The History of Extra-corporeal Membrane Oxygenation (ECMO): From Start to COVID 1536189618, 9781536189612

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MEDICAL PROCEDURES, TESTING AND TECHNOLOGY

THE HISTORY OF EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO) FROM START TO COVID

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MEDICAL PROCEDURES, TESTING AND TECHNOLOGY

THE HISTORY OF EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO) FROM START TO COVID

MICHAEL S. FIRSTENBERG EDITOR

Copyright © 2021 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. We have partnered with Copyright Clearance Center to make it easy for you to obtain permissions to reuse content from this publication. Simply navigate to this publication’s page on Nova’s website and locate the “Get Permission” button below the title description. This button is linked directly to the title’s permission page on copyright.com. Alternatively, you can visit copyright.com and search by title, ISBN, or ISSN. For further questions about using the service on copyright.com, please contact: Copyright Clearance Center Phone: +1-(978) 750-8400 Fax: +1-(978) 750-4470 E-mail: [email protected].

NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the Publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data ISBN: 978-1-5361(eBook)

Published by Nova Science Publishers, Inc. † New York

CONTENTS Preface

Introduction

Chapter 1

Chapter 2

The Practice and Principles of Extra-Corporeal Membrane Oxygenation (ECMO) – Volume 3 Jeffrey Phillip Jacobs and Eric Yates Pruitt The History of Extra-Corporeal Membrane Oxygenation From Start to COVID Ahmed S. Said and Kenneth E. Remy The Genesis and Evolution of Extracorporeal Membrane Oxygenation Benjamin Smood, Asad A. Usman, Mark Helmers, Christian Bermudez and Rita Carrie Karianna Milewski An Introduction to VA-ECMO: Physiology, Indications, and Principles of Management Benjamin Smood, Matthew Woods, Jason J. Han, Christian Bermudez and Rita Carrie Karianna Milewski

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Contents

vi Chapter 3

Chapter 4

Chapter 5

Chapter 6

Chapter 7

Disaster Preparedness for ECMO Programs and Adapting ECMO Programs to Face the COVID19 Pandemic Allison Ferreira and Kim Delacruz

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Special Considerations for ECMO Cannulation and Decannulation for COVID-19 Patient Joseph Dovidio and Hitoshi Hirose

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The Use of ECMO for Treatment of Severe ARDS Due to Coronavirus Disease 2019 Olivia Giddings and Rana Hejal

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Frontline Experience with Extracorporeal Life Support for COVID-19 Patients Vitali Karaliou, Jennifer Hanna, Matthew N. Libby, Courtney Petersen, William M Novick and Michael S. Firstenberg Extracorporeal Membrane Oxygenation (ECMO) in COVID-19: The Role of Lung Transplantation Asishana Osho, Jerome Crowley, Philip J Spencer, Masaki Funamoto, Nathaniel Langer and Mauricio Villavicencio

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About the Editor

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Index

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PREFACE: THE PRACTICE AND PRINCIPLES OF EXTRA-CORPOREAL MEMBRANE OXYGENATION (ECMO) – VOLUME 3 Jeffrey Phillip Jacobs, MD and Eric Yates Pruitt, MD Department of Surgery, University of Florida, Gainesville, Florida, US

INTRODUCTION Dr. Michael Firstenberg is to be congratulated for creating and editing an essential three volume compendium about extracorporeal membrane oxygenation (ECMO) entitled, “The Practice and Principles of ExtraCorporeal Membrane Oxygenation (ECMO)”. It is our honor to write this Preface to Volume 3 of this magnificent summary of the state of the art and science of ECMO. We recommend all three volumes of this textbook as essential reading for all health care professionals with interest in ECMO. The first 2 volumes of this compendium cover all of the details of ECMO overall, describing both basic and advanced concepts. This third volume discusses the early history of ECMO and then includes five chapters discussing the extremely timely topic of the role of ECMO in the treatment of patients diagnosed with Coronavirus Disease 2019 (COVID-

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19). Volume 3, therefore, in many ways, spans the start of ECMO, to the current state of ECMO today: ECMO from start to finish! However, the status of ECMO in this very moment is in no way the actual finish, because ECMO will continue to evolve in parallel with the evolution of medicine and humanity. All of us have had our very existence impacted by the COVID-19 pandemic; indeed, life as we know it has changed dramatically and stunningly and rapidly and globally. The evolution of the treatment of patients with COVID-19 is unlike any event ever seen in medicine. As of October 24, 2020, 42,299,535 patients around the world have been diagnosed with COVID-19, with 1,145,739 associated deaths (2.71% mortality worldwide) [1]. Meanwhile, in the United States of America, as of October 24, 2020, 8,497,011 patients have been diagnosed with confirmed COVID-19, with 224,005 associated deaths to date (2.64% mortality in the USA) [1]. Most deaths in patients with COVID-19 are due to severe respiratory failure, with a smaller group succumbing to combined pulmonary and cardiac failure. Several recent publications have documented that ECMO facilitates salvage and survival of select critically ill patients with COVID-19 [2, 3, 4, 5]. Early data from Wuhan, China reported an alarmingly high rate of mortality of 83% (5 out of 6) in COVID-19 patients supported with ECMO [6, 7]; however, more recent data reveal improved survival of COVID-19 patients supported with ECMO [2, 3, 4, 5]. Both recent individual institutional reports [2, 3, 5], as well as recent reports from multi-institutional registries [4], have demonstrated promising results and improvements in survival. Indeed, it is clear that ECMO facilitates salvage and survival of select critically ill patients with COVID-19. It is a fact that much remains to be learned about the treatment of patients with COVID-19 and the role of ECMO in this treatment. Clinical guidelines for the management of patients with COVID-19 have been released by the World Health Organization (WHO) [8] and the Centers for Disease Control and Prevention (CDC) of the United States [9]. The Extracorporeal Life Support Organization (ELSO) [10] and The American Society for Artificial Internal Organs (ASAIO) [11] have also

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both published guidelines regarding the role of ECMO in treating patients with COVID-19. Nevertheless, the role of ECMO in the management of these challenging patients remains promising but unclear. Volume 3 of this three-volume compendium about ECMO entitled, “The History of Extra-Corporeal Membrane Oxygenation (ECMO) – From Start to COVID” provides a treasure chest of information about the use of ECMO to support the sickest of patients with COVID-19. This information is valuable and will save lives!!! Moreover, many of the lessons that we learn about the use ECMO in patients with COVID-19 will be applicable to all patients supported with ECMO regardless of their underlying disease. We congratulate Dr. Firstenberg and all of the authors for the publication of this timely and valuable information, and we encourage all health care professional with an interest in ECMO to read these important contributions.

REFERENCES [1]

[2]

[3]

Coronavirus COVID-19 Global Cases by the Center for Systems Science and Engineering (CSSE) [https://coronavirus.jhu.edu/map. html]. Accessed October 4, 2020. Jacobs JP, Stammers AH, St Louis J, Hayanga JWA, Firstenberg MS, Mongero LB, Tesdahl EA, Rajagopal K, Cheema FH, Coley T, Badhwar V, Sestokas AK, Slepian MJ. Extracorporeal Membrane Oxygenation in the Treatment of Severe Pulmonary and Cardiac Compromise in Coronavirus Disease 2019: Experience with 32 Patients. ASAIO J. 2020 Jul;66(7):722-730. doi: 10.1097/MAT.00 00000000001185. PMID: 32317557. Kon ZN, Smith DE, Chang SH, Goldenberg RM, Angel LF, Carillo JA, Geraci TC, Cerfolio RJ, Montgomery RA, Moazami N, Galloway AC. Extracorporeal Membrane Oxygenation Support in Severe COVID-19. Ann Thorac Surg. 2020 Jul 17:S00034975(20)31152-8. doi: 10.1016/j.athoracsur.2020.07.002. Epub ahead of print. PMID: 32687823; PMCID: PMC7366119.

x [4]

[5]

[6]

[7]

[8]

[9]

Jeffrey Phillip Jacobs and Eric Yates Pruitt Barbaro RP, MacLaren G, Boonstra PS, Iwashyna TJ, Slutsky AS, Fan E, Bartlett RH, Tonna JE, Hyslop R, Fanning JJ, Rycus PT, Hyer SJ, Anders MM, Agerstrand CL, Hryniewicz K, Diaz R, Lorusso R, Combes A, Brodie D; Extracorporeal Life Support Organization. Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry. Lancet. 2020 Sep 25:S01406736(20)32008-0. doi: 10.1016/S0140-6736(20)32008-0. Epub ahead of print. PMID: 32987008; PMCID: PMC7518880. Jacobs JP, Stammers AH, St Louis J, Hayanga JWA, Firstenberg MS, Mongero LB, Tesdahl EA, Rajagopal K, Cheema FH, Patel K, Esseghir F, Coley T, Sestokas AK, Slepian MJ, Badhwar V. Multiinstitutional Analysis of 100 consecutive patients with COVID-19 and Severe Pulmonary Compromise treated with Extracorporeal Membrane Oxygenation (ECMO): Outcomes and Trends Over Time. The Annals of Thoracic Surgery. In Review. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 Feb 24. pii: S22132600(20)30079-5. doi: 10.1016/S2213-2600(20)30079-5. [Epub ahead of print] Erratum in: Lancet Respir Med. 2020 Apr;8(4):e26. PMID: 32105632. Henry BM. COVID-19, ECMO, and lymphopenia: a word of caution. Lancet Respir Med. 2020 Apr;8(4):e24. doi: 10.1016/S22132600(20)30119-3. Epub 2020 Mar 13. PMID: 32178774. World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance. 3 March 2020. [https://www.who.int/docs/defaultsource/coronaviruse/clinical-management-of-novel-cov.pdf]. Accessed April 7, 2020. Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19). [https://www.cdc.gov/

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coronavirus/2019-ncov/hcp/clinical-guidance-managementpatients.html]. Accessed April 7, 2020. [10] Bartlett RH, Ogino MT, Brodie D, et al. Initial ELSO guidance document: ECMO for COVID-19 patients with severe cardiopulmonary failure. ASAIO J 66:472–474, 2020 [11] Rajagopal K, Keller S, Akhanti B, et al. Advanced pulmonary and cardiac support of COVID-19 patients: Emerging recommendations from ASAIO - A “Living Working Document.” ASAIO J 66:588– 598, 2020.

Introduction

THE HISTORY OF EXTRA-CORPOREAL MEMBRANE OXYGENATION FROM START TO COVID Ahmed S. Said1 and Kenneth E. Remy1,2, 1

Department of Pediatrics, Division of Pediatric Critical Care, Washington University, St. Louis, MO 2 Department of Internal Medicine, Division of Pulmonary and Critical Care, Washington University, St. Louis, MO

INTRODUCTION I remember it like it was yesterday. Called to an outside hospital to meet a previously healthy 7 year old girl that now was nearing the end of her young life with septic shock. She was maintained on 3 vasopressors and 1 inotrope, struggling in the Emergency Department with significant hypoxemia, decreased pallor, and mom and dad praying by her bedside. Prior to my arrival, I had already alerted our surgeon-in chief, if we could 

Corresponding Author’s E-mail: [email protected].

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get her back to our hospital on the 25 minute ambulance ride, she needed immediate cannulation. After conferring with my fellow, who was readying the patient for her journey, my six foot nine inch frame crept down on the ER floor, looked both parents in their eyes, and let them know that their child had a high likelihood of dying, but transferring her now for ECMO was her only shot at life. They agreed and strategically maneuvered back to our hospital with immediate cannulation. Forty-nine days later she was decannulated. Three weeks later she walked out of the hospital, alive with an entire life of smiles ahead of her. They called the pandemic the worst they had seen perhaps since the 1918 influenza pandemic. Some 91 years later, the H1N1 virus was wreaking havoc on many patients under my care in the adult and pediatric ICUs in New York City. I remember when this 23 year old woman entered the hospital in fulminant hypoxemic respiratory failure and 20 weeks pregnant. She was not only H1N1 positive but had evidence of Staphyloccocus aureus co-infection. And we couldn’t oxygenate her. No matter how many different modes of ventilation, recruitment maneuvers, attempts at increasing pulmonary blood flow, or red blood cell transfusions, our patient would not increase her saturation above 75%. With a high likelihood of death for her and her unborn child, we were faced to a difficult decision, to cannulate or not. In the pediatric world, this would have been an easier decision as years of ECMO didn’t see the same level of intracranial hemorrhage or complications as seen in our adult counterparts. And yet in 2009 in The Lancet Cesar was published [1] and we learned that adults could be placed on ECMO with new protocols and survive without disability at 6 months. We had no other option. We cannulated her for VV ECMO without anticoagulation to protect her unborn child from possible hemorrhage. Almost ten years later, I still remember a year later from that 2 week episode when she walked into the ICU with her 9 month old in arms alive. ECMO saved two lives and many more during a pandemic. I thought I would never see another pandemic like the one I remembered from H1N1 in NYC or my time with Ebola in Africa. The world is now thrust 11 months into the greatest pandemic in over one

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hundred years ago. Early in this horror, I recall a colleague in my profession entering the ICU with hypoxemia after his SARS-CoV-2 respiratory swab was positive. “I just can’t catch my breath, please do everything and anything to keep me alive.” This was March and early in our experiences here in St. Louis. He advanced to endotracheal intubation. His blood was viscous. I am sure his endothelium was ridden with microthrombotic disease attempting to stead off the constellation of innate immune overactivation against a storm of adaptive immune exhaustion. He developed septic shock. His hypoxemia worsened. He was going to die. Yet I made a promise to him that we would try anything and everything to keep him alive. Two young children at home, a spouse, and a team of medical colleagues were looking for a miracle. Four weeks later, we decannulated him from VA ECMO and 2 weeks later, he went home. Supporting his body while it recovered from perils of COVID-19 disease allowed that miracle. I remember that morning as if it was a yesterday, a 7-month-old infant with Trisomy 21, known to have a small atrial septal defect and mild pulmonary hypertension was admitted arriving from clinic with Rhinoviral upper respiratory infection and mild respiratory distress. His rapid progression after intubation with refractory hypoxemia necessitated swift action. He was cannulated to VV ECMO at the bedside with immediate improvement in his gas exchange. One week later, with now superimposed staphylococcal pneumonia, we were struggling to keep his oxygen saturations above the low 80’s with worsening systemic oxygen delivery. An additional arterial cannula was added and he was transitioned to VVA support. Forty-one days later, he was successfully decannulated and 92 days after admission, he was discharged home on slightly higher supplemental oxygen than his previous baseline, tolerating feeds and growing with a future ahead of him. She was referred to us for progressive end stage lung disease and for possible lung transplant evaluation. Within 72 hours, this 8 year old who had previously only on been on supplemental oxygen at home, was under continuous neuromuscular blockade, increasing ventilator settings and inhaled nitric oxide with hypoxemic and hypercarbic respiratory failure.

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We needed something to bridge her and proceeded to VV ECMO, fully knowing that her only chance at survival was a lung transplant. While cannulated she underwent tracheostomy so that she could maximize rehabilitation for a transplant. A week later, I could not tell you the elation of her parents as her continuous sedatives were stopped; she was awake in bed, and actively participating in physical therapy. One month later while on ECMO, she had a daily routine of scheduled rehab therapies and had a life potentially ahead. Eighty three days after the decision to place her on ECMO support, she successfully underwent lung transplantation. She now cannot stop telling family and friends about this miracle called ECMO as she enjoys a life with new lungs. These vignettes from our 20-year experiences with pediatric and adult ECMO highlight the many successes that this bridge to recovery and bridge to transplant can allow. The first successful case of neonatal ECMO was in 1975. Esperanza was a full term baby with persistent pulmonary hypertension of the newborn and resultant refractory hypoxemia. She was successfully supported with “venoarterial cardiopulmonary bypass with a membrane oxygenator” till recovery of her pulmonary hypertension [2]. Over the following 45 years, the field of extracorporeal support has evolved in every aspect. This has included the indications for ECMO initiation, that have continued to expand with growing numbers of patients supported for longer durations of time and a shrinking number of contraindications for ECMO support. It is not uncommon for institutions to report patients supported for longer durations and for conditions previously deemed fatal or even worse, unsupportable. Clinicians and investigators continue to collaborate to expand the modalities of providing extracorporeal support for pathophysiologies previously deemed not survivable. The international community has developed great enthusiasm in understanding the impact of ECMO support on a patient’s short and long-term outcomes with renewed international collaborative efforts have focused on understanding this complex physiology. Refractory septic shock, cardiogenic shock from myocardial infarction, refractory hypoxemia from an emerging pandemic pathogen, a bridge to lung or heart transplantation, refractory status asthmaticus, and many other

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indications; ECMO does not just provide a bridge to recovery or transplant but rather provides an opportunity at life when previously it was not possible. Not all outcomes in ECMO are favorable but families and patients are given that ‘Hail Mary pass’ and clinicians can ‘rest’ a patient while the overwhelming inflammation or disease process burns its fire out. In this textbook, accomplished authors will provide the evolution of this modality, demonstration of how it can be deployed in austere pandemics, and offer insights into manners to improve outcomes under these conditions. During conditions of great duress in a pandemic, ECMO offers a beacon of hope (ironically ‘Esperanza’ in Spanish) for some patients while new disease pathophysiologies and therapies are elucidated.

REFERENCES [1]

[2]

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):1351-63. Bartlett RH. Esperanza: The First Neonatal ECMO Patient. ASAIO J. 2017;63(6):832-43.

In: The History of Extra-Corporeal … ISBN: 978-1-53618-961-2 Editor: Michael S. Firstenberg © 2021 Nova Science Publishers, Inc.

Chapter 1

THE GENESIS AND EVOLUTION OF EXTRACORPOREAL MEMBRANE OXYGENATION Benjamin Smood, Asad A. Usman, Mark Helmers, Christian Bermudez and Rita Carrie Karianna Milewski* Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA, US

ABSTRACT Even before the discovery of elemental oxygen, philosophers, alchemists, polyhistors, and scientists postulated about the ability to sustain life with extracorporeal circulation and respiration. In this chapter, a brief history of the genesis and evolution of modern extracorporeal membrane oxygenation is described since the mid-17th century. In doing so, early hypotheses, experimental studies, and applications of extracorporeal perfusion and oxygenation are described. Additionally, the natural progression from short duration cardiopulmonary bypass in cardiac surgery to prolonged mechanical circulatory support is presented, Corresponding Author’s E-mail: [email protected].

*

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Benjamin Smood, Asad A. Usman, Mark Helmers et al. alongside how indications have progressed to include both respiratory and circulatory support. This chapter is intended to provide a brief historical context for modern extracorporeal membrane oxygenation technology, which will be the remaining focus of this textbook.

Keywords: cardiopulmonary bypass, ECMO, extracorporeal membrane oxygenation, mechanical circulatory support

INTRODUCTION To appreciate the modern advances and current state of extracorporeal membrane oxygenation (ECMO), it is helpful to understand the historical hypotheses and scientific experiments that evolved over the past halfmillennium. Such a foundation provides important perspective for the revolutionary milestones of the past half-century, which now permit the routine use of ECMO for prolonged mechanical circulatory support in critically ill patients.

EARLY HYPOTHESES AND STUDIES IN EXTRACORPOREAL MEMBRANE OXYGENATION In the mid-17th century, little was known regarding human respiratory physiology aside from early postulations that ambient air was the “food of life” [1, 2]. Supported by evidence from canine vivisections, in 1667 Robert Hooke submitted that the inflation and deflation of lungs was not essential to life, and that the lungs themselves may not be required for vitality. Hook presented these findings to the Royal Society, hypothesizing “whether suffering the blood to circulate through a vessel, so as it may be openly exposed to fresh Air, will not suffice for the life of an Animal” [3, 4]. It would be another century before oxygen was discovered in the 1770s, elucidating the nature of respiratory gases and igniting an interest in combustible gases and the burgeoning field of respiratory physiology [5].

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Julien Jean César Legallois published the first practical hypothesis of artificial circulation in 1812, writing that “if the place of the heart could be supplied by injection—and if, for the regular continuance of this injection, there could be furnished a quantity of arterial blood, whether natural, or artificially formed, supposing such a formation is possible—then life might be indefinitely maintained in any portion” [6-8]. However, his early perfusion studies failed due to blood coagulation [4, 6, 8], and another decade would pass before Prevost and Dumas would describe methods to defibrinate blood, which importantly contributed to the foundation of perfusion studies [4, 9]. Using these methods, James Phillips Kay showed that lower extremity muscular contraction could be restored if carotid arterial blood was injected into the abdominal aorta of rabbits in 1828 [7, 8, 10, 11]. In 1851, Charles Brown-Séquard observed restored muscular fasciculations, skin elasticity, and pulsation of the radial artery after reperfusing the extremities of criminals decapitated hours earlier [7, 1215]. In 1858, he then demonstrated that recently sacrificed animals resumed movements of the eyes, nose, and mouth if oxygenated blood was injected into arterial trunks of the head [4, 11, 16]. The first experience with isolated organ perfusion was published in 1849 after Carl Eduard Loebell injected arterial blood into isolated porcine kidneys to compare the amount of urine produced with delivered blood volume [4, 7, 17, 18]. As investigations into artificial oxygenation and perfusion evolved further, Ludwig and Schmidt (among their many contributions to the field) were the first to develop and use ‘direct contact’ artificial oxygenation in extracorporeal circulation [4, 19]. Shaking defibrinated blood in ambient air, they used arterialized blood to perform perfusion experiments in canines, concluding that, “undoubtedly an artificial stream of arterial blood conserves the viability of muscles and nerves and also restores it in these structures when excitability has been exhausted” [4, 7, 19-21]. Undoubtedly, other investigators and scientific achievements are worthy of mention; however, a more extensive review of this early history is beyond the scope of this introductory chapter.

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EARLY APPLICATIONS OF EXTRACORPOREAL OXYGENATION AND ARTIFICIAL PERFUSION It was not until 1882 that artificially oxygenated blood was utilized with simultaneous artificial perfusion [4, 7, 22]. Attempting to identify where blood urea nitrogen was produced, Waldemar von Schröder advanced the technology of direct-contact extracorporeal oxygenation by developing the first simple bubble oxygenator that dispensed air directly into the bloodstream [8, 22]. The method consisted of bubbling air into a trough of venous blood, thereby increasing pressure and forcing oxygenated blood into an arterial reservoir to perfuse the isolated organ [4, 7, 11]. However, this required interruptions in blood flow as venous blood was transferred to an arterial reservoir [7]. In contrast, using novel methods in 1885, Max von Frey and Max Gruber first demonstrated techniques to oxygenate blood without interrupting flow [11, 23]. Recognized as the first film oxygenator in a closed-circuit perfusion system that could continuously perfuse organs, their model was designed such that venous blood entering the circuit could be spread as a thin film in contact with the air over a mechanically rotated glass cylinder, thereby permitting gas exchange [4, 7, 8, 21, 23]. This remarkably advanced device utilized a 10mL syringe to produce pulsatility and return circulating volume to a reservoir, and even incorporated a ‘preheater’ to regulate the temperature of arterial blood [7]. In essence, this revolutionary design by von Frey and Gruber was capable of temporarily replacing the function of the lung and laid the foundation for future technologic advances that would permit extracorporeal oxygenation with mechanical circulatory support [7]. Nevertheless, the complexity and expense of von Frey and Gruber’s design was dissuading, leading Carl Jacobj to develop the first closedcircuit perfusion system using a bubble oxygenator in 1890 (inspired by von Schröder’s design) [7, 24]. Interestingly, he later modified this device in 1895 so that an isolated lung could serve as the system’s oxygenator, hoping that this would minimize damage to the blood resulting from direct contact with the air [7, 11, 25]. Whereas previous experiments had used

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defibrinated blood to prevent clotting, Jacobj was the first to use pharmacologic anticoagulation, specifically the leech extract hirudin [7], two decades before the discovery of heparin by Jean McLean in 1916 [4, 21, 26]. The importance of these early experimental efforts cannot be understated, as many of the first film and bubble oxygenators used in early cardiopulmonary bypass for open heart surgery would be derived from similar designs [4, 7]. Indeed, countless other milestones and investigators are fascinating and worthy of reference [21]. However, the ordered timeline and subsequent advances in artificial oxygenation and perfusion throughout the first two decades of the 20th century are beyond the scope of this chapter [4, 7]. Suffice it to say that by the early 1950s, a number of novel methods for cardiopulmonary bypass had been developed for clinical use in cardiac surgery (including Mustard’s heterologous primate lung oxygenator and Lillihei’s notable series with cross circulation) [27]. Throughout this decade, it was largely a race to see which method would prove most successful [4, 27].

