Critical Care of COVID-19 in The Emergency Department 2021

Critical Care of
COVID-19 in the
Emergency
Department
Joseph R. Shiber
Editor
123
Critical Care of COVID-19
in the Emergency Department
AL GRAWANY
Joseph R. Shiber
Editor
Critical Care
of COVID-19
in the Emergency
Department
Editor
Joseph R. Shiber
Departments of Emergency Medicine, Neurology and Surgery
University of Florida Health Science Center
Jacksonville, FL, USA
ISBN 978-3-030-85635-9 ISBN 978-3-030-85636-6 (eBook)

https://doi.org/10.1007/978-3-030-85636-6
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2021
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher,
whether the whole or part of the material is concerned, specifically the rights of translation,
reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any
other physical way, and transmission or information storage and retrieval, electronic adaptation,
computer software, or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specific statement, that such names are
exempt from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in
this book are believed to be true and accurate at the date of publication. Neither the publisher nor
the authors or the editors give a warranty, expressed or implied, with respect to the material
contained herein or for any errors or omissions that may have been made. The publisher remains
neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
AL GRAWANY
Preface
Prior to COVID-19, I would typically complete one or two death certificates

per month but at times during the worst phases of the pandemic, I would
complete nearly one per day. COVID has caused so much illness and death,
as well as severe stress on healthcare providers which is still ongoing and
may take significant time and efforts (counselling, peer support, time away
from work) to remedy. When asked to lead a project on the care of critically
ill ED patients with COVID, I was certain that this book could offer some
guidance to the frontline clinicians in the ED, inpatient units, and ICUs, as
well as hopeful that it could help support all of us during these terrible times.
This book is written almost exclusively by physicians trained in emer-
gency medicine and critical care, and will focus predominantly on adult
patients. It will offer a concise interpretation of the most recent medical lit-
erature as well as the important recommendations based on the author’s expe-
riences during clinical encounters.
Over the last 9 months caring for ICU patients with COVID-19 illness, I
have seen the many ways that this infection can cause severe illness and suf-
fering. Pulmonary infiltrates with extreme hypoxemia often without frank
respiratory distress is most common, but there have been many other vascular
system complications including ischemic stroke, STEMI, pulmonary emboli,
and peripheral arterial thrombosis that have occurred even when on therapeu-
tic dose anticoagulation. Sinus bradycardia not due to any medication or
other cause is so common that I have begun to refer to it in my daily notes as
COVID-cardia, and I avoid any AV nodal blocking agents including dexme-
detomidine in order to reduce the risk of worsening the heart rate.
Because I have been involved in cases where the fear of COVID as well as
the overwhelming cognitive pressure of the pandemic has caused missed or
delayed diagnosis of other serious illnesses, I will remind all of us to still
keep an open differential diagnosis while looking to rule in/out the other life-
threatening conditions. These cases include hypoxemic patients who have
had two to three negative COVD tests at primary care offices, urgent care
centers, and now in the ED but were not immediately considered for their
Pneumocystis pneumonia from unrecognized advanced HIV/AIDS, or their
severe community acquired pneumonia, or their common iliac DVT with
ongoing pulmonary emboli. Also be cautious to not let the COVID testing
process slow down the actual definitive care, such as in a young lady in hem-
orrhagic shock from hemoperitoneum caused by rupture of a large ovarian
cyst, who was delayed going to the OR awaiting her COVD test to return (-)
v
vi Preface
since she was tachycardic and tachypneic with low-grade fever. Conversely, I
was involved in the care of a young man with a VPS (ventricular peritoneal
shunt) who had headache and nausea/vomiting who despite a normal brain
CT and neurological examination had his shunt revised due to the assumption
that there was an underlying equipment dysfunction, only to test COVID (+)
on POD 0.
During these last 9 months, I have adapted my practice in order to address
the most common COVID illness in the ICU, severe hypoxemia without
respiratory distress, by primarily using high flow nasal cannula (HFNC) even
with an additional non-rebreather mask to help keep SaO2 >88-90% since
intubation doesn’t appear to add much benefit to many of these patients. I also
use a frequent positional change regimen (typically every 2 hours while
awake: laying supine, sitting up or at least reverse Trendelenburg, right and
left lateral decubitus, and prone if the patient can tolerate it) as well as getting
the patient out of bed to chair and even walking around in the room if possi-
ble. Proning becomes important specifically if the patient has been lying flat
for extended periods (if our patients had been traditionally cared for lying
face down, then our crucial treatment would now be “supining” as the lung
doesn’t function well for extended periods in only one position).
I truly hope this book will help in the care of our patients as well as be of
some solace to my colleagues. Please recall the quote that is indeed quite fit-
ting for our profession especially during this pandemic:
“To cure sometimes, to relieve often, to comfort always.” Dr. Edward
Trudeau (1848–1915)
Stay Well,
Joseph “Joe” Shiber
Jacksonville, FL, USA Joseph R. Shiber

