8):712-6. 42. Ostadal P, Kruger A, Vondrakova D, Janotka M, Psotova H, Neuzil P. Noninvasive assessment of hemodynamic variables using near-infrared spectroscopy in patients experiencing cardiogenic shock and individuals undergoing venoarterial extracorporeal membrane oxygenation. J Crit Care. 2014 Aug;29(4):690.e11-15. 43. Wong JK, Smith TN, Pitcher HT, Hirose H, Cavarocchi NC. Cerebral and lower limb near-infrared spectroscopy in adults on extracorporeal membrane oxygenation. Artif Organs. 2012 ;36(8):659-667 44. Petroni T, Harrois A, Amour J, et al. Intraaortic balloon pump effects on macrocirculation and microcirculation in cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation. Crit Care Med. 2014;42(9):2075-2082. 45. Massetti M, Tasle M, Le Page O, et al. Back from irreversibility: extracorporeal life support for prolonged cardiac arrest. Ann Thorac Surg 2005;79:178–183. 46. Chen YS, Lin JW, Yu HY et al. Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis. Lancet 2008;372(9638):554 – 561. 47. Zhao Y, Xing J, Du Z, Liu F, Jia M, Hou X. Extracorporeal cardiopulmonary resuscitation for adult patients who underwent post-cardiac surgery. Eur J Med Res. 201512;20:83. 48. Shin TG, Choi JH, Jo IJ, et al. Extracorporeal cardiopulmonary resuscitation in patients with inhospital cardiac arrest: A comparison with conventional cardiopulmonary resuscitation. Crit Care Med. 2011;39(1):1-7. 49. Blumenstein J, Leick J, Liebetrau C, et al. Extracorporeal life support in cardiovascular patients with observed refractory

Extracorporeal Cardiopulmonary Resuscitation

in-hospital cardiac arrest is associated with favourable short and long-term outcomes: A propensity-matched analysis. Eur Heart J Acute Cardiovasc Care. 2015 Oct 26. pii: 2048872615612454 50. Chen YS, Yu HY, Huang SC, et al. Extracorporeal membrane oxygenation support can extend the duration of cardiopulmonary resuscitation. Crit Care Med. 2008;36(9):2529-2535. 51. Chen YS, Lin JW, Yu HY, et al. Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis. Lancet. 2008 16;372(9638):554-561. 52. Belohlavek et al. Hyperinvasive approach in cardiac arrest. Czech Republic: Charles University in Prague;2012. https://clinicaltrials.gov/ct2/show/NCT01511666 53. Schober A. Emergency cardiopulmonary bypass for cardiac arrest. Medical Univesity of Veenna;2012. https://clinicaltrials.gov/ ct2/show/NCT01605409 54. Leick J, Liebetrau C, Szardien S, et al. Door-to-implantation time of extracorporeal life support systems predicts mortality in patients with out-of-hospital cardiac arrest. Clinical research in cardiology : official journal of the German Cardiac Society 2013;102:661-669. 55. Lebreton G, Pozzi M, Luyt CE, et al. Outof-hospital extra-corporeal life support implantation during refractory cardiac arrest in a half-marathon runner. Resuscitation 2011;82:1239-1242. 56. Kim S, Jung J, Park J, Park J, Hong Y, Lee S. An optimal transition time to extracorporeal cardiopulmonary resuscitation for predicting good neurological outcome in patients with out-of-hospital cardiac arrest: a propensity-matched study. Crit Care 2014;18:535.

57. Sakamoto T, Morimura N, Nagao K, et al. Extracorporeal cardiopulmonaryresuscitation versus conventional cardiopulmonary resuscitation in adults without-of-hospital cardiac arrest: a prospective observational study. Resuscitation 2014;85:762–768 58. Choi DS, Kim T, Ro YS, et al. Extracorporeal life support and survival after out-ofhospital cardiac arrest in a nationwide registry: A propensity score-matched analysis. Resuscitation. 2016;99:26-32. 59. Huang SC, Wu ET, Chen YS, etal. Extracorporeal membrane oxygenation rescue for cardiopulmonary resuscitation in pediatric patients. Crit Care Med 2008;35(5):1607– 1613 60. Kane DA, Thiagarajan RR, Wypij D,et al. Rapid-response extracorporeal membrane oxygenation to support cardiopulmonary resuscitation in children with cardiac disease. Circulation 2010122(suppl):S241–S248. 61. Alsoufi B, Al-Radi OO, Nazer RI, et al. Survival outcomes after rescue ECPR in pediatric patients with refractory cardiac arrest. J Thorac Cardiovasc Surg 2007;134:952–959. 62. Chan T, Thiagarajan RR, Frank D, Bratton SL. Survival after extracorporeal cardiopulmonary resuscitation in infants and children with heart disease. J Thorac Cardiovasc Surg 2008136(4):984–992 63. Stub D, Bernard S, Pellegrino V, etal. Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial). Resuscitation. 2015;86:88-94. 64. Kacer J, Lindovska M, Surovcik R, et al. Refractory cardiogenic shock due to extensive anterior STEMI with covered left ventricular free wall rupture treated with awake VA-ECMO and LVAD as a double bridge to heart transplantation - collaboration of three cardiac centres. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015;159(4):681-687.

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65. Scherer M, Moritz A, Martens S. The use of extracorporeal membrane oxygenation in patients with therapy refractory cardiogenic shock as a bridge to implantable left ventricular assist device and perioperative right heart support. J Artif Organs. 2009;12(3):160-165 66. Abrams DC, Prager K, Blinderman CD, Burkart KM, Brodie D. Ethical dilemmas encountered with the use of extracorporeal membrane oxygenation in adults. Chest 2014;145:876–82.13. 67. Tigard D.Emergency Preservation and Resuscitation Trial: A Philosophical Justification for Non-Voluntary Enrollment. Bioethics. 2015 Dec 8 68. Kutcher ME, Forsythe RM, Tisherman SA. Emergency preservation and resuscitation for cardiac arrest from trauma. Int J Surg. 2015 pii: S1743-9191(15)01279-0.

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46 General Considerations for VA-ECMO Implantation in Adults with Cardiocirculatory Impairment Pascal Leprince, MD, PhD, Ciro Mastroianni, MD, PhD, Antonella Galeone, MD, PhD, Cosimo D’Alessandro, MD, Guillaume Lebreton, MD

Venoarterial ECMO (VA-ECMO) is used to stabilize hemodynamics in patients experiencing severe cardiogenic shock (CS) of several etiologies. Because the indications for VA-ECMO are already treated in Chapter 44, the following paragraphs will focus on another aspect of indication which includes two topics: timing (ie, when patients are cannulated too early or too late) and the place of ECMO among other temporary circulatory support devices. Both topics require review of the advantages and inconvenience of VA-ECMO.

where cardiac surgery is not available and when a patient cannot be transferred. In such a situation, bringing the ECMO team to the patient can be lifesaving. Moreover, since cannulation can be either percutaneous or surgical, it can be performed by a surgical team or interventional cardiologists, intensivists, etc. This shortens the timing for the decision process and improves local availability.

Peripheral VA-ECMO is Fast and Easy to Implant

ECMO can fully support the circulation, up to 5-6 liters/min, depending on the cannula diameter, independent of heart function (ie, no need for residual cardiac function or adequate right ventricular function). Moreover, the presence of an oxygenator makes the circulatory efficiency independent of the oxygenation status of the patient. This is very useful in this population of cardiogenic shock patients who do experience a high rate of pulmonary edema.

These two words (fast and easy) are probably the two major positive characteristics qualifying ECMO as an emergency or rescue device. Indeed, ECMO in the field of cardiogenic shock, could be compared to an external emergency defibrillator used for life-threatening cardiac rhythm disturbances. The main benefit of ECMO relates to the fact that patients can be cannulated rapidly for ECMO at the bedside and requires only surgical material when performing an open cannulation. Another major advantage of ECMO is that patients can be cannulated in the cardiac ICU without need to transfer the patient to an operating room. However, this becomes especially critical in medical centers

Peripheral VA-ECMO is Efficient as a Circulatory Support Device

ECMO is Cost Effective At present, cost has become increasingly important in patient care. Cost effectiveness is even more crucial in rescue situations for two reasons. First, such situations are associated with a high risk of death, despite optimal care. 517

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Thus, in the current era of cost control, the amount of money spent has to be balanced with the quantity of life saved. For instance, the use of ECMO in out of hospital refractory cardiac arrest (OHCA) well illustrates this concept. In this situation, ECMO is associated with a 10 to 15% rate of survival,1 even in well selected patients. No health system can afford to spend thousands and thousands of dollars for such results, even if the outcome for survivors cannot be contested. Second, physicians have greater involvement in cost control and thus, employing a high cost device, carries greater weight. ECMO Does Not Unload the Left Ventricle The main drawback of peripheral VA-ECMO is that it does not unload the left ventricle (LV) and actually increases LV afterload. This might impair the chance of recovery of LV function and is one of the main components in the development of pulmonary edema while on ECMO support. Of course, this risk can be prevented by the use of an intraaortic balloon pump or other techniques for unloading,2,3 which each have their own potential complications. Moreover, when the LV remains unloaded, stagnation of blood in cardiac cavities which can lead to clot formation and in the extreme, to a full thrombosis of left side cavities, particularly in case of acute myocardial infarction. ECMO Decreases the Transpulmonary Flow Although the LV is not unloaded while on ECMO, the right ventricle (RV) is well preserved. However, the higher the ECMO flow, the lower the filling of the right ventricle and as a consequence, the transpulmonary flow is lower. Although ECMO reduces pulmonary vascular pressures it may have a negative impact on lung perfusion and thus increase the risk of lung injury and infectious complications. These risks are greater with a larger central cannula that fully unloads the RV, with nearly no pulmonary 518

blood flow. In this situation, complete thrombosis of the pulmonary vascular bed can occur. This is why, in our institution, central ECMO is prohibited. As soon as we have to open the chest, we used biventricular Levitronix support. ECMO is Associated with a High Rate of Complications Although life-saving, ECMO can be associated with potentially devastating complications.4 Vascular, neurological, infectious, and pulmonary complications can indeed lead to patient death or impair recovery and long-term quality of life in survivors. Many complications are related to patient severity and the urgency of cannulation. Although earlier cannulation may decrease the rate of complication, the relationship between timing of ECMO and the severity of the patient’s status before cannulation has not yet been determined. Early cannulation makes most sense when there is a higher chance for short term recovery and decannulation. The best example is fulminant myocarditis or drug poisoning situations where patients can become hemodynamically unstable in very short order but can rapidly recover good ventricular function within one week. On the other hand, using ECMO as a bridge for transplantation does not make sense since patients can experience complications which can preclude transplantation or worsen outcome. ECMO Requires the Patient to Stay in Bed Femoral VA-ECMO requires the patient to remain on bedrest. Even mobilization for nursing care can be dangerous. This negatively impacts muscle strength, impairing the chance for recovery. This furthers the argument to use ECMO in an emergency but not as a bridge to transplantation.

General Considerations for VA-ECMO Implantation in Adults with Cardiocirculatory Impairment

ECMO and Hemodynamic Criteria

ECMO and Neurological Status

Peripheral VA-ECMO should be used in cardiogenic shock only if the clinical status contraindicates or is not compatible for a ventricular assist device (VAD) or total artificial heart (TAH) implantation. The definition of cardiogenic shock includes systolic blood pressure below 90 mmHg, cold extremities, skin color, and low urine output. These patients can be classified as Intermacs class 1 and beyond. Intermacs class 2 patients can be ECMO candidates when time for cannulation to VAD implantation appears inadequate. It is difficult to define a threshold for the use inotropic drugs and clinical parameters that necessitate using mechanical circulatory support (MCS). However, worsening hemodynamic deterioration or shock (as defined previously) despite use of two inotropes/vasopressor (10 mcg/Kg/min dobutamine, 0.4 mcg/Kg/min epinephrine or norepinephrine) and elevated serum lactate levels should be considered strong indication for emergent MCS. Because it is difficult to predict when a patient on inotropic support is going to decompensate, ECMO can provide a backup tool. Manuscripts have shown good results of transplantation after ECMO.5 However, the data supporting this strategy remain limited 5,6 and thus one should consider survival and ECMO related complications which can produce longterm sequela. At the opposite extreme, with severely unstable patients receiving very high doses of inotropes/vasopressors and/or with profound metabolic impairment (pH lower than 7, lactate higher than 16), the futility of ECMO use should be discussed. However, examples of good outcome in patients in whom initial conditions would have appeared as noncompatible with survival exist and therefore doubt should go to the benefit of the patient.

Very often patients with severe cardiogenic shock receive sedation and mechanical ventilation. Moreover, many of them have experienced cardiac arrest. In such situations, the question of neurological integrity should be raised but may be difficult to answer. Potentially, the only option to evaluate neurologic status is to cannulate for VA-ECMO. Neurological status may then be assessed when good circulatory support is established and sedation can be weaned. Thus, starting ECMO without insight into neurological status at the time of cannulation makes sense. Furthermore, the team should have a low threshold to discontinue ECMO if a patient, once stabilized on ECMO, appears to have severe neurological lesions not compatible with an acceptable quality of life. Of course, in the case of brain death, the patient should be considered for organ donation (even cardiac graft donation in case of recovery). ECMO and Cardiac Arrest Refractory cardiac arrest is the extreme situation in which the borderline between efficiency and futility is minimal. Studies show that peripheral VA-ECMO is associated with good survival in patients experiencing inhospital refractory cardiac arrest as long as the cardiac arrest is witnessed, CPR is high quality, and time from arrest to ECMO is short. 7 Of course, the story differs for patients experiencing an out-of-hospital cardiac arrest. In order to avoid futility, the two major parameters to consider include durations of no-flow and lowflow states. In this situation, no-flow duration is often impossible to define and if it is the case, ECMO is generally contraindicated except if the patient is hypothermic or shows signs of life during resuscitation. There is no clear cut low-flow duration, but in a study by Cheng et al.,8 60 minutes was definitely associated with poor results. However, due to the rarity of such 519

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a situation, the decision process is still on a case to case basis. ECMO vs. Other Short-Term Circulatory Support Devices ECMO is the most versatile of the shortterm circulatory support devices for the reasons described previously: it can be placed without any adjunctive visualization method such as echocardiography or fluoroscopy; cannulation can be percutaneous or surgical depending on the physician available; it can provide a full circulatory support; it works for LV, RV, or biventricular failure. Of course, if one center can afford to have several systems, temporary short-term LVAD like the Impella c-VAD, the tandem heart, or the PHP are preferred in patients experiencing moderate shock due to LV dysfunction, as they unload the LV and thus might help recovery. This is even more true if the patient is managed in the cath lab by interventional cardiologists who will feel more confident implanting such devices. On the other hand, in severe cardiogenic shock, the percutaneous LVAD might not be efficient enough to stabilize the patients. VA-ECMO and Contraindications Because VA-ECMO as a rescue MCS that can provide a chance of survival for unstable patients, contraindications should be considered with caution and the patient deserves the benefit of the doubt. Moreover, the decision to cannulate to ECMO does not require an outcome plan. Thus, few contraindications remain and the main one is probably the impossibility to cannulate, such as in severe multivessel disease or situations in which ECMO is inefficient such as uncontrolled hemorrhagic shock. As mentioned earlier, cardiac arrest per se is not a contraindication but unknown duration of noflow or extended duration of low-flow should serve as contraindications. Similarly, an ECMO 520

mobile unit should deny a patient already under CPR resuscitation at the time of phone call. Age is often considered a potential contraindication. Maximum age threshold varies depending on the patient and the underlying disease. Postcardiotomy VA-ECMO can be justified in older patients when the situation is well controlled and the potential for recovery is high. A word of caution regarding patients undergoing mitral valve surgery as they have a high risk of thrombosis due to the decrease of transmitral flow. In this situation, particularly if there is no left ventricular ejection, it is better to assure a transpulmonary flow by using a biventricular support with two centrifugal pumps, one right and one left. Conclusion ECMO is a very efficient circulatory support device, but every attempt action should be made to avoid the use of ECMO. In the setting of chronic heart failure, patients should be undergo transplantation and/or use of VAD prior to any deterioration. This is equally true in patients experiencing myocardial infarction in whom cardiogenic shock is recognized early enough so they can be assisted with a temporary LVAD instead of ECMO. Similarly, primary care centers should consult referral centers in order to discuss patients on a case by case basis and should refer the patient before dramatic hemodynamic compromises require ECMO as the only solution.

General Considerations for VA-ECMO Implantation in Adults with Cardiocirculatory Impairment

References 1. Kagawa E, Inoue I, Kawagoe T, et al. Assessment of outcomes and differences between in- and out-of-hospital cardiac arrest patients treated with cardiopulmonary resuscitation using extracorporeal life support. Resuscitation. 2010;81(8):968-973. 2. Peterss S, Pfeffer C, Reichelt A, et al. Extracorporeal life support and left ventricular unloading in a non-intubated patient as bridge to heart transplantation. Int J Artif Organs. 2013;36(12):913-916. 3. Cheng A, Swartz MF, Massey HT. Impella to unload the left ventricle during peripheral extracorporeal membrane oxygenation. ASAIO J. 2013;59(5):533-536. 4. Cheng R, Hachamovitch R, Kittleson M, et al. Complications of extracorporeal membrane oxygenation for treatment of cardiogenic shock and cardiac arrest: a meta-analysis of 1,866 adult patients. Ann Thorac Surg. 2014;97(2):610-616. 5. Ting M, Wang CH, Tsao CI, et al. Heart transplantation under mechanical circulatory support for acute fulminant myocarditis with cardiogenic shock: 10 years” experience of a single center. Transplant Proc. 2016;48(3):951-955. 6. Hayanga JW, Aboagye JK, Hayanga HK, Luketich JD D’Cunha J. Extracorporeal membrane oxygenation as a bridge to lungre-transplantation: Is there a role. J Heart Lung Transplant 2016;35(7):901-905. 7. Chen YS, Lin JW, Yu HY, et al. Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis. Lancet. 2008;372(9638):554-561. 8. Le Guen M, Nicolas-Robin A, Carreira S, et al. Extracorporeal life support following out-of-hospital refractory cardiac arrest. Crit Care. 2011;15(1):R29. 521

47 Cannulation for ECMO in Adult Patients with Cardiac Failure Syed T. Hussain, MD, José Luis Navia, MD

The indications for extracorporeal membrane oxygenation (ECMO) are well established. ECMO can replace the function of both heart and lungs.1-8 The basic ECMO circuit consists of a centrifugal pump, coupled with a hollow fiber membrane oxygenator and oxygen blender, and a heparin-coated circuit (Figure 47-1). ECMO circulates and oxygenates the blood and also acts as a temporary substitute for the entire circulatory system. ECMO functions under the same principles of cardiopulmonary bypass (CPB), with duration of support being the most important difference. While CPB is typically employed for hours during cardiac surgery, ECMO is designed to support circulation

Figure 47-1. ECMO system used at the Cleveland Clinic: a centrifugal pump, oxygenator, and heat exchanger.

for longer duration. ECMO can rapidly restore systemic blood flow during cardiogenic shock. ECMO has undergone significant technological advancement over the last decade, and the evolution has taken place in both the centrifugal pumps and oxygenators that constitute the main components of most adult ECMO circuits. Evolution of ECMO technology has improved the ease with which patients are cared for, especially those with postcardiotomy cardiogenic shock; however, it has done little to impact the overall survival rates, reflecting that comorbidities associated with patients still drive outcomes.9 Venoarterial (VA) ECMO is used primarily for cardiogenic shock due to profound left ventricular (LV) or right ventricular (RV) failure.1-5 The typical scenarios for VA-ECMO are cardiac arrest due to various etiologies, postcardiotomy shock, cardiac emergencies such as recent myocardial infarction with shock, as a bridge to left ventricular assist device, or acute heart or lung transplant allograft dysfunction. The specific indications for ECMO are discussed elsewhere in the book. In this chapter, various cannulation techniques and their indications are discussed. Access for initiation of ECMO can be challenging and cannulation technique should be based on type of support needed, patient’s age and size, and specific clinical situation. The decision regarding the place for ECMO cannula523

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tion (ICU, operating room, etc.) should be based on clinical scenario and ability to transport the patient safely to the OR with adequate ventilation and hemodynamic support.1-5 For patients with postcardiotomy shock, central cannulation is typically used, because it is easy to switch the CPB circuit to ECMO with the existing cannulas. Alternatively, in cases in which immediate support is necessary, such as acute cardiogenic shock after myocardial infarction, peripheral access by way of a peripheral vessel using the Seldinger technique or open arteriotomy may be easier, and quicker (Figures 47-2, 47-3). The latter avoids the need for repeat sternotomy for decannulation and reduces risk of bleeding and infection; however, limb ischemia and unsatisfactory upper body perfusion are potential risks. A rapid assessment of the specific clinical scenario and patient-related factors are required to select the best strategy and cannulation site. Central ECMO cannulation may be used in patients who require postcardiotomy support through right atrial (for venous return) and ascending aortic cannulation (for arterial outflow). The size of the venous cannula limits the extracorporeal flow and the size of the arterial cannula determines the ECMO system pres-

sure. The choice of the cannula size should be based on the patients’ body surface area and the required blood flow. For adults, typical cannula sizes range from 16-20 Fr for arterial, and 1828 Fr for venous.1-3,9,10 The venous return could also be achieved through a long venous cannula placed in the femoral vein. Central cannulation is often set up in postcardiotomy cases, and switching from CPB to ECMO is an easy procedure. After stopping the CPB flow, the existing cannulas are clamped and disconnected from the CPB circuit, and then reconnected to the ECMO circuit. All air must be evacuated from the system. We do not routinely insert a pulmonary vent or left atrial pressure monitoring line. The purse string suture should be hemostatic and the tourniquets would be kept in the chest (or attached to the skin) in cases of central aortic cannulation. This obviously requires return to operating room for decannulation. The lines have to be secured meticulously to avoid accidental catastrophic dislodgement. Axillary artery cannulation is another option to allow chest closure and provide antegrade flow and combines the advantages of central cannulation and peripheral approach for ECMO. This will be discussed in more detail later in the chapter. Central cannulation allows better ECMO flow and ventricular unloading as it allows use of a larger size cannula, especially in patients with a large body surface area in which periph-

Figure 47-2. The setup for venoarterial peripheral ECMO with cannulation of right femoral artery and vein. A distal perfusion cannula is attached to the arterial limb of ECMO circuit.

Figure 47-3. Venoarterial ECMO with cannulation of left femoral artery and vein. Notice the perfusion cannula distal to the arterial cannula, and attached to the arterial limb of the circuit via a Luer lock.

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Cannulation for ECMO in Adult Patients with Cardiac Failure

eral cannulation may not deliver adequate flow. ECMO flow is limited by the maximum size of the vessel for access and the size and position of the cannula used.9.10 In patients with BSA >2 m2, peripheral ECMO flow may not be sufficient to prevent multiorgan failure. Central cannulation also provides antegrade oxygenated blood flow to the coronary and cerebral circulation. With peripheral ECMO, the cardiac output of the failing heart competes with retrograde ECMO flow from the femoral aortic cannula, producing admixing in the thoracic aorta, and perfusing arch and coronaries with desaturated blood.1,3 Major disadvantages of central cannulation are need for open chest and higher risk of bleeding, although the need for open chest may also be unrelated to ECMO. There is also higher risk of mediastinal infection. Prolonged central cannulation can cause serious injury to aorta and right atrium. Peripheral Cannulation Peripheral cannulation is probably the most common approach for ECMO initiation in noncardiac surgical situations like primary cardiogenic shock, cardiopulmonary arrest, acute myocardial infarction, etc., when immediate ECMO support is needed. In adults, femoral artery and vein cannulation, either performed percutaneously or by direct cutdown on the vessel, is the preferred approach when peripheral ECMO initiation is chosen, because of the large size of the adult femoral vessels (unless there is a suspicion or history of significant peripheral vascular disease) and technical ease (Figures 47-2, 47-3). Although presence of bounding femoral pulse can facilitate the identification of the femoral vessels, the vast majority of patients that require VA-ECMO for cardiac failure are unlikely to have bounding pulses. Occasionally, with the use of catecholamine during resuscitation or during external cardiac massage, a femoral pulse may be palpated. An ultrasound can facilitate the identification of

the femoral vessels if time allows, but in most clinical situations it may not be feasible. If ECMO is being placed during CPR, it is preferable to have two personnel trying simultaneously, working on both groins to try locating the femoral artery and vein. If possible, we prefer the right femoral vein for venous cannulation and left femoral artery for arterial cannulation, both due to venous anatomy and minimize leg ischemia by avoiding the arterial and venous cannulation in the same leg. Following the Seldinger technique, the guidewire is advanced from the femoral vein towards the right atrium and from the femoral artery into the aorta. The vessels are progressively dilated using progressive dilators, and the cannulas are introduced over the wires. We typically give about 5000 units of heparin bolus once the wires are in place (Figure 47-4). The venous cannula tip is aimed to be in the mid right atrium and ideally in the SVC-RA junction for optimum drainage. The arterial cannula is inserted for its whole length and lies in the iliac artery. The cannulas are connected to the ECMO circuit after making sure the lines are meticulously deaired. It is very important to secure the cannulas to the skin with multiple sutures. In case of hemodynamic instability, rapid

Figure 47-4. Peripheral arterial and venous cannula used for venoarterial ECMO. The arterial cannula has Luer lock mechanism. The bottom figure shows the kit required for percutaneous puncture of the artery, along with the guidewire and dilators.

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conversion to open technique is necessary if the initial attempts at percutaneous insertion fail. Since leg ischemia is a major concern, distal leg perfusion cannula should be routinely inserted. A 6-8 Fr distal perfusion cannula placed in the superficial femoral artery, and spliced into the arterial perfusion limb of the ECMO circuit is used to establish adequate perfusion of the leg.3 If the ECMO indication was emergent, this usually has to wait for the patient to stabilize and then an attempt to insert a distal perfusion catheter/cannula downstream to the arterial cannula is made, usually percutaneously under ultrasound guidance and connected to the arterial limb of the ECMO circuit. If the ECMO is done electively, the guidewire for the distal perfusion cannula should be inserted initially as it is easier to locate the femoral pulse distally before the before the arterial ECMO cannula. Modifications to improve arterial flow in the cannulated limb may include sewing an 8 mm graft on the femoral artery or cannulating contralateral venous and arterial vessels, and decrease peripheral limb ischemia, particularly when femoral artery is small or diseased. The disadvantages of peripheral cannulation via femoral artery are interference of distal flow to the cannulated limb, resulting in leg ischemia, and potentially unsatisfactory upper body oxygenation.11-13 Use of a side graft on the axillary artery is an option for ECMO arterial cannulation.3,14-16 The advantages include lack of atherosclerosis of axillary artery, even in patients with iliac femoral disease, central support with antegrade flow in the aorta, potentially minimizing atherosclerotic embolization, and the preferential delivery of oxygenated blood to the heart and brain. The axillary artery is exposed below the clavicle, and after administration of 5000 units of heparin, and 8 mm vascular graft is sewn in end-to-side fashion and connected to the arterial limb of the ECMO circuit (Figure 47-5). We prefer a more medial approach to the axillary artery as it avoids the surrounding brachial plexus roots 526

encountered during a more lateral deltopectoral approach.3,14-16 The complications reported with axillary artery cannulation include hypoperfusion of the ipsilateral arm and damage to the artery, both reduced with the use of an interposition graft.17 The most significant adverse effect associated with using axillary artery side graft technique as an outflow site for VA-ECMO is hyperperfusion syndrome in nearly 20% of patients, with almost half of them requiring some type of intervention to treat compartment syndrome.14 The reasons for the development of hyperperfusion syndrome are multiple and can be broadly divided into two categories: 1) those causes resulting from arterial outflow obstruction; and 2) those associated with venous outflow obstruction. Among the arterial obstructive causes, narrowing of axillary artery causing reduction of lumen and resulting preferential flow down the arm can cause hyperperfusion. A similar pattern can be expected with prolonged axillary graft use on the axillary artery in patients with atherosclerotic aortic arch disease and/or acute type A dissections in which the head vessels are involved. Venous obstructive causes can include

Figure 47-5. ECMO axillary circuit: venous inflow through the right femoral vein, and arterial inflow through interposition graft over the right axillary artery.

Cannulation for ECMO in Adult Patients with Cardiac Failure

bleeding into the surrounding space, causing a compressive hematoma, or if drainage to the arm is impeded by either a venous cannula or deep vein thrombus, or both. The initial management of hyperperfusion syndrome should be guided depending on its etiology. If arterial causes are suspected, the initial management should include: 1) elevating the arm and; 2) decreasing ECMO flow. If these maneuvers fail to relieve the syndrome, and concerns regarding the condition of the arm continue to occur, an effort to relocate the outflow for VA-ECMO should be pursued. If the cause of hyperperfusion syndrome is venous obstruction, therapy should be aimed at addressing the etiology causing the decreased venous return, including evacuation of the hematoma and wide drainage achieved with sump catheters. In cases in which a cannula is placed in the axillary vein for VA-ECMO drainage, another vein should be selected for cannulation—preferably the femoral vein. For patients in whom deep venous thrombosis is suspected, or diagnosed by radiologic modalities, no alternative is possible other than changing the arterial cannulation site, as previously described. It is important to note that the venous outflow can also be impeded in cases of cardiac tamponade and relieving this problem will also assist in upper extremity drainage. The incidence of brachial plexopathy is very low and is not permanent.14 Chamogerorgakis et al.14 reported their experience with 81 patients supported on ECMO using arterial inflow by a side graft sewn to the axillary artery. One hundred sixty-six patients underwent femoral arterial cannulation and 61 patients underwent femoral arterial cannulation. The most common complication in the axillary artery group was hyperperfusion syndrome of the ipsilateral upper extremity in 24.7%, and bleeding from the outflow graft in 17.3% of patients. Lower extremity ischemia and fasciotomy were more frequent after femoral arterial cannulation (16% and 10.8% respectively). The

cannulation method was not a predictor of inhospital outcomes. The arterial cannulation strategy should depend on the specific clinical scenario. In our practice, for patients with ongoing chest compression, percutaneous femoral artery cannulation is the most commonly used technique for VA-ECMO support (Edwards Fem-Flex II arterial, 16, 18 or 20 Fr. Edward Lifesciences, Irvine, CA).10 For postcardiotomy cases, central aortic cannulation is the first choice. However, if either the axillary artery was already exposed before sternal reentry in redo sternotomy, or used for complex arch cases requiring deep hypothermia with antegrade cerebral perfusion, axillary artery is used. Venous drainage is achieved with either a long 20 Fr, 24 Fr, or 24 Fr cannula (Edward Lifesciences, Irvine, CA, Figure 47-4) placed in the common femoral vein or the right atrium when the chest is left open after median sternotomy.10 Early detection of limb ischemia and or compartment syndrome is paramount to minimizing the adverse effects. With the absence of pulsatile flow, bedside Doppler examination of distal arterial waveforms is an impractical and an unreliable method of monitoring limb perfusion. Effective monitoring of distal perfusion by pulse evaluations is difficult in patients on ECMO as they are in shock, on a circuit that provides nonpulsatile flow, and are often receiving vasopressors, leaving uncertainty regarding the adequacy of distal perfusion. Additionally, large time gaps can occur between evaluations. To minimize injuries to the lower extremities, improvement is needed in monitoring tissue perfusion to diagnose complications before they become irreversible. Transcutaneous continuous near-infrared spectroscopy monitoring of tissue oxygenation for the early detection of limb complications in extracorporeal membrane oxygenation has been recently described.18,19 This technique has the potential to hasten surgical correction of perfusion deficits and prevent development of compartment syndrome and 527

Chapter 47

limb complications in patients with ECMO (Figure 47-6). Our practice is to place a distal perfusion cannula in all patients, and if a limb complication is suspected clinically or by a unilateral drop in tissue oxygen saturation O2, we ensure the cannula is not kinked or thrombosed. If the issue cannot be resolved, we then take the patient to the operating room for placement of a chimney graft or an alternative inflow position such as the axillary artery. We use a perfusion cannula as a first-line treatment instead of the chimney graft because bleeding at the suture lines of the chimney graft can be problematic. ECMO flow should be high enough to allow “cardiac rest” and maintain adequate hemodynamics and organ perfusion (Target MAP 65-70 mmHg; SVO2 >55%). Total cardiac output is typically 60 ml/kg/min in adults. It is important to allow some blood flow to go through the right and left chambers to avoid stasis within the cardiac chambers. Ventricular ejections are

Figure 47-6. Lower extremity ischemia monitoring in peripheral ECMO using transcutaneous near-infrared spectroscopy. Sensors are placed on the calf of both lower extremities for continuous monitoring of tissue oxygenation to allow early detection of leg ischemia.

528

confirmed by pulsatility on the arterial waveform, or by observing aortic valve opening on the echocardiogram. If a mechanical valve is present, then maintaining opening and closing of the valve avoids thrombus formation. Echocardiogram should be done within 6 hours of initiating ECMO, if not done during insertion to assess the left ventricular decompression. ECMO unloads the right ventricle but does not completely unload the left ventricle, even though the LV preload is reduced. Lack of LV decompression on full ECMO flow may require additional measures including additional inotropic support, intraaortic balloon pump (IABP), Impella insertion, or separate venous drainage catheter in the main pulmonary artery (retrograde transpulmonary LV decompression). Patients with severe ventricular dysfunction with poor ejection should ideally have a left ventricular vent placed to prevent ventricular distension or thrombosis. For postcardiotomy patients, IABP decreases afterload that can adversely affect the injured heart, and it adds pulsatility to the continuous flow generated by the centrifugal pump. We routinely place Luer locks in the arterial and venous connectors during ECMO insertion to allow easy hemofiltration and continuous venovenous hemodialysis (CVVHD). CVVHD permits control of fluid balance by continuous ultrafiltration and can be adjusted for volume removal and also allows for dialysis if needed. Prior to placement of large bore perfusion cannulas and initiation of ECMO, a heparin bolus of 60 u/kg is usually administered to achieve ACT 180-200 s. Since many postcardiotomy patients may not have had the heparin reversed, no additional heparin is given. Post-ECMO continuous heparin infusion, unless contraindicated (uncontrolled surgical bleeding, recent surgery, stroke etc.), is started at 8-10 unit/kg/ hr and titrated to maintain a PTT between 45-55 s or ACT between 180-200 s. This maintains a balance that reduces both the rate of bleeding and clot formation inside the pump head and

Cannulation for ECMO in Adult Patients with Cardiac Failure

in the heart cavity. Any evidence of clotting in the pump head or tubing requires a change of these components. For actively bleeding patients, anticoagulation is delayed until the appropriate coagulation deficit is corrected and the bleeding is under control (1.5 mg/dL (>132 of AKI requires optimization of oxygen delivumol/L) with or without renal replacement ery by maintaining an adequate hemoglobin, therapy.17 While the exact mechanism of ECLS- oxygen saturation, and blood flow, along with associated AKI is not well understood, factors reduction of oxygen consumption via judicious including kidney disease pre-ECLS and system- sedation strategies, fever control, pain control, ic hypoperfusion are certainly major contribu- and prevention of hyperadrenergic states. Using tors. In the Acute Decompensated Heart Failure the lowest possible ECLS flow and pump speed National Registry (ADHERE) patients admitted with appropriately sized and positioned canfor acute decompensated heart failure (HF), nulas to keep central venous oxygen saturation 30% had a history of renal insufficiency, with levels above 60%, clear lactate, and maintain 21% having a serum creatinine concentrations an adequate urine output, minimizes the detri>2.0 mg/dL.44 Adverse organ cross talk is also mental effects of ECLS-associated hemolysis seen in Acute Respiratory Distress Syndrome and blood shear stresses49,59,60 This concept of situations of life threatening active bleeding, anticoagulation is discontinued and reversed using protamine, blood products, and antifibrinolytics guided by point of care (POC) testing. Hypothermia and acidosis should also be corrected, and ECLS pump flow rates maintained higher until bleeding is controlled.27 If active bleeding cannot be controlled with conventional methods, some advocate that judicious use of recombinant FVII may be safe in ECLS patients (n=30),28 while source control is considered with a surgical or interventional radiology consultation. The circuit and membrane oxygenator should be observed closely for development of clot. In situations where anticoagulation is required for coronary stents or prosthetic mitral valves, authors suggest control of bleeding for 12-24 hours prior to sequential reinitiation of POC-guided low dose systemic anticoagulation followed by an antiplatelet agent after another 12-24 hours.

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Adult Cardiac ECLS Acute Complication and Comorbidity Management

‘blood protective flow’ to protect the blood from hemolysis during ECLS is analogues to ‘lung protective ventilation’ being used to protect the lung from overdistention during mechanical ventilation for ARDS. CKD patients may need a higher mean arterial pressure to ensure adequate blood flow to the kidneys, although overshooting should be prevented as it can induce ischemia-reperfusion injury. A MAP of 70-85 is usually sufficient to avoid flow limitation.61 Optimizing the patient’s fluid status is important and remains challenging even with the use of serial echocardiograms and ultrasound assessments of the inferior vena cava (IVC). Empiric fluid challenges may be expeditious and pragmatic, but detrimental, as increasing evidence suggests excessive fluid may be harmful.54,62 In situations of IVC congestion, the use of diuretics is beneficial to decongest the kidney and improve renal perfusion pressure.63 Use of nephrotoxic medications must also be avoided. If necessary, dose adjustments should be based on estimated glomerular filtration rate (GFR), volume of distribution or measured blood levels (for drugs with available assays). Similar dose adjustments should be made for all drugs that are renally excreted. The overall aim is renal preservation and recovery; however, use of renal replacement therapy (RRT) is frequently necessary. Classic RRT indications in patients on ECMO include uremia, acidosis, electrolyte abnormalities, and fluid overload (most common). CKD patients already on hemodialysis and considered appropriate for ECMO support should be initiated on CRRT after ECMO initiation to avoid rapid fluid shifts and hemodynamic perturbations. Finally, CKD patients have increased risk of venous thromboembolism and synthetic erythropoietin or analogues are not recommended once on ECMO. New Infections New infections arise in 7-30% of patients and are associated with a 27% mortality but

studies have significant heterogeneity in the definitions.1-3,64,65 Risk factors for developing infections while on ECLS include older age, increased disease severity, duration of therapy, positive pre-ECLS culture, and mechanical complications during ECLS.20,64,65 The most common sources of infections include vascular access, bladder catheters, pulmonary and surgical wounds, with pneumonia, bacteremia, and wound infection being the most common presentations at a median of 5, 8, and 23 days post-ECLS initiation, respectively.64 Signs of infection (systemic inflammatory response syndrome [SIRS]) including tachypnea, tachycardia, hypotension, temperature variation, leukocytosis, and thrombocytopenia are challenging to distinguish from ECLS-related immune, hematologic, and metabolic changes. As a result, monitoring for other subtle changes that accompany sepsis is necessary. Increasing carbon dioxide results from the increased metabolism associated with sepsis and requires increasing the ECLS sweep to compensate. Increased insulin resistance as a result of circulating catecholamines requires increasing doses of insulin in a previously stable patient. Vasodilation and third spacing from sepsis-associated capillary leak results in hypotension and ‘chatter events’ frequently requiring decreased ECLS flow rates while undergoing fluid resuscitation. Sepsis associated coagulopathy resembling disseminated intravascular coagulation (DIC) can be difficult to distinguish from circuit associated sterile thrombosis. Tanaka et al. looked at a procalcitonin based algorithm (cutoff levels >2.0 ng/mL) to supplement the clinical signs of infection and found this had a sensitivity of 90% and specificity of 89% in this small retrospective adult cohort study (n=41),66 and other studies have shown this to be useful in pediatrics.67 Candida, methicillin resistant Staphylococcus aureus (MRSA) and nonlactose fermenting gram negative bacilli (Pseudomonas, Stenotrophomonas) infections are increasingly common, and appropriately broad spectrum antimicrobial 535

Chapter 48

coverage tailored to local antibiograms is recommended.20,64,65 Antibiotic pharmacokinetics are differentially affected by ECLS circuit sequestration, and this may effect patient outcome.68,69 For example, meropenem may require higher dosing and continuous infusion whereas vancomycin is unaffected.70,71 Infection prevention checklists and ‘ECLS bundles’ are recommended for insertion and maintenance of medical appliances; however, routine use of antibiotic prophylaxis is not recommended.72 Despite optimal care, vasodilatory septic shock can develop in patients receiving cardiac ECLS and preexisting sepsis is present with cardiogenic shock in up to 13% of cases in some series.17-19 ECLS flow should be increased to compensate for the additional metabolic demand targeting a cardiac index of >2.2 L/min/ m2 and central venous oxygen saturation >70%. 73 Peripheral ECLS cannulas can be inadequate to achieve target blood flow without excessive blood shear; thus, some advocate addition of a second venous drainage cannula or conversion to central cannula configuration. Patients who develop infections while on ECLS can be expected to have increased complications and a higher mortality.65 Lower Extremity Ischemia

tion, as well as monitoring distal blood flow post cannulation in order to distinguish between arterial embolism and low flow.32,33 When vessel caliber is too small to safely accommodate the cannula size necessary for adequate ECLS flow, distal perfusion catheters (anterograde via distal superficial femoral artery or retrograde via dorsalis pedis) or a cutdown approach with arterial vascular grafts may be employed to permit both anterograde and retrograde flow within the artery.31,34-37 Though difficult to monitor or quantitate, resting superficial femoral artery blood flow can be measured, and in the normal lower extremity is estimated at 150 ml/ min with an ankle pressure of >50 mmHg.38,39 For patients at high risk of peripheral ischemia, the addition of near-infrared spectroscopy (NIRS) and meticulous clinical examination with calf circumference measurements may also be of value by providing an early warning of limb hypo/hyperperfusion that may require intervention.40,41 Despite attempts at optimizing distal perfusion, compartment syndrome may occasionally require urgent fasciotomy and less commonly requires distal limb amputation.42 Other vascular injuries associated with arterial cannulation have occurred in 18% of patients (n=101) and include lacerations, arterial dissection, pseudoaneurysms, stenosis, and lymphoceles, all of which require surgical intervention.31

In patients with lower extremity arterial cannulation, meta analytic studies demonstrate that 11-17% develop distal ischemia, with 9-10% Acute Neurologic Events requiring fasciotomies, and 3-5% requiring amReported rates of acute neurologic computation.2,3,29 The risk of vascular complications is higher in patients with peripheral vascular plications vary widely from 2%-50%, with the disease, which may be present in 4% of those ELSO Registry reporting seizures in 2% and over the age of 40 and particularly prevalent acute intracranial hemorrhage in another 2% among patients who are diabetic, hypertensive, of adult patients receiving cardiac ECLS.4,5,24 hyperlipidemic, have chronic kidney disease, or The etiology of new ischemic events is believed are active smokers.30,31 Large diameter cannulas to be related to air or clot emboli; hence, the necessary for ECLS may occlude anterograde importance of systemic anticoagulation and air flow in native vessels contributing to distal filters for all intravenous lines.4,5,46 Neuroproischemia. Vascular ultrasound can be useful for tection with normothermia (36-37° C), euglysizing the femoral vessels during cannula selec- cemia (140-180 mmol/L), and optimization of 536

Adult Cardiac ECLS Acute Complication and Comorbidity Management

cerebral oxygen delivery is prudent. Cerebral blood flow can be monitored with transcranial Doppler (TCD) sonography,79,80 although this does not monitor for effects of differential hypoxia.81 Differential hypoxia occurs when oxygen desaturated blood ejected from the left ventricle mixes with oxygen rich retrograde blood flow from the ECLS circuit resulting in the potential to deliver poorly oxygenated blood to the coronary arteries and ascending arch of the aorta. Also termed Harlequin syndrome, this phenomenon was shown in one study to occur in 8% of peripheral cannulations.82 Right radial arterial catheterization and use of pulse oximetry on the right hand may be the best ways to obtain a surrogate estimate of ECLS-oxygenated blood delivered via femoral artery cannula to the cerebral circulation (see Figure 48-1).83 The addition of cerebral NIRS to monitor changes in cerebral perfusion may provide further guidance in select patients (Figure 48-1).84

Central cannulation is optimal for cerebral oxygen delivery but is associated with complications inherent to thoracotomy. With peripheral cannulation, adequate oxygenation of cerebral blood flow depends upon ECLS blood flow, arterial cannula location, native cardiac function and native lung function. Early in cardiac ECLS when native cardiac output is poor, systemic and cerebral arterial perfusion is maintained primarily by continuous ECLS blood flow. As native cardiac output improves, however, differential hypoxia may worsen cerebral oxygen delivery. This can be managed by improving the pulmonary shunt through mechanisms that include manipulation of the mechanical ventilator, reduction of native cardiac output by decreasing inotropes or increasing diuresis, improvement in ECLS blood flow by increasing pump rate or adding an extra venous drainage cannula, or the addition of a venous return cannula (conversion to venous-arterial venous [V-AV] configuration).85 Intraaortic balloon pump support may also improve cerebral blood flow during cardiac recovery when arterial pulse pressure is increased above 10 mmHg.80 While an initial target MAP of 65 mmHg may be necessary, adjustments should be considered according to regional organ tissue perfusion pressure estimates.61 Neuroprognostication can be challenging in patients on ECLS with unexplained altered mental status. Neuroimaging with cranial computed tomography (CT) frequently demonstrates significant findings that change direction of care but may be underutilized due to patient transportation logistics.86 Electroencephalography (EEG) monitoring is recommended in critically ill patients with unexplained altered mental status, as up to 16% of them may have nonconvulsive seizures.87,88 Plasma brain injury biomarkers such as neuron specific enolase and S100b show promise for neuroprognostication but most data is from pediatrics at this time.89-91

Figure 48-1. Monitoring in the VA-ECMO patient.

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Hemolysis Hemolysis is seen in approximately a quarter of adult cardiac ECLS patients and is associated with increased morbidity and mortality.1,60 The fractured red blood cells release free hemoglobin into the plasma which scavenges endothelial nitric oxide resulting in microvascular vasomotor dysregulation and may promote thrombosis by von Willebrand factor-mediated platelet adhesion.74 The degree of hemolysis is routinely monitored by plasma free hemoglobin (PHb) levels, lactate dehydrogenase (LDH) levels, and change in urine color. PHb levels trending up over 100 mg/dL require further investigation including measurement of serum bilirubin and haptoglobin levels. Hypertriglyceridemia may result in overestimation of PHb measurement and should be considered in patients receiving propofol.75 Sudden increases to levels over 1000 mg/dL strongly suggest pump head thrombosis, and if associated with a decrease in platelets, heparin induced thrombocytopenia should be considered.47,76 Other technical causes of increased hemolysis include disproportionately high velocity blood flow through cannulas generating excessive negative pressures, centrifugal pump speeds >3500 RPM, and an increased pressure gradient across membrane oxygenator.59 Roller pumps have been associated with higher levels of hemolysis, but no difference has been observed between centrifugal pumps.77,78 Left Ventricular Overload and Pulmonary Edema The prevalence of adult cardiac ECLSassociated left ventricular (LV) overdistention and pulmonary edema was 11% in a small adult study, but has been reported to occur in over 60% of pediatric ECLS cases.92,93 Because VA-ECMO is a partial cardiopulmonary bypass system, some blood that is not captured by the venous drainage cannula continues through 538

the right ventricle, through the lungs to the left ventricle. With a competent aortic valve and poor LV function, peripheral ECLS pressurizes the aorta, resulting in proportionately excessive LV afterload. Without LV ejection into the aorta, the LV overdistends and rapidly results in severe pulmonary edema, pulmonary hemorrhage, and an increased risk of LV and aortic root thrombus formation. Detection of this phenomenon requires assessment of arterial line pulsatility (as a pulse pressure of 40 kg/ m2) adversely effects all major organ systems and in particular cardiovascular, respiratory, and metabolic function.101,102 Management of ECLS in the obese patient is complicated by difficulty with imaging due to fluoroscopy and ultrasound power, table weight limitations on CT scanners, unpredictable lipophilic drug bioavailability, and challenges with hemodynamic monitoring and vascular access.103-105 The higher prevalence of obesity hypoventilation syndrome and obstructive sleep apnea with associated pulmonary hypertension, elevated blood pressures, and increased biventricular ventricular mass and cardiac output further bring challenges to the management of the obese patient on ECLS. Initiation of peripheral VA-ECMO may require surgical cutdown procedures for cannulation, larger cannulas to achieve adequate blood flow, higher blood flow rates to adequately support basal oxygen consumption, and careful attention to wound care and pressure points for prevention of decubitus ulcer formation and infection. In addition, higher intrathoracic mechanical ventilation pressures and intraabdominal pressures may be present and can influence native

cardiac venous return and ECLS venous drainage flows in difficult to predict ways depending upon a patient’s active or passive ventilation pattern.106 With consideration for chronic hypertensive and diabetic microvascular diatheses, the target MAPs may need to be higher (MAP >75 mmHg) to maintain adequate tissue perfusion pressure and organ function. Optimization of oxygen delivery may be aided by the use of cerebral and limb NIRS.107 In addition, moderate glycemic control with a target of 140-180 mg/dL (7.7-10 mmol/L) and avoidance of hypoglycemia is recommended.108,109 Use of insulin infusions may minimize large glycemic variability which may be associated with increased mortality110 while avoiding subcutaneous punctures and associated erratic insulin absorption from vasoconstricted subcutaneous tissues. With attention to the care of morbidly obese critically ill patients, it may be possible to improve their outcomes over time.111,112 COPD affects 10% of adults and is frequently associated with other smoking related comorbidities such as reactive airway disease and CAD.100,113,114 COPD is associated with airflow limitation, chronic airway inflammation, cough, and increased secretions. Goals of managing mechanically ventilated COPD patients include resting respiratory muscles, maintaining bronchial hygiene, avoiding hyperventilation, minimizing the risk of barotrauma, and avoiding impairment of ECLS flows that result from dynamic hyperinflation. Initially the use of short acting bronchodilator and anticholinergic nebulizers and sedation is required to avoid air trapping and hyperventilation. The use of systemic steroids and antibiotics needs to be considered for acute exacerbations manifested by increased secretions and worsening airflow obstruction.115 Airway clearance techniques range from manual percussive chest physical therapy to intrapulmonary percussive ventilation therapy to fiberoptic bronchoscopy,116(Print though there is no clear evidence to support routine use in COPD exacerbations except in 539

Chapter 48

patients with bronchiectasis.115 Managing prolonged exhalation and reactive airways becomes challenging as patients emerge from sedation and during weaning from ECLS. Recognizing and managing dynamic hyperinflation (intrinsic positive end expiratory pressure) via waveforms on mechanical ventilator and end tidal CO2 monitor prevents associated complications such as increased work of breathing, barotrauma, and hemodynamic compromise.117,118 Unfortunately, inhaled beta agonist bronchodilators are frequently associated with tachycardia, which can detrimentally increase myocardial oxygen demand, especially in multimorbid patients with CAD. This becomes particularly important in peripherally cannulated patients with differential hypoxia where coronary arterial blood may be inadequately saturated (as described previously). Usual monitoring for cardiac ischemia is performed with serial electrocardiograms, cardiac serum biomarkers, and echocardiography. Aspirin and antithrombin therapy remain the usual management, as well as minimizing myocardial oxygen demand. Beta blockers may be considered in this situation; however, their pulmonary side effects may limit their use in multimorbidity.119 Insertion of an IABP was previously considered conventional therapy for augmenting myocardial diastolic perfusion during cardiogenic shock. This, however, has fallen out of favor since the SHOCK II trial.120 While the use of an IABP was not shown to improve microcirculation during ECLS in a recent small study, it can decrease LV end-diastolic pressure and pulmonary capillary wedge pressure.121 In evaluation of ongoing myocardial injury and prognostication of postcardiotomy cardiogenic shock, daily creatine kinase isoenzyme MB (CK-MB) relative index may be valuable.122,123 Summary Adult cardiac ECLS can support patients with cardiopulmonary compromise; however, careful attention must be paid to managing 540

acute complications and chronic comorbidities. An approach to monitoring and managing the complex interactions between the patients’ acute illnesses, chronic diseases, and ECLS is necessary to improve short and long-term outcomes (Table 48-1). As multimorbidity becomes more common, recognition of common patterns may assist providers in anticipating and avoiding complications.