FROM CARDIOPULMONARY BYPASS TO PROLONGED MECHANICAL CIRCULATORY SUPPORT — THE MEMBRANE OXYGENATOR The first human operation using a heart-lung machine in cardiac surgery was attempted by Clarence Dennis in 1951, but unfortunately, the patient did not survive [28]. Intending to repair an ostium secundum atrial septal defect, intraoperatively the surgical team instead encountered an ostium primum defect with irreparable abnormalities of the tricuspid and mitral valves [29]. Two years later in 1953, more than half a century after von Frey and Gruber developed their artificial lung allowing for continuous organ perfusion, John Gibbon and his team would complete the first successful open heart surgery on cardiopulmonary bypass [11, 27, 30]. Using a roller pump and film oxygenator, the Gibbon heart-lung machine

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was able to temporarily replace cardiac and pulmonary function for extracorporeal oxygenation and circulation [4, 30-32]. John Kirklin and colleagues soon published an impressive series of successful operations using the modified Mayo-Gibbon heart-lung machine, meanwhile other commercially available oxygenators were developed and used throughout the 1960s and 1970s [4, 11, 33]. Among these was the DeWall bubble oxygenator (popularized by Walt Lillihei), which became available worldwide, and by some estimates was used in 90% of open heart surgeries by the mid-1970s [4, 34]. Despite these revolutionary advances, cardiopulmonary bypass with early bubble and film oxygenators could only be supported for a few hours. Longer support was limited by consequences of blood trauma and other complications arising from prolonged exposure to the artificial circuit and direct contact between blood and air surfaces [4, 35, 36]. As such, additional innovations in mechanical circulatory support would be required if extracorporeal oxygenation could prove to be a viable therapy for patients requiring prolonged life support with mechanical circulation. Developing less-traumatic pumps and novel oxygenators would be a primary focus of forthcoming and improved designs. The prospect of membrane (as opposed to bubble or film) oxygenators held particular promise. Membrane oxygenators initially gained clinical enthusiasm in 1944 after keen observations by Willem Kolff’s group noticed the changing color of red arterial blood as it passed through a hemodialysis membrane [4, 36, 37]. By 1955, Kolff’s team had developed the first membrane oxygenator, and soon developed the first disposable membrane oxygenator for experimental use [4, 36, 38, 39]. A year later, George Clowes and colleagues developed the first clinically applicable membrane oxygenator using Teflon® [4, 21, 36, 40]. Alternative polymers were tested to identify an ideal membrane material, but by the end of the 1950s, silicone membranes appeared to have improved gas permeability compared to other biomaterials. As a result, the next decade would witness a transition away from bubble and film oxygenators, alongside a renewed focus towards developing ideal biomaterials and techniques for membrane oxygenation [41].

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For example, in 1963, Theodor Kolobow developed a novel hypobaric perfusion system that helped to prevent gas emboli during extracorporeal oxygenation [42, 43]. The novel technique stretched a solid silicone membrane to maximize its surface area and gas permeability [4, 42]. Later patented by the National Institutes of Health in 1970, Kolobow’s device would be the only solid silicone membrane oxygenator used for prolonged extracorporeal life support in the following decades [4, 43]. Despite the clinical promise of silicone membranes (which were used in the first successful clinical application of ECMO), their routine use for prolonged mechanical circulatory support was again limited by factors of durability, plasma leakage, and other complications [4, 36, 44-47]. As such, continued efforts were needed to develop an ideal membrane. Importantly, the early 1960s realized technologic advances in chemical and biomedical engineering that helped establish quantifiable methods for analyzing membrane permeability and blood flow properties. In this respect, the translational research of the 1960s formalized metrics of membrane oxygenator performance and reliability, which established clinical efficacy profiles that permitted wider acceptance and popularity among clinicians [41]. For example, an improved silicone material was introduced by Nora Burns in 1969, a modern equivalent of which continues to be marketed for use in long-term extracorporeal oxygenators [4, 41, 46, 48]. Nevertheless, an ideal membrane remained elusive. In an effort to overcome some of the remaining challenges, novel microporous membrane oxygenators were introduced [45, 49], and by the 1980s, hollow fiber membranes would almost entirely replace the firstgeneration oxygenators that had been previously used in cardiac surgery [4, 35, 47, 50, 51]. Although it was clear that membrane oxygenators were optimal candidates for supporting long-term extracorporeal oxygenation in critically ill patients [4, 43], microporous membranes continued to be plagued by their own shortcomings that limited their use in prolonged mechanical circulatory support. As a result, the majority of adult ECMO runs continued using silicone oxygenators until at least as late as 2008 [4, 45, 47, 49, 52]. Perhaps surprisingly, there were relatively few changes to

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basic ECMO equipment and technology, including membrane oxygenators, in the decades following the introduction of microporous membranes. However, with seeming abruptness, in the early 2000s there was a renaissance in membrane oxygenator innovation that ultimately revolutionized the field of ECMO [4, 45, 47, 53-58]. Specifically, novel polymethyl pentene (PMP) and nonporous hollow fiber membrane oxygenators appeared to optimize not only biocompatibility and durability, but also membrane permeability, gas exchange, and flow dynamics. As the design specifications of nonporous PMP membrane oxygenators are detailed elsewhere in this textbook (see ‘Oxygenators and Gas Exchange’ in the chapter ‘An Introduction to VA-ECMO: Physiology, Indications, and Principles of Management’), suffice it to say that these novel membrane oxygenators repeatedly demonstrated improved safety and efficacy in ECMO [4, 47, 56-62]. To demonstrate the remarkable advantages borne alongside these novel oxygenators, it is now estimated that PMP membrane oxygenators are preferentially used by 95% of ECMO centers in the United States [27, 49, 60, 63]. In this respect, perhaps no other innovation over the past twenty years has been as important to the continued growth and clinical application of prolonged mechanical circulatory support with ECMO [4, 41, 61]. Nevertheless, important clinical milestones leading up to the development of modern membrane oxygenators warrant acknowledgement.

A SHIFTING PARADIGM WITH EXPANDING INDICATIONS FOR ECMO In 1972, Donald Hill published the first successful use of ECMO using a Bramson membrane oxygenator in a 24-year-old man who had undergone emergent surgery for a traumatic aortic rupture [44, 65]. The young man developed acute respiratory distress syndrome (ARDS) four days after surgery, and was placed on partial venoarterial (VA)-ECMO. He

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was weaned successfully after 75 hours of support, with the authors concluding that “end-stage shock lung may be reversible if the patient receives adequate gas exchange through partial extracorporeal circulation with an appropriate membrane lung” [44]. Despite excitement from a number of other favorable reports in adults, a trial published in 1979 demonstrated no survival advantage using VA-ECMO in patients with ARDS [4, 65]. However, the utility of venovenous (VV)-ECMO in respiratory failure would be confirmed in multiple clinical trials years later [66-69]. Meanwhile, in 1975, Robert Bartlett successfully rescued a neonate suffering from respiratory failure as a result of meconium aspiration and chemical pneumonitis with three days of ECMO support [70]. He continued treating children and reported significantly improved results over conventional therapy [71, 72]. This ultimately led to the first prospective, randomized, controlled trial evaluating ECMO in neonatal respiratory failure [73]. In stark contrast to the early trials in adults [65, 74, 75], there appeared to be a clear survival advantage for children receiving ECMO for respiratory failure [76]. Thus, in 1989, the Extracorporeal Life Support Organization (ELSO) was founded and an ECMO registry comprised of almost 20 neonatal EMCO centers was established [77]. Although some questioned the methodologic validity of the first trials in neonates, reservations were quelled in 1995 after a randomized trial in the United Kingdom was stopped early because of the undeniable benefits of ECMO in neonates suffering from respiratory insufficiency [4, 76, 78, 79]. Throughout the 1990s, the indications for pediatric ECMO were expanded to include older children with heart and lung failure, in addition to post-operative cardiac failure [77]. Robert Bartlett’s observations from 1977—in which he submitted that “trials in cardiac failure and the infant age group in this series suggest that ECMO will have an even greater role in those applications''—were increasingly validated [71, 80]. Meanwhile, ECMO technology continued to advance, incorporating centrifugal flow pumps [62, 81-84], heparin-coated circuits [85], improved cannulas [62, 85, 86], and novel membrane oxygenators [49, 60, 87-91].

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Clinical trials in adult patients continued to show promising results. The landmark CESAR trial conducted from 2001 to 2006 demonstrated cost-effective, improved survival with freedom from major disability in adults with ARDS who received ECMO [66, 67]. These benefits were validated with additional trials that resulted from ECMO experience during the 2009 H1N1 influenza pandemic [68, 69, 77]. As a result, the clinical paradigm rapidly shifted and the use of ECMO garnered widespread acceptance as guidelines were developed, particularly for use in respiratory failure [60, 92]. However, significant work remained to determine if ECMO would demonstrate a similarly reliable therapy for patients with cardiac failure. Despite promising results, to date there are no prospective, randomized trials to support the use of ECMO in cardiac failure [80, 93-95]. As such, consensus regarding the optimal use of ECMO in the setting of cardiac failure remains ill-defined, and society-endorsed guidelines only exist for its use in cardiac arrest [96-99]. In any case, the following chapters will provide a review of the current literature and evidence, as well as best practices and important considerations for all healthcare providers who seek to better understand the utility of ECMO as a therapy for potentially life-saving mechanical circulatory support.

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[74] Morris, A. H., Wallace, C. J., Menlove, R. L., Clemmer, T. P., Orme, J. F., Jr, Weaver, L. K., Dean, N. C., Thomas, F., East, T. D., Pace, N. L., Suchyta, M. R., Beck, E., Bombino, M., Sittig, D. F., Böhm, S., Hoffmann, B., Becks, H., Butler, S., Pearl, J., & Rasmusson, B. (1994). Randomized clinical trial of pressurecontrolled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine, 149(2 Pt 1), 295–305. https://doi.org/10.1164/ajrccm.149.2.8306022. [75] Abrams, D., Combes, A., & Brodie, D. (2014). Extracorporeal membrane oxygenation in cardiopulmonary disease in adults. Journal of the American College of Cardiology, 63(25 Pt A), 2769– 2778. https://doi.org/10.1016/j.jacc.2014.03.046. [76] Wolfson P. J. (2003). The development and use of extracorporeal membrane oxygenation in neonates. Annals of Thoracic Surgery, 76(6), S2224–S2229. https://doi.org/10.1016/j.athoracsur.2003.09. 003. [77] Bartlett R. (2017). ECLS: Past, present, and future. Qatar Medical Journal, 2017(1), 8. https://doi.org/10.5339/qmj.2017.swacelso.8. [78] UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group. (1996). Lancet, 348(9020), 75–82. [79] Bennett, C. C., Johnson, A., Field, D. J., Elbourne, D., & UK Collaborative ECMO Trial Group (2001). UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation: follow-up to age 4 years. Lancet, 357(9262), 1094–1096. https://doi.org/10.1016/S0140-6736(00)04310-5. [80] Squiers, J. J., Lima, B., & DiMaio, J. M. (2016). Contemporary extracorporeal membrane oxygenation therapy in adults: Fundamental principles and systematic review of the evidence. The Journal of Thoracic and Cardiovascular Surgery, 152(1), 20–32. https://doi.org/10.1016/j.jtcvs.2016.02.067. [81] Hirschl RB. (1995). Devices, chapter 10. Zwischenberger, J. B., Bartlett, R. H. (Eds). ECMO: Extracorporeal Cardiopulmonary

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Support in Critical Care. Extracorporeal Life Support Organization, 150-190. Mendler, N., Podechtl, F., Feil, G., Hiltmann, P., & Sebening, F. (1995). Seal-less centrifugal blood pump with magnetically suspended rotor: rot-a-flow. Artificial Organs, 19(7), 620–624. https://doi.org/10.1111/j.1525-1594.1995.tb02391.x. Tamari, Y., Lee-Sensiba, K., King, S., & Hall, M. H. (1999). An improved bladder for pump control during ECMO procedures. The Journal of Extracorporeal Technology, 31(2), 84–90. Lawson, S., Ellis, C., Butler, K., McRobb, C., & Mejak, B. (2011). Neonatal extracorporeal membrane oxygenation devices, techniques and team roles: 2011 survey results of the United States' Extracorporeal Life Support Organization centers. The Journal of Extracorporeal Technology, 43(4), 236–244. Mangoush, O., Purkayastha, S., Haj-Yahia, S., Kinross, J., Hayward, M., Bartolozzi, F., Darzi, A., & Athanasiou, T. (2007). Heparinbonded circuits versus nonheparin-bonded circuits: an evaluation of their effect on clinical outcomes. European Journal of Cardiothoracic Surgery, 31(6), 1058–1069. https://doi.org/ 10.1016/j.ejcts.2007.01.029. Rais-Bahrami, K., Walton, D. M., Sell, J. E., Rivera, O., Mikesell, G. T., & Short, B. L. (2002). Improved oxygenation with reduced recirculation during venovenous ECMO: comparison of two catheters. Perfusion, 17(6), 415–419. https://doi.org/10.1191/ 0267659102pf608oa. Davies, A., Jones, D., Bailey, M., Beca, J., Bellomo, R., Blackwell, N., Forrest, P., Gattas, D., Granger, E., Herkes, R., Jackson, A., McGuinness, S., Nair, P., Pellegrino, V., Pettilä, V., Plunkett, B., Pye, R., Torzillo, P., Webb, S., & Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators. (2009). Extracorporeal membrane oxygenation for 2009 Influenza A (H1N1) Acute Respiratory Distress Syndrome. JAMA, 302(17), 1888–1895. https://doi.org/10.1001/jama. 2009.1535.

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[88] Beurtheret, S., Mastroianni, C., Pozzi, M., D'Alessandro, C., Luyt, C. E., Combes, A., Pavie, A., & Leprince, P. (2012). Extracorporeal membrane oxygenation for 2009 influenza A (H1N1) acute respiratory distress syndrome: single-centre experience with 1-year follow-up. European Journal of Cardiothoracic Surgery, 41(3), 691–695. https://doi.org/10.1093/ejcts/ezr082. [89] Hou, X., Guo, L., Zhan, Q., Jia, X., Mi, Y., Li, B., Sun, B., Hao, X., & Li, H. (2012). Extracorporeal membrane oxygenation for critically ill patients with 2009 influenza A (H1N1) -related acute respiratory distress syndrome: preliminary experience from a single center. Artificial Organs, 36(9), 780–786. https://doi.org/10.1111/ j.1525-1594.2012.01468.x. [90] Lequier, L., Horton, S. B., McMullan, D. M., & Bartlett, R. H. (2013). Extracorporeal membrane oxygenation circuitry. Pediatric critical care medicine: a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies, 14(5), S7–S12. https://doi.org/10.1097/ PCC.0b013e318292dd10. [91] Zangrillo, A., Biondi-Zoccai, G., Landoni, G., Frati, G., Patroniti, N., Pesenti, A., & Pappalardo, F. (2013). Extracorporeal membrane oxygenation (ECMO) in patients with H1N1 influenza infection: a systematic review and meta-analysis including 8 studies and 266 patients receiving ECMO. Critical Care, 17(1), R30. https://doi.org/ 10.1186/cc12512. [92] ELSO Guidelines for Adult Respiratory Failure v1.4. (2017a). Extracorporeal Life Support Organization. Retrieved June 8, 2020 from https://www.elso.org/Resources/Guidelines.aspx. [93] Napp, L. C., Kühn, C., & Bauersachs, J. (2017). ECMO in cardiac arrest and cardiogenic shock. Herz, 42(1), 27–44. https://doi.org/ 10.1007/s00059-016-4523-4. [94] Le Gall, A., Follin, A., Cholley, B., Mantz, J., Aissaoui, N., & Pirracchio, R. (2018). Veno-arterial-ECMO in the intensive care unit: From technical aspects to clinical practice. Anaesthesia,

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Critical Care & Pain Medicine, 37(3), 259–268. https://doi.org/ 10.1016/j.accpm.2017.08.007. Guglin, M., Zucker, M. J., Bazan, V. M., Bozkurt, B., El Banayosy, A., Estep, J. D., Gurley, J., Nelson, K., Malyala, R., Panjrath, G. S., Zwischenberger, J. B., & Pinney, S. P. (2019). Venoarterial ECMO for Adults: JACC Scientific Expert Panel. Journal of the American College of Cardiology, 73(6), 698–716. https://doi.org/10.1016/ j.jacc.2018.11.038. ELSO Guidelines for Adult Cardiac Failure v1.3 (2013). Extracorporeal Life Support Organization. Retrieved June 8, 2020 from https://www.elso.org/Resources/Guidelines.aspx. Link, M. S., Berkow, L. C., Kudenchuk, P. J., Halperin, H. R., Hess, E. P., Moitra, V. K., Neumar, R. W., O'Neil, B. J., Paxton, J. H., Silvers, S. M., White, R. D., Yannopoulos, D., & Donnino, M. W. (2015). Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation, 132(18 Suppl 2), S444–S464. https://doi.org/ 10.1161/cir.0000000000000261. Neumar, R. W., Shuster, M., Callaway, C. W., Gent, L. M., Atkins, D. L., Bhanji, F., Brooks, S. C., de Caen, A. R., Donnino, M. W., Ferrer, J. M., Kleinman, M. E., Kronick, S. L., Lavonas, E. J., Link, M. S., Mancini, M. E., Morrison, L. J., O’Connor, R. E., Samson, R. A., Schexnayder, S. M., Singletary, E. M., Hazinski, M. F. (2015). Part 1: Executive Summary: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation, 132(18), S315–S367. https://doi.org/10.1161/CIR.0000000000000252. ELSO General Guidelines (2017b). Extracorporeal Life Support Organization. Retrieved June 8, 2020 from https://www.elso.org/ Resources/Guidelines.aspx.

In: The History of Extra-Corporeal … ISBN: 978-1-53618-961-2 Editor: Michael S. Firstenberg © 2021 Nova Science Publishers, Inc.

Chapter 2

AN INTRODUCTION TO VA-ECMO: PHYSIOLOGY, INDICATIONS, AND PRINCIPLES OF MANAGEMENT Benjamin Smood, Matthew Woods, Jason J. Han, Christian Bermudez and Rita Carrie Karianna Milewski* Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, US

ABSTRACT Over the past decade, venoarterial (VA)-ECMO has increasingly been used in the setting of cardiogenic shock and for extracorporeal cardiopulmonary resuscitation (ECPR). In this chapter, basic concepts of VA-ECMO are introduced, including indications and contraindications. With an introduction to VA-ECMO circuit anatomy, important * Corresponding Author’s E-mail: [email protected].

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Benjamin Smood, Matthew Woods, Jason J. Han et al. physiologic and pathophysiologic relationships are highlighted, which are necessary to managing and monitoring patients on VA-ECMO. Additionally, an overview of potential complications and strategies for weaning are provided.

Keywords: ECLS, ECMO, ECPR, ELSO, extracorporeal membrane oxygenation, mechanical circulatory support

INTRODUCTION Depending on the etiology and severity of the underlying pathology, extracorporeal membrane oxygenation (ECMO) can be deployed with a number of cannulation strategies, including venovenous (VV-)ECMO and venoarterial (VA-)ECMO for respiratory and/or cardiac failure, respectively [1, 2]. As the use of VV-ECMO and pediatric ECMO are detailed elsewhere in this textbook, the remainder of this chapter will focus on VA-ECMO in adults with cardiac failure. Throughout the early 2000s, there was little experience—and even less evidence—supporting the use of ECMO in cardiac failure. However, in 2010, Joen-Rong Sheu and colleagues published data that had been collected since 1993, demonstrating that percutaneous coronary intervention supported with VA-ECMO improved 30-day outcomes in patients with myocardial infarctions and profound cardiogenic shock [3]. Over the next five years, important studies supporting the role of VAECMO in various etiologies of cardiac failure and cardiogenic shock would be reported [4]. However, as reviewed in Table 1, to date there are still no prospective, randomized controlled trials for the use of VA-ECMO in cardiac failure [4-9]. Nevertheless, the use of VA-ECMO for cardiac support has increased drastically, from less than 200 runs per year in 1997, to over 2,000 runs per year by 2016 [9].

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Table 1. Common etiologic indications for VA-ECMO Etiology/Indications for VA-ECMO Myocardial Infarction

Estimated Ranges of Mortality (%) 30-75

Post-Cardiotomy Cardiogenic Shock Primary Graft Dysfunction after Heart Transplant Bridge to Left Ventricular Assist Device and/or Transplant Fulminant Myocarditis

25-75

Septic Myocarditis

40-85

Pulmonary Embolism or Pulmonary Hypertension with Right Ventricular Failure Refractory Arrhythmias

30-100

15-75 0-50

20-50

Highest Quality of Evidence

Sources

Cohort studies (prospective) Cohort studies (prospective) Cohort studies (prospective) Cohort studies (retrospective)

[3, 102, 134, 214]

Cohort studies (retrospective) Cohort studies (retrospective) Cohort studies (retrospective)

[107, 136, 205, 226232] [110, 142, 233]

[215-218] [104-106, 219-222] [115, 116, 118, 223225]

[108, 109, 205, 234239]

10-50

Cohort studies [240-244] (propensity matched) ECPR and/or Cardiogenic 50-95 Cohort studies [96, 121, 123, 125, 126, Shock After Cardiac Arrest (propensity 128, 130, 132, 133, 245matched) 250] Selected investigations are provided with the highest quality of evidence available for etiologic indication. Adapted and modified from references [4-9].

The use of VA-ECMO for cardiac support is a rapidly evolving field, and it is clear that VA-ECMO has a role in prolonged mechanical circulatory support. In this chapter, the basic components of the modern VA-ECMO circuit will be illustrated, and recent evidence and guidelines are provided supporting current indications and contraindications for VAECMO. Furthermore, strategies for cannulation, management, and weaning, will be introduced while highlighting complications to be aware of in each stage of care, with the hope that this chapter can serve as a guide for physicians, trainees, and other healthcare providers seeking to gain an

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improved understanding of the fundamentals of VA-ECMO support and management.

ANATOMY OF THE MODERN VA-ECMO CIRCUIT Since the development of cardiopulmonary bypass for open heart surgery, the nascence and evolution of ECMO can be understood as a natural progression towards providing prolonged cardiopulmonary support in critically ill patients. Despite the many parallels and similarities between VA-ECMO circuits and those used in cardiac surgery, important differences should be noted and are provided in Table 2 [2, 10-13]. In order to manage patients on VA-ECMO and potential issues that may arise, providers must have a thorough understanding of at least the basic circuit components and their selection criteria. Thus, a brief overview of the modern VA-ECMO circuit anatomy is provided as well as suggestions for basic monitoring and management, as recommended by the Extracorporeal Life Support Organization (ELSO) and experienced centers [14-17]. Because this chapter serves as an introduction to the use of VA-ECMO in the setting of cardiac failure, only VA-ECMO circuits will be described, specifically with regards to peripheral (femoral) cannulation. In its most basic form, the modern VA-ECMO circuit includes a mechanical pump, oxygenator, and conduit tubing, which establishes a closed circuit of flow to the patient with indwelling inflow (i.e., venous) and outflow (i.e., arterial) cannulas. Significant technological advances in mechanical pumps [18-20], oxygenators [21-24], and cannulas have permitted safer and more efficacious use of ECMO over the past two decades [25, 26], such that it is now a generally accepted clinical practice with widespread use [20]. In describing the modern VA-ECMO circuit, recent technological advances and supporting evidence are described.

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Table 2. Similarities and differences in VA-ECMO and cardiopulmonary bypass Characteristics

VA-ECMO

Environment for cannulation Patient sedation Duration of support

Operating room, intensive care unit, emergency department, bedside, other General or local anesthesia Short-term or long-term (hours or days to weeks) Small Yes (to a lesser degree) No Centrifugal Short or long-term use No (closed circuit)

Priming volume Hemodilution Reservoir Pump Oxygenator Air-blood interface Arterial filter Cooling possibility Initial Heparin bolus Activated clotting time (ACT) Anticoagulation reversal Autotransfusion Pulsatility

No Limited Low dose (50-100 u/kg) 180-200s

No No Variable, target pulse pressure >10 mmHg to promote ejection Adapted and modified from references [10-13].

