The History of Extra Corporeal Membrane Oxygenation ECMO From Start

MEDICAL PROCEDURES, TESTING AND TECHNOLOGY
THE HISTORY OF EXTRA-

CORPOREAL MEMBRANE
OXYGENATION (ECMO)
FROM START TO COVID
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MEDICAL PROCEDURES,
TESTING AND TECHNOLOGY
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MEDICAL PROCEDURES, TESTING AND TECHNOLOGY
THE HISTORY OF EXTRA-

CORPOREAL MEMBRANE
OXYGENATION (ECMO)
FROM START TO COVID
MICHAEL S. FIRSTENBERG
EDITOR
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CONTENTS
Preface The Practice and Principles of

Extra-Corporeal Membrane Oxygenation
(ECMO) – Volume 3 vii
Jeffrey Phillip Jacobs and Eric Yates Pruitt
Introduction The History of Extra-Corporeal Membrane
Oxygenation From Start to COVID xiii
Ahmed S. Said and Kenneth E. Remy
Chapter 1 The Genesis and Evolution of Extracorporeal
Membrane Oxygenation 1
Benjamin Smood, Asad A. Usman, Mark Helmers,
Christian Bermudez and
Rita Carrie Karianna Milewski
Chapter 2 An Introduction to VA-ECMO: Physiology,
Indications, and Principles of Management 25
Benjamin Smood, Matthew Woods,
Jason J. Han, Christian Bermudez
and Rita Carrie Karianna Milewski
vi Contents
Chapter 3 Disaster Preparedness for ECMO Programs and

Adapting ECMO Programs
to Face the COVID19 Pandemic 117
Allison Ferreira and Kim Delacruz
Chapter 4 Special Considerations for ECMO Cannulation
and Decannulation for COVID-19 Patient 131
Joseph Dovidio and Hitoshi Hirose
Chapter 5 The Use of ECMO for Treatment of Severe ARDS
Due to Coronavirus Disease 2019 151
Olivia Giddings and Rana Hejal
Chapter 6 Frontline Experience with Extracorporeal Life
Support for COVID-19 Patients 163
Vitali Karaliou, Jennifer Hanna,
Matthew N. Libby, Courtney Petersen,
William M Novick and Michael S. Firstenberg
Chapter 7 Extracorporeal Membrane Oxygenation (ECMO)
in COVID-19: The Role of Lung Transplantation 187
Asishana Osho, Jerome Crowley,
Philip J Spencer, Masaki Funamoto,
Nathaniel Langer and Mauricio Villavicencio
About the Editor 199
Index 201
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 Extra-
Corporeal 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-
viii Jeffrey Phillip Jacobs and Eric Yates Pruitt
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
Preface ix
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] Coronavirus COVID-19 Global Cases by the Center for Systems

Science and Engineering (CSSE) [https://coronavirus.jhu.edu/map.
html]. Accessed October 4, 2020.
[2] 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.
[3] 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:S0003-
4975(20)31152-8. doi: 10.1016/j.athoracsur.2020.07.002. Epub
ahead of print. PMID: 32687823; PMCID: PMC7366119.
x Jeffrey Phillip Jacobs and Eric Yates Pruitt
[4] 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:S0140-
6736(20)32008-0. doi: 10.1016/S0140-6736(20)32008-0. Epub
ahead of print. PMID: 32987008; PMCID: PMC7518880.
[5] 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. Multi-
institutional 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.
[6] 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: S2213-
2600(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.
[7] Henry BM. COVID-19, ECMO, and lymphopenia: a word of
caution. Lancet Respir Med. 2020 Apr;8(4):e24. doi: 10.1016/S2213-
2600(20)30119-3. Epub 2020 Mar 13. PMID: 32178774.
[8] 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/default-
source/coronaviruse/clinical-management-of-novel-cov.pdf].
Accessed April 7, 2020.
[9] Interim Clinical Guidance for Management of Patients with
Confirmed Coronavirus Disease (COVID-19). [https://www.cdc.gov/
Preface xi
coronavirus/2019-ncov/hcp/clinical-guidance-management-
patients.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: kremy@wustl.edu.
xiv Ahmed S. Said and Kenneth E. Remy
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
Introduction xv
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.
xvi Ahmed S. Said and Kenneth E. Remy
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
Introduction xvii
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] 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.
[2] 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: Rita.Milewski@pennmedicine.upenn.edu.

*
2 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 half-
millennium. 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].
The Genesis and Evolution … 3
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, 12-
15]. 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.
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 closed-
circuit 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
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
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].
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 first-
generation 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
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
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].
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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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: Rita.Milewski@pennmedicine.upenn.edu.

26 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 VA-
ECMO 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].
An Introduction to VA-ECMO 27
Table 1. Common etiologic indications for VA-ECMO
Etiology/Indications for Estimated Highest Quality Sources

VA-ECMO Ranges of of Evidence
Mortality (%)
Myocardial Infarction 30-75 Cohort studies [3, 102, 134, 214]
(prospective)
Post-Cardiotomy 25-75 Cohort studies [215-218]
Cardiogenic Shock (prospective)
Primary Graft Dysfunction 15-75 Cohort studies [104-106, 219-222]
after Heart Transplant (prospective)
Bridge to Left Ventricular 0-50 Cohort studies [115, 116, 118, 223-
Assist Device and/or (retrospective) 225]
Transplant
Fulminant Myocarditis 20-50 Cohort studies [107, 136, 205, 226-
(retrospective) 232]
Septic Myocarditis 40-85 Cohort studies [110, 142, 233]
(retrospective)
Pulmonary Embolism or 30-100 Cohort studies [108, 109, 205, 234-
Pulmonary Hypertension (retrospective) 239]
with Right Ventricular
Failure
Refractory Arrhythmias 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, 245-
matched) 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 VA-
ECMO. 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
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.
Table 2. Similarities and differences in VA-ECMO and

cardiopulmonary bypass
Characteristics VA-ECMO Cardiopulmonary

Bypass
Environment for Operating room, intensive care unit, Operating room
cannulation emergency department, bedside, other
Patient sedation General or local anesthesia General anesthesia
Duration of support Short-term or long-term (hours or Short term (minutes to
days to weeks) hours)
Priming volume Small Large
Hemodilution Yes (to a lesser degree) Yes
Reservoir No Yes
Pump Centrifugal Centrifugal or roller
Oxygenator Short or long-term use Short-term use
Air-blood interface No (closed circuit) Yes (some closed circuits
exist)
Arterial filter No Yes
Cooling possibility Limited Yes (routine hypothermia)
Initial Heparin bolus Low dose (50-100 u/kg) High dose (300-400 u/kg)
Activated clotting time 180-200s >480s
(ACT)
Anticoagulation reversal No Protamine administration
Autotransfusion No Yes
Pulsatility Variable, target pulse pressure >10 Non-pulsatile
mmHg to promote ejection
Adapted and modified from references [10-13].
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
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
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.
Table 3. Recommendations for patient and circuit monitoring

on VA-ECMO
Monitoring Surrogates Target Values and/or Specific Parameters for

Evaluation
Hemodynamics and Gas Exchange
Volume CVP <5-10 mmHg
Status/Preload PAPsystolic <50 mmHg
PAPmean <25 mmHg
PCWP <15 mmHg
Systemic Perfusion Cardiac Index 2.2-2.8 L/min/m2
Oxygen extraction ScvO2 >70%
SvO2 >65%
Mean arterial pressure 50-90 mmHg
Pulse pressure >10 mmHg
Gas Exchange and Radial blood gas (right PaO2 100-150 mmHg
Ventilation radial) PaCO2 35-45 mmHg
Pulse oximetry or NIRS SaO2 >90%
Laboratory Values
Anemia/hemorrhage Hemoglobin >8.0 mg/dL
Anticoagulation Activated clotting time 180-200
End-organ perfusion, pH 7.35-7.45
function, and aerobic Lactate <2.0 mmol/L
respiration Urine output >0.5 ml/kg/hr
Venous congestion Liver enzymes AST 5-40 U/L
ALT 5-40 U/L
Hemolysis LDH <250 U/L
Indirect bilirubin <1 mg/dL
Plasma free hemoglobin <50 mg/dL
Reticulocytes 0.5-2.5%
Heparin-Induced Platelet count 150-400 x109/L
Thrombocytopenia
Hyperfibrinolysis D-dimer <0.5 mg/dL
Fibrinogen 200-400 mg/dL
Imaging
Chest X-Ray ECMO Circuit Cannula positioning
Cardiopulmonary Pneumothorax
function Pulmonary edema
Echocardiography Right ventricle Septum position
function/volume status TAPSE
Left ventricle Ejection fraction
function/recovery Aortic regurgitation
Distension
Aortic valve opening and closing
Monitoring Surrogates Target Values and/or Specific Parameters for

Evaluation
Imaging
Stasis/thrombosis
Pericardial effusion
Neurologic Status
Neurologic Status Neurologic status Spontaneous movements
Following commands
Herniation Pupils symmetric and reactive
Cerebral oxygenation NIRS
Arterial blood gas (right radial)
Sedation RASS
BIS
Paralysis Train of Four
ECMO Circuit
ECMO Circuit Tubing Chattering/chugging
Cracks in tubing/leaks
Cannulas Bleeding, signs of infection
Thrombus formation
Oxygenator FiO2
Sweep gas flow rate
Pre- and post- oxygenator blood gases
Thrombus formation
Pump RPM <5000
Flow rate
Inlet (venous) pressure (maximum -300 mmHg)
Outlet (arterial) pressure (maximum 400
mmHg)
Ischemia of the Tension
cannulated leg Leg circumference
NIRS on lower legs
Warmth
Doppler pulses
ALT = alanine transaminase, AST = aspartate aminotransferase, BIS = bispectral index, CI = cardiac
index (calculated by Fick formula or continuous cardiac output catheter), CVP = central venous
pressure, FiO2 = fraction of inspired oxygen, NIRS = near-infrared spectroscopy, PAP =
pulmonary artery pressure, PaCO2 = partial pressure of carbon dioxide, PaO2 = partial pressure of
oxygen, RASS = Richmond Agitation-Sedation Score, RPM = revolutions per minute, ScvO2 =
central venous oxygen saturation, SvO2 = venous oxygen saturation, TAPSE = tricuspid annular
plane systolic excursion. Adapted and modified from references [5, 52-54].
In order to avoid circuit leaks or blowout of components, modern

pumps are typically designed such that outflow pressures cannot exceed
400mmHg [17]. Pump flow rates are often monitored by ultrasound
detectors and displayed on the ECMO console, with circuit components

selected to provide full blood flow support (4-5L/min (typically
60cc/kg/min, maximum rate 10L/min) [17, 55]. It is important for
providers to monitor the set revolutions per minute (RPM), with maximal
rates not exceeding 4000 to 5000 RPM (Table 3) [29, 51, 55]. That is, if
there are acute, large elevations in RPM without associated changes in
flow, this should signal to the provider that the pump is working harder and
less efficiently, and potential causes should be sought [29].
Rarely, pumps may fail, and circuits should be equipped with an alarm
that will sound if there is electrical power failure. Modern circuits should
be equipped with a battery powered system that can sustain ECMO
functions for 30-60 minutes in the event of catastrophic electrical power
failure. In addition, all ECMO circuits should be equipped with a manual
hand crank that is capable of restoring forward flow until the mechanical
pump can be exchanged [17].
OXYGENATORS AND GAS EXCHANGE
Membrane Oxygenators
By definition, ECMO requires a mechanism for extracorporeal gas

exchange that is capable of mimicking native lung function. In most
contemporary ECMO circuits, this occurs within a nonporous hollow fiber
membrane oxygenator, which is usually equipped with integrated heat
exchanger device to allow for precise control of body temperature [29, 38].
Current membrane oxygenators have been meticulously designed to
improve their durability for prolonged durations of support, with optimized
parameters of membrane semipermeability, surface area, and blood flow
paths to allow for ideal gas exchange. These properties help to grade
oxygenators in terms of their ‘rated flow’ and/or ‘maximal oxygen
delivery’ [17]. The rated flow is the rate at which venous blood will be
fully saturated with oxygen as it leaves the oxygenator, whereas maximal
delivery defines how much oxygen can be delivered when running at the
rated flow [17]. Just as the circuit’s pump should be able to provide full
hemodynamic support, the membrane oxygenators selected for a VA-
ECMO circuit should, at a minimum, be able to meet the physiological
requirements for normal oxygen delivery and carbon dioxide removal (i.e.,
typically 3mL O2/kg/min) [17]. In most cases, the initial ratio for gas flows
to blood flow is set at 1:1, and then titrated to reach a targeted partial
pressure of carbon dioxide (PCO2) [17]. As such, one must understand the
parameters that can be adjusted to titrate gas exchange.
Oxygen Delivery and Sweep Gas Flows
To simplify its conceptualization, gas exchange occurring within a

membrane oxygenator is largely determined by diffusion gradients that are
established by the partial pressures of oxygen (PaO2) and PaCO2 arriving
in venous blood and the fresh gas supplied by the ECMO circuit (often
referred to as ‘sweep gas flow’). The oxygen delivered to the membrane
lung is influenced by a flowmeter regulating both sweep gas flow rates
(L/min) and a gas blender that regulates the fraction of oxygen delivered
(FiO2) [10, 50]. Both the sweep flow rate and FiO2 can be augmented by
the provider to titrate oxygenation and carbon dioxide removal to goal
parameters (Table 3) [50].
By increasing the sweep flow rate, gas delivered through the
membrane oxygenator is rapidly replaced by fresh air containing a low
concentration of carbon dioxide. As a result, the gradient for carbon
dioxide diffusion increases across the semipermeable membrane at
increasing sweep flow rates, which facilitates further carbon dioxide
elimination from the blood [50]. In many respects, sweep flow rate is
analogous to minute ventilation, and augmentation predominantly affects
carbon dioxide exchange rather than oxygenation [10, 50]. This is largely a
consequence of the high solubility of carbon dioxide, which reaches
diffusion equilibrium across the membrane almost instantaneously as fresh
air is delivered. In contrast, FiO2 prevails in regulating oxygenation, but
has a minimal effect on carbon dioxide extraction [56]. Of course, other
factors influence gas exchange, including the rate of blood flow within the
ECMO circuit, fluid viscosity, pH, and temperature [44, 54, 57]. Similarly,
net gas exchange also depends on the patient’s respiration with or without
mechanical ventilation [47, 58]. Although each of these factors must be
considered when evaluating blood gases and titrating gas exchange on VA-
ECMO, the relationships between sweep gas flow rates and FiO2 remain
fundamental to patient management.
Monitoring and Titrating Gas Exchange
Frequent blood gases should be taken from pre- and post-oxygenator