Adult Cardiac ECLS Acute Complication and Comorbidity Management Table 48-1. Approach to Monitoring and Managing the VA-ECMO patient. (Permission to use granted under Creative Commons Attribution License.) Rhythm

MAP Pulsatility

Flow (L/Min)

Gas Exchange

Oxygen Delivery: SvO2 and Lactate

Distal limb Ischemia Anticoagulation Temperature

Monitor for Dysrhythmias such as ventricular fibrillation that may prevent ventricular ejection Hypotension (MAP=COxSVR) (i) Inadequate VA-ECMO flow (ii) Inadequate DVR Lack of pulsatility on arterial waveform caused by (i) poor myocardial function (ii) excessive VA-ECMO support (iii) inadequate preload (iv) RV failure May result in (i) thrombus (ii) myocardial ischemia (iii) pulmonary edema (assess CXR, wedge( Low flows (assuming centrifugal pump) (i) Inadequate preload (a) hypovolemia (may see hemolysis, chattering) (b) mechanical obstructive (ii) Excessive afterload (thrombus, kink, SVR) (iii) Inadequate RPM Inadequate PaO2 inadequate or excessive CO2 elimination (i) VA-ECMO settings (a) FiO2 (b) VA-ECMO flow (c) Sweep gas flow rate (ii) Oxygenator function (a) Pre and postmembrane pressures (b) Pre and postoxygenator gases (iii) Upper body hypoxemia (femoral-femoral cannulation

Decreased SvO2 and increasing lactage suggest inadequate oxygen delivery (DO2=COxCaO2) (i) VA-ECMO flow (ii) Hemoglobin (iii) SaO2 Excessive oxygen consumption (ER=VO2/DOs) (i) Febrile (ii) Shivering Loss of pulses Cyanosis and coolness of limb Adequate heparinization by PTT Normothermia unless therapeutic hypothermia

Treatment Antiarrhythmics Cardioversion Pacing Ablation (i) See “Flow” below (ii) Start vasoconstrictor If poor myocardial function, consider: decreasing VA-ECMO flow starting or increasing inotrope starting or increasing vasodilator IABP Myocardial decompression

(i) Volume: crystalloid/colloid/transfusion Release of mechanical obstruction (ii) Exchange oxygenator, relieve cannula kink, vasodilator to decrease SVR (iii) Increase RPM (i) If hypoxemia, increase FiO2 or flow. If hypercarbia, increase sweep. If hypocarbia, decrease or add CO2 (ii) Increased AP and inadequate arterialization of postoxygenator gases suggest oxygenator malfunction (iii) Increase pulmonary venous O2 content Adjust ventilator settings. Treat etiology of pulmonary dysfunction. Increase VAECMO flow. Change to axillary/carotid cannulation. VA-V-ECMO. VV-ECMO (i) Increase VA-ECMO flow (ii) Transfuse (iii) Ensure adequate gas exchange (i) Antipyretics (ii) Consider agents such as meperidine or dexmedetomidine Femoral-femoral cannulation DP or PT anterograde perfusion catheter

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18. Lan C, Tsai PR, Chen YS, Ko WJ. Prognostic factors for adult patients receiving extracorporeal membrane oxygenation as mechanical circulatory support--a 14-year experience at a medical center. Artif Organs. Feb 2010;34(2):E59-64. 19. Schmidt M, Combes A. Infectious complications under ECMO. Reanimation. 2015;24(3):265-269. 20. Aubron C, Cheng AC, Pilcher D, et al. Infections acquired by adults who receive extracorporeal membrane oxygenation: Risk factors and outcome. Infection Control and Hospital Epidemiology. 2013;34(1):24-30. 21. Vogel AM, Lew DF, Kao LS, Lally KP. Defining risk for infectious complications on extracorporeal life support. J Pediatr Surg. 2011;46(12):2260-2264. 22. Carroll BJ, Shah RV, Murthy V, et al. Clinical Features and Outcomes in Adults With Cardiogenic Shock Supported by Extracorporeal Membrane Oxygenation. Am J Cardiol. Nov 15 2015;116(10):1624-1630. 23. Lee DS, Chung CR, Jeon K, et al. Survival After Extracorporeal Cardiopulmonary Resuscitation on Weekends in Comparison With Weekdays. Ann Thorac Surg. Jan 2016;101(1):133-140. 24. Paden ML, Conrad SA, Rycus PT, Thiagarajan RR. Extracorporeal Life Support Organization Registry Report 2012. Asaio J. May-Jun 2013;59(3):202-210. 25. Mazzeffi M, Greenwood J, Tanaka K, et al. Bleeding, Transfusion, and Mortality on Extracorporeal Life Support: ECLS Working Group on Thrombosis and Hemostasis. Ann Thorac Surg. Feb 2016;101(2):682-689. 26. Petricevic M, Milicic D, Boban M, et al. Bleeding and Thrombotic Events in Patients Undergoing Mechanical Circulatory Support: A Review of Literature. Thorac Cardiovasc Surg. Dec 2015;63(8):636-646. 27. Lequier LA, G. Al-Ibrahim, O. Bembea, M. Brodie, D. Brogan, T. Buckvold, S. Chicoine, L. Conrad, S. Cooper, D. Dalton, H.

Frischer, J. Harris, B. Mazor, R. Paden, M. Rintoul, N. Ryerson, L. Spinella, P. Teruya, J. Winkler, A. Wong, T. Massicotte, M. ELSO Anticoagulation Guidelines. 2014. http://www.elso.org. Accessed February 1, 2016. 28. Anselmi A, Guinet P, Ruggieri VG, et al. Safety of recombinant factor VIIa in patients under extracorporeal membrane oxygenation. Eur J Cardiothorac Surg. Jan 2016;49(1):78-84. 29. Bisdas T, Beutel G, Warnecke G, et al. Vascular complications in patients undergoing femoral cannulation for extracorporeal membrane oxygenation support. Ann Thorac Surg. Aug 2011;92(2):626-631. 30. Selvin E, Erlinger TP. Prevalence of and Risk Factors for Peripheral Arterial Disease in the United States: Results From the National Health and Nutrition Examination Survey, 1999–2000. Circulation. August 10, 2004 2004;110(6):738-743. 31. Aziz F, Brehm CE, El-Banyosy A, Han DC, Atnip RG, Reed AB. Arterial Complications in Patients Undergoing Extracorporeal Membrane Oxygenation via Femoral Cannulation. Ann Vasc Surg. 2014;28(1):178183. 32. Nanjayya VM, D. Ultrasound Guidance for Extra-corporeal Membrane Oxygenation. 2015. https://www.elso.org/Portals/0/Files/ elso_Ultrasoundguideance_ecmogeneral_guidelines_May2015.pdf. Accessed February 1, 2016. 33. El-Gengehe AT, Ammar WA, Baligh Ewiss E, Ghareeb Mahdy S, Osama D. Acute limb ischemia: role of preoperative and postoperative duplex in differentiating acute embolic from thrombotic ischemia. Cardiovasc Revasc Med. Jul-Aug 2013;14(4):197-202. 34. Jackson KW, Timpa J, McIlwain RB, et al. Side-Arm Grafts for Femoral Extracorporeal Membrane Oxygenation Cannulation. Ann Thorac Surg. 2012;94(5):e111-e112.

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35. Bürkle MA, Sodian R, Kaczmarek I, et al. Arterial Chimney Graft Cannulation for Interventional Lung Assist. Ann Thorac Surg. 2012;94(4):1335-1337. 36. Roussel A, Al-Attar N, Khaliel F, et al. Arterial vascular complications in peripheral extracorporeal membrane oxygenation support: a review of techniques and outcomes. Future Cardiology. 2013/07/01 2013;9(4):489-495. 37. Kimura N, Kawahito K, Ito S, et al. Perfusion through the dorsalis pedis artery for acute limb ischemia secondary to an occlusive arterial cannula during percutaneous cardiopulmonary support. J Artif Organs. 2005;8(3):206-209. 38. Holland CK, Brown JM, Scoutt LM, Taylor KJW. Lower extremity volumetric arterial blood flow in normal subjects. Ultrasound Med. Biol. 1998;24(8):1079-1086. 39. Huang SC, Yu HY, Ko WJ, Chen YS. Pressure criterion for placement of distal perfusion catheter to prevent limb ischemia during adult extracorporeal life support. J Thorac Cardiovasc Surg. Nov 2004;128(5):776-777. 40. Wong JK, Smith TN, Pitcher HT, Hirose H, Cavarocchi NC. Cerebral and lower limb near-infrared spectroscopy in adults on extracorporeal membrane oxygenation. Artif Organs. Aug 2012;36(8):659-667. 41. Steffen RJ, Sale S, Anandamurthy B, et al. Using Near-Infrared Spectroscopy to Monitor Lower Extremities in Patients on Venoarterial Extracorporeal Membrane Oxygenation. Ann Thorac Surg. 2014;98(5):1853-1854. 42. Avalli L, Sangalli F, Migliari M, et al. Early vascular complications after percutaneous cannulation for extracorporeal membrane oxygenation for cardiac assist. Minerva Anestesiol. Jan 2016;82(1):36-43. 43. Zhang Q-L, Rothenbacher D. Prevalence of chronic kidney disease in population-based

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organ function: implications for LVAD development. J Artif Organs. 2005;8(3):143148. 53. Marik PE, Cavallazzi R. Does the central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense. Crit Care Med. 2013;41(7):1774-1781. 54. Benes J, Kirov M, Kuzkov V, et al. Fluid Therapy: Double-Edged Sword during Critical Care? Biomed Res Int. 2015;2015:729075. 55. Lin CY, Chen YC, Tsai FC, et al. RIFLE classification is predictive of short-term prognosis in critically ill patients with acute renal failure supported by extracorporeal membrane oxygenation. Nephrology Dialysis Transplantation. 2006;21(10):28672873. 56. Chen YC, Tsai FC, Fang JT, Yang CW. Acute kidney injury in adults receiving extracorporeal membrane oxygenation. J Formos Med Assoc. Nov 2014;113(11):778785. 57. Ricci Z, Morelli S, Favia I, Garisto C, Brancaccio G, Picardo S. Neutrophil gelatinase-associated lipocalin levels during extracorporeal membrane oxygenation in critically ill children with congenital heart disease: Preliminary experience*. Pediatr Crit Care Me. 2012;13(1):e51-e54. 58. Chawla LS, Goldstein SL, Kellum JA, Ronco C. Renal angina: concept and development of pretest probability assessment in acute kidney injury. Crit Care. 2015;19:93. 59. Toomasian JM, Bartlett RH. Hemolysis and ECMO pumps in the 21st Century. Perfusion. Jan 2011;26(1):5-6. 60. Lehle K, Philipp A, Zeman F, et al. Technical-Induced Hemolysis in Patients with Respiratory Failure Supported with VenoVenous ECMO - Prevalence and Risk Factors. Plos One. 2015;10(11):e0143527. 61. DellaVolpe JD, Moore JE, Pinsky MR. Arterial blood pressure and heart rate regulation

in shock state. Curr Opin Crit Care. Oct 2015;21(5):376-380. 62. Schmidt M, Bailey M, Kelly J, et al. Impact of fluid balance on outcome of adult patients treated with extracorporeal membrane oxygenation. Intensive Care Med. Sep 2014;40(9):1256-1266. 63. Kingma JG, Simard D, Rouleau JR. Renocardiac syndromes: physiopathology and treatment stratagems. Canadian Journal of Kidney Health and Disease. 2015;2(1):1-10. 64. Sun HY, Ko WJ, Tsai PR, et al. Infections occurring during extracorporeal membrane oxygenation use in adult patients. J Thorac Cardiovasc Surg. Nov 2010;140(5):11251132 e1122. 65. Bizzarro MJ, Conrad SA, Kaufman DA, Rycus P. Infections acquired during extracorporeal membrane oxygenation in neonates, children, and adults. Pediatr Crit Care Med. May 2011;12(3):277-281. 66. Tanaka D, Pitcher HT, Cavarocchi NC, Diehl JT, Hirose H. Can procalcitonin differentiate infection from systemic inflammatory reaction in patients on extracorporeal membrane oxygenation? J Heart Lung Transplant. Nov 2014;33(11):1186-1188. 67. Rungatscher A, Merlini A, De Rita F, et al. Diagnosis of infection in paediatric venoarterial cardiac extracorporeal membrane oxygenation: role of procalcitonin and Creactive protein. Eur J Cardiothorac Surg. May 2013;43(5):1043-1049. 68. Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate Antimicrobial Treatment of Infections: A Risk Factor for Hospital Mortality Among Critically Ill Patients. Chest. 1999;115(2):462-474. 69. Shekar K, Roberts JA, McDonald CI, et al. Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation. Crit Care. 2012;16(5):R194. 70. Shekar K, Roberts JA, Ghassabian S, et al. Altered antibiotic pharmacokinetics during 545

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extracorporeal membrane oxygenation: cause for concern? J Antimicrob Chemother. Mar 2013;68(3):726-727. 71. Shekar K, Roberts JA, Barnett AG, et al. Can physicochemical properties of antimicrobials be used to predict their pharmacokinetics during extracorporeal membrane oxygenation? Illustrative data from ovine models. Crit Care. 2015;19(1):437. 72. O’Horo JC, Cawcutt KA, De Moraes AG, Sampathkumar P, Schears GJ. The evidence base for prophylactic antibiotics in patients receiving extracorporeal membrane oxygenation. Asaio J. 2016;62(1):6-10. 73. Park TK, Yang JH, Jeon K, et al. Extracorporeal membrane oxygenation for refractory septic shock in adults. Eur J Cardiothorac Surg. Feb 2015;47(2):e68-74. 74. Da Q, Teruya M, Guchhait P, Teruya J, Olson JS, Cruz MA. Free hemoglobin increases von Willebrand factor–mediated platelet adhesion in vitro: implications for circulatory devices. Blood. 2015-11-12 00:00:00 2015;126(20):2338-2341. 75. Venado A, Wille K, Belott SC, Diaz-Guzman E. Unexplained hemolysis in patients undergoing ECMO: beware of hypertriglyceridemia. Perfusion. Sep 2015;30(6):465468. 76. Makdisi G, Wang I-w. Extra Corporeal Membrane Oxygenation (ECMO) review of a lifesaving technology. J Thorac Dis. 2015;7(7):E166-E176. 77. Byrnes J, McKamie W, Swearingen C, et al. Hemolysis during cardiac extracorporeal membrane oxygenation: a case-control comparison of roller pumps and centrifugal pumps in a pediatric population. Asaio J. Sep-Oct 2011;57(5):456-461. 78. Palanzo DA, El-Banayosy A, Stephenson E, Brehm C, Kunselman A, Pae WE. Comparison of hemolysis between CentriMag and RotaFlow rotary blood pumps during extracorporeal membrane oxygenation. Artif Organs. Sep 2013;37(9):E162-166. 546

79. Belohlavek J, Skalicka H, Boucek T, et al. Feasibility of cerebral blood flow and oxygenation monitoring by continuous transcranial Doppler combined with cerebral oximetry in a patient with refractory cardiac arrest treated by extracorporeal life support. Perfusion. Nov 2014;29(6):534-538. 80. Yang F, Jia ZS, Xing JL, et al. Effects of intra-aortic balloon pump on cerebral blood flow during peripheral venoarterial extracorporeal membrane oxygenation support. J Transl Med. 2014;12:106. 81. Alwardt CM, Patel BM, Lowell A, Dobberpuhl J, Riley JB, DeValeria PA. Regional perfusion during venoarterial extracorporeal membrane oxygenation: a case report and educational modules on the concept of dual circulations. J Extra Corpor Technol. Sep 2013;45(3):187-194. 82. Rupprecht L, Lunz D, Philipp A, Lubnow M, Schmid C. Pitfalls in percutaneous ECMO cannulation. Heart Lung Vessel. 2015;7(4):320-326. 83. Chung M, Shiloh AL, Carlese A. Monitoring of the Adult Patient on Venoarterial Extracorporeal Membrane Oxygenation. The Scientific World Journal. 2014;2014:10. 84. Maldonado Y, Singh S, Taylor MA. Cerebral near-infrared spectroscopy in perioperative management of left ventricular assist device and extracorporeal membrane oxygenation patients. Current Opinion in Anesthesiology. 2014;27(1):81-88. 85. Cove ME. Disrupting differential hypoxia in peripheral veno-arterial extracorporeal membrane oxygenation. Crit Care. 2015;19(1):280. 86. Lidegran MK, Mosskin M, Ringertz HG, Frenckner BP, Linden VB. Cranial CT for diagnosis of intracranial complications in adult and pediatric patients during ECMO: Clinical benefits in diagnosis and treatment. Acad Radiol. Jan 2007;14(1):62-71. 87. Kurtz P, Gaspard N, Wahl AS, et al. Continuous electroencephalography in a surgi-

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cal intensive care unit. Intensive Care Med. Feb 2014;40(2):228-234. 88. Friedman D, Claassen J, Hirsch LJ. Continuous electroencephalogram monitoring in the intensive care unit. Anesth Analg. Aug 2009;109(2):506-523. 89. Bembea MM, Felling R, Anton B, Salorio CF, Johnston MV. Neuromonitoring During Extracorporeal Membrane Oxygenation: A Systematic Review of the Literature. Pediatr Crit Care Med. Mar 28 2015. 90. Bembea MM, Rizkalla N, Freedy J, et al. Plasma Biomarkers of Brain Injury as Diagnostic Tools and Outcome Predictors After Extracorporeal Membrane Oxygenation*. Crit Care Med. 2015;43(10):2202-2211. 91. Floerchinger B, Philipp A, Foltan M, et al. Neuron-specific enolase serum levels predict severe neuronal injury after extracorporeal life support in resuscitation. Eur J Cardiothorac Surg. Mar 2014;45(3):496501. 92. Frazier EA, Faulkner SC, Seib PM, Harrell JE, Van Devanter SH, Fasules JW. Prolonged extracorporeal life support for bridging to transplant: technical and mechanical considerations. Perfusion. Mar 1997;12(2):93-98. 93. Schwarz B, Mair P, Margreiter J, et al. Experience with percutaneous venoarterial cardiopulmonary bypass for emergency circulatory support. Crit Care Med. Mar 2003;31(3):758-764. 94. Myers TJ, Bolmers M, Gregoric ID, Kar B, Frazier OH. Assessment of arterial blood pressure during support with an axial flow left ventricular assist device. J Heart Lung Transplant. May 2009;28(5):423-427. 95. Naruke T, Inomata T, Imai H, et al. EndTidal Carbon Dioxide Concentration Can Estimate the Appropriate Timing for Weaning Off From Extracorporeal Membrane Oxygenation for Refractory Circulatory Failure. Int Heart J. 2010;51(2):116-120.

96. Douflé G, Roscoe A, Billia F, Fan E. Echocardiography for adult patients supported with extracorporeal membrane oxygenation. Crit Care. 2015;19(1):1-10. 97. Aiyagari RM, Rocchini AP, Remenapp RT, Graziano JN. Decompression of the left atrium during extracorporeal membrane oxygenation using a transseptal cannula incorporated into the circuit. Crit Care Med. Oct 2006;34(10):2603-2606. 98. Koeckert MS, Jorde UP, Naka Y, Moses JW, Takayama H. Impella LP 2.5 for left ventricular unloading during venoarterial extracorporeal membrane oxygenation support. J Card Surg. 2011;26(6):666-668. 99. Sung PH, Wu CJ, Yip HK. Is Extracorporeal Membrane Oxygenator a New Weapon to Improve Prognosis in Patients With Profound Cardiogenic Shock Undergoing Primary Percutaneous Coronary Intervention? Circulation journal : official journal of the Japanese Circulation Society. Feb 8 2016. 100. Garin N, Koyanagi A, Chatterji S, et al. Global Multimorbidity Patterns: A CrossSectional, Population-Based, Multi-Country Study. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. February 1, 2016 2016;71(2):205214. 101. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: Pathophysiology, evaluation, and effect of weight loss: An update of the 1997 American Heart Association Scientific Statement on obesity and heart disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006;113(6):898-918. 102. Joffe A, Wood K. Obesity in critical care. Curr Opin Anaesthesiol. Apr 2007;20(2):113-118. 103. Ull C, Buchwald D, Strauch J, Schildhauer TA, Swol J. Extremely obese patients treated with venovenous ECMO--an 547

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intensivist’s challenge. The American journal of emergency medicine. Nov 2015;33(11):1720 e1723-1724. 104. Erstad BL. Dosing of medications in morbidly obese patients in the intensive care unit setting. Intensive Care Med. 2003;30(1):18-32. 105. Swol J, Buchwald D, Dudda M, Strauch J, Schildhauer TA. Veno-venous extracorporeal membrane oxygenation in obese surgical patients with hypercapnic lung failure. Acta Anaesth Scand. 2014;58(5):534-538. 106. Pirrone M, Fisher D, Chipman D, et al. Recruitment Maneuvers and Positive EndExpiratory Pressure Titration in Morbidly Obese ICU Patients. Crit Care Med. Feb 2016;44(2):300-307. 107. Steffen RJ, Sale S, Anandamurthy B, et al. Using near-infrared spectroscopy to monitor lower extremities in patients on venoarterial extracorporeal membrane oxygenation. Ann Thorac Surg. Nov 2014;98(5):1853-1854. 108. Intensive versus Conventional Glucose Control in Critically Ill Patients. New England Journal of Medicine. 2009;360(13):12831297. 109. Lou S, Li J, Long C, Hei F, Yu K, Wang S. Is there an association between hyperglycemia and clinical outcome in adult patients receiving extracorporeal membrane oxygenation. J Extra Corpor Technol. Dec 2010;42(4):281-285. 110. Krinsley JS. Glycemic variability and mortality in critically ill patients: the impact of diabetes. J Diabetes Sci Technol. Nov 2009;3(6):1292-1301. 111. Nasraway SA, Jr., Albert M, Donnelly AM, Ruthazer R, Shikora SA, Saltzman E. Morbid obesity is an independent determinant of death among surgical critically ill patients. Crit Care Med. Apr 2006;34(4):964-970; quiz 971. 112. Wardell S, Wall A, Bryce R, Gjevre J, Laframboise K, Reid J. The association 548

between obesity and outcomes in critically ill patients. Canadian Respiratory Journal. 2015;22(1):23 - 30. 113. Diaz-Guzman E, Mannino DM. Epidemiology and prevalence of chronic obstructive pulmonary disease. Clin Chest Med. Mar 2014;35(1):7-16. 114. Nussbaumer-Ochsner Y, Rabe KF. Systemic manifestations of COPD. Chest. Jan 2011;139(1):165-173. 115. Disease GIfCOL. Global strategy for the diagnosis, management, and prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016. 2016; http://www.goldcopd.org/. Accessed February 1, 2016. 116. Chatburn RL. High-frequency assisted airway clearance. Respir Care. Sep 2007;52(9):1224-1235; discussion 12351227. 117. Marini JJ. Dynamic Hyperinflation and Auto–Positive End-Expiratory Pressure. Am J Respir Crit Care Med. 2011/10/01 2011;184(7):756-762. 118. Vidal Melo MF, Musch G, Kaczka DW. Pulmonary Pathophysiology and Lung Mechanics in Anesthesiology: A CaseBased Overview. Anesthesiology Clinics. 2012;30(4):759-784. 119. Guarracino F, Zangrillo A, Ruggeri L, et al. β-Blockers to Optimize Peripheral Oxygenation During Extracorporeal Membrane Oxygenation: A Case Series. J Cardiothor Vasc An. 2012;26(1):58-63. 120. Thiele H, Zeymer U, Neumann F-J, et al. Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial. The Lancet.382(9905):1638-1645. 121. Petroni T, Harrois A, Amour J, et al. Intraaortic balloon pump effects on macrocirculation and microcirculation in cardiogenic shock patients supported by venoarterial

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extracorporeal membrane oxygenation*. Crit Care Med. Sep 2014;42(9):2075-2082. 122. Loforte A, Montalto A, Ranocchi F, et al. Peripheral Extracorporeal Membrane Oxygenation System as Salvage Treatment of Patients With Refractory Cardiogenic Shock: Preliminary Outcome Evaluation. Artif Organs. 2012;36(3):E53-E61. 123. Zhang R, Kofidis T, Kamiya H, et al. Creatine kinase isoenzyme MB relative index as predictor of mortality on extracorporeal membrane oxygenation support for postcardiotomy cardiogenic shock in adult patients. Eur J Cardio-Thorac. October 1, 2006 2006;30(4):617-620. 124. Sun H-Y, Ko W-J, Tsai P-R, et al. Infections occurring during extracorporeal membrane oxygenation use in adult patients. J Thorac Cardiovasc Surg. 2010;140(5):1125-1132. e1122.

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49 Medical Management of the Adult with Cardiovascular Disease on Extracorporeal Life Support Alain Combes, MD, PhD

Introduction Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is an easily applicable and widely accepted treatment option for temporary circulatory assistance in patients with cardiogenic shock refractory to conventional medical therapies.1 This procedure provides prolonged cardiac and respiratory life support allowing myocardial recovery, or bridging to cardiac transplantation, or the implantation of a left ventricle assist device. Although significant advances in extracorporeal circuitry have improved the risk-benefit profile, the medical management of patients under VA-ECMO still requires great expertise that can be best provided in highly experienced centers.1,2 This chapter will review the general and specific ICU management of critically ill patients who received VA-ECMO for refractory cardiac failure. General ICU Management Patients on VA-ECMO should be managed in an intensive care environment.1,2 Standard monitoring should include monitoring of cardiac rhythm, invasive arterial and venous blood pressures, temperature, pulse oximetry, and urine output. It should be noted that most cardiac output measurement devices based

on the thermodilution technique will provide inaccurate values in VA-ECMO patients. If the patient’s heart is still pumping blood through the circulation, the arterial line should be placed in the right radial artery and the oximetry probe on the right hand to detect upper body hypoxia, a situation called “Harlequin” or “North-South” syndrome, which occurs when native lungs do not provide adequate blood oxygenation and a flow competition occurs between the heart and the ECMO device returning blood through the femoral artery.2 Patients on VA-ECMO may not require ventilatory support, especially when the system has been installed under local anesthesia and the patient suffers isolated cardiac failure without significantly impaired gas exchange. For those in whom invasive mechanical ventilation was initiated, ventilatory strategies that minimize ventilator-associated lung injury are recommended and weaning from ventilation attempted as soon as possible. Consequently, continued sedation is not required to support most VAECMO patients and should be discontinued at the earliest opportunity. Alternatively, analgesia should be titrated to provide comfort and allow pain-free interventions and nursing care. Acute kidney injury is common in patients supported with VA-ECMO. If needed, renal replacement therapy (see Chapter 62) will permit optimization of the fluid balance and 551

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allow the administration of adequate nutrition, intravenous drugs, and blood products without inducing fluid overload.3-5 Connecting a renal replacement device to the ECMO system is possible; however, lines should always be inserted after the ECMO blood pump, where pressures are positive, to minimize risks of air embolism through the circuit.3 Nutrition of patients on ECMO is not different from other ICU patients. Enteral nutrition should be should be initiated in the first days of ECMO support, and approximately 25 kcal/ kg/day should be achieved within a week of initiation. Parenteral nutrition may be required in patients who cannot tolerate enteral feeding.6,7 Daily physiotherapy should be encouraged in VA-ECMO patients, although cannulation of the femoral artery usually precludes out of bed mobilization.8,9 Monitoring of the ECMO Circuit The ECMO circuit should be monitored several times daily by the medical and nursing team caring for the patient and at least once every 24 hours by a perfusionist or another ECMO specialist.1,2 Circuit and cannula surveillance is intended to verify the correct functioning of the device and identify complications early, including fibrin deposits or clots on the ECMO membrane, clots in the cannulas or pump, bleeding, signs of inflammation or infection at the cannula insertion sites, unexpected drops in ECMO outflow, or the appearance of clinical or biochemical signs of intravascular hemolysis. If any of these complications occur, a combined multidisciplinary consultation should be conducted to establish the best therapeutic approach. Daily Echocardiography Monitoring Doppler echocardiography should be performed at least daily in patients on VA-ECMO to monitor RV and LV function and to detect complications.10,11 During peripheral VA ECMO, 552

RV and LV preload decrease while LV afterload increases because the retrograde aortic ECMO flow competes with the blood flow ejected from the LV.1,2,12,13 This situation may induce several complications. First, it may create or aggravate aortic regurgitation contributing to further LV dilation and mitral regurgitation resulting in severe pulmonary edema. Second, it may also result in a loss of pulsatility and closed aortic valve that might contribute to stasis and thrombosis in the ascending aorta and ventricular cavities. Doppler echocardiography should be repeated frequently in such situations to adjust blood flow on the ECMO machine, guide associated inotropic support, and anticoagulation. It may also help positioning a left-ventricle venting device such as the Impella catheter (see Chapter 64).14 Indices of LV and RV function should be evaluated daily, particularly in patients who might recover from severe heart failure.15-17 These indices include LV ejection fraction and LV outflow tract velocity-time integral, tissue Doppler lateral mitral annulus peak systolic velocity, RV size and function (tricuspid annular plane systolic excursion, tissue Doppler systolic velocity at tricuspid annulus), signs of paradoxical septum, tricuspid regurgitation, and assessment of pulmonary artery pressure. Importantly, Doppler echocardiography is the only reliable method to assess cardiac output in ECMO-supported patients, since thermodilution techniques are inaccurate because a significant amount of injected solution is drained from the right atrium to the circuit and because pulse-contour techniques are not possible in case of low pulsatility. Other complications detected by echocardiography in VA-ECMO patients are pericardial effusion and tamponade, inadequate position of the venous cannula or hypovolemia with collapse of the IVC around the cannula that might result in low ECMO flows.11

Medical Management of the Adult with Cardiovascular Disease on Extracorporeal Life Support

Management of Pulmonary Edema under VA-ECMO Because the ECMO system reinjects oxygenated blood countercurrent into the descending aorta, it increases in left ventricular afterload and, in 15–20% of the patients, is associated with severe hydrostatic pulmonary edema. The latter is even more frequent in patients with little or no residual LV ejection on ECMO. In this context, hydrostatic pulmonary edema is further aggravated by mitral regurgitation induced by LV dilation and increased LV end-diastolic pressure, resulting from poor LV unloading.18 Decreasing afterload by reducing ECMO flow to around 3 L/min and improving LV ejection with IV inotropes are first line therapeutic options. Insertion of an intraaortic balloon pump to restore pulsatility and to decrease cardiac afterload has also been associated with lower LV end-diastolic dimension and pulmonary artery pressures.19 Other therapeutic options20 are direct left ventricular unloading using the Impella® device,21,22 percutaneous atrial septostomy,23,24 percutaneous insertion of a transseptal left atrial cannula, or switch to central ECMO with intrathoracic cannulation of the left ventricle and aorta.25 Blood and Coagulation Issues The ideal anticoagulant for patients on ECMO that would be effective, easy to monitor, and to antagonize and with no drug interaction unfortunately does not exist. Therefore, unfractionated heparin remains the mainstay of continuous anticoagulation in these patients due to its quick onset of action and the ability to rapidly reverse its action.26 Monitoring of heparin relies mainly on the aPTT and anti-Xa activity, since the ACT was shown to provide unreliable values in patients receiving moderate to low dose heparin.27 The usual target is 50 to 70 seconds and 0.2 to 0.5 IU/ml for the aPTT and anti-Xa activity, respectively. Thromboelas-

tography which is a point-of-care functional test that measures viscoelastic properties of blood, and evaluates the whole clotting system and fibrinolysis might also provide some important information,28 although no robust scientific evidence exists to date showing its ability to decrease coagulation-related complications in ECMO patients. Hemorrhagic complications are among the most frequent adverse events on VA-ECMO.29 Minor bleeding in the nose, mouth or throat, or at cannula or lines insertion site is common and usually easily controlled with local pressure. Major bleeding is a less frequent but potentially life threatening. Gastrointestinal bleeding, massive ENT hemorrhage, or intracranial hemorrhage occur in less than 5% of the patients.30 Management of severe bleeding in VA-ECMO patients includes immediate stopping of IV anticoagulation, correction of coagulation disorders using blood products, and surgical correction of the bleeding cause, if any. Administration of recombinant factor VIIa was reported to be safe and efficient in controlling massive bleeding, especially in cardiothoracic surgery patients supported by ECMO.31 Fibrinolysis and thrombocytopenia that frequently occur in ECMO patients are associated with bleeding complications and might require circuit change. Heparin induced thrombocytopenia is a rare complication of heparin treatment related to platelet activating antibodies that should be diagnosed clinically when extensive thromboses are associated with thrombocytopenia.32 A high clinical suspicion of heparin induced thrombocytopenia should lead to immediate interruption of heparin infusion, removal of all heparin coated devices, and institution of alternative anticoagulant such as argatroban.33 Intravascular hemolysis is a complication of ECMO when highly turbulent flow, thrombosis, or cavitation occurs within the circuitry. Significant hemolysis is best detected by measuring

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LDH, haptoglobin, and especially plasma free hemoglobin. Cannula Site Related Complications Limb ischemia and compartment syndrome are of major concern in venoarterial ECMO.34-37 In order to minimize the likelihood of ischemia, cannula size should be selected based on the amount of support needed and the size of the artery.38 Insertion of a distal reperfusion cannula into the superficial femoral artery should be considered to perfuse blood to the extremity.30 In a metaanalysis of 20 studies of ECMO for cardiogenic shock or cardiac arrest,39 cannularelated complication rates (95% CI) were reported as follows: lower extremity ischemia, 16.9% (12.5-22.6); fasciotomy or compartment syndrome, 10.3% (7.3-14.5); lower extremity amputation, 4.7% (2.3-9.3). In other series of VA-ECMO patients, significant bleeding30,40 and infection41 at femoral cannula sites were reported in 10-30% and 10% (3.4 episodes per 1000 ECMO days), respectively. Nosocomial Infections Nosocomial infections occurring while on ECMO may have dreadful consequences. Indeed, risks of developing infections are markedly increased in these very sick patients, with disease-induced compromised immune systems who have many indwelling medical devices (ie, large ECMO cannulas, endotracheal tube, intraaortic balloon pump, and central venous catheter). In a series of 220 patients who underwent ECMO support for >48 hours for a total of 2,942 ECMO-days,41 64% developed nosocomial infections. Ventilator-associated pneumonia, bloodstream or cannula infections, and mediastinitis infections occurred respectively in 55%, 18%, 10%, and 11% of the patients. Increased critical condition at ICU admission was associated with subsequent development of nosocomial infections, but not antibiotics at the 554

time of ECMO cannulation. Infected patients had longer durations of mechanical ventilation, ECMO support, and hospital stays.41 The most common organisms responsible for infection include coagulase negative staphylococcus, Staphylococcus aureus, Pseudomonas aeruginosa, Enterobacter, Klebsiella, enterococcus, E. coli and Candida albicans.41-45 The risk of nosocomial infection is increased with longer ECMO support, in cases of associated mechanical ventilation, or if the patient has an autoimmune disease or receives immunosuppressant drugs.41-45 Standard measures to decrease the risk of nosocomial infections should be applied scrupulously. Blood, tracheal, or distal lung secretions, cannula insertion site and urine cultures should be performed rapidly if an infection is clinically suspected. Empiric antibiotics should be prescribed promptly to patients who have signs of sepsis or septic shock. Drug Pharmacokinetics Patients on ECMO require multiple medications including sedatives, analgesics, antibiotics and sometimes immunosuppressive drugs. Pharmacokinetics of drugs administered during ECMO is complex and very difficult to predict; notably due to a larger volume of distribution in patients treated, to the adsorption of drugs on PVC tubing and/or membrane oxygenator leading to an increase in drug clearance, to drug interactions and associated renal replacement therapy.46,47 The degree of drug uptake by the circuit depends on physicochemical characteristics of drugs.48-49 For example, lipophilic drugs and highly protein-bound drugs (eg, voriconazole propofol, Dexmedetomidine, and fentanyl) are significantly adsorbed in the circuit, while hydrophilic drugs (eg, β-lactam antibiotics, glycopeptides, oseltamivir, and aminoglycosides) are mostly affected by hemodilution and other pathophysiologic changes that occur during critical illness. Therapeutic drug monitoring is therefore of utmost importance

Medical Management of the Adult with Cardiovascular Disease on Extracorporeal Life Support

when drug dosage available, to prevent toxicity and monitor efficacy.

stolic velocities) did not discriminate between ultimately weaned and not weaned patients. Alternatively, Cavarocchi et al.51 showed in a Weaning from VA-ECMO series of 21 patients that ECMO was safely removed if both LV and RV functions tolerated Weaning success from VA-ECMO is de- volume challenge and demonstrated inotropic fined as device removal and no further require- reserve. Lastly, another study demonstrated ment for mechanical support due to recurring that an increase in strain and strain rate of 20 cardiac failure over the following 30 days.17 % at minimal ECMO flows, with a concomitant The first consideration for weaning is that the increase of EF, could predict successful weanetiology of cardiac failure is compatible with ing,16 while the strain and strain rate remained myocardial recovery.15,30 For example, patients unchanged in patients that could not be weaned. with terminal dilated cardiomyopathy who After VA-ECMO removal, vena cava thromboneeded ECMO support should be bridged to sis should also be searched by echography.52 cardiac transplantation or to a temporary VAD, unless a very specific decompensation factor Conclusion (such as rapid supraventricular arrhythmia, severe septic shock) can be cured. Second, the Cardiac ECMO is still a high risk and patient should have recovered a pulsatile arte- complex therapy for which complications are rial waveform with consistent opening of the frequent. To optimize patient outcomes, VAaortic valve for at least 24 hours, should be ECMO should be performed responsibly under hemodynamically stable, with baseline mean the supervision of a multidisciplinary medicalarterial pressure > 60 mmHg in the absence or surgical team. with low doses of catecholamines, and should The continuous medical management of have recovered from major metabolic distur- these patients in the intensive care unit is of bances. Third, pulmonary function should not utmost importance to achieve satisfactory clinibe severely impaired. If PaO2/FiO2 20-25% and tissue Doppler lateral mitral annulus peak systolic velocity ≥6 cm/s at minimal ECMO flow support were associated with successful weaning, while indices of LV-filling pressure (Mitral E wave and TDI dia555

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References 1. Rihal CS, Naidu SS, Givertz MM, et al. 2015 SCAI/ACC/HFSA/STS Clinical Expert Consensus Statement on the Use of Percutaneous Mechanical Circulatory Support Devices in Cardiovascular Care: Endorsed by the American Heart Assocation, the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia Intervencion; Affirmation of Value by the Canadian Association of Interventional Cardiology-Association Canadienne de Cardiologie d’intervention. J Am Coll Cardiol 2015; 65: e7-e26. 2. Abrams D, Combes A, Brodie D. Extracorporeal Membrane Oxygenation in Cardiopulmonary Disease in Adults. J Am Coll Cardiol 2014; 63: 2769-2778. 3. Chen H, Yu RG, Yin NN, Zhou JX. Combination of extracorporeal membrane oxygenation and continuous renal replacement therapy in critically ill patients: a systematic review. Crit Care 2014; 18: 675. 4. Han SS, Kim HJ, Lee SJ, et al. Effects of Renal Replacement Therapy in Patients Receiving Extracorporeal Membrane Oxygenation: A Meta-Analysis. Ann Thorac Surg 2015; 100: 1485-1495. 5. Haneya A, Diez C, Philipp A, et al. Impact of Acute Kidney Injury on Outcome in Patients With Severe Acute Respiratory Failure Receiving Extracorporeal Membrane Oxygenation. Crit Care Med 2015; 43: 1898-1906. 6. Ferrie S, Herkes R, Forrest P. Nutrition support during extracorporeal membrane oxygenation (ECMO) in adults: a retrospective audit of 86 patients. Intensive Care Med 2013; 39: 1989-1994. 7. Ridley EJ, Davies AR, Robins EJ, Lukas G, Bailey MJ, Fraser JF. Nutrition therapy in adult patients receiving extracorporeal membrane oxygenation: a prospective,

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multicentre, observational study. Crit Care Resusc 2015; 17: 183-189. 8. Abrams D, Javidfar J, Farrand E, et al. Early mobilization of patients receiving extracorporeal membrane oxygenation: a retrospective cohort study. Crit Care 2014; 18: R38. 9. Ko Y, Cho YH, Park YH, et al. Feasibility and Safety of Early Physical Therapy and Active Mobilization for Patients on Extracorporeal Membrane Oxygenation. Asaio j 2015; 61: 564-568. 10. Doufle G, Roscoe A, Billia F, Fan E. Echocardiography for adult patients supported with extracorporeal membrane oxygenation. Crit Care 2015; 19: 326. 11. Platts DG, Sedgwick JF, Burstow DJ, Mullany DV, Fraser JF. The role of echocardiography in the management of patients supported by extracorporeal membrane oxygenation. J Am Soc Echocardiogr 2012; 25: 131-141. 12. Werdan K, Gielen S, Ebelt H, Hochman JS. Mechanical circulatory support in cardiogenic shock. Eur Heart J 2014; 35: 156-167. 13. MacLaren G, Combes A, Bartlett RH. Respiratory dialysis is not extracorporeal membrane oxygenation. Crit Care Med 2011; 39: 2787-2788; author reply 2788-2789. 14. Gaudard P, Mourad M, Eliet J, et al. Management and outcome of patients supported with Impella 5.0 for refractory cardiogenic shock. Crit Care 2015; 19: 363. 15. Aissaoui N, El-Banayosy A, Combes A. How to wean a patient from veno-arterial extracorporeal membrane oxygenation. Intensive Care Med 2015; 41: 902-905. 16. Aissaoui N, Guerot E, Combes A, et al. Twodimensional strain rate and Doppler tissue myocardial velocities: analysis by echocardiography of hemodynamic and functional changes of the failed left ventricle during different degrees of extracorporeal life support. J Am Soc Echocardiogr 2012; 25: 632-640.

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17. Aissaoui N, Luyt CE, Leprince P, Trouillet JL, et al. Predictors of successful extracorporeal membrane oxygenation (ECMO) weaning after assistance for refractory cardiogenic shock. Intensive Care Med 2011; 37: 1738-1745. 18. Hanna BD. Left atrial decompression: Is there a standard during extracorporeal support of the failing heart? Crit Care Med 2006; 34: 2688-2689. 19. Petroni T, Harrois A, Amour J, et al. Intraaortic balloon pump effects on macrocirculation and microcirculation in cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation*. Crit Care Med 2014; 42: 2075-2082. 20. Rupprecht L, Florchinger B, Schopka S, et al. Cardiac decompression on extracorporeal life support: a review and discussion of the literature. Asaio j 2013; 59: 547-553. 21. Koeckert MS, Jorde UP, Naka Y, Moses JW, Takayama H. Impella LP 2.5 for left ventricular unloading during venoarterial extracorporeal membrane oxygenation support. J Card Surg 2011; 26: 666-668. 22. Cheng A, Swartz MF, Massey HT. Impella to unload the left ventricle during peripheral extracorporeal membrane oxygenation. Asaio j 2013; 59: 533-536. 23. Seib PM, Faulkner SC, Erickson CC, et al. Blade and balloon atrial septostomy for left heart decompression in patients with severe ventricular dysfunction on extracorporeal membrane oxygenation. Catheter Cardiovasc Interv 1999; 46: 179-186. 24. Aiyagari RM, Rocchini AP, Remenapp RT, Graziano JN. Decompression of the left atrium during extracorporeal membrane oxygenation using a transseptal cannula incorporated into the circuit. Crit Care Med 2006; 34: 2603-2606. 25. Rastan AJ, Dege A, Mohr M, et al. Early and late outcomes of 517 consecutive adult patients treated with extracorporeal membrane oxygenation for refractory post-

cardiotomy cardiogenic shock. J Thorac Cardiovasc Surg 2010; 139: 302-311, 311 e301. 26. Esper SA, Levy JH, Waters JH, Welsby IJ. Extracorporeal membrane oxygenation in the adult: a review of anticoagulation monitoring and transfusion. Anesth Analg 2014; 118: 731-743. 27. De Waele JJ, Van Cauwenberghe S, Hoste E, Benoit D, Colardyn F. The use of the activated clotting time for monitoring heparin therapy in critically ill patients. Intensive Care Med 2003; 29: 325-328. 28. Nair P, Hoechter DJ, Buscher H, Venkatesh K, Whittam S, Joseph J, Jansz P. Prospective observational study of hemostatic alterations during adult extracorporeal membrane oxygenation (ECMO) using pointof-care thromboelastometry and platelet aggregometry. J Cardiothorac Vasc Anesth 2015; 29: 288-296. 29. Walpoth BH, Walpoth-Aslan BN, et al. Outcome of survivors of accidental deep hypothermia and circulatory arrest treated with extracorporeal blood warming. N Engl J Med 1997; 337: 1500-1505. 30. Combes A, Leprince P, Luyt CE, et al. Outcomes and long-term quality-of-life of patients supported by extracorporeal membrane oxygenation for refractory cardiogenic shock. Crit Care Med 2008; 36: 1404-1411. 31. Repesse X, Au SM, Brechot N, et al. Recombinant factor VIIa for uncontrollable bleeding in patients with extracorporeal membrane oxygenation: report on 15 cases and literature review. Crit Care 2013; 17: R55. 32. Laverdure F, Louvain-Quintard V, et al. PF4-heparin antibodies during ECMO: incidence, course, and outcomes. Intensive Care Med 2016; 42: 1082-1083. 33. Greinacher A. CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. N Engl J Med 2015; 373: 252-261. 557

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34. Bisdas T, Beutel G, Warnecke G, et al. Vascular complications in patients undergoing femoral cannulation for extracorporeal membrane oxygenation support. Ann Thorac Surg 2011; 92: 626-631. 35. Aziz F, Brehm CE, El-Banyosy A, Han DC, Atnip RG, Reed AB. Arterial complications in patients undergoing extracorporeal membrane oxygenation via femoral cannulation. Annals of vascular surgery 2014; 28: 178-183. 36. Avalli L, Sangalli F, Migliari M, et al. Early vascular complications after percutaneous cannulation for extracorporeal membrane oxygenation for cardiac assist. Minerva Anestesiol 2016; 82: 36-43. 37. Tanaka D, Hirose H, Cavarocchi N, Entwistle JW. The Impact of Vascular Complications on Survival of Patients on Venoarterial Extracorporeal Membrane Oxygenation. Ann Thorac Surg 2016; 101: 1729-1734. 38. Takayama H, Landes E, Truby L, et al. Feasibility of smaller arterial cannulas in venoarterial extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg 2015; 149: 1428-1433. 39. Cheng R, Hachamovitch R, Kittleson M, et al. Complications of extracorporeal membrane oxygenation for treatment of cardiogenic shock and cardiac arrest: a meta-analysis of 1,866 adult patients. Ann Thorac Surg 2014; 97: 610-616. 40. Mirabel M, Luyt CE, Leprince P, et al. Outcomes, long-term quality of life, and psychologic assessment of fulminant myocarditis patients rescued by mechanical circulatory support. Crit Care Med 2011; 39: 1029-1035. 41. Schmidt M, Brechot N, Hariri S, et al. Nosocomial infections in adult cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation. Clin Infect Dis 2012; 55: 1633-1641. 42. Burket JS, Bartlett RH, Vander Hyde K, Chenoweth CE. Nosocomial infections in 558

adult patients undergoing extracorporeal membrane oxygenation. Clin Infect Dis 1999; 28: 828-833. 43. Hsu MS, Chiu KM, Huang YT, Kao KL, Chu SH, Liao CH. Risk factors for nosocomial infection during extracorporeal membrane oxygenation. J Hosp Infect 2009; 73: 210216. 44. Bizzarro MJ, Conrad SA, Kaufman DA, Rycus P. Infections acquired during extracorporeal membrane oxygenation in neonates, children, and adults. Pediatr Crit Care Med 2011; 12: 277-281. 45. Sun HY, Ko WJ, Tsai PR, et al. Infections occurring during extracorporeal membrane oxygenation use in adult patients. J Thorac Cardiovasc Surg 2010; 140: 1125-1132. e1122. 46. Shekar K, Fraser JF, Smith MT, Roberts JA. Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care 2012. 47. Shekar K, Roberts JA, Ghassabian S, et al. Altered antibiotic pharmacokinetics during extracorporeal membrane oxygenation: cause for concern? J Antimicrob Chemother 2013; 68: 726-727. 48. Wildschut ED, Ahsman MJ, Allegaert K, Mathot RA, Tibboel D. Determinants of drug absorption in different ECMO circuits. Intensive Care Med 2010; 36: 2109-2116. 49. Lemaitre F, Hasni N, Leprince P, et al. Propofol, midazolam, vancomycin and cyclosporine therapeutic drug monitoring in extracorporeal membrane oxygenation circuits primed with whole human blood. Crit Care 2015; 19: 40. 50. Lemaitre F, Luyt CE, Roullet-Renoleau F, et al. Impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (H1N1) influenza. Ther Drug Monit 2012; 34: 171-175.