Cardiopulmonary Bypass Operating room General anesthesia Short term (minutes to hours) Large Yes Yes Centrifugal or roller Short-term use Yes (some closed circuits exist) Yes Yes (routine hypothermia) High dose (300-400 u/kg) >480s Protamine administration Yes Non-pulsatile

MECHANICAL PUMPS Modern Centrifugal Pumps As a general prerequisite, VA-ECMO circuits should be capable of supporting the entire cardiac output of a patient at full flows (i.e., approximately 3L/m2/min or 60-80mL/kg/min in adults) [17]. To do this, a mechanical pump is required. Although any pump may be used (i.e., roller, axial, peristaltic, or centrifugal pumps), an important advance in the development of ECMO has been the evolution of newer generation centrifugal pumps over the past decade, which have largely replaced

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traditional roller pumps [18, 19, 20, 27, 28, 29]. A number of structurally modified centrifugal pumps are currently used in clinical practice, including the Thoratec Centrimag (Abbott, Pleasanton, CA, United States of America) and Maquet RotaFlow (Getinge, Rastatt, Germany). Despite early concerns that centrifugal blood pumps had higher rates of hemolysis and kidney failure [19, 29], modern designs appear to not only be safer, but also perform better than traditional roller and older centrifugal pumps [20, 29-36]. Centrifugal pumps use kinetic energy from a rapidly spinning impeller to provide a forward driving force to support blood flow. These pumps may contain magnetically levitated impellers that lack a central bearing, such that the impeller remains suspended in a patient’s own blood allowing for totally non-occlusive, uniform and unidirectional flows [37-39]. Combined with other technological advances, such as the use of heparin-primed circuits to reduce the need for anticoagulation [26, 38, 40-42], these designs allow for less blood stagnation and shear stress, limiting heat production and minimizing traumatic damage to circulating blood and the circuit tubing [29, 35, 36]. With centrifugal flow pumps, there is minimal risk of tubing rupture, as well as less hemolysis. This minimizes microvascular occlusion related to plasma free hemoglobin, which mitigates the pathologic inflammatory responses and peripheral vasoconstriction associated with VA-ECMO [18, 29, 35, 37, 43-45]. However, even modern centrifugal pumps are not free of limitations, and there is some evidence that centrifugal pumps may have higher risks for non-surgical bleeding, although the mechanism of this is unclear [20, 29, 46]. Because an entire chapter in this textbook is dedicated to anticoagulation strategies in ECMO, this subject will not be described here. However, it is worth noting that at pump flows less than 2L/min, a greater degree of anticoagulation may be needed [47].

Basic Pump Management Newer centrifugal pumps do not require a reservoir, in part because flow is driven by active venous suction independent of gravity, which

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allows them to be smaller and minimize the necessary circuit priming volumes [37, 39, 40, 44, 48, 49]. However, because of a lacking reservoir, venous drainage may become temporarily occluded with some frequency in the setting of hypovolemia, kinking of the cannula, or physiologic valsalva maneuvers (i.e., coughing, etc.) [29]. In these circumstances, as flow is occluded, the impeller continues spinning and creates a vacuum in the pump head, which may promote hemolysis as gas volume expands and gas solubility decreases, particularly at pressures exceeding 600 mmHg [29, 44]. As a consequence of the suction generated by the impeller’s continual spinning, one of the main challenges of centrifugal pumps is their inability to maintain set flow rates [43, 44]. Although some newer models have modifications designed to mitigate this, it is important to recognize that centrifugal pumps are particularly dependent on, and susceptible to changes in preload and afterload [17, 50, 51]. Suggestions for monitoring and targets for managing ECMO circuits have been described previously and are provided for reference in Table 3 [5, 52-54]. Central venous pressures should be kept at 5-10mmHg to permit adequate drainage [17]. Providers must also monitor inlet (venous) and outlet (arterial) cannula pressures. Inlet pressures should not routinely exceed -300mmHg, as higher suction can cause (or represent) drainage occlusion (i.e., ‘suck-down’ events) and potentially hemolysis [29]. One sign of a suck-down event is ‘chattering’ or ‘chugging’, terms which are used to describe erratic movements of the venous circuit tubing that results from changes in pressure and flow as the vasculature collapses and distends around the inflow cannula [29]. It is important to distinguish such chattering from normal pulsatility that may be generated by myocardial contractility, which can be accomplished by simply taking the patient's pulse while watching the cannula to see if the pulsations appear to correlate physiologically or occur in pathological desynchrony.

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Table 3. Recommendations for patient and circuit monitoring on VA-ECMO Monitoring

Volume Status/Preload

Systemic Perfusion

Gas Exchange and Ventilation

Anemia/hemorrhage Anticoagulation End-organ perfusion, function, and aerobic respiration Venous congestion Hemolysis

Heparin-Induced Thrombocytopenia Hyperfibrinolysis

Chest X-Ray

Echocardiography

Surrogates

Target Values and/or Specific Parameters for Evaluation Hemodynamics and Gas Exchange CVP 90% Laboratory Values Hemoglobin >8.0 mg/dL Activated clotting time 180-200 pH 7.35-7.45 Lactate 0.5 ml/kg/hr Liver enzymes AST 5-40 U/L ALT 5-40 U/L LDH 95%, a target SvO2 should be >65-70% (i.e., an O2ER ~2530%) [10, 17, 54, 174, 196]. When SvO2 remains persistently 65-70%; however, lower thresholds of 8g/dL are typically used to account for hemodilution and limit antigen exposure in patients who may ultimately need transplantation (Table 3) [10, 17, 54]. As has hopefully been demonstrated, continuous intensive care monitoring is necessary to evaluate and scrutinize the hemodynamic interdependence of volume status, LV unloading, inotropy and afterload reduction in order to optimize the management of patients requiring VAECMO [54]. Meticulous attention to clinical details is necessary, and caregivers should be highly experienced in managing VA-ECMO. Routine indices of evaluation should include metrics of gas-exchange and perfusion with continuous assessment for end-organ injury and proper ECMO circuit configuration [54]. In this manner, moment-to-moment decisions can be made in patient care and provide important insight regarding when weaning and decannulation may be appropriate.

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WEANING AND COMPLICATIONS Weaning from VA-ECMO Determining the optimal timing of weaning from VA-ECMO must balance the benefit of awaiting further myocardial recovery with the risk of ECMO-related complications, such as device or cannula malfunction, bleeding, embolization/thrombosis, end-organ dysfunction or ischemia, neurological complications and infection. There is a sense of urgency in weaning from VA-ECMO, as complications are severe and often carry prognostic implications after weaning. However, premature weaning can lead to hemodynamic collapse, which may be terminal or require reinitiation of mechanical circulatory support. As such, prior to weaning, one must ask important questions of the patient’s clinical status, including if cardiac and/or respiratory function has adequately recovered, if further recovery is anticipated, if removal of mechanical assistance will be welltolerated, or if the patient is a suitable candidate for more definitive therapies, including open heart surgery with revascularization, placement of a durable ventricular assist device, or transplantation [7]. The emergence of various temporary and durable mechanical circulatory support platforms such as ventricular assist devices in the modern era, as well as the option of directly bridging to heart transplantation from VA-ECMO allow for multiple weaning strategies with excellent outcomes. Although the definition varies widely, the chance of successfully weaning from VA-ECMO ranges from roughly 30-75%, depending on the underlying etiology of cardiac failure [204]. Successful outcomes are often defined as survival without requiring additional mechanical circulatory support at 30 days. Factors that confer a higher risk of mortality after decannulation include higher age, extremes in body mass index, and other comorbidities [205]. Patient characteristics such as original indication for VA-ECMO (e.g., post-cardiotomy myocardial stunning, fulminant myocarditis, acute pulmonary embolism, intractable ventricular arrhythmia, primary graft dysfunction, ECPR), as well as the availability of

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a left ventricular vent (e.g., Impella device), are also important prognostic factors for a successful wean. Although biomarkers are often non-specific for recovery, general indicators of cardiac ischemia or global hypoperfusion such as lactate, metabolic acidosis, and laboratory evidence of end-organ injury (e.g., creatinine, liver enzymes) should be optimized prior to weaning. At a baseline, VA-ECMO patients undergo routine and as-needed echocardiograms based on clinical findings to aid in optimizing unloading conditions. Weaning trials may be indicated once there are signs of hemodynamic stability and myocardial recovery. Myocardial recovery and improved contractility might be clinically demonstrated by consistently improved pulsatility or improved myocardial function with echocardiography [14, 206]. However, assessment of myocardial recovery on VA-ECMO remains a multifactorial and relatively imprecise science, though most sources agree that assessing hemodynamic and echocardiographic stability at minimal VA-ECMO support is sufficient in simulating ventricular function at nearly full loading conditions. Still, there are no clear, validated diagnostic tests to predict if weaning will be successful. As a broad template for weaning, once vasoactive medications and inotropes are optimized, VA-ECMO flows can gradually be reduced while monitoring for hemodynamic and end-organ evidence suggesting that VAECMO support continues to be needed. Typically, flows are gradually reduced to 50%, and then 25% of full support [17]. If ventricular and valve function remain adequate, the circuit may be clamped for a trial completely off VA-ECMO support for 30 minutes to 4 hours. However, it is important that the pump continues to recirculate blood and that cannula are routinely flushed (every 10 minutes) with heparinized saline in order to prevent stasis and thrombosis, in the event that VA-ECMO continues to be needed [14]. Alternatively, other programs have institutional weaning protocols that consist of stepwise reduction of ECMO flows by an interval of 0.5 L/min down to the minimal level required to prevent thrombosis (1 L/min) [204]. At our institution, patients remain adequately anticoagulated and are

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maintained at 1 L/min for 30 minutes during this process. Inadequate recovery typically manifests itself quickly, either on echocardiographic assessment or as acute hemodynamic derangement (particularly hypotension or a rise in pulmonary pressures and central venous pressure). Importantly, correlating echocardiography with invasive hemodynamic monitoring can often provide the mechanism for weaning failure, such as valvular failure, right or left ventricular dysfunction, presence of regional ischemia, dynamic obstruction, tamponade, or pulmonary hypertension. However, if a patient remains hemodynamically stable (on less than maximal vasoactive and/or inotropic support), while demonstrating endorgan perfusion and oxygen delivery, decannulation may be considered [14]. At our institution, all VA-ECMO decannulation procedures, both central and peripheral, take place in the operating room with pulmonary arterial catheter and transesophageal echocardiographic monitoring. Mechanical support is weaned while inotropic support is augmented with a plan to then taper this pharmacologic support over the ensuing 24-72 hours. Epinephrine is our primary choice of inotropic agent, while milrinone is added as a second agent if the patient has a component of right ventricular dysfunction and the patient can tolerate it hemodynamically. Femoral arterial cannulation sites are primarily repaired by cutdown. The femoral venous cannula is removed with the application of hemostatic Usutures at the level of the skin, which are removed on the first postoperative day.

End-Organ Complications on VA-ECMO As has hopefully been demonstrated, VA-ECMO support is not without limitations, and timely weaning as tolerated is necessary to minimize the risk of serious adverse events and end-organ complications resulting from mechanical circulatory support. Because there are entire chapters dedicated to various types of complications that can occur on ECMO within this textbook, this will serve as only a brief overview that

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should guide focused monitoring and management of patients on VAECMO. In some respect, having already described the contraindications to VA-ECMO within this chapter, it becomes easier to understand potential complications [9, 96]. Patients are at risk of serious hematologic complications affecting several organ systems. Of course, devastating hemorrhagic or embolic strokes may develop if the necessary anticoagulation becomes supra- or subtherapeutic, respectively. Similarly, despite anticoagulation, patients are typically bed bound and immobile for prolonged periods on VA-ECMO, and thus providers must be aware of the potential of deep vein thrombosis and the potential for pulmonary emboli, especially if there are acute changes in cardiopulmonary function. Meanwhile, as is the case whenever heparin is used, providers must always be cognizant of the potential for heparin-induced thrombocytopenia, and routinely monitor platelet counts in addition to signs of thrombosis or other sequelae of this disease process (Table 3). Moreover, the profound changes in flow dynamics that occur in the setting of diminished pulsatility cause inflammatory responses that disrupt endothelial cell signaling, function, and homeostasis. Although the exact mechanisms remain unclear, it is generally recognized that these changes predispose patients to bleeding events, be it in the brain, gastrointestinal tract, or elsewhere [20, 46]. This highlights the importance of maintaining an adequate pulse pressure and monitoring patients to ensure that there is adequate LV ejection for reasons other than simply preventing LV stasis and the associated risks of thrombus formation and potential embolization. In addition, particularly when using peripheral VA-ECMO in the setting of poor native lung function or diminished gas exchange, providers must also be aware that changes in ventricular function and ejection may affect the location of the interface at which oxygen rich blood reinfused by the ECMO circuit mixes with poorly oxygenated blood being ejected out of the heart. This phenomenon, known as ‘watershed physiology’ or ‘Harlequin syndrome’ can lead to clinically significant aberrations in cerebral and upper body oxygenation if oxygenated blood from the ECMO circuit is unable to reach the aortic arch [5]. As such, providers must

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monitor both upper and lower body oxygenation, and intervene to ensure that adequately oxygenated blood reaches the brain (Table 3). As is the case whenever there are indwelling lines in a patient, providers must constantly be aware of the risks of infection and meticulously work to keep cannulas and other invasive monitoring devices sterile. Although vasoplegia and elevated inflammatory markers are commonly observed with the use of ECMO (due to the systemic inflammatory response elicited from blood contacting the nonendothelialized circuit), there should be a very low threshold for obtaining cultures and initiating antibiotics, especially when there additional clinical signs of infection, such as fever or clinical deterioration [12, 95].

RECENT RESULTS AND FUTURE DIRECTIONS Current trends indicate that the use of VA-ECMO will continue rising [97]. Future investigations should therefore seek to better define patient selection criteria and indications for VA-ECMO, while optimizing management and weaning strategies. Such efforts could dramatically improve patient outcomes. As an important first step, recent studies have identified predictors of survival and success. Among patients who survived 24 hours after weaning from VA-ECMO for cardiogenic shock, a retrospective study by Sertic et al. found an inhospital survival rate of 64.2%, with a 3-year survival of 51.4% [207]. Their study found that patients with comorbidities, specifically prior myocardial infarction and diabetes, as well as individuals with prolonged ECMO runs and hypoxemia at the time of weaning, were less likely to survive. Thus, while there are evident predictors of survival, further investigations are needed to determine how such results might affect candidacy for VA-ECMO. Meanwhile, these findings suggest that future studies may be warranted to determine if alternative mechanical circulatory support modalities should be used when prompt weaning from VA-ECMO is not achieved.

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Lai et al. published a study of 14 patients who required multiple ECMO runs from 2011 to 2019 [208]. Among these, four (28.6%) patients survived to hospital discharge. No patient requiring continuous renal replacement therapy during their first ECMO run survived, and no patient who suffered a serious neurologic injury survived to discharge. Interestingly, all patients required renal replacement therapy in their second run. A better understanding of the implications of multiple ECMO runs and identifying individuals with a higher likelihood of survival might help to guide clinical decision making in the future [208]. The utilization of VA-ECMO to provide perfusion for donor organs is also an area of potential growth and expansion. Bronchard et al. illustrated that patients with brain death on VA-ECMO had similar outcomes in kidney transplantation [209]. Consideration has been given to the utilization of postmortem ECMO for potential transplant donors with controlled circulatory death, but remains under-studied [210]. Ex-vivo VAECMO for donor organs using mobile circuits has shown promise in case studies for renal and liver transplantation [211]. Meanwhile, the PROCEED II trial showed similar results in cardiac transplantation when organs were transported in cold storage or with perfusion by the Organ Care System (a pump similar in concept to VA-ECMO) [212]. Although evidence supporting the use of ECPR is compelling, future investigations should seek to control for variables known to effect survival in cardiac arrest. Specifically, accounting for the time to CPR initiation, quantitative metrics of CPR quality, candidate selection, and complications of ECMO cannulation might improve the power of future analyses. As experience with VA-ECMO continues to grow, additional efforts will be needed to permit meaningful analyses of large data as it is collected. For example, the ELSO database stratifies adult cardiac ECMO runs by diagnoses of cardiac arrest, cardiogenic shock, cardiomyopathy, congenital defect, myocarditis, and other [213]. However, the “other” category accounts for a majority of entries to date, which may make more targeted analyses challenging, or limit the broad applicability of conclusions drawn from this data. Similarly, a “cardiac run” can include cannulation strategies other than just VA-ECMO, underscoring the

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importance of defining a study population with inclusion and exclusion criteria when analyzing large data [213]. As such, more specific classification systems might improve future analyses [9]. As ECMO runs become longer, adaptive systems for monitoring and goal-directed management remain an exciting area for future research. Patient mobility and quality might be improved as ECMO circuits continue to be made smaller and less cumbersome. Meanwhile, improved circuit coatings or other novel technologies may prevent pathologic inflammatory responses arising on ECMO, or eliminate the need for anticoagulation and the incidence of thrombotic and hemorrhagic complications observed in the modern era [81]. In any case, innovations certainly remain undiscovered, but have the potential to transform the future of ECMO.

CONCLUSION The basic circuit anatomy, indications and contraindications of VAECMO have been described. Additionally, an emphasis has been placed on the fundamental physiologic principles relevant to VA-ECMO, and the pathophysiologic changes that occur in response to its initiation. Understanding the foundations of hemodynamic support and gas-exchange are of paramount importance when managing patients on VA-ECMO and supporting them to successful decannulation. In this respect, this chapter focuses on the governing principles that practitioners should be comfortable with when making clinical decisions and treating patients supported with VA-ECMO. One must recognize that no single parameter serves as a global surrogate for adequate perfusion or adequate hemodynamic support. Rather, each must be interpreted in totality of the patient’s clinical picture.

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In: The History of Extra-Corporeal … ISBN: 978-1-53618-961-2 Editor: Michael S. Firstenberg © 2021 Nova Science Publishers, Inc.

Chapter 3

DISASTER PREPAREDNESS FOR ECMO PROGRAMS AND ADAPTING ECMO PROGRAMS TO FACE THE COVID19 PANDEMIC Allison Ferreira and Kim Delacruz Department of Emergency Medicine, University of California Los Angeles, Los Angeles, CA Department of Cardiothoracic Surgery, University of California Los Angeles, Los Angeles, CA

ABSTRACT Disaster preparedness requires planning on an individual and program level with detailed attention to human factors, supplies, and processes to maximize the use of available resources. However, in addition to the limitations on ECMO utilization by supply limitations and human factors, the utilization of general critical care services may impose additional restrictions on the number of ECMO runs that can be offered. The lessons being learned at the time of this chapter’s publication to prepare ECMO programs during the COVID19 pandemic give further

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Keywords: disaster preparedness, ECMO, ethics, COVID19

INTRODUCTION The World Health Organization (WHO) defines a public health emergency as the imminent threat of illness caused by epidemic or pandemic disease that poses a substantial risk of a significant number of human fatalities or long-term / permanent disability [1]. A public health emergency might reach disaster proportions when it evolves to seriously disrupt community function causing widespread material and economic losses beyond the community’s ability to cope [2]. Of note, the scale of an incident which results in a disaster scenario is independent from its resulting impact; a relatively small increase in demand for healthcare services may exceed the local resources’ capacity if ICU or ECMO resources utilization is already high before the incident. Furthermore, depending on the specific nature of the public health emergency or mass casualty incident, ECMO may play a significant role. Historically, contagious respiratory epidemics have led to an increased demand for ECMO, as in the 2009 H1N1 Influenza pandemic, Severe Acute Respiratory Syndrome, Middle East Respiratory Syndrome, and now COVID19. ECMO has also been employed in mass casualty incidents including the 2015 Formosa Water Park explosion in Taiwan which resulted in 375 patients with second- and third- degree burns over 20% TBSA with a single institution performing 6 simultaneous ECMO runs for burn-related ARDS [3]. The literature also describes the use of ECMO to rescue avalanche victims with accidental deep hypothermic cardiac arrest [4-7]. Disaster preparedness requires planning on an individual and program level with detailed attention to human factors, supplies, and processes to maximize the use of available resources. However, in addition to the limitations on ECMO utilization by supply limitations and human

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factors, the utilization of general critical care services may impose additional restrictions on the number of ECMO runs that can be offered. The lessons being learned at the time of this chapter’s publication in the face of the COVID19 pandemic give further granularity to disaster preparedness and will be highlighted here as an example.

ELEMENTS OF DISASTER PREPAREDNESS Inventory and Preparation Although the very nature of disaster is that the threat is imminent and it will never be possible to anticipate every need in a crisis, several steps are key (see Table 1) [8, 9]. Central to the disaster preparedness response is an inventory of personnel, equipment, and facilities to identify rate-limiting factors which may limit the provision of ECMO services under high demand situations. Building redundancy into the system allows more resilience. Crucially, the number of human resources (perfusion, intensivists specialized in ECMO, nurses experienced in caring for ECMO patients) is limited. Tracking of human capital should focus on the most limited number of staff from the core ECMO team. The cancellation of elective surgical cases, if appropriate in the specific disaster scenario, may permit re-allocation of existing intensivist and perfusionist resources. Programs may consider hiring outside contractors to supplement the specialized team, if there is ample warning, before personal demands (such as childcare, personal property damage, illness, or quarantine) reduce the number of available team members. Close tracking of ECMO circuits and their components as well as awareness of key components’ supply chains is essential so that shortages can be anticipated in advance. Strategic stockpiling during times when there is no system stress offers the advantage of secure supply chains and the possibility of increasing department par levels for crucial equipment like oxygenators; stockpiling is often impossible when a crisis is looming

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as vendors may limit allocation to minimize interruptions to global supply chains. Established standard par levels should be identified vs. surge par levels. Once the surge has passed, the team should consider returning to standard par levels to avoid financial loss, as the shelf life on most disposables is 18- 24 months. Table 1. Inventory and preparation for disaster scenarios  Identify current ECMO utilization and capacity.  Inventory key personnel, equipment, and processes to identify rate-limiting factors  Build redundancy where possible (staffing, equipment supply chains may be interrupted)  Identify key challenges specific to executing patient care and program tasks in the disaster scenario (i.e., PPE consumption in the case of infectious disease) to shape processes and protocols  Perform simulation to hone processes in face of specific anticipated challenges (i.e., performing procedures in PPE)  Develop a procedure for team debriefing and rapid process improvement

EHR-based dashboards can be used to keep track of the remaining ECMO capacity based on human resource and supply capacity at any given time. The most useful dashboards auto populate the information so as to not depend on any single person for the information gathering. This will ensure that information is always up to date and ensures that high patient census, illness, or quarantine will not prevent timely dashboard updates. Once a surge or disaster state is looming, it will be essential to identify pre-disaster ECMO utilization and capacity, to consider the impact of general ICU conditions, and to refine program goals.

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IMPACT OF DEMAND FOR GENERAL CRITICAL CARE SERVICES In addition to the limitations on ECMO utilization by supply limitations and human factors, the utilization of general critical care services may impose additional restrictions on the number of ECMO runs that can be offered. Overwhelming demands on the system as a whole for limited resources (i.e., ventilators, ICU beds, ICU nurses, intensivists, PPE) may downscale or even prevent the use of ECMO, which is a resource-intensive service [8, 10]. A hierarchical pyramid which implicitly acknowledges that specialization may have to be surrendered when fundamental pillars of healthcare and community are threatened has been proposed [11]. ECMO programs should consider how ECMO fits into the greater schema of critical care during a disaster.

REVISING PROGRAM SCOPE AND PROTOCOLS FOR A SPECIFIC DISASTER Once the nature of likely disaster and utilization of ECMO and ICU resources is apparent, more detailed preparations are possible (see Table 2). ECMO candidate criteria should be reviewed and/or modified as appropriate. Regional or national collaboration can help ensure consistent criteria for ECMO candidacy and provide a framework for regionalization of ECMO care, especially if mobile ECMO programs exist. Accordingly, some elements of the ECMO program (including ECPR, mobile ECMO, bride to transplant, for example) may need to be scaled back or suspended due to high demand for ECMO and/or critical care resources.

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Table 2. Key considerations for ECMO programs in disaster scenarios  Evaluate how ECMO fits into the greater critical care schema during a disaster  Refine and modify ECMO candidate criteria based on disease data and available resources  Coordinate with regional and national ECMO programs to keep guidelines consistent on ECMO candidacy, regionalization, and whether resources will be shared between programs  Consider elements of ECMO program that may need to be scaled back or suspended depending on overall demand  Review current protocols to identify where and when cross-training and/or remote management can be identified and expedited

In times of crisis, different hospital systems should consider working with local government to become one entity to facilitate cohorting, sharing staff, resources, etc. For example, ECMO care in a city may be regionalized such that disaster ECMO patients go to one or two ECMO centers. Other centers could send resources (oxygenators and ECMO capital) to them to allow centralized care. Of note, this would involve making complex financial arrangements and will require emergency credentialing for sharing staff resources, which is already commonly used by mobile ECMO programs. If the disaster involves a communicable disease, processes modifications must be made according to infection control guidelines. Important considerations include cohorting, use of personal protective equipment, and minimizing surface and supply contamination. A review of patient transport guidelines (whether within one hospital or between hospitals) should be undertaken with a focus on infection control. It may be possible to set up remote monitoring to minimize staff exposure and PPE use, or to train and delegate certain tasks (like making changes to sweep gas flow) to nursing staff who have already donned PPE. Procedural simulation of how to perform essential procedures in the appropriate PPE. Plans for handling accidental decannulation, pump failure, air in the circuit, and cardiac arrest should be prepared in advance and practiced in PPE [8] if these procedures are to be performed.