sources in order to evaluate the membrane lung’s efficacy [17]. Pre-
oxygenator blood gases can provide important information regarding
oxygen consumption and extraction, whereas post-oxygenator blood gases
help to quantify the gas contents of arterial blood being delivered to the
patient by the ECMO circuit. Rapid or gradual changes in pre- and post-
oxygenator blood gases should prompt investigation into potential causes
of membrane malfunction. Similarly, pre-, post-, and transmembrane
pressures should be monitored closely, as dynamic changes can indicate
important physiologic or pathologic conditions. Normal transmembrane
pressure gradients should not exceed 50mmHg (Table 3), and these values
are displayed on some modern ECMO consoles [29, 59].
Systemic hypertension, volume overload, kinking, and/or thrombus
formation within the arterial cannula may increase circuit resistance and
cause reciprocal elevations in pre- and post-oxygenator pressures without
affecting the transmembrane pressure gradient [43]. Meanwhile, acute rises
in the transmembrane gradients suggest that the oxygenator’s internal
resistance has been significantly increased, which is most commonly due
to thrombus formation on the oxygenator’s membrane. Providers should
routinely inspect the circuit for evidence of thrombi, which can be
accomplished with the simple use of a flashlight to inspect the oxygenator
and circuit tubing for dark, immobile areas signifying clot formation
(Table 3) [17]. Whereas pre-oxygenator clots are typically of little concern,
post-oxygenator clots should be taken very seriously and may warrant an

oxygenator or circuit exchange, as these can embolize with devastating
effects.
The Evolution of Polymethyl Pentene and Nonporous Hollow

Fiber Membrane Oxygenators
Of important note, the early bubble and film oxygenators that

revolutionized the field of cardiac surgery were limited in their duration of
use, in large part due to the trauma associated with direct blood-gas contact
at the mixing interphase. As such, their application to prolonged
mechanical circulatory support were limited, but served as important
blueprints for the evolution of oxygenators that were capable of sustaining
prolonged extracorporeal cardiopulmonary support [60-62]. Important
milestones needed to bring ECMO to clinical practice for use as prolonged
mechanical circulatory support were realized throughout the 1960s and
1970s as targeted efforts sought to develop novel membrane oxygenators
that could both minimize traumatic damage to circulating blood and
maximize gas exchange with sufficient durability for prolonged
mechanical support [60, 62].
Silicone membrane oxygenators showed early promise for ECMO and
were even used in the first successful clinical applications [60, 63, 64].
However, there were significant limitations in durability and
manufacturing [62, 65]. As a result, alternative materials and designs were
developed, including microporous polypropylene membrane oxygenators
[44, 65]. By the 1980s, novel microporous hollow fiber membrane
oxygenators would almost entirely replace the first-generation oxygenators
that had been previously used in cardiac surgery operating rooms
throughout the country [60, 62, 66-68]. However, despite their tremendous
success in cardiopulmonary bypass, early microporous hollow fiber
membranes were plagued by their own shortcomings, including excessive
cytoplasm leakage that was incompatible with prolonged mechanical
circulatory support [44, 65]. As such, an ideal membrane that could
support prolonged ECMO remained elusive. Perhaps surprisingly, over the

next several decades, there were relatively few changes to basic ECMO
equipment and technology, such that in 2000, it is estimated that roughly
75% of adult ECMO runs continued to be carried out using silicone
oxygenators [60, 62, 65].
However, in the early 2000s, there was a surge in membrane
oxygenator innovation [21-24, 60, 62, 65, 69-71]. Specifically, the advent
of polymethyl pentene (PMP) and nonporous hollow fiber membrane
oxygenators revolutionized the field of ECMO. Their design mitigated the
adverse consequences of direct contact blood-gas exchange and cytoplasm
leakage that was characteristic of early silicone and microporous
membrane oxygenators [13, 60, 62, 65, 69, 70, 72]. These durable
membranes optimized parameters for gas exchange and biocompatibility,
including flow resistance and membrane permeability, and oxygenator
durability, and the demonstrated improved safety and efficacy throughout
the 2000s [13, 17, 20 24, 38, 44, 60, 62, 69, 70, 72, 73]. PMP and
nonporous membranes are largely responsible for the increased simplicity,
safety and efficacy of modern ECMO circuits, and perhaps no other
innovation in the past two decades has been as integral to the modern
application and success of prolonged mechanical circulatory support with
ECMO [60, 62, 73].
These revolutionary membrane oxygenators are manufactured by
weaving PMP into long, nonporous hollow fibers that are assembled into
fine sheets and stacked one on top of another. This design allows for the
separation of blood and sweep gas flows in order to optimize gas exchange
with minimal hematologic [29, 59, 74-77]. As Figure 1 demonstrates, in
nonporous membrane oxygenators, blood flows between and around the
hollow fibers, while gas flow is delivered through the hollow fibers and
can diffuse across the membrane in the absence of microporosities [39, 44,
76, 77]. To illustrate the influence of this revolutionary technology, in
2008 more than 65% of ECMO centers still used silicone oxygenators [78].
In contrast, it is now estimated that 95% of ECMO centers in the United
States prefer to use PMP membrane oxygenators [38, 44, 61, 73]. As such,
there are a number of commercially available PMP, nonporous hollow
fiber membranes, including the Maquet Quadrox D (Maquet, Hirrlingen,

Germany) and NovaLung (Xenios, Helibronn, Germany) [39].
Figure 1. A simplified schematic for blood oxygenation in nonporous and microporous

membrane oxygenators. Figure reproduced with permission from reference [76].
OTHER CIRCUIT COMPONENTS AND

VA-ECMO CANNULATION
Priming the Circuit and Storage of the ECMO Circuit
The ECMO circuit is primed under sterile conditions with an isotonic

electrolyte solution and typically stored for several days (but no more than
30 days) prior to use; however, it may be primed at the time of use [17, 29,
79]. Common internal diameters of circuit tubing are 3/16,” 1/4,” 3/8,” and
1/2.” The tubing length and width determine resistance to flow throughout
the circuit, such that wider tubing allows for higher flows at any given
pressure, but simultaneously increases the priming volume and therefore

hemodilution of the patient as ECMO support is initiated [17].
Cannulation Strategies and Cannula Selection
Although there are a number of cannulation strategies for VA-ECMO,

in the setting of acute hemodynamic collapse, peripheral (femoral) vessel
cannulation is often the easiest and most expeditious vascular access [1, 5,
80, 81]. However, providers who will be initiating VA-ECMO should be
familiar with alternative techniques, as circumstances arise in which
peripheral vessels cannot be cannulated (i.e., tortuous vessels, morbid
obesity, etc.), or when cannulation strategies may need to be switched
during the course of management [1, 17, 80, 81]. For example, in cases of
simultaneous pulmonary failure on VA-ECMO, an intricate cannulation
strategy employing so-called venoarterial-venous-ECMO (VAV-ECMO)
might need to be instituted. VAV-ECMO consists of a triple cannulation
configuration that allows for venous inflow (inferior vena cava) drainage,
as well as both arterial and venous outflow cannulation (superior vena cava
or pulmonary artery, depending on right ventricular function). This allows
pre-oxygenated blood to return to the lungs and ultimately the heart to
ensure that blood ejected from the heart is sufficiently oxygenated,
particularly during lung protective mechanical ventilation [1, 82]. This
strategy has proven successful in circumstances in which both body
oxygenation and lung recovery are needed, although further prospective
studies are warranted [1, 83-85]. Because an entire chapter in this textbook
is devoted to cannulation techniques, alternative methods will not be
further discussed, and the remainder of this chapter will infer the use of
peripheral (i.e., femoral) VA-ECMO unless otherwise indicated.
To access the femoral vessels for peripheral cannulation, it is
preferable to obtain percutaneous access with a Seldinger technique,
although operators can cut down to the vessels for exposure or utilize a
combination of these techniques [17]. With percutaneous cannulation, all
operators should routinely use ultrasound guidance to reduce the risk of
complications. In selecting which vessels to cannulate, the left common

femoral artery and right femoral vein are preferred, particularly because
the venous cannula will have a more direct route to the inferior vena cava
without having to cross midline. Once confirmation of venous and femoral
access is obtained and controlled with a wire, a heparin bolus should be
administered at 50-100U/kg (or empirically 5,000-10,000U) prior to
proceeding with dilation and cannulation, although alternative
anticoagulation strategies may be necessary if the patient has a history of
heparin-induced thrombocytopenia or other concerns regarding
anticoagulation [16, 17, 86].
After heparinization, cannulas can similarly be inserted using a
Seldinger technique with gradual dilation. The wire should be checked
after insertion of each dilator to ensure that it moves without resistance in
order to identify kinks or bends. It is imperative that meticulous attention is
given to wire placement and vessel dilation to avoid catastrophic vascular
injury [17]. Likewise, cannulation should be performed by an experienced
provider to avoid vascular injury.
Selection criteria for venous and arterial cannulas in VA-ECMO varies
depending on the institution. Blood flow resistance is directly proportional
to the length of the cannula and inversely proportional to the radius of the
cannula to the fourth power, therefore, the internal diameter of these
cannulas is by far the most important determinant of maximal blood flow
[17]. As mentioned above, some advocate that the ECMO circuit should be
capable of supporting total cardiopulmonary bypass at its maximal flow in
the event that complete hemodynamic support is needed. However, there is
evidence that the rates of survival and successful recovery are similar
among patients receiving only partial flow support, such that smaller
cannulas may be used with the potential benefit of minimizing
complications [2, 87-90]. In most circumstances, a 15-17F arterial cannula
alongside a 23F or 25F venous cannula are adequate for small females or
large males, respectively. Some centers will routinely place a superficial
femoral artery cannula in the arterial limb to ensure perfusion to the distal
limb, though this may not be necessary if there is adequate monitoring of
perfusion and blood flow.
With the venous and arterial cannulas in place, the ECMO circuit can
be completed by connecting the cannulas to the circuit tubing, ensuring
that no air enters the circuit. Prior to initiating bypass, the activating
clotting time (ACT) should be >300, and the water bath of the ECMO
circuit should be initiated to allow for heat exchange [17, 43]. Once flow is
established, it is imperative to visually inspect the circuit to make certain
that dark, venous blood is being removed from the venous cannula, and
that oxygen is flowing to the oxygenator with red, arterial blood being
returned to the patient. A heparin infusion can be started with a target ACT
of 180 to 200s (Table 3).
INDICATIONS AND CONTRAINDICATIONS
The simplest guidelines for ECMO in adult cardiac failure are defined
by ELSO, merely stating that the “indication for ECMO in adult cardiac
failure is cardiogenic shock” [14, 53]. The American College of
Cardiology Foundation/American Heart Association Guidelines provide
Class IIa recommendations, stating that mechanical circulatory support is
beneficial in carefully selected patients with stage D heart failure in whom
cardiac recovery or definitive management (e.g., transplantation) is
anticipated or planned. In such cases, nondurable mechanical circulatory
support is reasonable as a bridge to recovery or decision in carefully
selected patients with acute, profound hemodynamic compromise [91].
Importantly, these guidelines do not specify the use of VA-ECMO as the
method of choice for mechanical circulatory support. Rather, definitive
guidelines for the use of VA-ECMO are only provided in the setting of
cardiac arrest when VA-ECMO is used as extracorporeal cardiopulmonary
resuscitation (ECPR) [92, 93]. Underscoring that there is insufficient
evidence to support the routine use of ECPR, these guidelines state that
extracorporeal cardiopulmonary resuscitation (ECPR) may be considered
(Class IIb recommendation) in select patients for whom there is a
potentially reversible etiology of cardiac arrest and in whom a limited
period of mechanical circulatory support is expected [4, 92-95].
Despite the lack of clarity in consensus guidelines, there are a number

of generally accepted and evolving indications for VA-ECMO, as provided
in Table 4 [9, 53, 54, 96]. These indications can broadly be grouped into
two classes: VA-ECMO for refractory cardiogenic shock, and
extracorporeal cardiopulmonary resuscitation (ECPR) for refractory
cardiac arrest (Table 4) [6, 9, 54]. To date, there have been nearly 25,000
and more than 8,000 ECMO runs in adult cardiac failure and ECPR,
respectively [97]. In patients with either cardiogenic shock refractory to
conventional therapies or cardiac arrest, the primary goal in the setting of
profound hemodynamic compromise is to provide immediate
cardiopulmonary stabilization and prevent end-organ damage, while
providing adequate cardiac unloading to minimize further injury and
promote recovery [94].
Table 4. General indications for VA-ECMO in cardiogenic shock

and inclusion criteria for Extracorporeal Cardiopulmonary
Resuscitation (ECPR)
Indications for VA-ECMO in Cardiogenic Shock