Medical Management of the Adult with Cardiovascular Disease on Extracorporeal Life Support

51. Cavarocchi NC, Pitcher HT, Yang Q, et al. Weaning of extracorporeal membrane oxygenation using continuous hemodynamic transesophageal echocardiography. J Thorac Cardiovasc Surg 2013; 146: 1474-1479. 52. Cooper E, Burns J, Retter A, et al. Prevalence of Venous Thrombosis Following Venovenous Extracorporeal Membrane Oxygenation in Patients with Severe Respiratory Failure. Crit Care Med 2015; 43: e581-584.

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50 Nursing Management of Adults with Cardiovascular Disease on Extracorporeal Life Support Chirine Mossadegh, RN, Gail Faulkner, RGN, RSCN

Introduction

Management of the ECMO Device

In the last ten years, extracorporeal membrane oxygenation (ECMO) has emerged as first line therapy for circulatory failure refractory to conventional treatment. Peripheral venoarterial ECMO (PVA-ECMO) has many advantages as salvage therapy compared to other circulatory assistance systems: it can be implanted rapidly at patient’s bedside, even in remote locations with the mobile ECMO team. It allows biventricular assistance with a high and stable blood flow, combined with a pulmonary assistance, making it suitable for most severe patients. Once implanted, ECMO allows time to assess the best management strategy for the patient. However, ECMO provides only shortterm support. Complications may occur after 7 to 15 days of ECMO therapy, and the technique usually does not allow patient rehabilitation, which is crucial for patient improvement. The management of these patients is an ongoing challenge for an Intensive Care Unit team given the complexity of the technique. There are several sides to the management of adult patients with cardiovascular diseases on ECLS: the management of the ECMO device; preventing complications; and adapting the specifics of extracorporeal life support (ECLS) to the regular monitoring of the patient in a Critical Care Unit

It seems obvious, but to ensure the efficiency of the therapy, the team managing the patient must understand and be able to analyze the parameters of the device itself. The management of the ECMO device is more commonly called the “circuit check,” which is the responsibility of the ECMO specialist. A check list ensures that the team has not forgotten any specific surveillance of the circuit: • The ECMO cart must be placed near the patient bed on brake position. • The ECMO system must be correctly connected to a secure plug (most commonly a red power outlet). All the ECLS devices have a light indicating if ECMO is plugged in or on battery. • The gas module must be securely connected to the gas sources (wall or tank). The gas module has to be safely connected to the oxygenator gas inlet port without any kink and leak. • The absence of kinks and tensions on the whole circuit (cannulae, gas, and power hoses) must be checked. • Must check and ensure security of the cannula(e) and check placement with the aid of chest x-ray and reviewed with the MDT. 561

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• A thorough look of all circuit components with a flashlight, looking for thrombin and/or clots. The more complex the circuit (bridges, pigtails, stop cocks), the higher the risk to develop thrombin and clots. • Check the security of all connectors and the presence of tie bands in the appropriate places. • The heater has to be correctly connected to the heat exchanger, the water level has to be full and the temperature set point adjusted to therapeutic goal. • Write down the parameters of ECMO support to aid guidance and decision making for optimal patient management. • The circulatory parameters: the Rotation Per Minute (RPM) and the blood flow. The therapeutic goal is the blood flow. The ECMO specialist in charge of the pump has to control the evolution of the blood flow in correlation with the RPM. • The flow rate must be high enough to provide adequate perfusion pressure and venous oxyhemoglobin saturation but low enough to provide sufficient preload to maintain left ventricular output. • The ventilatory parameters: the sweep gas flow should adjust regarding the PaCO2 and the FiO2 regarding the PaO2. • The pressures: some devices are measuring the venous pressure, the arterial pressure, and the ∆P but most ECMO teams add pigtails connected to pressure monitors. Like the circulatory parameters, the absolute pressure itself is not relevant but its evolution through time. • The pump head must be placed securely and the ECMO specialist must check for disengagement. • The alarms: they must be set regarding your therapeutic goal. Since the pump is nonocclusive, we recommend to maintain the blood flow above 2 L/min to avoid any back flow. The specialist must also know on which mode your ECMO is working. 562

In a free mode, when an alarm is activated the circuit will keep working but when on Intervention mode, as soon as an alarm is set on, the pump stops working and an immediate action must be set to resolve the problem. The choice of the mode depends of your human resources. If a nurse or a perfusionist is constantly at the patient bedside the intervention mode is possible, but if a nurse is taking care of more than one ECMO patient and cannot intervene immediately when the pump stops, the free mode will be safer. • The equipment needed in case of an emergency: clamps, emergency hand crank, emergency supplies at the bedside must be available; which include appropriate sized connectors/shears/tubing/rapid access line, fluid, tie-gun and tie-straps/sterile gloves, etc. Vigilance in checking the circuit and attention to detail by the ECMO specialist is of paramount importance. Effective communication and escalation to the Duty ECMO consultant/ Duty ECMO coordinator must be in a timely manner to ensure timely decision making. Preventing Complications ECLS is potentially life-saving for the patient in severe cardiogenic shock refractory to regular treatment, but it also comes with side effects. One of the key points of ECMO management includes preventing and detecting complications. The ECMO specialist role is an extended role and staff must be adequately/expertly trained to recognize the signs and complications of bleeding, infection, and mechanical failure of ECMO components. Specific training and ongoing assessment is crucial to ensure clinical competence and skill is maintained to the highest standards to minimize these risks (see Chapter 67). Attention to detail, vigilance in assessment, and implementation of care in a

Nursing Management of Adults with Cardiovascular Disease on Extracorporeal Life Support

timely manner are paramount, along with effective communication and escalation to the senior team in the event of complications. Protocols and procedures must be in place to support all team members in order to alleviate stress and improve practice in this highly charged environment. The partnership between the ECMO coordinator, consultant, and specialist is unique. Together the team approach must verbalize and implement patient management goals, which include review and assessment of daily patient/ circuit parameters; for example, maintaining cardiovascular stability, fluid management, ACT management, and sedation guidelines. Communication must be clear, concise, and consistent and shared with all members of the MDT. This will enable all team members to have a clear understanding of patient management. The nursing care of the patient must be individual, goal directed, and holistic. Bleeding

ECMO the anti-factor Xa can also be a better indicator of the heparin management. Bleeding on ECMO can be problematic. The sensitive balance between procoagulants and anticoagulants must be well understood by those who manage patients on ECMO. The ECMO specialist has to check systematically for the presence of bleeding: • In the mouth, throat and nose: there can be small but continuous bleeding, making mouth care difficult. It is also difficult for families to see their loved ones in such a state. • At the insertion point of all catheters and not only at the ECMO entry point, all IV lines, probes, etc. • The brain: check the neurological status of the patient for any signs of intracranial hemorrhage: pupillary response, the level of consciousness2 • The aspect of the lung secretions for the presence of blood • The aspect of the gastric lavage for the presence of blood • The aspect of the urine and stools for the presence of blood

Bleeding is the most frequent and serious complication on ECMO, occurring in approximately 34% for adult cardiac ECMO according to the ELSO Registry.1 As an extracorporeal device, ECMO requires continuous systemic In the case of severe bleeding, the adminanticoagulation (heparin infusion) to prevent istration of blood products, packed red blood fibrin and clot formation in the circuit. The cells (PRBC), fresh frozen plasma (FFP), and implantation can be surgical, with a cutdown platelets is common (see Chapter 8). This forms and a bolus of 5000 UI of heparin is most com- part of the daily parameters prescribed as a monly injected at the initiation of ECMO flow, guide for the Duty ECMO specialist and ECMO enhancing the risk of bleeding. In the immedi- team members. If the patient does not respond ate post-cannulation phase, the challenge is to to transfusion and a decrease of the heparin balance the control of postoperative bleeding infusion rate, the discontinuation of heparin with minimizing the formation of clots in the is possible with strict control of the aPPT and ECMO circuit. The task is worsened by bleeding ACT and a thorough check of the oxygenator already occurring after an open heart surgery. and cannulas for clots and thrombin. To prevent bleeding, a very strict control of In a worst case scenario, using recombinant the hemostasis is necessary: the heparin infusion factor VIIa has be done by several teams with rates have to be titrated to obtain an aPPT ratio a major decrease of bleedings.3 between 1.8 and 2 depending on the cardiac patient condition. For patients receiving VA-

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Thromboembolic Risk Effective anticoagulation treatment avoids bleeding but also prevents formation of clots and thrombin that result from cell lysis caused by the turbulence of the ECMO pump and blood stagnation. They are easily visualized with a flashlight within the tubing and connectors: dark clots and white fibrin strands often begin near stopcocks or other areas of turbulence. All areas of clot identified must be clearly documented and escalated to the Duty ECMO team. Each hour, the ECMO specialist must carefully monitor the entire circuit with a flashlight: the cannulas, the connectors, the pigtails, stopcocks, the pump, and the oxygenator. The challenge for the nurse and team is to assess “normal” clots, which are small and have no harmful risk to the circuit or the patient. They are frequently seen at the bottom of the oxygenators, where blood stagnation is unpreventable. The “bad” clots are the ones becoming an obstacle to the blood flow, the gas outlet, and causing pressure changes through the membrane or that may dislodge and travel to the patient. Again vigilance and attention to detail is of paramount importance: detection, documentation, and escalation to prevent untoward incidents and patient compromise. Depending on institutional strategy, the team either changes the component or the entire circuit. The assessment of changing an oxygenator must not depend on the presence of clots but mostly on the efficiency of the membrane to perform gas exchange properly. The pressure (ΔP) monitoring represents adjunctive data to assess the occlusion of the component (oxygenator or pump). Hemolysis The spinning and trauma of blood cells due to the ECMO flow causes them to break, producing bleeding and loss of blood components. Before clinical signs appear, early 564

detection is possible by measuring daily free plasma hemoglobin (normal >50 mg/L) usually associated with a drop of platelets and red cells counts. Clinically, hemolysis produces a characteristic reddish color of the urine or the effluent bag if the patient has no urine output. In the most serious cases, other external or internal bleedings can occur. Ultimately, with no adequate treatment, the patient develops disseminated intravascular coagulation. The treatment consists of replacing the blood loss with PRBC, platelets, and FFP and potentially changing the ECMO circuit. Differential Hypoxia Differential hypoxia is also called the Harlequin syndrome, two circulation syndrome, or north/south syndrome. Cerebral hypoxia is a commonly overlooked complication of peripheral VA-ECMO. In extreme cardiac dysfunction, if the heart is not beating and the aortic valve is not opening, ECMO provides 100% of the patient blood flow and oxygenation. The ECMO blood flow infused into the femoral artery flows in a direction retrograde to the native blood flow. Upon return of the heart function, when the heart recovers pulsatility and the aortic valve begins to open, fully saturated blood from the pump mixes with the blood ejected from the native ventricle in the aorta. The location of this mixing cloud depends on the amount of ECMO support provided and the degree of left ventricular function. The mixing cloud begins proximally in the aorta with poor left ventricular ejection function and/or with increases in ECMO flow. However, the mixing cloud moves distally in the aorta when the ventricle recovers and/or the ECMO flow is decreased. During severe respiratory failure due to pulmonary edema, the typical VA-ECMO flow rate (80% of full cardiac output) can result in desaturated blood from the left ventricle perfusing the aortic arch and coronary arteries and fully saturated

Nursing Management of Adults with Cardiovascular Disease on Extracorporeal Life Support

infusion blood perfusing the lower body. The patient’s head appears blue; whereas, the lower extremities appear pink. To diagnose differential hypoxia, saturation and blood gases should be measured in the right radial artery, which reflects the patient’s cardiac output. To correct and treat this hypoxia, most teams add a jugular cannula to deliver oxygen to the brain. Decannulation Inadvertent decannulation is the most feared complication. The key to prevention is not necessarily sedating your patient but check the fixation of the cannulas.4 The ECMO specialist must visualize the entire ECMO circuit, check the sutures, and the absence of tension on the cannulas before any mobilization of the patient. Limb Ischemia The femoral artery is partially or totally occluded by the return ECMO cannula. To prevent limb ischemia, it is recommended to insert a reperfusion line in the superficial femoral artery and connect it to the reinjection cannula to allow leg perfusion.5-7 The nurse should monitor the leg by comparing the temperature of both legs by touch or using oximetry or NIRS, and the aspect of the leg, its stiffness and color, development of blisters, or evidence of foot necrosis. The reperfusion line must always be visible through a translucid dressing, so the nurse can check the absence of kinks, clots, and/or fibrin. The same ischemia can occur with axillary cannulation. A reperfusion line can be inserted to allow perfusion in the arm.

Adopting the Specifics of ECLS to Patient Regular Monitoring in a Critical Care Unit Pain and Sedation Unlike VV-ECMO patients, VA-ECMO patients are more commonly awake and even extubated. Some teams cannulate to ECMO on nonsedated and extubated patients with local anesthetics. Pharmacokinetics of pain and sedation drugs such as propofol, midazolam, or opioids differ on ECMO (see Chapter 71).8 The circuit traps or binds medication, so higher dosages of sedation or pain killers may be required to obtain the same level of comfort for the patient. Protocols for management of pain and sedation should be reassessed for ECMO patients to adjust dosages. All members of the MDT must be involved in this aspect of patient management with periodic review of sedation agents and their effectiveness. Infection Infection can be a potential issue for ECMO patients, especially those receiving central cannulation directly accessing the heart. With peripheral cannulation, groin infections are frequent. Daily monitoring of white blood count, cell blood culture, and PCT can allow early detection although regular blood cultures are a source of debate. The nurse should regularly check the integrity of the cannula dressing and a daily assessment of the insertion point of the cannulas looking for redness, swelling, bleeding, or potential infection. The usual institutional protocols can be hard to follow for VA-ECMO patients due to massive bleeding or the size of the cannulas compared to a central venous catheter. The ICU team should adjust their protocols. The use of chlorhexidine gluconate-impregnated sponges could reduce the infection rate, diminish the frequency of

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dressings up to seven days, and allow a visual on the insertion point as proven in central lines.9 Hemodynamic Monitoring The ECMO pump is a nonpulsatile device and generates a laminar flow. Right after cannulation, most VA-ECMO patients have poor or no heart pulsatility and the pump delivers most if not all the patient blood flow. Hence, the measured arterial blood pressure can appear as a dampened or flat arterial line, with MAP, SAP, and DAP numbers being identical. When monitoring these patients, the aim is to maintain the MAP above 65 mmHg. The recovery of a pulsatile blood pressure can be a sign of left ventricular function improvement. Fluid Management Finding the right balance between hypovolemia and fluid overload is more complex for patients undergoing VA-ECMO, especially after cardiac surgery. Massive blood loss frequently occurs after heart surgery and ECMO itself can worsened this loss. Hypovolemia induces hypotension and unstable and low ECMO flows. The variation of flow also increases fibrin and clot formation. At the bedside, the nurse should suspect hypovolemia with chattering of the lines associated with sudden variations of the ECMO flow. The nurse must then administer enough volume to maintain an efficient ECMO flow (MAP >65 mmHg). However, giving large volumes in association with muscle relaxants and vasodilators can contribute to large amounts of unavoidable peripheral edema. Fluid overload should be treated by diuretics. For unresponsive patients (urine output less than 0.5 mL/kg/hr, positive fluid balance >500 mL in the past 24 hours), renal replacement therapy should be started. Also, inefficient fluid management often results in pulmonary edema. In VA-ECMO pa566

tients with poor or no cardiac function, ECMO flow generates increased afterload, causing pulmonary edema. Implanting an IABP at ECMO initiation can help prevent it.10 The treatment of this edema includes unloading the left ventricle. If conventional treatment such as the use of diuretics proves ineffective, several approaches are then possible: the atrioseptostomy, implanting an Impella® (Abiomed), or unloading both ventricles by implanting a central double ECLS.11-14 Skin Care Skin care has always been a challenge for nurses in the ICU. ICU patients are relatively immobile in bed, often sedated, and thus at high risk of developing bed sores. Preventing pressure bed sores for ECMO patients resembles efforts in any other ICU patient. For conscious patients, the difficulty is the prohibition of moving one leg, sometimes even both if an IABP has been implanted. Infection and heparin infusion can also provoke skin abrasion or hematoma. For cardiac patients, edema is unavoidable especially after heart surgery. ECMO patients in addition to these preexisting skin alterations must face other potential skin damages: cannula sutures are tight and over time lesions can appear; edema plus the pressure of the cannula on the skin can lead to unavoidable pressure sores. Protecting the skin from the cannulas can be done with foam dressings or hydrocolloids already used for regular patients. To fix the cannulas without damaging more skin, some attachment devices such as the horizontal tube attachment from Hollister® (Hollister, Inc., Libertyville, IL) are composed of hydrocolloid, allowing skin protection and an additional fixation.

Nursing Management of Adults with Cardiovascular Disease on Extracorporeal Life Support

Mobilizing VA-ECMO Patients Mobilizing VA-ECMO patients is more difficult than a usual ICU patient. At least one additional team member (ideally two) must be at bedside to control the cannulas and the pump. Also the length of the tubing may not facilitate mobilization. To prevent adverse events, the team must have a complete visual on the ECMO circuit, check cannulae and tubing fixation, and move the ECMO cart if necessary to avoid any kinks or tension while turning the patient to prevent bed sores or wash him/ her. Extreme caution is necessary. The key is to have a nominated team member involved in the procedure and that person must effectively communicate the responsibilities of all team members involved. Vigilance by the ECMO specialist to prevent rather than treat is essential to any expert practicing in this role.

from ECMO cannulation the entire scope of management, and the probability that their loved one might not survive. Staff and family members require support from all members of the MDT. Effective, clear, honest, two-way communication is key from referral, consent, and throughout the ECMO run by all members of the MDT caring for the patient and family. The time spent undertaking this process can be stressful and time consuming and team members often find a negative outcome from ECMO difficult and challenging. Regular communication/meetings to discuss plans of care are essential.

Psychological Support It is of paramount importance for all team members involved in direct patient care and management to be trained and competent in all aspects of ECMO care. ECMO is implanted when conventional treatment has failed. This is an emergency therapy, allowing stabilization of the patient before assessing options, the “bridge to” therapy: • Bridge to recovery: the heart recovers and the ECMO can be withdrawn. • Bridge to bridge therapy: the patients will be implanted with a VAD. This is considered for patients with a possibility of longterm recovery. It allows the patient to go back home. • Bridge to transplant. • A destination therapy: when ECMO is the last resort and is ineffective. A procedure for end of life care must then be set up. Families and patients need to be counseled accordingly, they have to know and understand 567

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References 1. ELSO. (2015). ECLS Registry Report: International Summary. 2. Luyt CE, Bréchot N, Demondion P, et al. et al. Brain injury during venovenous extracorporeal membrane oxygenation. Intensive Care Med. 2016;42(5):897-907. 3. Repessé X, Au SM, Bréchot N, et al. Recombinant factor VIIa for uncontrollable bleeding in patients with extracorporeal membrane oxygenation: report on 15 cases and literature review. Crit Care. 2013;17(2):R55. 4. Linden V, Palmer K, Reinhard J, et al. High survival in adult patients with acute respiratory distress syndrome treated by extracorporeal membrane oxygenation, minimal sedation, and pressure supported ventilation. Intensive Care Med. 2000;26(11):16301637. 5. Russo CF, Cannata A, Vitali E, Lanfranconi M.(2009)Prevention of limb ischemia and edema during peripheral venoarterial extracorporeal membrane oxygenation in adults. J Card Surg. 2009;24(2):185-187. 6. Kasirajan V, Simmons I, King J, Shumaker MD, SeAnda A, Higgins RS. Technique to prevent limb ischemia during peripheral cannulation for extracorporeal membrane oxygenation. Perfusion. 2002;17(60):427428. 7. Greason KL, Hemp JR, Maxwell JM, Fetter JE, Moreno-Cabral RJ. Prevention of distal limb ischemia during cardiopulmonary support via femoral cannulation. Annals Thorac Surg. 1995;60(1):209-210. 8. Shekar K, Roberts JA, Smith MT, Fing YL, Fraser JF. The ECMO PK Project: an incremental research approach to advance understanding of the pharmacokinetic alterations and improve patient outcomes during extracorporeal membrane oxygenation. BMC Anesthesiol. 2013;13:7.

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9. Timsit JF, Schwebel C, Bouadma L, et al. Chlorhexidine-impregnated sponges and less frequent dressing changes for prevention of catheter-related infections in critically ill adults: a randomized controlled trial. JAMA. 2009;301(12):1231-1241. 10. Petroni T, Harrois A, Amour J, et al. Intraaortic balloon pump effects on macrocirculation and microcirculation in cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation. Crit Care Med. 2014;42(9):2075-2082. 11. Seib PM, Faulkner SC, Erickson CC, et al. Blade and balloon atrial septostomy for left heart decompression in patients with severe ventricular dysfunction on extracorporeal membrane oxygenation. Catheter Cardiovasc Interv. 1999;46(2):179-186. 12. Ward KE, Tuggle DW, Gessouroun MR, Overholt ED, Mantor PC. Transseptal decompression of the left heart during ECMO for severe myocarditis. Ann Thorac Surg. 1995;59(3):749-751. 13. Cheng A, Swartz MF, Massey HT. Impella to unload the left ventricle during peripheral extracorporeal membrane oxygenation. ASAIO J. 213;59(5):533-536. 14. Koeckert MS, Jorde UP, Naka Y, Moses JW, Takayama H. Impella LP 2.5 for left ventricular unloading during venoarterial extracorporeal membrane oxygenation support. J Card Surg. 2011;26(6):666-668.

51 The Weaning Process and Decannulation in Adult Cardiac Patients Fabio Guarracino, MD, Rubia Baldassarri, MD

Venous-arterial (VA) extracorporeal membrane oxygenation (ECMO) provides mechanical circulatory support for patients in refractory cardiogenic shock, cardiac arrest, or with acute refractory cardiorespiratory illness. Due to the technical characteristics, high invasivity, risks of complications, and pathophysiologic pattern of the extracorporeal circuit, VA-ECMO is a therapeutic strategy and not a therapy. VA-ECMO should be terminated after a short to medium term duration after the expected goals (eg, a bridge to recovery, bridge to the implantation of a ventricular assist device (VAD), bridge to decision, or bridge to transplant), for which VA-ECMO was initiated, have been achieved.1 In this context, the timing of weaning from mechanical support is a crucial step in the procedure that primarily depends on the indications for implantation.1,2 Indeed, because the anticipated disconnection from an extracorporeal device can negatively affect the clinical outcome, delayed weaning from VA-ECMO and the consequent prolonged circulatory support significantly increase the risk of complications.3 Because VA-ECMO is either an invasive procedure or requires high doses of anticoagulant drugs for the duration of circulatory support, the associated risk of periprocedural complications is very high.1 The first consideration in the decision to terminate extracorporeal circulatory support is whether

the expected goals for which VA-ECMO was implemented have been achieved.1,2,4 Weaning Well-defined and universally accepted weaning strategies or protocols are not actually available. Although the Extracorporeal Life Support Organization (ELSO) guidelines for adult cardiac failure recommend a protocol for weaning from VA-ECMO, the weaning process is still highly dependent on the single center’s experience and individual clinical practice.5 According to the ELSO guidelines, the first step in ECMO weaning is the prompt recognition of the clinical signs of cardiac recovery within 1 week of the initiation of the procedure for patients subjected to VA-ECMO as a bridge to recovery. Expected early signs of recovery within one week of support Patients on VA-ECMO are commonly subjected to continuous clinical and hemodynamic monitoring to assess either the effectiveness of the mechanical support or the suitability for weaning from ECMO. Weaning should be initiated as soon as possible in the presence of hemodynamic stability and adequate peripheral perfusion indexes with lower doses of inotropic support. Weaning from mechanical support 569

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should be considered when hemodynamic sta- the circulatory support can be further decreased bility is accompanied by signs of myocardial to 25% of the adequate CO.7,8 recovery and cardiac function improvement that can be confirmed via echocardiographic Echocardiography in the Weaning Process assessments of cardiac recovery. The presence Because improvement of left ventricle (LV) of adequate mean arterial pressure, cardiac index (CI), and pulse pressure (≥30 mmHg) contractility and opening of the aortic valve values during conditions of optimized inotropic (AV) are among the most important signs of support is suggestive of hemodynamic improve- myocardial recovery, the use of echocardiograment in addition to decreases in the pulmonary phy with the transthoracic (TTE) and especially artery wedge pressure (PAWP) and the central the transesophageal (TEE) approaches are funvenous pressure (CVP) with respect with the damental to the guidance of the weaning process. baseline values recording at the time of the Although no standardized echocardiographic protocols guiding weaning from VA-ECMO are initiation of VA-ECMO. Therefore, the prompt recognition of the available, some echocardiographic parameters clinical signs of cardiac recovery and adequate have been universally recognized as good preassessments of hemodynamic stability should dictors of successful weaning.3,7 The most used guide the timing of weaning from VA-ECMO. weaning strategy is based on the reduction of For these reasons, VA-ECMO should be the pump flow (at a minimum level of 1-1,5 l/ stopped at the appropriate time based on both min for not more than 30 minutes to reduce the the clinical condition of the patient and the risk of thrombosis of the circuits) while clinical, indications for device implantation. hemodynamic, and echocardiographic assessments are performed to evaluate the cardiac With evidence of improved aortic pulsatility performance and the suitability of the disconand contraction on echocardiography, the nection from extracorporeal support. When the inotropes should be optimized and the flow native LV recovers and improves in contractility, reduced to 50% then 25% of the adequate the reduction of the pump flow is followed by cardiac output. an increase in the LV ejection fraction (EF). According to the Frank-Starling law, as LV filling When signs of myocardial recovery and increases due to the reduction of pump flow, improved cardiac function are present, the flow the improved LV contractility allows for AV of VA-ECMO can be progressively reduced opening and the ejection of blood through the to assess the suitability of weaning from the LV outflow tract (LVOT) when the LV systolic device. An LV EF ≥35-40% on full circulatory pressure surpasses the aortic pressure. In adsupport and optimized inotropic support is dition to evaluations of the LV EF and the LV considered to be a good predictor of successful size, adjunctive echocardiographic parameters weaning.6 If increased myocardial contractility have been suggested as indicators of successand improved cardiac function are present, the ful weaning. An EF of up to 20-25% has been reduction of the pump flow by approximately considered to be a good predictor of effective 50% can be attempted. In conditions of lower weaning from VA-ECMO.6 The measurement circulatory support, if the cardiac output (CO) of the aortic velocity time integral (VTI) and is sufficient to maintain adequate end-organ the application of tissue Doppler imaging (TDI) perfusion and hemodynamic stability, the car- during any step of ECMO flow reduction have diac function does not worsen, and neither LV recently been considered for the monitoring of dilatation nor mitral regurgitation occur, then the weaning process. The combination of an EF 570

The Weaning Process and Decannulation in Adult Cardiac Patients

of up to 20-25%, a VTI ≥10 cm and a systolic S wave velocity (Sa) ≥6 cm as measured at the level of the lateral annulus of the mitral valve with TDI has been considered to be predictive of successful weaning.6-8 Echocardiographic evaluation of the right ventricle (RV) should also be considered during the weaning process. However, it should be remembered that acute RV failure can be undetectable even when minimal flow occurs. A baseline echocardiographic evaluation should be performed at the beginning of the weaning process and repeated during the progressive reduction of the pump flow to collect data regarding the changes in myocardial contractility, cardiac function and eventual acute heart decompensation.

Flush the cannulae with heparinized saline continuously or flash from the circuit every 10 minutes to avoid cannula thrombosis.

Anticoagulation should be continued during the off trials, and the lines and cannulas should be periodically clamped to avoid stagnation and risk of intracannula thrombosis. When successful off trials occur, the circuit lines can be cut, and the cannulas can be locked after heparinization. Although the cannulas can be left in place for approximately 24 hours after the termination of mechanical support to allow for the reinitiation of the VA-ECMO procedure in unstable patients, the cannulas should be removed as soon as possible to limit complications. Weaning from ECMO is effective when extracorporeal support can be removed without the Clamp the circuit and allow recirculation for recurrence of mechanical support for refractory cardiogenic shock over the 30 days subsequent a trial period of 30 minutes to 4 hours. to disconnection of the device.6 A recent study reported the effectiveness Weaning from VA-ECMO can be attempted when a pump flow less than 30% of the native of levosimendan in improving weaning from cardiac function is sufficient to provide ad- VA-ECMO. The authors reported an increased equate circulatory support and organ perfusion weaning rate in patients on VA-ECMO who with low respiratory pressure and inotropic received levosimendan at the time of weaning.9 support. According to the ELSO guidelines, According to the ELSO recommendations, the weaning from mechanical support should not optimization of the inotropic therapy should be be performed when the pump flow accounts achieved to enhance cardiac recovery in patients for as much as 30-50% of the patient’s cardiac who have received extracorporeal circulatory support.5 function.5 When circulatory support is 70 mmHg or an oxygen saturation ≥95% and therefore

Pregnancy and Extracorporeal Life Support

oxygenation targets on ECMO are somewhat and transfusion targets from the University of higher in this patient group.23 The PaCO2 should Alabama includes targets such as anti-factor be maintained at 30-32 mmHg when possible, Xa goals of 0.2-0.5, ACT of 160-180, platelet which is considered normal level in pregnancy. counts >50,000 and antithrombin levels of Marked respiratory alkalosis (50%. The lab values are followed closely and reduce uterine blood flow and cause constriction the heparin is adjusted accordingly (see Chapof the uterine artery; this reduces uterine blood ters 7 and 8).2 flow to the feto-placental circulation and results in fetal hypoxia. Increased PaCO2 can also be Drug Therapy detrimental as it can result in fetal respiratory acidosis.22 The pharmacokinetics of drugs is particuHypertension represents an important con- larly complex due the alterations that occur in cern in pregnant women. The risk of intracere- normal pregnancy25 in addition to those that bral hemorrhage increases exponentially once occur due to the presence of the ECMO circuit.26 The effects of ECMO on pharmacokinetics the blood pressure rises above 160/100 (mean arterial pressure of 125 mmHg). Therefore, primarily include sequestration in the circuit, blood pressure control requires special atten- increased volume of distribution, and decreased tion. Initial management involves controlling drug elimination. Lipophilic drugs and highly blood pressure with intravenous hydralazine protein-bound drugs (eg, voriconazole and fenor labetalol infusion, particularly in a fully tanyl) are significantly sequestered in the circuit anticoagulated patient. Magnesium sulphate is and hydrophilic drugs (eg, β-lactam antibiotics, used to reduce cerebral irritability and the risk glycopeptides) are significantly affected by hemodilution and other pathophysiologic changes of eclampsia (seizures).23,24 that occur during ECMO.26 Fetal Monitoring Pregnancy further contributes to a significantly increased volume of distribution As delivery is based on indications to of hydrophilic substrates. Clinically, a larger improve maternal health, emergency delivery volume of distribution could therefore necesdue to concerns with fetal health is likely to be sitate a higher initial and maintenance dose of detrimental to the healthy mother. Therefore, hydrophilic drugs to obtain therapeutic plasma tests for fetal well-being should usually be concentrations. limited to assessing viability ie, presence of a Additionally, because of the decrease in fetal heartbeat. serum albumin concentrations (hemodilution despite increased production) and other drugAnticoagulation binding proteins during pregnancy, drugs that are highly protein bound may display higher Heparin does not cross the placental bar- free levels due to decreased protein binding rier and therefore can be administered using availability and thus higher bioactivity. Diconventional targets for maintenance of the goxin, midazolam, and phenytoin are examples ECMO circuit. However, in general, given the of medications primarily bound to albumin.25 increased risk and implications of major hem- Therapeutic drug monitoring, whenever posorrhage, anticoagulation regimes are generally sible to monitor for under dosing or toxicity is more conservative in pregnant women, aiming therefore strongly recommended, particularly for low-normal therapeutic values. An example for this group of ECMO patients. of an anticoagulation strategy with monitoring 587

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In regards to administration of drugs, a risk benefit decision-making process with the input of specialists with knowledge of the effects of the medication on the mother and the fetus should be employed. In these lifesaving situations maternal health is key, potentially fetotoxic medication or medication where the effect on the fetus has not been studied can be justified if there is no safe alternative. For example, steroids can potentially result in malformations of the fetus if used in the first trimester.27 Benzodiazepines and opiates, which are almost universally required during ECMO therapy, may result in neonatal depression or withdrawal polyhydramnios and floppy infant syndrome.28 Many drugs administered in critical illness and during extracorporeal circulation have limited or no approval during pregnancy. While essential medications still need to be delivered, drugs should be chosen according to the least risk for maternal and fetal morbidity. Complications of ECMO The major reported complications from available case reports and series is bleeding. In one small series during the H1N1 pandemic, major bleeding occurred in 57.1% (4 of 7) of pregnant women while on ECMO, leading to relatively large volumes of packed red blood cell transfusion (median volume transfused was 3,500 ml) and was the main cause of death.29 The bleeding sites were intracranial or multiple sites in cases with fatal hemorrhage, and uterine or pulmonary hemorrhage were more often recorded in cases of nonfatal bleeding. Other sites of bleeding included hemothorax, upper gastrointestinal haemorrhage, nonfatal fetal intracranial haemorrhage, vaginal bleeding, and bleeding from the cannulation and tracheostomy sites. Other published ECMO-related complications in this patient cohort include hemolysis, cannula dislodgment, and ineffective flow rate resulting from uterine compression, which improved after emergency cesarean section, and 588

nosocomial infections including bloodstream, respiratory, urinary tract, and line-related infections.30,31 Timing and Mode of Delivery Timing of the delivery depends primarily on maternal health. As the pregnancy progresses the diaphragmatic elevation worsens and with the increasing oxygen requirements of the fetus in late pregnancy, sufficient control of gas exchange remains challenging. Any decision to deliver the fetus should be discussed and documented clearly as a multidisciplinary team including the ECMO team, adult intensivists, obstetric anesthetists, obstetricians, and the neonatal teams. Women who received ECMO therapy at early gestations have recovered and been successfully extubated and brought to term, with good maternal and neonatal outcomes. However, in the later stages of pregnancy, if the causative pulmonary or cardiac pathology appears to have resolved but satisfactory objective tests of pulmonary or cardiac function remain suboptimal, it is reasonable to deliver the fetus. Delivery may also be appropriate if patients experience severe complications of pregnancy including preeclampsia, placental abruption, or chorioamnionitis as the risk of developing coagulopathies and maternal death is high. Often when planning delivery, an unheparinized circuit can be run for up to 6 hours in the case of VA-ECMO and longer in the case of VV-ECMO.32 Once the plan for delivery has been made, then consideration regarding the mode of delivery becomes crucial. Case reports have demonstrated good outcomes with spontaneous vaginal births while on ECMO. Similarly, in cases of fetal death vaginal birth is appropriate.33 Planned vaginal birth by induction of labor is often more challenging due to the patient being cared for in units without direct maternity cover. The risk of intrapartum fetal hypoxia and acidosis is high; oxygenation, blood pressure,

Pregnancy and Extracorporeal Life Support

and pain control are more challenging. Provision should be made for emergency operative delivery if complications arise.34 Therefore most units would consider elective cesarean section at a time when the obstetric, cardiothoracic, ECMO, anesthetic (both cardiovascular and obstetric anesthetists), and neonatal teams are present. Fetal and Neonatal Considerations Timing of delivery should generally be approached taking into consideration the interests of the mother; when the delivery is deemed to improve her respiratory or cardiovascular status. The neonatal morbidity and survival depends significantly on the gestation of delivery. The Epicure data is a comprehensive review of survival both short and long term of infants born at the extremes of prematurity.35 Survival is poor at less than 23 weeks’ gestation. Certainly from 24 weeks’ gestation an experienced neonatal team should be present. A course of antenatal steroids (such as dexamethasone 12 mg intramuscularly, 2 doses at least 12 hours apart) has been shown to improve neonatal outcome by reducing the incidence of neonatal respiratory distress and neonatal intraventricular haemorrhage. Antenatal steroid treatment should be considered, if not contraindicated, for all women when preterm delivery is being contemplated between 24-36 weeks’ gestation.36 Specific Complications of Pregnancy to Consider during ECMO Preeclampsia Preeclampsia commonly complicates pregnancy. In severe forms it can be a primary cause for ARDS. However, there is a possibility that it may develop in an already unwell patient. Therefore, clinical suspicion if the blood pressure is difficult to control, and daily urinalysis is required.37,38 HELLP syndrome (an acronym for

hemolysis, elevated liver function tests and low platelets) is part of the spectrum of preeclampsia with evidence of hemolysis, elevated liver enzymes (transaminases), and low platelets. In severe preeclampsia (BP >160/100, greater than 3g protein in 24 hour urine collection) cerebral irritability attributed to cerebral edema, can lead to eclamptic fits. Vigilance for signs of agitation clonus or brisk reflexes is required with a low threshold for starting magnesium sulphate (4g loading dose over 20 minutes and maintenance at 2 g/hour). Both fetal and maternal mortality in the event of an eclamptic fit is increased significantly; magnesium sulphate has been shown to reduce the incidence of the first and subsequent eclamptic fits. Severe hypertension (BP >160/100) is also associated with intracranial hemorrhage if this occurs on a fully anticoagulated circuit, mortality is high. Severe hypertension can be managed with IV labetalol or hydralazine. As preeclampsia is related to abnormal placentation, early consideration for delivery is required once the patient has been stabilized; therefore, timely involvement of the anesthetic and obstetric teams is crucial.39 Chorioamnionitis In cases of rupture of membranes, ascending infection may result. Chorioamniotis is a primary cause of ARDS. In addition, the risk of developing coagulopathy and DIC is high. Broad spectrum antibiotics should be used early and failure to respond will require consideration of delivery or terminating the pregnancy if unviable. Abruption This is defined as bleeding from the placental bed. If severe such hemorrhage can result in fetal death, maternal coagulopathy, and DIC; in addition, the risk of spontaneous miscarriage or labor is increased. Therefore, management

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of the anemia and coagulopathy should be considered as well as delivery.

ECMO possibly remains underutilized, potentially due to the concerns of increased maternal and fetal bleeding. A recent systematic review Fetal Death and metaanalysis summarizes the same group of publications.19 Patients with profound shock or other sigThe experience in the puerperal period is nificant systemic illness have significant risk heavily concentrated around the 2009 H1N1 inof fetal demise. The diagnosis can be made fluenza pandemic with 48 patients (45 VV and by ultrasound. The retained fetus may cause 3 VA) receiving ECMO. Survival was 92% for the patient to develop significant coagulopa- the mother and 74% for the fetus. The overall thy. Therefore, once stabilized, consideration maternal and fetal survival in the 67 patients should be made to deliver the fetus. Vaginal was 80% and 70% respectively. One has to be delivery is a reasonable option. Due to the risk mindful of publication bias towards successful of catastrophic bleeding, once developing signs outcomes, which almost certainly applies to of labour, temporary cessation of heparin should this patient group. The most common site of bleeding reported be considered. Uterotonics should be available to ensure the uterus contracts and controls was around the tracheostomy and ECMO cannula. Delivery of the fetus was mostly deferred, bleeding after delivery. but in one case the fetus was successfully delivered by cesarean while the mother remained Postpartum Hemorrhage on ECMO. As in other adult patients, outcomes Once the placenta has delivered, significant appeared to be better if the duration of mechanibleeding can occur due to atony. Uterotonics cal ventilation was 10% immature neutrophils The exact values that define many of these parameters vary with age and can be found in the consensus statements of various societies.2-3 Severe sepsis occurs when organ dysfunction, hypoperfusion, or hypotension are present. Septic shock is defined as severe sepsis with hypotension and hypoperfusion which persist despite adequate fluid replacement. The definition of refractory septic shock varies4 but the most comprehensive and apposite is that of the American College of Critical Care Medicine (ACCM): Shock that persists despite goal-directed use of inotropes, vasopressors, vasodilators, and maintenance of metabolic and hormonal homeostasis.5 Sepsis is one of the leading causes of mortality and morbidity worldwide. Although case fatality rates appear to be falling in some countries, population-based mortality rates and hospitalization rates with severe sepsis are increasing.6,7 In high income countries, adult patients admitted to the intensive care unit (ICU) with a diagnosis of severe sepsis have hospital mortality rates between 27–32%.7-10 In the USA, children hospitalized with severe sepsis have mortality rates of up to 10%.10,11 The mortality in children admitted to ICU with a diagnosis of septic shock is approximately 17%.7 The most 613

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This chapter will outline the indications and important determinant of the likelihood of death 12,13 contraindications for ECMO in sepsis, review is the development of shock. Sepsis was historically regarded as a con- the hemodynamic responses to infection in patraindication to ECMO. In the 1990s, however, tients of all ages and the implications these have a number of studies demonstrated that it could for cannulation strategies, discuss circuit manbe lifesaving in neonatal and pediatric septic agement in sepsis, and summarize outcomes. shock,14-17 a view strengthened by recent re- The chapter will focus on the use of ECMO as ports involving larger numbers of patients.18-20 circulatory support in refractory septic shock, ECMO for refractory septic shock in neonates which requires more detailed consideration than is now regarded as a standard indication for isolated respiratory failure from sepsis. extracorporeal support, with survival rates of approximately 75-80%.5,19, 21 However, uni- Indications versal acceptance of ECMO for septic shock It was suspected for many years that septic in older patients has been limited by the retrospective uncontrolled studies on the subject, patients being placed on ECMO for respiratory historically poor outcomes in some centers, support of sepsis-induced ARDS or bacterial lack of comparative evaluation of cannulation pneumonia had worse outcomes than similar strategies, and perhaps by an under-appreciation patients without sepsis. This has been shown of the pathophysiological and hemodynamic not to be the case and neither sepsis nor bacteresponses to infection with changes in age. The remia at the initiation of ECMO are predictors American College of Critical Care Medicine of poor outcome.22,23 However, the acquisi(ACCM) recommends that ECMO be consid- tion of new nosocomial infection during an ered for refractory septic shock in children, but ECMO run can be detrimental.24-27 Pneumonia they anticipate survival rates no higher than or sepsis-induced ARDS often present without 50%.5 Whether better survival can be achieved significant circulatory dysfunction, in which with newer and safer types of ECMO technol- case the indications and cannulation strategies ogy remains a question awaiting multicenter for ECMO are similar as for other causes of evaluation. No comparable guidelines exist for hypoxic respiratory failure (see Chapters 9, adult patients. 18, and 36). Some of these patients may have Sepsis is predominantly associated with hypotension, caused by many factors including only one pulmonary pathophysiological re- severe hypoxia, hypercapnia, pulmonary hysponse (ie, acute respiratory distress syndrome; pertension or right heart dysfunction. However, ARDS) but a multitude of hemodynamic re- these secondary cardiovascular effects usually sponses including dilation and failure of one improve substantially with adequate venoveor both ventricles, an increase in pulmonary nous (VV) ECMO, with its attendant effects on vascular resistance, and a fall in systemic vascu- oxygenation, acid-base balance, carbon dioxide, lar resistance, all of which may exist in relative temperature, and intrathoracic pressure. isolation or in combination.4,5 ECMO can be In pediatric septic shock, the indication for used to support patients with severe sepsis and ECMO is straightforward only in principle: It any combination of: has been regarded as the therapy of last resort, • ARDS when shock is refractory and continues to prog• Right heart failure ress despite all attempts at ventilation, fluid, • Left heart failure, and/or pharmacological, and disease-modifying thera• Combined cardiogenic and distributive py, or when cardiac arrest has ensued. However, the exact criteria when ECMO should be instishock 614

ECMO for Septic Shock

tuted have not been the subject of prospective study and clinicians must rely on clinical experience and judgment. The ACCM summarized one approach in a consensus statement on the hemodynamic management of pediatric septic shock.5 The rapidity of shock progression and physiological decline is more important than the absolute amount of inotropic support, but in general ECMO should be considered if a child: • Is receiving doses of >1 mcg/kg/min of epinephrine or its equivalent (ie, an inotrope score28 >100) • Has had aggressive fluid replacement and other pharmacological strategies described by the ACCM consensus statement5 • Continues to deteriorate with worsening hypotension, rising lactates, or rapidly progressive multiorgan dysfunction despite treatment The speed at which ECMO can be initiated is institution-dependent and this must be borne in mind by clinicians seeking to try every possible less invasive strategy in children with rapidly progressive shock. Although several children have been successfully resuscitated from cardiac arrest caused by progressive septic shock and yet completely recovered,18 it is clearly more desirable to intervene before arrest occurs. The timing of this will depend on how quickly an institution can mobilize an emergency ECMO team. Parallels can be drawn to fulminant myocarditis, where the exact timing of mechanical support is based on clinical experience and institutional resources, rather than by prospectively studied, specific criteria. There have been increasing reports of ECMO for adult septic shock,29-32 with survival rates ranging from 15%-71%. Poorer outcomes have been seen using peripheral venoarterial (VA) ECMO in patients with distributive shock, in patients who have had cardiac arrest as a result of septic shock, and in patients older than 60 years.29-30 Better outcomes have been seen

in young adults who present with distributive shock then develop progressive left ventricular dysfunction and are placed on ECMO before cardiac arrest occurs.32 Contraindications The standard contraindications to ECMO apply in septic patients, such as preexisting severe neurological dysfunction or incurable malignancy.33 An additional consideration is the septic oncology patient. Oncology patients have been regarded as poor ECMO candidates, but this view is anachronistic and outcomes are acceptable in some instances. One exception to this is allogeneic bone marrow transplant recipients, who have dismal outcomes.34 Children who have received stem cell transplantation and require ECMO have somewhat better outcomes but survival to hospital discharge is still only 10%.35 Neutropenic sepsis is not a contraindication to ECMO per se, but it is difficult to do because of the other morbidities that often coexist in this patient group – such as thrombocytopenia – and long-term survival may not be as good as for other indications. Nonetheless, successful outcomes have been reported.36 The type of infecting organism should not be regarded as a major determinant of the appropriateness of ECMO although some organisms, most notably Bordetella pertussis and herpes simplex virus (HSV) in infants, are associated with poorer outcomes.37,38 In the absence of other contraindications, the infecting microbe usually has minimal bearing on whether ECMO is offered or not, and is often not known at the time. Cannulation Strategies Cannulation is one of the most important management issues in ECMO for sepsis and must be individually tailored to the patient’s circulatory and respiratory status. An understanding of the pathophysiology of septic 615

Chapter 56

shock coupled with adequate hemodynamic information is vital in planning an appropriate cannulation strategy. For sepsis-induced isolated respiratory failure requiring ECMO, VV cannulation is preferred because it is associated with better outcomes. VV-ECMO avoids the complications of VA-ECMO such as systemic embolization, arterial trauma, and increased left ventricular afterload, while preserving pulmonary blood flow, pulsatile systemic flow, and oxygenation of blood in the systemic ventricle and thus the coronary arteries.43,44 VV-ECMO is also preferred in those patients with ARDS that persists after resolution of shock, when the patient is ready to be weaned off mechanical circulatory support but not ready to cease extracorporeal gas exchange because of ongoing respiratory failure. In these instances, consideration should be given to changing to VV cannulation if it is anticipated that lung recovery will require more than 1-2 days of further ECMO. If ECMO is being considered primarily as circulatory support for refractory septic shock, then the patient’s hemodynamic response to sepsis must first be established. Septic shock has three principle hemodynamic manifestations based on the most compromised part of the circulation: right heart failure, left heart failure with poor systemic oxygen delivery, or distributive shock with poor oxygen extraction.5 In advanced cases a mixture of these may occur, eg, adult patients who present with distributive shock but later develop progressive ventricular failure, or children with a combination of cardiogenic and vasoplegic shock.18,20,32 Right heart failure associated with persistent pulmonary hypertension of the newborn is the most frequent manifestation of septic shock in neonates. Right heart failure from a combination of sepsis-induced ventricular dysfunction and high positive pressure ventilation can also be seen in older patients. After the neonatal period, septic children suffer from left ventricular failure with preserved vasomotor tone and 616

impaired oxygen delivery. The age at which a child will alter their hemodynamic response from left heart failure (‘cold’ shock) to distributive shock (‘warm’ shock) is highly variable and cannot be reliably predicted from the child’s age. However, by late adolescence and into adulthood, the near universal hemodynamic response to sepsis is distributive shock. This response is characterized by a reduction in ventricular function, an increase in heart rate, a reduction in vasomotor tone, and often by a reduction in oxygen extraction at a mitochondrial level. The categorization of shock requires a combination of clinical assessment, blood tests (eg, venous oximetry, lactate), and echocardiography, with or without measurement of cardiac output, and is best done by an experienced intensivist.5 Possible ECMO cannulation strategies become apparent once the hemodynamic pattern of shock has been identified (Table 56-1). Those with right heart failure and concomitant respiratory failure can be supported with VV-ECMO if the shock is not particularly advanced, as the consequent reduction in intrathoracic pressure and optimization of oxygenation and carbon dioxide clearance may be sufficient to improve myocardial performance and peripheral circulation, especially in small children. Otherwise, peripheral VA-ECMO or central ECMO can be used. In left heart failure, peripheral or high flow central ECMO is appropriate. Serial echocardiograms must be performed to monitor left heart distension. If this is worsening, then steps should be taken to alleviate it before left atrial distension and hypertension lead to pulmonary edema or pulmonary hemorrhage. Increasing circuit flow may limit atrial distension; if unsuccessful, then percutaneous atrial septostomy can be performed on peripheral ECMO, or a left atrial vent cannula can be inserted on central ECMO, ie, biatrial drainage. If the femoral artery is used in older children or adults then some centers advocate the routine use of an anterograde perfusion cannula

ECMO for Septic Shock Table 56-1. ECMO cannulation strategies in septic shock. Hemodynamic Typical Pattern Patient Neonate Right heart failure

Cannulation Options VV -

Peripheral* VA (carotid) Central* VA

-

Left heart failure

Young child

Peripheral VA (carotid or femoral)

-

Central VA

-

Distributive

Older child or adult

Central VA

-

Mixed shock (eg, cardiogenic and vasoplegic) Concomitant refractory cardiac and respiratory failure

Any age

Central VA

-

Any age

Central VA

-

VAV

-

-

Advantages

Caveats

Ref

Cannot provide complete circulatory support Inappropriate in advanced shock

45

Limited flows Slight increase in neurological complications Requires cardiac surgeon to cannulate Increased risks of bleeding and infection

14,15,18, 65

As above Femoral cannulation requires anterograde perfusion to avoid limb ischemia As above

16-18

-

ECMO unnecessary / inappropriate unless prearrest physiology

18,20

-

As above

18,20

-

As above

18,20

-

Technically difficult in smaller children May be associated with higher rates of hemolysis because of the gate clamp on the respiratory limb

66

Prevents systemic embolization Avoids differential cyanosis Fast May use 1 cannula Direct circulatory support Fast

-

Allows the highest flow rates Prevents differential cyanosis As above

-

May be associated with better outcomes in children Only strategy likely to achieve sufficiently high circuit flows As above

-

May be associated with better outcomes in children Avoids risks of central cannulation Facilitates easy and immediate adjustment of the proportion of respiratory and circulatory support Prevents differential cyanosis

-

-

-

-

18

18,20

*Peripheral: Drains deoxygenated blood via jugular vein, femoral vein, or both. Returns oxygenated blood to carotid artery (young children [70%, and lation settings should be reduced to lung-protecrestoration of age-appropriate mean arterial tive settings (eg, rate 5-10/min, peak inspiratory pressures. In sepsis, this often requires very pressure 150-200 ml/kg/min). Although 1 g/L) triggered by the septic process. Smaller doses had a six-fold independent increase in the risk of are often sufficient in adult patients. Occasiondying compared to those who did not.52 Similar ally very large doses of heparin may be required findings have been seen in adult patients.53 (eg, >30 U/kg/hr). In these patients, antithromInotropes can usually be weaned com- bin levels may be low, in which case there pletely or to minimal doses within a few hours may be a role for administering intravenous of achieving goal-directed circuit flows. Vaso- antithrombin concentrate, aiming for 100-120% constrictors may be necessary to maintain age of the reference value. In particularly difficult appropriate mean arterial pressures but it is not cases of DIC and hemorrhage, thromboelasunusual to see hypertension ensue around this tography can be useful in identifying the most time, particularly with the high flows of central important elements of coagulopathy which can ECMO, in which case short-acting vasodilators then be targeted for treatment. 620

ECMO for Septic Shock

Other measures such as effective empiric Most patients on ECMO for septic shock antibiotics and immediate treatment of any recover quickly and do not require ECMO for septic foci are vital. The pharmacokinetics of more than 3-4 days. Failure of the heart to reantibiotics for patients receiving extracorporeal cover after seven days should trigger a search life support have been inadequately studied. As for additional pathologies such as myocardial failure to provide adequate and timely empiric infarction or bacterial myocarditis, and is usuantibiotics has been associated with substantial ally a poor prognostic indicator. Occasionally, increases in mortality,54,55 initial antibiotics patients suffer from persistent ARDS, necessishould be given as early as possible, cover all tating conversion to VV-ECMO when the circulikely pathogens, and be at the maximum dose latory component of their illness resolves. This recommended by standard formularies, espe- scenario is seen particularly with disseminated cially those with a wide therapeutic index such Staphylococcus aureus and can be challenging as β-lactam antibiotics.56 to deal with, as necrotizing staphylococcal The role of other extracorporeal life support pneumonia can cause substantial lung parenmodalities in sepsis to remove inflammatory chymal destruction. After a trial of prolonged mediators or modulate the immune response VV-ECMO in some patients with this condition, is controversial. These techniques, classified the only option other than withdrawal of supas Extracorporeal Blood Purification (EBP), port, may be to perform lung transplantation include continuous renal replacement therapy directly from ECMO. However, this scenario (CRRT), plasmapheresis, plasma exchange, and is uncommon and some patients can still be hemoperfusion.57 CRRT is frequently required successfully weaned. in septic patients on ECMO to compensate for sepsis-induced acute kidney injury and provide Outcomes adequate solute clearance, as well as to prevent ECMO for neonatal sepsis is associated severe volume overload from blood product, nutrient, and drug administration. Although some with survival rates of approximately 75%.21 investigators have seen hemodynamic benefits This age group is unique in having sufficient in children receiving high-flux CRRT,5 CRRT data to comment on pathogen-specific outcomes. should not been regarded as standard manage- In one survey sent to 16 ICUs worldwide, 117 ment for septic patients on ECMO unless the septic patients were identified, 107 of whom patient has incipient renal failure or fluid over- were neonates.39 Survival in patients with Gramload.58-59 Plasma exchange and plasmapheresis positive, Gram-negative or viral sepsis was 77%, have shown some promise in small trials but 60%, and 40% respectively, although the study again cannot be considered standard therapy was published nearly two decades ago and it is and await proper evaluation in large prospec- likely that outcomes are better now. One study tive multicenter studies.48,60,61 Many other forms of neonates on ECMO with herpes simplex viof EBP are undergoing phase II or III trials. rus showed survival to hospital discharge was One prospective, randomized, controlled trial only 25%.37 The survival rate in infants infected of intraabdominal sepsis and shock showed with Bordetella pertussis receiving ECMO is decreased mortality with the use of polymyxin even lower. Data from the ELSO Registry reveal that B hemoperfusion.62 However, this finding was a secondary endpoint, just achieved statistical survival in children after the neonatal period significance, and has not been duplicated in with isolated respiratory failure from bacterial or viral pneumonia are 59% and 65% respecmore recent randomized controlled trials.63 tively.21 The corresponding figures for adult 621

Chapter 56

patients are 61% and 66%. Fifty-four percent of both adults and children with ARDS have survived, but this includes all causes of ARDS and is not specific to sepsis. However, as noted above, there is no reason to believe that outcomes are different in septic patients.22,23 In pediatric septic shock, historical experience suggests that the use of ECMO in children is associated with survival to hospital discharge of 50% at best.5,18 However, the use of high flow, central ECMO with modern circuitry and intensive care is associated with survival rates approaching 75%.18,20 Hopefully, further assessment will support these more recent, improved survival figures, which are comparable to survival in neonatal sepsis. The increasing use of ECMO for adult septic shock has demonstrated that peripheral ECMO for distributive shock is most likely unhelpful but that peripheral ECMO for severe sepsis-induced cardiogenic shock, occasionally seen in younger adults, can save up to 70% of patients.32 The use of central ECMO for adult distributive septic shock has been successfully reported in isolated cases but, thankfully, is almost never required.64 Conclusions Our understanding of ECMO for septic shock has progressed considerably in the last 25 years, through being regarded by many practitioners in the early 1990s as a complete contraindication, to modern published case series demonstrating 75% survival. ECMO is generally required very early in the course of sepsis, usually before antibiotics have taken effect.20 The beneficial effects it exerts on reversing shock and halting the evolution of multiorgan failure are usually immediately apparent, particularly with central cannulation. As the technological advancements in ECMO circuitry have made extracorporeal support safer than ever before, it is interesting to speculate whether in time ECMO will move higher up the 622

algorithm of pediatric septic shock management. Instead of being the therapy of last resort, it may become a more widely accepted treatment for septic shock, instituted earlier in the course of illness to prevent the establishment of multiorgan failure. Septic shock remains a rare indication for ECMO in experienced centers, yet up to 17% of children admitted to ICU with this diagnosis die.7 While not all of these deaths can be prevented, some of these patients probably could be rescued with ECMO. With wider acceptance of sepsis as an indication for ECMO and greater engagement of institutions to refer to ECMOcapable centers, we believe this figure may fall. Extracorporeal therapy, whether it is ECMO, EBP, or both, holds the promise of significantly improving outcomes in septic shock. The use of ECMO as mechanical circulatory support for adult septic shock is unlikely to be required except in rare instances of young adults with significant ventricular impairment and septic shock.