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Leadership should also be cognizant of the added psychosocial stress to team members when making logistical plans particularly when there is some risk to healthcare providers when responding to the crisis. It is essential to review current protocols to identify where and when crosstraining and/or remote management can be expedited. Creating modified protocols and performing simulations may help with team expectations and stress.

ETHICAL CONSIDERATIONS In crisis circumstances, it is imperative that healthcare professional triage patients to maximize the potential benefits of available treatments, even if some patients who would typically receive and might benefit from treatment may not receive treatment, may have initiation postponed, discontinued, or even die [12-14]. Some important ethical considerations for ECMO in times of scarcity are listed in Table 3. Table 3. Ethical considerations  Will disaster victims be treated differently than other current or future ECMO patients?  Consider the total number of ECMO circuits available and how many will be allocated for disaster victims vs other indications  Consider how offering ECMO services affects the provision of other critical care resources  Consider the anticipated benefit to patients from ECMO vs. risks to healthcare workers  Allocation of limited ECMO resources in a circumstance where rationing is necessary: first-come, first-served or based on distributive justice

Consider the total number of ECMO circuits available and how many will be allocated for disaster victims vs other indications such as postcardiotomy shock. Will all ECMO patients be treated with the same set of

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rules or are disaster victims treated as a separate cohort? When considering whether and how to offer ECMO to disaster victims, the anticipated benefit to patients from ECMO should be weighed against any risks to healthcare workers by provisioning that care. A discussion of ECMO allocation should include a schema such as first-come, first-served or based on distributive justice. If a first-come first-served strategy is not employed and a trial of ECMO will be time or equipment-limited, who will determine when a patient’s trial is over? How often will the patient's clinical progress be reviewed? Will the oxygenator be replaced when the first fails? Will emergency rescue procedures be performed? Ramanathan suggests using predetermined consensus criteria for ECMO rationing if needed [8]. Medical ethicists, medicolegal experts, and/or risk management can be important allies in these challenging scenarios. Processes will be required to keep abreast of and respond to rapidly changing information. A procedure for team debriefing and rapid process improvement as additional knowledge is gained will improve team confidence under stressful working conditions and streamline care.

AN EXAMPLE: ECMO IN THE COVID-19 PANDEMIC Early Experience with ECMO in COVID-19 Patients COVID-19, a severe respiratory illness caused by SARS Co-V 2, was declared a pandemic by the WHO on March 11, 2020, less than 3.5 months after the initial outbreak in Wuhan, China. Critically ill patients develop severe ARDS frequently requiring weeks of mechanical ventilation [15, 16]. The virus spreads by contact and respiratory droplets and 6000 healthcare workers were infected in Wuhan, China, the epicenter of the pandemic, with 2,000 healthcare worker deaths. As new information developed about the survival of the virus on various surfaces and the spread of disease by asymptomatic carriers [17, 18], PPE shortages accelerated [19]. The WHO recommended ECMO be considered in selected patients, partially based on the success of ECMO in H1N1 [8]. It

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appeared initially that most patients responded well to a long course of conventional ARDS ventilator management and proning. The first several case series from Wuhan cited 15 ECMO runs but did not report patientlevel data [15, 16, 20, 21] making the early ECMO experience difficult to interpret. Overall, there were poor outcomes in patients sick enough to require ECMO based on early experience, partially due to age factors and the comorbidities of the sickest patients; Yang 2020 reported survival of only one of six COVID19 positive ECMO patients [20]. Henry 2020 suggests that ECMO cannulation may increase IL6 and promote lymphopenia, both of which carry a worse prognosis in COVID19 [22]. Another consideration is the incidence of fulminant viral myocarditis and sudden cardiac death after the resolution of respiratory failure, which may require conversion of cannulation strategy (from VV to VA) and clear procedures for handling a coding COVID patient. Initial data showed a high case fatality rate for elderly patients, with an inflection point over age 60 and up to a 15% mortality in patients over 80. There was poor survival for COVID patients after cardiac arrest, although whether ECMO was applied here is unknown [15, 16].

Disaster Preparedness for COVID-19 An early inventory identified supply chain issues with our oxygenators, which were produced in Italy, one of the countries hit hardest early in the pandemic. We were able to diversify our sourcing before supply chains became interrupted. Collaboration with peer institutions permitted coordination of care standards and ECMO indications. Based on the available disease-specific evidence, we restricted our eligibility criteria for VV ECMO in COVID positive or persons under investigation given the limited information on survival benefit and risk to cannulating providers. This guidance is consistent with the recommendations of Extracorporeal Life Support Organization (ELSO) [23].

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Identifying Key Challenges: Minimizing PPE Burn Rate As the pandemic began to spread around the world, it quickly became apparent that PPE was a rate-limiting element. Our operating procedures were modified to minimize exposure, contamination, and PPE use given the incidence of community spread. Our mobile ECMO program specified that cannulation would not be performed at outside hospitals. COVIDECMO patients were not eligible for our standard ambulation protocols. On an individual patient level, in order to minimize PPE use, pre- and post-membrane blood gases would be drawn every 72h unless clinically indicated based on the fact that our most commonly used oxygenator rarely fails in the first 72h. Anticoagulation was monitored by PTT drawn by an RN and sent in a biohazard specimen bag to the laboratory to minimize the number of handoffs and potential surface contamination with running ACTs (where a staff member brings a sample to the dirty utility room and all surfaces contacted would require decontamination). Perfusionists would perform a circuit check every 24 hours for clot and fibrin burden unless clinically indicated. Afterwards, the perfusionist would not enter the COVID positive room unless clinically indicated to manage fluctuations in ECMO support. The primary nurse was tasked with making adjustments to sweep, etc. We planned strategic deployment of personnel to care for COVID-19 positive patients and to respond to codes to minimize staff exposure and PPE consumption. This was particularly important because of the small, specialized team of 11 perfusionists; even if brief, a significant loss of human resources would seriously limit the number of patients we could care for on ECMO, especially when some provider attrition was expected due to quarantine, illness, high-risk comorbidities, and childcare.

Ethical Issues in Preparations for COVID-19 Our ECPR program was suspended given the prevalence of community spread in our city in light of risks to cannulating providers and the dismal

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survival of these patients reported in the literature to date. When planning for the pandemic, we agreed that in the event that an emergency procedure was required (such as air embolism, circuit clot, accidental decannulation, pump or oxygenator failure), the safety of the clinical team (including donning proper PPE) would take priority. Early on in the pandemic, ELSO recommended that in absence of lung or cardiac recovery after approximately 21 days on ECMO, further ECMO is considered futile and the patient should be transitioned to conventional management. Our multidisciplinary ECMO team worked closely with the critical care committee and hospital ethics to develop ICU surge plans and guiding principles for triage when high demand requires the standard of care to shift. At the highest levels of hospital surge, equipment-limited trials would become time-limited trials as ECMO patients would be considered by an independent triage officer with all others for limited ICU bed resources. Most importantly, as the pandemic progressed, these program modifications were continuously re-evaluated and modified to adapt to changing circumstances, and to return to routine practice when appropriate.

CONCLUSION Disaster preparedness requires planning on an individual and program level with detailed attention to human factors, supplies, and processes to maximize the use of available resources. However, in addition to the limitations on ECMO utilization by supply limitations and human factors, the utilization of general critical care services may impose additional restrictions on the number of ECMO runs that can be offered. The lessons being learned at the time of this chapter’s publication in the face of the COVID-19 pandemic give further granularity to disaster preparedness and are highlighted as an example.

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Glossary of Humanitarian Terms. WHO ReliefWeb. https://www. who.int/hac/about/definitions/en/. Health Emergency and Disaster Risk Management Framework. Geneva: World Health Organization; 2019.Licence: CC BY-NC-SA 3.0 IGO. Chiu YJ et al. ECMO may be a lifesaving modality in patients with burn and severe ARDS: Experience of formosa water park dust explosion disaster in Taiwan (2018). Burns 44; 118–123. Cimpoesu D et al. Cardiac arrest in special circumstances - recent advances in resuscitation (2019). Am. J. Ther. e276-e283. Dunne, Ben, Erasmia Christou, Oonagh Duff, and Christopher Merry. “Extracorporeal-assisted rewarming in the management of accidental deep hypothermic cardiac arrest: a systematic review of the literature.” Heart, Lung and Circulation 23, no. 11 (2014): 1029-1035. Sawamoto, Keigo, Steven B. Bird, Yoichi Katayama, Kunihiko Maekawa, Shuji Uemura, Katsutoshi Tanno, and Eichi Narimatsu. “Outcome from severe accidental hypothermia with cardiac arrest resuscitated with extracorporeal cardiopulmonary resuscitation.” The American journal of emergency medicine 32, no. 4 (2014): 320-324. Ruttmann, Elfriede, Annemarie Weissenbacher, Hanno Ulmer, Ludwig Müller, Daniel Höfer, Juliane Kilo, Walter Rabl et al. “Prolonged extracorporeal membrane oxygenation-assisted support provides improved survival in hypothermic patients with cardiocirculatory arrest.” The Journal of thoracic and cardiovascular surgery 134, no. 3 (2007): 594-600. Ramanathan, K et al. “Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases” (2020) Lancet Respir. Med. Epub ahead of print. https://doi.org/10.1016/S2213-2600(20)30121-1. Sprung C and Kesecioglu J. “Chapter 5. Essential equipment, pharmaceuticals, and supplies. Recommendations and standard operating procedures for intensive care unit and hospital preparations for an influenza epidemic or mass disaster.” Intensive Care Med. (2010) 36 (Suppl 1): S38–S44.

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[10] MacLaren G, Fisher D, Brodie D. Preparing for the Most Critically Ill Patients With COVID-19: The Potential Role of Extracorporeal Membrane Oxygenation. JAMA. Published online February 19, 2020. doi:10.1001/jama.2020.2342. [11] Shekar, Kiran. Provision of ECMO During COVID-19 and Other Pandemics. 20 March 2020. Webinar. [12] Christian, Michael D., Charles L. Sprung, Mary A. King, Jeffrey R. Dichter, Niranjan Kissoon, Asha V. Devereaux, and Charles D. Gomersall. “Triage: care of the critically ill and injured during pandemics and disasters: CHEST consensus statement.” Chest 146, no. 4 (2014): e61S-e74S. [13] Institute of Medicine, Crisis Standards of Care: A Systems Framework for Catastrophic Disaster Response, Committee on Guidance for Establishing Crisis Standards of Care for Use in Disaster Situations, 2012. National Academies Press (US): Washington, DC. [14] Powell, TK and GS Birkhead. Allocation of ventilators in a public health disaster. Disaster Med. Public Health Prep., 2008. 2(1): 20-26. [15] Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507513. doi: 10.1016/S0140-6736(20)30211-7. [16] Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. Published Feburary 7, 2020. JAMA 2020. doi: 10.1001/jama.2020.1585. [17] Hu, Z., Song, C., Xu, C. et al. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Sci. China Life Sci. (2020). https://doi.org/10.1007/ s11427-020-1661-4. [18] van Doremalen, Neeltje, Trenton Bushmaker, Dylan H. Morris, Myndi G. Holbrook, Amandine Gamble, Brandi N. Williamson, Azaibi Tamin et al. “Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1.” New England Journal of Medicine (2020).

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[19] Livingston, E and A Desai. Sourcing Personal Protective Equipment During the COVID19 Pandemic. Published March 28, 2020. JAMA 2020. dog: 10.1001/jama.2020.5317. [20] Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a singlecentered, retrospective, observational study. Lancet Respiratory Medicine. Published February 24, 2020. doi: 10.1016/S2213-2600(20) 30079-5. [21] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.doi: 10.1016/S0140-6736(20)30183-5. [22] Henry BM. Covid-19, ECMO, and lymphopenia: a word of caution. Lancet Respir Med 2020 Epub ahead of print. March 13, 2020 https://doi.org/10.1016/ S22132600(20)301193. [23] ELSO Guidance Document: ECMO for COVID-19 Patients with Severe Cardiopulmonary Failure. Extracorporeal Life Support Organization. 24 March 2020.

In: The History of Extra-Corporeal … ISBN: 978-1-53618-961-2 Editor: Michael S. Firstenberg © 2021 Nova Science Publishers, Inc.

Chapter 4

SPECIAL CONSIDERATIONS FOR ECMO CANNULATION AND DECANNULATION FOR COVID-19 PATIENT Joseph Dovidio and Hitoshi Hirose* Department of Surgery, Thomas Jefferson University, Philadelphia, PA, US

ABSTRACT Introduction The primary organ affected in the novel Coronavirus disease 19 (COVID-19) is the lung and acute respiratory distress syndrome (ARDS) is a major cause of death. Extracorporeal membrane oxygenation (ECMO) has been utilized to bridge to recovery for those refractory to optimized ventilator support. In this chapter we would like to share the pitfalls of ECMO cannulation/decannulation and anticoagulation specific for COVID-19.

*

Corresponding Author’s E-mail: [email protected].

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Patient Selection Due to limited resources, specific selection criteria will apply to the COVID-19 patient. Multi-disciplinary discussion may be necessary to determine the candidacy of the patient for ECMO.

ECMO Cannulation Veno-venous (VV) ECMO is the primary choice for COVID-19. Due to the need for the limitation of exposure to the patient and simplicity of the cannulation, classic femoral-right jugular (Fem-R IJ) cannulation is recommended. The utilization of Avalon cannula which requires fluoroscopy and echocardiography was discouraged. In case of hemodynamic instability due to cardiac dysfunction during VV ECMO, veno-venous-arterial (VVA) or veno-arterial (VA) conversion may be necessary to provide enough perfusion support, although this conversion should be done only by experienced personnel.

Anticoagulation Due to known hypercoagulable state due to COVID-19, anticoagulation protocols need to be modified based on each ECMO center’s experience, although excessive anticoagulation may result in bleeding complications.

Decannulation Single surgeon decannulation without assistant at bedside can be done for COVID-19 patients. Placement of purse string suture and use of FemoStop device will facilitate hemostasis.

Conclusions For the patient with COVID-19, certain limitation of ECMO should be applied, especially regarding limitation of personnel who will be exposed to the patient.

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Keywords: ECMO, COVID-19, ARDS, respiratory failure, cannulation, decannulation, techniques

INTRODUCTION Coronavirus disease 19 (COVID-19) primarily affects the respiratory system. Patients may develop acute respiratory distress syndrome (ARDS) [1]. The degree of ARDS may be case by case but some patients may develop severe ARDS requiring extracorporeal membrane oxygenation (ECMO) for oxygenation and/or ventilation support. Human-to-human transmission is major route of COVID-19 infection, and the infection rate of the health care personnel (HCP) in China was reported to be 5%, which is not negligible for health care providers (HCPs) who provide care to COVID-19 patients [2]. To minimize the chance of exposure to the virus, the patient should be placed in an isolation room and HCPs must wear appropriate personal protective equipment (PPE) whenever providing care to the COVID-19 patients. Although the ECMO procedure is not aerosol generating itself, the number of HCPs and equipment utilized during the procedure should be minimized. Due to the limited availability of personnel and equipment during the ECMO procedure, cannulation and decannulation methods should be standardized at each institution. This chapter provides examples of specific potential issues that may occur with ECMO cannulation and decannulation for COVID-19 patients.

Patient Selection The patient selection for ECMO during the COVID-19 pandemic may be different from usual ECMO inclusion and exclusion criteria [3]. The inclusion criteria should be the same as routine respiratory ECMO including: severe ARDS refractory to optimized ventilator support and appropriate adjunctive therapy including prone positioning, paralysis, and nitric oxide or epoprostenol. However, exclusion criteria may be more

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restricted than non-COVID-19 patients, due to the limitations of resources during this pandemic. In addition to conventional respiratory ECMO criteria, additional exclusion criteria were added (Figure 1). Due to the high mortality in the elderly patient with COVD 19 [4], the age limit was lowered to ~65. Ongoing multi-organ dysfunction (liver and kidney) was considered to be a contraindication for ECMO. Many of the patients with COVID-19 had bacterial co-infection [5]. Septic shock (with positive blood culture) from bacterial infection and requirement of high dose vasopressor support is another contraindication for ECMO. The primary mode of ECMO should be VV ECMO, which requires normal cardiac function [3]. VA ECMO should be reserved for only those who had severe but reversible cardiac dysfunction, such as COVID-19 related myocarditis. If the patient has long-standing heart failure with decreased cardiac function, the secondary damage caused by COVID-19 may not be reversible. It is important to evaluate cardiac function prior to ECMO and determine if the patient is feasible for VV ECMO. If the patient had reduced cardiac function, VA cannulation may be necessary. COVID-19 infection causes some degree of systemic inflammatory response syndrome (SIRS) requiring vasopressor support [6]. In order to optimize outcome of ECMO, it is essential to distinguish whether the vasopressor requirement is due to SIRS and not due to either cardiac dysfunction or overwhelming bacteremic septic shock. Complex patient candidacy selection for ECMO should be discussed among multidisciplinary (critical care, pulmonary, and cardiac surgery) tele-conference. To maintain resources and to avoid exhaustion of resources, daily ECMO census update, including available number of ECMO pumps, ICU status, and availability of qualified nursing staff to take care of ECMO patients, is necessary in ECMO centers at this time. During the COVID-19 pandemic, we no longer offer a mobile ECMO program due to the concern of exposure of required personnel including ECMO surgeon, perfusionist and transfer nurses at the local site. The degree of usage of PPE may vary between institutions. Instead of cannulating the patients at local hospital, we asked that the local cardiac surgeon places ECMO there and transports the patient to our facility. The

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ECMO circuit at the local site may not be compatible for transport, and these circuits need to be switched out at the local hospital in order to transport using a compatible ECMO circuit, such as CardioHelp or Rota flow system.

Contraindications VV ECMO COVID 19 Standard contraindications Age >70 BMI >45 with high risk of vascular access Mechanical ventilation >7 days Multiorgan failure End stage liver disease Irreversible neuro damage Contraindications of anticoagulation Cardiac arrest without ROSC Relative contraindications Age >65 BMI >35 Mechanical ventilation >5 days Active bacterial blood stream infection Severe commodities: severe COPD, cirrhosis, chronic CHF Inability of access neuro status High lactate related to low perfusion status Limited activity at home No family or appropriate POA Considering VA cannulation Cardiac arrest with ROSC Poor LV or RV function Known pulmonary hypertension Figure 1. Contraindications for COVID-19 VV ECMO.

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If the patient requires air-transport, the CardioHelp system is necessary for safe transport. We recommend that the local hospital is in contact with the ECMO center before cannulating ECMO to ensure the compatibility of the equipment, availability of transport team, and to discuss transport strategy [7]. ECPR for patients with COVID-19 is discouraged [3]. On development of cardiac arrest in the patient with COVID-19, there is always delay of the initiation of cardiopulmonary resuscitation (CRP) due to the requirement of PPE before entering the room. The utility of the Lucas system may be useful in selected cases to minimize the personnel exposure during CPR. VA ECMO can be considered in selected patients after achievement of return of spontaneous circulation (ROSC).

Cannulation The difference in cannulation of COVID-19 patients is based in the setting of limiting personnel exposure to the room of the patient with COVID-19. One ECMO surgeon, one assistant surgeon, one perfusionist, and one nurse should be in the room during cannulation. All cannulation should be performed in the ICU without transport to either the operating room or catheterization lab unless an issue occurs during bedside cannulation. Since Avalon dual lumen ECMO cannula placement always requires fluoroscopy and echocardiography [8], which requires additional personnel including radiology technicians and an echocardiography technician, the utilization of the Avalon cannula was discouraged [3]. Instead, right internal jugular vein-femoral vein cannulation is relatively easy to perform (Figure 2), since it does not require fluoroscopy or echocardiography for placement. Due to the presence of PPE (Figure 3), communicating could be difficult between the HCPs involved in the cannulation. The personnel in the room and outside of room should have clear roles and responsibilities. Clear and simple commands from the ECMO surgeon are necessary and re-verbalizing order should be mandated.

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Figure 2. Typical veno-venous ECMO configuration for COVID-19 patients using right femoral vein for drainage and right internal jugular for return.

The ECMO surgeon should follow the same protocolized cannulation methods during each individual cannulation and any deviation from the standard cannulation should be discussed with the perfusionist, assistant, and in-room nurse before cannulation. We preferred to keep one “runner” just outside of the room, this role is responsible for bringing necessary equipment to the room, place necessary orders, and communicate with other personnel. Microphone/speaker device use as communication system between inside and outside the room was found to be useful, generally in the form of a baby monitor or a walkie talkie (Figure 4).

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Figure 3. Personal protection equipment (one surgeon and one nurse in the room).

Figure 4. Example of communication method between inside and outside of patient room.

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Cannulation equipment consisted of routine cannulation equipment and bedside ultrasound. Bolus dose of heparin (5000 – 7500 units) was determined by weight/body habitus and the nurse in the room should have it drawn but not to be given to the patient until surgeon prompts, in case of a vascular access complication. In the event volume resuscitation is needed, at least one large bore peripheral access or additional femoral venous sheath considered to be placed contralateral to the side of the cannulation. Due to the anatomy of the venous system, the preferred cannulation site is right internal jugular (R IJ) and right femoral vein. A single surgeon is required for both R IJ and R femoral venous access under ultrasound and dilation of the vessel (Figure 5). The R IJ access may be achieved using a regular central line kit to avoid handling the routine long wire and potential contamination due to lack of the assistant.

Figure 5. Example of single surgeon ECMO cannulation for COVID-19 patients.

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Figure 6. Alternative veno-venous ECMO configuration using bilateral femoral vein access.

The femoral access wire should be exchanged to stiff wire. The ECMO circuit is passed to the surgeon and circuit tubing is extended appropriately to meet the length of the circuit tubing allowing to reach to the groin and neck. Then one assistant could be scrubbed in to assist handling the long wire. First, R IJ cannulation is performed over the guidewire. If this R IJ cannulation is not successful, the case should be considered to convert to femoral-femoral VV cannulation (Figure 6). After placement of the R IJ cannula, appropriate drainage needs to be confirmed with opening the end of the cannula. At this time, the desired dose of the heparin should be given to the patient. The R IJ cannula is then connected with the ECMO circuit. An additional heparin in 5cc normal saline is given via the side port of the R IJ cannula (Figure 7) to prevent to clot formation inside of the R IJ cannula.

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Figure 7. Example of return cannula.

At least one stitch is placed to the R IJ cannula to secure the cannula. After completion of R IJ cannulation, then the femoral cannula should be placed next. The length of the femoral cannula to be inserted in the patient needs to be measured before insertion. The anatomical landmark used to measure the desired length of the femoral cannula is the xyphoid process. Femoral cannula is placed over the guide wire. After confirmation of the drainage from the cannula, the cannula is connected to the ECMO circuit. Clamps are removed and the ECMO is started by the perfusionist. Lastly, the ECMO cannula position is confirmed by chest x-ray. The appropriate position of the R IJ cannula is in the superior vena cava (SVC), and the tip of the femoral cannula in the right atrium-inferior vena cava junction to minimize the shunt of VV ECMO (Figure 8). A mispositioned cannula should be corrected based on the x-ray finding (Figure 9) before the ECMO surgeon scrubs out of the room in order to maintain sterile conditions. If there is more than one surgeon is available for the ECMO cannulation, R IJ and femoral cannulation can be done simultaneously; however, in COVID19, the exposure to the COVID positive patient should be minimized and there may not be enough personnel to scrub in more than 1 surgeon.

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Figure 8. Example of appropriately cannulated VV ECMO using right internal jugular and right femoral vein.

Figure 9. Inappropriately placed drainage cannula, which is observed in the superior vena cava (SVC), next to the return cannula. This causes significant shunt between return and drainage cannula.

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Figure 10. In VV ECMO with right internal jugular and femoral vein, increase of ECMO flow may not helpful to improve systemic oxygenation due to increase of shunt between return and drain cannula.

Some centers recommend use of the larger cannula to avoid clot formation of the ECMO cannula and circuit; however, we have not experienced the cannula clotting issue using above mentioned cannulation technique. Our standard size of the return cannula was 18-20 Fr (OptiSite cannula, Edwards Lifesciences, Irvine, CA), and drain cannula was 22-24 Fr (VFEM femoral venous cannula, Edwards Lifesciences, Irvine, CA). Using these configurations, we are able to achieve 5-6 L/min of ECMO flow if necessary. However ECMO flow should be determined by patient body habitus, and degree of the shunt flow between return and drain cannula (Figure 10). Use of oversized cannula may lead to catastrophic venous injury.