Cardiac index<2.0 (despite high-dose inotropes, vasopressors)
Systolic blood pressure <90 mmHg
Decrease in mean arterial pressure by >30 mmHg for >30 minutes
Central venous oxygen saturation <65%
Clinical/laboratory signs of persistent or progressive malperfusion (rising creatinine, hepatic
enzymes, hyperlactatemia >5.5 mmol/L)
Failed intra-aortic balloon pump
Inclusion Criteria for ECPR
Age ≤ 70 years
Acute and likely reversible pathology
Witnessed arrest
No flow cardiac arrest <5 minutes (or bystander cardiopulmonary resuscitation within 5 minutes)
Cardiac arrest without ROSC within 10-20 minutes of professional CPR
Cardiac arrest with <60 minutes of resuscitation with high quality CPR
End-tidal CO2 >10 mmHg after 20 minutes of cardiopulmonary resuscitation
VA-ECMO should be considered in patients with cardiogenic shock refractory to conventional and
optimized medical therapy. For patients being considered for ECPR, all inclusion criteria should
be met, when clinically available. CPR = cardiopulmonary resuscitation, ROSC = return of
spontaneous circulation. Adapted and modified from references [6, 9, 54].
Indications for VA-ECMO in Cardiogenic Shock
ELSO identifies common etiologies of cardiogenic shock that may

warrant VA-ECMO, such as acute myocardial infarction, myocarditis,
peripartum cardiomyopathy, decompensated chronic heart failure, and
post-cardiotomy shock, although others certainly exist (Table 1) [9, 17, 54,
96]. Clinical manifestations include diminished cardiac output with end-
organ hypoperfusion refractory to volume resuscitation, the requirement of
two inotropes or vasopressors, and/or the assistance of an intra-aortic
balloon pump, among others [98, 99]. Quantitatively, this is demonstrated
by a persistent cardiac index <2.0 L/min/m2, systolic blood pressure
<90mmHg, and/or pulmonary capillary wedge pressure ≥24mmHg (Table
4) [6, 9, 54]. Under these conditions, myocardial demand may supersede
oxygen delivery, and a vicious circle ensues as metabolic disturbances
exacerbate one another, and the patient precipitously declines. Defined by
the Interagency Registry for Mechanically Assisted Circulatory Support
(INTERMACS) as Profile 1, VA-ECMO is indicated in the proverbial
‘crash and burn’ patient in whom definitive life-sustaining intervention is
needed within hours [5, 91, 94 100, 101].
Whatever the indication, scrutinized patient selection is important to
optimizing favorable outcomes [91]. A number of clinical scores have been
developed for patient-specific prognostication [47, 74, 94]. Nevertheless,
ECMO itself is not a cure to underlying disease. Rather, it is a platform of
support that is only indicated for hemodynamic stabilization in patients
awaiting more definitive cardiac replacement therapy (i.e., durable
ventricular assist device or transplantation), or in whom myocardial
recovery may reasonably be anticipated with or without therapeutic
intervention (i.e., percutaneous coronary intervention, pulmonary
embolectomy, etc.) [9, 91, 95].
As demonstrated in Table 1, there is evidence that VA-ECMO
improves survival in the setting of acute myocardial infarction complicated
by cardiogenic shock [3, 102], post-cardiotomy shock [9, 103], primary
graft dysfunction after cardiac transplantation [104-106], fulminant
myocarditis [107], massive pulmonary embolism [108, 109], and even
septic shock [4, 7, 8, 110, 111]. Meanwhile, only about 1% of patients will
receive VA-ECMO while awaiting heart transplantation [112-114]. Thus,
the power of current investigations is limited, which poses challenges
when attempting to draw conclusions and broadly apply the use of VA-
ECMO to other patients at the top of the heart transplant waiting list (i.e.,
Status 1). Nevertheless, some evidence suggests that VA-ECMO improves
survival in patients with cardiogenic shock awaiting high-urgency cardiac
transplantation [114-118].
Indications for VA-ECMO as Extracorporeal

Cardiopulmonary Resuscitation (ECPR)
VA-ECMO has increasingly been used in the form of ECPR in the

setting of cardiac arrest, with evidence of improved long-term neurologic
outcomes [9, 119, 120]. As described above, the American Heart
Association’s recommendations for ECPR remain the only society-
endorsed, evidence-based indication for VA-ECMO [9, 92, 93, 95].
However, these guidelines underscore the importance of proper patient
selection and emphasize that routine use of ECPR is not indicated [92, 93,
121]. ECPR should only be considered in patients who are considered to
have an easily reversible inciting event (i.e., acute coronary artery
occlusion, pulmonary artery embolism, refractory ventricular arrhythmia,
profound hypothermia, cardiac injury, myocarditis, drug intoxication, etc.)
or when ECPR can serve as a bridge to left ventricular assist device
implantation or cardiac transplantation [92, 93]. Guidelines published by
ELSO cite these recommendations and reiterate that ECPR should be
reserved for patients who have received excellent resuscitation [15]. The
importance of early and quality conventional CPR is part of established
inclusion criteria that must be met when considering ECPR (Table 4) [5, 6,
9, 54].
Mortality rates in ECPR among centers appear to be influenced by four
primary factors, including immediate and sufficient bystander CPR, time
from arrest to ECPR, a standard operating procedure for ECPR initiation,
and patient selection [5]. Because the time to basic life support CPR is the
single-most important determinant of survival after cardiac arrest [9], the
indication for ECPR, first and foremost, requires a witnessed arrest with no
more than 5 minutes of downtime (i.e., no-flow time) prior to initiation of
conventional CPR (Table 4) [6, 9, 54, 122]. In out-of-hospital arrests, some
centers require that emergency medical services arrive within 15 minutes
of witnessed arrest [123]. If these criteria are met, one must then consider
how long conventional CPR should be continued without return of
spontaneous circulation (ROSC) prior to considering and/or initiating VA-
ECMO [92].
Some data suggests that more than 75% of patients who survive
cardiac arrest with good functional outcomes achieve ROSC within 10-15
minutes of conventional CPR. Each minute of conventional CPR is
associated with increasingly poor outcomes, and beyond 15 minutes, some
evidence suggests that survival with good neurologic recovery falls to ~2%
[124]. Nevertheless, if conventional CPR does last more than 10 to 20
minutes, there appears to be a survival benefit for patients receiving ECPR
compared to conventional CPR [125, 126]. Delays in initiating ECPR are
associated with poorer outcomes [121, 127-129]. Therefore, it is
recommended that clinicians and providers consider initiating ECPR early
after cardiac arrest, rather than waiting until conventional CPR and
traditional methods of resuscitation have completely failed [9, 121, 129].
Specifically, it is recommended that providers begin the ECPR
assessment when there is a failure to achieve ROSC within 10-15 minutes
of high-quality CPR, as it takes time to initiate ECMO teams and deploy
the therapy [8, 9, 119]. Ideally, the time from witnessed arrest to
cannulation and initiation of ECPR can be achieved within 20 minutes [9,
119, 129-132]. An optimal timeline for expedient candidate assessment
and initiation of VA-ECMO is provided in Figure 2 [9].
Some evidence indicates that outcomes are improved if conventional
CPR is limited to 35 minutes [133], whereas ELSO has recommended that
it is medically futile to proceed with ECPR if conventional CPR has failed
to achieve ROSC within 30 minutes [15]. Although ECPR may be
considered in cases of prolonged CPR when good perfusion and metabolic
support are documented, outcomes are significantly worse at 60 minutes

after cardiac arrest, which is the maximal interval many centers use to
determine if patients are eligible for ECPR eligibility [9, 129, 131, 132,
134].
Figure 2. Optimal Timeline for Initiating Extracorporeal Cardiopulmonary

Resuscitation (ECPR) in Cardiac Arrest.
The time from cardiac arrest to CPR initiation (No Flow) should be a maximum of 5
minutes. Ideally, ECPR (ECLS Flow) will commence within 15 minutes of cardiac
arrest, and within 10 minutes of initiating CPR (Low Flow). However, it is reasonable
to consider ECPR within 25 minutes of cardiac arrest, and within 20 minutes of CPR.
Some guidelines suggest that after 30 minutes of CPR, ECPR should not be
considered. Meanwhile, it is generally accepted that ECPR should never be initiated
after 60 minutes of CPR. BLS = basic life support, ECLS = extracorporeal life support
(i.e., ECPR = extracorporeal cardiopulmonary resuscitation), OHCA = out-of-hospital
cardiac arrest. Figure reproduced with permission from reference [9].
When determining if ECPR is indicated, other inclusion criteria should

be met (Table 4) [6, 9, 53, 54, 96]. In an effort to reduce the incidence of
futile interventions, most centers require that patients be ≤70 years of age
to be considered for ECPR [9, 14, 123, 131, 135, 136]. Similarly, the
presence of an initial shockable rhythm (ventricular fibrillation or
ventricular tachycardia) in cardiac arrest has consistently demonstrated a
survival advantage in resuscitation compared to pulseless electrical activity
or asystole [125, 135, 137-141]. The majority of patients surviving ECMO
after cardiac arrest have an initial shockable rhythm, and its presence has
been identified as an independent predictor of survival [74, 142]. As such,
it is included in prognostic scores evaluating the potential utility of ECPR
and should be considered requisite inclusion criteria when evaluating

ECPR candidacy (Table 4) [9, 47, 94]. When additional clinical data is
available, other considerations should be made. For example, in intubated
patients in whom ECPR is being considered, an end-tidal CO2 of at least
>10 mmHg should be confirmed, as poor ventilation after 20 minutes of
convention CPR is associated with extremely poor survival [92, 93, 121,
131].
However, because ECPR is a life-sustaining therapy that is often
considered in emergent situations where relevant clinical data is obscure or
incomplete, a trial of ECPR may be initiated in an attempt to stabilize a
patient while their prognosis is assessed and/or further information is
elucidated regarding their desire for heroic measures and continued life-
support [93]. In any case, ECMO in the setting of either cardiogenic shock
or cardiac arrest is only indicated if there is a clearly delineated objective
with an anticipated means of decannulation [5, 9].
Decision Making and Defining Objective of VA-ECMO
Providers must recognize that ECMO itself is not a cure to underlying

pathologies. Rather, its use is indicated as salvage therapy to temporarily
stabilize patients as a bridge to recovery or more definitive therapies
(Table 5) [5, 9]. Among other strategies, VA-ECMO may be used as a
bridge-to-recovery (with or without additional anticipated interventions), a
bridge-to-destination therapy (i.e., a durable left ventricular assist device),
a bridge-to-transplant, or as a bridge-to-decision making regarding the next
steps in patient care [9].
If ECMO is determined to be a ‘bridge-to-recovery’, providers should
have a reasonable expectation that the patient has a reversible condition
that will recover with sufficient medical support and/or additional
therapeutic interventions [94].
Table 5. Strategic objectives to consider when determining patient

candidacy for VA-ECMO
Objective Example Indications Principles of Support Goals or

Expectations
Bridge-to- Cardiac arrest Temporary hemodynamic Decannulation with
Recovery Acute myocardial stabilization and maintenance of recovery
infarction end-organ perfusion while
Myocarditis medical management is
Post-cardiotomy shock optimized, with or without
Bridge-to- Primary graft additional therapeutic
Therapy dysfunction interventions
Pulmonary embolism
Refractory Prevent further myocardial
arrhythmias injury by decreasing preload and
work
Bridge-to- Terminal heart failure Temporary hemodynamic Transplant
Transplant complicated by stabilization and maintenance of
cardiogenic shock end-organ perfusion while
awaiting transplant
Bridge-to- Terminal heart failure Temporary hemodynamic Left ventricular assist
Destination complicated by stabilization and maintenance of device
cardiogenic shock end-organ perfusion until
definitive cardiac replacement Total artificial heart
therapy can occur (with or
Bridge-to- without intended future
Bridge transplant)
Bridge-to- Cardiac arrest Temporary hemodynamic Bridge-to-recovery
Decision stabilization and maintenance of
Stabilization for end-organ perfusion while Bridge-to-transplant
transport to tertiary evaluating reversibility of end-
facility organ damage, definitive Bridge-to-Destination
therapeutic interventions, and/or
goals of care Bridge-to-Bridge
VA-ECMO should always be considered as temporary hemodynamic support. Its use is only indicated
if a clear objective is defined. In emergent situations, it may be unclear if a patient is a candidate
for recovery, durable mechanical circulatory support, or transplantation. In such cases, VA-
ECMO may still be indicated as a ‘bridge-to-decision’ while providers determine if end-organ
damage is reversible and recovery is possible, with or without additional therapeutic interventions
or more definitive therapies. Adapted and modified from references [5, 9].
Meanwhile, ECMO as a bridge-to-destination therapy may be

considered in cases where a patient requires hemodynamic stabilization
while awaiting more durable mechanical circulatory support (i.e., a durable
ventricular assist device), with or without subsequent bridge to

transplantation (i.e., bridge-to-bridge therapy). While some patients may
already be on the waitlist for heart transplantation, others may be newly
listed after initiating VA-ECMO as a bridge-to-transplant (Table 5)
[5].However, as noted above, in emergent situations it may be unclear if a
patient is a candidate for recovery, durable mechanical circulatory support,
or transplantation. In such cases, VA-ECMO may still be indicated as a
‘bridge-to-decision’ while providers determine if end-organ damage is
reversible and recovery is possible, with or without more definitive
therapies. In one study, the median duration of VA-ECMO used as a
bridge-to-decision was eight days [117]. In this respect, although the
duration of VA-ECMO support is typically much shorter than the long-
term (i.e., >21 days) uses of VV-ECMO in respiratory failure, VA-ECMO
can prolong survival in patients being considered for more definitive
therapies [81].
Notice though, that in none of the aforementioned objectives is VA-
ECMO itself considered destination or palliative therapy. When any
provider is asked to evaluate a patient for ECMO eligibility, they must not
only assess if appropriate indications and inclusion criteria have been met,
but they must also define the objectives of ECMO. That is, when
evaluating an ECMO candidate, among the first questions asked should be,
“What will this individual be bridged to?” (Table 5). If there is not a
potential path towards ECMO weaning, decannulation, and survival,
ECMO is contraindicated.
Contraindications for ECMO
Contraindications and exclusion criteria for VA-ECMO can reasonably

be understood as reciprocals to the aforementioned indications and
requisite inclusion criteria (Table 6). However, because ECMO is a life-
saving support system, the only absolute contraindication to therapy is a
pre-existing condition that is incompatible with recovery, which ELSO
broadly defines as unrecoverable heart function in patients who are not
candidates for transplantation or a durable ventricular assist device, severe