ECMO for Septic Shock

References 1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:801-810. 2. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International sepsis definitions conference. Crit Care Med 2003;31:1250-1256. 3. Goldstein B, Giroir B, Randolph A, et al. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:2-8. 4. Annane D, Bellisant E, Cavaillon JM. Septic shock. Lancet 2005;365:63-78. 5. Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med 2009;37:666-688. 6. Kaukonen KM, Bailey M, Suzuki S, et al. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA 2014; 311:1308-1316 7. Schlapbach L, Straney L, Alexander J, et al. Mortality related to invasive infections, sepsis, and septic shock in critically ill children in Australia and New Zealand, 2002-2013: a multicenter retrospective cohort study. Lancet Infect Dis 2015; 15:46-54 8. Barnato AE, Alexander SL, Linde-Zwirble WT, Angus DC. Racial variation in the incidence, care, and outcomes of severe sepsis: analysis of population, patient, and hospital characteristics. Am J Respir Crit Care Med 2008;177:279-284. 9. Levy MM, Dellinger RP, Townsend SR, et al. The surviving sepsis campaign: results of an international guideline-based performance improvement program targeting

severe sepsis. Crit Care Med 2010;38:367374. 10. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303-1310. 11. Watson RS, Carcillo JA, Linde-Zwirble WT, et al. The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med 2003;167:695-701. 12. Watson RS, Carcillo JA. Scope and epidemiology of pediatric sepsis. Pediatr Crit Care Med 2005;6:S3-S5 13. Leclerc F, Leteurtre S, Duhamel A, et al. Cumulative influence of organ dysfunctions and septic state on mortality of critically ill children. Am J Resp Crit Care Med 2005;171:348-353. 14. McCune S, Short BL, Miller MK, Lotze A, Anderson KD. Extracorporeal membrane oxygenation therapy in neonates with septic shock. J Pediatr Surg 1990;25:479-482. 15. Hocker JR, Simpson PM, Rabalais GP, Stewart DL, Cook LN. Extracorporeal membrane oxygenation and early-onset group B streptococcal sepsis. Pediatrics 1992;89:1-4. 16. Beca J, Butt W. Extracorporeal membrane oxygenation for refractory septic shock in children. Pediatrics 1994;93:726-729. 17. Goldman AP, Kerr SJ, Butt W, et al. Extracorporeal support for intractable cardiorespiratory failure due to meningococcal disease. Lancet 1997;349:466-469. 18. MacLaren G, Butt W, Best D, Donath S, Taylor A. Extracorporeal membrane oxygenation for refractory septic shock in children: one institution’s experience. Pediatr Crit Care Med 2007;8:447-451. 19. Bartlett RH. Extracorporeal support for septic shock. Pediatr Crit Care Med 2007;8:498-499. 20. MacLaren G, Butt W, Best D, Donath S. Central extracorporeal membrane oxygen623

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ation for refractory pediatric septic shock. Pediatr Crit Care Med 2011;12:133-136. 21. Extracorporeal Life Support Organization (ELSO). ECLS registry report, International Summary. January 2016. 22. Meyer DM, Jessen ME. Results of extracorporeal membrane oxygenation in children with sepsis. The Extracorporeal Life Support Organization. Ann Thor Surg 1997;63:756-761. 23. Rich PB, Younger JG, Soldes OS, Awad SS, Bartlett RH. Use of extracorporeal life support for adult patients with respiratory failure and sepsis. ASAIO J 1998;44:263266. 24. Montgomery VL, Strotman JM, Ross MP. Impact of multiple organ dysfunction and nosocomial infections on survival of children treated with extracorporeal membrane oxygenation after heart surgery. Crit Care Med 2000;28:526-531. 25. Burket JS, Bartlett RH, Vander Hyde K, Chenoweth CE. Nosocomial infections in adult patients undergoing extracorporeal membrane oxygenation. Clin Infect Dis 1999;28:828-833. 26. O’Neill JM, Schutze GE, Heulitt MJ, Simpson PM, Taylor BJ. Nosocomial infections during extracorporeal membrane oxygenation. Intensive Care Med 2001;27:12471253. 27. Hsu MS, Chiu KM, Huang YT, et al. Risk factors for nosocomial infection during extracorporeal membrane oxygenation. J Hosp Infection 2009;73:210-216. 28. Wernovsky G, Wypij D, Jonas RA, et al. Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants. Circulation 1995;92:2226-2235. 29. Huang CT, Tsai YJ, Tsai PR, Ko WJ. Extracorporeal membrane oxygenation resuscitation in adult patients with refractory septic shock. J Thorac Cardiovasc Surg 2013;146:1041-1046. 624

30. Park TK, Yang JH, Jeon K, et al. Extracorporeal membrane oxygenation for refractory septic shock in adults. Eur J Cardiothorac Surg 2015;47:e68-74. 31. Cheng A, Sun HY, Lee CW, et al. Survival of septic adults compared with nonseptic adults receiving extracorporeal membrane oxygenation for cardiopulmonary failure: a propensity-matched analysis. J Crit Care 2013; 28:532.e1-10. 32. Brechot N, Luyt CE, Schmidt M, et al. Venoarterial extracorporeal membrane oxygenation support for refractory cardiovascular dysfunction during severe bacterial septic shock. Crit Care Med 2013; 41:16161626 33. Extracorporeal Life Support Organization. ELSO general guidelines. Available at: http://www.elso.org/resources/Guidelines. aspx. Accessed January 2016 34. Gupta M, Shanley TP, Moler FW. Extracorporeal life support for severe respiratory failure in children with immune compromised conditions. Pediatr Crit Care Med 2008;9:380-385. 35. Di Nardo M, Locatelli F, Palmer K, et al. Extracorporeal membrane oxygenation in pediatric recipients of hematopoietic stem cell transplantation: an updated analysis of the Extracorporeal Life Support Organization experience. Intensive Care Med 2014; 40:754-756 36. Smith S, Butt W, Best D, MacLaren G. Long-term survival after extracorporeal life support in children with neutropenic sepsis. Intensive Care Med 2016 [in press] 37. Prodhan P, Wilkes R, Ross A, et al. Neonatal herpes virus infection and extracorporeal life support. Pediatr Crit Care Med 2010;11:599-602. 38. Pooboni S, Roberts N, Westrope C, et al. Extracorporeal life support in pertussis. Pediatr Pulmonol 2003;36:310-315. 39. Stewart DL, Dela Cruz TV, Ziegler C, Goldsmith LJ. The use of extracorporeal

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membrane oxygenation in patients with gram-negative or viral sepsis. Perfusion 1997;12:3-8. 40. Kahn JM, Muller HM, Kulier A, KeuschPreininger A, Tscheliessnigg KH. Venoarterial extracorporeal membrane oxygenation in acute respiratory distress syndrome caused by leptospire sepsis. Anesth Analg 2006;102:1597-1598. 41. Minette MS, Ibsen LM. Survival of candida sepsis in extracorporeal membrane oxygenation. Pediatr Crit Care Med 2005;6:709711. 42. Crowley MR, Katz RW, Kessler R, et al. Successful treatment of adults with severe Hantavirus pulmonary syndrome with extracorporeal membrane oxygenation. Crit Care Med 1998;26:409-414. 43. Keckler SJ, Laituri CA, Ostlie DJ, St Peter SD. A review of venovenous and venoarterial extracorporeal membrane oxygenation in neonates and children. Eur J Pediatr Surg 2010;20:1-4. 44. Kinsella JP, Gerstmann DR, Rosenberg AA. The effect of extracorporeal membrane oxygenation on coronary perfusion and regional flow distribution. Pediatr Res 1992;31:8084. 45. Roberts N, Westrope C, Pooboni SK, et al. Venovenous extracorporeal membrane oxygenation for respiratory failure in inotrope dependent neonates. ASAIO J 2003;49:568571. 46. Court O, Kumar A, Parrillo JE, Kumar A. Clinical review: myocardial depression in sepsis and septic shock. Crit Care 2002;6:500-508. 47. Parker MM, Shelhamer JH, Bacharach SL, et al. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 1984;100:483-490. 48. Carcillo JA. Multiple organ system extracorporeal support in critically ill children. Pediatr Clin North Am 2008;55:617-646.

49. MacLaren G, Butt W, Best D. Pediatric septic shock guidelines and extracorporeal membrane oxygenation management. Crit Care Med 2009;37:2143-2144. 50. Taylor A, Cousins R, Butt WW. The longterm outcome of children managed with extracorporeal life support: an institutional experience. Crit Care Resusc 2007;9:172177. 51. Pinsky MR. Hemodynamic evaluation and monitoring in the ICU. Chest 2007;132:2020-2029. 52. Lou S, MacLaren G, Best D, Delzoppo C, Butt W. Hemolysis in pediatric patients receiving centrifugal-pump extracorporeal membrane oxygenation: prevalence, risk factors, and outcomes. Crit Care Med 2014; 42:1213-20 53. Omar HR, Mirsaeidi M, Socias S, et al. Plasma free hemoglobin is an independent predictor of mortality among patients on extracorporeal membrane oxygenation support. PLoS One 2015; 10:e0124034 54. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34:1589-1596. 55. Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in fivefold reduction of survival in human septic shock. Chest 2009;136:1237-1248. 56. Lipman J, Boots R. A new paradigm for treating infections: “go hard and go home”. Crit Care Resusc 2009;11:276-281. 57. House AA, Ronco C. Extracorporeal blood purification in sepsis and sepsis-related kidney injury. Blood Purif 2008;26:30-35. 58. MacLaren G, Butt W. Controversies in paediatric continuous renal replacement therapy. Intensive Care Med 2009;35:596602. 59. Selewski D, Cornell TT, Blatt NB, et al. Fluid overload and fluid removal in pediatric patients on extracorporeal membrane 625

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oxygenation requiring continuous renal replacement therapy. Crit Care Med 2012; 40:2694-2699 60. Busund R, Koukline V, Utrobin U, et al. Plasmapheresis in severe sepsis and septic shock: a prospective, randomized, controlled trial. Intensive Care Med 2002;28:1434-1439. 61. Stegmayr BG, Banga R, Berggren L, et al. Plasma exchange as rescue therapy in multiple organ failure including acute renal failure. Crit Care Med 2003;31:1730-1736. 62. Cruz DN, Antonelli M, Fumagalli R, et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA 2009;301:2445-2552. 63. Payen DM, Guilhot J, Launey Y, et al. Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial. Intensive Care Med 2015; 41:975-984 64. MacLaren G, Cove M, Kofidis T. Central extracorporeal membrane oxygenation for septic shock in an adult with H1N1 influenza. Ann Thorac Surg 2010; 90:e34-5 65. Teele SA, Salvin JW, Barrett CS, et al. The association of carotid artery cannulation and neurologic injury in pediatric patients supported with venoarterial extracorporeal membrane oxygenation. Pediatr Crit Care Med 2014; 15:355-61 66. MacLaren G, Conrad S, Dalton H. Extracorporeal Life Support. In: Roger’s Textbook of Pediatric Intensive Care. Fifth Edition. Shaffner H, Nichols D (Eds). Lippincott Williams & Wilkins 2015; 581-599

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57 Extracorporeal Life Support for Severe Cardiotoxic Drug Poisoning Nicolas Bréchot, MD, PhD, Philippe Léger, MD, Pascal Leprince, MD, PhD, Alain Combes, MD, PhD

Introduction Poisoning is a frequent and severe condition. Despite major improvements due to specific antidotes, refractory cardiovascular dysfunction still accounts for a high proportion of deaths in poisoned patients. As cardiovascular impairment is only transient, there is a strong rationale for using extracorporeal life support (ECLS) for this condition. The recourse to the technique is strongly supported by animal studies, and gave promising results in case reports and small cohort studies in humans. However, the optimal timing for ECLS implantation remains inadequately defined. Apart from cardiovascular failure, ECLS may be useful in poisoned patients presenting acute respiratory distress syndrome (ARDS) refractory to conventional management. ECLS for Poisoning-induced Cardiovascular Failure Epidemiology The 2014 annual report of the American Association of Poison Control Centers mentioned more than two million poison exposures in the U.S., more than 600.000 of them managed in healthcare facilities.1 Among them, cardiovas-

cular drugs are of particular concern, representing 4% of the total exposures, but 13% of deaths. Particularly, calcium channel blockers and betablockers accounted for 60% of the deaths due to cardiovascular drug intoxication. Moreover, many other substances not referred to as cardiovascular drugs can have cardiovascular effects, ie, noncardiovascular pharmaceuticals (antipsychotics, antidepressants, antihistamines), drugs (cocaine, amphetamines), rural toxicants (organophosphates, pesticides), industrial or household toxicants (aluminium phosphide, trichloroethylene), and plants (digitalis, colchicine, yew). Specifically, a large panel of substances have membrane stabilizing properties at high doses (Table 57-1), which are associated with a marked increase in mortality.2 Usual presentations of severe cardiotoxic drug poisoning include rapid progression to severe cardiogenic shock, high degree atrioventricular block, asystole, pulseless ventricular tachycardia, or ventricular fibrillation. Time of shock onset after ingestion varies largely from one patient to another, depending on galenic formulation, ingested dose, and co-ingested molecules. It is approximately 2 hours for class I antiarrythmics,3 6 hours for polycyclic antidepressants, chloroquine, beta-blockers, and immediate release calcium channel blockers,4-7 and up to 18-24 hours for the modified release form of the calcium channel blocker verapamil.7 627

Chapter 57

Alternatively, cardiovascular failure is unlikely to occur beyond these times. First Line Management Nonspecific ICU support after drug poisoning includes fluid management and correction of electrolyte disturbances, catecholamines, atropine in case of severe bradycardia, and molar sodium bicarbonate in case of QRS enlargement (Figure 57-1). Mechanical ventilation is initiated in case of respiratory or neurologic failure. Single-dose activated charcoal may be used up to two hours after ingestion of life-threatening toxics in patients with intact or protected airways.8 Specific Antidotes Specific antidotes have considerably improved the prognosis of patients with cardiovascular impairment after poisoning (Table 57-2). Table 57-1. Drugs responsible for membrane stabilizing activity at high doses.25 Pharmacological Class Beta-blockers

Class I Anti-arrhythmics

Polycyclic antidepressants Antimalarial agents Selective serotonin reuptake inhibitors Dopamine and norepinephrine uptake inhibitors Anti-epileptics Phenothiazines Opioids Recreational agents

628

Example of Substances Propanolol, acebutolol, nadoxolol, pindolol, penbutolol, labetalol, oxprenolol Flecainide, quinidine, lidocaine, disopyramide, cibenzoline, propafenone, procainamide Imipramine, amitriptyline, desipramine, clomipramine, dosulepin, doxepin, maprotiline Chloroquine, quinine Venlafaxine, citalopram, escitalopram Bupropion Carbamazepine, phenytoin Thioridazine Dextropropoxyphene Cocaine

However, mortality is still 10-20% when cardiovascular failure occurs,3,6,9 and may reach 90% when cardiovascular dysfunction is refractory to conventional treatments.3,10 Role for ECLS Considering that myocardial dysfunction observed after poisoning with cardiotoxics is transient, there is a strong rationale for using mechanical circulatory assistance in the most severe patients. First attempts in humans used heart surgery cardiopulmonary bypass as a salvage therapy, which led to disappointing results due to a high rate of bleeding complications.11-14 However, major technical improvement in ECMO technique in the last decade has considerably decreased complications and venoarterial Table 57-2. Main specific antidotes available during drug poisoning. Type of Intoxication

Beta-blockers

Calcium-channel blockers

Membrane stabilizing activity drugs Local anaesthetics

Cardiac glycosides

Antidote - Glucagon: 2-5 mg IV bolus, then 2-10 mg/h continuous infusion [37] - Glucose-insuline: 1 UI/kg IV bolus followed with 1-10 UI/kg/h infusion+ adequate glucose [38-40] - Discuss intravenous lipid emulsion for lipophilic agents: 1.5 ml/kg IV bolus then 0.25 ml/kg/min infusion [41] - Calcium salts: 1g IV bolus/15-20 min, 4 doses followed with 50 mg/kg/h infusion - Glucose-insuline: 1 UI/kg IV bolus followed with 1-10 UI/kg/h infusion+ adequate glucose [38-40] - Discuss intravenous lipid emulsion for lipophilic agents: 1.5 ml/kg IV bolus then 0.25 ml/kg/min infusion [41] - 8,4 % sodium bicarbonate: 1-3 mmol/kg IV bolus if QRS enlargement/arrhythmia. Maintain ph5 mmol/L cardiogenic shock mesenteric infarction Half-molar neutralization if high-risk patient: male age>55 years underlying heart disease atrio-ventricular block bradycardia4.5 mmol/L

Extracorporeal Life Support for Severe Cardiotoxic Drug Poisoningt

ECMO is now the first-line salvage therapy in case of drug poisoning. It can be initiated at patient’s bedside, even in remote hospitals with mobile ECMO rescue teams.15 It provides a high and stable blood flow to reverse organ dysfunction for the time needed to clear toxics from the body. Animal Studies ECLS has been studied to date in three major animal models of drug poisoning. In a model of lidocaine poisoning in dogs consisting of a 30 mg/kg IV injection, 8 dogs received ECLS support during 90 minutes and were compared to 8 dogs treated conventionally (mechanical ventilation, vasopressors, cardioversion, and antiarrhythmics). All dogs in the ECLS group survived, compared to only two in the control

group. Interestingly, ECLS-treated animals had a drug clearance comparable to normal individuals in this experiment.16 In a model of cardiac arrest following desipramine infusion in dogs, ECLS also rescued all animals (6/6), while only 1/6 animals survived in the conventional treatment group.17 Lastly, in a model of amitriptyline poisoning in which 20 swine were receiving 0.5 mg/kg/min amitriptyline until blood pressure dropped below 30 mmHg for 1 min (near-lethal toxicity), ECLS rescued all animals (10/10), while 9/10 died in the conventional treatment group.18 Human Studies To date ECLS has been used as a salvage therapy in humans presenting with cardiogenic shock or arrhythmia refractory to conventional

Figure 57-1. Proposed algorithm for the management of cardiovascular failure in patients intoxicated with cardiotoxic agents. (Adapted from Baud FJ, et al.25)

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treatment (Table 57-3). In 2009, Daubin, et al. reported the outcomes of 17 patients assisted with peripheral venoarterial ECMO (PVAECMO) for acute poisoning.19 Fifteen suffered from cardiotoxic intoxication including 11 with membrane stabilizing agents, combined with various antipsychotic drugs. All had severe myocardial dysfunction at the time of ECMO implantation, were receiving high dose catecholamines, and suffered multiple organ failure. Seven were implanted under cardiopulmonary resuscitation due to refractory cardiac arrest, with a mean low-flow time of 101 ± 55 min. Time from admission to ECLS was 6.4 ± 7 hrs. Implantation was performed in the operating room for 13 patients and at the bedside for four. Fifteen patients were weaned from ECMO, and 13 (76%) were discharged alive without neurological sequelae. Mean ECMO duration was short (4.5 ± 2.4 days), but a high rate of complications occurred: 6 episodes of limb ischemia and 2 cannulation site bleeding. Authors concluded that despite a high morbidity associated with the technique, PVA-ECMO could rescue patients with refractory myocardial dysfunction associated with drug poisoning. The largest cohort to date reported in 2012 the outcomes of 62 patients with severe shock or persistent (>30 min) cardiac arrest after drug poisoning.20 Fourteen of them underwent PVAECMO, whereas 48 were managed conventionally. Patients treated with or without ECLS at ICU admission were on high dose vasopressors and had comparable drug ingestion histories, Simplified Acute Physiology Score (SAPS II score) (66±18), Sequential Organ Failure Assessment (SOFA) score (median: 11 [IQR, 9-13]), Glasgow Coma Scale score (median: 3 [IQR, 3-11]), need for ventilator support (n=56) and extrarenal support (n=23). Survival rate was 86% in the ECLS group, compared to only 48% in patients who received conventional therapies and none of the patients with persistent cardiac arrest survived without ECLS support. In multivariate analysis, adjusting for SAPS II 630

and beta-blocker intoxication, ECLS support remained significantly associated with lower mortality (Adjusted Odds Ratio, 0.18; 95% CI, 0.03-0.96; p=0.04). Interestingly, none of the 6 ECLS-treated patients who were intoxicated with membrane stabilizing agents died; whereas death occurred in 15 of the 23 patients managed conventionally in this setting. In a sensitivity analysis of the 52 intoxicated patients who did not have cardiac arrest, ECLS remained associated with survival (OR for death 0.28; 95% CI 0.05-1.48, p=0.17), although the difference did not reach statistical significance. The mean time from admission to ECLS was short (8 ± 7hrs), as well as ECLS duration (6 ± 2.9 days). Special attention should be paid to patients presenting with refractory cardiac arrest following drug poisoning, since they are reported to have better outcomes after ECLS support than patients with cardiac arrest from other etiologies. For example, in a cohort of 40 refractory cardiac arrest patients rescued with ECMO, only 8 (20%) survived with a good neurological outcome, but the survival rate was 67% in poisoned patients.21 Similarly, of the 4 survivors of a cohort of 17 refractory cardiac arrest rescued by ECLS, 3 were cardiotoxic-poisoned patients who underwent CPR for up to 180 min before ECMO, and were alive at 1-year followup without sequelae. Pertinently, two of these patients survived despite elevated plasma lactate concentrations before cannulation (39.0 and 20.0 mmol/l).22 The reasons for better outcomes in this setting remain unknown, although it has been hypothesized that early hypothermia occurring in many poisoned patients may protect the brain.19,23,24 Future Directions The optimal timing for ECMO initiation is a crucial issue, which remains undefined in poisoned patients. ECLS is still considered a salvage therapy for which benefits and risks should be carefully weighted. However, concor-

Extracorporeal Life Support for Severe Cardiotoxic Drug Poisoningt

Table 57-3.. Summary of clinical cases reporting the use of ECLS after poisoning. Study Cardiovascular Failure McVey, 1991 [73] Rooney, 2009 [45] Escajeda, 2015 [85] Goodwin, 1993 [47] Williams, 1994 [48] Gillart, 2008 [49] * Hendren, 1989 [13] Holzer, 1999 [52] Maclaren, 2005 [54] Rygnestad, 2005 [76] Kolcz, 2007 [53] * De Rita, 2011 [72] Durward, 2003 [11] Frazee, 2014 [14] Weinberg, 2014 [29] Yasui, 1997 [61] Corkeron, 1999 [60] Auzinger, 2001 [59] Reynolds, 2015 [84] *Tecklenburg, 1997 [75] Behringer, 1998 [82] Jouffroy, 2013 [90] Koschny, 2014 [88] *Haas, 2008 [46] Panzeri, 2010 [78] Fitzpatrick, 1994 [12] *Lai, 2005 [50] * Shenoi, 2011 [51] * Froehle, 2012 [67] Megarbane, 2006 [55] * Marciniak, 2007 [65] De Vroey, 2009 [57] Yoshida, 1998 [58] Lannemyr, 2012 [74] Pasic, 2000 [81] Boisrame-Helms, 2015 [86] Thooft, 2014 [87] Hassanian-Moghaddam, 2015 [83] Elkalioubie, 2011 [69] Kamijo, 1999 [70] Respiratory Failure * Scalzo, 1990 [62] * Moller, 1992 [63] * Bille, 2011 [64] * Garrettson, 1992 [66] * Daugherty, 2011 [68] McCunn, 2000 [56] Bertram, 2013 [89] Tang, 2015 [71] Chian, 2009 [77] Pizon, 2004 [79]

Agent

Cannulation Type

Refractory CA

Survival

Propranolol Acebutolol Metoprolol Tricyclic ADS Tricyclic ADS Tricyclic ADS Verapamil Verapamil Verapamil tricyclic ADS Verapamil, sotalol Verapamil, propranolol Verapamil, propranolol Diltiazem Diltiazem Amlodipine, Lisinopril Flecainide Flecainide Flecainide Flecainide Quinidine Digoxin Colchicine Carvedilol, amlodipine, amitriptyline, and others Amiodarone Yew Aconite poisoning Arsenic Bupropion Mepivacaine Carbamazepine Ibuprofen Cocaine Disopyramide Quetiapine Prajmalium Colchicum Autumnale poisoning Taxus intoxication Aluminium phosphide Tramadol Organo phosphate

PVA PVA PVA PVA PVA PVA CVA PVA PVA PVA CVA CVA CVA CVA PVA PVA PVA PVA PVA VA PVA PVA

+ + + + + + + + + + + + + -

+ + + + + + + + + + + + + + + + + + +

PVA

+

+

PVA PVA CVA VA VA CVA PVA PVA PVA PVA PVA CVA

+ + + + +

+ + + + + + + + + + +

PVA

-

+

PVA PVA PVA

+ +

+ + +

PVA

-

+

Hydrocarbon aspiration PVA Hydrocarbon aspiration PVA Hydrocarbon aspiration PVA Lidocaine (ARDS) PVA Methadone (ARDS) PVA Carbon monoxide VV Paraquat VV Paraquat (ARDS) VV Zinc Cholride inhalation VV Opiods (ARDS) VV Chlorexidine gluconate Ishigami, 2001 [80] VV (ARDS) *=pediatric case; CA=cardiac arrest; ADS=antidepressants; PVA=peripheral venoarterial; CVA=central venoarterial; VV=venovenous

+ + + + + + + + +

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dant data suggest that early ECMO implanta- the most severe patients. Very early transfer on tion before multiple organ failure is associated ECMO of patients severely intoxicated with with far better outcomes than implantation as a cardiotoxics or membrane stabilizing agents to salvage therapy in dying patients. these referral centers will undoubtedly be asFailure to sustain mean arterial pressure >50 sociated with improved outcomes. We propose mmHg, cardiac index >2 l/min/m² and Doppler an algorithm for the management of patients echocardiography aortic velocity time integra- with cardiotoxic drugs poisoning in Figure 57-1. tion (VTI) ≥7 cm despite high doses catecholamines are parameters of utmost importance Venovenous ECLS for Poisoning-induced to guide ECMO decision. Although the dose Respiratory Failure ingested is usually poorly correlated with the outcome,25 plasma concentrations can be helpful Poisoning is associated with a high risk of to predict the risk of cardiovascular impairment secondary acute respiratory distress syndrome, and sudden cardiac arrest for substances like due to direct toxicity of the poison, aspiration chloroquine26 or verapamil.27 Serum lactate pneumonia following coma, and multiple organ measured in the emergency department has also failure after cardiovascular compromise.31-35 been shown to predict the fatality risk for many However, case reports of refractory ARDS resdrugs,28 but can be falsely reassuring in case of cued with venovenous ECMO are scarce, and beta-blocker overdose because of the inhibition mostly concern irreversible pulmonary lesions of beta-adrenergic receptor stimulation.9 due to paraquat poisoning in which ECMO Another important issue will be to deter- served as a bridge to transplantation (Table 57mine the role of ECLS for poisoning-induced 3). Estimating the reversibility of pulmonary refractory vasoplegia, for which vasopressors lesions is of crucial importance before installing have low efficacy. Venoarterial ECMO might venovenous ECMO.36 Nevertheless, the overall contribute to reverse cardiovascular failure in potential of recovery from ARDS appears to be this setting.29 quite good after poisoning,31-35 as it was reported ECLS could also interfere with specific for aspiration pneumonia refractory to convenantidotes, mainly due to adsorption on the mem- tional treatment supported by VV-ECMO.36 brane, and doses of antidotes under ECMO have to be better defined. For example, combined use Conclusion of intravenous lipid emulsion and extracorpoMortality remains very high in patients real membrane oxygenation may be associated with fat deposition in the ECMO circuits and intoxicated with cardiotoxic and membrane staincreased blood clot formation, although the bilizing agents. In the last decade, case reports clinical implications of this observation remains and small cohort studies reported very promising results with early initiation of VA-ECMO in controversial.30 Lastly, since ECMO is a complex, high this setting, even for patients who had refractory risk, and costly modality, at present it should be cardiac arrest before ECMO. Better definition conducted in centers with sufficient experience, of the indications and the optimal timing for volume, and expertise to ensure it is used safely. ECMO will be the challenge of future trials. Additionally, since the successful delivery Networks of hospitals at the local, regional, or interregional level should be created around of ECMO requires highly experienced staff each ECMO center located in tertiary refer- and a minimum number of cases per year, orral hospitals and each ECMO network should ganization of ECMO programs on a regional ideally create mobile ECMO teams to retrieve or national level is needed to provide the best, 632

Extracorporeal Life Support for Severe Cardiotoxic Drug Poisoningt

safest, and most efficient care possible to this specific group of patients. A mobile ECMO rescue team should also be available to retrieve the most severely intoxicated patients.

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74. Lannemyr L, Knudsen K (2012) Severe overdose of quetiapine treated successfully with extracorporeal life support. Clin Toxicol (Phila) 50: 258-261. 75. Tecklenburg FW, Thomas NJ, Webb SA, Case C, Habib DM (1997) Pediatric ECMO for severe quinidine cardiotoxicity. Pediatr Emerg Care 13: 111-113. 76. Rygnestad T, Moen S, Wahba A, Lien S, Ingul CB, et al. (2005) Severe poisoning with sotalol and verapamil. Recovery after 4 h of normothermic CPR followed by extra corporeal heart lung assist. Acta Anaesthesiol Scand 49: 1378-1380. 77. Chian CF, Wu CP, Chen CW, Su WL, Yeh CB, et al. (2009) Acute respiratory distress syndrome after zinc chloride inhalation: survival after extracorporeal life support and corticosteroid treatment. Am J Crit Care 19: 86-90. 78. Panzeri C, Bacis G, Ferri F, Rinaldi G, Persico A, et al. (2010) Extracorporeal life support in a severe Taxus baccata poisoning. Clin Toxicol (Phila) 48: 463-465. 79. Pizon AF, Brooks DE (2004) Fentanyl patch abuse: naloxone complications and extracorporeal membrane oxygenation rescue. Vet Hum Toxicol 46: 256-257. 80. Ishigami S, Hase S, Nakashima H, Yamada H, Dohgomori H, et al. (2001) Intravenous chlorhexidine gluconate causing acute respiratory distress syndrome. J Toxicol Clin Toxicol 39: 77-80. 81. Pasic M, Potapov E, Kuppe H, Hetzer R (2000) Prolonged cardiopulmonary bypass for severe drug intoxication. J Thorac Cardiovasc Surg 119: 379-380. 82. Behringer W, Sterz F, Domanovits H, Schoerkhuber W, Holzer M, et al. (1998) Percutaneous cardiopulmonary bypass for therapy resistant cardiac arrest from digoxin overdose. Resuscitation 37: 47-50. 83. Hassanian-Moghaddam H, Zamani N, Rahimi M, Hajesmaeili M, Taherkhani M, et al. (2015) Successful Treatment of Aluminium 638

Phosphide Poisoning by Extracorporeal Membrane Oxygenation. Basic Clin Pharmacol Toxicol. 84. Reynolds JC, Judge BS (2015) Successful treatment of flecainide-induced cardiac arrest with extracorporeal membrane oxygenation in the ED. Am J Emerg Med 33: 1542 e1541-1542. 85. Escajeda JT, Katz KD, Rittenberger JC (2015) Successful treatment of metoprololinduced cardiac arrest with high-dose insulin, lipid emulsion, and ECMO. Am J Emerg Med 33: 1111 e1111-1114. 86. Boisrame-Helms J, Rahmani H, Stiel L, Tournoud C, Sauder P (2015) Extracorporeal life support in the treatment of colchicine poisoning. Clin Toxicol (Phila) 53: 827-829. 87. Thooft A, Goubella A, Fagnoul D, Taccone FS, Brimioulle S, et al. (2014) Combination of veno-arterial extracorporeal membrane oxygenation and hypothermia for out-ofhospital cardiac arrest due to Taxus intoxication. CJEM 16: 504-507. 88. Koschny R, Lutz M, Seckinger J, Schwenger V, Stremmel W, et al. (2014) Extracorporeal life support and plasmapheresis in a case of severe polyintoxication. J Emerg Med 47: 527-531. 89. Bertram A, Haenel SS, Hadem J, Hoeper MM, Gottlieb J, et al. (2013) Tissue concentration of paraquat on day 32 after intoxication and failed bridge to transplantation by extracorporeal membrane oxygenation therapy. BMC Pharmacol Toxicol 14: 45. 90. Jouffroy R, Lamhaut L, Petre Soldan M, Vivien B, Philippe P, et al. (2013) A new approach for early onset cardiogenic shock in acute colchicine overdose: place of early extracorporeal life support (ECLS)? Intensive Care Med 39: 1163.

58 ECMO as Bridge to Lung Transplantation Darryl Abrams, MD, Daniel Brodie, MD, Matthew Bacchetta, MD, Shaf Keshavjee, MD

Introduction

Cannula Configurations

Invasive mechanical ventilation (IMV) may be necessary to support patients with endstage, irreversible respiratory failure who are awaiting lung transplantation. However, the use of IMV has traditionally been associated with poor posttransplant outcomes, which may be attributable to, among other factors, higher pretransplant severity of illness, deconditioning from immobility, and ventilator-associated complications.1,2 Extracorporeal membrane oxygenation (ECMO) can support patients in whom IMV is insufficient to maintain adequate gas exchange, although ECMO has also traditionally been associated with poor posttransplant survival, likely owing to similar issues of illness severity and immobility, suboptimal timing of ECMO initiation and patient selection, and circuitassociated complications (eg, bleeding, thrombosis), especially when older generation circuit components were used.1,2 However, temporal trends suggest that posttransplant outcomes are improving for patients supported with ECMO as a bridge to transplantation (BTT)2-5 in the context of improved risk-benefit profiles for extracorporeal technology,6,7 advances in cannulation design and technique,8,9 and changes in both the timing of initiation of ECMO and the management strategies once patients are supported with ECMO.2,3,10-16

Venovenous ECMO is the preferred cannulation strategy for patients with respiratory failure in the absence of concomitant cardiac failure or clinically significant pulmonary arterial hypertension (Table 58-1). Traditional venovenous cannulation involves insertion of a drainage cannula into the inferior vena cava (IVC) via the femoral vein and placement of a reinfusion cannula into the superior vena cava Table 58-1. ECMO configuration considerations for patients awaiting lung transplantation. Physiologic Abnormalities Hypercapnia without hypoxemia Hypoxemia with no pulmonary hypertension Hypoxemia with mild pulmonary hypertension Hypoxemia with moderate to severe pulmonary hypertension

ECMO Configuration Venovenous Arteriovenous Femoral artery to femoral vein Venovenous Venovenous, consider venoarterial Venoarterial Internal jugular vein to subclavian artery Femoral vein to femoral artery (+/- internal jugular venous return, i.e. venoarterial venous) Venovenous via dual-lumen cannula with atrial septal defect or atrial septostomy Arteriovenous Pulmonary artery to left atrium

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(SVC) via the internal jugular vein.17 Although this approach can be performed expediently at the bedside without the need for fluoroscopic guidance, such a configuration limits the patient’s ability to perform active physical therapy, particularly ambulation, although early mobilization has been reported with such an approach.12 It may also lend itself to excess recirculation of reinfused oxygenated blood, thereby compromising its effectiveness.18 There are multiple alternative cannulation strategies based on physiologic and pragmatic considerations in caring for the patient (Figure 58-1). An alternative strategy that both limits recirculation and maximizes the potential for early mobilization is upper-body venovenous cannulation. With the advent of bicaval, dual-lumen cannulae that achieve both drainage

and reinfusion via a single internal jugular venous insertion site, femoral cannulation can be avoided altogether.8,9 When properly positioned, drainage ports are located in the IVC and SVC and reinfusion flow is directed toward the tricuspid valve, minimizing recirculation. To ensure proper cannula placement, imaging guidance, including fluoroscopy and transesophageal echocardiography, is recommended during cannulation.19 For patients awaiting lung transplantation who have concomitant compromise of cardiac function, a venoarterial configuration may be necessary.20 This scenario is most commonly encountered in patients with pulmonary arterial hypertension with associated right ventricular dysfunction.21-23 Traditional venoarterial ECMO involves cannulation of both the femoral vein

Figure 58-1. Algorithm of cannulation strategies for ECMO as bridge to transplant. BTT bridge to transplant, MOF multiorgan failure, MDR multidrug resistant, PH pulmonary hypertension, ECLS extracorporeal life support, VV venovenous, VA venoarterial, VVA venovenous arterial, A arterial, ASD atrial septal defect, PA-LA pulmonary artery to left atrium, SCA subclavian artery, RIJ right internal jugular vein, DLC dual lumen cannula. Adapted from Biscotti M, Sonett J, Bacchetta M. ECMO as bridge to lung transplant. Thoracic surgery clinics 2015; 25:17-25, Figure 7.

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and femoral artery. This configuration may not achieve adequate upper-body oxygenation in patients with sufficiently preserved native cardiac output and marked impairment in native gas exchange, as would be expected in those awaiting lung transplantation, so that deoxygenated blood is ejected into the ascending aorta and aortic arch.20,24 When patients on femoral venoarterial ECMO have inadequate oxygenation of the coronary and cerebral vasculature, then conversion to a hybrid configuration that returns oxygenated blood to both the femoral artery and internal jugular vein may be necessary.24 However, this configuration, known as venoarterial venous ECMO, adds greater complexity to management and further limits rehabilitation. Alternatively, an exclusively upper-body venoarterial cannulation strategy may be considered.25,26 Venous blood can be drained from the right atrium via the internal jugular vein and reinfused into the subclavian artery via an end-to-side graft.21,25 Direct cannulation of the subclavian artery is avoided to prevent compromise of blood flow to the upper extremity. This approach minimizes the amount of retrograde flow needed to reach the aortic arch, thereby maximizing upper-body oxygenation

while avoiding femoral cannulation. However, because this strategy requires an open surgical approach to the subclavian artery, it cannot be performed emergently at the bedside for a patient needing venoarterial support and may necessitate a two-stage procedure. An alternative upper-body approach that may be considered in patients with pulmonary arterial hypertension and atrial septal defects is the use of a bicaval, dual-lumen cannula in the internal jugular vein with orientation of the reinfusion jet toward the defect instead of the tricuspid valve, thereby creating an oxygenated right-to-left shunt while offloading the right ventricle.21,22,27 Patients with an atrial septostomy, either created for management of their pulmonary hypertension or for the purpose of attempting this strategy, may likewise be appropriate for this configuration.28,29 A pumpless strategy, most suitable in cases of severe pulmonary hypertension and for which a sternotomy is required, involves insertion of a low resistance oxygenator between the main pulmonary artery and the left atrium.23,30 This approach has the added benefit of truly unloading the right ventricle and allowing right ventricular failure and hepatic congestion to recover. Table 58-2 characterizes the relative ef-

Table 58-2. Relative effect of different ECMO configurations on physiology and management. 2-site VV

VV VV via via DLC DLC with ASD +++ +++

Femoral VA

Upperbody VA

Hybrid PAconfigurations LA (VVA or VAV) ++ +++

Upper-body +++ -/+ +++ oxygen delivery RV ++/+++ +++ +++ ++ +++ unloading* Effect on +++ ++ ++/+++ LV afterload Mobilization + +++ +++ -/+ +++ -/+ +++ potential Cannulation + ++ ++ + +++ ++ +++ difficulty DLC=dual-lumen cannula; ASD=atrial septal defect; mPAP=mean pulmonary arterial pressure; PA-LA=pulmonary artery to left atrium; RV=right ventricle; LV=left ventricle; VV=venovenous; VA=venoarterial; VAV=venoarterial venous; VVA=venovenous arterial (-)=negligible; (+)=low; (++)=moderate; (+++)=high *Based on chronic RV loading conditions. The effect of relieving any component of RV loading due to acute hypoxemia or hypercapnia will be variable. Adapted from Biscotti M, Sonett J, Bacchetta M. ECMO as bridge to lung transplant. Thoracic surgery clinics 2015; 25:17-25, Table 1.

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fects of the different cannulation configurations on physiologic parameters and management. Patient Selection and Timing of ECMO Initiation

transfusion that has the potential to limit suitable allograft availability. Optimal timing of ECMO initiation remains uncertain and is subject to individual transplant centers’ practices and experience.35,36 Algorithms for patient selection and configuration approaches have been proposed.37,38 Ultimately, more research is needed to better determine optimal patient selection and timing, including the development of prediction models to identify those patients at greatest risk for death while still being appropriate ECMO candidates.

Appropriate patient selection remains as crucial an aspect of achieving success with ECMO as BTT.31 There are no randomized trials evaluating which patients with endstage respiratory failure are most likely to benefit from ECMO in this setting. Inherently, patients with the highest expected pretransplant mortality are also the most critically ill and Patient Management Strategies would likely benefit the most from ECMO. However, if the patients are too ill at the time Minimization of Sedation and Endotracheal of cannulation, ECMO may be insufficient to Extubation reverse the consequences of severe hypoxemia or hypercapnia, particularly if they require high The association between IMV and poor levels of IMV support and are deconditioned or posttransplant outcomes calls attention to the immobilized because of the need for sedatives need for alternative management strategies to or neuromuscular blocking agents. The effects support patients with severe respiratory failure of severe hypoxemia on end organ function, who would otherwise require IMV support. In such as renal function, may also preclude select patients, ECMO may provide sufficient transplant if not intervened on rapidly enough. gas exchange to allow the removal or avoidBecause physical deconditioning is considered ance of IMV altogether.10,12,21,39,40 Endotracheal by many transplantation centers to be a strong extubation has the potential advantages of rerelative contraindication to lung transplantation, duced dyspnea, minimization or avoidance of initiation of ECMO in order to optimize active dynamic hyperinflation from positive-pressure physical therapy before the development of ventilation, elimination of ventilator-associated significant weakness may improve outcomes.3,32 complications and the systemic inflammatory Likewise, patients with endstage respiratory response syndrome associated with maximal failure, particularly those with severe pulmo- mechanical ventilation that may compromise nary arterial hypertension, are at high risk for transplant candidacy or worsen the posttranssudden cardiac death.33,34 Initiation of ECMO plant prognosis.10,13 In the setting of ECMOprior to the onset of cardiac arrest and irre- supported gas exchange, patients may require versible extrapulmonary end-organ function less sedation to manage respiratory symptoms. maximizes the opportunity for successful lung An approach that combines ECMO with avoidtransplantation. ance of both sedation and IMV is sometimes reAlthough it is important to initiate ECMO ferred to as “awake ECMO,” although the term prior to the development of contraindications is incomplete because this strategy involves to transplantation, ECMO itself may introduce more than simply reducing sedation. This apthe risk for important pretransplant complica- proach has been shown to be well-tolerated in a tions, including hemorrhage necessitating blood subset of pretransplant patients.10,40,41 For those patients who appear to require a secured airway 642

ECMO as Bridge to Lung Transplantation

and IMV, consideration should be made for early tracheostomy to maximize patient comfort and facilitate airway clearance. In patients with septic lung diseases such as cystic fibrosis, tracheostomy, and IMV with frequent bronchial toilet may minimize decruitment of the lungs and development of uncontrollable sepsis that would preclude transplantation. Regardless of the amount of ECMO and IMV support required, maintaining pretransplant patients awake and able to participate in physical therapy should remain a priority.