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VVA or VA Conversion In the case of development of hemodynamic compromise or hypoxia despite appropriate VV ECMO flow, the clinician should assess cardiac function by echocardiography. In COVID-19, patients may develop primary COVID-19 myocarditis, stress induced cardiomyopathy, or demand ischemia due to hyperinflammatory state [9]. If decreased cardiac function is observed during VV ECMO, the first line of the treatment is inotropes. If moderate dose of inotrope support is not enough to stabilize hemodynamics, veno-venous arterial (VVA) conversion may be necessary. To do this VVA conversion from those who are already on VV ECMO between R IJ and femoral veins, an additional arterial cannula needs to be placed as a return cannula. The return cannula should be “Y’d” to R IJ and newly placed arterial cannula. In the event the patient develops cardiac arrest or severe biventricular failure during VV ECMO, full VA ECMO conversion needs to be considered. Both R IJ and femoral venous cannulas should be “Y’d” together for drainage and a newly placed arterial cannula should be used for return, making VA ECMO using a 2-limb venous drainage cannula. These VVA or VA conversions require the temporary stop of the ongoing VV ECMO and should only be performed by experienced personnel. Failure or malapportioned Y connector to the circuit may cause catastrophic complications.

Anticoagulation There is a concern of hypercoagulable state and potential disseminated intravascular coagulopathy (DIC) in patients with COVID-19 [10]. The anticoagulation during ECMO can be achieved with unfractionated heparin [11], although in the setting of COVID-19 anticoagulation monitoring may need to be modified related to a hypercoagulable state [3, 12]. Bleeding complications often encountered in patients on ECMO include nasopharyngeal, cannulation site and gastrointestinal bleed. [13] Escalation

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of anticoagulation in ECMO patients with COVID-19 should be monitored closely for possible bleeding complications. In patients with on-going bleeding, anticoagulation should be stopped temporarily. Despite the previous report of ECMO circuit thrombosis in the COVID-19 population [8], we have not encountered any cannula thrombosis, pump thrombosis or acute development of oxygenator clot formation, although routine circuit checks are mandatory in all ECMO patients regardless of COVID status.

DECANNULATION Pre-Decannulation Assessment In the COVID-19 patient, the recovery of lung function may not be straight-forward. The respiratory function may deteriorate suddenly despite multiple days of recovery of lung infiltrate on x-ray. The treatments used for COVID-19 [14], such as interleukin inhibition, steroid therapy, may modify the course of the ARDS related to COVID-19. The ECMO weaning process should be slower than typical VV ECMO weaning seen in non-COVID-19 patients. ECMO sweep gas should be discontinued at least 12-24 hours prior to decannulation. The recovery of respiratory function should be able to be identified from chest x-ray, ventilator lung mechanics, and arterial blood gas (ABG). A potential second run of ECMO is always technically more difficult than the first ECMO run because of the limitation of access sites. The timing of decannulation should be discussed in a multidisciplinary meeting similar to cannulation.

Decannulation Due to the COVID-19 person-to-person infection risk, the number of personnel involved in decannulation should be limited: one surgeon, one perfusionist is the minimum possible in the procedure room. The decannulation procedure should be done at bedside in the ICU and travel to

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the operating room should be avoided in order to prevent potential contamination of the operating room. One “runner” should be stay outside of the procedure room in case of emergency. The ECMO flow is turned down to 1.5-2 l/min just prior to draping the patient. Hemodynamic monitoring is necessary including patient oxygen saturation, then repeat ABG is taken. Anticoagulation is continued during the bedside decannulation procedure to avoid clot formation during low flow of ECMO. After confirming appropriate ABG with low ECMO flow, local anesthetics are given to the cannulation site. FemoStop is prepared for femoral cannulation site [15]. Sutures holding cannula are removed. Double purse string statues are applied around each cannula [16]. The ECMO circuit is clamped at the bottom of the circuit and cannulation site.

Figure 11. Example of use of FomoStop device to facilitate hemostasis of the groin cannulation site.

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An additional heparinized saline (2500-5000 units in maximum 7cc of normal saline) is given to the side port of the R IJ cannula just enough to fill the inner lumen of the cannula to prevent clot formation. Femoral cannula is removed first as purse string sutures are tied off. At least 5 minutes of manual pressure is applied, and then the FemoStop device (Abott, Lake Bluff, IL) is applied in order to facilitate hemostasis from the groin (Figure 11). After that, R IJ cannula is then removed as purse string sutures are tied off. Manual pressure is applied to the R IJ cannulation site until hemostasis is achieved. Systemic heparin is then turned off. If assistants are available for decannulation, simultaneous R IJ and femoral decannulation can be achieved and FemoStop or single dose of heparin may not be necessary.

CONCLUSION In COVID-19, the number of personnel to scrub in the COVID-19 room is limited whenever possible. The ECMO surgeon should understand these limitations and the procedure should be protocolized so that the cannulation and decannulation procedures can be done smoothly and safely with limited staff and resources.

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Liang W, Liang H, Ou L, Chen B, Chen A, Li C, Li Y, Guan W, Sang L, Lu J, Xu Y, Chen G, Guo H, Guo J, Chen Z, Zhao Y, Li S, Zhang N, Zhong N, He J; China medical treatment expert group for COVID-19. Development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with covid-19. JAMA Intern Med. 2020 May 12. doi: 10.1001/ jamainternmed.2020.2033. [Epub ahead of print]. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary

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Joseph Dovidio and Hitoshi Hirose of a report of 72 314 cases from the Chinese center for disease control and prevention. JAMA. 2020 Feb 24. doi: 10.1001/ jama.2020.2648. [Epub ahead of print]. A consensus document from an international group of interdisciplinary ECMO providers. Extracorporeal life support organization COVID-19 interim guideline. https://www.elso.org/ Portals/0/Files/pdf/guidelines%20elso%20covid%20for%20web_Fin al.pdf [Accessibility verified May 13, 2020]. Liang W, Liang H, Ou L, Chen B, Chen A, Li C, Li Y, Guan W, Sang L, Lu J, Xu Y, Chen G, Guo H, Guo J, Chen Z, Zhao Y, Li S, Zhang N, Zhong N, He J; China Medical Treatment Expert Group for COVID-19. Development and Validation of a Clinical Risk Score to Predict the Occurrence of Critical Illness in Hospitalized Patients with COVID-19. JAMA Intern Med. 2020 May 12. doi: 10.1001/ jamainternmed.2020.2033. [Epub ahead of print]. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020 May;8:475-481. Zhu H, Rhee JW, Cheng P, Waliany S, Chang A, Witteles RM, Maecker H, Davis MM, Nguyen PK, Wu SM. Cardiovascular complications in patients with COVID-19: Consequences of viral toxicities and host immune response. Curr Cardiol Rep 2020 21; 22-32. Ramanathan K, Antognini D, Combes A, Paden M, Zakhary B, Ogino M, MacLaren G, Brodie D, Shekar K. Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases. Lancet Respir Med 2020;8:518-526. Shaheen A, Tanaka D, Cavarocchi NC, Hirose H. Veno-venous extracorporeal membrane oxygenation (VV ECMO) indications, preprocedural considerations, and technique. J Card Surg 2016; 31:248-252.

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[15] Bisdas T, Beutel G, Warnecke G, Hoeper MM, Kuehn C, Haverich A, Teebken OE. Vascular complications in patients undergoing femoral cannulation for extracorporeal membrane oxygenation support. Ann Thorac Surg. 2011;92:626-631. [16] Heller A, Dollerschell J, Burk J, Haines H, Kozinn J. Safety of intensivist-led bedside decannulation of internal jugular bi-caval dual-lumen veno-venous extracorporeal membrane oxygenation cannulas and report of technique. Anaesthesiol Intensive Ther 2016;48:211-214.

In: The History of Extra-Corporeal … ISBN: 978-1-53618-961-2 Editor: Michael S. Firstenberg © 2021 Nova Science Publishers, Inc.

Chapter 5

THE USE OF ECMO FOR TREATMENT OF SEVERE ARDS DUE TO CORONAVIRUS DISEASE 2019 Olivia Giddings, MD, PhD and Rana Hejal*, MD Division of Pulmonary, Critical Care and Sleep Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland Ohio, US

ABSTRACT On March 11, 2020 coronavirus 2019 was declared a pandemic. According to the World Health Organization, as of June 28, 2020 there have been nearly 10 million cases and 500,000 deaths worldwide. Approximately 20% of patients with COVID-19 require hospitalization and approximately 5% require ICU level care. COVID-19 can cause pneumonia and ARDS, the primary cause of death after infection is respiratory failure. To date there is no highly effective treatment specific to COVID-19. While there are multiple ongoing clinical trials, some which have shown early success, the mainstay of therapy remains supportive care. In this chapter we will discuss evidence for use of ECMO for treatment of ARDS due to other viral illnesses, review current *

Corresponding Author’s E-mail: [email protected].

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Keywords: COVID-19, ARDS, ECMO

INTRODUCTION In December 2019 a novel coronavirus was identified in Wuhan, the capitol city of Shubei Province, in western China. On March 11, 2020, the World Health Organization (WHO) officially declared the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a pandemic [1]. Within the next six months, SARS-CoV-2, would go on to infect almost 10 million people, and cause 500,000 deaths, a mortality rate of roughly 4.7% [2]. Rates of hospitalization and disease severity differ from region to region, however, approximately 20% of those infected will develop severe COVID-19, defined by SpO2 less than 94% while breathing room air, and 5% will require ICU level care [3, 4]. The vast majority of patients who develop critical illness have ARDS. Mortality in patients requiring intubation has been reported to be as high as 88% [4].

HISTORY OF ECMO FOR ARDS DUE TO VIRAL PNEUMONIA ECMO has seen increasing use as a rescue therapy for ARDS from multiple causes over the last 10 years as reviewed in the previous chapter. ARDS, however, is a heterogeneous syndrome, which may not respond the same to specific therapies depending on the underlying etiology. There is data to suggest that ECMO to treat ARDS secondary to viral pneumonia improves mortality and improves patient outcomes. In 2009 a novel strain of influenza to which there was no historic immunity, caused a worldwide pandemic. This led to a surge in ICU

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admissions for hypoxic respiratory failure, and in severe cases, acute respiratory distress syndrome (ARDS). Implementation of veno-venous (VV) extracorporeal membrane oxygenation (ECMO) for refractory hypoxemia despite mechanical ventilation was used for treatment of H1N1 associated ARDS and shown to be successful. Davies et al., published an observational study of all patients with ARDS secondary to H1N1 or influenza A, in Australia and New Zealand placed on ECMO between June 1 and August 31, 2009. They described the course of 68 patients, of whom, 78% were successfully weaned from ECMO and 71% had survived to ICU discharge [5]. Pham et al., went on to perform a retrospective cohort study to try to compare the outcomes of patients placed on ECMO to those who received standard management. This study identified 123 patients treated with ECMO from July 29, 2009 and March 26, 2011. The authors were able to identify well-matched cohorts who received standard management with low tidal volume ventilation. In this well matched cohort study, there was no difference in survival seen for the two groups. Interestingly, the unmatched ECMO group, which was significantly younger than the matched group, had significantly greater survival than the matched cohorts [6]. This raises the importance selecting the appropriate patient population for treatment with ECMO. More definitive evidence for the efficacy of ECMO in treating viral induced ARDS can be found in Middle Eastern respiratory syndrome. Again, another novel coronavirus, MERS-CoV, was first identified in 2012. Between 2012 and 2016 approximately 2000 people were infected and there was significant concern the MERS-CoV could result in a worldwide pandemic similar to H1N1. The over all mortality rate from MERS is around 35%. In 2018, Alshahrani et al., published a retrospective study comparing patients who developed ARDS from MERS and were treated with ECMO to those treated with lung protective ventilation. This was a small study of 35 patients, 17 treated with ECMO and 18 with conventional therapy. In this study there was a significant survival benefit in the ECMO group (in hospital mortality 65 vs. 100%, p < 0.02). Of note, patients who had required mechanical ventilation with FiO2 > 0.9 and

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plateau pressure >30cmH2O for more than 7 days prior were excluded from receiving ECMO [7]. Since H1N1 and MERS, the use of ECMO has become significantly more common as an adjunctive method of gas exchange to mechanical ventilation in severe ARDS patients with refractory hypoxemia. There have been no randomized, controlled clinical trials to examine the efficacy of ECMO in treating ARDS due to viral pneumonia. In the absence of strong evidence, and the suggestion of improved outcomes in patients treated with ECMO (in the appropriate patient population); the overall recommendation has been that ECMO should be considered for treatment of refractory hypoxemia in patients with COVID-19 who do not improve despite optimal ventilator management and rescue therapies such as prone positioning and inhaled nitric oxide.

HISTORY OF ECMO IN COVID-19 In the early stages of the pandemic there was a paucity of data on the efficacy of ECMO for treatment of refractory hypoxemia due to COVID19. Despite the lack of data multiple guidelines for treatment of severe ARDS secondary to COVID-19 included consideration of ECMO. These recommendations were based on the possible survival benefit seen in Saudi Arabia during the MERS outbreak, as well as possible benefit shown in a post-hoc Bayesian analysis of the EOLIA trial. Both the World Health Organization clinical management guidelines, published on March 13, 2020, and the Surviving Sepsis Campaign: Guidelines on Management of Critically Ill Adults with Coronavirus-19, published on March 27, 2020, suggested the use of ECMO in patients in whom ventilation optimization and other rescue therapies had failed [8, 9]. Unfortunately, the initial experience with ECMO for critical COVID19 disease, during the early stages of the pandemic was disappointing and disheartening. While ECMO is an accepted treatment for severe ARDS refractory to other measures, the initial reports of its use for patients with COVID-19 showed very little success. Two reviews of small case series

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published in late March and early April 2020 reported a composite mortality of 83 and 94% [10, 11]. As COVID-19 continued to spread to additional countries case reports began to appear in the literature of successful treatment with ECMO. Osho et al., described their experience with six patients who underwent VV ECMO for severe ARDS secondary to COVID-19. At the time of publication four of six patients were successfully decannulated and two had been discharged from the hospital. One patient died of hemorrhagic stroke [12]. Huette et al., published a series of 12 patients in Canada who underwent ECMO for ARDS secondary to COVID-19. 8 of 12 survived and were discharged from the ICU. 8 of 12 patients required renal replacement therapy. All patients were treated with inhaled nitric oxide, neuromuscular blockade and prone positioning prior to initiation of ECMO. Median P:F ratio at time of ECMO initiation was 76 [13]. A review of the literature including 331 cases of COVID-19 patients who underwent ECMO performed by Melhuish et al., showed an overall mortality of 46% [14]. The Extracorporeal Life Support Organization (ELSO) maintains a registry of all patients who have undergone ECMO at member sites from around the world. As of June 28, 2020, 1,632 patients with suspected or confirmed COVID-19 have been placed on ECMO. 983 patients have completed their run and 544 patients have been discharged from the hospital alive (survival rate 55%). The majority of those placed on ECMO were in North America (1035) and Europe (425). The median age of those on ECMO is 49, and 73% are male. 91% underwent veno-venous EMCO. Median length of hospital stay is 27 days and median duration of intubation prior to ECMO initiation is 4 days. Complications have included stroke (1%), intracranial hemorrhage (ICH) (5%), and renal failure (23%) [15]. For comparison in the EOLIA trial there were no cases of ischemic stroke in the ECMO group and 3 out of 124 patients (2%) developed hemorrhagic stroke [16]. A retrospective review of 23,951 who underwent ECMO between 2001 and 2011 in the United States, 4.1% developed ischemic stroke and 3.6% developed ICH [17]. While it is difficult to compare the efficacy of ECMO with standard care as the range of mortality for ventilated patients varies dramatically from region to region and center

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to center, an overall survival rate of 55% for patients who have undergone ECMO is certainly encouraging in the face of such a devastating disease.

ECMO UTILIZATION IN ARDS DUE TO COVID-19 ELSO has developed and frequently revises a document of guidelines and best practices in the use of ECMO in patients with COVID-19. It is a dynamic document and will continue to be updated as more information is available. It can be found at online at: https://www.elso.org/Portals/0/Files/ pdf/ELSO%20COVD%20MATV66N7_Text_issueproof%206-15-20[1]. pdf [18]. As the care of patients with COVID-19 is rapidly changing with increased experience and any recommendations made at the time of writing this chapter may quickly become out of date we will not summarize these recommendations. Instead we will describe our process for patient selection for use of ECMO in the setting of COVID-19. ECMO and skilled ECMO teams, like ventilators, ICU beds, ICU nurses, respiratory therapists and all others who provide highly skilled, specialized care to the most critically ill patients, are a limited resource. In the setting of a global pandemic these systems can quickly become over run. In resource-limited scenarios, or in health care systems that can quickly become stretched beyond capacity, it is of the utmost importance to use these limited resources on those with the greatest chance of survival. The ELSO guidelines address this problem. It is critical that healthcare systems develop guidelines for increased numbers of critically ill patients and resource allocation prior to reaching their maximum capacity. It is also critical that these plans are designed at an institutional and regional level by teams including all stakeholders, the moral quandary of resource allocation should not be placed on individual physicians. With these concerns in mind, our team developed guidelines to determine which patients are most likely to benefit from this limited resource.

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After confirming that ECMO would be consistent with the patient’s goals and wishes we use a combination of validated tools to attempt to stratify patients into likelihood of good versus poor outcome with ECMO. It has been determined in multiple studies that the longer a patient is ventilated prior to initiation of ECMO, the poorer the outcome. Therefore patients who have required mechanical ventilation for more than 7 days on maximal settings prior to consideration of ECMO are usually considered poor candidates. This underscores the importance of early referral to an ECMO capable center. We then use the Sequential Organ Failure Assessment (SOFA) score to estimate ICU mortality [19]. While different cut offs will need to be used at different centers depending on resources and experience, we exclude patients with a SOFA score greater than 14 as this correlates to mortality of greater than 90% in the ICU patients who are critically ill. We use the validated Respiratory ECMO Survival Prediction (RESP) score to estimate likelihood of ECMO survival, as a general rule we exclude patients in risk group V as these patients have an overall in hospital survival rate of only 18% [20]. Our center has a “shock team” that consists of critical care physicians and cardiothoracic surgeons who are consulted on every patient for whom ECMO is considered as a salvage therapy. Once a patient is identified as a possible candidate for ECMO the “shock team” is consulted and the decision is made as a group about whether or not to place the patient on ECMO. We feel that it is important that the entire team be involved in these decisions in order to provide appropriate care.

DISCUSSION ECMO is an invaluable resource for treatment of hypoxemia refractory to mechanical ventilation strategies and rescue therapies including recruitment maneuvers, prone positioning, and inhaled nitric oxide or epoprostenol. Experience in prior epidemic viral pneumonias suggests a survival benefit for patients with severe ARDS and refractory hypoxemia when used in the appropriate settings and patient populations. It has been

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recommended by the WHO and critical care societies, that ECMO be considered for treatment of severe ARDS secondary to COVID-19 and early experience suggests that it is beneficial. Of course randomized, clinical trials would be ideal to determine its true efficacy, the best timing of initiation and the ideal patient population in which it should be instituted, however, designing and implementing such a trial is rife with ethical difficulties of withholding a potentially life saving therapy from the control group. In response to the COVID-19 outbreak and to assist in pandemic planning both locally and globally, a research collaborative has been assembled. The aim of this prospective/retrospective observational study is to describe the clinical features, ICU requirements, pulmonary dysfunction, coagulation derangements, mechanical ventilation strategies, ECMO characteristics and complications of COVID-19 infections. The scientific title of this study is Covid-19 Critical Care Consortium Incorporating the Extra Corporeal Membrane Oxygenation for 2019 novel Coronavirus Acute Respiratory Disease (ECMOCARD) [21]. Real time data is being collected. Soon observations will be reported to assist the critical care community in revising their guidelines and protocols and generate further research hypothesis to study.

REFERENCES [1]

[2] [3]

WHO Director-General’s opening remarks at the media briefing on COVID-19 - 11 March 2020. https://www.who.int/dg/speeches/detail/ who-director-general-s-opening-remarks-at-the-media-briefing-oncovid-19-11-march-2020. Accessed June 28, 2020. WHO Coronavirus (COVID-19) World Health Organization Overview. https://covid19.who.int/. Accessed June 28, 2020 2020. Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J., et al., Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020.

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Richardson S., Hirsch J. S., Narasimhan M., Crawford J. M., McGinn T., Davidson K. W., et al., Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020. [5] Australia, New Zealand Extracorporeal Membrane Oxygenation Influenza I., Davies A,. Jones D., Bailey M., Beca J., et al., Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome. JAMA. 2009; 302 (17): 188895. [6] Pham T., Combes A., Roze H., Chevret S., Mercat A., Roch A., 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 (3): 276-85. [7] Alshahrani M. S., Sindi A., Alshamsi F., Al-Omari A., El Tahan M., Alahmadi B., et al., Extracorporeal membrane oxygenation for severe Middle East respiratory syndrome coronavirus. Ann Intensive Care. 2018; 8 (1): 3. [8] World Health Organization. (2020). Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: interim guidance, 13 March 2020. World Health Organization. https://apps.who.int/iris/handle/10665/331446. [9] Alhazzani W., Moller M. H., Arabi Y. M., Loeb M., Gong M. N., Fan E., et al., Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19). Crit Care Med. 2020; 48 (6): e440-e69. [10] Henry B. M., Lippi G. Poor survival with extracorporeal membrane oxygenation in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19): Pooled analysis of early reports. J Crit Care. 2020; 58: 27-8. [11] Namendys-Silva S. A. ECMO for ARDS due to COVID-19. Heart Lung. 2020; 49 (4): 348-9.

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[12] Osho A. A., Moonsamy P., Hibbert K. A., Shelton K. T., Trahanas J. M., Attia R. Q., et al., Veno-venous Extracorporeal Membrane Oxygenation for Respiratory Failure in COVID-19 Patients: Early Experience From a Major Academic Medical Center in North America. Ann Surg. 2020. [13] Huette P., Beyls C., Guilbart M., Coquet A., Berna P., Haye G., et al., Extracorporeal membrane oxygenation for respiratory failure in COVID-19 patients: outcome and time-course of clinical and biological parameters. Can J Anaesth. 2020. [14] Melhuish T. M., Vlok R., Thang C., Askew J., White L. Outcomes of extracorporeal membrane oxygenation support for patients with COVID-19: A pooled analysis of 331 cases. Am J Emerg Med. 2020. [15] ELSO COVID-19 Registry Dashboard. https://www.elso.org/ Registry/FullCOVID19RegistryDashboard.aspx. Accessed June 28, 2020. [16] Combes A., Hajage D., Capellier G., Demoule A., Lavoue S., Guervilly C., et al., Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2018; 378 (21): 1965-75. [17] Nasr D. M., Rabinstein A. A. Neurologic Complications of Extracorporeal Membrane Oxygenation. J Clin Neurol. 2015; 11 (4): 383-9. [18] Extracorporeal Life Support Organization Coronavirus Disease 2019 Interim Guidelines: A Consensus Document from an International Group of Interdisciplinary Extracorporeal Membrane Oxygenation Providers. https://www.elso.org/Portals/0/Files/pdf/ELSOCOVDMA TV66N7_Text_issueproof6-15-20%5B1%5D.pdf. Accessed June 28, 2020. [19] Ferreira F. L., Bota D. P., Bross A., Melot C., Vincent J. L. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001; 286 (14): 1754-8.

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[20] Schmidt M., Bailey M., Sheldrake J., Hodgson C., Aubron C., Rycus P. T., 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): 1374-82. [21] COVID-19 Critical Care Consortium Incorporating the Extra Corporial membrane Oxygenation for 2019 novel Coronavirus Acute Respiratory Disease. (ECMOCARD) https://www.elso.org/COVID 19/ECMOCARD.aspx.

In: The History of Extra-Corporeal … ISBN: 978-1-53618-961-2 Editor: Michael S. Firstenberg © 2021 Nova Science Publishers, Inc.

Chapter 6

FRONTLINE EXPERIENCE WITH EXTRACORPOREAL LIFE SUPPORT FOR COVID-19 PATIENTS Vitali Karaliou1, Jennifer Hanna2, Matthew N. Libby2, Courtney Petersen3, William M Novick4,5 and Michael S. Firstenberg4, Trauma Center and Department of Surgery, St. Luke’s University Health Network, Bethlehem, PA, US 2 Department of Cardiothoracic and Vascular Surgery, The Medical Center of Aurora, Aurora, CO, US 3 Specialty Care Perfusion Services, Nashville TN, US 4 William Novick Global Cardiac Alliance, Memphis, TN USA 5 University of Tennessee Health Science Center, Department of Surgery-Global Surgery Institute 1

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Corresponding Author’s E-mail: [email protected].