chronic organ dysfunction or failure, and poor compliance resulting from
financial, cognitive, psychiatric, or social limitations [14]. Other clinical
scenarios in which severe underlying comorbidities are likely to be
worsened by VA-ECMO should generally be regarded as absolute
contraindications, including recent intracranial or active traumatic
hemorrhage (due to the need for systemic anticoagulation), or the presence
of aortic dissection (due to high-pressure flows) [9, 94, 143]. Of course, the
presence of a do not resuscitate order should also exclude further
consideration for VA-ECMO.
Table 6. VA-ECMO contraindications
Contraindications to VA-ECMO
Underlying conditions incompatible with life or that severely diminishes prognosis (i.e., severe
anoxic brain injury, malignancy with metastases or expected survival <3 years, chronic respiratory
disease, dialysis, cirrhosis, etc.)
Unrecoverable heart function (if not a candidate for transplant or ventricular assist device)
Severe frailty or poor preexisting functional status
Compliance barriers for rehabilitation (cognitive, psychiatric, social, etc.)
Ethical considerations (Do Not Resuscitate orders, patient’s will)
Age >70 years (except failure to wean from cardiopulmonary bypass)
Contraindications to anticoagulation (recent cerebral hemorrhage, heparin-induced
thrombocytopenia, etc.)
Technical limitations to cannulation (morbid obesity, severe peripheral vascular disease, amputated
limbs)
Moderate aortic dissection
Moderate aortic regurgitation
Unwitnessed arrest or downtime >5 minutes
Futility (lack of ROSC after 30-60 CPR; >60 minutes of conventional CPR)
Baseline lactate >15 mmol/L
Baseline pH <6.8
Because VA-ECMO is a life-saving support system, the only absolute contraindications are those that
prohibit meaningful recover. Examples include, unrecoverable heart function in patients who are
not candidates for heart transplant or left ventricular assist devices, advanced age (though cut-off
limits by center) or chronic organ dysfunction. CPR = cardiopulmonary resuscitation, ROSC =
return of spontaneous circulation. Adapted and modified from references [5, 6, 17, 50, 54].
However, most other contraindications are only relative, which ELSO

describes as conditions that would be incompatible with normal life if a
patient recovers, pre-existing conditions affecting quality of life (poor

neurologic status, end-stage malignancy), or other conditions where VA-
ECMO would prove futile (i.e., patients with a very poor or fatal primary
diagnosis) [5, 17]. Other predictors of mortality may still be considered as
relative, rather than absolute, contraindications [5, 6, 9, 17, 50, 54]. For
example, at many centers, moderate or worse aortic insufficiency is near
absolute contraindication, as it typically worsens on VA-ECMO due to the
high-pressure, retrograde flow. Importantly, this increases ventricular wall
stress, myocardial injury, and minimizes the likelihood of successful
decannulation [5]. However, progressive insufficiency can be minimized or
eliminated with the use of a venting strategy [144-146]. Even severe
coagulopathy and the risk of systemic bleeding is only a relative
contraindication, as some centers will employ VA-ECMO entirely without
anticoagulation, or with alternative antithrombin agents if there is a
contraindication to unfractionated heparin [5, 9, 41, 147, 148]. Meanwhile,
severely limited vascular access (peripheral artery disease, amputated
limbs, and even morbid obesity) may pose challenges to successful
cannulation, though alternative access or central cannulation strategies may
still be utilized [1, 2, 9, 80, 82, 148].
PHYSIOLOGIC AND PATHOPHYSIOLOGIC

HEMODYNAMIC EFFECTS OF VA-ECMO
Normal Mechanics of the Left Ventricle
Although VA-ECMO may maintain vital organ perfusion, it can

negatively impact intracardiac filling pressures, myocardial wall stress, and
oxygen consumption [9, 57, 99, 148-150]. However, in order to understand
the hemodynamic and pathophysiologic effects of VA-ECMO, one must
first have a foundational understanding of normal cardiac physiology and
mechanics.
Figure 3. Basic Pressure-Volume Loop Analysis. (Top) Plotting left ventricular

pressure (LVP) in systole and diastole over time allows the creation of a (Bottom)
pressure volume loop (PVL). PVLs are created by plotting LVP against LV volume
throughout one cardiac cycle. PVLs allow one to infer each of the four phases of the
cardiac cycle: (a) ventricular filling, (b) isovolumetric contraction, (c) ventricular
ejection, and (d) isovolumetric relaxation. From the PVL, we can identify (1) mitral
valve closing and end-diastolic volume (EDV), (2) aortic valve opening, (3) aortic
valve closing and end-systolic volume (ESV), and (4) mitral valve opening. The stroke
volume (SV) is identified as the width of the PVL, or the difference between ESV and
EDV. The PVL is bounded by the end-diastolic pressure-volume relationship
(EDPVR) and end-systolic pressure-volume relationship (ESPVR). The EDPVR is a
relatively non-linear plot that reflects pressure-volume relationships in the setting of
complete myofilament inactivation throughout LV diastole. The slope of the EDPVR
reflects LV elastance (ΔP/ΔV) or ‘stiffness’, which is the reciprocal of compliance. In
contrast, the ESPVR is a relatively linear line that describes LVP and LV volume
relationships at the maximum state of myocardial activation near end-systole. The
tangent (slope) of the ESPVR at end-systole represents a relatively fixed state of LV
contractility (i.e., inotropy). Figures reproduced with permission from reference [152].
Figure 4. Overview of Pressure-Volume Loops and Relations.

(A) Normal pressure–volume loop (PVL), is bounded by the end-systolic pressure–
volume relationship (ESPVR) and end-diastolic pressure–volume relationship
(EDPVR). ESPVR is approximately linear with slope end-systolic elastance (Ees) and
volume–axis intercept (Vo). Effective arterial elastance (Ea) is the slope of the line
extending from the end-diastolic volume (EDV) point on the volume axis through the
end-systolic pressure–volume point of the loop. (B) Slope of the Ea line depends on
total peripheral resistance (TPR) and heart rate (HR), and its position depends on EDV.
(C) The ESPVR shifts with changes in ventricular contractility, which can be a
combination of changes in Ees and Vo. Changes in contractility can be indexed by
V120, the volume at which the ESPVR intersects 120 mm Hg. ESV = end-systolic
volume; LV = left ventricular. Ea is a surrogate for afterload, whereas Ees is a
surrogate for inotropy. Figures and legend reproduced with permission from reference
[57].
Pressure-volume loops (PVLs) can provide important information

regarding myocardial contractility, relaxation, stroke volume (SV), cardiac
output (CO), cardiac work, and even oxygen consumption throughout the
cardiac cycle, which will allow for relatively simple illustrations of how
VA-ECMO affects cardiovascular physiology [57, 151]. Derived from
pressure and volume measurements obtained over time in systole and
diastole, PVLs are created by plotting left ventricular (LV) pressure against
volume throughout one complete cardiac cycle, as demonstrated in Figure
3 [152, 153]. Although time is not directly plotted on the PVL,
understanding the derivation of these diagrams allows one to infer the
phases of the cardiac cycle: isovolumetric relaxation, ventricular filling,
isovolumetric contraction; and ejection [57, 99, 100, 148, 149, 151, 153-
155]. The PVL is bounded by the end-systolic pressure-volume
relationship (ESPVR) and end-diastolic pressure-volume relationship
(EDPVR) (Figure 3, Figure 4) [57, 151, 152]. These are derived from
regression analyses developed with data obtained in controlled laboratory
experiments, such as occlusion of the inferior vena cava with pressure and
volume measurements over several heart beats as preload (defined as end-

diastolic volume, EDV) subsequently diminishes [153, 156]. The ESPVR
is a relatively linear line that describes LV pressure and volume
relationships at the maximum state of myocardial activation near end-
systole [57, 149, 152, 157]. The tangent (slope) of the ESPVR at the end-
systolic point is often referred to as ‘end-systolic elastance’ (Ees) and
represents a relatively fixed state of LV contractility (i.e., inotropy). In
contrast, the EDPVR is a relatively non-linear plot that reflects pressure-
volume relationships in the setting of complete myofilament inactivation
throughout LV diastole [153]. The slope of the EDPVR reflects LV
elastance (elastance=ΔP/ΔV) or ‘stiffness’, which is the reciprocal of
compliance, and may reflect pathologic structural changes of the
myocardium [57, 95, 153].
In addition to EDV, EDPVR and ESPVR, one must also understand
the principles of afterload as depicted on PVLs. Afterload relates the total
peripheral resistance to the tension muscle fibers experience and the
pressures the LV must work against in order to eject blood throughout the
entirety of ejection [57]. To simplify its depiction on PVLs, afterload is
often assumed by the slope of the ‘effective arterial elastance’ (Ea) line,
which is drawn from the volume-intercept at the EDV and extends through
the end-systolic pressure point (Figure 4) [57]. Although their
mathematical derivations differ, Ea is assumed to be an appropriate
surrogate for afterload as it relates variables of total peripheral resistance to
other parameters affecting SV [57]. That is, at a constant SV and EDV,
changes to systolic blood pressure will be similarly reflected by changes in
Ea. It is important to note that Ea, SV, EDV, and inotropy are often
depicted as isolated changes on basic PVLs in order to aid in
conceptualizing their independent effects on cardiac mechanics (Figure 5)
[152, 156]. However, in reality there is significant ventricular-vascular
coupling with significant interdependence between these variables in both
normal and diseased myocardium [57, 158, 159].
Ventricular-Vascular Coupling: Interdependence of Preload,

Afterload and Inotropy
As EDV (i.e., preload) increases, the PVL widens and gets taller,
representing the heart’s augmented stoke volume and peak systolic
pressure resulting from length-dependent contractility, consistent with the
Frank-Starling mechanism (Figure 5) [57, 158, 159]. That is, during
myocardial contraction of a normal healthy heart, as EDV increases,
sarcomeres are stretched further and return to a similar end-systolic
volume, increasing ejection (ESV) [153, 156]. Of course, this is an overly
simplified illustration. In reality, with an augmented EDV, the myocardium
experiences increased ventricular-wall stress and stroke volume, and
therefore CO and systemic arterial pressures rise. As a result, afterload
(Ea) increases as the heart experiences greater resistance throughout
ejection [158, 159]. Thus, the velocity of contracting myofibrils actually
somewhat slows, and the end-systolic volume (ESV) slightly increases, but
to a lesser degree than EDV. Thus, as preload (i.e., EDV) increases, the
augmented SV is slightly less than what it would be in the absence of such
interdependent ventricular-vascular coupling (Figure 6) [152, 156, 158,
159]. Meanwhile, these diagrams draw distinctions between length-
dependent contractility affected by EDV (i.e., the Frank-Starling
mechanism) and length-independent inotropic contractility (Ees) [57, 158].
However, the respective actin-myosin cross-bridging and excitation-
contraction coupling occurring within the myocardium do not occur in
isolation, which further underscores the interdependence of EDV on both
afterload and inotropy [152, 158, 159].
With this understanding, it is no surprise then that changes in afterload
have similar effects on other variables [152, 160]. For example, as
afterload increases, the heart will continue to eject blood only up until the
point at which isobaric equilibrium is reached with the systemic arterial
pressure, at which point the aortic valve closes. Because the maximum
pressure the heart can generate is less at lower volumes, an increased
afterload will also increase the ESV with a resulting diminution of SV.
Figure 5. Isolated Changes in (A) Preload, (B) Afterload, and (C) Inotropy as Depicted
with Pressure-Volume Loops.
Assuming all other variables remain constant, (A) as preload (end-diastolic volume)
increases, sarcomeres will be stretched further and return to a similar end-systolic
volume, thereby increasing stroke volume (width of the pressure-volume loop) in
accordance with the Frank-Starling mechanism). (B) With an isolated increase in
afterload, the end-systolic volume becomes slightly reduced, and stroke volume
diminishes. (C) If only inotropy increases, more blood is ejected, end-systolic volume
decreases. Thus, stroke volume increases. However, panels A-C are overly simplified,
and should only serve to aid in conceptualizing isolated changes in preload, afterload,
and inotropy. In reality, there are interdependent effects among each of these variables,
such that an effect on any single parameter will cause changes to each of the others to
varying degrees. Figures reproduced with permission from reference [156].
Figure 6. Interdependent Effects of (A) Preload, (B) Afterload, and (C) Inotropy as
Depicted with Pressure-Volume Loops.
In a healthy heart, (A) increasing preload (end-diastolic volume) increases stroke
volume (SV) as a result of the Frank-Starling mechanism. As SV increases, so too does
cardiac output (CO), systemic arterial pressure, and thus afterload. (B) When there is a
primary increase in afterload, end-systolic volume increases, as does end-diastolic
volume, albeit to a lesser degree. Therefore, SV decreases. (C) When inotropy is
augmented, end-diastolic volume is reduced to a lesser degree than end-systolic
volume. As such, SV and CO increase. Although this increases systemic arterial
pressure and afterload, the effect on SV is modest compared to the inotropic effects. As
a result, the net effect is an increase in SV. Figures reproduced with permission from
reference [159].
As more blood remains in the ventricle after ejection, the EDV rises
(Figure 6) [152, 159, 160]. However, in a healthy heart, the compensatory
increases in EDV that are produced by elevations in afterload actually
serve to augment contractility (for reasons previously described), such that
there are only minimal effects on CO and SV.
Pressure-Volume Relationships in Acute Cardiogenic Shock
PVLs can help illustrate the ventricular-vascular coupling that occurs