ECMO Use in the Intraoperative and Posttransplantation Settings Intraoperative ECMO

Proper physical conditioning is of the utmost importance for optimizing patient outcomes posttransplantation. Ambulation in patients receiving IMV has been demonstrated to be both safe and effective at minimizing ICU-associated complication.42,43 ECMO, when combined with a strategy that minimizes sedation and IMV, is also safe and promotes active physical therapy, including ambulation, prelung transplantation.12,44-46 An interdisciplinary approach, along with carefully planned processes, may help minimize complications and maximize effectiveness of physical therapy.12

ECMO may be employed during lung transplantation as an alternative approach to traditional cardiopulmonary bypass as a means of providing cardiopulmonary support and controlled, low-pressure lung reperfusion. In fact the use of ECMO for intraoperative support in lung transplantation is becoming the preferred method of support in many centers. Its use varies by institutional practice and may be influenced by individual transplant recipient risk factors, such as the presence of pulmonary hypertension.50 In comparison with cardiopulmonary bypass, which has traditionally been associated with a marked systemic inflammatory response, high anticoagulation needs, significant bleeding risk, and increased risk of primary graft dysfunction,51,52 ECMO has been reported to result in lower posttransplant mechanical ventilation requirements, ICU and hospital lengths of stay, rates of hemorrhage, transfusion requirements, and need for reoperation.53,54 However, overall survival did not differ between groups.53-55

Restrictive Transfusion Strategy

ECMO Posttransplantation

ECMO may increase the risk for important pretransplant complications, including hemorrhage, with the need for blood transfusions that may limit the availability of suitable lung allografts. Lower anticoagulation targets and conservative transfusion strategies with lower transfusion threshold can help mitigate these risks.11 An even more restrictive transfusion strategy than is usually applied to critically ill patients,47-49 balanced against the risks of endorgan insufficiency and inability to participate in physical therapy, may be appropriate to further minimize complications of transfusions in the pretransplant population.

Primary graft dysfunction (PGD) is a form of acute lung injury that is the leading cause of early death after lung transplantation.56 ECMO may be used in patients with PGD to support gas exchange and minimize pulmonary airway pressures in order to facilitate allograft recovery.57 One study evaluating outcomes of ECMO-supported severe PGD, compared to non-ECMO-supported transplant recipients, reports reasonable survival rates (82% vs. 97% 30-day survival), particularly when ECMO is instituted early.58 However, long-term allograft function was significantly worse (peak percentpredicted FEV1: 58% vs. 83%, p=0.006).

Early Mobilization

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Outcomes of ECMO as BTT Several retrospective, single-center observational studies have demonstrated posttransplant survival for ECMO-supported transplant candidates comparable to those not receiving ECMO.3,4,41 A systematic review of 441 ECMO-supported patients across 14 studies, all of which were performed retrospectively, reported survival to transplant ranging from 10% to 50% and 1-year posttransplant survival ranging from 50% to 90%.36 The wide survival ranges highlight the need for careful patient selection, and differing organ availability across transplant centers with consequent variability in the length of time required to bridge a patient with ECMO. Higher volume centers may have better ECMO outcomes,59 though this must be balanced against the potential for higher expected pretransplant mortality of these complex patients at these centers. Limitations to Bridge to Transplant ECMO has an emerging role in its ability to support patients with advanced, irreversible respiratory failure who are awaiting lung transplantation. With current technology, pretransplant patients receiving ECMO are committed to an intensive care environment until transplantation. A significant limitation to ECMO is the lack of a destination device with which people can be managed long term, conceptually similar to a ventricular assist device for advanced cardiac failure. Given both the limited availability of donor organs and the potential for complications that compromise a patient’s candidacy while awaiting transplantation, a significant proportion of patients receiving ECMO as BTT will not survive to transplantation.3,36,37 The potential for patients to be awake and no longer a candidate for transplantation, but simultaneously dependent on ECMO for survival, has been called the “bridge to nowhere”, creating ethical dilemmas including whether, when, 644

and how to withdraw life sustaining therapy, and further highlights the importance of patient selection for both ECMO and lung transplantation.60 Whenever possible, recognition of and discussion about this scenario with the patient and surrogates prior to initiation of ECMO may facilitate decisionmaking if this situation were to occur. Palliative care consultation may also be appropriate to help with both decisionmaking and minimization of suffering. Conclusions In the context of advances in extracorporeal technology, combined with evolving approaches to both timing of ECMO initiation and management of patients receiving ECMO, there is an increasing body of evidence to suggest that ECMO has an important role in bridging carefully selected patients to lung transplantation at centers with expertise in both. Cannulation and management strategies that facilitate an awake, extubated approach to maximize physical therapy are recommended when appropriate in order to optimize posttransplant outcomes.

ECMO as Bridge to Lung Transplantation

References 1. Mason DP, Thuita L, Nowicki ER, Murthy SC, Pettersson GB, Blackstone EH. Should lung transplantation be performed for patients on mechanical respiratory support? The US experience. J Thorac Cardiovasc Surg 2010;139(3):765-773 e761. 2. George TJ, Beaty CA, Kilic A, Shah PD, Merlo CA, Shah AS. Outcomes and temporal trends among high-risk patients after lung transplantation in the United States. J Heart Lung Transplant 2012;31(11):11821191. 3. Javidfar J, Brodie D, Iribarne A, et al. Extracorporeal membrane oxygenation as a bridge to lung transplantation and recovery. J Thorac Cardiovasc Surg 2012;144(3):716721. 4. Dellgren G, Riise GC, Sward K, et al. Extracorporeal membrane oxygenation as a bridge to lung transplantation: a long-term study. Eur J Cardiothorac Surg 2015;47(1):95-100; discussion 100. 5. Hoopes CW, Kukreja J, Golden J, Davenport DL, Diaz-Guzman E, Zwischenberger JB. Extracorporeal membrane oxygenation as a bridge to pulmonary transplantation. J Thorac Cardiovasc Surg 2013;145(3):862867; discussion 867-868. 6. Klein M, Dauben HP, Schulte HD, Gams E. Centrifugal pumping during routine open heart surgery improves clinical outcome. Artif Organs 1998;22(4):326-336. 7. Morgan IS, Codispoti M, Sanger K, Mankad PS. Superiority of centrifugal pump over roller pump in paediatric cardiac surgery: prospective randomised trial. Eur J Cardiothorac Surg 1998;13(5):526-532. 8. Wang D, Zhou X, Liu X, Sidor B, Lynch J, Zwischenberger JB. Wang-Zwische double lumen cannula-toward a percutaneous and ambulatory paracorporeal artificial lung. ASAIO J 2008;54(6):606-611.

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patients with pulmonary hypertension and atrial septal defects. J Thorac Cardiovasc Surg 2012;143(4):982-984. 28. Hoopes CW, Gurley JC, Zwischenberger JB, Diaz-Guzman E. Mechanical support for pulmonary veno-occlusive disease: combined atrial septostomy and venovenous extracorporeal membrane oxygenation. Semin Thorac Cardiovasc Surg 2012;24(3):232234. 29. Camboni D, Akay B, Sassalos P, et al. Use of venovenous extracorporeal membrane oxygenation and an atrial septostomy for pulmonary and right ventricular failure. Ann Thorac Surg 2011;91(1):144-149. 30. Strueber M, Hoeper MM, Fischer S, et al. Bridge to thoracic organ transplantation in patients with pulmonary arterial hypertension using a pumpless lung assist device. Am J Transplant 2009;9(4):853-857. 31. Pierre AF, Keshavjee S. Lung transplantation: donor and recipient critical care aspects. Curr Opin Crit Care 2005;11(4):339344. 32. Hoopes CW, Kukreja J, Golden J, Davenport DL, Diaz-Guzman E, Zwischenberger JB. Extracorporeal membrane oxygenation as a bridge to pulmonary transplantation. J Thorac Cardiovasc Surg 2013. 33. Benza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest 2012;141(2):354-362. 34. Delcroix M, Naeije R. Optimising the management of pulmonary arterial hypertension patients: emergency treatments. European respiratory review : an official journal of the European Respiratory Society 2010;19(117):204-211. 35. Biscotti M, Sonett J, Bacchetta M. ECMO as bridge to lung transplant. Thoracic surgery clinics 2015;25(1):17-25. 36. Chiumello D, Coppola S, Froio S, Colombo A, Del Sorbo L. Extracorporeal life support

ECMO as Bridge to Lung Transplantation

as bridge to lung transplantation: a systematic review. Crit Care 2015;19:19. 37. Strueber M. Extracorporeal support as a bridge to lung transplantation. Curr Opin Crit Care 2010;16(1):69-73. 38. Javidfar J, Bacchetta M. Bridge to lung transplantation with extracorporeal membrane oxygenation support. Curr Opin Organ Transplant 2012;17(5):496-502. 39. Abrams D, Brodie D. Emerging indications for extracorporeal membrane oxygenation in adults with respiratory failure. Annals of the American Thoracic Society 2013;10(4):371-377. 40. Olsson KM, Simon A, Strueber M, et al. Extracorporeal membrane oxygenation in nonintubated patients as bridge to lung transplantation. Am J Transplant 2010;10(9):2173-2178. 41. Mohite PN, Sabashnikov A, Reed A, et al. Extracorporeal Life Support in “Awake” Patients as a Bridge to Lung Transplant. Thorac Cardiovasc Surg 2015. 42. Bailey P, Thomsen GE, Spuhler VJ, et al. Early activity is feasible and safe in respiratory failure patients. Crit Care Med 2007;35(1):139-145. 43. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 2009;373(9678):1874-1882. 44. Turner DA, Cheifetz IM, Rehder KJ, et al. Active rehabilitation and physical therapy during extracorporeal membrane oxygenation while awaiting lung transplantation: a practical approach. Crit Care Med 2011;39(12):2593-2598. 45. Ko Y, Cho YH, Park YH, et al. Feasibility and Safety of Early Physical Therapy and Active Mobilization for Patients on Extracorporeal Membrane Oxygenation. ASAIO J 2015. 46. Pruijsten R, van Thiel R, Hool S, Saeijs M, Verbiest M, Reis Miranda D. Mobilization

of patients on venovenous extracorporeal membrane oxygenation support using an ECMO helmet. Intensive Care Med 2014;40(10):1595-1597. 47. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: Anemia and blood transfusion in the critically ill--current clinical practice in the United States. Crit Care Med 2004;32(1):39-52. 48. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999;340(6):409-417. 49. Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients. JAMA 2002;288(12):1499-1507. 50. Marczin N, Royston D, Yacoub M. Pro: lung transplantation should be routinely performed with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2000;14(6):739745. 51. McRae K. Con: lung transplantation should not be routinely performed with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2000;14(6):746-750. 52. Diamond JM, Lee JC, Kawut SM, et al. Clinical risk factors for primary graft dysfunction after lung transplantation. Am J Respir Crit Care Med 2013;187(5):527-534. 53. Machuca TN, Collaud S, Mercier O, et al. Outcomes of intraoperative extracorporeal membrane oxygenation versus cardiopulmonary bypass for lung transplantation. J Thorac Cardiovasc Surg 2015;149(4):11521157. 54. Biscotti M, Yang J, Sonett J, Bacchetta M. Comparison of extracorporeal membrane oxygenation versus cardiopulmonary bypass for lung transplantation. J Thorac Cardiovasc Surg 2014;148(5):2410-2415. 55. Bermudez CA, Shiose A, Esper SA, et al. Outcomes of intraoperative venoarte647

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rial extracorporeal membrane oxygenation versus cardiopulmonary bypass during lung transplantation. Ann Thorac Surg 2014;98(6):1936-1942; discussion 19421933. 56. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report-2012. J Heart Lung Transplant 2012;31(10):1073-1086. 57. Gulack BC, Hirji SA, Hartwig MG. Bridge to lung transplantation and rescue posttransplant: the expanding role of extracorporeal membrane oxygenation. Journal of thoracic disease 2014;6(8):1070-1079. 58. Hartwig MG, Walczak R, Lin SS, Davis RD. Improved survival but marginal allograft function in patients treated with extracorporeal membrane oxygenation after lung transplantation. Ann Thorac Surg 2012;93(2):366-371. 59. Barbaro RP, Odetola FO, Kidwell KM, et al. Association of hospital-level volume of extracorporeal membrane oxygenation cases and mortality. Analysis of the extracorporeal life support organization registry. Am J Respir Crit Care Med 2015;191(8):894-901. 60. Abrams DC, Prager K, Blinderman CD, Burkart KM, Brodie D. Ethical dilemmas encountered with the use of extracorporeal membrane oxygenation in adults. Chest 2014;145(4):876-882.

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59 ECLS in Heart Transplantation John H. Smith, MD, Sebastian C. Tume, MD, Bill Jakobleff, MD, Yu Xia, MD

Introduction Heart transplantation is considered for heart failure when the expected result will be a meaningful survival advantage compared with conventional medical or surgical therapy. In the last 50 years of cardiac transplantation there have been developments in surgical technique, technology, immunology, and logistics, which have contributed to improved recipient survival. The number of patients listed for heart transplantation outstrips the organ supply and each year more potential recipients are added to the list than hearts that become available.1 This dearth of organs has forced innovations:

Twenty-five years ago ECMO was the only widely available and reliable means of supporting the circulation for 24 hours to several weeks. Other medium and long-term support devices have surpassed it. Although infants awaiting transplantation still usually receive support with ECMO, only 12% of adolescents receive ECMO. The ISHLT registry reported that 29% of children were bridged to heart transplantation with some form of mechanical circulatory support (MCS) in 2012, but only 4% received ECMO alone.5 For short-term support in children, ECMO has the clear advantages of its nearly ubiquitous availability and easy deployability and as such provides a ‘bridge to decision’ or a ‘bridge to a bridge’.

• Transplanting across blood groups in children2 Pretransplant ECMO • Greater willingness to consider marginal donors Adults • Investigating the possibility of using hearts from deceased cardiac donors (DCD).3 Because of the scarcity of organs and • Development of implantable mechanical lengthy waiting lists, half of all heart transplant hearts / assist devices4 recipients are bridged to transplant with MCS, Currently the most influential development almost all of whom receive durable LVADs. is that of implantable ventricular assist devices Less than 1% of all patients are bridged directly has in(VAD) in the treatment of heart failure in adults. with ECMO, although this proportion 6 With alterations in the cost profile and technical creased slightly in recent years. In patients with acute cardiopulmonary developments of the devices; combined with failure, ECMO is easier to implement and less better patient selection and followup, these are costly than durable MCS. However, long-term transforming the treatment of heart failure. 649

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use is associated with an increased risk of thy in the pediatric heart failure study showed thromboembolic events, infection, and multior- that children could be transplanted successfully gan dysfunction. Should a patient not qualify for but that ECMO use pretransplant was associated VAD implantation due to severe hemodynamic with death. Brown showed that although costly, instability or organ dysfunction, ECMO can sta- ECMO proved a cost effective method of bridgbilize the patient, improve end-organ function, ing to transplant in cardiac failure; however, the and allow evaluation for VAD and transplant. comparison group in this study was derived The use of ECMO in this “bridge-to-bridge” from the era before durable mechanical support strategy was initially avoided by some centers was available.16 Paracorporeal pumps were used in some as it was associated with a decrease in survival following VAD implantation.7 These poor out- centers in the 1990s,18 especially in adolescomes may be due to the inability to unload the cents.19 The paracorporeal devices provided left ventricle resulting in pulmonary edema and a longer duration of support than ECMO.21,22 the resultant increased necessity for right-sided A trial of the Berlin Heart was designed23 ussupport following LVAD in patients initially ing ECMO patients as a comparison group as supported with ECMO. However, Pagani et al. Almond24 showed in a retrospective study that found that LVAD survival after ECMO support fewer than half the children supported with did not differ compared to a group of patients ECMO as a bridge to transplantation survived undergoing initial LVAD support despite higher to hospital discharge. initial acuity in the ECMO group.8,9 Lebreton The EXCOR trial clearly demonstrated the demonstrated that the bridge-to-bridge strategy superiority of the Berlin Heart Excor device was viable, adding that physiologic improve- over the historical ECMO control group for the ments on ECMO support were associated with medium and long-term survival of children with better survival following MCS implantation.10 cardiomyopathy, albeit with a significant risk of both bleeding and stroke in the study group.25 The constraint in the organ supply comOutcome bined with increasing demand for hearts has In summary, while ECMO may not play lengthened waiting times. 26-28 However, no a major role in bridging adults directly to single VAD exists that satisfactorily supports transplantation, it can stabilize a critically ill patients in all age groups. ECMO still has a patient to allow for further MCS and transplant place in the short-term support and stabilization of children with incipient collapse (eCPR) while evaluation. the child’s condition is reviewed and the options assessed. These usually include: Pediatrics Bridging to transplant with ECMO was reported in the 90s.11 Del Nido showed that support could be provided in dilated cardiomyopathy and postoperative heart failure.12 Barziv suggested that support for cardiomyopathy in children achieved acceptable outcomes as the waiting times were shorter.13 In 2009, both Mah14 and Kirk15 reviewing the outcomes respectively in children listed for transplantation in the U.S. and those with dilated cardiomyopa650

• Recovery from a coexistent problem or surgery • Stability with a good neurological outcome and assessment for VAD • Severe brain injury or unstable multiorgan failure that precludes further support and results in a palliative care pathway

ECLS in Heart Transplantation

Outcome

Cannulation for ECMO

Analysis of Pediatric Heart Transplant Study (PHTS) database 1993-2013 revealed that 8% of children listed for transplant received ECMO support. Survival at 12 months after listing and 3 years after transplantation was significantly lower in those on ECMO support compared with those on VAD support (50% vs. 76%, and 64% vs. 84% respectively). Also, patients younger than 1 year old had the worst survival when transplanted from ECMO support. This high risk profile and the poor outcomes associated with ECMO support have led to aggressive investigation of alternative methods of pediatric MCS.28

Patient and vessel size, clinical context, and unit experience determine cannulation strategy. An open chest cannulation is done using the aorta and the right atrium, usually after cardiac surgery; this option exists for any age, but is made more difficult by prior sternotomies. In children under 15 kg the neck vessels are commonly used to provide ECMO. When the child weighs more than 15 kg we cannulate the femoral vessels. Appropriate cannula sizes are detailed in the chart in Table 59-1. Standard neck cannulation for circulatory assist is the normal practice in infants but is associated with neurological damage compared with direct or femoral cannulation in children.32 This tendency might be lessened by an ‘inkwell’ cannulation into a graft sewn to the carotid which would minimize the chance of carotid occlusion (Figure 59-1). Femoral cannulation is easy to deploy and more straightforward during an arrest situation but has two disadvantages. The cannula can obstruct arterial flow to the leg; this can

The Decision for ECMO vs. VAD in the Child or Adult Pretransplant De novo Heart Failure We now assess and triage to VAD should patients merit medium term support and be eligible for transplant. Myocarditis When a high index of suspicion for this disease exists then ECMO is easy to deploy and has been successful.29-31 ECMO should only be used for a brief interval; after more than 7-10 days we would convert to a VAD although the use of the cheaper centrifugal pumps in a simple LV support configuration may be equally effective, less expensive, and complex. Emergency Situations Emergency situations dictate the use of ECMO because of ease of deployment and ability to stabilize the child/adult, allow assessment, and bridge to decision.

Figure 59-1. Inkwell cannulation of Goretex graft applied end to side of carotid artery, this child had cardiomyopathy. It is also possible to tunnel the Goretex graft to a remote skin incision so that it does not become colonized with bacteria, this makes the cannulation more durable and decannulation easier.

651

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be monitored by clinical examination and oximetry33 and should be quickly addressed by antegrade distal perfusion of the limb should concerns arise.34 (Figures 59-2 and 59-3) The possibility also exists of differential flow of oxygenated blood to different parts of the body due to the inadequate mixing of less well oxygenated blood from the heart flowing principally to the upper part of the body, the so called “Harlequin Syndrome.”35 This can be minimized by draining the SVC with the femoral venous drainage cannula, not something that is routinely attempted.36 Femoral cannulation is not directly associated with cerebral injury.

Left-Sided Decompression after ECMO in the Context of Heart Failure When the heart fails, the systemic ventricle cannot generate sufficient stroke volume which decreases cardiac output (CO) and perfusion pressure of the end organs and coronary arteries. In this setting ECMO enhances CO but the increase in both the diastolic and mean arterial pressures augments afterload on the left ventricle (LV). To eject, the LV must generate a systolic pressure at least equal to aortic diastolic pressure. Despite the increase in arterial pressure and improved CO the LV pressure volume

Table 59-1. Cannula size table taken from Texas Children’s Hospital (Courtesy of S.C. Tume). Patient Weight

< 2kg 2-2.9 kg 3-3.9 kg 4-4.9 kg 5-5.9 kg 6-6.9 kg 7-7.9 kg 8-8.9 kg 9-9.9 kg 10-12 kg 13-14 kg 15-16 kg 17-18 kg 19-20 kg 21-25 kg 26-30 kg 31-35 kg 36-40 kg 41-45 kg 46-50 kg 51-60 kg 61-65 kg 66-70 kg >70 kg

652

Neck (Medtronic Biomedicus)

Groin (Maquet HLS)

Venous

Arterial

8/10 10 12 12 12 14 14 14 14 14 14 14 May need neck cannula due to size

8 8 10 10 10 10 10 12 12 12 14 14

Venous

Central (Medtronic DLP) Arterial

Rt Atrial 14 16 16 18 20 20 20 20 20 20 22 22

Tubing Lt Atrial

Arterial

12 12 12 14 14 14 16 16 16 16 18 18

8 8 10 10 12 12 12 12 12 14 14 14

1/4 1/4 1/4 1/4 1/4 ¼ ¼ ¼ ¼ 3/8 3/8 3/8

19

15

22

18

14

3/8

19 19 21 21 23 25 25 29 29 29 29

15 15 15 15 17 17 17 19 21 21 21

24 24 24 24 26 26 26 28 28 28 30

18 18 18 18 18 20 20 20 20 20 20

14 16 16 16 16 16 16 18 20 20 22

3/8 3/8 3/8 3/8 3/8 3/8 3/8 3/8 3/8 3/8 3/8

ECLS in Heart Transplantation

relationship shows a significantly larger pressure volume area (PVA) and MVO2 due to an increase in LV preload and afterload. In heart failure the systemic ventricle cannot generate enough pressure to eject and stoke volume is further compromised. The arterial waveform pulsatility becomes diminished. Blood returning from the bronchial and Thebesian veins along with the decrease in LV emptying result in a gradual (usually) filling and then distension of the left heart (seen best on cardiac ultrasound) with a consequent rise in left atrial and pulmonary venous pressure that can result in frank pulmonary edema.37 The case for action is clear when frank pulmonary edema occurs. Decisionmaking is less easy when the child does not experience pulmonary edema and the ECMO works well. Assessment should include:

ited in children because of patient size and poor synchrony with higher heart rates.39 • Atrial septostomy or placement of the left atrium or left ventricle drain Atrial septostomy can be performed using a balloon or blade to dilate or perforate the atrial septum. This is commonly accomplished in the catheterization laboratory under TEE and fluoroscopy. Left atrial drain can be placed by the interventional cardiologist percutaneously in the catheterization laboratory with the use of TEE. This allows for direct drainage of blood from (Figure 59-4) the left atrium and can be incorporated into the ECMO circuit.40,41

• Clinical examination • Regular cardiac ultrasounds • Chest radiographs Should the left side be distended the options include: • Inotropes and vasodilators to enhance LV emptying and reduce afterload promoting aortic valve opening38 • An intraaortic balloon pump (IABP) may be used as detailed in the experience of the Paris group. Use of this mode remains lim-

Figure 59-2. Lower limb perfusion in femoral VA ECMO for cardiac support. The arrow indicates the perfusion cannula for the leg.

Figure 59-3. Calf oximetry: a near infrared spectroscopy transducer applied to the calf of a child on VA-ECMO to check for evidence of limb ischemia.

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Central cannulation and LA drain placement. Performed by a surgeon as open operation (sternotomy) or via an intercostal incision. (Figure 59-5) In complex (redo, etc.) cases a left ventricular apical drain can be placed (Figure 59-6)

compliance with treatment of pediatric patients and our inability to fully rehabilitate on ECMO, most centers elect not to extubate children on VA ECMO support although the practice appears to be evolving.

Our cardiologists usually decompress the left atrium in the catheterization laboratory. Cannulae used are between 8-15 Fr. Decision to Wean or Transfer to VAD from ECMO In the field of cardiac support, ECMO has become a short-term treatment. If there is no indication of myocardial recovery within one week, we would change to VAD support, given hemodynamic stability, resolving multiorgan failure, controlled hemostasis, good fluid balance, appropriate assessment, and consent. The data in our center suggests that ECMO before VAD does little harm.42 Ventilator Management Standard lung protective ventilation strategies are used. Due to concerns about poor Figure 59-6. Apical ventricular drain in a redo transplant placed for left-sided decompression.

Figure 59-4. Percutaneous left atrial decompression in a patient on VA-ECMO for congestive heart failure.

654

Figure 59-5. Intercostal placement of venous cannula and left atrial drain in a redo ECMO support.

ECLS in Heart Transplantation

Transfusion We apply normal blood product protocols to maintain oxygen carrying capacity and the coagulation profile (see Chapter 8). Given the sensitivity of the ‘new’ PRA assay it is hard to know how much, if any, harm we are doing by further transfusions. As has been frequently noted, patients on VAD appear to produce many antibodies. ECLS after Heart Transplantation Primary Graft Dysfunction A feared complication of heart transplantation is primary graft dysfunction (PGD), which occurs in 2-26% of adult heart transplant recipients and in up to a third of pediatric transplants and is associated with increased morbidity and mortality.6,43-51 Pathogenesis is complex and the causes numerous, including donor brain death and associated hemodynamic instability due

to sympathetic volatility and cytokine release, cold followed by warm ischemic injury, and reperfusion injury. Numerous risk factors have been identified (see Table 59-2, after Kobashigawa47), but only one validated risk score has been reported (RADIAL).52 Most studies of PGD were limited by variable definitions used by different centers. As a result, ISHLT consensus guidelines were established in 2014 to standardize diagnosis and more consistent reporting (Table 59-3, after Kobashigawa47). Diagnosis of PGD must be made within 24 hours of transplant and exclude secondary causes such as bleeding, technical issues, and hyperacute rejection. In pediatric practice, there are more marked size discrepancies between donor and recipient hearts.53 There is a similar relationship between ischemic time and hypotension after transplantation but a higher chance of pulmonary hypertension complicating the procedure.54,55

Table 59-2. Risk factors for primary graft dysfunction, after Kobashigawa.47 Donor Risk Factors Age Cause of death

Recipient Risk Factors Age Weight

Trauma Cardiac dysfunction

Mechanical support Congenital heart disease

Inotropic support

Re-operations

Comorbidities

Comorbidities, renal or liver dysfunction LVAD explant Ventilator dependent

Cardiac arrest downtime Drug abuse Left ventricular hypertrophy Valvular disease Hormone treatment Wall motion abnormalities Sepsis Marginal donor allocation Troponin trend Hypernatremia

Multiorgan transplant Allosensitization High PVR Infection

Procedural Factors Ischemic time Donor recipient sex mismatch Weight mismatch None cardiac organ donation Procurement team experience Center volume Cardioplegic solution Increased blood transfusion Emergency or elective transplant

Retransplant

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Intraoperative Assessment for ECMO Requirement After a period of reperfusion, the assessment of donor cardiac function is done by visual inspection, TEE or epicardial echo in smaller patients, near infrared spectroscopy (NIRS), and hemodynamic measurement. Laboratory adjuncts include arterial blood lactate, base deficit, and mixed venous saturation. Patients commonly require low dose inotrope and vasodilator requirements but those who remain hemodynamically unstable (CVP >15, SBP 20 and CI < 2 L/ min /m2 with hypotension < 70 mm HG for more than one hour

i.

on high dose inotropes, score > 10 newly placed IABP independent of inotropes

ii. Severe PGD LV PGD right ventricle: PGD-RV

656

Diagnosis requires both i and ii, or iii alone

Dependence on single or biventricular support more than an IABP including ECMO i. RAP > 15 mm Hg, PCWP < 15 and CI < 2 L/ min /m2 ii. TPG < 15 mmHg and PA systolic pressure < 50 mm Hg iii. Need for RVAD

ECLS in Heart Transplantation

of a strategy to deal with the waiting list, the use of ECMO may be routine.63 Cannulation Strategies

with mixture of deoxygenated blood, and potential for distal limb ischemia and other vascular complications. Insertion of a distal perfusion catheter is highly recommended in this setting. If this is not done, then careful observation of the limb for compartment syndrome is mandatory; calf oximetry may be helpful.64

Cannulation varies by center and may depend on surgeon preference and anticipated support requirements.47,50 The bypass circuit can be converted to ECMO by using the atrial Aims of Support and aortic cannulae, which allow higher flows, The goal of ECMO after heart transplanantegrade flow through the aortic arch, and decreased peripheral vascular complications. tation is to allow for the allograft to rest and There will be an aortic cannula, an atrial cannula, recover while maintaining adequate organ and a vent to drain the left side. When antici- perfusion. Hemodynamics should be closely pating poor function, the surgeon may create monitored and cardiac recovery frequently an ASD prior to implantation (the adequacy of assessed with echocardiography. Neurologic, this shunt needs to be assessed on ultrasound renal, hepatic, pulmonary, and other end-organ perfusion should be maintained, and appropripostoperatively). Tunnelling the cannula and closing the ster- ate replacement therapy used when indicated. num reduce the chance of infection (Figure 59-7). In the immediate postoperative period one Upon graft recovery, however, decannulation can run without heparin until hemostasis is asrequires reopening the sternum which allows sured; this strategy requires ready availability for visual inspection of cardiac function, the of another circuit in case of circuit thrombodrainage of pericardial fluid collections, and sis. After restarting anticoagulation, the team should monitor for cerebrovascular events and biopsy if acute rejection is suspected.50 Femoral cannulation obviates the need to re- gastrointestinal hemorrhage. If acute rejection open the sternum, but drawbacks include lower is suspected, endomyocardial biopsies should achievable flow, retrograde flow down the arch be obtained via right heart catheterization and immunosuppression augmented as indicated. Assessing Recovery

Figure 59-7. Posttransplantation. Tunnelled cannulae; venous and left atrial drain on the left hand margin, tunnelled aortic cannula on the right hand margin.

Recovery usually occurs between 2-5 days after implantation.65 Evidence of recovery includes return of pulsatility in the presence of adequate but not excessive inotrope use. If the overall condition of the patient allows, elective reduction in flow and echo assessment with RV filling should follow.66 If propitious, weaning continues to idling and the patient can then be ‘clamped off’ ECMO prior to decannulation. Decannulation takes place in the operating theatre. The chest is left open for 24 hours or more and closed later.67

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Outcomes Prior to the advent of ECMO and other modes of mechanical support, early graft failure invariably led to mortality in the absence of retransplantation. In recent reports, graft recovery allowing for decannulation typically occurred within 2-5 days. Successful weaning of ECMO has been reported in 60-100% of patients and 30-day or survival-to-discharge reported between 46-100%.44,49,50,68 In children who require ECMO after transplantation the survival typically reaches 50-60%.60,62,69 If a patient survives the early period, ECMO-treated PGD is not associated with decreased survival at 1 or 5 years.45,51,52 The choice of mechanical assist device vs. ECMO support for severe PGD remains understudied. Taghavi found similar survival between patients supported with RVAD or ECMO in isolated right-sided dysfunction but overall graft recovery was improved in the ECMO-treated patients.70 PGD has also been successfully managed with the Levitronix Centrimag, although a direct comparison with ECMO was not been made.71 Failure to Recover Donor Heart Should the graft not recover then a critical assessment of the anatomy of the donor heart with ultrasound, CT, and catheter is required. A biopsy to assess degree of rejection is usually easily accomplished on ECMO. If rejection occurs, we augment and review immunosuppression and assess the comorbidities. A discussion on the likelihood and feasibility of successful medium term support to recovery or retransplantation should then take place.72,73 Late Graft Failure Late graft failure can be supported with ECMO. Late graft failure usually occurs due to acute cellular mediated rejection or chronic 658

allograft vasculopathy. When indicated, ECMO should be considered soon after presentation to provide support during periods of augmentation of immunosuppression. Kittleson showed improved outcomes when ECMO is used as preemptive therapy as opposed to an element of cardiopulmonary resuscitation; survival to discharge was 79% in the former group, although only 26% were alive at one year.74,75 ECMO deployed to support augmentation of immunosuppression may be effective and allow assessment of recovery, VAD, or retransplantation. The latter is less likely to be successful within one year of the initial transplant, and is a cofactor for early death in 6-17 year olds.5,74 Conclusion ECMO is still used in the acute care of children with heart failure and will save lives. Newer forms of circulatory support are usually deployed to bridge to transplant because of longer waiting times and have satisfactory outcomes. Whether the relatively poor outcomes of bridge to transplant with ECMO are due to ECMO or variables such as sedatives, dependency, and inability to rehabilitate is unclear. ECMO has a small role in the treatment of adult heart failure, probably restricted to acute resuscitation as a ‘bridge to decision’ or ‘bridge to a bridge’.

ECLS in Heart Transplantation

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Extracorporeal Membrane Oxygenation. Artif Organs. 2012;36(8):659-667. 34. Roussel A, Al-Attar N, Khaliel F, et al. Arterial vascular complications in peripheral extracorporeal membrane oxygenation support: a review of techniques and outcomes. Future Cardiol. 2013;9(4):489-495. 35. Hoeper MM, Tudorache I, Kühn C, et al. Extracorporeal membrane oxygenation watershed. Circulation. 2014;130(10):864-865. 36. Cove ME. Disrupting differential hypoxia in peripheral veno-arterial extracorporeal membrane oxygenation. Crit Care. 2015;19:280. 37. Combes A, Leprince P, Luyt CE, et al. Outcomes and long-term quality-of-life of patients supported by extracorporeal membrane oxygenation for refractory cardiogenic shock. Crit Care Med. 2008;36(5):14041411. 38. Stub D, Bernard S, Pellegrino V, et al. Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial). Resuscitation. 2015;86:88-94. 39. Petroni T, Harrois A, Amour J, et al. Intraaortic balloon pump effects on macrocirculation and microcirculation in cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation. Crit Care Med. 2014;42(9):2075-2082. 40. Cheung MMH, Goldman AP, Shekerdemian LS, Brown KL, Cohen GA, Redington AN. Percutaneous left ventricular “vent” insertion for left heart decompression during extracorporeal membrane oxygenation. Pediatr Critic Care Med. 2003;4(4):447-449. 41. Aiyagari RM, Rocchini AP, Remenapp RT, Graziano JN. Decompression of the left atrium during extracorporeal membrane oxygenation using a transseptal cannula incorporated into the circuit. Crit Care Med. 2006;34(10):2603-2606. 42. De Rita F, Hasan A, Haynes S, et al. Outcome of mechanical cardiac support in

children using more than one modality as a bridge to heart transplantation. Eur J Cardiothorac Surg. 2015;48(6):917-922. 43. Carmena MDGC, Bueno MG, Almenar L, et al. Primary graft failure after heart transplantation: characteristics in a contemporary cohort and performance of the RADIAL risk score. J Heart Lung Transplant. 2013;32(12):1187-1195. 44. D’Alessandro C, Aubert S, Golmard JL, et al. Extra-corporeal membrane oxygenation temporary support for early graft failure after cardiac transplantation. Eur J Cardiothorac Surg. 2010;37(2):343-349. 45. D’Alessandro C, Golmard JL, Barreda E, et al. Predictive risk factors for primary graft failure requiring temporary extracorporeal membrane oxygenation support after cardiac transplantation in adults. Eur J Cardiothorac Surg. 2011;40(4):962-969. 46. Ibrahim M, Hendry P, Masters R, et al. Management of acute severe perioperative failure of cardiac allografts: a single-centre experience with a review of the literature. Can J Cardiol. 2007;23(5):363-367. 47. Kobashigawa J, Zuckermann A, Macdonald P, et al. Report from a consensus conference on primary graft dysfunction after cardiac transplantation. J Heart Lung Transplant. 2014;33(4):327-340. 48. Lim JH, Hwang HY, Yeom SY, Cho HJ, Lee HY, Kim KB. Percutaneous extracorporeal membrane oxygenation for graft dysfunction after heart transplantation. Korean J Thorac Cardiovasc Surg. 2014;47(2):100105. 49. Listijono DR, Watson A, Pye R, et al. Usefulness of extracorporeal membrane oxygenation for early cardiac allograft dysfunction. J Heart Lung Transplant. 2011;30(7):783-789. 50. Marasco SF, Vale M, Pellegrino V, et al. Extracorporeal membrane oxygenation in primary graft failure after heart transplan-

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tation. Ann Thorac Surg. 2010;90(5):15411546. 51. Seguchi O, Fujita T, Murata Y, et al. Incidence, etiology, and outcome of primary graft dysfunction in adult heart transplant recipients: a single-center experience in Japan. Heart Vessels. 2016;31(4):555-562. 52. Segovia J, Cosío MD, Barceló JM, et al. RADIAL: a novel primary graft failure risk score in heart transplantation. J Heart Lung Transplant. 2011;30(6):644-651. 53. Huang J, Trinkaus K, Huddleston CB, Mendeloff EN, Spray TL, Canter CE. Risk factors for primary graft failure after pediatric cardiac transplantation: importance of recipient and donor characteristics. J Heart Lung Transplant. 2004;23(6):716-722. 54. Mitchell MB, Campbell DN, Ivy D, et al. Evidence of pulmonary vascular disease after heart transplantation for Fontan circulation failure. J Thorac Cardiovasc Surg. 2004;128(5):693-702. 55. Hoskote A, Carter C, Rees P, Elliott M, Burch M, Brown K. Acute right ventricular failure after pediatric cardiac transplant: predictors and long-term outcome in current era of transplantation medicine. J Thorac Cardiovasc Surg. 2010;139(1):146-153. 56. Mitchell MB, Campbell DN, Bielefeld MR, Doremus T. Utility of extracorporeal membrane oxygenation for early graft failure following heart transplantation in infancy. J Heart Lung Transplant. 2000;19(9):834839. 57. Kavarana MN, Sinha P, Naka Y, Oz MC, Edwards NM. Mechanical support for the failing cardiac allograft: a singlecenter experience. J Heart Lung Transplant. 2003;22(5):542-547. 58. Marasco SF, Esmore DS, Negri J, et al. Early institution of mechanical support improves outcomes in primary cardiac allograft failure. J Heart Lung Transplant. 2005;24(12):2037-2042.

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59. Rodrigues W, Carr M, Ridout D et al. Total donor ischemic time: Relationship to early hemodynamics and intensive care morbidity in pediatric cardiac transplant recipients. Pediatr Crit Care Med. 2011;12(6):660-666. 60. Kaushal S, Matthews KL, Garcia X, et al. A multicenter study of primary graft failure after infant heart transplantation: Impact of extracorporeal membrane oxygenation on outcomes. Pediatr Transplant. 2014;18(1):72-78. 61. Mettler B. Graft failure after infant heart transplantation: Impact of extracorporeal membrane oxygenation on outcomes. Pediatr Transplant. 2014;18(1): 1-2. 62. Su JA, Kelly RB, Grogan T, Elashoff D, Alejos JC. Extracorporeal membrane oxygenation support after pediatric orthotopic heart transplantation. Pediatr Transplant. 2015;19(1):68-75. 63. Kirk R, Griselli M, Smith J, Crossland D, Hasan A. Elective extracorporeal membrane oxygenation bridge to recovery in otherwise” unusable” donor hearts for children: Preliminary outcomes. J Heart Lung Transplant. 2013;32(8):839-840. 64. Wong JK, Cavarocchi NC. Near-Infrared Spectroscopy in Adult Patients Receiving Extracorporeal Membrane Oxygenation. Ann Thorac Surg. 2015;100(2): 766. 65. Fiser SM, Tribble CG, Kaza AK, et al. When to discontinue extracorporeal membrane oxygenation for postcardiotomy support. Ann Thorac Surg. 2001;71(1):210-214. 66. Aissaoui N, Luyt CE, Leprince P, et al. Predictors of successful extracorporeal membrane oxygenation (ECMO) weaning after assistance for refractory cardiogenic shock. Intensive Care Med. 2011;37(11):17381745. 67. Simmonds J, Dominguez T, Longman J, et al. Predictors and outcome of extracorporeal life support after pediatric heart transplantation. Ann Thorac Surg. 2015;99(6):2166-2172.

ECLS in Heart Transplantation

68. Lima EB, da Cunha CR, Barzilai VS, et al. Experience of ECMO in primary graft dysfunction after orthotopic heart transplantation. Arq Bras Cardiol. 2015;105(3):285291. 69. Tissot C, Buckvold S, Phelps CM, et al. Outcome of extracorporeal membrane oxygenation for early primary graft failure after pediatric heart transplantation. J Am Coll Cardiol. 2009;54(8):730-737. 70. Taghavi S, Zuckermann A, Ankersmit J, et al. Extracorporeal membrane oxygenation is superior to right ventricular assist device for acute right ventricular failure after heart transplantation. Ann Thorac Surg. 2004;78(5):1644-1649. 71. Thomas HL, Dronavalli VB, Parameshwar J, Bonser RS, Banner NR:Steering Group of the UK Cardiothoracic Transplant Audit.. Incidence and outcome of Levitronix CentriMag support as rescue therapy for early cardiac allograft failure: a United Kingdom national study. Eur J Cardiothorac Surg. 2011;40(6):1348-1354. 72. Kanter KR, Vincent RN, Berg AM, Mahle WT, Forbess JM, Kirshbom PM. Cardiac retransplantation in children. Ann Thorac Surg. 2004;78(2):644-649. 73. Mahle WT. Cardiac retransplantation in children. Pediatr Transplant. 2008;12(3):274280. 74. Kittleson MM, Patel JK, Moriguchi JD, et al. Heart transplant recipients supported with extracorporeal membrane oxygenation: outcomes from a single-center experience. J Heart Lung Transplant. 2011;30(11):12501256. 75. Perri G, Hasan A, Cassidy J, et al. Extracorporeal life support after paediatric heart transplantation. Eur J Cardiothorac Surg. 2012;42(4):696-701.

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60 Immunodeficiency and ECLS Matteo Di Nardo, MD, Veronica Armijo-Garcia, MD, Thomas Staudinger, MD, Gerry Capatos, MD, Heidi Dalton, MD

Introduction Traditionally, Extracorporeal Life Support (ECLS) has been reserved for patients suffering acute cardiac or respiratory failure due to reversible diseases expected to have a good quality of life after recovery. Concerns whether ECLS should be offered to immunocompromised patients have led to many thought-provoking discussions in the past. Furthermore, the lack of specific criteria for ECLS use in the immunocompromised renders patient selection more challenging. This chapter provides current insights and, where possible, new selection criteria for ECLS use in patients with solid and blood cell tumors, patients receiving hematopoietic stem cell transplantation (HSCT), and patients with autoimmune diseases or HIV.

disease that may not differ from cancer patients who were never admitted to the ICU.1,2 Thus, a general reluctance to admit critically ill cancer patients to the ICU can no longer be justified.3 ECLS Utilization in Patients with Malignancy

Previously, limited use of ECLS for patients with cancer was most likely influenced by cancer-related mortality as well as the ideology of ECLS being a support modality offered only to acutely ill patients with no underlying chronic illness. Since 2009, reports describing ECLS use for patients (pediatric and adult) with malignancy have been published, implying increased use in this population, most likely due to improved oncologic survival and more widespread ECLS use in complex patient populations.6,7 A 2008-2012 analysis of the ExECLS Support in Pediatric and Adult tracorporeal Life Support Organization (ELSO) Patients with Solid Organ and Blood Cancer Registry documented that 178 pediatric patients with malignancy received ECLS, doubling utiSurvival for adult and pediatric patients lization compared to that reported previously.6 with malignancy over the last 30 years has mark- Furthermore, several pediatric and adult cases edly improved due to advancements in aggres- of successful use of ECLS as a bridge to therasive chemotherapeutic regimens and supportive peutic interventions or chemotherapy have been measures. During the last decade, a large body recently published.8,9 of evidence suggests that adult ICU survivors An analysis by Gow and colleagues of 72 regain favorable quality of life, tolerate the adult cancer patients in the ELSO Registry from continuation of anticancer therapy, and have 1992-2008 reported an overall survival rate of long-term survival defined by their underlying 32%. Most patients had solid tumors and respi665

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ratory failure but ECLS for cardiac indications pre-ECLS arrest compared to 18% in the era surprisingly yielded better outcomes. Compared prior to 2008.6,7 to the general ECLS population, survival was significantly lower. Of note, infections occurred Indications, Contraindications and Specific more commonly in cancer patients, whereas Considerations bleeding events did not.7 In another study of 14 Indications and contraindications for ECLS adult patients with hematological malignancy, VV-ECLS was used for ARDS due to pneu- in patients with malignancy reflect those applied monia in 11 patients. Three patients received to most other patients. However, insights into VA-ECLS due to septic cardiomyopathy, or life the underlying malignancy should be investithreatening circulatory and respiratory failure gated prior to acceptance of candidacy. Such dedue to massive mediastinal bulky disease. Five tails include but are not limited to 5-year disease patients received rescue chemotherapy during survival, secondary organ involvement, degree ECLS. Overall survival reached 50%. All sur- of immune suppression, expected time course vivors had hematological remission and were for return of white blood cells and ongoing infections. An analysis by Green et al. from the alive at followup after 36 months.10 A review of children from the ELSO Reg- 1990s found that patients most likely to benefit istry from 1994-2007 by Gow et al. included from ECLS had a mortality risk of 50-75%.13 107 patients with oncologic disease (HSCT Patients suffering from malignancies with a patients were excluded) with 35% survival 5-year survival of less than 50%, irrespective of to discharge.11 More recently, an abstract by their acute critical illness, should be considered Armijo-Garcia et al. reported 178 ECLS pa- less favorable candidates for meaningful longtients with malignancy (also excluding HSCT term benefit from ECLS but this may vary by patients) from 2008-2012, with 48% survival local practice. Of course, the more severe the to discharge despite similar complication rates acute illness, the worse the prognostic outcome. compared to those documented previously. Type A collaborative effort between the critical care of malignancy (hematologic or solid) did not physician, the oncologist, the ECLS physician, impact survival.6 Compared to ECLS patients and the family is necessary to make the most without malignancy, pediatric ECLS cancer considered but difficult decision. patients from 2008-2012 had increased rates Several other distinct considerations should of gastrointestinal hemorrhage, leukopenia, be taken into account when using ECLS in hyperglycemia, myocardial stun, and receipt patients with malignancy: of inotropes. However, after multivariate re• A clear understanding of goals of support gression analysis, none of these complications as well as criteria for potential withdrawal translated into an increased mortality risk for is critical for both the medical team and the the patients with malignancy.12 family. A clear communication strategy and Over the last two decades, survival durthe skills of the palliative care team may ing acute, severe illness supported by ECLS prove helpful in situations of withdrawal. has paralleled improvement in survival from • Typical complications of cancer patients primary oncologic disease. In the pediatric include infection and bleeding, often due population with malignancy, this improved to leukopenia and thrombocytopenia. Most survival is notable in light of increased severity patients receive broad spectrum antibiotics of illness, as evidenced by the 31% of the pediand are susceptible to opportunistic infecatric patients from 2008-2012 who experienced tions, making extensive diagnostic tests inevitable. Use of heparin coated tubing 666

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in patients with platelet counts lower than 20000 µL may obviate heparin infusions in the first few ECLS days without significant impact to circuit function, as long as adequate flows can be achieved given the circuit configuration, oxygenator, and patient size. Heparin-free ECLS should be undertaken with more caution in children 100 days ).22 No patient was admitted during the peri-transplant period or within 100 days after the engraftment survived, probably because in the first three months after engraftment patients have not completed their immune reconstitution. Therefore, the use of ECLS for severe respiratory failure in this setting is considered a strong contraindication by many. Unfortunately, appropriate selection of the “best” candidate and proper timing for ECLS in HSCT patients remain difficult, given the limited clinical experience and reported outcomes.23-25 Technical Considerations In ECLS candidates with severe respiratory or cardiac failure after HSCT, physicians should evaluate the underlying disease (eg, hematologic disease [benign vs malignant], inborn errors of metabolism, or immune deficiency); the conditioning regimen (myeloablative vs. nonmyeloablative); type of HSCT (autologous vs. allogeneic); graft source and its manipulation as well as the human leukocyte antigen (HLA) matching. Use of ECLS to Manage Respiratory Failure after HSCT Pulmonary infections in HSCT patients (mostly in the early phase after HSCT) are often life threatening and difficult to manage. Therefore, prompt initiation of broad spectrum antimicrobial therapy is warranted. Specific antiviral and antifungal therapy is added after 667

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empirically or confirmation of infection.26 loimmune injury to the lung by transplanted Respiratory failure preceding engraftment is stem cells. ECLS may serve as a bridge to lung an absolute contraindication because of the transplantation in BOOP and other endstage inability of the immune system to clear infec- lung diseases.32,33 Transfusion related acute lung injury tion without the support of the innate and the adaptive immune responses.27,28 ECLS after (TRALI) may occur in HSCT patients after the engraftment remains at least a relative contra- administration of large amounts of blood prodindication and should be used only when the ucts. However, its management rarely requires patient has achieved a good level of immune ECLS. Transplantation associated thrombotic reconstitution and when the chance of lung microangiopathy (TA-TMA) is generally asrecovery appears good within a reasonable sociated with pulmonary hypertension leading timeframe (~4 weeks of ECLS). The advent of to hypoxemic respiratory failure and right heart specific therapeutic strategies such as infusion dysfunction, and has a high mortality rate. The of virus-specific cytotoxic T lymphocytes or exact mechanism remains unknown. No proven donor T-cells after engraftment has improved therapies have been found and ECLS is not the outcome of some HSCT patients, providing recommended. Pulmonary venoocclusive (pVOD) disease them protection against infections and disease 23-25 relapse. These newer therapies may expand is a rare cause of pulmonary hypertension following allogeneic HSCT. The frequency of the range of ECLS use in HSCT patients. Other noninfectious causes of acute lung pVOD is particularly high in recipients who injury after HSCT are related to immune have concurrent interstitial pneumonia and recovery. Early diagnosis and appropriate hepatic veno-occlusive disease. Considering therapy can help sidestep ECLS use. Idiopathic the absence of a proven therapy for this disease, pneumonia syndrome (IPS) includes a group of ECLS is not recommended. 26 diseases characterized by noninfectious lung involvement after HSCT, which may affect the Use of ECLS to Manage Heart Failure after parenchyma, endothelium, or airway epithelium. HSCT By definition, IPS requires no active infections, cardiogenic causes, or renal failure/fluid Congestive heart failure can complicate overload as causes of respiratory compromise. HSCT, especially in patients receiving auThe pathophysiology undergirding IPS remains tologous transplantation. Potentially cardiounclear, but may depend on the transplant pro- toxic exposures in HSCT include myeloablative cedure itself (myeloablative conditioning, use conditioning with high dose chemotherapy of calcineurin inhibitors, GVHD, HLA disparity, (alkylators, anthracyclines, antimetabolites, allogeneic transplantation, etc.).26 IPS29,30 in- antimicrotubules and antibodies), and total cludes the peri-engraftment respiratory distress body irradiation. Cardiovascular followup after syndrome (PERDS), diffuse alveolar hemor- HSCT aids selection of the best candidates for rhage (DAH) and bronchiolitis obliterans with ECLS as a bridge to recovery or as a bridge to organizing pneumonia (BOOP). PERDS and a ventricular assist device system.34,35 less severe DAH can often be adequately managed without ECLS. However, severe forms of Vascular Access DAH31 may require ECLS. BOOP represents a late complication of HSCT and occurs almost Appropriate cannulae to attain adequate exclusively in allogeneic recipients with GVHD, flows to meet metabolic and hemodynamic suggesting that it may represent a form of al- needs may represent a challenge, since these 668