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ABSTRACT Novel coronavirus infection discovered in 2019 caused a worldwide pandemic that changed healthcare in 2020. This led to a shortage of supplies starting from protective personal equipment, mechanical ventilators, intensive care unit (ICU) beds and medical staff up to cancellation of elective surgeries to alleviate the stress on the healthcare systems and following the triage model where care is prioritized to those with more chances of survival. Quarantines and lockdowns due to coronavirus disease, declared states of emergency in addition to the lack of effective treatment and no preventive vaccine created a challenging environment for many countries. Although most of the patients experienced mild to moderate clinical manifestation, a wide range is observed from asymptomatic carrier state to symptoms like fever, anosmia, dyspnea, cough, fatigue, myalgias, sore throat, dysgeusia, congestion, nausea, vomiting, and diarrhea, in some cases, the disease progressed to acute respiratory distress syndrome (ARDS) with multiple organ failure leading to an overwhelming surge in patients requiring ICU admission. The mortality rate increased significantly in patients requiring mechanical ventilation. This new pandemic environment brings the most difficult questions on how far we should and can go saving critically ill patients when conventional measures are exhausted and extracorporeal life support (ECLS) is the next step. This review summarizes ECLS guidelines developed in relation to viral ARDS and current recommendations on extracorporeal life support for COVID-19 (coronavirus disease 2019) patient management as well as future perspectives and ongoing changes in critical care in this new healthcare environment.

Keywords: coronavirus, COVID-19, SARS-CoV-2, ECMO

INTRODUCTION In 2019, a newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19), with one of the clinical manifestations being an acute respiratory distress syndrome, brought back attention to the development of new extracorporeal life support (ECLS) guidelines, its logistics, and specifics of support deployment in the ongoing pandemic.

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In extrapolating from past events, all previous cornerstones in the history of ECLS already mentioned or repeated certain principles of current extracorporeal membrane oxygenation (ECMO) management applied to COVID-19 patients. For example, the pandemic associated with influenza A (H1N1) that affected Australia and New Zealand in 2009, provided insight into the value of ECLS in the treatment of virus-induced respiratory failure (reported mortality rate at 21% in ECMO-supported patients) [1]. The H1N1 Specific Supplements to the Extracorporeal Life Support Organization (ELSO) General Guidelines described aspects of ECMO support in patients with respiratory failure due to H1N1 and indications: an estimated 50% mortality risk with a FiO2 of 0.8 and/or a requirement for two vasoactive drugs. The indication for cannulation was an estimated 80% mortality risk with a PaO2:FiO2 < 80 on an FiO2 of 1.0 and PPlat or high-frequency oscillatory ventilation pressure over 30cmH2O, and/or an ongoing requirement with vasoactive drugs [2]. It was also recommended that there should be a low threshold for failure of the optimal conventional management due to rapid H1N1 disease progression to arrest within 24 hours or less. Early ECMO initiation was supported by a reported survival of 72% for patients on ECMO within 6 days of intubation, and only 30% for patients on ECMO after 7 days of intubation. Obesity and pregnancy were not seen as contraindications, nor was age on its own a contraindication, but patient health status pre-H1N1 was markedly important. During the H1N1 pandemic that happened more than 10 years ago, the availability of ECMO beds was seriously considered, as this was a resource-intensive time. The COVID-19 era harkens back to this time. In anticipation of an H1N1 pandemic in the USA in 2009, it was recommended that a plan be developed in anticipation of dealing with the consequent ECMO cases and a potential intensive care unit (ICU) bed shortage, as well as in consideration of a potential decline of ECLS use or referral to another center [2]. Later, the flagship clinical trials CESAR and EOLIA advocated for continuous development of the ECLS guidelines and clinical practices. The CESAR study supported ECMO as a treatment option in severe respiratory

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failure (63% of patients assigned to ECMO support survived to 6 months without disability versus 47% of those assigned to conventional management) and highlighted the importance of protective mechanical ventilation strategies [3]. Table 1. EOLIA trial inclusion and exclusion criteria [4] Inclusion criteria ARDS Intubation and ventilation for < 7 days. Optimization of MV:  FiO2 ≥ 80%  VT 6 cc/kg, PBW  PEEP ≥ 10 cmH2O Adjunctive therapies allowed/encouraged:  iNO  Recruitment maneuvers  HFOV  Almitrine infusion  Neuromuscular blocking agents  Prone positioning One of the following:  PaO2:FiO2 ratio < 50 mmHg for >3 hrs*  PaO2:FiO2 < 80 mmHg for >6 hrs  Arterial blood pH 60 mmHg for >6 hrs**

Exclusion criteria Age < 18 years MV > 7 days Pregnancy Weight > 1 kg/cm (height) BMI >45 kg/m2 Long-term chronic respiratory insufficiency treated with O2 or NIV Cardiac failure requiring VA ECMO Heparin induced thrombocytopenia Cancer with a life expectancy < 5 years Moribund condition or a Simplified Acute Physiology Score (SAPS-II) > 90 Current non–drug-induced coma after cardiac arrest Irreversible neurologic injury Decision to withhold or withdraw life sustaining therapies Expected difficulty in obtaining vascular access for ECMO in the femoral or jugular veins, or a situation in which the ECMO device was not immediately available.

* Despite MV optimization and adjunctive therapies. ** Respiratory rate increased to 35/minute with MV settings adjustment to keep Pplat ≤32 cm H2O. First, VT reduction by 1 mL/kg decrements to 4 mL/kg, then PEEP reduction to a minimum of 8 cm H2O. ARDS – acute respiratory distress syndrome, MV – mechanical ventilation, VT – tidal volume, PBW predicted body weight, PEEP - positive end-expiratory pressure, iNO inhaled nitric oxide, HFOV - high-frequency oscillatory ventilation, PaO2:FiO2 ratio - ratio of partial pressure of arterial oxygen (PaO2), Pplat - plateau pressure. BMI - body mass index. NIV - non-invasive ventilation, ECMO – extracorporeal membrane oxygenation.

However, the results of the following EOLIA trial demonstrated rather inconclusive results: 60-day mortality was not significantly lower in ECMO supported patients compared with standard mechanical ventilation

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in severe acute respiratory distress syndrome (ARDS). However, a positive clinical outcome was suggested in cases of early ECMO support initiation, and standard management was associated with a high failure rate and subsequent need for ECMO support. Despite its controversial findings, the EOLIA trial results and inclusion criteria became fundamental for the development of COVID-19 ECMO guidelines (Table 1). Generally, a patient may be supported by ECMO for cardiac or pulmonary failure caused by a life-threatening infection when conventional management is not sufficient, and the benefit outweighs the risk of ECMO use. Therefore, extracorporeal life support is not always an answer. In 2014, the Ebola outbreak in Africa that, within months, became a global epidemic was an extreme example of just that. The Ebola virus disease is characterized by cardiopulmonary failure accompanied by multiple organ failure and uncontrolled hemorrhage. Additionally, there is high risk for healthcare staff exposure. At that time, ELSO issued a position statement against using ECLS for support of patients with severe Ebola virus [5]. Coronavirus outbreaks leading to ARDS development are not a new occurrence. In 2002, severe acute respiratory syndrome caused by coronavirus (SARS-CoV) occurred in China. However, extracorporeal life support was not used at that time [6]. In 2012 to 2015, there was another coronavirus epidemic due to Middle East respiratory syndrome (MERS) with severe cardiopulmonary failure caused by a coronavirus (MERS‐CoV). ECMO as a rescue therapy was used for patients with hypoxemic respiratory failure due to MERS. Patients on ECMO had lower mortality compared to the control group (65% vs 100%; p = 0.02) [7]. In 2019, a new pandemic coronavirus SARS-CoV-2 started spreading worldwide, causing fatal pneumonia from COVID-19 and rapidly exhausting healthcare resources. Many COVID-19 patients developed severe respiratory insufficiency progressing to acute respiratory distress syndrome with a need for management in the intensive care unit. In this new context, ECMO, previously proven to be a life-saving technology, was not seen as a feasible option. Critical care resources were limited due to the pandemic, especially in smaller or less-experienced centers or where ECMO initiation requires additional resources and the coordination of

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multidisciplinary teams like cardiothoracic surgeons, cardiologists, intensivists, specialized nurses, and perfusionists. In addition to staff shortages, there was an extreme shortage of mechanical ventilators, ICU beds, and even personal protective equipment. All of these concerns left no place for the generous application of ECMO at the beginning of the SARSCoV-2 pandemic. Initial outcome reports about extracorporeal life support for COVID-19 patients came from China. However, there was not enough data to develop a true assessment of outcomes, advocate for its use, or develop guidelines that would be cognizant of resource concerns. More comprehensive analyses became available when robust infection control measures provided somewhat of a grip on the coronavirus pandemic that partially alleviated the strain on the healthcare system.

DEVELOPMENT OF ECMO GUIDELINES FOR COVID-19 ECMO use increased when COVID-19 reached pandemic levels, as the clinical management began to evolve based on experiences from previous pandemics, when existing guidelines regarding ECMO implementation began to be employed, and when one of the first retrospective studies from Wuhan, China, describing initial attempts regarding ECMO in COVID-19 patients was released [8, 9]. In March 2020, ELSO published the initial ECMO guidelines for COVID-19 patients requiring extracorporeal support. These guidelines were based on limited experience available at the time and were provided with the intention of frequent updates as new information became available [10]. ELSO argued against establishing new ECMO centers specifically designated for COVID-19 patients because of the strain on healthcare resources that was already occurring due to the pandemic. It mentioned that ECMO should be initiated early if it does not limit ICU resources for other patients. Initial ELSO guidelines for COVID-19 patients also included recommendations that ECLS should be provided to patients with a good prognosis and should be avoided in cases of advanced age, multiple co-

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morbidities, or multi-organ failure. Prolonged ventilation (>7 days) was mentioned as a non-specific contraindication for support of COVID-19 patients. Per the guidelines, extracorporeal cardiopulmonary resuscitation (ECPR), in general, should be avoided. However, experienced centers may provide it in cases of in-hospital arrests for patients without multiple comorbidities or multiple organ failure. For cardiac support, the consideration of the veno-arterial (VA) form was suggested. The inclusion and exclusion criteria from the EOLIA trial were acknowledged in the suggested ARDS algorithm management for COVID-19 patients (Figure 1). ECMO support could be considered in patients with progressive respiratory failure deterioration (PaO2:FiO2 < 150 mmHg) and ineffectiveness of conventional measures.

Figure 1. ARDS algorithm management from the Initial ELSO Guidance Document: ECMO for COVID-19 Patients with Severe Cardiopulmonary Failure [10].

With the surge of the coronavirus pandemic in 2020, there were more ECMO cases and, consequently, new data became available. A consensus

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document from an International Group of Interdisciplinary Extracorporeal Membrane Oxygenation Providers was published by ELSO in the form of COVID-2019 interim guidelines after more than 800 cases of ECMO support were reported [11]. Patient triage and ECMO provisions based on system capacity were described in detail, and a specific plan of action was proposed (Table 2). Table 2. ECMO provisions based on system capacity [11] Conventional Capacity System is running within capacity, judicious ECMO case selection  Capacity exists  Judicious patient selection  Offer VV, VA ECMO in selected COVID-19 patients based on usual criteria  Offer ECMO for non-COVID-19 indications  ECPR only is expert centers Contingent Capacity Tier 1 System is running within expanded capacity: triage to maximize ECMO capacity to outcome  Expanded capacity  Triage to maximize resource/benefit ratio  VV, VA ECMO in younger COVID-19 patients with single organ failure  Judicious ECMO use for non-COVID-19 indications  ECPR not offered Contingent Capacity Tier 2 Expanded capacity close to saturation, restrictive ECMO selection criteria  Capacity saturated  Restrictive ECMO criteria for all indications  Prioritize non-COVID-19 indications with better chance of survival  VV ECMO in younger, single organ failure COVID-19 patients  VA ECMO and ECPR not offered Crisis Capacity System is running within capacity, judicious ECMO case selection  Capacity overwhelmed  ECMO is not feasible in both COVID-19 and non-COVID-19 patients  Triage ICU admissions  Consider ceasing all futile care to create capacity in the system ECMO – extracorporeal membrane oxygenation, VV – veno-venous, VA – venoarterial, COVID-19 – coronavirus disease 2019, ECPR – extracorporeal cardiopulmonary resuscitation, ICU – intensive care unit

The updated guidelines also provided revised selection criteria and a more detailed approach for COVID-19 patient management (Figure 2 and

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Table 3). The maximization of the traditional therapies for ARDS were strongly recommended before initiation of veno-venous (VV) ECMO. It was suggested that mobile ECMO devices may help with support en route. However, early transfer (with PaO2:FiO2 ≤ 100 mmHg) to ECMO centers was advised if no portable device was available.

Figure 2. Conventional VV ECMO indications for ARDS as per ELSO Interim guidelines (differences from the initial guidelines are in red) [11].

With the ongoing growth of the pandemic, the development of realtime registries and systems for surveillance, centralization, and real-time discussions to guide the use of a limited resource such as ECMO helped to coordinate clinical decisions. This approach was developed in Japan, and initial clinical experience with COVID-19 patients on ECMO yielded more favorable outcomes with more data available for analysis [12]. It is expected that there will be continual changes to recent guidelines even in the setting of one pandemic. With more experience and new data coming from published studies and ECMO databases around the world, there will be a more comprehensive understanding of ECLS for COVID-19 patients.

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Relative contraindications Age ≥ 65 years Obesity with BMI ≥ 40 Immunocompromised status  No legal medical decision maker available  Advanced chronic underlying systolic heart failure  High dose vasopressor requirement (and not under consideration for VA or VVA ECMO)

Absolute contraindications Advanced age Clinical Frailty Scale Category ≥ 3 Mechanical ventilation > 10 days Significant underlying co-morbidities: ˗ CKD ≥ III ˗ Cirrhosis ˗ Dementia ˗ Baseline neurologic disease which would preclude rehabilitation potential ˗ Disseminated malignancy ˗ Advanced lung disease ˗ Uncontrolled diabetes with chronic end-organ dysfunction ˗ Severe deconditioning ˗ Protein-energy malnutrition ˗ Severe peripheral vascular disease ˗ Other pre-existing life-limiting medical condition ˗ Non-ambulatory or unable to perform activities  Severe multiple organ failure  Severe acute neurologic injury, e.g., anoxic, stroke  Uncontrolled bleeding  Contraindications to anticoagulation  Inability to accept blood products  Ongoing CPR ECMO – extracorporeal membrane oxygenation, COVID-19 (coronavirus disease 2019), ELSO – extracorporeal life support organization, VA – venoa-arterial, VVA - veno-venous arterial; CKD - chronic kidney disease; CPR - cardio-pulmonary resuscitation.   

   

SPECIFICS OF ECMO MANAGEMENT IN THE COVID-19 PATIENT POPULATION Young COVID-19 patients with isolated respiratory failure and minimal co-morbidities may be appropriate candidates for early ECLS initiation. Patients with severe COVID-19 respiratory failure, advanced age with multiple underlying diseases (e.g., diabetes, asthma, chronic obstructive pulmonary disease [COPD], cardiovascular compromise), and especially patients on prolonged conventional therapy including high settings on mechanical ventilation, chemical paralysis and vasopressor support may not benefit from ECMO support. The strategy of late support initiation of ECMO as a salvage for critically ill patients when all

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conventional measures are exhausted may potentially lead to unfavorable outcomes. At the same time, during a worldwide pandemic, ECLS should be considered only in established ECMO centers, and the development of new programs should not be undertaken solely with the intention of supporting COVID-19 patients [13].

Survival Early experience from China after utilization of ECMO in COVID-19 patients as a rescue therapy was characterized by infrequent use, lack of any detailed management algorithms, and reported high mortality rates (Table 4). Table 4. Early clinical studies of ECMO for COVID-19 Study

Patients on ECMO

ECMO outcome

Type of study

Yang et al. [9] Guqin et al. [14]

Total number of COVID patients 710 221

6 10

Retrospective Retrospective

Guan et al. [15] Huang et al. [16] Zhou et al. [17] Chen et al.8 Wang et al. [18]

1099 41 191 99 138

5 2 3 3 4

Died: 5 (83.3%). On ECMO: 1 Died: 3 (30%). On ECMO: 5 Discharged: 2 N/A N/A Died: 3 (100%) Died: 1 (33%) N/A

Retrospective Prospective Retrospective Retrospective Retrospective

To decrease the morbidity in COVID-19 patients by facilitating the implementation of effective interventions, there was an attempt to find certain predictive signs that correlated with severity of the disease. A higher risk of severe illness was observed in patients age ≥63 years, with an absolute lymphocyte value of ≤1.02×109/L, and a C-reactive protein level of ≥65.08mg/L. [19]. One of the earliest clinical experiences from the United States was described in the real-time cohort study by Jacobs et al. [20]. During this study, 68% (22 of 32) of patients were reported to be alive, with 53.1% (17

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of 32) alive on ECMO and only 33.3% (5 of 15) surviving to decannulation. The survival in the group treated with only veno-venous support was 41.7%. Patients with VA support had a worse prognosis in comparison to patients with VV support only. Comorbidities of COVID-19 patients on ECMO in this study included: obesity (43.8%), diabetes (34.4%), heart disease (12.5%), cancer (9.4%), and asthma (9.4%) [20]. A recently published study from Europe reported 17 patients supported with ECMO after severe ARDS developed due to COVID-19 [21]. Sixteen patients were supported with VV ECMO and one was supported with VA ECMO for cardiogenic shock due to pulmonary embolism as a complication of initial respiratory failure. Reported mortality was 35.5% (6 patients). One patient was still mechanically ventilated in the ICU. 10 patients were weaned from the ventilator (3 patients were still hospitalized, 7 patients were discharged) [21]. For comparison, the combined mortality rate of all COVID-19 patients admitted to the ICU (24 studies including 10,150 patients) was 41.6% (95%CI 34.0–49.7%) according to the systematic review with metaanalysis done by Armstrong et al. in 2020 [22].

ECMO Type and Cannulation According to ELSO guidelines, the cannulation of COVID-19 patients should happen preferably in the same designated COVID-19 environment to minimize the risk of transmission. This limits temporary patient transfer for cannulation purposes to catheterization laboratories or operating rooms. Dual lumen cannulas for veno-venous support was discouraged due to longer insertion time and possible malpositioning that would require repeated use of visualization techniques [11]. Two cannulas in femoro-femoral or jugular-femoral VV ECMO may be placed at the bedside without visualization techniques, especially in the case of an unstable patient or rapid hemodynamic deterioration. However, ELSO recommends the use of a plain x-ray, vascular ultrasound and echocardiography, or fluoroscopy over blind cannulation [11]. A higher

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rate of recirculation observed with a double cannula strategy needs to be considered, as well as an increased risk of local bleeding complications and a lack of active ambulation in comparison with a dual lumen single cannula approach. The advantages of a two cannulas technique (specifically femoral-femoral) include higher flow rates, rapid deployment, and some distance between operator and the patient’s airway [11, 23]. However, the cannulation type may still depend on an institution or a strategy chosen by the ECMO team. An interesting strategy for routine bedside ECMO cannulation was developed at the Hennepin County Medical Center in Minneapolis, Minnesota, using a portable fluoroscopy bed placed to the side of the ICU bed followed by bi-caval dual lumen cannula insertion with fluoroscopic guidance [24]. If conditions do not allow for the use of fluoroscopy, a transthoracic echocardiogram or portable chest x‐ray, which can be easily arranged for in any facility, may help to confirm guidewire and cannula positioning. Twenty-three cases of dual‐lumen bi-caval cannula insertion at bedside were reported. It was also suggested that the described strategy may be considered for COVID-19 patients as well [24]. In June 2020, Falcoz et al. from the Strasburg University Hospital reported cannulation using a bi-caval dual lumen cannula in 12 out of 16 patients (remaining 4 patients with a jugulofemoral approach) supported with VV ECMO for severe ARDS due to COVID-19 [21]. There are no specific recommendations for VA ECMO cannulation in COVID-19 patients in the ELSO guidelines except to avoid using a dual lumen cannula for a veno-veno-arterial (VVA) configuration and to instead utilize three separate cannulas [11]. Considering the high risk of cardiovascular complications in COVID-19 patients, a femoral arterial line for blood pressure monitoring may be placed in critically ill patients, as this line can potentially be rewired and upgraded to an arterial ECMO cannula if cardiac support is needed. Perceptions surrounding ECPR underwent certain changes in light of the COVID-19 pandemic as well. Because of the complexity of ECPR and the need for a highly skilled team extensively trained for establishing ECMO support during active cardiopulmonary resuscitation, ECMO

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centers that do not provide ECPR should not initiate this service during times of limited resources [23]. Also, ECPR for out-of-hospital cardiac arrests as well as pre-hospital ECPR were not recommended. It was suggested that experienced ECMO centers may consider ECPR for inhospital arrests for selected non-COVID-19 patients. Evaluation of the potential risk of personnel contamination in short supply should be considered during ECPR, as well as previously reported poor outcomes associated with conventional CPR after in-hospital cardiac arrests in COVID-19 patients [11, 25].

Renal Replacement Therapies and Blood Purification The general population of ECMO patients have a high risk of developing acute kidney injury (AKI) that may require different modalities of renal replacement therapy [26]. It was theorized that an systematic component of severe COVID-19 is a cytokine storm syndrome due to cytokine overproduction [27, 28]. Sometimes it develops after a delay, when initially mild clinical manifestations quickly progress to severe and lead to multiple organ failure. Patients with severe COVID-19 requiring ECMO support are at high risk of developing acute kidney injury and controlling the virus-activated inflammatory response may play an important role in the management of COVID-19 patients. The successful management of septic shock and the severe systemic inflammatory response syndrome while on ECMO is well known and described in the literature. This approach may also be accompanied by extracorporeal cytokine absorbers and different types of renal replacement therapies [28, 29]. One of the recent clinically-based recommendations advocating for the deployment of cytokine removal technologies for COVID-19 patients recommended its use in patients with a combination of high levels of IL-6 and IL-8, high Sequential Organ Failure Assessment (SOFA) scores, hemodynamic instability requiring vasopressors, and immunological or coagulation dysregulation [30].

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However, the development of acute kidney failure in COVID-19 patients on ECMO may indicate progression to an unfavorable prognosis, and the consideration of subsequent interventions should include consideration of institutional capacity during an ongoing pandemic, where escalation of care may overwhelm the healthcare system and make extracorporeal support impossible for other critically ill patients. Potentially, future combined platforms of ECMO with renal replacement therapy may decrease the burden on staff and the amount of separate interventions required to be present at the bedside [30].

Anticoagulation COVID-19 patients are predisposed to cardiovascular thrombotic and hemorrhagic events. The endotheliopathy and pulmonary vascular microthromboses are some of the pathophysiological characteristics of SARS-CoV-2 that can trigger disseminated intravascular coagulopathy and contribute to an increased incidence of arterial thromboembolism (3.7%) and venous thromboembolism (27%) [31]. The initial procoagulant effect of ECMO right after initiation of support is related to the exposure to artificial surfaces and coagulation cascade activation. This is exacerbated by the “cytokine storm” and development of sepsis with COVID-19 progression [32]. While the science is still in evolution, there is a considerable concern that the “cytokine storm”, specifically the immunologic response to infection and potential hypercoaguable state, is a major source for morbidity and mortality in these patients [13]. The hypermetabolic sequelae of infection, when coupled with the impaired oxygenation and ventilation from the associated respiratory failure, is a difficult problem even when patients are supported adequately on ECMO. Even with what would be perceived adequate ECMO flow, circuit and oxygenator function, and gas exchanged, anecdotal reports of profound metabolic and respiratory acidosis often remain. There is concern that such an overwhelming activation of the inflammatory system – as manifested by

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substantial elevations in cytokines (interlukin-6, ferritin) and reactive proteins (fibrinogen, CRP and D-dimer) correlate with disease severity and outcomes. Early in the pandemic experience there were concerns that systemic markers of inflammation, such as a profound leukopenia, were associated with worse outcomes [9]. Current therapies are aimed towards attenuating this autoimmune response – the scope of which is still rapidly evolving [13]. This topic is addressed in more detail in the blood purification chapter in this volume. COVID-19 patients treated in the ICU and non-survivors had leukocytosis with lymphopenia, an elevated creatinine, blood urea nitrogen, serum transaminases and procalcitonin, as well as signs of disseminated intravascular coagulation [8, 23]. One of the most frequently observed complications was sepsis [17]. The most common means of anticoagulation monitoring on ECMO is achieved by utilization of the activated clotting time (ACT) and activated partial thromboplastin time (aPTT). However, it may be difficult to achieve adequate consistent anticoagulation in COVID-19 patients. Both ACT and aPTT are not accurate enough for heparin effect monitoring, and, therefore, additional means of anticoagulation monitoring are required. Multiple factors can cause an ACT prolongation in addition to heparin including hypothermia, hemodilution, thrombocytopenia and hypofibrinogenemia. An elevated Creactive protein can significantly affect aPTT, which leads to an overestimation of the effect of heparin. Anti-factor Xa showed better correlation with the effect of heparin than ACT and PTT, as it measures heparin effect without being susceptible to interference from elevated acute phase reactants. Monitoring with anti-factor Xa requires less heparin dose adjustments and reduces the time to achieve target anticoagulation on ECMO. Due to a high risk of thromboses, therapeutic anticoagulation with higher targets of anticoagulation (anti-Xa 0.5-0.7 UI/mL) should be considered in all COVID-19 patients [21]. Thromboelastography (TEG) might be an additional tool for detection of hypercoagulable states and can facilitate early detection of deficiencies in coagulation cascade components to assist in the prevention of bleeding. Thrombocytopenia as a complication of COVID-19 may be initially

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difficult to differentiate from heparin induced thrombocytopenia (HIT) in patients on ECMO. The direct thrombin inhibitors like bivalirudin, that has no effect on platelet factor 4 and is safe in HIT, might also be considered [33].