with physiologic changes in inotropy, such as during rest or exercise
(Figure 6). Similarly, abrupt myocardial insults (in either the presence or
absence of a chronically diseased heart) can help elucidate the
interdependence of inotropy, EDV, and afterload as it relates to acute
exacerbations of heart failure and/or cardiogenic shock (Figure 7) [95, 153,
159]. For example, when there is an acute, pathologic decline in inotropy
(Ees), the PVL becomes bounded by a new ESPVR that is shifted
downward and rightward, suggesting that the injured ventricle is unable to
generate similar peak systolic pressures at any given volume (Figure 7) [9,
95, 148, 161, 162]. However, in the absence of an underlying
cardiomyopathy, the EDPVR does not radically change, as the intrinsic
myocardial structure itself remains relatively unchanged (Figure 6, Figure
7) [95]. In any case, as inotropy diminishes, SV declines in conjunction
with pathologic elevations in ESV and EDV, underscoring the
interdependence of preload, afterload, and inotropy [95, 153, 159]. The
combined result of these effects can be illustrated with a PVL that shifts
rightward towards the higher-sloping fringe of the EDPVR, representing
the increased elastance of an overfilled ventricle (Figure 7) [95, 153]. As
the EDV becomes effectively maximized, even small changes in EDV
have disproportionate effects on LV pressure, which may exacerbate
myocardial injury as the heart struggles to compensate and efficiently
generate the force required for ejection. Clinically, this is manifested by
the typical presentations of acute heart failure and/or cardiogenic shock,
which include inadequate perfusion, pulmonary edema, etc.
Patients who are fortunate enough to survive such an acute event will
often go on to develop a dilated cardiomyopathy, which results from the
subsequent myocardial remodeling that takes place. In these circumstances,
contractility becomes chronically diminished at the same time that the
intrinsic myocardial compliance increases. The net effect is a reduction in
maximal CO, which varies to some degree depending on the etiology of
the underlying cardiomyopathy [9, 95, 148]. In any case, this pathologic
state can be illustrated by a PVL that continues to be bounded by a shifted
ESPVR (as previously described) representing diminishes inotropy, in
addition to an EDPVR that has also transitioned downward and rightward
and is reflective of a dilated ventricle with increased intrinsic compliance,
as illustrated in Figure 7 [9, 95, 153, 162]. Because of this, although the
EDV may be significantly increased even at steady states, the filling
pressures may not necessarily be significantly elevated [95, 153, 162].
However, it is imperative to understand that, although the intrinsic
myocardial compliance may be increased in dilated cardiomyopathy, the
net effect is that the heart functions within a state of relatively increased
elastance compared to non-diseased myocardium. This can be appreciated
in Figure 7 by recognizing how the PVL cumulatively shifts rightward
along the EDPVR boundary in the setting of chronic heart failure, even in
the absence of acute cardiogenic shock [95]. Because pathologic
myocardial remodeling disrupts ventricular-vascular coupling and
compounds the dysfunctional effects of impaired contractility, in this
setting there is very little cardiac reserve to compensate for even minor
disturbances in preload, afterload, or other inotropic determinants. That is,
small hemodynamic perturbations can significantly disrupt steady state
cardiopulmonary physiology and lead to potentially fatal myocardial
dysfunction with imbalances in myocardial and end-organ oxygen supply
and demand [9, 57, 95, 151, 163].
Regardless of what specific event incites an acute exacerbation of
myocardial dysfunction, the body responds with a milieu of subsequent
neurohormonal and hemodynamic changes in an effort to restore adequate
end-organ perfusion. However, this often results in a vicious, and
potentially fatal pathophysiologic spiral, whereby compensatory changes
intended to augment cardiac output and systemic arterial pressure in fact

only serve to potentiate progressive disturbances in myocardial oxygen
supply and demand, such that acute cardiogenic shock, end-organ failure,
and total hemodynamic collapse become all but inevitable [5, 9, 98, 164,
165] . The precise neurohormonal disturbances and underlying systemic
comorbidities of acute cardiogenic shock may differ in patients with
previously normal myocardial function compared to those who present
with a history of chronic heart failure, thus initial treatments may differ to
some extent [98, 166-169].
Figure 7. Pressure-Volume Loops Illustrating the Hemodynamics of Acute

Cardiogenic Shock amongst Patients with Previously Normal Heart Function and Prior
Heart Dysfunction.
Pressure-volume loops during acute cardiogenic shock (red) in the setting of (A)
previously normal myocardial function (black) and (B) chronic heart failure. Note in
both cases (red end-systolic pressure volume relationship [ESPVR] line in the case of
acute CS; blue ESPVR in the case of acute cardiogenic shock [CS] on top of chronic
heart failure [HF]). The slope of the line created by the end-systolic pressure-volume
relationship decreases resulting in both decreased stroke volumes and increased
ventricular volumes and filling pressures. LV indicates left ventricular. Figures and
legend reproduced with permission from reference [95].
Regardless, in such circumstances of acute cardiogenic shock with

hemodynamic collapse, conventional methods of resuscitation often prove
futile, and early support with VA-ECMO may be indicated to provide life-
sustaining end-organ perfusion as the heart recovers or alternative more
durable therapies are pursued [5, 9, 121, 129]. However, it is important to
recognize that VA-ECMO induces profound changes with respect to the
relationships that govern physiologic hemodynamics and cardiac function,

and one must be keenly aware of the potential limitations and the resulting
complications that arise from pathophysiologic disturbances when
managing patients on VA-ECMO in acute cardiogenic shock.
Hemodynamic Consequences of VA-ECMO
In VA-ECMO, although blood is removed by a venous cannula

positioned near the inferior vena cava, it is important to recognize that the
left heart is not actually unloaded [5, 82, 95]. In part, this is because some
right-to-left cardiac flow is permitted in order to prevent stasis and clotting
within the right ventricle and pulmonary vasculature, such that it is rare for
VA-ECMO flows to exceed 80% of full hemodynamic support (i.e.,
complete cardiopulmonary bypass) for any significant period of time [10].
In addition, multiple sources of blood bypass the venous outflow cannula,
including drainage from thesbian veins as well as bronchial circulation
returning to the left atrium [10, 95, 144]. However, even more important is
the fact that when VA-ECMO is initiated, a proportion of the oxygenated
blood is delivered retrograde towards the proximal aorta, which causes the
LV to experience a profound elevation in afterload as ECMO flow rates are
increased, as illustrated in Figure 8 [9, 57].
Assuming that most patients receiving VA-ECMO will have a baseline
cardiac dysfunction that reflects the pathophysiologic changes observed in
acute cardiogenic shock, the LV will reach a maximum state of inotropy
that is relatively diminished compared to healthy hearts. As previously
described, this can be represented by a PVL that has been shifted towards
the region of increasing slope along the EDPVR boundary, again
appreciated in Figure 8 [9, 57, 95]. In this setting, because myocardial
contractility cannot be further augmented, the LV necessarily relies on
Frank-Starling mechanisms to overcome additional increases in afterload.
In other words, at higher ECMO flow rates, as the LV experiences a larger
afterload, the residual ESV and EDV increase, meanwhile the SV
diminishes.
Figure 8. Ventricular Effects of VA-ECMO.

(A) Impact of extracorporeal membrane oxygenation (ECMO) on pressure–volume
loops, showing flow-dependent increases of end-diastolic pressures (EDPs), increases
of effective arterial elastance, and decreases in LV stroke volume. ECMO-dependent
increases in EDP can be partially mitigated by decreases in TPR (B), and/or
improvements in Ees (C). CGS = cardiogenic shock; RA-Ao = right atrium to aorta;
other abbreviations as in Figure 4. Figures and legend reproduced with permission
from reference [57].
As a result, at higher ECMO flows, ejection is reduced, and the pulse

pressure narrows as the interval between aortic valve opening and closing
shortens. Consequently, the LV may become distended as preload (EDV)
increases. In this respect, a fundamental understanding of these
interdependent relationships becomes essential to appropriately monitoring
and managing patients on VA-ECMO. For example, it now becomes clear
why a pulse pressures of at least 10 mmHg should be targeted in patients
on VA-ECMO (see ‘Monitoring and Managing Patients on VA-ECMO’
(Table 3) [5, 10, 95]. Not only do appropriate pressure gradients promote
adequate coronary perfusion, but they also importantly permit sufficient
ventricular ejection, which reduces the risk of LV stasis, thrombus
formation, and the potential for devastating emboli. Similarly,
determinants of LV preload must be routinely assessed in order to prevent
additional complications of congestion, including pulmonary edema, as
well as over distention that increases myocardial work and oxygen
consumption, and reduces the likelihood of successful myocardial recovery
(Table 3) [5, 9, 57, 95, 100, 145, 146, 163]. Thus, although VA-ECMO
provides potentially life-sustaining end-organ perfusion, without close
observation and meticulous management, an already fragile heart can
become further damaged.
Just as higher ECMO flows increase the afterload experienced by the
LV, decreasing flows helps to promote ventricular ejection, such that only
the minimal flows required for life-sustaining end-organ perfusion should
be maintained on VA-ECMO. However, reduced flows also come at the
expense of diminished hemodynamic support, which some patients may be
unable to tolerate [95, 146, 170, 171]. Even if weaning is tolerated, a
patient’s underlying disease state may not sufficiently support LV
unloading if myocardial function remains severely diminished [57, 95, 170,
171. As such, additional therapeutic interventions or pharmacologic
strategies may be needed to promote LV unloading and/or permit adequate
ejection, as LV unloading has been identified among the most important
factor in myocardial recovery and weaning from VA-ECMO [95, 100].
Although various strategies exist to unload or vent the LV at higher ECMO
flows, including the use of the percutaneous Impella device, this topic is
covered extensively in its own chapter, and thus will not be elaborated
upon here [6, 144-146]. Other potential pharmacologic and mechanical
interventions to optimize hemodynamic and myocardial support may
include vasodilators, inotropic agents, and/or the concomitant use of an
intra-aortic balloon pump [54, 57, 95]. For example, reducing total
peripheral resistance or augmenting inotropy by 50% has the potential to
restore myocardial mechanics to levels that mirror baseline cardiogenic
shock in the absence of VA-ECMO (Figure 8) [54, 57, 95]. However,
refractory hypotension and vasoplegia or poor vascular access may limit
the clinical practicality of these interventions.
It is imperative to recognize that these examples and illustrations are
merely simplified models of complex interdependent relationships that
coexist in real-world physiology, and the moment-to-moment
hemodynamic changes in physiology must be considered alongside
innumerable other clinical parameters when managing such critically ill
patients. For example, concomitant use of positive pressure ventilation can
decrease LV afterload while increasing right ventricular afterload, which
depending on cardiac function, may unload the LV at the expense of
worsening right heart failure [7, 58, 172, 173]. Meanwhile, the systemic
inflammatory response elicited from blood contact with the non-
endothelialized ECMO circuit can have profound effects on perfusion
pressures and capillary permeability, which has its own set of unique
complications, and may further confound the etiology and management of
hemodynamic instability [12, 95].
Regardless, this overview should provide a sufficient foundation for
further study of LV hemodynamics both in healthy myocardium and
diseased states, as well as in the setting of acute cardiogenic shock with or
without VA-ECMO support. Understanding these fundamental concepts is
the first step to developing the necessary clinical foundation that is
required to care for patients on VA-ECMO and will allow providers to give
patients the best opportunity for survival while minimizing potential
complications. In this respect, it is imperative to not only understand the
pathophysiologic effects of mechanical circulation when using VA-ECMO,
but also the fundamental cardiopulmonary physiology of gas exchange,
delivery, and consumption that will drive patient monitoring and

management [10].
Cardiopulmonary Physiology Considerations in VA-ECMO
A masterful understanding of cardiopulmonary physiology and gas

exchange is essential to caring for patients requiring VA-ECMO [5, 13].
Because meticulous derivations and applications of the biophysical
principles governing cellular metabolism and oxygenation in mechanical
support are available elsewhere, only a broad overview of cardiopulmonary
physiology and pathophysiology will be reviewed as it pertains to
managing and monitoring patients requiring VA-ECMO, with the hope that
this introduction will inspire further self-study [10, 47].
Table 7. Selected equations in hemodynamic and

cardiopulmonary physiology
CaO2 = (1.34 * Hb * SaO2) + (0.0031 * PaO2)

CI=CO/BSA, L/min/m2
DO2=CO*CaO2
O2ER=VO2/DO2
VO2=125*BSA
VO2=CO*(CaO2-CvO2)
BSA = body surface area, CaO2 = arterial oxygen content, CvO2 = venous oxygen content, CI = cardiac
index, CO = cardiac output, DO2 = oxygen delivery, O2ER = oxygen extraction ratio, VO2 =
oxygen metabolic consumption. Adapted and modified from references [10, 174].
Homeostatic cardiorespiratory physiology may be most simply

understood as a balance in oxygen delivery (DO2) that adequately meets
the demands of metabolic consumption. DO2 is therefore defined by both
CO and arterial oxygen content (CaO2) and may be defined as
DO2=CO*CaO2 (Table 7). CO is an absolute flow rate (L/min) determined
by heart rate and SV, but may be related to body surface area (BSA) to
define a cardiac index (CI) that provides a relative value accounting for
expected variances related to patient size (CI=CO/BSA, L/min/m2).
Because the amount of dissolved oxygen in the blood is typically <1%,

CaO2 is primarily driven by arterial hemoglobin oxygen saturation (SaO2)
and the amount of hemoglobin (Hb) available to deliver oxygen [174].
Assuming that arterial and venous blood flow are similar, it follows
that oxygen consumption (VO2) can be related by the difference in arterial
and venous oxygen content (CvO2), where VO2=CO*(CaO2-CvO2) (Table
7). In fact, it was the recognition of this relationship that allowed for the
first calculations of CO, with blood samples measuring oxygen content and
spirometry quantifying VO2 [175]. Now known after its namesake as the
‘Fick principle’, this equation continues to be used to calculate CO [175-
181]. However, because direct spirometry to measure VO2 is arduous and
impractical in most clinical settings (although it remains the gold standard
quantitative method), metabolic consumption is usually estimated as
VO2=125*BSA, or from a number of other previously derived correlations
[177, 180-182]. On the other hand, modern advances in technology have
allowed CO to be measured through invasive monitoring, such as with
thermodilution, to then solve for VO2 [183, 184]. However, estimations of
VO2 are notoriously inaccurate, and even invasive ‘measurements’ of CO
can be misleading, as they are actually calculated values that depend on
proper technique and functioning electronic sensors [54, 174, 185-187]. In
spite of these limitations, whichever method is used to quantify these
values, understanding the relationship between DO2 and VO2 in normal
and disease state physiology is critically important to interpreting lab
values while monitoring and managing patients on VA-ECMO.
In the resting adult, DO2 is about 5 times what is needed for VO2
(600mLO2/min/m2 vs 125mLO2/min/m2, respectively), as demonstrated in
Figure 9 [10, 188]. In other words, under normal physiologic conditions,
only about 20% of delivered oxygen is taken up by peripheral tissues for
metabolism, which is often termed the oxygen extraction ratio
(O2ER=VO2/DO2), where normal values range from 0.2-0.3 (i.e., 20-30%)
[174]. Thus, under normal circumstances, a physiologic SaO2 of 95-100%
(PaO2=90-100mmHg) will be accompanied by venous oxygen saturations
(SvO2) of 65-75% (PvO2=35-45mmHg). Even under normal stress where
VO2 is elevated (i.e., exercise, sympathetic activation, mild illness), these
relationships persist as a result of compensatory rises in DO2. This is

driven predominately by acute augmentation of CO, as other parameters of
DO2 cannot be acutely altered (i.e., hemoglobin concentration,
SaO2>100%) [10, 174]. Similarly, even if DO2 declines, VO2 often remains
unaffected because of compensatory increases in the O2ER that continue to
sustain sufficient oxidative metabolism, as depicted in Figure 9 [10, 174,
188-191].
Figure 9. Relationships in Oxygen Delivery and Consumption.