AL GRAWANY
Contents
1 Overview of the COVID-19 Infection�� 1

Gina Hurst, Jayna Gardner-Gray, Jacqueline Pflaum-Carlson,
and Jeff Coursen
2 Management of Undifferentiated Critically Ill
COVID-19 Patients�� 11
Quincy K. Tran
3 Personal Protection During Patient Care and Procedures�� 19
Mark Sutherland, David Gordon, and Michael Winters
4 Evaluation and Diagnosis of COVID Illness�� 33
Danny VanValkinburgh and Brian T. Wessman
5 Noninvasive Respiratory Support for COVID-19 �� 43
Josiah Smith, Nicholas Goodmanson, and Matthew Niehaus
6 Mechanical Ventilation in the COVID-19 Patient�� 49
Katelin Morrissette, Skyler Lentz, and Jarrod Mosier
7 ECMO and Rescue Therapies for Severe Hypoxemia�� 63
Emily Ball, Keith Azevedo, and Jonathan Marinaro
8 COVID-19: Cardiac Arrest Management�� 73
Casey T. Carr and Torben K. Becker
9 COVID-19-Related Cardiac Illness�� 87
Christopher J. Hogan
10 COVID Cardiovascular Illness �� 99
Timothy J. Ellender and Joseph R. Shiber
11 COVID-19 Renal Illnesses�� 111
Marie-Carmelle Elie-Turenne and Kruti Shah
12 COVID-19 Hepatic Illness�� 123
Kimberly Boswell
13 Hematologic Emergencies in Patients with Covid-19 �� 131
Jessica Waters, Rory Spiegel, and Michael T. McCurdy
14 COVID-19 Neurologic Illnesses�� 141
David Poliner and Wan-Tsu Wendy Chang
vii
viii Contents
15 Pharmacological Agents for COVID-19 Patients�� 151

Donald Johnson, Randi Searcy, and Beranton Whisenant
16 Point of Care Echocardiography in the
COVID-19 Patient�� 167
Daniel Haase, William A. Teeter, Jaskirat Gill, and
Adnan Javed
17 Inter-Hospital Transfer of the Critically Ill
COVID-19 Patient�� 175
Adam B. Schlichting, Zeid Kalarikkal, and Nicholas M. Mohr
18 Surge Planning �� 189
Daniel Eraso and Brian Wright
19 Surgical Emergencies�� 199
T. Shane Hester
Index�� 207
AL GRAWANY
Contributors
Keith Azevedo Critical Care and Emergency Medicine at the University of