Infectious Risk, Healthcare Staff and Patient Safety One of the major concerns associated with the use of ECMO for COVID is the theoretical risk of infection of the healthcare team. ECMO, as discussed above, is extremely resource intensive – especially as the patients who require support tend to be extremely critically-ill. As such, since the routine care of a patient on ECMO requires continuous and active care, management, and engagement by many members of the healthcare team (the least of which are bedside critical care nurses and ‘ECMO specialists’), there are substantial concerns regarding the risk of COVID infection of these providers. It is well known that many healthcare workers, even with reports of adequate protection (a topic that remains in evolution as of the writing of this chapter), have developed COVID, presumably from caring for infected contagious patients – and, tragically, many of them died. What is not known, however, is what the risks are for the team providing ECMO care. Data is limited in this area, but fortunately unpublished surveys of ECMO teams and perfusionists have not demonstrated any clearly identifiable trends or increased risk to the providers. While the absence of objective data does not negate the possibility of a risk – and one that might be substantial – it does emphasize that collectively, there must be an acknowledgement of the problem. As such, patients must be kept in strict isolation precautions, to the best of the ability of the institution given concerns of limited resources, and the team must be also aware of potential risks to themselves and also adhere to established principles (and evolving guidelines and recommendations) regarding the appropriate care of potentially highly contagious patients. While there are many actions that can be taken to reduce risks, the most important steps are without a doubt the simplest, like having all

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monitors, screens, and displays facing outward so that critical information can be monitored without having to enter into a patient’s room, coordinating all clinical efforts to minimize time spent in a room with a patient, and writing key data (ventilator settings, if they cannot be seen, vasoactive and intravenous drip rates, etc.) on the glass doors separating the patient with erasable markers (Figure 3). Handwashing, appropriate masks/respirators, gowns, gloves, and minimization of breaks in the ventilator circuit must be emphasized.

Figure 3. Representative “COVID-ECMO” room in which the bedside nurse and ECMO-specialist are both wearing appropriate personal protective equipment. All attempts at having the monitors, medication pumps, and other key equipment facing the glass closed doors are made to facilitate reviewing their status without having to enter the room. In addition, as can be seen in the upper right corner of the glass window, erasable black markers are used to assist in communicating key information between those in and outside of the room.

Furthermore, appropriate filters on the ventilator must be used (and out of the scope of this discussion). While there are concerns that waste gases from the ECMO circuit and oxygenator (not to mention various fluids) might contain virus, such concerns remain theoretical and the risks are currently speculative. This includes future consideration into the varying theoretical viral load, if any, between use of the two main oxygenator

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material types, polypropylene (PP) and polymethylpentene (PMP). The fundamental concept, and one that is well-established in cardiac surgery, is to assume everyone is an infection risk and to “be careful”.

Adjunctive Therapy It is important to remember that ECMO, regardless of veno-veno or veno-arterial, is a supportive therapy. It is not inherently curative. The fundamental purpose of ECMO is to maintain the oxygenation needs of the body during the acute phase of organ injury. Once a patient is started on ECMO, it must be recognized that the goal of therapy is to correct the underlying pathologic problem as soon as possible while minimizing the risk for further damage. The lungs and/or heart need to rest and recover, a process that often takes time and attention to details to minimize the risk for complications or to reduce the severity of them if and when they do develop. The challenge in dealing with COVID-19 patients is that the spectrum of clinical problems that they can present with is extremely heterogeneous and, at least as of the time of writing, robust and effective therapies are lacking. Unlike infectious bacterial pneumonias where targeted antibiotics, combined with a lung-protective strategy, are cornerstones to treatment (for example), there is still extensive debate surrounding the “best” or most effective therapies for the critically-ill COVID patients. This is clearly illustrated in the early experiences described by Jacobs, in which no singular therapy was shown to be more effective than any other and often patients were treated with multiple different combination therapy [20]. A common theme when dealing with ECMO patients is to allow time for the lungs (and/or heart) to heal and by reducing the risks for further organ injury from barotrauma, such as either iatrogenic over-pressurization of the lung, alveoli over-distention, and spontaneous pneumothorax. While the evidence and best-practices are still evolving regarding the treatment options for COVID infections, providers must be open-minded and kept abreast of the latest therapies – a concept that helps to explain why, at least historically, patients who are sent to

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“ECMO Centers” for evaluation and management, even if they did not receive ECMO, tended to have better outcomes than those patients managed at centers that did not offer ECMO.

CONCLUSION ECMO is an established therapy for acute cardiopulmonary failure that is refractory to maximal medical therapy. Respiratory complications secondary to COVID-19, unfortunately, are common and appear to be associated with major morbidity and/or mortality. Evolving data is demonstrating that despite the significant mortality associated with the use of ECMO in the setting of an acute COVID-19 infection, the outcomes appear better than current therapies. Nevertheless, ECMO remains extremely resource intensive, limited in availability – in part due to cost and access, and still somewhat controversial with regards to the overall net benefit in the context of whether it might consume resources that might be better allocated to several patients. Despite the concerns and evolving understanding regarding patient selection, management protocols, guidelines, and outcomes, it would be unethical to proceed without, at least a basic consideration for ECMO, if available, for a potentially eligible patient.

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In: The History of Extra-Corporeal … ISBN: 978-1-53618-961-2 Editor: Michael S. Firstenberg © 2021 Nova Science Publishers, Inc.

Chapter 7

EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO) IN COVID-19: THE ROLE OF LUNG TRANSPLANTATION Asishana Osho1, Jerome Crowley2, Philip J Spencer3, Masaki Funamoto1, Nathaniel Langer1 and Mauricio Villavicencio1 1

Division of Cardiac Surgery, Massachusetts General Hospital, Boston, MA, US 2 Division of Cardiac Anesthesia, Massachusetts General Hospital, Boston, MA, US 3 Division of Cardiac Surgery, Westchester Medical Center, Valhalla, NY, US

ABSTRACT The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has demonstrated a wide spectrum of clinical presentations ranging from asymptomatic sub-clinical infection to respiratory failure requiring prolonged mechanical ventilation and extra-corporeal membrane

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Asishana Osho, Jerome Crowley, Philip J Spencer et al. oxygenation (ECMO). While the effects of COVID-19 on long term pulmonary function remain largely unknown, it is likely that lung transplantation will feature in treatment conversations for patients with irrecoverable pulmonary damage secondary to SARS-CoV-2 infection. This chapter highlights several critical considerations for providers as they are faced with difficult questions about lung transplantation as a therapeutic option for those patients who develop COVID-19 respiratory failure requiring ECMO.

Keywords: ECMO, COVID-19, lung transplantatation, extracorporeal membrane oxygenation, Coronavirus

INTRODUCTION The coronavirus disease pandemic of 2019 has created new challenges for modern healthcare systems. As millions worldwide recover from acute infection with the virus, practitioners will need to be prepared to deal with the long-term effects that may be associated with the disease. Difficult decisions will have to be made about whether transplantation is within the realm of therapies that should be made available to patients who develop acute or chronic lung disease associated with COVID-19 infection. Many parallels have been drawn between the pathophysiology of classic acute respiratory distress syndrome (ARDS) and that of acute respiratory illness due to COVID-19 [1, 2]. Each condition presents with a broad spectrum of derangements in pulmonary and acid-base equilibrium with ambiguous rules affecting severity in any given case. Additionally, both COVID-19 respiratory failure and ARDS appear to follow very loose guidelines in the realms of clinical presentation and associated imaging findings. Most relevant to the present discussion, both appear to lead – in the most severe cases – to diffuse alveolar injury with loss of normal pulmonary architecture and function [1]. Although the long-term pulmonary effects of COVID-19 remain unknown, the similarities to ARDS in the early phase of disease suggested that the initial damage to the pulmonary epithelium may stimulate abnormal accumulation of extracellular matrix components and lead to widening of the interstitial

Extracorporeal Membrane Oxygenation (ECMO) in COVID-19 189 connective tissue, further lung damage, pulmonary fibrosis and ultimately respiratory failure. Of note, lung transplantation if not often offered as a therapy for ARDS with no large series described in the literature [3]. As in ARDS, COVID-19 respiratory failure presents several challenges for providers seeking to offer lung transplantation as a therapeutic option to patients with acute pulmonary failure. The acute presentation of this disease in in direct conflict with the philosophy of careful, thorough candidate evaluation and donor matching that is espoused in most transplant programs. This is confounded by uncertainty about prospects for recovery, both of the lungs and of any other organ systems that may have been involved in the systemic illness from COVID-19 [4]. Furthermore, the unknown natural history of COVID-19 infection raises concern about future pathology in transplanted lungs as there remains some possibility of reactivation of infection in previous victims or ongoing hyperactivity of the recipient’s immune system. This concern is highlighted in recent studies suggesting that IgG and IgM antibody levels are most reliably detected in hosts between 15 and 35 days from the time of initial infection [5, 6]. Thus far there is inconclusive evidence about how long these antibodies persist. It goes without saying that such uncertainty about the systemic immune milieu cannot be reassuring to anyone seeking to provide transplantation to patients who might be at risk of receiving a new organ in the midst of heightened immune activation. This picture of clouded further by uncertain risks of performing major cardiothoracic surgical procedures in patients who are acutely infected with COVID-19. Studies have hinted at relatively high rates of pulmonary complications (up to 50%) in patients with acute COVID-19 infection undergoing major surgery, with thirty-day mortality of almost 40% in patients who develop post-operative pulmonary complications [7, 8]. Of great interest to the transplant provider is the risk of amplification of illness severity in immunocompromised hosts. Although it is unclear how immunosuppression affects the clinical presentation with COVID-19 there was some initial speculation that being immunocompromised could be protective [9]. This theory is driven by early studies suggesting that the virus anchors to the lung via the angiotensin converting enzyme (ACE) 2

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receptor. In its uninhibited form this receptor helps minimize inflammation in the lung. When inhibited by the COVID-19 virus, this inhibition is lost, exposing the lung to damage by systemic immune system driven inflammatory actors. It would follow then that immunocompromised patients would generate a less robust attack on their own lungs given the medication induced stunting of their immune systems. In reality however there is some suggestion that this theory may be incorrect, or incomplete. Early studies have highlighted increased severity of disease in immunocompromised solid organ recipients hospitalized with COVID-19 [10, 11, 12]. One particular report of COVID-19 in a patient with a history of lung transplantation noted an almost 20% decrease in baseline FEV1 due to COVID-19 with an associated doubling of oxygen requirement even though the patient was relatively asymptomatic [12]. At our center, three previous lung recipients and one heart-lung recipient tested positive for COVID-19. All patients presented with hypoxia and all required prolonged admission to the hospital (All > 1 week) despite some initial attempts to manage symptoms at home. One patient passed away from progressive hypoxia early during the hospital stay and another required intubation for 11 days. Notably, all patients had a prolonged period of positive COVID-19 testing, remaining positive for the virus at least 2 months after the initial diagnosis despite receiving treatment. Put together, these concerns about acuity, necessity (if patients could ultimately have pulmonary recovery), prolonged COVID positive status and futility (If COVID-19 reactivation or re-infection could eventually destroy transplanted lungs) have undoubtedly limited the use of lung transplantation as a therapy in COVID-19. Notwithstanding, there have been a few reports of lung transplantation in patients with COVID-19 respiratory failure. Chen et al., From the Wuxi Lung Transplant Center in China describe outcomes following lung transplantation in three male patients with COVID-19 who suffered ongoing deterioration of pulmonary function despite subsequently negative corona virus tests and systemic support with extra-corporeal membrane oxygenation (ECMO) [13]. All three patients had undergone tracheostomy, with ECMO durations of 7, 15 and 19 days. In two cases, adequate support

Extracorporeal Membrane Oxygenation (ECMO) in COVID-19 191 was provided with only veno-venous extra-corporeal membrane oxygenation (VV-ECMO), while one patient required veno-arterio-venous ECMO (VAV ECMO). Donors were tested and confirm to be negative for COVID-19. Two of these three patient survived post-transplant to extubation while one passed away during transplantation due to ventricular fibrillation and intractable bleeding. Another series from the First Affiliated Hospital, Hangzhou, China reports outcomes in two patients on VV-ECMO for COVID-19 respiratory failure who successfully underwent lung transplantation after approximately two weeks of extracorporeal support [14]. One of these patients had primary graft dysfunction requiring several days of ECMO post-transplant. While innovative, these early reports of lung transplantation in COVID-19 do little to address previously outlined concerns. The reservations about possible allograft loss due to future reinfection or reactivation of COVID-19 are self-evident – It is too early to know how the natural history of systemic COVID-19 infection might affect immunocompromised lung recipients. The question of necessity also remains unanswered. Several early reports describing ECMO use in COVID-19 suggest that patients may recover pulmonary function after long ECMO runs, upwards of the durations noted in the two early reports of COVID-19 lung transplantation [15, 16, 17]. This is backed by data from the Extracorporeal Life Support Organization (ELSO) which is compiled from almost 2000 patients placed on ECMO for COVID-19 [18]. Over 25% of patients in the ELSO COVID-19-ECMO registry were on ECMO for greater than 3 weeks, with many demonstrating pulmonary recovery even after such long periods on the circuit [18]. More globally, these reports highlight the needs of only one group of patients who suffer from COVID19 respiratory failure. As outlined below, the question of lung transplantation will come up at several points along the spectrum of recovery for patients with severe COVID-19. Potential issues are highlighted, related to each of these possible pathways:

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COVID-Positive Patients Who Are Unable to Separate from ECMO This group of patients presents issues discussed above, most uniquely as they relate to acuity of presentation and uncertainty about prospects for recovery following the initial systemic COVID-19 infection. In this group, transplant providers may struggle to perform the detailed evaluation that typically precedes lung transplantation. Further limitations related to confirmation of COVID-19 status in donors and recipients, uncertainty about resolution of other systemic manifestations of COVID-19 and lack of clarity about what constitutes “enough” time on ECMO may limit confidence about the appropriateness of transplantation at this stage. Additionally, these decisions are bound to be accompanied by considerable pressure on providers and potentially limited by availability of donor organs during critical time periods. That said, early evidence as highlighted above suggests that reasonable outcomes can be achieved in the short term. In practice, the severity of clinical and imaging presentations for these patients may lead providers to consider pursuing transplantation. This is especially true in young, otherwise healthy individuals with findings of pulmonary fibrosis on computed tomography. Figure 1 demonstrates imaging findings in an otherwise healthy mother of 5 who required ECMO for severe COVID-19 respiratory failure. Clearly it is difficult to hope for pulmonary recovery in such a case, and equally difficult to refuse lifesaving therapy given the social context.

COVID-Positive Patients Who Come off ECMO but Are Unable to Be Liberated from the Ventilator Patients who are able to separate from ECMO but remain ventilatordependent present a unique set of challenges for providers. The issues with acute presentation will likely be less relevant, giving way instead to concerns related to complications from prolonged hospitalization, deconditioning and ability to tolerate lung transplantation given prolonged

Extracorporeal Membrane Oxygenation (ECMO) in COVID-19 193 periods of severe pulmonary debilitation. Concerns about potential complications of future reactivation of COVID-19 will also come to the fore, as will long term issues associated with tracheostomy placement and ventilator dependence. Thus far there are no reports in the literature of lung transplantation from this stage of COVID-19 recovery. Indeed this scenario may be less common as the preference in patients with pulmonary failure is often to stay on ECMO and wean off the ventilator which would allow the patient to ambulate and possibly engage in rehabilitation prior to transplantation. The complications associated with such extended ECMO runs including infection, bleeding and other anticoagulation related issues (like heparin induced thrombocytopenia) are not trivial and may ultimately affect individual candidacy for transplantation.

Figure 1. Chest radiograph and representative CT scan image of a young, otherwise healthy individual with severe COVID-19 respiratory failure requiring extracorporeal membrane oxygenation (ECMO). Images demonstrate severe parenchymal and airway infiltration with minimal aeration and few areas of normal visible lung tissue.

COVID-Positive Patients Who Come off ECMO and Are Liberated from the Ventilator, but Are Unable to Achieve Meaningful Functional Recovery Patients who are able to separate from both ECMO and mechanical ventilation but are unable to make meaningful functional recovery may be considered for lung transplantation if they are otherwise robust and have a presentation consistent with COVID-19 lung damage. Considerations

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related to clearance of the systemic infection remain but are mitigated by the relative stability that will allow for testing under controlled situations and potentially for full transplantation workup to characterize residual lung function and outline the contribution of comorbidities. In these patients, maximizing rehabilitation will be crucial to ensure that losses are not driven primarily by general deconditioning from acute illness. As noted above, concerns about future reactivation of COVID-19 remain at the fore. As in (2) above, there are yet to be reports in the literature about transplantation from this stage.

COVID-Positive Patients Who Come off ECMO, Are Extubated and Achieve Meaningful Functional Recovery in the Short-toMedium Term But Eventually Develop End-Stage Pulmonary Disease Requiring Evaluation for Transplantation Patients with severe respiratory failure due to COVID-19 who recover and have a reasonable interval of pulmonary convalescence before regressing represent the population of patients most similar to the current pool of lung transplant recipients. These patients will likely be classified as having chronic lung disease – whether initiated by COVID-19 or existing in the background with full manifestation due to acute COVID-19 infection. Whatever the case, these patients are likely to have adequate intervals from their acute COVID-19 infection to trust that they have countered the acute systemic infection. At the same time, there will be enough of an interval to have a reasonable idea about the prospects of pulmonary recovery. It is also anticipated that there will be enough stability in this setting for patients to undergo full pre-transplant workup, listing and allocation. There may however be downstream sequelae of COVID-19, even this far out, but the increased duration of time since infection will almost certainly be favorable for transplant evaluation.

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CONCLUSION In all, it is clear that the story of lung transplantation in patients requiring ECMO for COVID-19 respiratory failure is multi-faceted and very much still in development. Long term studies of COVID-19 positive cohorts will be necessary to understand the downstream effects of this illness. Transplantation in these populations presents unique challenges depending on the particular stage. Lung transplantation in scenarios with such uncertainty must be carried out with a careful consideration of appropriate stewardship of scarce donor lungs. Indeed professional societies may need to consider creation of guidelines to help providers navigate lung transplant evaluation in previous COVID-19 patients. There is some early work toward this goal from professional transplantation societies who have outlined key principles for considering lung transplantation at different stages of the individual patient and health system experience with COVID-19 [19, 9]. Ultimately, the foundational principles of utility, justice and efficiency that we are reminded of by these early reports will need to be the cornerstone of robust guidelines to steer the field of lung transplantation in this unprecedented era.

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Asishana Osho, Jerome Crowley, Philip J Spencer et al. “COVID-19: The Potential Treatment of Pulmonary Fibrosis Associated with SARS-CoV-2 Infection.” Journal of Clinical Medicine 9 (6): 1917. https://doi.org/10.3390/jcm9061917. Chang, Youjin, Sang Oh Lee, Tae Sun Shim, Sae Hoon Choi, Hyung Ryul Kim, Yong-Hee Kim, Dong Kwan Kim, et al., 2018. “Lung Transplantation as a Therapeutic Option in Acute Respiratory Distress Syndrome.” Transplantation 102 (5): 829–37. https:// doi.org/10.1097/TP.0000000000002004. Garcia-Basteiro, Alberto L, Gemma Moncunill, Marta Tortajada, Marta Vidal, Caterina Guinovart, Alfons Jiménez, Rebeca Santano, et al., 2020. “Seroprevalence of Antibodies against SARS-CoV-2 among Health Care Workers in a Large Spanish Reference Hospital.” Nature Communications 11 (1): 3500. https://doi.org/10.1038/s41 467-020-17318-x. Deeks, Jonathan J, Jacqueline Dinnes, Yemisi Takwoingi, Clare Davenport, René Spijker, Sian Taylor-Phillips, Ada Adriano, et al., 2020. “Antibody Tests for Identification of Current and Past Infection with SARS-CoV-2.” The Cochrane Database of Systematic Reviews 6: CD013652. https://doi.org/10.1002/14651858.CD013652. COVIDSurg Collaborative, Dmitri, Aneel Bhangu, James C Glasbey, Elizabeth Li, Omar M Omar, Joana FF Simoes, Tom EF Abbott, et al., 2020. “Mortality and Pulmonary Complications in Patients Undergoing Surgery with Perioperative SARS-CoV-2 Infection: An International Cohort Study.” Lancet (London, England) 396 (10243): 27–38. https://doi.org/10.1016/S0140-6736(20)31182-X. Harky, Amer, Runzhi Chen, and Mark Pullan. 2020. “Examining the Impact of COVID‐19 on Cardiac Surgery Services: The Lessons Learned from This Pandemic.” Journal of Cardiac Surgery, July, jocs.14783. https://doi.org/10.1111/jocs.14783. Aslam, Saima, and Mandeep R Mehra. 2020. “COVID-19: Yet Another Coronavirus Challenge in Transplantation.” The Journal of Heart and Lung Transplantation : The Official Publication of the International Society for Heart Transplantation 39 (5): 408–9. https://doi.org/10.1016/j.healun.2020.03.007.

Extracorporeal Membrane Oxygenation (ECMO) in COVID-19 197 [10] Keller, Brian C., Anh Le, Mahdee Sobhanie, Nora Colburn, Pamela Burcham, Justin Rosenheck, Molly Howsare, et al., n.d. “Early COVID‐19 Infection after Lung Transplantation.” American Journal of Transplantation. Accessed July 5, 2020. https://doi.org/ 10.1111/AJT.16097. [11] Pereira, Marcus R., Sumit Mohan, David J. Cohen, Syed A. Husain, Geoffrey K. Dube, Lloyd E. Ratner, Selim Arcasoy, et al., 2020. “COVID‐19 in Solid Organ Transplant Recipients: Initial Report from the US Epicenter.” American Journal of Transplantation 20 (7): 1800–1808. https://doi.org/10.1111/ajt.15941. [12] Aigner, Clemens, Ulf Dittmer, Markus Kamler, Stephane Collaud, and Christian Taube. 2020. “COVID-19 in a Lung Transplant Recipient.” The Journal of Heart and Lung Transplantation : The Official Publication of the International Society for Heart Transplantation 39 (6): 610–11. https://doi.org/10.1016/j.healun. 2020.04.004. [13] Chen, Jing-Yu, Kun Qiao, Feng Liu, Bo Wu, Xin Xu, Guo-Qing Jiao, Rong-Guo Lu, et al., 2020. “Lung Transplantation as Therapeutic Option in Acute Respiratory Distress Syndrome for COVID-19Related Pulmonary Fibrosis.” Chinese Medical Journal, April. https://doi.org/10.1097/CM9.0000000000000839. [14] Han, Weili, Manhua Zhu, Jun Chen, Jing Zhang, Shengmei Zhu, Tong Li, Hongliu Cai, Qiang Fang, Guoqing Wei, and Tingbo Liang. 2020. “Lung Transplantation for Elderly Patients With End-Stage COVID-19 Pneumonia.” Annals of Surgery. https://doi.org/10.1097/ SLA.0000000000003955. [15] Li, Xin, Zhen Guo, Bailing Li, Xiaolin Zhang, Rui Tian, Wei Wu, Zhongwei Zhang, et al., 2020. “Extracorporeal Membrane Oxygenation for Coronavirus Disease 2019 in Shanghai, China.” ASAIO Journal (American Society for Artificial Internal Organs : 1992), March, 1. https://doi.org/10.1097/MAT.0000000000001172. [16] AA, Osho, Moonsamy P, Hibbert KA, Shelton KT, Trahanas JM, Attia RQ, Bloom JP, et al., 2020. “Veno-Venous Extracorporeal Membrane Oxygenation for Respiratory Failure in COVID-19

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Patients: Early Experience From a Major Academic Medical Center in North America.” Annals of Surgery. https://doi.org/10.1097/ SLA.0000000000004084. [17] Ñamendys-Silva, Silvio A. 2020. “ECMO for ARDS Due to COVID19.” Heart & Lung, March. https://doi.org/10.1016/j.hrtlng.2020. 03.012. [18] (ELSO), Extracorporeal Life Support Organization. 2020. “ECMO in COVID-19. Full COVID-19 Registry Dashboard.” Extracorporeal Life Support Organization (ELSO). 2020. https://www.elso.org/ Registry/FullCOVID19RegistryDashboard.aspx. [19] Holm, Are M, Mandeep R Mehra, Andrew Courtwright, Jeffrey Teuteberg, Stuart Sweet, Luciano Potena, Lianne G Singer, et al., 2020. “Ethical Considerations Regarding Heart and Lung Transplantation and Mechanical Circulatory Support during the COVID-19 Pandemic: An ISHLT COVID-19 Task Force Statement.” The Journal of Heart and Lung Transplantation : The Official Publication of the International Society for Heart Transplantation 39 (7): 619–26. https://doi.org/10.1016/j.healun.2020.04.019.