(Above) The relationship between oxygen consumption (VO2) and oxygen delivery
(DO2). Normal resting values for adults are shown. DO2 is endogenously regulated to
5 times VO2 (designated N). If delivery is limited to less than 5:1, the venous content
and saturation falls, as relatively more oxygen is extracted to maintain normal VO2. If
delivery falls below the critical level of 2:1, oxygen supply dependency and anaerobic
metabolism occurs (designated Dep). (B) The relationship between oxygen
consumption and delivery at an elevated metabolic rate (increased VO2). The 5:1
relationship exists as in (A). If delivery cannot supply twice consumption, supply
dependency occurs. The conditions in the case example are identified as C1, C2, and
C3. Figures and legend reproduced with permission from reference [188].
Only once DO2 falls to a critically low level will VO2 be significantly
affected [174, 192]. In pathologic states where there is severely inadequate
perfusion or oxygenation (i.e., cardiogenic shock, respiratory failure, etc.)
and/or excessive metabolic consumption (i.e., sepsis), cellular demands
begin to exceed oxygen deliverance and circulatory failure ensues (i.e.,
shock) [193]. Typically, this occurs only once O2ER exceeds 50% (i.e.,
DO2 falls to less than double VO2), again demonstrated in Figure 9 [10,
174, 188, 192]. At this point, aerobic, oxygen-dependent metabolism is
unable to adequately sustain energy production, and tissues increasingly
rely on anaerobic metabolism [10, 188]. This is clinically manifested by a
worsening lactic acidosis and progressive end-organ dysfunction [10, 174].
Although injuries may be initially reversible, if action is not taken to
normalize perfusion and oxygenation (at most within a few hours), fatal
cardiovascular collapse becomes all but inevitable [10, 174, 192].
Some advocate that close monitoring of CO, SaO2, SvO2, and Hb are
needed to quantify values for DO2 and VO2 to ensure that DO2 remains
supernormal (i.e., >600ml/min/m2), or that the DO2/VO2 ratio remains >3:1
[10, 54, 174, 194, 195]. However, there are controversies regarding the
practical utility of using cumbersome calculations to define DO2 in
everyday practice, and the clinical reliability of these formulas which can
introduce mathematical coupling errors when relating DO2 to VO2, as both
are calculated from similar parameters [174]. That is to say that although
the DO2/VO2 relationship remains important conceptually, rigid
management strategies that merely augment CO with overly-aggressive
fluid resuscitation or adrenergic pharmacotherapies to achieve target values
of DO2 and DO2/VO2 are at best be ineffective, and potentially harmful in
critically ill patients [174, 194, 195]. As such, the indications for VA-
ECMO can be conceptually understood as a means to restore the
physiologic relationships between DO2 and VO2, but there remain other
important considerations in monitoring and managing patients on VA-
ECMO.
Monitoring and Managing Patients on VA-ECMO
The fundamental principle for monitoring and managing patients on

VA-ECMO is ensuring that adequate perfusion is maintained that allows
for sufficient end-organ oxygenation [10, 17, 53, 54]. However, the broad
indications, clinical variety, remarkable complexity, and lack of
randomized controlled trials makes it challenging to establish specific
targets that are broadly applicable to all patients [4, 7, 14, 17, 53, 148].
Nevertheless, a brief overview of generally accepted goal parameters are
described for adults requiring VA-ECMO in the setting of cardiac failure,
and provided for reference in Table 3 [5, 10, 52-54].
VA-ECMO should be started with initial flows that allow for full
hemodynamic support and cardiopulmonary bypass (approximately
3L/m2/min or 60-80mL/kg/min in adults), which can be determined by
increasing flows until the arterial waveform becomes nonpulsatile [10, 17,
52, 53, 70]. However, after a patient has been hemodynamically stabilized
for 6-12 hours, flows should be reduced until a pulse pressure of 10-
15mmHg is attained to promote forward blood flow through the lungs and
heart (Table 3) [10, 17]. If myocardial function is so depressed that such
pulsatility cannot be achieved, venting strategies should be urgently
considered and implemented to reduce LV pressures, limit further
myocardial stress, and minimize stasis [144-146]. In this respect,
echocardiography remains the best method for evaluating myocardial
function, and particular attention should be paid to opening and closing of
the aortic valve (Table 3) [10, 95].
As flows are titrated to promote pulsatility, one must ensure that an
adequate mean arterial pressure (MAP) is maintained. Current ELSO
guidelines recommend that initial MAPs ranging from 50-70mmHg are
acceptable, with some providers favoring lower limits at first to promote
LV unloading and ejection [17, 196]. As myocardial function improves,
both pulse pressure and MAP should increase, and MAPs as high as
90mmHg may be tolerated (Table 3). This may explain why poorer
outcomes are observed in patients with MAPs persistently less than
70mmHg [9, 17, 197]. Some patients may require adrenergic or vasoactive
pharmacotherapies to sustain acceptable MAPs, but it should be a priority

to wean and eliminate these drugs as soon as adequate LV unloading and
perfusion can be maintained in their absence [10, 17, 54, 99, 197]. This is
because, although MAP may serve as an appropriate marker of adequate
global perfusion and autoregulation under normal physiologic conditions,
it is not an appropriate surrogate for capillary perfusion pressure in the
setting of profound hypotension mitigated by artificial vasoconstriction, or
venous congestion, both of which can affect microcirculation and end-
organ perfusion [198]. As such, not only should continuous (invasive)
arterial pressures be monitored, but it is imperative that patients have
continuous SaO2 monitoring with continuous or at least frequent SvO2
measurements [10, 54, 199]. Note that when possible, the arterial line
should be placed in the right radial artery in order to adequately assess
arterial oxygenation and potential hypoxemia of the upper body and head
(Table 3) [50].
Although a number of hemodynamic target values exist to guide the
management of patients on VA-ECMO [54, 200], each represents only an
isolated metric of hemodynamic status, and none serve as an adequate
surrogate for a complete assessment of the relationship defining the
balance between sufficient tissue oxygenation that is capable of meeting
metabolic demands. Clear markers of end-organ injury may be reflected by
progressive oliguria, rising aminotransferases, etc. (Table 3) [17].
Clinically correlating these observations while trending CI, SvO2 and
lactate can be particularly helpful, as these values are less susceptible to
the mathematical coupling errors that occur when calculating DO2 and VO2
that have been previously described [174, 201]. Supporting this, lactate has
been identified as a superior prognosticator of clinical outcomes compared
to either DO2 or VO2 [174, 202]. Meanwhile, maintaining normal SvO2 and
central venous saturations have shown improved outcomes with less organ
dysfunction, shorter hospital stays, and lower mortality in cardiac surgery
and shock [174, 201, 203].
This is likely in part due to the fact that, as detailed earlier, SVO2 is a
relatively accurate depiction of the O2ER when compared to SaO2, and
may provide the most practical and reliable surrogate for oxygen
deliverance [174]. However, once again, this assumes that there is a normal
microcirculatory function to permit efficient end-organ capillary gas
exchange, and thus the entire clinical picture must be considered.
Most would agree that, assuming the SaO2 can be adequately
maintained >95%, a target SvO2 should be >65-70% (i.e., an O2ER ~25-
30%) [10, 17, 54, 174, 196]. When SvO2 remains persistently <65-70%,
interventions may be warranted to improve DO2. Recalling that
DO2=CO*CaO2, augmented hemodynamic support may be warranted by
means of increasing VA-ECMO flows, or volume resuscitation with
crystalloid, while respecting the need to maintain pulsatility and LV
ejection. If SaO2 is appropriately maintained but the patient is anemic, one
might consider administering blood products to a Hb goal of 12-14g/dL to
improve CaO2 and DO2 with the aim of restoring SVO2 to >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 VA-
ECMO [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.
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 re-
initiation 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 well-
tolerated, 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
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 VA-
ECMO 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
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 end-
organ 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 U-
sutures 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
should guide focused monitoring and management of patients on VA-

ECMO. 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
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 non-
endothelialized 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 in-
hospital 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.
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 VA-
ECMO 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
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 VA-

ECMO 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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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
118 Allison Ferreira and Kim Delacruz
granularity to disaster preparedness and are highlighted here as an

example.
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
Disaster Preparedness for ECMO Programs … 119
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
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.
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.
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.
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 cross-
training 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 post-
cardiotomy shock. Will all ECMO patients be treated with the same set of
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
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 patient-
level 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].
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. COVID-
ECMO 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
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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Müller, Daniel Höfer, Juliane Kilo, Walter Rabl et al. “Prolonged
extracorporeal membrane oxygenation-assisted support provides
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[8] Ramanathan, K et al. “Planning and provision of ECMO services for
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emerging infectious diseases” (2020) Lancet Respir. Med. Epub ahead of
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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.
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Dichter, Niranjan Kissoon, Asha V. Devereaux, and Charles D.
Gomersall. “Triage: care of the critically ill and injured during
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[13] Institute of Medicine, Crisis Standards of Care: A Systems Framework
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disaster. Disaster Med. Public Health Prep., 2008. 2(1): 20-26.
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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: Hitoshi.Hirose@jefferson.edu.
132 Joseph Dovidio and Hitoshi Hirose
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.
Special Consideration for ECMO Cannulation … 133
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
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 multi-
disciplinary (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
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.

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.
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).
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.
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.

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.
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.
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.
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.
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 on-
going 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
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
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.
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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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: rana.hejal@uhhospitals.org.
152 Olivia Giddings and Rana Hejal
trends of use of ECMO in ARDS secondary to COVID-19, and describe

our current practice for use of ECMO in patients with refractory
hypoxemia due to COVID-19.
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
The Use of ECMO for Treatment of Severe ARDS … 153
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
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 COVID-
19. 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 COVID-
19 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
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
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.
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
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.
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COVID-19 - 11 March 2020. https://www.who.int/dg/speeches/detail/
who-director-general-s-opening-remarks-at-the-media-briefing-on-
covid-19-11-march-2020. Accessed June 28, 2020.
[2] WHO Coronavirus (COVID-19) World Health Organization
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Characteristics of 138 Hospitalized Patients With 2019 Novel
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[4] 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): 1888-
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[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.
[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.
[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.
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,
1
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

Corresponding Author’s E-mail: msfirst@gmail.com.
164 Vitali Karaliou, Jennifer Hanna, Courtney Petersen et al.
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.
Frontline Experience with Extracorporeal Life Support. 165
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
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 Exclusion criteria

ARDS Age < 18 years
Intubation and ventilation for < 7 days. MV > 7 days
Optimization of MV: Pregnancy
 FiO2 ≥ 80% Weight > 1 kg/cm (height)
 VT 6 cc/kg, PBW BMI >45 kg/m2
 PEEP ≥ 10 cmH2O Long-term chronic respiratory insufficiency
Adjunctive therapies allowed/encouraged: treated with O2 or NIV
 iNO Cardiac failure requiring VA ECMO
Heparin induced thrombocytopenia
 Recruitment maneuvers
Cancer with a life expectancy < 5 years
 HFOV
Moribund condition or a Simplified Acute
 Almitrine infusion
Physiology Score (SAPS-II) > 90
 Neuromuscular blocking agents
Current non–drug-induced coma after cardiac
 Prone positioning
arrest
One of the following: Irreversible neurologic injury
 PaO2:FiO2 ratio < 50 mmHg for >3 hrs* Decision to withhold or withdraw life
 PaO2:FiO2 < 80 mmHg for >6 hrs sustaining therapies
 Arterial blood pH <7.25, PaCO2 > 60 mmHg Expected difficulty in obtaining vascular
for >6 hrs** 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
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
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 SARS-
CoV-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-
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 co-
morbidities or multiple organ failure. For cardiac support, the considera-
tion 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
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
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 real-

time 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.
Table 3. Indications and contraindications for ECMO

in COVID-19 infected adults (ELSO interim guidelines) [11]
Relative contraindications Absolute contraindications