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patients usually have at least one long-term central venous catheter. This kind of catheter, placed in preparation for the transplant, should be promptly removed to allow the insertion of the ECLS cannulae and a short-term central venous catheter should be placed before ECLS. Management of Coagulation after HSCT

Bleeding frequently complicates HSCT since thrombocytopenia occurs during the post engraftment period, especially after haploidentical stem cell transplantation. Therefore, adequate management of coagulation is mandatory. The use of unfractionated heparin should be properly tailored because the risk of thrombosis increases in long ECLS runs, especially when daily platelet transfusions occur. We suggest that platelet counts be maintained over 30,000/ µL with an ACT level at 170-180 sec or an APTT level between 60-70 sec. Fibrinogen levels should be maintained at 200 mg% and antithrombin activity at 100%. Some centers report ECLS runs without anticoagulation using high-flow venovenous circuits. Close observation of bleeding diatheses and clotting events is obligatory in such patients. In cases of refractory bleeding, thrombocytopenia and acquired von Willebrand syndrome should be considered.36

of HAART, bacteria also became important causative agents of ARF. Despite the use of HAART, patients with PJ pneumonia (PJP) requiring ICU admission and specifically those requiring mechanical ventilation for ARF have a high mortality, approaching 85% in high income countries, and 100% in resource poor countries. However, the overall mortality of hospitalized PJP patients has not decreased since the introduction of HAART, irrespective of the country.42 In the past, HIV patients and particularly those with PJP were considered poor candidates for ECLS. However, advances in antiretroviral therapy (ART) increased HIV patient survival, thereby impacting the ECLS candidacy of HIV patients.43-47 Following the advent of HAART, treatment compliant HIV positive patients now attain a nearly normal life expectancy. Therefore HIV has become a chronic illness in which acute exacerbations of a reversible nature should be treated aggressively or when the initial presentation of HIV is due to an opportunistic infection (eg, PJP). Resolution of the acute illness and initiation of HAART appears to restore relatively normal lifespan. ECLS may form part of the treatment in these situations.48-50 ECLS in Patients with PJP: the South Africa Experience

In South Africa, a middle income nation with the highest number of new HIV infections worldwide,51 PJP is the most common opportunistic infection causing ARF. Patients ECLS in Adult Human Immunodeficiency with HIV requiring conventional mechanical Virus (HIV) Patients ventilation (CMV) have high mortality.52 In the experience of the group in Cape Town, South Pulmonary infection and respiratory failure Africa, the use of early ECLS has improved are the most common causes of ICU admis- outcomes. Of 18 patients with PJP (of 25 total sion in Human Immunodeficiency Virus (HIV) HIV positive patients treated with VV-ECLS), positive patients.38-40 Before the Highly Active 11 survived (61%). Although patient numbers Antretroviral Therapy (HAART) era (before the are small, the 61% survival of PJP patients and year 2000), Pneumocystis jiroveci (PJ) was the 68% overall survival suggests that ECLS could primary pathogen responsible for acute respi- be considered as an option in the most severe ratory failure (ARF).41 After the introduction HIV patients presenting with ARF due to PJP. 669

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Additionally, patients who received more than reported 25% mortality for patients receiving 5 days of ventilation without ECLS had a pre- ARVs, compared to 63% mortality for those dicted mortality of 90%, suggesting that early not taking them. Therefore, we recommend initiation of ARVs at admission (for the patient ECLS is key for any possible benefit. not already on ARVs) for patients with ARF.59 The combination of antiretroviral therapy and ECLS Candidate Selection for HIV+/PJP+ steroids to treat PJP and/or IRIS has dramatiMany scoring systems have been used at cally decreased AIDS-associated complications ICU admission to determine best outcomes for and mortality. In conclusion, with the advent of new HIV patients.53 From the South African experience, the most significant predictors of mortality antiretroviral drugs and initiatives to improve in patients with PJP and ARF were identified diagnostic testing and medication compliance, during the course of their illness, rather than HIV/AIDS patients can be managed as a comat ICU admission. Prolonged mechanical ven- plex, chronic condition. Because these patients tilation before ECLS, presence of multiorgan have attained a life expectancy comparable to failure, multi-organism infections, inotropic the general population, more aggressive care support before ECLS, older age, and cachexia modalities such as ECLS should be considered were significant predictors of mortality. It is during periods of acute, reversible illness. noteworthy that CD4 count, PaO2 and the MurECLS in Adult and Pediatric Autoimmune ray Score did not predict outcome. Diseases Antiretroviral Drugs (ARVs) and ECLS Patients with autoimmune diseases may Powel et al.41 found that, in a high income suffer acute respiratory failure due to infeccountry, 40% of HIV positive patients pre- tions complicating immunosuppressive therapy senting with ARF were receiving ARVs and or, more rarely, from direct lung involvement 44% were not. PJP occurred less frequently of autoimmune-mediated inflammatory proin patients compliant with ARVs. Survival for cesses. Thorough investigation for infectious HIV positive, critically ill patients continues to agents including opportunistic infections and improve in the current era of ART. Paradoxi- initiation of broad spectrum anti-infectious cally, antiretroviral therapy has not been directly therapy are warranted at presentation. In cases linked to improved outcomes in patients admit- of inflammatory processes, appropriate immuted to ICU. Therefore, improved survival may nosuppressive therapy can be lifesaving. ECLS be due to other contributing factors, including for noninfectious causes of acute respiratory failure due to autoimmune-mediated pulmonary improved ICU care.54,55 Initiation of ARVs in the ICU can introduce complications has been rare. A number of case challenges and additional comorbidities, includ- reports, however, prove that under selected ciring difficulty in drug delivery and absorption, cumstances, ECLS successfully supports such incorrect dosing, drug reactions, medication patients through their illness. Lung involvement by autoimmune diseases interactions, effects on viral resistance, and development of Immune Reconstitution In- can be multifaceted. In patients with systemic flammatory Syndrome (IRIS).56 Despite these lupus erythematosus (SLE), ARDS rates are difficulties, initiation of ARVs improves the low (3.5%), usually due to secondary infection. outcome of critically ill patients, especially Even more rarely, SLE patients suffer lung those with PJP.43,44,47,57,58 Rodger and colleagues failure due to lupus pneumonitis, vasculitis, 670

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or DAH.60 Thromboembolic events including pulmonary embolism or myocarditis may impair both pulmonary and cardiac performance and, rarely, lead to cardiogenic shock.61 A thorough diagnostic approach to differentiate these syndromes from infectious complications is mandatory including extensive lab workup, CT scan, bronchoscopy, and sometimes lung biopsy.62,63 In cases of pulmonary involvement by the underlying autoimmune disease itself, rapid initiation of immunosuppressive therapy (typically steroids and cyclophosphamide), sometimes together with plasmapheresis, should be the priority. In cases of life-threatening respiratory (or, more rarely, cardiac) failure, ECLS may buy time until recovery. Diffuse alveolar hemorrhage with underlying autoimmune disease such as SLE, polyarteritis nodosa, or other autoimmune illnesses has been successfully managed with ECLS support.64 ANCA-positive pulmonary vasculitis (eg, Wegener´s granulomatosis and microscopic polyangitis) appears most common.65 Autoimmune diseases rarely present initially as DAH, with an incidence of less than 5%, but the fatality rate can reach 50%.66 Bleeding in these cases is not a contraindication for ECLS and anticoagulation may often be withheld or minimized without exacerbation of bleeding.67 Fortunately, 90% of ANCA-positive vasculitis associated alveolar haemorrhage patients respond rapidly to immunosuppressive therapy.68 Acute SLE-associated myocarditis or massive pulmonary embolism due to antiphospholipid syndrome or other thrombogenic states rarely leads to the need for VA-ECLS. Although ECLS in acute myocarditis can successfully bridge the patient to recovery,69 pulmonary hypertension due to antiphospholipid syndrome usually yields high complication and mortality rates when managed with ECLS.70 The use of ECLS to manage pediatric autoimmune disease remains uncommon, limited to brief reports,71-72 usually in the setting of hemophagocytic lymphohistiocytosis

(HLH). 73-74 HLH is a rare life-threatening disorder characterized by severe inflammation with uncontrolled proliferation and activation of lymphocytes and macrophages, secreting large quantities of cytokines (“cytokine storm”). The hallmark of HLH is the emergence of hemophagocytosis, a process in which histiocytes actively engulf blood cells and their precursors. The uncontrolled growth is nonmalignant and does not appear clonal as in Histiocytosis X. HLH can be classified as primary and secondary. The pathophysiology of this syndrome remains murky, but involves perforin-mediated cytolytic pathways used by natural killer (NK) and CD8 T-lymphocytes. Primary HLH is an autosomal recessive monogenic disorder while secondary HLH represents a similar clinical syndrome with no known genetic basis. Secondary HLH is thought to occur in the context of an underlying immunologic disease, such as malignancy or an autoimmune or inflammatory disorder. Secondary HLH associated with rheumatic disease is also referred to as “macrophage activation syndrome” (MAS). Clinical manifestations of both primary and secondary HLH can be generally triggered by an infection, including viral, bacterial, fungal, and protozoan microorganisms, and can be facilitated by immunomodulating therapies. Diagnostic criteria for HLH are subtle,71 but early diagnosis and treatment may improve outcomes. Primary HLH is difficult to control and usually requires HSCT. Secondary HLH appears to respond more readily to immunosuppressive therapies but mortality remains high in both forms (70% in certain subtypes). The use of ECLS to manage this disease remains controversial due to its poor results. Virus associated hemophagocytic syndrome (VAHS) was reported during the 2009 influenza (H1N1) pandemic.75-78. A recent review of the ELSO Registry79 reported only 30 children treated for HLH. Survival to hospital discharge was 30%, but no prognostic data could be identified in patient selection for ECLS.

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In conclusion, patients with acute respiratory or cardiac failure complicating autoimmune diseases represent a poorly studied and complex population. The decision to support with ECLS should be discussed with the appropriate teams (hematology-oncology, rheumatology, infectious diseases) as well as family members while aggressive therapy for the primary disorder is instituted.

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of patients with hematopoietic stem cell transplants admitted to the intensive care unit. J Transplant 2009; 2009: 917294. 18. Demaret P, Pettersen G, Hubert P, et al. The critically-ill pediatric hemato-oncology patient: epidemiology, management, and strategy of transfer to the pediatric intensive care unit. Ann Intensive Care 2012; 2(1):14 19. Afessa B, Azoulay E. Critical care of the hematopoietic stem cell transplant recipient. Crit Care Clin 2010; 26(1):133-50 20. Gow KW, Wulkan ML, Heiss KF, et al. Extracorporeal membrane oxygenation for support of children after hematopoietic stem cell transplantation: the Extracorporeal Life Support Organization experience. J Pediatr Surg 2006; 41(4):662-667 21. Di Nardo M, Locatelli F, Palmer K, et al. Extracorporeal membrane oxygenation in pediatric recipients of hematopoietic stem cell transplantation: an updated analysis of the Extracorporeal Life Support Organization experience. Intensive Care Med. 2014 May;40(5):754-6 22. Wohlfarth P, Beutel G, Lebiedz P, et al. Veno-venöse ECMO bei Patienten mit ARDS nach allogener Stammzelltransplantation. Med Klin Intensivmed Notfmed 2015; 110:293–321 23. Di Nardo M, Li Pira G, Amodeo A. et al. Adoptive immunotherapy with antigenspecific T cells during extracorporeal membrane oxygenation (ECMO) for adenovirusrelated respiratory failure in a child given haploidentical stem cell transplantation. Pediatr Blood Cancer 2014; 61(2):376-9 24. Wolfson RK, Kahana MD, Nachman JB, et al. Extracorporeal membrane oxygenation after stem cell transplant: clinical decisionmaking in the absence of evidence. Pediatr Crit Care Med 2005; 6(2):200-3 25. Dalton HJ. Extracorporeal membrane oxygenation in immunocompromised patients: Avoiding the incurable or missing

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opportunities? Pediatr Crit Care Med 2008; 9(4):442-4 26. Azoulay E. Pulmonary Involvement in patients with Hematological malignancies. Springer Edition 2011 27. Di Nardo M, Locatelli F, Di Florio F, et al. Extracorporeal membrane oxygenation as a bridge to allogeneic T-cell depleted hematopoietic stem cell transplantation in infants with severecombined immune deficiency: is it feasible? Intensive Care Med 2014; 40 (10): 1600-1 28. Hsiao LT, Chung FP, Chiou TJ, et al. The limitations of extracorporeal membrane oxygenation as a bridge to allogeneic hematopoietic stem cell transplantation. Intensive Care Med 2014; 40(12): 1971-2 29. Liao WI, Tsai SH, Chiu SK. Successful use of extracorporeal membrane oxygenation in a hematopoietic stem cell transplant patient with idiopathic pneumonia syndrome. Resp Care 2013; 58(2):e6-10 30. Koinuma T, Nunomiya S, Wada M, et al. Concurrent treatment with tumor necrosis factor-alpha inhibitor and veno-venous extracorporeal membrane oxygenation in a post-hematopoietic stem cell trasplant patient with idiopathic pneumonia syndrome: a case report. J Intensive Care 2014; 2 (1):48 31. Morris SH, Haight AE, Kamat P, et al. Successful use of extracorporeal life support in a hematopoietic stem cell transplant patient with diffuse alveolar hemorrhage. Pediatr Crit Care Med 2010; 11(1):e4-7 32. Stretch R, Bonde P. Successful use of extracorporeal membrane oxygenation for respiratory failure in pulmonary chronic graft-versus-host disease ASAIO J 2014; 60(1):122-123 33. Cheng GS, Edelman JD, Madtes DK, et al. Outcomes of Lung Transplantation after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2014; 20(8):1169-75

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34. Armenian SH, Gelehrter SK, Chow EJ. Strategies to prevent anthracycline-related congestive heart failure in survivors of childhood cancer. Cardiol Res Pract 2012; 2012:713294. 35. Meserve EE, Lehmann LE, Perez-Atayde AR, et al. Cyclophosphamide-associated cardiotoxicity in a child after stem cell transplantation for B-thalassemia major: case report and review of the literature. Pediatr Dev Pathol 2014; 17(1):50-4 36. Kalbhenn J, Schmidt R, Nakamura L, et al. Early diagnosis of acquired von Willebrand Syndrome (AVWS) is elementary for clinical practice in patients treated with ECMO therapy. J Atheroscler Thromb 2015;22:265-71 37. Annich G, Lynch W, MacLaren G, Wilson JM, Bartlett RH. Extracorporeal Cardiopulmonary Support 4h Edition. 38. Narasimhan M, Posner AJ, DePalo VA et al Intensive care in patients with HIV infection in the era of highly active antiretroviral therapy. Chest 2004;125:1800-1804 39. Akgun KM, Tate JP, Pisani M et al. Medical ICU admission diagnoses and outcomes in Human immunodeficiency virus-infected and virus uninfected veterans in the Combination Antiretroviral era. Crit Care Med 2013;41:1458-1467 40. Cribbs S, Tse C, Andrews J et al. Characteristics and Outcomes of HIV-infected patients with severe sepsis: Continued risk in the Post-Highly avctive antiretroviral therapy era. Crit Care Med 2015;43:16381645 41. Powell K, Davis JL, Morris AM et al. Survival for patients with HIV admitted to the ICU continues to improve in the current era of combination antiretroviral therapy. Chest 2009;135:11-17 42. Llibre J, Revollo B, Vanegas S, et al. Pneumocystis jirovecii pneumonia in HIV1-infected patients in the late-HAART era

in developed countries. Scand J Infect Dis 2013;45:635-644 43. De Rosa FG, Fanelli V, Corcione S et al. Extracorporeal Membrane Oxygenation (ECMO) in three HIV-positive patients with acute respiratory distress syndrome. BMC Anaesthesiology 2014,14:37 44. Goodman JJ, Goodman LF, Satish K, et al. Extracorporeal Membrane Oxygenation as adjunctive therapy for refractory hypoxemic respiratory failure in HIV-positive patients with severe pneumocystis jirovecii pneumonia. Clin Pulm Med 2013; Vol. 20 No. 3: 117-120 45. Gutermann H, van Roy B, Meersseman W et al. Successful Extracorporeal Lung Assistance for Overwhelming Pneumonia in a Patient with undiagnosed Full Blown AIDSA controversial therapy in HIV patients. Thorac Cardiov Surg 2005;53:252-254 46. Samalavicius R, Serpytis M, Ringaitine D et al. Successful use of extracorporeal membrane oxygenation in a human immunodeficiency virus infected patient with severe acute respiratory distress syndrome. AIDS Research and Therapy 2014, 11:37 47. Cawcutt K, Gallo de Moraes A, Lee S. et al. The Use of ECMO in HIV/AIDS with Pneumocystis jirovecii Pneumonia: A Case Report and Review of the Literature. ASAIO J 2014 48. Weber R, Ruppik M, Rickenbach M, et al. Decreasing mortality and changing patterns of causes of death in the Swiss HIV Cohort Study. HIV Med 2013; 14: 195–207. 49. Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord. All-cause mortality in treated HIV-infected adults with CD4 ≥500/mm3 compared with the general population: evidence from a large European observational cohort collaboration. Int J Epidemiol 2012; 41(2): 433–45. 50. Nakagawa F, Lodwick RK, Smith CJ, et al. Projected life expectancy of people with 675

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HIV according to timing of diagnosis. AIDS 2012; 26: 335–43 51. South African National HIV Prevalence, Incidence and Behaviour Survey 2012. 52. Shaddock EJ, Richards G, Murray J. Lung fibrosis in deceased HIV-infected patients with Pneumocystis pneumonia. SAJHIVMED 2012, Vol. 13, No. 2 53. Fei MW, Kim EJ, Sant CA et al. Prediciting mortality from HIV-associated pneumocystis pneumonia at illness presentation: an observational cohort study. Thorax 2009;64:1070-1076 54. Greenberg J, Lennox J, Martin G. Outcomes for critically ill patients with HIV and severe sepsis in the era of Highly active antiretroviral therapy. J Crit Care 2012; 27(1):51-57 55. Miller RF, Allen E, Copas A et al. Improved survival for HIV infected patients in the intensive care unit in the era of highly active antiretroviral therapy. Thorax 2006; 61:716-721 56. Morris A, Masur H, Huang L. Current issues in critical care of the human immunodeficiency virus infectred patient. Crit Care Med 2006 Vol 43 (1):42-49 57. Morris A, Wachter RM, Luce J et al. Improved survival with highly active antiretroviral therapy in HIV infected patients with severe Pneumocystis carinii pneumonia. AIDS 2003;17:73-80 58. Zolopa AR, Andersen J, Komarov L et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections:L A multicentre randomised strategy trial. PLoS ONE 2009;4:e5575 59. Rodger AJ, Lodwick R, Schechter M et al. INSIGHT SMART, ESPRIT study groups: Mortality in well controlled HIV in continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with general population. AIDS 2013; 27:973-979

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60. Kim WU, Kim SI, Yoo WH, et al. Adult respiratory distress syndrome in systemic lupus erythematosus: Causes and prognostic factors: A single center retrospective study. Lupus 1999; 8: 552-557 61. Swigris JJ, Fischer A, Gillis J, et al. Pulmonary and thrombotic manifestations of systemic lupus erythematosus. Chest 2008; 133: 271-280 62. Demoruelle MK, Kahr A, Verilhac K, et al. Recent-onset systemic lupus erythematosus complicated by acute respiratory failure. Arth Care Res 2013; 65: 314-323 63. Staudinger T, Roeggla M, Kettenbach J, et al. Respiratory failure in sytemic lupus erythematosus: decisive differentiation between acute pneumonitis and infection. Brit J Rheumatol 1997; 36: 295-297 64. Patel JJ, Lipchik RJ. Systemic lupusinduced diffuse alveolar haemorrhage treated with extracorporeal membrane oxygenation: a case report and review of the literature. J Intensive Care Med 2014; 29: 104-109 65. Yusuff H, Malagon I, Robson K, et al. Extracorporeal membrane oxygenation for life-threatening ANCA-positive pulmonary capillaritis. A review of UK experience. Heart Lung Vessels 2015; 7: 159-167 66. Gomez-Puerta JA, Hernandez-Rodriguez J, Lopez-Soto A, et al. Antineutrophil cytoplasmatic antibody-associated vasculitides and respiratory disease. Chest 2009; 136: 1101-1111 67. Abrams D, Agerstrand CL, Biscotti M, et al. Extracorporeal membrane oxygenation in the management of diffuse alveolar hemorrhage. ASAIO J 2015; 61:216-218 68. Barnes SL, Naughton M, Douglass J, et al. Extracorporeal membrane oxygenation with plasma exchange in a patient with alveolar haemorrhage secondary to Wegener´s granulomatosis. Intern Med J 2012; 42: 341-342

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69. Leung MC, Harper RW, Boxall J. Extracorporeal membrane oxygenation in fulminat myocarditis complicating systemic lupus erythematosus. Med J 2002; 176: 374-375 70. Repéssé X, Freund Y, Mathian A, et al. Successful extracorporeal membrane oxygenation for refractory cardiogenic shock due to the catastrophic antiphospholipid syndrome. Ann Intern Med 2010; 153:487488 71. Filipovich AH. Hempophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am Soc Hematol Educ Program 2009; 127-131 72. Brisse E, Wouters C, Matthys P. Hemophagocytic lymphohistiocytosis (HLH): a heterogeneous spectrum of cytochinedriven immune disorders. Cytokine and Growth Factor Rev 2015; 26(3):263-280. 73. Williams F, Cheng A, Fortenberry J, et al. Extracorporeal membrane oxygenation for hemophagocytic lymphohistiocytosis secondary to ehrlichiosis. Crit Care Med. 2015; 43(12 Suppl 1):306. 74. Lucchese G, Faggian G, Luciani GB Pediatric veno-arterial extracorporeal membrane oxygenation in fulminant hemophagocytic lymphohistiocytosis. Artif Organs 2013; 37(7):671-3. 75. Henter JI, Palmkvist-Kaijser K, Holzgraefe B, et al. Cytotoxic therapy for severe swine flu A/H1N1. Lancet 2010; 18;376(9758):2116 76. Beutel G, Wiesner O, Eder M, et al. Virusassociated hemophagocytic syndrome as a major contributor to death in patients with 2009 influenza A (H1N1) infection. Crit Care 2011;15(2):R80 77. Wu ET, Huang SC, Sun LC, et al. Reactive hemophagocytic syndrome treated with extracorporeal membrane oxygenation. Pediatr Int 2008; 50(5):706-8. 78. Kitazawa Y, Saito F, Nomura S, et al. A case of hemophagocytic lymphohistiocytosis after the primary Epstein-Barr virus infection.

Clin Appl Thromb Hemost 2007;13(3):3238 79. Cashen K, Chu R, Klein J, Rycus P, Costello JM. Extracorporeal membrane oxygenation use in pediatric hemophagocytic lymphohistiocytosis patients. Critical Care Medicine 2014; 42 (12) (Supplement 1): A1610-1611.

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61 Procedures on ECLS Peter P. Roeleveld, MD, Giles J. Peek, MD, FRCS, CTh, FFICM

Introduction The evolution of ECLS circuitry and management techniques over the last 45 years has enabled more complex procedures and operations to be performed safely on patients receiving ECLS. This change has altered patient selection as we no longer need to deny patients the chance of ECLS support solely on the basis of their need for invasive surgery. Nevertheless, surgical and interventional procedures on ECLS carry the risk of life threatening bleeding which should not be underestimated. This chapter initially addresses the basic principles and decisionmaking framework for successful procedures on ECLS and then provides an overview of such procedures. With increased use of mechanical circulatory support (MCS), surgical procedures in ECLS patients have become more frequent and more diverse. In 1992, Atkinson et al. found that 14% of pediatric ECLS patients received surgical procedures (excluding cannulation and decannulation).1 A more recent query of the National Inpatient Database showed that noncardiac surgical procedures were performed in 47.8% of adult ECLS patients.2 The most common procedures included general surgical procedures (predominantly abdominal exploration/bowel resection), vascular procedures (control of vascular hemorrhage), and thoracic

procedures (lung biopsy, exploratory thoracotomy, lobectomy).2 In a retrospective review of adult cardiac ECLS patients, 21% underwent noncardiac surgical procedures.3 High mortality rates occurred in patients who received noncardiac procedures (NCP) on ECLS with a trend to worse survival than when NCP were not performed. Tracheostomy was the most common procedure followed by laparotomy and fasciotomy. Other documented procedures included open cholecystectomy, urologic procedures, craniotomy with hematoma evacuation, pericardial window, and vascular procedures.3 Prolonged experience with surgical interventions in children on ECLS indicates that such procedures are technically feasible with the best results achieved when the patient undergoes rapid postprocedural decannulation.1,4 Hirikati et al. described 48 procedures in 37 neonates on ECLS and concluded that cardiac defects, diaphragmatic hernia, lobar emphysema, and other conditions can be safely corrected. However, hemorrhagic and thoracic complications, and multiple surgical interventions were associated with significantly higher mortality in children on ECLS.1,4 Data demonstrate that few areas of the body and procedures are not amenable to intervention providing that the proceduralists are sufficiently expert and take the necessary precautions.

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Decision Threshold-Three Questions The first question that the proceduralist must ask is “can the procedure be avoided?” This question is more useful than “is the procedure necessary?” because it focuses attention on what the consequences would be for the patient if the procedure were not performed. An example of this could be a child on VVECMO for left sided pneumonia with a large left hemothorax that has been slowly growing for the last week. A chest drain or thoracotomy would carry a risk of bleeding, but without the procedure the child is unlikely to inflate the pneumonic lung sufficiently to separate from ECLS. A caveat to this question is “does this procedure achieve the therapeutic aim with the least risk to the patient?” The second question the operator should ask is “when is the best time to perform the procedure?” In the case given above it is clearly safe to wait to perform the procedure semi-electively allowing preparation of an ideal team and operating environment. Many procedures will need to be performed emergently (eg, drainage of a tension hemothorax that impedes venous drainage). Some procedures can be deferred until after decannulation (eg, grafting a burn or repairing a fractured bone). This question relates in part to the balance between the need for the procedure and the need to ensure optimal operating conditions by transfusing clotting factors and platelets, altering heparin infusions, and administrating antifibrinolytics. The third question the operator should ask is “am I the right person to perform this procedure?” Stirling Moss, the famous British racing driver of the 1950s and 60s had a rule that he would never drive at more that 80% of his capacity so that he always had some driving ability in reserve to cope with unforeseen circumstances. The operator should therefore ensure that the proposed procedure falls well within their competency. In general terms, for a more complex procedure the best operator 680

should be called upon within the timeframe allowable in question 2. General Principals Preparation and Communication Prior to performing procedures on ECLS patients, a thorough briefing during which all equipment requirements, proposed procedures, areas of responsibility and authority, and potential complications with their solutions are discussed. The specific questions of antibiotic prophylaxis, heparin management, and the preparation of a primed standby circuit should be addressed at this briefing. There should always be someone present who is thoroughly knowledgeable with regard to the hemodynamic consequences and limitations of the extracorporeal support. Don’t Let Air into the Circuit Venting the left atrium, right atrium, manipulating stopcocks, and cannula bungs can entrain air into the circuit. In addition, cardiac catheterization can allow air to enter around the hemostatic sheath after catheter introduction if the venous pressure is low and the pump RPM is creating significant suction. Obtain Absolute Hemostasis (if possible) With many procedures, residual bleeding often persists but usually settles quickly. When operating on ECLS one should strenuously attempt to assure total hemostasis including aggressive packing, draining, and sometimes closing the cavity or wound to achieve tamponade or leaving it open to facilitate exploration. Bleeding from irritation around a tracheostomy can be easily controlled by removing the tracheostomy, intubating the patient orally, and packing the tracheostomy wound. Usually, in

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several days the oral tube can be removed and the tracheostomy tube replaced.

or blood products in case of inadequate ECLS support.

General Measures

Patient Transport

Specific protocols for performing procedures during ECLS can increase safety and decrease complications. These procedures can be interventional, surgical, diagnostic, therapeutic, or any combination of these. Specific procedures require unique approaches.

The team should be notified prior to transporting patients for procedures. Support from surgeons, perfusionists, and/or the VAD team, should immediately be available in case of accidental decannulation or other mechanical complications during transport (see Chapter 55). A backup ECLS circuit should remain available during transport and the procedure.

Anticoagulation

Antifibrinolytics (aminocaproic acid/Ami- Anesthetic Considerations car, aprotinin, and tranexamic acid) successfully appear to reduce bleeding complications.5-7 Rapid sequence induction/intubation should Amicar significantly reduced the rate of surgical be considered for VAD patients because of the site bleeding in 298 pediatric ECMO patients greater risk of aspiration due to the placement undergoing surgical procedures but was associ- and pressure of the device into the upper left ated with increased numbers of circuit .5 The abdomen and/or esophagus.8 authors used 100 mg/kg as bolus followed by 30 mg/kg/hr for 72 hrs. No difference in thrombotic Electrocautery complications (CNS infarct or major vessel The interference from electrocautery may thrombosis) occurred. Tranexamic acid significantly reduced bleeding at the surgical site in disrupt the ECLS circuit. Ideally, the return pad neonates undergoing congenital diaphragmatic should be placed such that the current will not hernia repair while on ECLS.7 Aprotinin has pass through the area of the mechanical device. effectively been used to control bleeding from Bipolar electrocautery should also be used cannulation sites in adult ARDS patients during whenever possible. Because the “auto” mode prolonged ECLS (see Chapter 8).6 As stated of the VAD is susceptible to decreased flows in the ELSO anticoagulation guidelines: “both with electrocautery interference, they should aminocaproic acid and tranexamic acid are be changed to a “fixed rate” mode.9,10 used in many centers in an effort to prevent hemorrhagic complications in ECLS patients ECMO Circuit Related Procedures having surgical procedures.”5 When changing the ECLS circuit, or its parts, interruption of cardiopulmonary support ECLS Management should be as brief as possible. Some centers Alterations in clotting and bleeding pre- have devised ways to replace ECLS without cipitated by procedures or by manipulating interrupting support by implanting a parallel anticoagulation can impact ECLS effectiveness. circuit.11 Others simply go as quickly as possible It may be necessary to prepare, prior to proce- while temporarily increasing standard intensive dures, to support the patient with conventional care support, such as ventilation and/or inotromeasures, such as ventilation, inotropes, and/ pes, if necessary. Training for these events can 681

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decrease the likelihood of complications (see Chapter 67). Revision of ECLS cannulas may be necessary to improve positioning, upgrade size, or removal of cannula related clots. Migration of cannulas can also occur during ECMO, potentially compromising flow or causing injury to surrounding tissue, including the right ventricle, right atrium, or inferior vena cava. Therefore, malposition of the cannula should be corrected expeditiously using fluoroscopic equipment, echocardiography, and/or guidewires.12 Diagnostic Procedures Radiologic Procedures Ultrasound, roentgenograms, and computed tomography (CT) are standard diagnostic procedures for patients on ECLS. Ultrasound studies and most plain radiographs can be performed safely at the bedside. Other radiological investigations, including CT-scans, require careful attention during transfer to safely complete the studies.13-15 Clinically significant findings, leading to changes in patient management were identified in the majority of chest CT scans of 19 children not progressing after 7-18 days on respiratory ECLS.14 When interpreting CT-angiography, one should consider that VA-ECLS changes filling and blood flow of the cardiac chambers and pulmonary vessels as well as altering the path of the injected contrast.16 In 2006, Lidegran et al. reported the successful use of a mobile ECMO circuit to perform magnetic resonance imaging (MRI) in an animal model without interference.13 The ECMO circuit and the MRI scanner did not interfere with each other. However, wire-enforced cannulas could not be used. Hitherto, no commercially available ECLS system exists which is certified compatible with MRI.

Transesophageal Echo Transesophageal echocardiography (TEE) has become an important diagnostic tool in ECLS, frequently impacting clinical management.17-19 In VAD and respiratory ECLS patients, TEE can determine appropriate cannula placement, especially dual-lumen VV-ECMO cannulas.20 In cardiac ECLS patients, TEE can diagnose (residual) cardiac defects or pericardial effusion, evaluate ventricular function, determine the need for left atrial decompression, facilitate (bedside) atrial septostomy or interatrial stenting, and guide weaning. 21-23 Systemic anticoagulation does not contravene performance of TEE.24,25 Contraindications and complications in ECLS patient are similar to those in non-ECLS patients. Although TEE is considered safe, even in neonates, and complications occur rarely, the benefit-risk ratio should be examined in each case.17 Bronchoscopy In patients on VV or VA-ECLS, flexible bronchoscopy, bronchoalveolar lavage (BAL), and bronchial washings have been found to be safe, providing diagnostic information to the clinician and therapeutic benefit to the patient.26-29 Indications include persistent atelectasis, secretions clearance, evaluation of suspected pulmonary infection with BAL, or foreign body aspiration.30 No major complications (eg, hemodynamic changes, endotracheal tube dislodgement, significant bleeding) were seen in three retrospective pediatric reports and one adult report, without adjusting standard ECMO anti-coagulation.26-28 Spontaneously resolving blood-tinged secretions occurred after approximately 20-30% of flexible bronchoscopies. Cardiac Catheterization Residual anatomic lesions have a strong negative influence on survival among ECLS

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patients after cardiac operations. When echocardiography does not definitely exclude or diagnose residual lesions in these patients, cardiac catheterization can provide insight into adequacy of the surgical repair and hemodynamics.31 Cardiac catheterization improves outcomes in ECPR patients.32 Other indications include assessment of coronary anatomy, endomyocardial biopsy, electrophysiologic study, arrhythmia ablation, transcatheter patent ductus arteriosus (PDA) or ventricular septal defect (VSD) closure, and left heart decompression.31,33-37 In a retrospective study no major complications occurred in 28 cardiac catheter studies in 22 children on ECLS.31 In another retrospective study of 60 cardiac catheterizations in ECLS patients by Booth et al. complications included two myocardial perforations (3%), one during atrial stenting for LV decompression, and the other was presumed to be through the left ventricular free wall.33 Both patients received management with epicardial drains. In both studies, medical management was adjusted based on cardiac catheterization data in approximately 80%.31,33 Callahan et al. described 36 pediatric patients undergoing a total of 40 cardiac catheter studies. They noted no complications related to patient transport, one nonvascular complication (hypotension), and five vascular complications (compartment syndrome, limb edema, oozing from cannulation site, temporary pulse loss, venous thrombus). Survival to discharge was 72%. Unexpected diagnostic information was found in more than half (52%) of catheterizations.38 Tachyarrhythmias in children on ECLS have been safely managed with ablation. Silva et al. describe 39 patients, median age 5.5 months, on MCS because of tachyarrhythmias. The majority could be treated with antiarrhythmic medication. Thirteen patients (33%) underwent successful ablation without complications related to MCS or anticoagulation.35 In adults with tachycardia-induced cardiomyopathy, ablation of the aberrant rhythm focus has been safe and successful. Scherrer et al. describe

a 24 year-old woman with atrial tachycardia induced cardiomyopathy on VA-ECMO for cardiogenic shock. She reverted to sinus rhythm after successful ablation using radiofrequency technique.39 Cheruvu et al. describe a successful accessory pathway ablation in a 63 year-old male on ECMO for cardiogenic shock due to SVT and atrial fibrillation.40 Rizkallah et al. describe an 18 year-old man with idiopathic ventricular tachycardia (VT), who was resuscitated onto ECLS. After stabilization on ECLS, a successful ablation was performed without complications, with successful decannulation 24 hours later.41 Vascular access for catheterization in ECLS patients can prove challenging, especially in small children or in adult patients cannulated through the femoral vessels. The use of ultrasound-guided percutaneous puncture of femoral vessels is advocated. 31 Sometimes surgical cutdown is necessary. Some centers have made adjustments in their ECLS circuits, providing access for the cardiac catheter through an accessory limb connected to the arterial cannula, terminated with a hemostatic valve.42-44 Cardiac catheterization can be carried out safely during ECLS and may facilitate diagnosis and effective management of residual lesions.31,33,38 Endoscopy Gastrointestinal (GI) bleeding occurs in 3% to 6% of patients receiving ECLS.45 It may require transfusions and diagnostic or therapeutic interventions such as gastroduodenoscopy and/ or colonoscopy. Endoscopic electrocautery can safely help control GI bleeding.46 Surgical Procedures General Vascular Access The insertion of central venous lines and arterial catheters can be challenging in the ECLS 683

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patient due to the increased risk of bleeding and the presence of edema. Catheter insertion should be performed by experienced caregivers. Surgical cutdowns may be a safer or necessary option.

of PDT were low and comparable to those of other critically ill patients when performed by experienced operators.52 There are two case reports in the literature of tracheostomy in children on ECLS (8, 13, and 17 yrs old).53,54 Two procedures were performed Thoracotomy Drains on ECLS and the third tracheostomy occurred 6 days prior to ECLS but the patient developed Pneumothorax and hemothorax occur in bleeding from the site which requiring surgical up to 10% of patients on ECMO.47,48 Placing correction without further complications. No a chest tube carries a significant risk of bleed- comments addressed specific surgical teching complications.49 A recent analysis of the niques or anticoagulation strategies. Agar et population-based, Kids inpatient database al. describe 11 pediatric patients (median age (KID) demonstrated that chest drain placement 69.5 months) who underwent tracheostomy; 10 did not affect survival rates.50 The assessment received tracheostomy for prolonged respiraof the necessity for a chest tube or whether a tory support and one underwent the procedure patient can be decannulated without the drain to manage tracheal stenosis with no complicamay prove difficult. Jackson et al. proposed that, tions.55 in children on ECLS, indications for chest tube placement include situations in which pleural Cesarean Section collections compromise pump flow or oxygenation, indicating tension physiology, or when Extracorporeal life support is increasingly they preclude weaning from ECLS.49 being used in patients with peripartum cardiomyopathy (see Chapter 53).53 Successful Tracheostomy cesarean section has been reported in women on ECLS.56-60 In two reports, heparin was disPlacement of a tracheostomy can be helpful continued for several hours periprocedurally during the prolonged ECLS support by enabling and standard (Pfannenstiel) cesarean section spontaneous breathing, minimizing sedation, was performed without bleeding or thromboand encourage physiotherapy and ambulation. embolic complications.56,57 Both infants were In 2015, an international survey among 173 approximately 30 weeks gestation and one adult respiratory ECLS centers on the manage- survived without sequela.56 The other infant ment of mechanical ventilation, reported that survived with major neurological impairment 71.3% of centers performed tracheostomy on due to intraventricular hemorrhage. Two reECLS.51 Braune et al. reported a retrospective ports described the use of ECLS directly prior study of 118 percutaneous dilational tracheos- to emergency cesarean section to facilitate tomies (PDT) in adult ECLS patients.52 Heparin anesthesia and maintain adequate circulation was paused one hour prior to the procedure in women with peripartum cardiomyopathy.58,59 and restarted directly after. Hematologic and Park et al. used fluoroscopy-assisted insertion of coagulation parameters were within normally a guidewire during cannulation of the inferior accepted ranges for ECLS patients. Minor vena cava (IVC) because of concerns of IVC bleeding from the tracheostomy site occurred injury compressed by the gravid uterus. After in approximately 30% of cases. The authors cannulation, no heparin was started and an concluded that with careful optimization of uneventful emergency cesarean section was percoagulation management, complication rates formed. Anticoagulation was started 3 days after 684

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delivery.58 The only other report of cesarean section during MCS describes 3 women with peripartum cardiomyopathy, supported with an intraaortic balloon pump with no maternal complications.60 One infant was stillborn, the other two survived uneventfully. Miscellaneous

bracket fixation to the fractured femur has also been reported (Table 61-1).68 Chou et al. describe two burn patients with ARDS who underwent several escarotomies on ECLS. By maintaining ACTs under 140 seconds, keeping platelets above 100x109, and infusing desmopressin, they encountered no hemorrhagic complications.70

Other infrequent general surgical proce- Abdominal Surgery dures in ECLS patients include reports of liver transplantation,61 gastrorrhaphy,62 and debrideLaparotomy for bowel resection (eg, in trauma patients or neonates with necrotizing enment of soft tissue infections.63 terocolitis), abcess removal, relief of abdominal compartment syndrome, or placement of periTrauma and Burn Patients toneal catheters can be necessary procedures in patients during ECLS support.71,72 Thoracic Trauma Abdominal compartment syndrome (ACS) In a recent study of 85 patients in the ELSO can cause abdominal ischemia, limit venous reRegistry with blunt thoracic trauma, 12 patients turn, and impair the ability to maintain adequate (14.1%) underwent invasive procedures on ECLS flows. ACS, defined by progressive intraECLS including cranial, thoracic, abdominal, or abdominal distension and intra-abdominal presvascular operations, thoracostomy tube place- sures >15 mmHg in children and >20 mmHg ments, and tracheostomy placements (see Chap- in adults, has many different causes.73 ACS can ter 54).64 Hemorrhagic complications occurred be alleviated by decompressive laparotomy or, in one-third of all 85 patients, including surgi- when significant ascites is present, by placing cal site bleeding (14%), cannula site bleeding a PD-catheter.71,74-77 (19%), and hemolysis or disseminated intravasOkhuysen-Cawley et al. described successcular coagulation (8%). Subjects with injuries ful placement of a peritoneal dialysis catheter at high risk for hemorrhage or who underwent via small infraumbilical incision in a child with invasive procedures were not more likely to Table 61-1. Technique for lung surgery on have a hemorrhagic complication.64 Strategies ECLS. to decrease the risk of bleeding involve withholding anticoagulation therapy temporarily or, HOW TO PERFORM LUNG SURGERY ON ECMO if possible, postponing the procedure until after separation from ECLS. Increase ECMO flow to maximal possible Airway and lung surgery can safely be fa- Disconnect the ventilator and deflate both the lungs cilitated by ECLS, often electively during lung Perform the surgery transplantation or pneumonectomy, which is Maintain arterial saturations at > 75% and appropriate beyond the scope of this chapter (see Chapter blood pressure for age 65-67 58). However, in chest trauma patients with bag ventilation with 100% FIO2 for a few breaths airway disruption, ECLS can be used to guar- Hand can be used when the patient becomes desaturated antee oxygenation delivery during repair of Decortication is easier with the lung ventilated rather than the airway.68,69 Closed reduction and external collapsed 685

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decisive treatment, patient selection, management of anticoagulation, and early estimation of prognosis.82 Krenzlin et al. described discouraging results in 11 adults and one child on ECLS, requiring craniotomy for life-threatening intraparenchymal hemorrhage of whom 75% experienced recurrence despite correction of coagulation abnormalities. Nine patients (75%) died in hospital, two survived in a vegetative state, and one survived with severe disability.82 Wilson et al. described 36 of 330 adult LVAD patients who suffered ICH.83 With suspension of anticoagulation, no device failures were seen. Intraparenchymal hemorrhage had the worst outcome with a 59% 30-day mortality. Traumatic subarachnoid hemorrhages had no deaths at 30 days while traumatic subdural hemorrhages had a 13% mortality at 30 days. Five of their patients with intraparenchymal hemorrhage underwent a neurosurgical surgical intervention and 4 died. No patient with an initial GCS 100-150x109, and fibrinogen >2 g/l. No studies report on bronchoscopic transbronchial lung biopsy in pediatric ECLS patients probably because of concerns of bleeding. Air leaks rarely occur, probably due to low thoracopulmonary compliance, low tidal volumes, and low ventilating pressures in patients supported with ECLS.92

Congenital Diaphragmatic Hernia Repair of congenital diaphragmatic hernia can safely be done on ECMO.93 The ideal timing of surgery is has been the focus of debate for many years (see Chapter 10). Most centers use antifibrinolytics for 24-72 hours to control postoperative bleeding.7,93,94 Specific Surgical Procedures in Cardiac ECLS Sternotomy/Thoracotomy Blood clots can fill the pericardial or pleural space impairing venous return or pump flow, especially in ECLS patients with central cannulation. Clot debridement may prove necessary in these patients. In neonates with shunt dependent circulation, clotting or obstruction of the systemic pulmonary shunt may lead to acute hypoxia or loss of systemic circulation, sometimes requiring MCS. Revision of the shunt can be safely performed on ECLS or after conversion to bypass, leading to improved outcomes.95,96 Unloading the Left Ventricle (Left-vent) When the left ventricle (LV) functions poorly it can become over distended during ECLS resulting in acute pulmonary venous congestion and edema, or inadequate myocardial recovery. Treatment is decompression of the LV. Elective LV decompression may reduce duration of ECLS97 and can be done surgically by cannulating the left atrium or a pulmonary vein, percutaneously by atrial stenting or balloon atrial septostomy,36,98-100 or via the transdiaphragmatic route.101 In adults and children, echocardiographically guided percutaneous blade and balloon atrial septostomy can be performed safely at the bedside.102-104 Barbone et al. describe introducing a pigtail catheter in the femoral artery in 4 patients, advancing through 687

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the aortic valve into the LV under TEE guidance.105 Ruprecht et al. have reviewed cardiac decompression during ECLS.106 Intracardiac Operations The removal of intracardiac clots, infective endocarditis,107 or surgery for residual lesions usually requires transfer to CPB in the operating room. Two examples for using the ECLS circuit for support: 1) a patient on VV-ECMO can have their BT shunt revised on ECLS, vascular clamps are applied to the shunt and pulmonary artery to control blood loss. A cell saver can be useful; 2) A patient on VA ECMO can have their coronary arteries grafted using OPCAB equipment and techniques. (Table 61-2)

Conclusion Few procedures in the lexicon of the surgeon, interventionist, or obstetrician cannot be performed safely on ECLS with good preparation, we must merely await the patient circumstances which embolden the pioneering protagonists.

Table 61-2. Technique for heart surgery on ECMO. HOW TO PERFORM HEART SURGERY ON ECMO

688

Use the ECLS circuit for support

The ECMO circuit is used to maintain oxygen delivery and circulatory support whilst the surgery is performed.

Use the ECLS circuit for DHCA

Simple procedures such as repair of obstructed total anomalous pulmonary venous drainage can be carried out by cooling on VA ECLS to around 14 oC. Cardioplegia is given by hand syringe (if the heart hasn’t already stopped) and the operation can be carried out. Care must be taken to prevent distention of the heart during cooling and rewarming, sometimes some slow cardiac massage is helpful. Use of a cell saver is essential.

Convert to CPB

• Cool patient to 32 oC whilst opening the chest on ECLS • Give 3mg/Kg Heparin and allow to circulate, check ACT >500 sec. • Clamp ECLS circuit, connect CPB circuit to ECLS cannulae, or additional cannulae if necessary. Go on CPB • Connect ends of ECLS circuit together and recirculate, turn the sweep off. Flash sweep for a few seconds if blood becomes dexoygenated. Check ACT, blood gas periodically. • Perform the surgery. • If patient will not come off CPB then reconnect to the same ECLS circuit if it is clean. If it was due to be changed, prime a new one. Deal with bleeding following recipe in chapter 7. • If the patient does come off CPB their passivated ECLS circuit can be kept on standby for 6-12 hours.