New Mexico, Departments of Emergency and Internal Medicine, Albuquerque,
NM, USA
Emily Ball Surgical Critical Care Fellow at the University of New Mexico,
Departments of Surgery and Emergency Medicine, Albuquerque, NM, USA
Torben K. Becker Division of Critical Care Medicine, Department of
Emergency Medicine, University of Florida – Health, Gainesville, FL, USA
Kimberly Boswell R Adams Cowley Shock Trauma Center, University of
Maryland School of Medicine, Baltimore, MD, USA
Casey T. Carr Division of Critical Care Medicine, Department of Emergency
Medicine, University of Florida – Health, Gainesville, FL, USA
Wan-Tsu Wendy Chang Departments of Emergency Medicine and
Neurology, Program in Trauma, University of Maryland School of Medicine,
Baltimore, MD, USA
Jeff Coursen Ascension Healthcare, St. Louis, MO, USA
Marie-Carmelle Elie-Turenne Department of Emergency Medicine,
University of Alabama at Birmingham, Birmingham, AL, USA
Timothy J. Ellender Department of Emergency Medicine, Indiana
University School of Medicine, Indianapolis, IN, USA
Daniel Eraso University of Florida Jacksonville, Jacksonville, FL, USA
Jayna Gardner-Gray Henry Ford Hospital, Detroit, MI, USA
Jaskirat Gill Surgical Critical Care Fellow, Program in Trauma/Surgical
Critical Care, R Adams Cowley Shock Trauma Center, University of Maryland
School of Medicine, Baltimore, MD, USA
Nicholas Goodmanson Advocate Christ Medical Center and Advocate
Lutheran General Hospital/University of Illinois at Chicago, Chicago, IL,
USA
David Gordon Department of Medicine, University of Maryland School of
Medicine, Baltimore, MD, USA
ix
x Contributors
Daniel Haase Departments of Emergency Medicine and Surgery, Program

in Trauma/Surgical Critical Care, R Adams Cowley Shock Trauma Center,
University of Maryland School of Medicine, Baltimore, MD, USA
Christopher J. Hogan VCU School of Medicine, Richmond, VA, USA
Gina Hurst Henry Ford Hospital, Detroit, MI, USA
Adnan Javed University of Florida College of Medicine - Jacksonville,
Department of Emergency Medicine, Jacksonville, FL, USA
Donald Johnson UF Health Jacksonville: SICU, Jacksonville, FL, USA
Zeid Kalarikkal Aurora Critical Care Service, Aurora Emergency Medicine
Services, Milwaukee, WI, USA
Skyler Lentz Department of Medicine, Division of Pulmonary and Critical
Care Medicine, University of Vermont Medical Center, Burlington, VT, USA
Department of Surgery, Division of Emergency Medicine, University of
Vermont Larner College of Medicine, Burlington, VT, USA
Jonathan Marinaro University of New Mexico Center for Adult Critical
Care, University of New Mexico ECMO Program, Department of Emergency
Medicine, Albuquerque, NM, USA
Department of Emergency Medicine and Critical Care, University of New
Mexico, Albuquerque, NM, USA
Michael T. McCurdy University of Maryland School of Medicine,
Baltimore, MD, USA
Nicholas M. Mohr Department of Emergency Medicine, Division of Critical
Care, Department of Anesthesia, University of Iowa Carver College of
Medicine, Iowa City, IA, USA
Katelin Morrissette Department of Medicine, Division of Pulmonary and
Critical Care Medicine, University of Vermont Medical Center, Burlington,
VT, USA
Jarrod Mosier Department of Emergency Medicine, University of Arizona
College of Medicine, Tucson, AZ, USA
Division of Pulmonary, Allergy, Critical Care and Sleep, Department of
Medicine, University of Arizona College of Medicine, Tucson, AZ, USA
Matthew Niehaus University Hospitals Cleveland Medical Center/Case
Western Reserve University, Cleveland, OH, USA
Jacqueline Pflaum-Carlson Henry Ford Hospital, Detroit, MI, USA
David Poliner Section of Neurocritical Care and Emergency Neurology,
Department of Neurology, University of Maryland Medical Center, Baltimore,
MD, USA
Adam B. Schlichting Medical Respiratory Intensive Care Unit, Aurora St.
Luke’s Medical Center, Aurora Critical Care Service, Aurora Emergency
Medicine Services, Milwaukee, WI, USA
AL GRAWANY
Contributors xi
Randi Searcy UF Health North: North ICU, Jacksonville, FL, USA