 Age ≥ 65 years  Advanced age
 Obesity with BMI ≥ 40  Clinical Frailty Scale Category ≥ 3
 Immunocompromised  Mechanical ventilation > 10 days
status  Significant underlying co-morbidities:
 No legal medical decision ˗ CKD ≥ III
maker available ˗ Cirrhosis
 Advanced chronic ˗ Dementia
underlying systolic heart ˗ Baseline neurologic disease which would
failure preclude rehabilitation potential
 High dose vasopressor ˗ Disseminated malignancy
requirement (and not ˗ Advanced lung disease
under consideration for ˗ Uncontrolled diabetes with chronic end-organ dysfunction
VA or VVA ECMO) ˗ 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
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 Total Patients ECMO outcome Type of study

number of on
COVID ECMO
patients
Yang et al. [9] 710 6 Died: 5 (83.3%). On ECMO: 1 Retrospective
Guqin et al. [14] 221 10 Died: 3 (30%). On ECMO: 5 Retrospective
Discharged: 2
Guan et al. [15] 1099 5 N/A Retrospective
Huang et al. [16] 41 2 N/A Prospective
Zhou et al. [17] 191 3 Died: 3 (100%) Retrospective
Chen et al.8 99 3 Died: 1 (33%) Retrospective
Wang et al. [18] 138 4 N/A 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
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 meta-
analysis 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
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 jugulo-
femoral 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
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 in-
hospital 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].
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
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 C-
reactive 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
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
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
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
“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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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
188 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
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
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 immuno-
compromised 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 COVID-
19 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:
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 life-
saving 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 ventilator-
dependent 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
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
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-to-
Medium 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.
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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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
200 About the Editor
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
aorta, 3, 61, 62
A
aortic insufficiency, 52
aortic regurgitation, 51
acute infection, 188
aortic valve, 53, 56, 63, 69
acute kidney failure, 177
arrest, 42, 43, 45, 46, 47, 49, 51, 128, 165
acute lung injury, 105
arrhythmia, 45, 72
acute respiratory distress syndrome, 8, 19,
arterial blood gas, 145
22, 90, 131, 133, 153, 159, 164, 166,
artery, 3, 41, 45, 52, 70, 89, 100
167, 188
assessment, xvii, 18, 46, 70, 71, 73, 74, 105,
adult respiratory distress syndrome, 20
113, 168, 183
adults, xiv, 9, 10, 20, 26, 29, 67, 69, 79, 86,
asymptomatic, 124, 129, 164, 187, 190
90, 95, 97, 98, 100, 105, 111, 172
atrial septal defect, xv, 5
age, 9, 20, 47, 51, 72, 125, 134, 155, 165,
168, 172, 173
air embolism, 127 B
airway infiltration, 193
aminotransferases, 70 bacteremia, 107
anatomy, 25, 28, 78, 139 bacterial infection, 134
angiotensin converting enzyme, 189 barotrauma, 181
antibody, 189 bilateral, 140
anticoagulant, 101 bilirubin, 32
anticoagulation, xiv, 5, 29, 30, 32, 41, 51, biocompatibility, 8, 38
52, 75, 78, 81, 90, 126, 131, 132, 144, biomarkers, 73
146, 172, 177, 178, 186, 193 biomaterials, 6
anti-factor Xa, 178
202 Index
bleeding, 30, 52, 72, 75, 84, 85, 132, 145, cardiopulmonary bypass, xvi, 1, 2, 5, 6, 11,
172, 175, 178, 191, 193 12, 13, 14, 16, 28, 29, 37, 41, 51, 61, 69,
blood, xiv, xv, 2, 3, 4, 6, 7, 15, 21, 29, 30, 80, 84, 87, 88, 96, 108
32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, cardiovascular physiology, 54
43, 55, 56, 57, 61, 64, 66, 69, 71, 73, 75, catheter, 33, 74, 94, 115
76, 81, 83, 84, 105, 107, 126, 134, 166, cell signaling, 75
172, 175, 178, 186 cerebral hemorrhage, 51
blood flow, xiv, 4, 7, 30, 34, 36, 38, 41, 66, CESAR, xiv, xvii, 10, 18, 165, 183
69 challenges, 7, 31, 45, 52, 120, 188, 189,
blood pressure, 43, 107, 175 192, 195
blood urea nitrogen, 4, 178 chronic heart failure, 44, 59, 60, 101
body mass index, 72, 166 chronic kidney disease, 172
body weight, 166 chronic obstructive pulmonary disease, 172
brain, 51, 75, 76, 77 circulation, 1, 3, 5, 6, 9, 11, 14, 19, 43, 46,
burn, 44, 118, 128 51, 61, 64, 136
clinical application, 7, 8, 37
clinical presentation, 187, 188, 189
C
clinical problems, 181
clinical trials, 9, 151, 154, 158, 165
candidates, 7, 51, 157, 172
coagulopathy, 52, 144, 177, 186
cannulation, xiv, 26, 27, 28, 29, 40, 41, 46,
combination therapy, 181
51, 52, 74, 77, 79, 89, 125, 126, 131,
community, xvi, 118, 121, 126, 158
132, 133, 134, 136, 137, 139, 140, 141,
complications, xiv, 6, 7, 26, 27, 41, 61, 63,
143, 144, 145, 146, 147, 150, 165, 174,
64, 72, 74, 75, 77, 78, 86, 110, 132, 144,
175, 185
148, 150, 158, 175, 178, 181, 182, 186,
cardiac arrest, 10, 22, 42, 43, 45, 46, 47, 48,
189, 192
77, 79, 90, 91, 92, 96, 97, 98, 99, 100,
configuration, 40, 71, 79, 90, 137, 140, 175
115, 116, 118, 122, 125, 128, 136, 144,
congestive heart failure, 104
166, 176, 185
consensus, 10, 43, 108, 124, 129, 148, 169,
cardiac catheterization, 106
184
cardiac output, 29, 33, 44, 54, 57, 60, 65,
considerations, vi, 10, 48, 65, 68, 86, 122,
105, 106
131, 148, 188, 193
cardiac reserve, 59
consumption, 54, 65, 66, 67, 68, 106, 120,
cardiac surgery, 1, 5, 7, 14, 28, 37, 70, 104,
126
110, 134, 181, 199
contamination, 122, 126, 139, 146, 176
cardiac tamponade, 107
coronavirus, vi, vii, ix, xi, 129, 130, 131,
cardiogenic shock, xvi, 22, 25, 26, 42, 43,
133, 147, 149, 151, 152, 153, 154, 158,
44, 48, 49, 58, 59, 60, 61, 62, 64, 68, 76,
159, 160, 161, 164, 167, 169, 170, 172,
77, 79, 85, 91, 92, 93, 94, 104, 109, 110,
183, 184, 187, 188, 196, 197
111, 112, 174
cytokine storm, 176, 177, 186
cardiomyopathy, 44, 58, 59, 77, 144
Index 203
176, 177, 178, 179, 180, 181, 182, 183,

D
184, 185, 186, 187, 188, 190, 191, 192,
193, 194, 195, 198
database, 77, 95, 109
ECMO cannulation, vi, 39, 77, 125, 131,
deaths, viii, 124, 151, 152
132, 133, 139, 141, 175, 185
decannulation, vi, 48, 49, 50, 52, 71, 72, 74,
ECMO sweep gas, 145
78, 122, 127, 131, 132, 133, 145, 147,
ELSO, viii, xi, 9, 16, 22, 23, 26, 28, 42, 44,
150, 174
45, 46, 50, 51, 69, 77, 79, 81, 88, 89, 92,
decannulation., 78, 145, 174
99, 107, 110, 125, 127, 130, 155, 156,
diastolic pressure, 53, 54, 62
160, 165, 167, 168, 169, 170, 171, 172,
dilated cardiomyopathy, 59
174, 175, 183, 191, 198
dilation, 41, 139
emergency, 29, 46, 97, 99, 116, 118, 122,
disability, xiv, 10, 118, 166
124, 127, 128, 146, 164, 184
disaster, 118, 119, 120, 121, 122, 123, 127,
EOLIA, 154, 155, 165, 166, 169
128, 129
epidemic, 118, 128, 157, 167
disaster preparedness, vi, 117, 118, 119,
epithelium, 188
125, 127
equilibrium, 35, 56, 188
disease progression, 165
equipment, 8, 38, 119, 120, 122, 124, 127,
diseases, 128, 148, 172
128, 133, 136, 137, 138, 139, 164, 168,
disseminated intravascular coagulation, 178
180
distributive justice, 123, 124
ethical considerations, 51, 123, 198
drainage, 31, 40, 61, 137, 140, 141, 142,
etiology, 26, 42, 59, 64, 72, 152
144
evidence, xiv, 2, 10, 20, 26, 27, 28, 30, 36,
durability, 7, 8, 34, 37, 38
41, 42, 44, 45, 46, 73, 77, 79, 84, 125,
151, 153, 154, 181, 189, 192
E evolution, viii, xvii, 1, 28, 29, 37, 177, 179
exclusion, 50, 78, 133, 166, 169
ECMO, v, vi, vii, viii, ix, x, xi, xiv, xv, xvi, exposure, 6, 40, 71, 122, 126, 132, 133, 134,
xvii, 2, 7, 8, 9, 10, 13, 16, 17, 19, 20, 21, 136, 141, 167, 177
22, 23, 25, 26, 27, 28, 29, 30, 31, 32, 33, extracellular matrix, 188
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, extracorporeal membrane oxygenation, v,
45, 46, 47, 48, 49, 50, 51, 52, 54, 60, 61, vi, vii, ix, x, xvii, 1, 2, 16, 17, 18, 19, 20,
62, 63, 64, 65, 66, 68, 69, 70, 71, 72, 73, 21, 22, 26, 62, 79, 80, 81, 82, 83, 84, 85,
74, 75, 76, 77, 78, 79, 80, 81, 82, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,
86, 87, 88, 89, 90, 91, 95, 100, 107, 108, 99, 100, 101, 107, 109, 110, 111, 112,
110, 111, 112, 115, 117, 118, 119, 120, 113, 114, 115, 116, 128, 129, 131, 133,
121, 122, 123, 124, 125, 126, 127, 128, 148, 149, 150, 153, 159, 160, 161, 165,
129, 130, 131, 132, 133, 134, 135, 136, 166, 170, 172, 182, 183, 184, 185, 186,
137, 139, 140, 141, 142, 143,144, 145, 187, 188, 193, 197
146, 147, 148, 151, 152, 153, 154, 155, extraction, 32, 35, 36, 65, 66, 107
156, 157, 158, 159, 164, 165, 166, 167,
168, 169, 170, 171, 172, 173, 174, 175,
204 Index
heparin induced thrombocytopenia, 166,

F
179, 193
history, vii, 1, 3, 11, 16, 41, 60, 87, 165,
fiber, 7, 8, 16, 17, 34, 37, 38, 39, 81, 82, 89
189, 190, 191
fiber membranes, 7, 37, 39
hospitalization, 151, 152, 192
financial, 51, 120, 122
human, 2, 5, 14, 108, 110, 117, 118, 119,
formation, 3, 33, 36, 63, 75, 140, 143, 145,
120, 121, 126, 127, 133
146, 147
human capital, 119
Frank-Starling mechanism, 56, 57, 61
human resources, 119, 126
hypothermia, 29, 45, 91, 128, 178
G hypoxemia, xiii, xv, xvi, 70, 76, 152, 153,
154, 157
gastrointestinal tract, 75 hypoxia, 106, 144, 190
graft dysfunction, 44, 72, 94, 111, 191
guidance, x, xi, 40, 125, 159, 175
guidelines, viii, 10, 27, 42, 43, 45, 47, 69, I
122, 148, 154, 156, 158, 164, 165, 168,
immune activation, 189
170, 171, 172, 174, 175, 179, 182, 188,
immune response, 148
195
immune system, 189, 190
guiding principles, 127
infection, x, xiv, 22, 33, 72, 76, 122, 133,
134, 145, 149, 151, 159, 164, 167, 168,
H 177, 179, 181, 182, 187, 188, 189, 190,
191, 192, 193, 194
H1N1, xiv, 10, 19, 21, 22, 118, 124, 153, inferior vena cava, 40, 41, 54, 61, 141
154, 159, 165, 182, 183 inflammation, xvii, 178, 190
health, vii, ix, 118, 133, 156, 165, 195 inflammatory responses, 30, 75, 78
health care, vii, ix, 133, 156 influenza, xiv, 10, 19, 22, 128, 152, 153,
health care professionals, vii 159, 165
health care system, 156 influenza A, 21, 159, 182
health status, 165 infrared spectroscopy, 33
heart disease, 174 initiation, xvi, 45, 46, 47, 72, 77, 78, 123,
heart failure, 42, 49, 58, 60, 64, 85, 91, 93, 136, 155, 157, 158, 165, 167, 171, 172,
101, 134, 172, 200 177
heart rate, 54, 65 injury, iv, 41, 43, 45, 49, 51, 52, 58, 70, 71,
heart transplantation, xvi, 45, 50, 72, 94, 95, 73, 77, 143, 166, 172, 176, 181, 188
96, 110, 111, 112 insertion, 41, 141, 174, 175
hemodynamic instability, 64, 132, 176 institutions, xvi, 125, 134
hemoglobin, 30, 32, 66, 67 intensive care unit, 22, 29, 80, 128, 149,
hemorrhage, xiv, 32, 51, 155, 167 164, 165, 167, 170
hemorrhagic stroke, 155 intervention, 26, 44, 79, 93, 101, 102
hemostasis, 132, 146, 147, 149 intra-aortic balloon pump, 43, 44, 64, 104
Index 205
ischemia, 72, 73, 74, 144 mechanical circulatory support, 1, 2, 4, 5, 6,

isolation, 56, 133, 179 7, 8, 10, 26, 27, 37, 38, 42, 49, 72, 74,
issues, 28, 125, 133, 191, 192 76, 86, 101, 111, 113, 198
mechanical ventilation, 36, 40, 86, 105, 124,
153, 154, 157, 158, 164, 166, 172, 187,
K
193
mechanical ventilator, 164, 168
kidney, 15, 30, 77, 134, 176
medical, xv, 43, 46, 48, 49, 147, 164, 172,
kidney failure, 30
182
kidney transplantation, 77
medication, 180, 190
medicine, viii, 22, 82, 84, 86, 107, 110, 128,
L 184
membrane permeability, 7, 8, 38
left atrium, 61 membranes, 6, 7, 15, 38
left ventricle, 102 metabolic acidosis, 73
legend, 54, 60, 62, 67 metabolic disturbances, 44
liver, 73, 77, 134 metabolism, 13, 65, 66, 67, 68, 107
liver enzymes, 73 modifications, 31, 122, 127
liver transplant, 77 morbidity, 173, 177, 182
liver transplantation, 77 mortality, viii, 19, 52, 70, 72, 104, 109, 125,
local anesthesia, 29 134, 152, 153, 155, 157, 164, 165, 166,
local anesthetic, 146 167, 173, 174, 177, 182, 184, 189
local government, 122 mortality rate, 152, 153, 164, 165, 173, 174
lumen, 136, 147, 150, 174, 175 myocardial infarction, xvi, 26, 44, 49, 76,
lung disease, xv, 172, 188, 194 79, 93, 99, 102, 103, 110, 116
lung function, 34, 75, 145, 194 myocarditis, 44, 45, 72, 77, 94, 109, 112,
lung transplantatation, 188 113, 134, 144
lung transplantation, xvi, 111, 188, 189, myocardium, 55, 56, 59, 64
190, 191, 192, 193, 195 myosin, 56
M N
majority, 7, 47, 77, 152, 155 New England, 15, 87, 107, 108, 129, 195
malignancy, 51, 52, 172 nitric oxide, xv, 133, 154, 155, 157, 166
management, viii, x, xi, 27, 28, 36, 40, 42, North America, 14, 16, 89, 155, 160, 198
49, 63, 64, 65, 68, 70, 71, 75, 76, 78, 91, nurses, 119, 121, 134, 156, 168, 179
92, 95, 122, 123, 125, 127, 128, 153, nursing, 122, 134
154, 159, 164, 165, 166, 167, 168, 169,
170, 173, 176, 179, 182
measurements, 54, 66, 70 O
obesity, 40, 51, 52, 174