Procedures on ECLS

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real membrane oxygenation. J Amer Coll Cardiac Surg 6 2002;40(9):1681-1686. 34. Brown KL, Shekerdemian LS, Penny DJ. Transcatheter closure of a patent arterial duct in a patient on veno-arterial extracorporeal membrane oxygenation. Intensive Care Med. Apr 2002;28(4):501-503. 35. Silva JN, Erickson CC, Carter CD, et al. Management of pediatric tachyarrhythmias on mechanical support. Circulation. Aug 2014;7(4):658-663. 36. Alkhouli M, Narins CR, Lehoux J, Knight PA, Waits B, Ling FS. Percutaneous Decompression of the Left Ventricle in Cardiogenic Shock Patients on Venoarterial Extracorporeal Membrane Oxygenation. Journal Cardiac Surg. Mar 2016;31(3):177182. 37. Kommineni M, Lang RM, Russo MJ, Shah AP. Percutaneous transcatheter closure of infarct related ventricular septal defects assisted with portable miniaturized extracorporeal membrane oxygenation: a case series. Cardiovasc Revascularization Med. Jul-Aug 2013;14(4):241-245. 38. Callahan R, Trucco SM, Wearden PD, Beerman LB, Arora G, Kreutzer J. Outcomes of pediatric patients undergoing cardiac catheterization while on extracorporeal membrane oxygenation. Ped Cardiol. Mar 2015;36(3):625-632. 39. Scherrer V, Lasgi C, Hariri S, et al. Radiofrequency ablation under extracorporeal membrane oxygenation for atrial tachycardia in postpartum. J Cardiac Surg. Sep 2012;27(5):647-649. 40. Cheruvu C, Walker B, Kuchar D, Subbiah RN. Successful ablation of incessant AV reentrant tachycardia in a patient on extracorporeal membrane oxygenation. Heart Lung Circ. Jan 2014;23(1):e12-15. 41. Rizkallah J, Shen S, Tischenko A, Zieroth S, Freed DH, Khadem A. Successful ablation of idiopathic left ventricular tachycardia in an adult patient during extracorporeal mem-

brane oxygenation treatment. Can J Cardiol. Dec 2013;29(12):1741 e1717-1749. 42. Thuys C, MacLaren G, d’Udekem Y, Eastaugh L. Vascular access for pediatric coronary angiography on extracorporeal membrane oxygenation. World J Ped Congen Heart Surg. Jan 2015;6(1):126-129. 43. Ucer E, Fredersdorf S, Jungbauer C, et al. A unique access for the ablation catheter to treat electrical storm in a patient with extracorporeal life support. Europace. Feb 2014;16(2):299-302. 44. Endemann DH, Philipp A, Hengstenberg C, et al. A simple method of vascular access to perform emergency coronary angiography in patients with veno-arterial extracorporeal membrane oxygenation. Intensive Care Med. Dec 2011;37(12):2046-2049. 45. Brogan TV, Thiagarajan RR, Rycus PT, Bartlett RH, Bratton SL. Extracorporeal membrane oxygenation in adults with severe respiratory failure: a multicenter database. Intensive Care Med. Dec 2009;35(12):2105-2114. 46. Sarosiek K, Hirose H, Pitcher HT, Cavarocchi NC. Adult extracorporeal membrane oxygenation and gastrointestinal bleeding from small bowel arteriovenous malformations: a novel treatment using spiral enteroscopy. J Thorac Cardiothorac Surg. May 2012;143(5):1221-1222. 47. Zwischenberger JB, Cilley RE, Hirschl RB, Heiss KF, Conti VR, Bartlett RH. Life-threatening intrathoracic complications during treatment with extracorporeal membrane oxygenation. J Ped Surg. Jul 1988;23(7):599-604. 48. Gross GW, Dougherty CH. Pleural hemorrhage in neonates on extracorporeal membrane oxygenation and after repair of congenital diaphragmatic hernia: imaging findings. AJR. Apr 1995;164(4):951-955. 49. Jackson HT, Longshore S, Feldman J, Zirschky K, Gingalewski CA, Gollin G. Chest tube placement in children during 691

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extracorporeal membrane oxygenation (ECMO). J Ped Surg. Jan 2014;49(1):51-53; discussion 53-54. 50. Tashiro J, Perez EA, Lasko DS, Sola JE. Post-ECMO chest tube placement: A propensity score-matched survival analysis. J Ped Surg. May 2015;50(5):793-797. 51. Camporota L, Nicoletti E, Malafronte M, et al. International survey on the management of mechanical ventilation during ECMO in adults with severe respiratory failure. Minerva Anestesiologica. Nov 2015;81(11):1170-1183, 1177 p following 1183. 52. Braune S, Kienast S, Hadem J, et al. Safety of percutaneous dilatational tracheostomy in patients on extracorporeal lung support. Intensive Care Med. Oct 2013;39(10):17921799. 53. Hayes D, Jr., Galantowicz M, Preston TJ, Lloyd EA, Tobias JD, McConnell PI. Tracheostomy in adolescent patients bridged to lung transplantation with ambulatory venovenous extracorporeal membrane oxygenation. Jap J Artif Organs : Mar 2014;17(1):103-105. 54. Hayes D, Jr., Lloyd EA, Yates AR, McConnell PI, Galantowicz M, Preston TJ. Pediatric ambulatory ECMO. Lung. Dec 2014;192(6):1005. 55. Agar NJ, Berkowitz RG. Airway complications of pediatric extracorporeal membrane oxygenation. Ann Otol Rhinol Laryngol. Jun 2011;120(6):353-357. 56. Lysenko L, Zaleska-Dorobisz U, Blok R, et al. A successful cesarean section in a pregnant woman with A (H1N1) influenza requiring ECMO support. Kardiochi Torakochirurgia Pol. Jun 2014;11(2):216-219. 57. Panarello G, D’Ancona G, Capitanio G, et al. Cesarean section during ECMO support. Minerva Anestesiologica. Jun 2011;77(6):654-657. 58. Park SH, Chin JY, Choi MS, Choi JH, Choi YJ, Jung KT. Extracorporeal membrane 692

oxygenation saved a mother and her son from fulminant peripartum cardiomyopathy. J Obstet Gynecol Res. Jul 2014;40(7):19401943. 59. Kim HY, Jeon HJ, Yun JH, Lee JH, Lee GG, Woo SC. Anesthetic experience using extracorporeal membrane oxygenation for cesarean section in the patient with peripartum cardiomyopathy: a case report. Kor J Anesthe. May 2014;66(5):392-397. 60. Gevaert S, Van Belleghem Y, Bouchez S, et al. Acute and critically ill peripartum cardiomyopathy and ‘bridge to’ therapeutic options: a single center experience with intra-aortic balloon pump, extra corporeal membrane oxygenation and continuousflow left ventricular assist devices. Crit Care. 2011;15(2):R93. 61. Landsman IS, Karsanac CJ. Case report: pediatric liver retransplantation on an extracorporeal membrane oxygenationdependent child. Anesth Analg. Nov 2010;111(5):1275-1278. 62. Howell CG, Hatley RM, Davis JB, Kanto WP. Successful gastrorrhaphy on ECMO. J Ped Surg. Dec 1988;23(12):1161-1162. 63. Firstenberg MS, Abel E, Blais D, et al. The use of extracorporeal membrane oxygenation in severe necrotizing soft tissue infections complicated by septic shock. Am Surgeon. Nov 2010;76(11):1287-1289. 64. Jacobs JV, Hooft NM, Robinson BR, et al. The use of extracorporeal membrane oxygenation in blunt thoracic trauma: A study of the Extracorporeal Life Support Organization database. J Traum Acute Care Surg. Dec 2015;79(6):1049-1054. 65. Liston DE, Richards MJ. Venoarterial extracorporeal membrane oxygenation (VA ECMO) to facilitate combined pneumonectomy and tracheoesophageal fistula repair. J Cardiothorac Vasc Anesth. Aug 2014;28(4):1021-1023. 66. Redwan B, Ziegeler S, Freermann S, et al. Intraoperative veno-venous extracorporeal

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lung support in thoracic surgery: a singlecentre experience. Interact Cardoivasc Thorac Surg. Dec 2015;21(6):766-772. 67. Ius F, Kuehn C, Tudorache I, et al. Lung transplantation on cardiopulmonary support: venoarterial extracorporeal membrane oxygenation outperformed cardiopulmonary bypass. J Thorac Cardiovasc Surg. Dec 2012;144(6):1510-1516. 68. Zhou R, Liu B, Lin K, et al. ECMO support for right main bronchial disruption in multiple trauma patient with brain injury--a case report and literature review. Perfusion. Jul 2015;30(5):403-406. 69. Ballouhey Q, Fesseau R, Benouaich V, Leobon B. Benefits of extracorporeal membrane oxygenation for major blunt tracheobronchial trauma in the paediatric age group. Eur J Cardiothorac Surg. Apr 2013;43(4):864-865. 70. Chou NK, Chen YS, Ko WJ, et al. Application of extracorporeal membrane oxygenation in adult burn patients. Artif Organs. Aug 2001;25(8):622-626. 71. Prodhan P, Imamura M, Garcia X, Byrnes JW, Bhutta AT, Dyamenahalli U. Abdominal compartment syndrome in newborns and children supported on extracorporeal membrane oxygenation. ASAIO J. Mar-Apr 2012;58(2):143-147. 72. Rollins MD, Deamorim-Filho J, Scaife ER, Hubbard A, Barnhart DC. Decompressive laparotomy for abdominal compartment syndrome in children on ECMO: effect on support and survival. J Ped Surg. Jul 2013;48(7):1509-1513. 73. Beck R, Halberthal M, Zonis Z, Shoshani G, Hayari L, Bar-Joseph G. Abdominal compartment syndrome in children. Ped Crit Care Med. Jan 2001;2(1):51-56. 74. Lam MC, Yang PT, Skippen PW, Kissoon N, Skarsgard ED. Abdominal compartment syndrome complicating paediatric extracorporeal life support: diagnostic and

therapeutic challenges. Anaesth Intensive Care. Sep 2008;36(5):726-731. 75. Okhuysen-Cawley R, Prodhan P, Imamura M, Dedman AH, Anand KJ. Management of abdominal compartment syndrome during extracorporeal life support. Ped Crit Care Med. Mar 2007;8(2):177-179. 76. Maj G, Calabro MG, Pieri M, Melisurgo G, Zangrillo A, Pappalardo F. Abdominal compartment syndrome during extracorporeal membrane oxygenation. J Cardiothora Vasc Anesth. Oct 2012;26(5):890-892. 77. Augustin P, Lasocki S, Dufour G, et al. Abdominal compartment syndrome due to extracorporeal membrane oxygenation in adults. Ann Thorac Surg. Sep 2010;90(3):e40-41. 78. Yeo JH, Sung KH, Chung CY, et al. Acute compartment syndrome after extracorporeal membrane oxygenation. Jap J Ortho Sci. Mar 2015;20(2):444-448. 79. Brodt J, Gologorsky D, Walter S, Pham SM, Gologorsky E. Orbital compartment syndrome following extracorporeal support. J Cardiac Surg. Sep 2013;28(5):522-524. 80. Avalli L, Maggioni E, Sangalli F, Favini G, Formica F, Fumagalli R. Percutaneous leftheart decompression during extracorporeal membrane oxygenation: an alternative to surgical and transeptal venting in adult patients. ASAIO J. Jan-Feb 2011;57(1):38-40. 81. Friesenecker BE, Peer R, Rieder J, et al. Craniotomy during ECMO in a severely traumatized patient. Acta Neurochirurgica. Sep 2005;147(9):993-996; discussion 996. 82. Krenzlin H, Rosenthal C, Wolf S, et al. Surgical treatment of intraparenchymal hemorrhage during mechanical circulatory support for heart-failure--a singlecentre experience. Acta Neurochir. Sep 2014;156(9):1729-1734. 83. Wilson TJ, Stetler WR, Jr., Al-Holou WN, Sullivan SE, Fletcher JJ. Management of intracranial hemorrhage in patients with

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101. Eudailey KW, Yi SY, Mongero LB, Wagener G, Guarrera JV, George I. Trans-diaphragmatic left ventricular venting during peripheral venous-arterial extracorporeal membrane oxygenation. Perfusion. Nov 2015;30(8):701-703. 102. O’Connor TA, Downing GJ, Ewing LL, Gowdamarajan R. Echocardiographically guided balloon atrial septostomy during extracorporeal membrane oxygenation (ECMO). Ped Cardiol. Jul 1993;14(3):167168. 103. Seib PM, Faulkner SC, Erickson CC, et al. Blade and balloon atrial septostomy for left heart decompression in patients with severe ventricular dysfunction on extracorporeal membrane oxygenation. Catheter Cardiovasc Interv. Feb 1999;46(2):179-186. 104. Dahdouh Z, Roule V, Lognone T, Sabatier R, Massetti M, Grollier G. Atrial septostomy in cardiogenic shock related to H1N1 infection. Acute Cardiac Care. Mar 2013;15(1):7-9. 105. Barbone A, Malvindi PG, Ferrara P, Tarelli G. Left ventricle unloading by percutaneous pigtail during extracorporeal membrane oxygenation. Interact Cardiovasc Thorac Surg. Sep 2011;13(3):293-295. 106. Rupprecht L, Florchinger B, Schopka S, et al. Cardiac decompression on extracorporeal life support: a review and discussion of the literature. ASAIO J. Nov-Dec 2013;59(6):547-553. 107. Noyes AM, Ramu B, Parker MW, Underhill D, Gluck JA. Extracorporeal Membrane Oxygenation as a Bridge to Surgery for Infective Endocarditis Complicated by Aorto-Atrial Fistula and Cardiopulmonary Collapse. Texas Heart J. Oct 2015;42(5):471-473.

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62 Extracorporeal Elimination Meral Patel, MD, Rachel Sirignano, MD, Ryan Barbaro, MD, Matthew L. Paden, MD

Extracorporeal life support (ECLS) was Injury Network’s (AKIN) criteria, and the traditionally thought of as providing isolated Kidney Disease Improving Global Outcomes temporary cardiac and/or pulmonary support for (KDIGO) guidelines, have been validated and patients. However, as providers have become allow classification by both urine output or semore comfortable with this technology, the rum creatinine.5-7 Depending on the age, ECLS patients supported have become more complex, mode, and definition used, AKI occurs widely, often with multiple secondary organ failures with reports of its presence in 19-71% of neothat require supportive therapy. The cardiac nates, 20-72% of pediatric, and up to >70% of and pulmonary support that ECLS provides adult ECLS patients.8-12 In many of those same becomes the “platform” upon which multiple studies, an association is established between organ support therapies can be delivered. In AKI and increased mortality. In addition to this chapter, we discuss the use of other extra- diagnosing AKI by urine output and creatinine corporeal therapies, such as continuous renal measures, the concept of fluid overload (FO) replacement therapy (CRRT) and the use of as another manifestation of kidney dysfunction that negatively impacts organ function apheresis procedures during ECLS. and mortality is well established.13-15 In ECLS patients, FO has been associated with impaired Acute Kidney Injury (AKI) during ECLS oxygenation, increased duration of ECLS, and AKI commonly complicates critical illness mortality.16-20 Since both AKI and FO are asand is a risk factor for death in critically ill sociated with increased mortality, treatment of patients of all ages and also for those receiving these comorbidities has been recommended in ECLS. A complete review of this complicated an attempt to improve ECLS outcomes. However, indications for treatment of AKI topic is beyond the scope of this chapter, but assessments of this topic have been completed and FO are not well established. In non-ECLS for neonatal, pediatric, and adult ICU patients.1-3 patients, consensus recommendations by the Historically, the literature on AKI has been dif- ADQI on pharmacological and mechanical fluid ficult to assess, due to multiple differing defini- removal have been published.21,22 With ECLS tions of the condition.4 Recently, standardized patients, indications for treatment are broadly scores, such as the Acute Dialysis Quality divided into AKI, FO, electrolyte disturbances Initiative’s (ADQI) Risk, Injury, Failure, Loss, not amenable to medical therapy, and removal Endstage (RIFLE) criteria, the Acute Kidney of drugs/toxins. Usage varies greatly by ECLS 697

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center.23 The Extracorporeal Life Support Organization (ELSO) guidelines addressing AKI and FO state,

by passing a solution of electrolytes on the nonblood side of the filter, in a counter current direction to the blood flow. This allows equilibration of solutes and water down their “the goal of fluid management is to return concentration gradients in the plasma and the the extracellular fluid volume to normal (dry dialysate to occur. Diffusive clearance is more weight) and maintain it there. The reason is that effective at small solute removal (individual edema caused by critical illness or iatrogenic electrolytes, urea, etc.), compared to larger crystalloid fluid infusion causes lung and myo- molecules. Alternately, convective therapies, cardial failure, adding to the primary problem… such as continuous venovenous hemofiltration When the patient is hemodynamically stable (CVVH), utilize the transmembrane pressure (typically 12 hours) diuretics are instituted and to create a volume of ultrafiltrate by pushing continued until dry weight is achieved. If the water through the membrane. Convective mass diuretic response is not sufficient to achieve transfer occurs providing the ultrafiltrate with negative fluid balance, or if the patient is in small and medium sized solutes, the size of overt renal failure, continuous hemofiltration is which is determined by membrane properties. added to the extracorporeal circuit to maintain Commonly used membranes allow convective fluid and electrolyte balance.”24 clearance of molecules between 500-5000 Daltons. Currently, Chen et al. provide the most Technically, three main methods for introcomprehensive evidence based literature review ducing CRRT into an ECLS circuit exist and of the topic of concomitant CRRT and ECLS 27 use and review of this work is strongly encour- have been reviewed. The first involves having aged.25 Besides expert opinion, little guidance a separate vascular access point that is not a part exists in the medical literature regarding criteria of the ECLS circuit and using a commercially for timing of renal replacement therapy (RRT) available device. This standalone method repreinitiation, or optimal performance during ECLS. sents the simplest approach in a patient who has While RRT can be intermittent or continuous, a vascular catheter prior to ECLS cannulation. CRRT is the most common form used during In this setting, CRRT is managed similar to the ECLS and will be the focus of the following patient who is not on ECLS, with the exception that reductions or elimination of CRRT circuit sections.23 anticoagulation is often possible due to the patient’s ECLS anticoagulation. Placing a new Technical Aspects of CRRT during ECLS dialysis catheter after ECLS cannulation is not Renal support therapies work by isolating routinely recommended due to the increased blood on one side of a semipermeable mem- risk of bleeding due to ECLS anticoagulation. The second method to provide concomitant brane, the properties of which permit solute CRRT and ECLS involves inserting a hemofiland volume exchange through it. Seminars in Dialysis provides an entire issue with a review ter in a shunt created post-pump in the ECLS of CRRT technology, physiology, and modes circuit. The pump flow drives blood through for a more detailed look at this topic.26 In gen- the hemofilter, producing the ultrafiltrate. The eral, multiple modes of providing CRRT exist; volume of ultrafiltrate produced is controlled however, the most commonly used techniques by standard IV pumps and is measured using rest on the principles of diffusion or convection. a bedside urimeter. The ultrafiltrate can be Diffusion based therapies, such as continuous discarded, if the user is seeking to provide only venovenous hemodialysis (CVVHD), work slow continuous ultrafiltration (SCUF), or a 698

Extracorporeal Elimination

replacement fluid containing desired electro- ple factors, including ECLS circuit design, type lytes can be delivered to provide continuous of ECLS pump, and CRRT device software. In venovenous hemofiltration (CVVH). The now general, for roller head pump based ECLS, the treated blood is returned to the ECLS circuit CRRT device can be integrated in the prepump prepump. This method of “in-line” hemofiltra- venous limb of the circuit. In this manner, the tion was the first method used to provide CRRT CRRT pumps blood to the CRRT device and during ECLS, and has the advantages of being returns it to the ECLS circuit. Pressure within simple, inexpensive, and can be performed by the venous limb is usually adequate to allow the the ECLS specialist. However, it has multiple CRRT pressure monitoring software to function. disadvantages. The shunt that returns blood Alternately, in a centrifugal pump based ECLS prepump creates recirculation to the CRRT cir- circuit, it is recommended that the CRRT decuit, reducing its efficiency, but this is usually of vice be connected postpump to reduce the risk insubstantial magnitude. Thus ECLS pump flow of air entrainment due to the negative pressure does not equal patient flow. Consequently, flow in the prepump venous line. Additionally, the must be monitored distal to the shunt. Using software on many CRRT devices will not allow this technique for SCUF can contribute to the the device to start with the magnitude of negadevelopment of multiple electrolyte anomalies, tive pressures seen in the venous line. In this especially in the smaller children, and is not scenario, blood returns from the CRRT circuit recommended. The in-line circuit often has no to the ECLS circuit distal to the postpump vepressure monitoring, which makes identification nous CRRT line, but still pre-oxygenator. This of hemofilter clotting, rupture, or other malfunc- configuration reduces recirculation through tion more difficult. The most important disad- the CRRT device, and additionally allows the vantage of this method relates to inaccuracy in oxygenator to act as a clot and air trap before fluid balance. The IV pumps that are used to blood returns to the patient. The advantages to control ultrafiltrate production as well as deliver using a commercially available CRRT device replacement fluids are not engineered to be used during ECLS include improved fluid balance in this manner. They are not pumps at all, but accuracy compared to the inline method, builtrather flow restrictors, and have a significant er- in standard pressure and flow monitoring, lonror rate (~12.5%) when used in this fashion.28 In ger filter life, and a device engineered for the a laboratory setup of in-line CRRT during ECLS, purpose of providing CRRT.29-31 However, no the difference between prescribed and measured commercially available CRRT device has been ultrafiltration rate was as high as 34 mL/hour specifically designed and approved for use dur(>800 mL/day).29 Thus, careful monitoring of ing ECLS. The disadvantages of this approach both volume of ultrafiltrate created, as well as include device costs and training requirements. replacement fluid delivered, is essential. This can be accomplished either volumetrically or by Outcomes of CRRT during ECLS the use of highly accurate scales (+/- 1 gram) but increases nurse/ECLS specialist workload While the theoretical advantages and diswhich contributes to the reduction of the use of advantages of the differing methods of CRRT this technique. during ECLS are presented above, few outcome Currently, the preferred method to provide data compare these approaches. Santiago et CRRT during ECLS involves introducing a al. examined children on ECLS who received commercially available CRRT device into the concomitant CRRT (2 “in-line”, 6 commercial ECLS circuit. Optimal connection of the CRRT CRRT device, 11 stand alone) and found all device into the ECLS circuit depends on multi- methods “adequate” for fluid and electrolyte 699

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control.31 Additionally, of the 6 children with ELSO centers in the United States and Canada a CRRT device incorporated into the ECLS cir- formed the Kidney Injury During Membrane cuit, they found increased filter life (138.4 hour) Oxygenation (KIDMO) research network to compared to the 36.8 hours seen in other non- further investigate the relationship between AKI, ECLS children with standalone CRRT and 27.2 RRT use, and survival in patients 3.0, and either centers that generally show worse survival in dialysis/hemofiltration/CAVHD required). This patients who require concomitant CRRT/ECLS. limited definition differs markedly from the RI- Tsai et al. evaluated 104 ECLS and acute FLE and KDIGO AKI scoring systems. ECLS dialysis patients and found 76% mortality.33 complications are entered in the ELSO Registry Similarly, Wu et al. described a 70% mortality once per run and no duration information is rate in 102 noncoronary artery bypass graft obtained. Using this definition, the presence of patients receiving ECLS and dialysis support.34 this complication in each age category of respi- Finally, Keilstein et al. reported 83% mortality ratory failure is associated with worse survival in 120 patients receiving ECLS and RRT.35 The (Table 62-1) compared to the overall survival mortality rate in these case series significantly of these groups (74%, 58%, 58%). Similar data exceeds that seen in the ELSO Registry for all exist for the cardiac population. Both kidney adults (60%), all adult respiratory (48%), or injury and the use of RRT are associated with all adult cardiac (70%). The high mortality increased mortality. A subset of six pediatric could be due to a more pronounced effect of Table 62-1. Renal complications and survival from 2016 ELSO Registry report.

Creatinine 1.5-3 Creatinine > 3 Renal replacement therapy

700

Neonatal respiratory failure n (% reported, % survival) 1901 (7, 50) 373 (1, 37) 6124 (21, 50)

Pediatric respiratory failure n (% reported, % survival) 651 (9, 34) 306 (4, 33) 3170 (44, 42)

Adult respiratory failure n (% reported, % survival) 1490 (16, 45) 874 (9, 45) 3731 (41, 48)

Extracorporeal Elimination

AKI in the adult population, higher population mortality of ECLS patients who develop AKI is of cardiac patients in these case series, center greater than patients without AKI. The details specific differences, publication bias, or incor- of optimal treatment of AKI, including the use rect ELSO Registry data. Regardless of the of CRRT during ECLS remain poorly defined, etiology of the disparity, this combination of rely on expert opinion, and vary between ECLS diseases leads to substantial mortality. Multiple centers. Use of CRRT does not appear to inpapers have created prediction models that crease the rate of chronic renal failure at the identify maximum serum free hemoglobin dur- time of discharge. Additional multiple center ing ECLS, lactate level prior to ECLS initiation, data and trials with standardized protocols is SAPS3 score, use of intraaortic balloon pumps, needed to better inform the management of AKI and APACHE IV score at dialysis initiation as during ECLS. potential modifiable risk factors for improving outcome.33,34,36 Now identified, these factors Apheresis during ECLS provide opportunities to test clinical strategies to improve patient survival. Apheresis techniques are methods for Despite limited data, the concern of precipi- separating the blood into its individual compotating chronic renal failure in patients treated nents. Commonly used therapeutic apheresis with concomitant CRRT and ECLS appears procedures are therapeutic plasma exchange unwarranted. Five studies with 123 survivors of (TPE), erythrocytapheresis, leukapheresis, and ECLS/CRRT specifically address renal recov- photopheresis. These therapies have an evolvery.37-41 Only 3 patients (2.4%) did not recover ing history in medical care and comprehensive renal function (2 transplanted, one with high reviews of this topic are available.43 Apheresis creatinine, but not dialysis dependent). All 3 therapies now represent the standard of care for patients presented with complications of newly diseases such as acute stroke in sickle cell disdiagnosed primary kidney disease (pulmonary ease or thrombotic thrombocytopenic purpura hemorrhage from Wegener’s granulomatosis and may play a valuable role in the treatment of [2] and polyangiitis). Less is known about the other diseases. Use of this established technoladult population, with the largest study being ogy has been increasing in critically ill patients, the description of 100 patients at University especially those requiring ECLS. Concomitant of Michigan from 1990-1996, of whom 14 ECLS was once considered a contraindication received CRRT and ECLS, that contains the to apheresis–the patients were just “too sick.” overall comment that “all but 2 of the 54 survi- Increasingly, physicians are willing to provide vors are leading normal, healthy lives”.42 Due these therapies during ECLS and even to place to the lack of strong outcome evidence and patients on ECLS to achieve the cardiorespiratolong-term followup, continued surveillance of ry stability necessary to complete the clinically ECLS/CRRT patients appears warranted. indicated apheresis procedure. This chapter aims to review the limited clinical experience Summary of Concomitant CRRT and ECLS with apheresis during ECLS and methods to Use provide these tandem procedures successfully. Therapeutic cytapheresis, involves the CRRT use for the treatment of AKI and FO removal of a specific cellular element. In is commonly practiced by the ECLS community. erythrocytapheresis, red blood cells (RBCs) Methods of providing these therapies together are removed from the blood and replaced with are not standardized, and no commercially banked RBCs. The most common use for erythavailable product exists. In all populations, rocytapheresis is in the setting of complications 701

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from sickle cell disease, but has other rare uses in the extracorporeal circuit. Citrate is most as well. Leukapheresis is the removal of white commonly used outside of the ECLS setting; blood cells (WBCs) from the blood. Most however, often the heparin provided for ECLS commonly, this is done to harvest stem cells for anticoagulation suffices for this circuit as well. bone marrow transplantation, but also has indi- An extensive review of the mechanisms of these cations in acute leukemias with hyperviscosity anticoagulation techniques is provided in other syndrome leading to organ failure and has been chapters of this text. suggested as a potential therapy for life threatening pertussis infection. Photopheresis involves Indications application of ultraviolet light to the blood in order to modulate immune responses through No ELSO guidelines pertaining to indicadestruction of WBCs that have absorbed a pho- tions for the use of apheresis procedures on tosensitizing agent. Currently, this is used in ECLS currently exist. Instead, the decision graft vs. host disease in hematopoietic stem cell to proceed with apheresis should be based on transplant (HSCT) patients, but also has a role in evidence of effectiveness for the underlying disboth acute and chronic rejection of organ trans- ease and regardless of ECLS support. General plantation recipients. TPE separates and then indications for apheresis procedures are set forth replaces the plasma from the blood. TPE aims by the American Society for Apheresis (ASFA). to remove large molecular weight substances Periodically, AFSA publishes a set of evidence (such as cytokines and antibodies), or highly based guidelines for the use of apheresis, with protein bound molecules while also restoring the last being in 2016.45 These guidelines depleted coagulation factors, proteins, and en- review the medical evidence for apheresis use zymes to regain the homeostasis necessary for by disease, and present a one page summary of clinical recovery.44 TPE is the most commonly recommendations. This summary provides a provided apheresis procedure during ECLS, and list of the therapies, an evidence based grading will be the focus of this review. system for recommending therapy, biologic raCommercially available apheresis devices tionale for the mechanism of apheresis therapy, separate the blood into its component parts a critical review of the clinical literature, and either by centrifugation or filtration. Histori- proposed prescriptions for therapy that include cally, centrifugation techniques are the most both method and duration. Based on the clinicommonly used; however, the introduction of cal evidence review, the ASFA indications for plasma filters that can be used in conjunction TPE are split into categories I-IV. For category with CRRT devices has increased filtration I, apheresis is considered a first line therapy; usage over the last decade. One advantage for category II, it is a second line therapy; for of using dedicated centrifugal apheresis de- category III, data are unclear on the use of vices is the ability to perform many different apheresis and for category IV, evidence suggests apheresis procedure types that are not limited apheresis is harmful or ineffective. Category I indications for apheresis in to only TPE, as when using the CRRT devices with a plasma filter. A lack of evidence to patients on ECLS may include diffuse alveolar suggest clinical outcome superiority between hemorrhage secondary to Wegener’s Granucentrifugation and filtration exists, and choice lomatosis or Goodpasture’s syndrome, severe of method is based on local equipment, staffing cryoglobulinemia, atypical hemolytic uremic resources, and physician experience. Regard- syndrome (HUS) with factor H antibodies, ABO less of method, an anticoagulant is used to avoid incompatible liver or renal transplant, antibody excessive thrombosis due to activation of blood mediated transplant rejection, thrombotic 702

Extracorporeal Elimination

thrombocytopenic purpura (TTP), hyperviscos- tor inhibitors, dermatomyositis/polymyositis, ity syndromes, and fulminant Wilson’s disease. atypical HUS with membrane cofactor protein Similarly, category II indications which may be mutations, refractory immune thrombocytopeseen during ECLS include acute disseminated nia, inclusion body myositis, POEMS syndrome encephalomyelitis, catastrophic antiphospho- (polyneuropathy, organomegaly, endocrinopalipid syndrome, ABO-incompatible HSCT, thy, monoclonal gammopathy and skin changes atypical HUS with complement mutations, syndrome), ABO incompatible deceased donor mushroom poisoning/overdose, humoral renal renal transplant, schizophrenia, lupus nephritis, transplant rejection, severe sickle cell related and either Quinine or Gemcitabine associated acute chest syndrome, and severe cerebral lu- thrombotic microangiopathy.45 Other relative pus.45 Perhaps most commonly, based on review contraindications that need to be considered are of the current literature, TPE has also been related to the effect of citrate when used either frequently used during ECLS for the manage- as an anticoagulant for the procedure or for the ment of sepsis with multi-organ dysfunction blood products that are being used during the syndrome (MODS) and thrombocytopenia as- procedure. Briefly, citrate’s anticoagulation sociated multi-organ failure (TAMOF).46 These effects are due to the depletion of free, ionized uses are listed as category III indications in the extracellular calcium upon which many steps in the coagulation cascade are dependent. Howmost recent AFSA guidelines. As often occurs at the frontier of medical ever, cardiac function may also be negatively care, there will be diseases and clinical scenar- affected (especially in the neonatal population) ios where there is either none or little evidence by low ionized calcium. Additionally, because for the use of apheresis techniques. Essentially of the anticoagulant effect of large amounts of all cases of concomitant use of apheresis and citrate, bleeding may be exacerbated in patients ECLS fall into this category. The ASFA guide- who are already bleeding. In both cases, the lines provide guidance for the clinician in this negative effects of citrate on calcium can be scenario, referring to assessing the approach by mitigated by infusion of additional calcium. using a modified set of McLeod’s Criteria which As is common with complicated patients on help the user demonstrate a biologic rationale ECLS, a thorough weighing of the risks and for the procedure.45 In cases where guidelines benefits of the procedure, both in the short and are not present, prior to initiating treatment cli- long time horizons, should guide the provision nicians should document their reasoning behind of this therapy. why the chosen apheresis procedure provides a mechanism of action that would address the Technical Aspects of Apheresis during ECLS current disease, why that apheresis procedure Similar to the CRRT methods discussed will potentially improve the patient’s condition, the proposed therapeutic plan and duration, and above, apheresis procedures can be provided as how the clinician will assess the efficacy of this stand alone therapy through a separate venous access or provided using the ECLS circuit for therapy. venous access. No evidence exists to suggest a superiority to either method, although integraContraindications tion using the ECLS circuit appears to be more Based on 2016 evidence based AFSA guide- common in the literature likely due to ease of lines, apheresis is ineffective or even harmful use and the potential complications of attaining in patients with amyloidosis, amyotrophic new venous access on an anticoagulated patient. lateral sclerosis, alloantibody coagulation fac703

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For stand alone therapy, apheresis procedures can be done in patients with two large bore peripheral catheters, but ideally patients should have a double lumen central venous line designed for dialysis that is greater than or equal to 7F or a preexisting subcutaneous port designed for apheresis use. Commercially available automated blood cell separators control fluid balance and maintain normal plasma volume to perform the apheresis procedure. Most apheresis circuits have an extracorporeal volume of approximately 350 mL. For patients who weigh 50% underdosing in this child. monitoring of total circuit anticoagulation both For TPE, depending on disease, the ASFA during and immediately after apheresis should guidelines usually recommend processing of be considered. Emphasizing again that none of 1-1.5 PV, which are replaced with either al- the commercially available apheresis devices bumin or fresh frozen plasma (FFP).45 Strict are engineered or validated for use during ECLS, dosing to the individual mL is not necessary for it is not surprising that issues may arise. For apheresis procedures, and practically the dose example, many of the commercially available can be rounded to the nearest unit of product apheresis devices will not run without a bag of (albumin or FFP). This is because for a solely anticoagulant attached and running. During plasma based molecule that can be removed by ECLS when this is not needed and additional anTPE, it is estimated that you remove 63.2% with ticoagulation may be harmful, a bag of normal processing of 1 PV, 77.7% with 1.5 PV, 86.5% saline can be substituted for the citrate allowwith 2 PV, and 95% with 3 PV. If processing ing the apheresis device to mitigate this error. more plasma results in greater reductions, then Similarly, many of the commercially available why do the recommendations usually call for apheresis devices calculate estimated blood and 1-1.5 PV therapies? Many of the molecules plasma volumes based on Nadler’s formula and that we are targeting with TPE are not solely provider entered weight and height. As seen confined to the blood compartment, and will above, when the much larger values are providredistribute with time necessitating multiple ed based on patient plus extracorporeal volume, therapies over time. Additionally, the benefit the devices will often alarm over the concern of increased percentage removal must be bal- that a very large exchange has been ordered and anced by both the time that it takes to perform either may fail to run, or default to providing the the therapy as well as the blood product utiliza- procedure over very extended periods of time tion. When providing apheresis therapies, one (>8 hours). In this situation, either providing must be mindful that while the focus is on the the therapy over the extended duration is posremoval of a target molecule, that many other sible, or more commonly, adjusting the patient blood components can also be removed. Drug weight that is entered to reflect a patient with a dosing in particular is exceptionally compli- similar native (non-ECLS) blood volume. For cated with the use of these multiple methods of example, the 10 kg patient on ECLS described extracorporeal elimination, such as when using above with a total blood volume of 1700 mL ECLS, CRRT, and apheresis concomitantly. could be entered as a 24 kg patient and this While some guidelines and pharmacokinetics would allow processing of a similar volume of data exist, much additional work needs to be plasma over a much more reasonable time (~2 performed and careful, daily, repeated, clinical hours). In any circumstance where one is conassessment of the effect of each prescribed drug sidering overriding or altering manufacturers recommended usage, a formal protocol should 705

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be established and adhered to, with multiple independent practitioners checking the calculations prior to initiating each procedure. Use and Outcomes of Apheresis during ECLS Upon review of the current literature, 172 reports described patients across the world who have been treated with TPE during ECLS (Table 62-2). No randomized clinical trial on any disease has been published that contains the use of apheresis techniques during ECLS. Individual case reports and case series make up the majority of the published literature. Dyer et al. provides the single largest experience of 293 concomitant apheresis and ECLS procedures in 76 adult and pediatric patients.47 In this cohort, the most common pediatric and adult indication was multisystem organ failure and humoral transplant rejection, respectively. They utilized both ECLS and apheresis teams to provide this combined therapy, providing anticoagulation to the ECLS circuit with heparin and citrate for the apheresis circuit. Citrate related complications of hypocalcemia (47% pediatric, 27% adult) and

hypotension (22% pediatric, 34% adult) were both seen and successfully managed. Looking at the remainder of the reported cases in the literature, the most common indications for use were sepsis with either TAMOF or MODS.44,48,5154 Nguyen et al. summarized the rationale for the use of TPE in this cohort of patients.46 The next most prevalent category of use was for antibody removal in active autoimmune diseases55-64 and organ transplantation.65-69 Individual case reports exist for use in ingestions,70-72 hypoxic ischemic encephalopathy,73 hemophagocytic lymphohistiocytosis,74 severe hemolysis while on cardiopulmonary bypass for cardiac transplant,75 and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome associated myocarditis.76 There is significant heterogeneity in these case reports, due to the variety of rare diseases, differences in techniques of ECLS (mode, equipment, etc.), differences in techniques of apheresis (centrifugation vs. filtration, dose, timing of initiation, etc.), and lack of severity of illness scoring. Combined, these factors make commenting on outcomes such as complica-

Table 62-2. Case reports of therapeutic plasma exchange during ECLS. Reference Dyer et al

N

47

53 pediatric 23 adults 293 procedures Sirignano et 30 pediatric al51 9 ECLS/21 CPB 180 procedures Kawai et al44

Dellgren et al69

Hei et al75

706

14 pediatric 51 procedures

11 pediatric incompatible heart transplants 11 procedures 2 pediatric 3 adult 5 procedures

Outcome Measure Resolution of apheresis indications

Result

Year(s)/Center

Apheresis Anticoagulation Equipment Spectra or ECLS Heparin Optia Apheresis Citrate

Successful in 45%

2005-2012 USA - UNC

Survival

79% Survival

2012-2015 USA - CHOA

Optia

PICU survival Organ Failure Index Vasoactive Score

71% survival Improvement in organ failure and vasoactives

2005-2013 USA University of Michigan

If on ECLS Heparin CRRT, Apheresis Citrate Prisma/ PrismaFlex

Survival

8/11 survivors 1990-1999 Canada

Survival Free hemoglobin reduction

All 5 survived 2002-2007 Reduction in China free hemoglobin

No CRRT, Spectra or Optia Spectra

Prisma

ECLS Heparin only

CPB Heparin only

CPB Heparin only

Apheresis Complications Hypocalcemia Hypotension Clot formation in the ECLS circuit Air in line Clot formation Pump malfunction Hypocalcemia Transient hypotension New onset rash

Extracorporeal Elimination

tions and survival difficult. As has been done with the ELSO Registry for ECLS, capturing additional data about patient, prescription, and device related factors in an international database would allow the accrual of data that may allow definition of best practices and ultimately improve outcomes. Summary of Apheresis during ECLS Use of apheresis procedures during ECLS is technologically feasible and rarely used. Guidance related to the appropriateness of apheresis techniques during ECLS, as well as timing and dosing information should be aided by using the ASFA guidelines. When evidence for use is not present in the medical literature, reliance on the modified McLeod’s criteria and the underlying pathophysiology of the disease is necessary. Variation exists on how apheresis procedures are performed during ECLS and anticoagulation strategies. To best describe the potential benefits and harms of this rare combination of procedures, a worldwide registry approach is needed.

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References 1. Selewski DT, Charlton JR, Jetton JG, et al. Neonatal acute kidney injury. Pediatrics 2015;136(2):e463-73. 2. Fortenberry JD, Paden ML, Goldstein SL. Acute kidney injury in children : an update on diagnosis and treatment. Pediatr Clin North Am. 2013 Jun;60(3):669-88. 3. Honore PM, Jacobs R, Hendrickx I, et al. Prevention and treatment of sepsis-induced acute kidney injury:an update. Ann Intensive Care 2015;5(1):51-61. 4. Bellomo R, Kellum JA, Ronco C. Defining and classifying acute renal failure: from advocacy to consensus and validation of the RIFLE criteria. Intensive Care Med 2007;33(3):409-13. 5. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, the ADQI workgroup. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–R212. 6. Mehta RL, Kellum JA, Shah SV, et al. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. 7. Kidney Disease: Improving Global Outcomes (KDIGO.. KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int Suppl.2008;109:S1–S99. 8. Askenazi DJ, Ambalavanan N, Hamilton K, et al.. Acute kidney injury and renal replacement therapy independently predict mortality in neonatal and pediatric noncardiac patients on extracorporeal membrane oxygenation. Pediatr Crit Care Med 2011;12(1):e1-6. 9. Smith AH, Hardison DC, Worsen CR, Fleming GM, Taylor MB. Acute renal failure 708

during extracorporeal support in the pediatric cardiac patient. ASAIOJ 2009;55:412-6. 10. Lou S, MacLaren G, Paul E, Best D, Delzoppos C, Butt W. Hemofiltration is not associated with increased mortality in children receiving extracorporeal membrane oxygenation. Pediatr Crit Care Med 2015;16:161-6. 11. Gadepalli SK, Hirschl RB. Extracorporeal life support: Updates and controversies. Seminars Pediatr Surg 2015;24:8-11. 12. Luo XJ, Wang W, Sheng-shou H, et al.. Extracorporeal membrane oxygenation for treatment of cardiac failure in adult patients. Interactive Cardiovasc Thorac Surg 2009;9:296-300. 13. Arikan AA, Zappitelli M, Goldstein SL, Naipaul A, Jefferson LS, Loftis LL. Fluid overload is associated with impaired oxygenation and morbidity in critically ill children. Pediatr Crit Care Med 2012;13(3)253-8. 14. Sutherland SM, Zappitelli M, Alexander SR, et al. Fluid overload and mortality in children receiving continuous renal replacement therapy: the prospective pediatric continuous renal replacement therapy registry. Am J Kidney Dis. 2010 Feb;55(2):316-25 15. Davison D, Basu RK, Goldstein SL, Chawla LS. Fluid management in adults and children: core curriculum 2014. Am J Kidney Dis. 2014 Apr;63(4):700-12. 16. Roy BJ, Cornish JD, Clark RH. Venovenous extracorporeal membrane oxygenation affects renal function. Pediatrics. 1995;95:573–578. 17. Swaniker F, Kolla S, Moler FW, et al. Extracorporeal life support outcome for 128 pediatric patients with respiratory failure. J Ped Surg. 2000;35(2):197–202. 18. Weber TR, Kountzman B. Extracorporeal membrane oxygenation for nonneonatal pulmonary and multiple organ failure. J Pediatr Surg. 1998;33:1605–1609.

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19. Kelly RE, Phillips JD, Foglia RP, et al. Pulmonary edema and fluid mobilization as determinants of the duration of ECMO support. J Pediatr Surg. 1991;26:1016–1022. 20. Selewski DT, Cornell TT, Blatt NB, et al. Fluid overload and fluid removal in pediatric patients on extracorporeal membrane oxygenation requiring continuous renal replacement therapy. Crit Care Med 2012;40(9):2694-9. 21. Goldstein SL, Bagshaw SM, Cecconi M, et al. Pharmacological management of fluid overload. Br. J. Anaesth 2014;114(5):75663. 22. Rosner MH, Osterman M, Murugan R, et al. Indications and management of mechanical fluid removal in critical illness. Br. J. Anaesth 2014;114(5):764-71. 23. Fleming GM, Askenazi DJ, Bridges BC, et al. A multicenter international survey of renal supportive therapy during ECMO: the Kidney Intervention During Extracorporeal Membrane Oxygenation (KIDMO) group. ASAIO J. 2012 Jul-Aug;58(4):407-14. 24. Extracorporeal Life Support Organization – General Guidelines for all cases. http:// www.elso.org/Resources/Guidelines.aspx. Last accessed 9/22/2016. 25. Chen H, Yu R, Yin N, Zhou J. Combination of extracorporeal membrane oxygenation and continuous renal replacement therapy in critically ill patients: a systematic review. Critical Care 2014;18:675. 26. Multiple authors. Semin Dial. 2009 MarApr;22(2):1-193. 27. Askenazi DJ, Selewski DT, Paden ML, et al. Renal replacement therapy in critically ill patients receiving extracorporeal membrane oxygenation. Clin J Am Soc Nephrol 2012 7:1328-36. 28. Jenkins R, Harrison H, Chen B, Arnold D, Funk J. Accuracy of intravenous infusion pumps in continuous renal replacement therapies. ASAIO J. 1992 OctDec;38(4):808-10.

29. Sucosky P, Dasi LP, Paden ML, Fortenberry JD, Yoganathan AP. Assessment of current continuous hemofiltration systems and development of a novel accurate fluid management system for use in extracorporeal membrane oxygenation. J Med Devices 2008;2:035002. 30. Symons JM, McMahon MW, Karamlou T, Parrish AR, McMullen MM. Continuous renal replacement therapy with an automated monitor is superior to a free-flow system during extracorporeal life support. Pediatr Crit Care Med 2013;14(9):e404-8. 31. Santiago MJ, Sanches A, Lopez-Herce J, et al. The use of continuous renal replacement therapy in series with extracorporeal membrane oxygenation. Kidney Int 2009;76:1289-92. 32. Shum HP, Kwan AM, Chan KC, Yan WW. The use of regional citrate anticoagulation continuous venovenous hemofiltration in extracorporeal membrane oxygenation. ASAIOJ 2014;60:413-8. 33. Tsai CW, Lin YF, Wu VC, et al. SAPS 3 at dialysis commencement is predictive of hospital mortality in patients supported by extracorporeal membrane oxygenation and acute dialysis. Eur J Cardio Thoracic Surg 2008;34:1158-64. 34. Wu VC, Tsai HB, Yeh YC, et al. Patients supported by extracorporeal membrane oxygenation and acute dialysis: acute physiology and chronic health evaluation score in predicting hospital mortality. Artif Organs 2010;34(10):828-35. 35. Kielstein JT, Heiden AM, Beutel G, et al. Renal function and survival in 200 patients undergoing ECMO therapy. Nephrol Dial Transplant. 2013 Jan;28(1):86-90. 36. Lv L, Long C, Liu J, et al. Predictors of acute renal failure during extracorporeal membrane oxygenation in pediatric patients after cardiac surgery. Artif Org 2016 May; 40(5):E79-83.

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37. Cavagnaro F, Kattan J, Godoy L, et al. Continuous renal replacement therapy in neonates and young infants during extracorporeal membrane oxygenation. Int J Artif Organs 2007;30:220-6. 38. Hoover NG, Heard M, Reid C, et al. Enhanced fluid management with continuous venovenous hemofiltration in pediatric respiratory failure patients receiving extracorporeal membrane oxygenation. Intensive Care Med 2008;34:2241-7. 39. Paden ML, Warshaw BL, Heard ML, Fortenberry JD. Recovery of renal function and survival after continuous renal replacement therapy during extracorporeal membrane oxygenation. Pediatr Crit Care Med 2011;12:153-8. 40. Wolf MJ, Chanani NK, Heard ML, Kanter KR, Mahle WT. Early renal replacement therapy during pediatric cardiac extracorporeal support increases mortality. Ann Thorac Surg 2013; 96:917-22. 41. Meyer RJ, Brophy PD, Bunchman TE, et al. Survival and renal function in pediatric patients following extracorporeal life support with hemofiltration. Pediatr Crit Care Med. 2001;2:238–242. 42. Kolla S, Awad SS, Rich PB, Schreiner RJ, Hirschl RB, Bartlett RH. Extracorporeal life support for 100 adult patients with severe respiratory failure. Ann Surg. 1997;226(4):544–66. 43. Ward, D. M. (2011), Conventional apheresis therapies: A review. J. Clin. Apheresis, 2011;26: 230–238. 44. Kawai Y, Cornell TT, Cooley EG, et al. Therapeutic plasma exchange may improve hemodynamics and organ failure among children with sepsis-induced multiple organ dysfunction syndrome receiving extracorporeal life support. Pediatr Crit Care Med. 2015 May;16(4):366-74. 45. Schwartz J, Padmanabhan A, Agui N, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based 710

approach from the Writing Committee of the American Society for Apheresis: the seventh special issue. J Clin Apher. 2016 Jun;31(3):149-62. 46. Nguyen TC, Carcillo JA. Bench-to-bedside review: Thrombocytopenia-associated multiple organ failure – a newly appreciated syndrome in the critically ill. Crit Care 2006;10(6):235. 47. Dyer M, Neal MD, Rollins-Raval MA, Raval JS. Simultaneous extracorporeal membrane oxygenation and therapeutic plasma exchange procedures are tolerable in both pediatric and adult patients. Transfusion. 2014 Apr;54(4):1158-65. 48. Bridges BC, Hardison D, Pietsch J. A case series of the successful use of ECMO, continuous renal replacement therapy, and plasma exchange for thrombocytopeniaassociated multiple organ failure. J Pediatr Surg. 2013 May;48(5):1114-7. 49. Hites M, Dell’Anna AM, Scolletta S, Taccone FS. The challenges of multiple organ dysfunction syndrome and extra-corporeal circuits for drug delivery in critically ill patients. Adv Drug Delivery Rev 2014;77:1221. 50. Jamal JA, Economou CJ, Lipman J, Roberts JA. Improving antibiotic dosing in special situations in the ICU: burns, renal replacement therapy and extracorporeal membrane oxygenation. Curr Opin Crit Care 2012;18:460-71. 51. Sirignano R, Meyer E, Fasano R, Paden ML. Tandem procedures associated with therapeutic apheresis: A multidisciplinary approach to a high volume pediatric center. Special Issue Abstracts From the American Society for Apheresis 37th Annual Meeting, May 4–7, 2016 Palm Springs, California. J. Clin. Apheresis, 2016; 31: 71–140. doi:10.1002/jca.21452. 52. Patel P, Nandwani V, Vanchiere J, et al: Use of therapeutic plasma exchange as a rescue therapy in 2009 pH1N1 influenza

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A—An associated respiratory failure and hemodynamic shock. Pediatr Crit Care Med 2011;12(2):e87-e89 53. Tabbutt S, Leonard M, Godinez RI et al: Severe influenza B myocarditis and myositis. Pediatr Crit Care Med 2004;5(4):403-406 54. Mok Q, Butt W: The outcome of children admitted to intensive care with meningococcal septicaemia. Intensive Care Med 1996;22:259-263. 55. Hofenforst-Schmidt W, Peterman A, Visouli A, et al: Successful application of extracorporeal membrane oxygenation due to pulmonary hemorrhage secondary to granulomatosis with polyangitis. Drug Des Devel Ther 2013;7:627-633. 56. Barnes SL, Naughton M, Douglass J, Murphy D: Extracorporeal membrane oxygenation with plasma exchange in a patient with alveolar hemorrhage secondary to Wegener’s granulomatosis. Intern Med J 2012;341-342 57. Ahmed S, Aziz T, Cochran J, Highland K: Use of extracorporeal membrane oxygenation in a patient with diffuse alveolar hemorrhage. Chest 2004;126:305-309 58. Yusuff H, Malagon I, Robson K, et al: Extracorporeal membrane oxygenation for life-threatening ANCA-positive pulmonary capillaritis. A review of UK experience. Heart Lung Vessel 2015;7(2):159-167. 59. Agarwal HS, Taylor MB, Grzeszczak MJ, et al: Extra corporeal membrane oxygenation and plasmapheresis for pulmonary hemorrhage in microscopic polyangitis. Pediatr Nephrol 2005;20:526-528 60. Kolovos NS, Schuerer DJE, Moler FW, et al: Extracorporeal life support for pulmonary hemorrhage in children: A case series. Crit Care Med 2002;30(3):577-580 61. Di Maria MV, Hollister R, Kaufman J: Care report: severe microscopic polyangiitis successfully treated with extracorporeal membrane oxygenation and immunosup-

pression in a pediatric patient. Curr Opin Pediatr 2008;20:740-742 62. Dalabih A, Pietsch J, Jabs K et al: Extracorporeal membrane oxygenation as a platform for recovery: A case report of a child with pulmonary hemorrhage, refractory hypoxemic respiratory failure, and new onset goodpasture syndrome. JECT 2012;44:7577 63. Gupta T, Khera S, Kolte D, et al: Back from the brink: Catastrophic antiphospholipid syndrome. Am J Med 2015;128(6):574-577 64. Dornan RIP: Acute postoperative biventricular failure associated with antiphospholipid antibody syndrome. Br J Anaesth 2004;92:748-754 65. Jhang J, Middlesworth W, Shaw R, et al: Therapeutic plasma exchange performed in parallel with extra corporeal membrane oxygenation for antibody mediated rejection after heart transplant. J Clin Apher 2007;22:333-338 66. Wang SS, Chou NK, Ko WJ, et al. Effect of plasmapheresis for acute humoral rejection after heart transplantation. Transplant Proc 2006;38:3692-3694 67. Saito S, Matsumiya G, Fukushima N et al: Successful treatment of cardiogenic shock caused by humoral cardiac allograft rejection. Circ J 2009;73:970-973 68. Stendahl G, Berger S, Ellis T et al: Humoral rejection after pediatric heart transplantation: a case report. Prog Transplant 2010;20(3):288-291 69. Dellgran G, Koirala B, Sakopoulus A, et al: Pediatric heart transplantation: improving results in high-risk patients. J Thorac Cardiovasc Surg 2001;121(4):782-791 70. Kolcz J, Peitrzyk J, Januszewska K, et al: Extracorporeal life support in severe propranolol and verapamil intoxication. J Intensive Care Med 2007;22(6):381-385 71. Koschny R, Lutz M, Seckinger J, et al: Extracorporeal life support and plasmapher-

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esis in a case of severe polyintoxication. J Emerg Med 2014;47(5):527-531 72. Maclaren G, Butt W, Cameron P, et al: Treatment of polypharmacy overdose with multimodality extracorporeal life support. Anaesth Intensive Care 2005;33:120-123 73. Wang KY, Singer HS, Crain B et al: Hypoxic-ischemic encephalopathy mimicking acute necrotizing encephalopathy. Pediatr Nephrol 2015;52:110-114 74. Kitazawa Y, Saito F, Nomura S, et al: A case of hemophagocytic lymphohistiocytosis after the primary Epstein-barr virus infection. Clin Appl Thromb Hemost 2007;13(3): 323-328 75. Hei FL, Irou SY, Ma J, Long C. Plasma exchange during cardiopulmonary bypass in patients with severe hemolysis in cardiac surgery. ASAIO Journal 2009;55(1):78-82 76. Lo MH, Huang CF, Chang LS et al: Drug reaction with eosinophilia and systemic symptoms syndrome associated myocarditis: a survival experience after extracorporeal membrane oxygenation support. J Clin Pharm Ther 2013;38(2):172-174.