ABOUT THE EDITOR

Michael S. Firstenberg, MD, FACC, FAIM Dr. Michael S Firstenberg is a board-certified thoracic surgeon. He is the current Director of Research and Special Projects for the William Novick Global Cardiac Alliance. Previously, he was Chief of Cardiothoracic and Vascular Surgery at the Medical Center of Aurora and

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Rose Hospitals. He currently holds appointments in the Colleges of Medicine and Graduate Studies at Northeast Ohio Medical University. He attended Case Western Reserve University Medical School, received his General Surgery training at University Hospitals in Cleveland, and completed Fellowships at The Ohio State University (Thoracic Surgery) and The Cleveland Clinic (Surgical Heart Failure). He is an active member of the Society of Thoracic Surgeons (STS), American Association of Thoracic Surgeons (AATS), the American College of Cardiology (ACC), and the American College of Academic International Medicine (ACAIM – for which he is a Founding Fellow and President-elect). He currently serves on several professional society committees. He is the author of well over 200 peer-reviewed manuscripts, abstracts, and book chapters. He has edited several textbooks on topics ranging from Medical Leadership, Patient Safety, Endocarditis, and Extracorporeal Membrane Oxygenation – all of which include topics that he has lectured on world-wide.

INDEX A acute infection, 188 acute kidney failure, 177 acute lung injury, 105 acute respiratory distress syndrome, 8, 19, 22, 90, 131, 133, 153, 159, 164, 166, 167, 188 adult respiratory distress syndrome, 20 adults, xiv, 9, 10, 20, 26, 29, 67, 69, 79, 86, 90, 95, 97, 98, 100, 105, 111, 172 age, 9, 20, 47, 51, 72, 125, 134, 155, 165, 168, 172, 173 air embolism, 127 airway infiltration, 193 aminotransferases, 70 anatomy, 25, 28, 78, 139 angiotensin converting enzyme, 189 antibody, 189 anticoagulant, 101 anticoagulation, xiv, 5, 29, 30, 32, 41, 51, 52, 75, 78, 81, 90, 126, 131, 132, 144, 146, 172, 177, 178, 186, 193 anti-factor Xa, 178

aorta, 3, 61, 62 aortic insufficiency, 52 aortic regurgitation, 51 aortic valve, 53, 56, 63, 69 arrest, 42, 43, 45, 46, 47, 49, 51, 128, 165 arrhythmia, 45, 72 arterial blood gas, 145 artery, 3, 41, 45, 52, 70, 89, 100 assessment, xvii, 18, 46, 70, 71, 73, 74, 105, 113, 168, 183 asymptomatic, 124, 129, 164, 187, 190 atrial septal defect, xv, 5

B bacteremia, 107 bacterial infection, 134 barotrauma, 181 bilateral, 140 bilirubin, 32 biocompatibility, 8, 38 biomarkers, 73 biomaterials, 6

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bleeding, 30, 52, 72, 75, 84, 85, 132, 145, 172, 175, 178, 191, 193 blood, xiv, xv, 2, 3, 4, 6, 7, 15, 21, 29, 30, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 55, 56, 57, 61, 64, 66, 69, 71, 73, 75, 76, 81, 83, 84, 105, 107, 126, 134, 166, 172, 175, 178, 186 blood flow, xiv, 4, 7, 30, 34, 36, 38, 41, 66, 69 blood pressure, 43, 107, 175 blood urea nitrogen, 4, 178 body mass index, 72, 166 body weight, 166 brain, 51, 75, 76, 77 burn, 44, 118, 128

C candidates, 7, 51, 157, 172 cannulation, xiv, 26, 27, 28, 29, 40, 41, 46, 51, 52, 74, 77, 79, 89, 125, 126, 131, 132, 133, 134, 136, 137, 139, 140, 141, 143, 144, 145, 146, 147, 150, 165, 174, 175, 185 cardiac arrest, 10, 22, 42, 43, 45, 46, 47, 48, 77, 79, 90, 91, 92, 96, 97, 98, 99, 100, 115, 116, 118, 122, 125, 128, 136, 144, 166, 176, 185 cardiac catheterization, 106 cardiac output, 29, 33, 44, 54, 57, 60, 65, 105, 106 cardiac reserve, 59 cardiac surgery, 1, 5, 7, 14, 28, 37, 70, 104, 110, 134, 181, 199 cardiac tamponade, 107 cardiogenic shock, xvi, 22, 25, 26, 42, 43, 44, 48, 49, 58, 59, 60, 61, 62, 64, 68, 76, 77, 79, 85, 91, 92, 93, 94, 104, 109, 110, 111, 112, 174 cardiomyopathy, 44, 58, 59, 77, 144

cardiopulmonary bypass, xvi, 1, 2, 5, 6, 11, 12, 13, 14, 16, 28, 29, 37, 41, 51, 61, 69, 80, 84, 87, 88, 96, 108 cardiovascular physiology, 54 catheter, 33, 74, 94, 115 cell signaling, 75 cerebral hemorrhage, 51 CESAR, xiv, xvii, 10, 18, 165, 183 challenges, 7, 31, 45, 52, 120, 188, 189, 192, 195 chronic heart failure, 44, 59, 60, 101 chronic kidney disease, 172 chronic obstructive pulmonary disease, 172 circulation, 1, 3, 5, 6, 9, 11, 14, 19, 43, 46, 51, 61, 64, 136 clinical application, 7, 8, 37 clinical presentation, 187, 188, 189 clinical problems, 181 clinical trials, 9, 151, 154, 158, 165 coagulopathy, 52, 144, 177, 186 combination therapy, 181 community, xvi, 118, 121, 126, 158 complications, xiv, 6, 7, 26, 27, 41, 61, 63, 64, 72, 74, 75, 77, 78, 86, 110, 132, 144, 148, 150, 158, 175, 178, 181, 182, 186, 189, 192 configuration, 40, 71, 79, 90, 137, 140, 175 congestive heart failure, 104 consensus, 10, 43, 108, 124, 129, 148, 169, 184 considerations, vi, 10, 48, 65, 68, 86, 122, 131, 148, 188, 193 consumption, 54, 65, 66, 67, 68, 106, 120, 126 contamination, 122, 126, 139, 146, 176 coronavirus, vi, vii, ix, xi, 129, 130, 131, 133, 147, 149, 151, 152, 153, 154, 158, 159, 160, 161, 164, 167, 169, 170, 172, 183, 184, 187, 188, 196, 197 cytokine storm, 176, 177, 186

Index D database, 77, 95, 109 deaths, viii, 124, 151, 152 decannulation, vi, 48, 49, 50, 52, 71, 72, 74, 78, 122, 127, 131, 132, 133, 145, 147, 150, 174 decannulation., 78, 145, 174 diastolic pressure, 53, 54, 62 dilated cardiomyopathy, 59 dilation, 41, 139 disability, xiv, 10, 118, 166 disaster, 118, 119, 120, 121, 122, 123, 127, 128, 129 disaster preparedness, vi, 117, 118, 119, 125, 127 disease progression, 165 diseases, 128, 148, 172 disseminated intravascular coagulation, 178 distributive justice, 123, 124 drainage, 31, 40, 61, 137, 140, 141, 142, 144 durability, 7, 8, 34, 37, 38

E ECMO, v, vi, vii, viii, ix, x, xi, xiv, xv, xvi, xvii, 2, 7, 8, 9, 10, 13, 16, 17, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 54, 60, 61, 62, 63, 64, 65, 66, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 84, 85, 86, 87, 88, 89, 90, 91, 95, 100, 107, 108, 110, 111, 112, 115, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 139, 140, 141, 142, 143,144, 145, 146, 147, 148, 151, 152, 153, 154, 155, 156, 157, 158, 159, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175,

203

176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 190, 191, 192, 193, 194, 195, 198 ECMO cannulation, vi, 39, 77, 125, 131, 132, 133, 139, 141, 175, 185 ECMO sweep gas, 145 ELSO, viii, xi, 9, 16, 22, 23, 26, 28, 42, 44, 45, 46, 50, 51, 69, 77, 79, 81, 88, 89, 92, 99, 107, 110, 125, 127, 130, 155, 156, 160, 165, 167, 168, 169, 170, 171, 172, 174, 175, 183, 191, 198 emergency, 29, 46, 97, 99, 116, 118, 122, 124, 127, 128, 146, 164, 184 EOLIA, 154, 155, 165, 166, 169 epidemic, 118, 128, 157, 167 epithelium, 188 equilibrium, 35, 56, 188 equipment, 8, 38, 119, 120, 122, 124, 127, 128, 133, 136, 137, 138, 139, 164, 168, 180 ethical considerations, 51, 123, 198 etiology, 26, 42, 59, 64, 72, 152 evidence, xiv, 2, 10, 20, 26, 27, 28, 30, 36, 41, 42, 44, 45, 46, 73, 77, 79, 84, 125, 151, 153, 154, 181, 189, 192 evolution, viii, xvii, 1, 28, 29, 37, 177, 179 exclusion, 50, 78, 133, 166, 169 exposure, 6, 40, 71, 122, 126, 132, 133, 134, 136, 141, 167, 177 extracellular matrix, 188 extracorporeal membrane oxygenation, v, vi, vii, ix, x, xvii, 1, 2, 16, 17, 18, 19, 20, 21, 22, 26, 62, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 99, 100, 101, 107, 109, 110, 111, 112, 113, 114, 115, 116, 128, 129, 131, 133, 148, 149, 150, 153, 159, 160, 161, 165, 166, 170, 172, 182, 183, 184, 185, 186, 187, 188, 193, 197 extraction, 32, 35, 36, 65, 66, 107

Index

204 F

fiber, 7, 8, 16, 17, 34, 37, 38, 39, 81, 82, 89 fiber membranes, 7, 37, 39 financial, 51, 120, 122 formation, 3, 33, 36, 63, 75, 140, 143, 145, 146, 147 Frank-Starling mechanism, 56, 57, 61

G gastrointestinal tract, 75 graft dysfunction, 44, 72, 94, 111, 191 guidance, x, xi, 40, 125, 159, 175 guidelines, viii, 10, 27, 42, 43, 45, 47, 69, 122, 148, 154, 156, 158, 164, 165, 168, 170, 171, 172, 174, 175, 179, 182, 188, 195 guiding principles, 127

H H1N1, xiv, 10, 19, 21, 22, 118, 124, 153, 154, 159, 165, 182, 183 health, vii, ix, 118, 133, 156, 165, 195 health care, vii, ix, 133, 156 health care professionals, vii health care system, 156 health status, 165 heart disease, 174 heart failure, 42, 49, 58, 60, 64, 85, 91, 93, 101, 134, 172, 200 heart rate, 54, 65 heart transplantation, xvi, 45, 50, 72, 94, 95, 96, 110, 111, 112 hemodynamic instability, 64, 132, 176 hemoglobin, 30, 32, 66, 67 hemorrhage, xiv, 32, 51, 155, 167 hemorrhagic stroke, 155 hemostasis, 132, 146, 147, 149

heparin induced thrombocytopenia, 166, 179, 193 history, vii, 1, 3, 11, 16, 41, 60, 87, 165, 189, 190, 191 hospitalization, 151, 152, 192 human, 2, 5, 14, 108, 110, 117, 118, 119, 120, 121, 126, 127, 133 human capital, 119 human resources, 119, 126 hypothermia, 29, 45, 91, 128, 178 hypoxemia, xiii, xv, xvi, 70, 76, 152, 153, 154, 157 hypoxia, 106, 144, 190

I immune activation, 189 immune response, 148 immune system, 189, 190 infection, x, xiv, 22, 33, 72, 76, 122, 133, 134, 145, 149, 151, 159, 164, 167, 168, 177, 179, 181, 182, 187, 188, 189, 190, 191, 192, 193, 194 inferior vena cava, 40, 41, 54, 61, 141 inflammation, xvii, 178, 190 inflammatory responses, 30, 75, 78 influenza, xiv, 10, 19, 22, 128, 152, 153, 159, 165 influenza A, 21, 159, 182 infrared spectroscopy, 33 initiation, xvi, 45, 46, 47, 72, 77, 78, 123, 136, 155, 157, 158, 165, 167, 171, 172, 177 injury, iv, 41, 43, 45, 49, 51, 52, 58, 70, 71, 73, 77, 143, 166, 172, 176, 181, 188 insertion, 41, 141, 174, 175 institutions, xvi, 125, 134 intensive care unit, 22, 29, 80, 128, 149, 164, 165, 167, 170 intervention, 26, 44, 79, 93, 101, 102 intra-aortic balloon pump, 43, 44, 64, 104

Index ischemia, 72, 73, 74, 144 isolation, 56, 133, 179 issues, 28, 125, 133, 191, 192

K kidney, 15, 30, 77, 134, 176 kidney failure, 30 kidney transplantation, 77

L left atrium, 61 left ventricle, 102 legend, 54, 60, 62, 67 liver, 73, 77, 134 liver enzymes, 73 liver transplant, 77 liver transplantation, 77 local anesthesia, 29 local anesthetic, 146 local government, 122 lumen, 136, 147, 150, 174, 175 lung disease, xv, 172, 188, 194 lung function, 34, 75, 145, 194 lung transplantatation, 188 lung transplantation, xvi, 111, 188, 189, 190, 191, 192, 193, 195

M majority, 7, 47, 77, 152, 155 malignancy, 51, 52, 172 management, viii, x, xi, 27, 28, 36, 40, 42, 49, 63, 64, 65, 68, 70, 71, 75, 76, 78, 91, 92, 95, 122, 123, 125, 127, 128, 153, 154, 159, 164, 165, 166, 167, 168, 169, 170, 173, 176, 179, 182 measurements, 54, 66, 70

205

mechanical circulatory support, 1, 2, 4, 5, 6, 7, 8, 10, 26, 27, 37, 38, 42, 49, 72, 74, 76, 86, 101, 111, 113, 198 mechanical ventilation, 36, 40, 86, 105, 124, 153, 154, 157, 158, 164, 166, 172, 187, 193 mechanical ventilator, 164, 168 medical, xv, 43, 46, 48, 49, 147, 164, 172, 182 medication, 180, 190 medicine, viii, 22, 82, 84, 86, 107, 110, 128, 184 membrane permeability, 7, 8, 38 membranes, 6, 7, 15, 38 metabolic acidosis, 73 metabolic disturbances, 44 metabolism, 13, 65, 66, 67, 68, 107 modifications, 31, 122, 127 morbidity, 173, 177, 182 mortality, viii, 19, 52, 70, 72, 104, 109, 125, 134, 152, 153, 155, 157, 164, 165, 166, 167, 173, 174, 177, 182, 184, 189 mortality rate, 152, 153, 164, 165, 173, 174 myocardial infarction, xvi, 26, 44, 49, 76, 79, 93, 99, 102, 103, 110, 116 myocarditis, 44, 45, 72, 77, 94, 109, 112, 113, 134, 144 myocardium, 55, 56, 59, 64 myosin, 56

N New England, 15, 87, 107, 108, 129, 195 nitric oxide, xv, 133, 154, 155, 157, 166 North America, 14, 16, 89, 155, 160, 198 nurses, 119, 121, 134, 156, 168, 179 nursing, 122, 134

O obesity, 40, 51, 52, 174

Index

206

occlusion, 30, 31, 45, 54, 102 open heart surgery, 5, 28, 72 organ, 3, 4, 5, 32, 43, 44, 49, 50, 51, 52, 59, 63, 68, 69, 70, 71, 72, 73, 74, 75, 79, 131, 134, 164, 167, 169, 170, 172, 176, 181, 189, 190 overproduction, 176 ox, 3, 4, 40, 61, 75 oxygen, xv, 1, 2, 10, 33, 34, 35, 36, 42, 43, 44, 52, 59, 60, 63, 65, 66, 67, 68, 71, 74, 75, 105, 106, 107, 108, 146, 166, 190 oxygen consumption, 36, 52, 63, 66, 67, 105, 106

P pandemic, vi, viii, xiv, xvi, 10, 117, 118, 119, 124, 125, 126, 127, 128, 130, 133, 134, 148, 151, 152, 153, 154, 156, 158, 159, 164, 165, 167, 168, 169, 171, 173, 175, 177, 178, 184, 185, 186, 188, 196, 198 pathophysiology, 65, 80, 103, 108, 188 patient care, 48, 71, 120 patient selection, 44, 45, 46, 76, 80, 132, 133, 156, 170, 182 perfusion, 1, 3, 4, 5, 7, 14, 32, 41, 46, 49, 52, 58, 59, 63, 64, 68, 69, 70, 71, 74, 77, 78, 87, 110, 119, 132 peripheral vascular disease, 51, 172 permission, iv, 39, 47, 53, 54, 57, 60, 62, 67 permit, 2, 4, 31, 63, 71, 77, 119 physiology, xvi, 2, 52, 59, 64, 65, 66, 75, 102, 108 pneumonia, x, xv, 129, 130, 148, 151, 152, 154, 167, 183, 184, 185 polymethylpentene, 17, 18, 181 polypropylene, 37, 181 population, 78, 83, 145, 153, 154, 158, 176, 194

principles, 20, 55, 65, 78, 79, 84, 165, 179, 195 procedures, 21, 74, 81, 120, 122, 124, 125, 126, 128, 147, 189 prognosis, 48, 51, 112, 125, 168, 174, 177 psychosocial stress, 123 public health, 118, 129 pulmonary artery, 33, 40, 45, 105 pulmonary artery pressure, 33 pulmonary capillary wedge pressure, 44 pulmonary edema, 58, 63 pulmonary embolism, 44, 72, 94, 113, 114, 174 pulmonary hypertension, xv, xvi, 74 pumps, 6, 9, 28, 29, 30, 31, 33, 34, 83, 84, 134, 180

R recommendations, iv, xi, 42, 45, 108, 125, 154, 156, 164, 168, 175, 176, 179 recovery, xvi, xvii, 32, 40, 41, 42, 43, 44, 46, 48, 49, 50, 63, 72, 73, 74, 85, 127, 131, 145, 189, 190, 191, 192, 193, 194 redundancy, 119, 120 regionalization, 121, 122 rehabilitation, xvi, 51, 172, 193, 194 renal replacement therapy, 77, 155, 176, 177, 185 requirement, 44, 134, 136, 165, 172, 190 requirements, 17, 35, 88, 149, 158 resistance, 36, 38, 39, 41, 54, 55, 56, 64 resource allocation, 156 resource utilization, 112 resources, 117, 118, 119, 121, 122, 123, 127, 132, 134, 147, 156, 157, 167, 168, 176, 179, 182 respiration, 1, 32, 36 respiratory acidosis, 177 respiratory failure, viii, xiv, xv, xvii, 9, 10, 15, 18, 19, 22, 50, 68, 87, 88, 90, 125,

Index 133, 151, 153, 160, 161, 165, 166, 167, 169, 172, 174, 177, 183, 187, 188, 189, 190, 191, 192, 193, 194, 195, 197 respiratory function, 72, 145 respiratory therapist, 156 response, 64, 76, 78, 80, 89, 104, 119, 134, 158, 176, 177 restrictions, 117, 119, 121, 127 risk, 30, 40, 52, 63, 72, 74, 75, 111, 113, 118, 123, 124, 125, 126, 145, 147, 149, 157, 165, 167, 173, 174, 175, 176, 178, 179, 181, 184, 189 risk factors, 111, 184 risk management, 124 risks, 30, 75, 76, 123, 124, 126, 179, 181, 189

207

superior vena cava, 40, 141, 142 supply chain, 119, 120, 125 surface area, 7, 34, 65 surveillance, 171 survival, viii, xvi, 9, 10, 41, 44, 46, 47, 50, 51, 64, 72, 76, 77, 85, 90, 93, 98, 99, 104, 107, 111, 112, 116, 124, 125, 127, 128, 153, 154, 155, 156, 157, 159, 161, 164, 165, 170, 174 survival rate, 76, 155, 157 survivors, 96, 114, 178 syndrome, 15, 75, 85, 87, 134, 152, 153, 159, 167, 176, 183, 186 systolic blood pressure, 44, 55 systolic pressure, 53, 54, 55, 56, 58, 60

T S saturation, xiv, 33, 43, 66, 67, 146, 170 schema, 121, 122, 124 science, vii, 73, 177 scope, 3, 5, 14, 87, 178, 180 secondary damage, 134 sepsis, 68, 108, 177, 178 septic shock, xiii, xv, xvi, 45, 100, 107, 108, 113, 134, 176 sequential organ failure assessment (SOFA), 157, 160, 176 services, iv, 46, 117, 118, 119, 121, 123, 127, 128, 148 severe acute respiratory syndrome, 152, 164, 167, 184, 187 shock, 9, 15, 26, 43, 44, 49, 58, 60, 68, 70, 84, 87, 93, 103, 107, 116, 123, 134, 157 shortage, 164, 165, 168 signs, 33, 43, 73, 75, 76, 173, 178, 185 simulation, 120, 122 stress, 30, 52, 56, 66, 69, 119, 123, 144, 164 stroke, 53, 54, 56, 57, 60, 62, 155, 172 stroke volume, 53, 54, 56, 57, 60, 62

target, 29, 42, 68, 70, 71, 178 team members, 119, 123 teams, 46, 156, 168, 179 techniques, 4, 6, 21, 40, 82, 133, 174 technological advances, 28, 30 technology, 2, 4, 8, 9, 16, 38, 66, 88, 167 textbook, vii, xvii, 2, 8, 26, 30, 40, 74 therapeutic interventions, 48, 49, 63 therapy, 6, 9, 10, 20, 43, 44, 46, 48, 49, 50, 77, 79, 91, 100, 103, 107, 108, 145, 151, 152, 153, 157, 158, 167, 172, 173, 181, 182, 189, 190, 192 thrombocytopenia, 41, 51, 75, 166, 178, 179, 193 thromboelastography, 149, 178 thrombosis, 33, 72, 73, 75, 145, 149 thrombus, 36, 63, 75 tracheostomy, xvi, 190, 193 transplant, xv, xvi, xvii, 45, 48, 49, 50, 51, 77, 94, 95, 112, 121, 189, 191, 192, 194, 195 transplant recipients, 194

Index

208

transplantation, 42, 44, 45, 49, 50, 51, 71, 72, 77, 85, 95, 111, 188, 189, 190, 191, 192, 193, 194, 195 transthoracic echocardiography, 108 trauma, 6, 37, 84 treatment, vii, viii, 101, 107, 108, 110, 112, 116, 123, 144, 147, 149, 151, 153, 154, 157, 164, 165, 181, 188, 190 trial, xvii, 9, 10, 18, 20, 48, 73, 77, 91, 104, 107, 110, 124, 154, 155, 158, 166, 169, 183

U ultrasound, 33, 40, 139, 174 United States, viii, 8, 18, 21, 30, 38, 82, 155, 173 upper respiratory infection, xv

V valve, 32, 53, 73, 108

variables, 55, 56, 57, 77, 108 vein, 41, 75, 136, 137, 139, 140, 142, 143 ventilation, xiv, 20, 35, 48, 64, 133, 153, 154, 165, 166, 169, 172, 177 ventricle, 32, 58, 59 ventricular fibrillation, 47, 99, 191 ventricular tachycardia, 47, 114 victims, 118, 123, 189 viral myocarditis, 125

W workers, 123, 124, 179 working conditions, 124 World Health Organization, viii, x, 118, 128, 151, 152, 154, 158, 159 worldwide, viii, 6, 151, 152, 153, 164, 167, 173, 188 Wuhan, viii, x, 124, 129, 130, 148, 152, 158, 168, 183, 184, 185