206 Index
occlusion, 30, 31, 45, 54, 102 principles, 20, 55, 65, 78, 79, 84, 165, 179,
open heart surgery, 5, 28, 72 195
organ, 3, 4, 5, 32, 43, 44, 49, 50, 51, 52, 59, procedures, 21, 74, 81, 120, 122, 124, 125,
63, 68, 69, 70, 71, 72, 73, 74, 75, 79, 126, 128, 147, 189
131, 134, 164, 167, 169, 170, 172, 176, prognosis, 48, 51, 112, 125, 168, 174, 177
181, 189, 190 psychosocial stress, 123
overproduction, 176 public health, 118, 129
ox, 3, 4, 40, 61, 75 pulmonary artery, 33, 40, 45, 105
oxygen, xv, 1, 2, 10, 33, 34, 35, 36, 42, 43, pulmonary artery pressure, 33
44, 52, 59, 60, 63, 65, 66, 67, 68, 71, 74, pulmonary capillary wedge pressure, 44
75, 105, 106, 107, 108, 146, 166, 190 pulmonary edema, 58, 63
oxygen consumption, 36, 52, 63, 66, 67, pulmonary embolism, 44, 72, 94, 113, 114,
105, 106 174
pulmonary hypertension, xv, xvi, 74
pumps, 6, 9, 28, 29, 30, 31, 33, 34, 83, 84,
P
134, 180
pandemic, vi, viii, xiv, xvi, 10, 117, 118,
119, 124, 125, 126, 127, 128, 130, 133, R
134, 148, 151, 152, 153, 154, 156, 158,
159, 164, 165, 167, 168, 169, 171, 173, recommendations, iv, xi, 42, 45, 108, 125,
175, 177, 178, 184, 185, 186, 188, 196, 154, 156, 164, 168, 175, 176, 179
198 recovery, xvi, xvii, 32, 40, 41, 42, 43, 44,
pathophysiology, 65, 80, 103, 108, 188 46, 48, 49, 50, 63, 72, 73, 74, 85, 127,
patient care, 48, 71, 120 131, 145, 189, 190, 191, 192, 193, 194
patient selection, 44, 45, 46, 76, 80, 132, redundancy, 119, 120
133, 156, 170, 182 regionalization, 121, 122
perfusion, 1, 3, 4, 5, 7, 14, 32, 41, 46, 49, rehabilitation, xvi, 51, 172, 193, 194
52, 58, 59, 63, 64, 68, 69, 70, 71, 74, 77, renal replacement therapy, 77, 155, 176,
78, 87, 110, 119, 132 177, 185
peripheral vascular disease, 51, 172 requirement, 44, 134, 136, 165, 172, 190
permission, iv, 39, 47, 53, 54, 57, 60, 62, 67 requirements, 17, 35, 88, 149, 158
permit, 2, 4, 31, 63, 71, 77, 119 resistance, 36, 38, 39, 41, 54, 55, 56, 64
physiology, xvi, 2, 52, 59, 64, 65, 66, 75, resource allocation, 156
102, 108 resource utilization, 112
pneumonia, x, xv, 129, 130, 148, 151, 152, resources, 117, 118, 119, 121, 122, 123,
154, 167, 183, 184, 185 127, 132, 134, 147, 156, 157, 167, 168,
polymethylpentene, 17, 18, 181 176, 179, 182
polypropylene, 37, 181 respiration, 1, 32, 36
population, 78, 83, 145, 153, 154, 158, 176, respiratory acidosis, 177
194 respiratory failure, viii, xiv, xv, xvii, 9, 10,
15, 18, 19, 22, 50, 68, 87, 88, 90, 125,
Index 207
133, 151, 153, 160, 161, 165, 166, 167, superior vena cava, 40, 141, 142
169, 172, 174, 177, 183, 187, 188, 189, supply chain, 119, 120, 125
190, 191, 192, 193, 194, 195, 197 surface area, 7, 34, 65
respiratory function, 72, 145 surveillance, 171
respiratory therapist, 156 survival, viii, xvi, 9, 10, 41, 44, 46, 47, 50,
response, 64, 76, 78, 80, 89, 104, 119, 134, 51, 64, 72, 76, 77, 85, 90, 93, 98, 99,
158, 176, 177 104, 107, 111, 112, 116, 124, 125, 127,
restrictions, 117, 119, 121, 127 128, 153, 154, 155, 156, 157, 159, 161,
risk, 30, 40, 52, 63, 72, 74, 75, 111, 113, 164, 165, 170, 174
118, 123, 124, 125, 126, 145, 147, 149, survival rate, 76, 155, 157
157, 165, 167, 173, 174, 175, 176, 178, survivors, 96, 114, 178
179, 181, 184, 189 syndrome, 15, 75, 85, 87, 134, 152, 153,
risk factors, 111, 184 159, 167, 176, 183, 186
risk management, 124 systolic blood pressure, 44, 55
risks, 30, 75, 76, 123, 124, 126, 179, 181, systolic pressure, 53, 54, 55, 56, 58, 60
189
T
S
target, 29, 42, 68, 70, 71, 178
saturation, xiv, 33, 43, 66, 67, 146, 170 team members, 119, 123
schema, 121, 122, 124 teams, 46, 156, 168, 179
science, vii, 73, 177 techniques, 4, 6, 21, 40, 82, 133, 174
scope, 3, 5, 14, 87, 178, 180 technological advances, 28, 30
secondary damage, 134 technology, 2, 4, 8, 9, 16, 38, 66, 88, 167
sepsis, 68, 108, 177, 178 textbook, vii, xvii, 2, 8, 26, 30, 40, 74
septic shock, xiii, xv, xvi, 45, 100, 107, 108, therapeutic interventions, 48, 49, 63
113, 134, 176 therapy, 6, 9, 10, 20, 43, 44, 46, 48, 49, 50,
sequential organ failure assessment (SOFA), 77, 79, 91, 100, 103, 107, 108, 145, 151,
157, 160, 176 152, 153, 157, 158, 167, 172, 173, 181,
services, iv, 46, 117, 118, 119, 121, 123, 182, 189, 190, 192
127, 128, 148 thrombocytopenia, 41, 51, 75, 166, 178,
severe acute respiratory syndrome, 152, 179, 193
164, 167, 184, 187 thromboelastography, 149, 178
shock, 9, 15, 26, 43, 44, 49, 58, 60, 68, 70, thrombosis, 33, 72, 73, 75, 145, 149
84, 87, 93, 103, 107, 116, 123, 134, 157 thrombus, 36, 63, 75
shortage, 164, 165, 168 tracheostomy, xvi, 190, 193
signs, 33, 43, 73, 75, 76, 173, 178, 185 transplant, xv, xvi, xvii, 45, 48, 49, 50, 51,
simulation, 120, 122 77, 94, 95, 112, 121, 189, 191, 192, 194,
stress, 30, 52, 56, 66, 69, 119, 123, 144, 164 195
stroke, 53, 54, 56, 57, 60, 62, 155, 172 transplant recipients, 194
stroke volume, 53, 54, 56, 57, 60, 62
208 Index
transplantation, 42, 44, 45, 49, 50, 51, 71, variables, 55, 56, 57, 77, 108
72, 77, 85, 95, 111, 188, 189, 190, 191, vein, 41, 75, 136, 137, 139, 140, 142, 143
192, 193, 194, 195 ventilation, xiv, 20, 35, 48, 64, 133, 153,
transthoracic echocardiography, 108 154, 165, 166, 169, 172, 177
trauma, 6, 37, 84 ventricle, 32, 58, 59
treatment, vii, viii, 101, 107, 108, 110, 112, ventricular fibrillation, 47, 99, 191
116, 123, 144, 147, 149, 151, 153, 154, ventricular tachycardia, 47, 114
157, 164, 165, 181, 188, 190 victims, 118, 123, 189
trial, xvii, 9, 10, 18, 20, 48, 73, 77, 91, 104, viral myocarditis, 125
107, 110, 124, 154, 155, 158, 166, 169,
183
W
U workers, 123, 124, 179

working conditions, 124
ultrasound, 33, 40, 139, 174 World Health Organization, viii, x, 118,
United States, viii, 8, 18, 21, 30, 38, 82, 128, 151, 152, 154, 158, 159
155, 173 worldwide, viii, 6, 151, 152, 153, 164, 167,
upper respiratory infection, xv 173, 188
Wuhan, viii, x, 124, 129, 130, 148, 152,
158, 168, 183, 184, 185
V
valve, 32, 53, 73, 108

The History of Extra Corporeal Membrane Oxygenation ECMO From Start

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MEDICAL PROCEDURES, TESTING AND TECHNOLOGY

THE HISTORY OF EXTRA-

FROM START TO COVID

Additional books and e-books in this series can be found

THE HISTORY OF EXTRA-

FROM START TO COVID

NOTICE TO THE READER

Library of Congress Cataloging-in-Publication Data

Published by Nova Science Publishers, Inc. † New York

Preface The Practice and Principles of

Chapter 3 Disaster Preparedness for ECMO Programs and

Jeffrey Phillip Jacobs, MD and Eric Yates Pruitt, MD

Dr. Michael Firstenberg is to be congratulated for creating and editing

both published guidelines regarding the role of ECMO in treating patients

[1] Coronavirus COVID-19 Global Cases by the Center for Systems

THE HISTORY OF EXTRA-CORPOREAL

Ahmed S. Said1 and Kenneth E. Remy1,2,

I remember it like it was yesterday. Called to an outside hospital to

hundred years ago. Early in this horror, I recall a colleague in my

We needed something to bridge her and proceeded to VV ECMO, fully

indications; ECMO does not just provide a bridge to recovery or transplant

[1] Efficacy and economic assessment of conventional ventilatory

THE GENESIS AND EVOLUTION

Benjamin Smood, Asad A. Usman, Mark Helmers,

Even before the discovery of elemental oxygen, philosophers,

Corresponding Author’s E-mail: Rita.Milewski@pennmedicine.upenn.edu.

alongside how indications have progressed to include both respiratory

Keywords: cardiopulmonary bypass, ECMO, extracorporeal membrane

To appreciate the modern advances and current state of extracorporeal

EARLY HYPOTHESES AND STUDIES IN EXTRACORPOREAL

In the mid-17th century, little was known regarding human respiratory

Julien Jean César Legallois published the first practical hypothesis of

EARLY APPLICATIONS OF EXTRACORPOREAL

defibrinated blood to prevent clotting, Jacobj was the first to use

FROM CARDIOPULMONARY BYPASS TO PROLONGED

The first human operation using a heart-lung machine in cardiac

was able to temporarily replace cardiac and pulmonary function for

For example, in 1963, Theodor Kolobow developed a novel hypobaric

basic ECMO equipment and technology, including membrane oxygenators,

A SHIFTING PARADIGM WITH EXPANDING

was weaned successfully after 75 hours of support, with the authors

Clinical trials in adult patients continued to show promising results.

[4] Lim M. W. (2006). The history of extracorporeal oxygenators.

décapitation. C R Acad Sci, 32:897-902. [Research on the restoration

[20] Schmidt A. (1867). Die Athmung innerhalb des Blutes. Zweite

Bramson membrane lung. Perfusion, 18(3), 185–189.

for ECMO: the recent progress. Annals of Thoracic and

[61] Undar, A., Wang, S., & Palanzo, D. A. (2013). Impact of

conventional ventilatory support versus extracorporeal membrane

[74] Morris, A. H., Wallace, C. J., Menlove, R. L., Clemmer, T. P.,

Support in Critical Care. Extracorporeal Life Support Organization,

Critical Care & Pain Medicine, 37(3), 259–268. https://doi.org/

Benjamin Smood, Matthew Woods,

Over the past decade, venoarterial (VA)-ECMO has increasingly

* Corresponding Author’s E-mail: Rita.Milewski@pennmedicine.upenn.edu.

physiologic and pathophysiologic relationships are highlighted, which are

Keywords: ECLS, ECMO, ECPR, ELSO, extracorporeal membrane

Depending on the etiology and severity of the underlying pathology,

Table 1. Common etiologic indications for VA-ECMO

Etiology/Indications for Estimated Highest Quality Sources

The use of VA-ECMO for cardiac support is a rapidly evolving field,

improved understanding of the fundamentals of VA-ECMO support and

ANATOMY OF THE MODERN VA-ECMO CIRCUIT