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63 Extracorporeal Carbon Dioxide Removal Darryl Abrams, MD, Daniel Brodie, MD, Antonio Pesenti, MD

Introduction

be considered in patients with acute respiratory failure without preexisting lung disease or in those with acute exacerbations of chronic lung disease either as a bridge to recovery (BTR) or as a bridge to transplantation (BTT). However, because no destination device for carbon dioxide removal currently exists, careful patient selection for ECCO2R will optimize outcomes in this setting, particularly among those patients with chronic lung disease.

Extracorporeal carbon dioxide removal (ECCO2R) is a form of extracorporeal life support in which the primary intention of the technique is the removal of carbon dioxide rather than the delivery of oxygen.1,2 For a given blood flow, extracorporeal support more efficiently exchanges carbon dioxide than oxygen, in large part due to the differences in how carbon dioxide and oxygen are transported within blood.1 Extracorporeal membrane oxygenation Considerations for ECCO2R (ECMO) traditionally requires large bore cannulae to achieve sufficient blood flow rates to meet Acute Respiratory Distress Syndrome oxygenation needs. In contrast, ECCO2R may be able to achieve clinically relevant carbon In severe forms of acute respiratory distress dioxide removal goals at blood flow rates as low syndrome (ARDS), the blood flow of ECCO R 2 as 200-1,500 ml per minute.3 Therefore, when would be insufficient to correct the severe the main intention of extracorporeal support is oxygenation impairments. However, ECCO R 2 carbon dioxide removal, smaller cannulae may is emerging as a potential strategy in more be used, which may, in turn, minimize the com- moderate forms of ARDS (Table 63-1).5 Lung plexity and risk of insertion and maintenance protective ventilation, targeting tidal volumes of the circuit.4,5 of 6 mL/kg predicted body weight (PBW) or ECCO2R may be used either to supplement less and plateau airway pressures less than or invasive mechanical ventilation (IMV) when equal to 30 cm of H O, has been demonstrated the ventilator alone is insufficient to manage to improve survival2in ARDS and remains the hypercapnia or to minimize the potentially current standard of care.6 However, both animal injurious effects of IMV. In selected patients, and human studies have suggested that targetit may allow for discontinuation of the ven- ing even lower tidal volumes and airway prestilator entirely, or even prevent endotracheal sures may further reduce ventilator-associated intubation and IMV altogether. ECCO2R may lung injury (VALI).7-10 Post hoc analysis of the 713

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ARMA trial demonstrated a linear relationship renewed interest in demonstrating efficacy of between plateau airway pressures and decreased such a strategy. Terragni et al. demonstrated a mortality that held true well below the 30 cm of reduction in inflammatory markers associated H2O targeted in the study, suggesting there is with VALI by lowering plateau airway pressures no safe upper limit of plateau airway pressure.8 from an average of 29 cm H2O to 25 cm H2O in Although lung protective ventilation (tidal vol- the context of ECCO2R-assisted reductions in umes and plateau airway pressures below the tidal volumes from approximately 6 to 4 mL/ current standard of care) may reduce mortality kg.9 In a subsequent study, Bein et al. randombeyond what can be achieved with the current ized subjects with moderate to severe ARDS to low respiratory system, compliance and dead either conventional lung protective ventilation space fraction may limit the ability to imple- or ECCO2R-assisted very low tidal volume ment such a strategy because of the develop- ventilation (3 mL/kg PBW).10 Although the ment of intolerable levels of hypercapnia and study did not show a difference in the primary acidemia. ECCO2R can facilitate the application outcome of ventilator-free days (VFD), post hoc of very low tidal volumes by correcting the ac- analysis showed a significant reduction in VFD companying respiratory acidosis, as has been in the ECCO2R group among those with more demonstrated in two prospective human stud- severe hypoxemia. Despite these findings, studies.9,10 This concept of using ECCO2R to manage ies have yet to demonstrate a significant clinical ventilation and minimize IMV in ARDS is not benefit from ECCO2R-assisted very low tidal new; Gattinoni and colleagues experimented volume ventilation.15 Additional data is needed with this strategy since the 1970s.4,11-13 However, to demonstrate both efficacy and an acceptable early efforts to show a benefit of ECCO2R- risk profile before such a strategy can be recfacilitated lung protective ventilation were ommended for use outside the research setting. unsuccessful, in part because of complications associated with early versions of the technol- Acute-on-Chronic Lung Disease ogy.14 With improvements in extracorporeal ECCO2R may be considered in patients with circuitry over the last several years, there is acute-on-chronic lung disease when hypercapnia and respiratory acidosis persist despite the Table 63-1. Considerations and contraindications for ECCO2R in respiratory failure. use of IMV, or when endotracheal intubation and IMV are judged to be too invasive. Acute exacerbations of chronic obstructive pulmonary Considerations disease (COPD) represent the most obvious ARDS to achieve very low tidal volume targets for such a strategy, particularly when ventilation (insufficient evidence to IMV contributes to dynamic hyperinflation recommend) Bridge to recovery from acute exacerbations of and the generation of intrinsic positive endhypercapnic respiratory failure expiratory pressure. Several case series have Status asthmaticus (low level evidence) demonstrated the ability of ECCO2R to correct Other chronic lung diseases (insufficient severe, acute respiratory acidosis,16-20 which in evidence to recommend) turn may improve dyspnea enough to facilitate Bridge to transplantation for end-stage respiratory failure extubation and mobilization.16,20 In some cirContraindications cumstances, ECCO2R may provide sufficient Severe hypoxemia for which higher blood flow gas exchange support to preclude the need for rates are needed IMV altogether, with the advantage of avoiding Terminal exacerbation of end-stage respiratory ventilator-associated complications.18,21-24 failure without eligibility for transplantation 714

Extracorporeal Carbon Dioxide Removal

Severe, refractory status asthmaticus is another obstructive lung disease process for which ECCO2R should be seriously considered, in particular because of the deleterious consequences of positive pressure ventilation on gas exchange and hemodynamic stability, although the data for such use remain limited to observational studies.25,26 Exacerbations or progression of chronic lung diseases other than COPD and asthma, when manifested as hypercapnia without significant hypoxemia, may likewise benefit from the initiation of ECCO2R, with or without IMV support. However, in all cases where a significant degree of chronic lung disease exists, there must be strong consideration for both the reversibility of the acute process, the potential for development of severe hypoxemia, and the eligibility of the patient for lung transplantation.27 There is no universally accepted threshold of pH or carbon dioxide for which ECCO2R is indicated. Timing of initiation of ECCO2R depends in large part on the intention of the therapy (eg, replacement vs. supplementation of IMV; BTR vs. BTT). Studies intending to better define the optimal patient population and threshold gas exchange abnormalities for which ECCO2R should be initiated are ongoing.28 Contraindications and Limitations Because extracorporeal carbon dioxide removal is more efficient than oxygenation,3,4,11-13 ECCO2R can be achieved with lower blood flow rates and smaller cannulae (often referred to as “catheters” in this setting) than what is required for oxygenation. Therefore, extracorporeal circuits specifically designed for ECCO2R-level blood flow will prove inadequate to achieve sufficient oxygenation in patients with concomitant severe hypoxemia. Patients who have severe hypoxemia or are at risk for developing severe hypoxemia are poor candidates for ECCO2R (Table 63-1). However, if severe hypoxemia develops, certain extracorporeal circuits may be

modified (eg, additional drainage cannula) to accommodate higher blood flow rates (ie, ECLS). The other major limitation to ECCO2R is the lack of a destination device. Patients with terminal exacerbations of endstage lung disease who are ineligible for lung transplantation should not be offered ECCO2R. For patients supported with ECCO2R who cannot achieve recovery or transplantation, the focus of clinical care should shift toward optimizing patient comfort and withdrawal of life sustaining therapy, as appropriate.29 Physiological Targets The physiological target of ECCO2R should be the patient’s arterial blood pH, rather than the partial pressure of carbon dioxide, because many patients with chronic lung disease who are candidates for ECCO2R will have chronic hypercapnia.16 In most circumstances, and without a significant concomitant metabolic acidosis, the sweep gas flow rate should be adjusted to achieve a near-normal pH. However, in the subset of patients receiving ECCO2R who have chronic hypercapnia and a compensatory metabolic alkalosis, and who may be candidates for lung transplantation, the sweep gas flow rate should be adjusted to achieve a slightly alkalemic pH (eg, 7.41-7.45) to allow for a gradual reversal of the alkalosis in anticipation of transplantation. The expected physiological effect of ECCO2R is mainly decreased minute ventilation. This in turn will increase the risk of alveolar collapse of the native diseased lung, which is usually managed by maintaining minimum airway pressure. At the same time, a decrease in alveolar partial pressure of oxygen, driven by the decreased alveolar ventilation, may require a compensatory increase in fraction of inspired oxygen (FiO2) to maintain arterial oxygenation, particularly when the baseline FiO2 is in the low range.30

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Circuit Configurations

blood flow, though this may require adapters to connect the smaller tubing to standard circuit components. In the context of lower blood flow, the extracorporeal membrane’s surface area and gas exchange efficiency are paramount. Novel strategies, including the incorporation of carbonic anhydrase, blood acidification, and electrodialysis, are being investigated as means of maximizing ECCO2R efficiency by increasing the amount of carbon dioxide available for removal.37-40 Of note, although neonatal and pediatric membranes are rated for lower blood flows, the surface area of these smaller devices, when combined with low blood flow, may be insufficient to achieve the desired carbon dioxide removal. More data is needed to define the optimal combination of blood flow, membrane surface area, and ancillary techniques for adequate carbon dioxide removal for a given disease state.

Either venovenous or arteriovenous circuits may be utilized to implement ECCO2R, as both configurations can remove carbon dioxide at low blood flow rates.21,23,31 However, it is important to recognize differences between the two strategies. Venovenous ECCO2R requires an extracorporeal pump (typically centrifugal) to generate blood flow.32 Centrifugal pumps generate negative pressures that may damage blood elements, although this phenomenon is less likely at low blood flow rates used in ECCO2R. Venovenous ECCO2R has the advantage of avoiding arterial cannulation, and may be accomplished with single-site venous access when using dual-lumen cannulae.16,33 Upper body single-site access is the preferred cannulation strategy for patients in whom ambulation is anticipated, although femoral venous cannulation is not a contraindication to ambulation.34 In contrast, arteriovenous ECCO2R relies on native cardiac output to generate blood flow Anticoagulation Strategy and Impact of Low through a pumpless extracorporeal circuit.31 It Extracorporeal Blood Flow requires femoral arterial cannulation,23 which may compromise distal limb perfusion and limit Thrombotic risk within the circuit genermobilization. ally increases as extracorporeal blood flow No consensus on the optimal extracorporeal rates decrease. This may be particularly true blood flow or cannula sizes for ECCO2R exists. with current ECCO2R technology, which tends Blood flow and cannula selection depend on to couple low blood flow rates with relatively the amount of carbon dioxide removal required, high extracorporeal membrane surface area. The which in turn relates to the underlying disease use of low levels of systemic anticoagulation state. In patients with exacerbations of COPD, blood flow rates in the published literature have Table 63-2. Extracorporeal blood flow rates and cannula sizes used in studies of ECCO2R. ranged from 177 mL/min to 1.7 L/min, with cannula sizes in venovenous ECCO2R varying ECCO2R Blood Cannula Size from two 12Fr single-lumen cannulae to 14Fr to Flow Rate (L/min) (Fr) 23Fr dual-lumen cannulae.16-18,23,35 Cannulae in COPD Abrams et al. 1.0-1.7 20-23 arteriovenous ECCO2R have ranged from 13Fr Burki et al. 0.43 15.5 to 15Fr for arterial cannulation and 13Fr to 17Fr Del Sorbo et al. 0.18-0.33 14 Gattinoni et al. 0.4-0.6 12 x2 for venous cannulation, the choice depends, in Kluge et al. 1.1 13-15 (arterial) part, on vessel diameter (Table 63-2).23,36 Like13-17 (venous) Roncon-Albuquerque et al 0.7-1.0 19 wise, smaller tubing diameter (1/4” or 3/16”) Facilitation of Lung Protective Ventilation in ARDS than what is commonly used for ECMO (3/8” Bein 1.2 15 (arterial) 17 (venous) or 1/2”) may be considered in the context of low Terragni 0.2-0.4 14 716

Extracorporeal Carbon Dioxide Removal

increases the thrombotic risk even further. The existing literature reports varying rates of circuit thrombosis at blood flow rates less than 600 mL/ min when activated partial thromboplastin times of 1.5 to 2.3 times baseline are targeted.17,18 More data is needed to determine the optimal level of anticoagulation for ECCO2R. Management Considerations in the Event of Circuit Failure In the event of circuit failure, management of patients should rely on conventional management of hypercapnia while the circuit malfunction is corrected. In endotracheally intubated patients, minute ventilation should be increased as needed. In nonendotracheally intubated patients, noninvasive positive-pressure ventilation should be considered. If noninvasive ventilatory support is insufficient, tracheal intubation and IMV should be initiated.

Conclusion With advances in extracorporeal technology, ECCO2R has reemerged as a potential management strategy for certain subsets of patients with respiratory failure. The ability to perform ECCO2R at low blood flow rates via smaller cannulae than are required for ECMO, effectively the equivalent of dialysis for the lung, could significantly alter the approach to hypercapnic respiratory failure. However, studies showing both a benefit on meaningful clinical outcomes and an acceptable risk profile are needed before such a strategy can be recommended for clinical use.

Weaning ECCO2R In patients receiving ECCO 2R as BTR, assessments of readiness to wean should be undertaken as the acute process resolves. In patients receiving IMV, the sweep gas flow rate may be reduced in order to maintain normal pH, while ventilator settings are liberalized within the limits of lung-protective ventilation as native lung function improves. In patients who are breathing without the assistance of the ventilator, the sweep gas flow rate may be incrementally lowered with corresponding assessments of both the patient’s respiratory status and pH by arterial blood gas to ensure adequate spontaneous ventilation without excess work of breathing. In patients with ARDS, respiratory system compliance should be taken into consideration as the tidal volumes are liberated, avoiding excessive plateau airway pressures. In acute exacerbations of COPD, close monitoring for dynamic hyperinflation or increased work of breathing should occur as ECCO2R is weaned. 717

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bon dioxide removal. Anesthesiology. Oct 2009;111(4):826-835. 10. Bein T, Weber-Carstens S, Goldmann A, et al. Lower tidal volume strategy ( approximately 3 ml/kg) combined with extracorporeal CO2 removal versus ‘conventional’ protective ventilation (6 ml/kg) in severe ARDS: the prospective randomized Xtravent-study. Intensive Care Med. May 2013;39(5):847-856. 11. Gattinoni L, Kolobow T, Agostoni A, et al. Clinical application of low frequency positive pressure ventilation with extracorporeal CO2 removal (LFPPV-ECCO2R) in treatment of adult respiratory distress syndrome (ARDS). Int J Artif Organs. Nov 1979;2(6):282-283. 12. Gattinoni L, Pesenti A, Caspani ML, et al. The role of total static lung compliance in the management of severe ARDS unresponsive to conventional treatment. Intensive Care Med. 1984;10(3):121-126. 13. Gattinoni L, Pesenti A, Mascheroni D, et al. Low-frequency positive-pressure ventilation with extracorporeal CO2 removal in severe acute respiratory failure. JAMA. Aug 15 1986;256(7):881-886. 14. Morris AH, Wallace CJ, Menlove RL, et al. Randomized clinical trial of pressurecontrolled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med. Feb 1994;149(2 Pt 1):295-305. 15. Bein T, Weber-Carstens S, Goldmann A, et al. Lower tidal volume strategy ( approximately 3 ml/kg) combined with extracorporeal CO(2) removal versus ‘conventional’ protective ventilation (6 ml/kg) in severe ARDS : The prospective randomized Xtravent-study. Intensive Care Med. Jan 10 2013. 16. Abrams DC, Brenner K, Burkart KM, et al. Pilot study of extracorporeal carbon dioxide removal to facilitate extubation and ambulation in exacerbations of chronic

Extracorporeal Carbon Dioxide Removal

obstructive pulmonary disease. Annals of the American Thoracic Society. Aug 2013;10(4):307-314. 17. Burki NK, Mani RK, Herth FJ, et al. A Novel Extracorporeal CO2 Removal System: Results of a Pilot Study of Hypercapnic Respiratory Failure in Patients With COPD. Chest. Mar 1 2013;143(3):678-686. 18. Del Sorbo L, Pisani L, Filippini C, et al. Extracorporeal CO2 Removal in Hypercapnic Patients At Risk of Noninvasive Ventilation Failure: A Matched Cohort Study With Historical Control. Crit Care Med. Sep 16 2014. 19. Abrams D, Roncon-Albuquerque R, Jr., Brodie D. What’s new in extracorporeal carbon dioxide removal for COPD? Intensive Care Med. May 2015;41(5):906-908. 20. Roncon-Albuquerque R, Jr., Carona G, Neves A, et al. Venovenous extracorporeal CO2 removal for early extubation in COPD exacerbations requiring invasive mechanical ventilation. Intensive Care Med. Dec 2014;40(12):1969-1970. 21. Terragni PP, Birocco A, Faggiano C, Ranieri VM. Extracorporeal CO2 removal. Contrib Nephrol. 2010;165:185-196. 22. Olsson KM, Simon A, Strueber M, et al. Extracorporeal membrane oxygenation in nonintubated patients as bridge to lung transplantation. Am J Transplant. Sep 2010;10(9):2173-2178. 23. Kluge S, Braune SA, Engel M, et al. Avoiding invasive mechanical ventilation by extracorporeal carbon dioxide removal in patients failing noninvasive ventilation. Intensive Care Med. Oct 2012;38(10):16321639. 24. Fuehner T, Kuehn C, Hadem J, et al. Extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation. Am J Respir Crit Care Med. Apr 1 2012;185(7):763-768. 25. Mikkelsen ME, Woo YJ, Sager JS, Fuchs BD, Christie JD. Outcomes using extra-

corporeal life support for adult respiratory failure due to status asthmaticus. ASAIO J. Jan-Feb 2009;55(1):47-52. 26. Brenner K, Abrams D, Agerstrand C, Brodie D. Extracorporeal carbon dioxide removal for refractory status asthmaticus: experience in distinct exacerbation phenotypes. Perfusion. Jul 10 2013. 27. Biscotti M, Sonett J, Bacchetta M. ECMO as bridge to lung transplant. Thoracic surgery clinics. 2015;25(1):17-25. 28. Sklar MC, Beloncle F, Katsios CM, Brochard L, Friedrich JO. Extracorporeal carbon dioxide removal in patients with chronic obstructive pulmonary disease: a systematic review. Intensive Care Med. Jun 25 2015. 29. Abrams DC, Prager K, Blinderman CD, Burkart KM, Brodie D. Ethical dilemmas encountered with the use of extracorporeal membrane oxygenation in adults. Chest. Apr 2014;145(4):876-882. 30. Gattinoni L, Kolobow T, Tomlinson T, White D, Pierce J. Control of intermittent positive pressure breathing (IPPB) by extracorporeal removal of carbon dioxide. Br J Anaesth. Aug 1978;50(8):753-758. 31. Bein T, Weber F, Philipp A, et al. A new pumpless extracorporeal interventional lung assist in critical hypoxemia/hypercapnia. Crit Care Med. May 2006;34(5):13721377. 32. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med. Nov 17 2011;365(20):19051914. 33. Javidfar J, Brodie D, Wang D, et al. Use of bicaval dual-lumen catheter for adult venovenous extracorporeal membrane oxygenation. Ann Thorac Surg. Jun 2011;91(6):1763-1768; discussion 1769. 34. Abrams D, Javidfar J, Farrand E, et al. Early mobilization of patients receiving extracorporeal membrane oxygenation: a

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retrospective cohort study. Crit Care. Feb 27 2014;18(1):R38. 35. Pesenti A, Rossi GP, Pelosi P, Brazzi L, Gattinoni L. Percutaneous extracorporeal CO2 removal in a patient with bullous emphysema with recurrent bilateral pneumothoraces and respiratory failure. Anesthesiology. Mar 1990;72(3):571-573. 36. Kohler K, Valchanov K, Nias G, Vuylsteke A. ECMO cannula review. Perfusion. Mar 2013;28(2):114-124. 37. Arazawa DT, Oh HI, Ye SH, et al. Immobilized Carbonic Anhydrase on Hollow Fiber Membranes Accelerates CO(2) Removal from Blood. Journal of membrane science. Jun 1 2012;404-404:25-31. 38. Zanella A, Mangili P, Redaelli S, et al. Regional blood acidification enhances extracorporeal carbon dioxide removal: a 48-hour animal study. Anesthesiology. Feb 2014;120(2):416-424. 39. Zanella A, Castagna L, Salerno D, et al. Respiratory Electrodialysis: a Novel, Highly Efficient, Extracorporeal CO Removal Technique. Am J Respir Crit Care Med. Jun 6 2015. 40. Abrams D, Brodie D. The clinical management of patients on partial/total extracorporeal support. Curr Opin Crit Care. Feb 2016;22(1):73-79.

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64 Other Forms of Extracorporeal Cardiovascular Support – IABP, IMPELLA, VAD Federico Pappalardo, MD, Giulio Melisurgo, MD

Introduction The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) I “crash and burn” and II “sliding on inotropes” profiles describe those patients who are in critical cardiogenic shock, despite escalating inotropic support.1 In such patients, mechanical circulatory support (MCS) is required to restore hemodynamics and maintain adequate systemic perfusion: ECMO, intraaortic balloon pump (IABP), Impella, and BiVAD with Levi-

tronix CentriMag are the most commonly used devices for short and intermediate-term support (Table 64-1).2 As a general rule, implantable assist devices (intracorporeal left assist devicesLVADs) or total artificial heart are not used in INTERMACS I patients. In clinical practice, there are also some patients with the most severe form of ventricular dysfunction in whom shock is refractory to a single device (INTERMACS 0). In such patients a single device approach is not enough and the simultaneous use of different devices

Table 64-1. Comparison of devices.

Pump mechanism Amount of support Arterial or outflow insertion Venous or inflow insertion Maximal duration of support Contraindications Complications

IABP Pneumatic 0.5-1 l/min 7-9 Fr femoral or axillary artery N/A

IMPELLA Axial 2.5-5 l/min 12-21 Fr femoral or axillary artery N/A

10 d

5-7 d

Severe aortic regurgitation Aortic dissection Bleeding Infection Thromboembolism Limb ischemia

Mechanical prosthetic aortic valve Left ventricular thrombus Bleeding Infection Thromboembolism Limb ischemia Hemolysis Valvular injury

CentriMag-BiVAD Centrifugal 10 l/min 22 Fr central cannulation 32 Fr central cannulation 30 d Mechanical prosthetic valves Bleeding Infection Thromboembolism

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is required to reduce the unacceptably high mortality rate. We can therefore recognize three clinical scenarios: • Use of ECMO in combination with other devices (IABP and/or Impella), in patients with shock refractory to other devices • Use of other devices (IABP and/or Impella) in combination with ECMO, in patients suffering shock refractory to ECMO or ECMO related complications • Use of other devices (paracorporeal CentriMag LVAD or BiVAD) in patients with overt cardiac contraindication to percutaneous peripheral support (eg, severe aortic regurgitation) Circulatory support devices other than ECMO differ in terms of cannulation feature, hemodynamic performance, durability, and pathophysiologic interaction with ECMO. Intraaortic Balloon Pump Prospective, randomized, and controlled trials have failed to demonstrate conclusive proof of IABP benefit,3 yet IABP remains the most commonly used form of circulatory support in the presence of hemodynamic instability. Indeed, ELSO guidelines for adult cardiac failure recommend ECMO implantation in patients with shock refractory to high-dose inotropes and IABP, defining the role of IAPB as first-line support. IABP is a balloon mounted on a 7.5-8 Fr catheter advanced from the common femoral artery into the aorta through a percutaneous femoral approach, with the proximal tip placed before the left subclavian artery. IABP can be easily placed bedside in unstable patients. Diastolic inflation of the balloon increases diastolic pressure, while systolic deflation, decreases afterload and promotes left ventricular (LV) blood outflow. The net effect is decreased myocardial oxygen consumption, modest ven722

tricular unloading and slightly increased cardiac output (0,5-1 l/min). Optimal hemodynamic effect from the IABP depends on several factors such as balloon diameter in relation to aortic diameter, balloon position in the aorta, proper timing of balloon inflation in diastole and deflation in systole, patient hear rate and rhythm. Moreover, patients must have some level of LV function for the IABP to be effective, since any increase in in cardiac output depends on the work of the heart itself. For these reasons inotropes are usually necessary during IABP support.4 IABP support can also last several weeks, but requires immobilization and related complications can limit its prolonged use. The alternative surgical axillary approach allows patients to be mobilized, allowing its prolonged use. A percutaneous technique for placing IABP in the left axillary-subclavian artery has also been described.5 Complications affecting patients with IABP are very low. The most common include limb ischemia and vascular trauma. However, smaller catheters (7 Fr) are now available, allowing safer use of IABP in patients with small vascular accesses. Thrombocytopenia from platelet deposition on the IABP membrane can also occur. There is evidence that in terms of working principle, IABP and ECMO are synergistic and complementary to each other.6 IABP utilization during ECMO helps to prevent LV distension, enhancing pulsatility and counteracting the ECMO induced increase in afterload, and reducing risk of left ventricular thrombosis. Moreover IABP generates some degree of pulsatility through diastolic augmentation, with potential beneficial effects on tissue perfusion.7 During the course of ECMO, timing of balloon inflation and deflation should always be based on ECG triggers, since low or absent intrinsic pulsatility may limit proper synchronization with pressure triggers. Contraindications for the IABP include significant aortic regurgitation, aortic dissection

Other Forms of Extracorporeal Cardiovascular Support – IABP, IMPELLA, VAD

and clinically significant aortic aneurysm, and severe peripheral arterial disease. IMPELLA The Impella (Abiomed Inc., Danvers, MA) is a nonpulsatile axial flow pump designed to propel blood from the left ventricle into the ascending aorta. Impella is deployed across the aortic valve in a retrograde fashion under fluoroscopic or echocardiographic guidance. Three versions for LV support are available: Impella 2.5, CP, and 5.0. Impella 2.5 and CP are inserted percutaneously via femoral artery: Impella 2.5 generates up to 2.5 l/min of flow and requires a 12 Fr catheter for insertion, while Impella CP generates up 4 l/min of flow and requires 14 Fr catheter (Figure 64-1). Impella 5.0 can generate 5 l/min of flow, but is a 21 Fr device that requires a surgical cut down to the femoral or axillary artery.8 Therefore pump selection should be made at baseline according to the expected flow required by the clinical conditions. Impella effectively unloads the LV and increases forward flow, reducing myocardial oxygen consumption, and reducing pulmonary capillary wedge pressure.4 The Impella is approved for use of up to five days, but in clinical practice longer time of support, up to several weeks, has been reported. Surgical implantation via axillary artery is also possible and would allow longer support. The

Figure 64-1. A) The Impella micro-axial flow pumps. B) Peripheral placement of the Impella catheters across aortic valve. (Courtesy of Abiomed, Inc., Danvers, MA; with permission)

most commonly reported complications are related to vascular access. Hemolysis due to mechanical erythrocyte shearing has also been reported. Patients supported with Impella may require ECMO implantation for persistence of shock. Such rescue ECMO implantation can be required either because the chosen Impella device is not able to provide adequate flow for the patient’s clinical conditions, or because of the occurrence of right ventricular failure. However Impella RP, a new addition to the Impella family, is now available to provide percutaneous support for the failing right ventricle. It is a catheter-mounted axial flow pump (22 Fr) inserted via the femoral vein and deployed across the pulmonary valve (Figure 64-2). The pump aspirates blood from the inferior vena cava, pumping it into the pulmonary artery, generating up to 4 l/min flow. Indeed, patients supported by ECMO may require Impella implantation to unload the LV9 since ECMO cannot do so. In the setting of severe LV dysfunction, the increased cardiac afterload from the retrograde flow of the peripheral cannulation can lead to increases in LV cavity

Figure 64-2. Impella RP catheter placement. (Courtesy of Abiomed, Inc., Danvers, MA; with permission)

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pressure and to pulmonary venous hypertension, with subsequent pulmonary edema and vascular injury (Figure 64-3). Furthermore, inadequate unloading of the LV, in association with stasis, can lead to thrombus formation within the ventricular cavity. This complication is a major determinant of poor outcome, limiting options for recovery, heart transplantation, or transition to a long-term VAD system. Clinicians should actively focus on its prevention. IABP could be considered a simple bedside strategy to prevent LV distension, but does not effectively unload the left ventricle once distension has occurred. Traditional management strategies for LV decompression account for several surgical techniques, based on the insertion of a left atrial or ventricular vent, by sternotomy or thoracotomy. However such procedures present a high risk of bleeding and infection complications in patients on ECMO; moreover, the chest is violated before other potential surgical therapies (long-term VAD, total artificial heart, or heart transplantation). The Impella is an attractive percutaneous option, because it not only decompresses the ventricle but also augments forward flow. Therefore, during ECMO support, Impella implantation should promptly be considered in absence of pulsatility within the arterial line tracing and in presence of LV smoke at echocardiography. However, lack

Figure 64-3. White lung during ECMO support.

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of any aortic valve opening might make the procedure extremely challenging during aortic valve crossing. During ECMO, assessment of proper positioning of the Impella axial pump can be challenging through the use of the displayed ventricular pressure tracing due to the absence of pulsatility. Echocardiography plays an indispensable role, allowing direct visualization of the pump across the aortic valve. Contraindications for the Impella are mechanical aortic valve or left ventricular thrombus. Aortic stenosis is a relative contraindication. Unlike IABP, severe aortic regurgitation is not an absolute contraindication, although it may reduce the net efficacy of the pump. Levitronix CentriMag CentriMag (Thoratec Inc., Pleasanton, CA) is an extracorporeal surgically implanted assist device, with magnetically levitated centrifugalflow pump that can provide up to 10 l/min.10 The pump has no contact between the impeller and the rest of the pump components, which leads to lower rates of hemolysis and pump thrombosis. The CentriMag system is versatile and can be used for univentricular or biventricular support. In LV support, an inflow cannula is placed in the left atrium or ventricle and the outflow cannula into the ascending aorta. In right ventricular support, the inflow is placed

Figure 64-4. A) CentriMag blood pump. B) Schematic diagram of possible CentriMag cannulation sites: LA and Ao for LV support vs. RA and PA for RV support. (Courtesy of Thoratec, Inc., Pleasanton, CA; with permission)

Other Forms of Extracorporeal Cardiovascular Support – IABP, IMPELLA, VAD

in the right atrium and the outflow cannula in the main pulmonary artery (Figure 64-4). Cannula positioning requires sternotomy, but a less invasive minithoracotomy approach can also be used. CentriMag system can provide longer term support compared to the other devices (ECMO, IABP, Impella).11 In fact although it is approved and recommended for short term use, duration of up to three months has been described, with pumps exchanged every 4 to 6 weeks to prevent fibrin formation.12 The pumps can be exchanged at the bedside or in the operating room. CentriMag implantation is usually used in patients without central neurologic damage who have no recovery of end-organ function and who might be a candidate for long-term LVAD or heart transplantation. As general rule, when this device is required in INTERMACS I patients, a biventricular support should always be considered regardless of the echocardiographic features of the right ventricle. This clinical scenario usually portends the need for a long period of time with high flow before a definitive surgical therapy can be applied. The most common complications are infection, bleeding and thromboembolic neurologic events. Anticoagulation IABP does not strictly require anticoagulation and there is variability in the use of anticoagulation during its support. Many centers routinely use anticoagulation, but others do not, particularly with 1:1 pumping.8 The Impella pump is continuously purged with a heparinized dextrose solution to prevent blood from entering the motor and forming thrombus and systemic anticoagulation is usually unnecessary.8 CentriMag bears a very low risk of pump thrombosis; however, the combined surface area of pump, cannulas, and tubing are still susceptible to thrombus formation, in particular

in the presence of low pump flow states (eg, low pump speed or hypovolemia). Usually, anticoagulation initiation can delayed for up to 24-72 hours postoperatively in order to reduce the risk of bleeding, then a low dose of systemic anticoagulant is started. If bleeding occurs during support, anticoagulation can be held for up to 72 hours, but higher pump flows should be maintained.11 Right Ventricular Failure Severe right ventricular (RV) failure can complicate acute myocardial infarction and open heart surgery; in particular LVAD implantation and heart transplantation.13 It is an increasingly common clinical problem associated with significant morbidity and mortality. Optimal management is not well established since the RV is known to be more resilient than the left ventricle after ischemic and surgical insults, but predicting the time needed for its recovery remains difficult. Furthermore, recovery is the only strategy that can be pursued for this condition. These reasons make device selection challenging, when RV failure is refractory to medical therapy and MCS is required. The most conventional approach requires open chest cannulation of the right atrium and the pulmonary artery and uses a temporary RVAD to support the failing right ventricle.14 Such strategy allows complete RV unloading and provides complete anterograde transpulmonary blood flow with adequate preload for the LV. Its major limitation is the risk of inherent bleeding and infectious complications. Percutaneous VA-ECMO is another approach, since ECMO supports the right ventricle and gas exchange. However its efficacy is burdened by the general complications of the device, so its use should be limited to patients with concomitant acute lung failure, when gas exchange has to be artificially maintained. Impella RP is a novel minimally invasive percutaneous RVAD, now available for tempo725

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rary support of the RV. The recent RECOVER RIGHT prospective trial demonstrate that Impella RP is safe and reliable in patients with severe RV failure refractory to medical treatment, with immediate and sustained hemodynamic benefit and favorable outcomes to 30 and 180 days.15 In our institution, we have adopted a step wise approach, using first a short-term percutaneous device (VA-ECMO or Impella RP). We proceed to surgical temporary RVAD only when recovery is not achieved in a few days and prolonged support is needed. The only exception might be the postcardiotomy setting. Mobilization

to prevent ventilator-associated pneumonia in ventilated patients or to allow for the ability to eat in nonventilated patients. Progressive mobility with these devices encompasses turning from side to side, and passive/active range of motion, avoiding the extremity in which the device is located. When prolonged support is required, an axillary placement approach for IABP or Impella should be considered. Surgical central implantation of the CentriMag ventricular assist device is another option. In fact, an early progressive mobility program permits such patients to be up in the chair a few days after implantation and tolerate up to 30-minute ambulation sessions (Figure 64-5). Safety measures are required during ambulation to not compromise the driveline to the devices.

An early mobility program for patients receiving MCS devices has resulted in successful outcomes such as increased tolerance Weaning to activity and decreased mortality rate. In fact, complications of prolonged bed rest in the inWeaning of MCS occurs once noncardiac tensive care unit are well known.16 Prolonged organ systems have recovered. In patients with bed rest increases risk of ventilator-associated irrecoverable end-organ and/or neurologic pneumonia, need for prolonged ventilation, length of ICU and hospital stays, occurrence of delirium, and workload of the cardiovascular system. In particular, in patients assisted by temporary MCS, avoiding deconditioning, muscle loss, and nutritional depletion is of paramount importance. In fact, all such conditions dramatically affect future definitive therapeutic options (heart transplantation or LVAD implantation). Early progressive mobility goals for patients receiving MCS devices are no different than any other ICU patients and allow physical reconditioning. However, more limitations and safety considerations exist when mobilizing these individuals.17 In fact, IABP, Impella, and peripheral VAECMO limit early mobilization because of the requirement for placement of cannulas within the femoral vessels. These devices require Figure 64-5. Ambulatory patient during the patient to adhere to bed rest. However the paracorporeal biventricular support with CentriMag. reverse Trendelenburg position should be used 726

Other Forms of Extracorporeal Cardiovascular Support – IABP, IMPELLA, VAD

dysfunction withdraw of mechanical support should be considered.11 In the weaning process, MCS support is decreased gradually (hours to days). If hemodynamics and other organ function remain adequate, the device is explanted or if hemodynamics and/or organ function deteriorate LVAD implantation or heart transplantation need to be considered. For this reason the weaning process starts as soon as possible, ideally at the moment of MCS implantation. In fact all patients who receive a temporary MCS should be assessed for advanced long-term heart failure therapies. When different devices are simultaneously required for MCS, weaning from the device which produces increased complications should be considered first. As a general rule, when ECMO is used, it should be the first device to be removed. Such strategy might reduce the duration of ECMO support, hasten its weaning, and eventually reduce its related complications.

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References 1. Cowger J, Shah P, Stulak J, et al. INTERMACS profiles and modifiers: Heterogeneity of patient classification and the impact of modifiers on predicting patient outcome. J Heart Lung Transplant: the official publication of the International Society for Heart Transplantation. Nov 6 2015. 2. Gilotra NA, Stevens GR. Temporary mechanical circulatory support: a review of the options, indications, and outcomes. Clin Med Insights. Cardiology. 2014;8(Suppl 1):75-85. 3. Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. New Engl J Med. Oct 4 2012;367(14):1287-1296. 4. Werdan K, Gielen S, Ebelt H, Hochman JS. Mechanical circulatory support in cardiogenic shock. Europ Heart J. Jan 2014;35(3):156-167. 5. Estep JD, Cordero-Reyes AM, Bhimaraj A, et al. Percutaneous placement of an intraaortic balloon pump in the left axillary/ subclavian position provides safe, ambulatory long-term support as bridge to heart transplantation. JACC. Heart failure. Oct 2013;1(5):382-388. 6. Ma P, Zhang Z, Song T, et al. Combining ECMO with IABP for the treatment of critically Ill adult heart failure patients. Heart Lung Circ. Apr 2014;23(4):363-368. 7. Gass A, Palaniswamy C, Aronow WS, et al. Peripheral venoarterial extracorporeal membrane oxygenation in combination with intra-aortic balloon counterpulsation in patients with cardiovascular compromise. Cardiology. 2014;129(3):137-143. 8. Rihal CS, Naidu SS, Givertz MM, et al. 2015 SCAI/ACC/HFSA/STS Clinical Expert Consensus Statement on the Use of Percutaneous Mechanical Circulatory Support Devices in Cardiovascular Care: Endorsed by the American Heart Assoca728

tion, the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia Intervencion; Affirmation of Value by the Canadian Association of Interventional Cardiology-Association Canadienne de Cardiologie d’intervention. J Am Coll Cardiology. May 19 2015;65(19):e7-e26. 9. Cheng A, Swartz MF, Massey HT. Impella to unload the left ventricle during peripheral extracorporeal membrane oxygenation. ASAIO J. Sep-Oct 2013;59(5):533-536. 10. John R, Liao K, Lietz K, et al. Experience with the Levitronix CentriMag circulatory support system as a bridge to decision in patients with refractory acute cardiogenic shock and multisystem organ failure. J Thoracic Cardiovasc Surg. Aug 2007;134(2):351-358. 11. Teuteberg JJ, Chou JC. Mechanical circulatory devices in acute heart failure. Crit Care Clin. Jul 2014;30(3):585-606. 12. Haj-Yahia S, Birks EJ, Amrani M, et al. Bridging patients after salvage from bridge to decision directly to transplant by means of prolonged support with the CentriMag short-term centrifugal pump. J Thoracic Cardiovasc Surg. Jul 2009;138(1):227-230. 13. Goldstein JA, Kern MJ. Percutaneous mechanical support for the failing right heart. Cardiology linics. May 2012;30(2):303310. 14. Aissaoui N, Morshuis M, Schoenbrodt M, et al. Temporary right ventricular mechanical circulatory support for the management of right ventricular failure in critically ill patients. J Thoracic Cardiovasc Surg. Jul 2013;146(1):186-191. 15. Anderson MB, Goldstein J, Milano C, et al. Benefits of a novel percutaneous ventricular assist device for right heart failure: The prospective RECOVER RIGHT study of the Impella RP device. J Heart Lung Transplant. Dec 2015;34(12):1549-1560. 16. Freeman R, Maley K. Mobilization of intensive care cardiac surgery patients on

Other Forms of Extracorporeal Cardiovascular Support – IABP, IMPELLA, VAD

mechanical circulatory support. Crit Care Nurs Quarterly. Jan-Mar 2013;36(1):73-88. 17. Chavez J, Bortolotto SJ, Paulson M, Huntley N, Sullivan B, Babu A. Promotion of progressive mobility activities with ventricular assist and extracorporeal membrane oxygenation devices in a cardiothoracic intensive care unit. Dimensions of critical care nursing: DCCN. Nov-Dec 2015;34(6):348-355.

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65 Implementing an ECLS Program Tracy Morrison, RN, James D. Fortenberry, MD

Given the complexity and resource intensity of extracorporeal membrane oxygenation (ECMO) delivery, an institution considering adding an ECMO service needs to use a planned approach when developing and maintaining a comprehensive program. A commitment to beginning ECMO at an institution should be taken with an understanding that much more than purchase of a pump and disposables must occur. The program marries technology with personnel commitment. As a hospital reacts to both internal and external environmental threats, the allocation of scarce resources can create internal competition within the institution for budget allocation. The present healthcare environment requires institutional agility when reviewing current programs or when considering implementation of a new program. The return on investment of an ECMO program for an institution can be complicated to ascertain. Thus taking a proactive and thoughtful approach to stepping into the ECMO world is essential. Planning for ECMO at an institution can be achieved through several paths. A recent overview provides one excellent approach.1 As seen in Figure 65-1, the process comprises a sixstep approach. Utilizing a process management methodology when designing and implementing a new project has been proven to increase the overall quality of the project effort.2

This chapter utilizes the Guergueruain approach while adopting a process management methodology developed by Motorola for project management and evaluation.2 The methodology is also built on six essential steps which have been modified to reflect the development of an ECMO program: 1. Identify the type of ECMO service 2. Identify the customers 3. Determine personnel needs and suppliers 4. Define processes and procedures 5. Eliminate mistakes and optimize processes 6. Continuously improve and sustain the program Identify the ECMO Service Any institution considering a new ECMO program should perform a needs assessment to identify the patients impacted when it becomes implemented. The need for a program should

Figure 65-1. A six step process for ECMO planning.

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be based on the planned development of new programs needing ancillary ECMO support (eg, new pediatric cardiac surgery program), existing services for which ECMO indications have become established (eg, adult respiratory units or postoperative cardiac surgery units), or in institutions where access to ECMO onsite would provide benefit over external transfer. Collecting data on the number of previous potential annual ECMO patients, based on transfers to other centers or patients who expired with an inability to transfer to an ECMO center, demonstrates the urgency to act when presenting a project proposal to senior leaders. Estimates of expected cases help administrative budgeting and planning. For instance, in one pediatric cardiac surgical study, ECMO volumes were estimated to be from 1 to 5% of the total annual pediatric cardiac surgical volume.3 Determination of minimal annual ECMO volumes needed to achieve or maintain best outcomes has been a source of much discussion and evaluation4 with conflicting findings, and is discussed in more detail in other chapters (see Chapter 68). Certainly existing local capacity of higher volume centers must be considered. However, processes and education likely play similarly important roles along with volume. Of note, approximately 33% of current ECMO programs are low-volume centers that care for fewer than 6 cases annually.5 Identifying the initial program scope is critical to success in meeting customer needs. In general, setting expectations by starting a program with a focused and limited scope may prove more effective. Guerguerian et al.1 provide excellent examples of scope setting (Figure 65-2). In particular, provision of extracorporeal cardiopulmonary resuscitation (ECPR) should await experience with more controlled cannulation and establishment of in-house capabilities. Achieving success with the “first cases” goes a long way to building confidence and buy-in. On the other hand, experiences with uncontrolled attempts to perform 732

ECPR in an inexperienced program can set the program back significantly. Identify Your Customer The customer of an ECMO center comprises a cast of players. First and foremost is the patient. As described above, the patient population must be identified. Ideally ECMO should be performed in a tertiary ICU with a staff experienced in caring for critically ill patients suffering from respiratory or cardiac failure. Some centers choose to initiate an ECMO service in one department and develop expertise and experience before integrating other patient populations into the program. Existing programs within the facility, such as the Neonatal Intensive Care Unit, can provide infrastructure and expert support during program development.4 Contacting and visiting an experienced ECMO with similar patients would be helpful. It would also be beneficial to benchmark with a similar institution that has recently started an

Figure 65-2. Examples of scope setting.

Implementing an ECLS Program

ECMO program to gain knowledge from their org/Resources/Guidelines) recommends that lessons learned and things to do differently. ECLS program director and ECLS coordinator Creating an institutional ECLS steering positions be created for patient management, sucommittee to oversee planning and implemen- pervision of staff training, and equipment maintation of the program enables the organization tenance. The ECLS medical director should be to succeed by utilizing key experts to define a board certified specialist in neonatology, or the type of ECLS program that best meets pediatric/adult critical care, cardiology, anesthe needs of the organization.1 Representa- thesiology, cardiothoracic or general surgery, tion on the steering committee should include or another specialist with documented ECLS multidisciplinary members from all hospital training and experience.7 The ECLS program departments that will be internal customers of director is responsible for overall training and the ECLS program including pharmacy, blood education of specialists, quality improvement, bank, laboratory, medicine, nursing, surgery, data verification and the credentialing of physirespiratory therapy, occupational and physi- cians.8 The ECLS coordinator should be a regcal therapy, and hospital leadership. Engaging istered nurse or registered respiratory therapist senior administration from the beginning and with significant experience in critical care or a sharing patient stories is critical for both philo- certified clinical perfusionist with ECLS experisophical and financial buy-in.6 The committee ence.7 The ECLS coordinator is responsible for should meet regularly and conduct debriefings staff supervision, training, equipment mainteafter small changes to intensive learning and im- nance, and data collection.8 The ECMO specialists and primer provide provement. Engaging not only fervent ECMO supporters but also institutional skeptics ad- care for the patient while on support. The spedresses concerns head on and in advance, rather cialist manages the ECMO circuit and may prothan having a program derailed by those with vide for the clinical needs of the patient as well, disagreement around ECMO benefit. Scenario depending on the staffing model. The ECMO planning by the steering committee during the primer prepares the ECMO circuit for patient initial phase of program development helps the use. The primer may be an ECMO specialist, new ECMO team identify potential strengths, physician, or a perfusionist.8 According to the weaknesses, and hospital core competencies “ELSO Guideline for Training and Education” that will benefit or expanded once the ECMO (www.elso.org/Resources/Guidelines), the program is operationalized.2 This may make the ECMO specialist should have a strong critical rather large initial expenditures of the ECMO care background with at least one year or exprogram more palatable to senior leaders as they perience in neonatal, pediatric, or adult critical can visualize the positive impact of the program care. ECMO specialists come from varied backgrounds including registered nurses, respiratory even on patients who do not receive ECLS. therapists, certified perfusionists, physicians, Identify the Employees and Equipment or specially trained biomedical engineers.9 Needed Registered nurses represent the preponderance of ECMO specialists, followed by respiratory A dedicated ECMO team needs to be cre- therapists and perfusionists.10 A specific job ated to support staff education and training and description should focus on ECMO specific as well as patient care. Team members include responsibilities and tasks. Spending time on ECLS medical director, coordinator, special- job design during the planning phase can aid ists, medical team, and primers. The “ELSO retention and satisfaction of team members.11 Guidelines for ECMO Centers” (www.elso. Specialists serve as the first line of defense for 733

Chapter 65

maintaining safety for patients since more than physically at the patient’s bedside. Guerguerian 73% of ECMO mechanical emergencies are as- et al.1 provide excellent examples of scope sociated with human error.12 Selecting the right setting at the bedside vs. “rounding” on the individual for the job then optimizing educa- ECMO machine every couple of hours. Utiliztion and training by using ELSO guidelines ing available hospital perfusion services to help choose equipment serves a new program well. improves performance and safety. In addition to specialists and primers, a A standardized approach to equipment selection successful ECMO program requires at least a will reduce education and training needs, imcore group of ECMO-trained physicians and proving quality and safety. Details on program surgeons. Approaches vary by institution, with equipment needs are provided elsewhere in this some training all ICU physicians to provide book (see Chapter 5). Policies and procedures ECMO care, and others utilizing a smaller core related to equipment maintenance and cleaning group. Similarly, for cannulation, center ap- must be formalized with records maintained by proach varies with some institutions utilizing the institution’s biomedical engineering departonly certain surgeons to perform cannulation. ment. The institutional