Kruti Shah Department of Emergency Medicine, University of Florida,
Gainesville, FL, USA
T. Shane Hester University of Florida College of Medicine – Jacksonville,
Joseph R. Shiber Departments of Emergency Medicine, Neurology and
Surgery, University of Florida Health Science Center, Jacksonville, FL, USA
Josiah Smith University Hospitals Cleveland Medical Center/Case Western
Reserve University, Cleveland, OH, USA
Rory Spiegel Departments of Emergency Medicine and Critical Care,
MedStar Washington Hospital Center, Washington, DC, USA
Mark Sutherland University of Maryland School of Medicine, Baltimore,
MD, USA
William A. Teeter Departments of Emergency Medicine, Program in
Trauma/Surgical Critical Care, R Adams Cowley Shock Trauma Center,
University of Maryland School of Medicine, Baltimore, MD, USA
Quincy K. Tran Department of Emergency Medicine, University of
The Critical Care Resuscitation Unit, The R Adams Cowley Shock Trauma
Center, University of Maryland School of Medicine, Baltimore, MD, USA
Danny VanValkinburgh Critical Care Medicine Fellow, Washington
University in Saint Louis School of Medicine, Barnes-Jewish Hospital,
St. Louis, MO, USA
Jessica Waters Department of Emergency Medicine, MedStar Washington
Hospital Center, Washington, DC, USA
Brian T. Wessman Washington University in Saint Louis, School of
Medicine, St. Louis, MO, USA
Beranton Whisenant UF Health Jacksonville, Departments of Emergency
Medicine and Critical Care, Jacksonville, FL, USA
Michael Winters Department of Emergency Medicine, University of
Brian Wright Stony Brook University, Stony Brook, NY, USA
Overview of the COVID-19
Infection
1
Gina Hurst, Jayna Gardner-Gray,
Jacqueline Pflaum-Carlson, and Jeff Coursen
Introduction well-being of our communities. This chapter will

aim to discuss the epidemiology, virology, and
The world was awakened to a new reality in the clinical presentation of SARS-Cov-2, to create a
dawn of 2020 when a novel coronavirus made foundation to explore this disease, its manifesta-
itself known as the source of a global pandemic. tions, and treatment options in greater detail
Coronavirus disease 2019 (COVID-19) was iden- throughout this book.
tified as the culprit of a respiratory illness arising
in China, in December of 2019, and quickly
spread globally. COVID-19 is caused by a novel Epidemiology
severe acute respiratory syndrome coronavirus
(SARS-Cov-2) which has also been referred to as In December of 2019, a cluster of atypical pneu-
2019-nCov. The manifestation of this illness var- monia cases of unknown etiology occurred in
ies in severity, as will be discussed later in the Wuhan, a city in the Hubei Province of China.
chapter, with hallmark features affecting the In January of 2020, testing confirmed the identi-
respiratory system. As of December 2020, the fication of a novel coronavirus in the throat of
global number of cases has exceeded 85 million one of the initial patients afflicted with this
with 1.8 million individuals dying as a result of atypical respiratory illness. This novel coronavi-
this infection. The burden of this illness extends rus was named severe acute respiratory syn-
far beyond the mortality of the disease, as the drome coronavirus-2 (SARS-CoV-2) [1, 2]. The
international medical community has been World Health Organization (WHO) declared the
stressed to respond to an illness with significant disease caused by SARS-CoV-2 as coronavirus
morbidity and yet unknown long-term impact. disease 2019 (COVID-19). Subsequently,
COVID-19 not only has staked a claim in the COVID-19 was declared a global pandemic in a
environment of medicine but also has had signifi- statement delivered by the WHO on March 11,
cant societal effect as it has impacted the econ- 2020. Several health organizations and institu-
omy along with the emotional and social tions have attempted to identify the source of
SARS-CoV-2 and origins of the COVID-19
G. Hurst (*) · J. Gardner-Gray · J. Pflaum-Carlson pandemic, resulting in several similar hypothe-
Henry Ford Hospital, Detroit, MI, USA ses of transmission.
e-mail: [email protected]; [email protected];
[email protected]
SARS-CoV-2 is not alone in its identification
as a highly infective organism; it belongs to a
J. Coursen
Ascension Healthcare, St. Louis, MO, USA
large family of viruses, some of which cause
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 1

J. R. Shiber (ed.), Critical Care of COVID-19 in the Emergency Department,
https://doi.org/10.1007/978-3-030-85636-6_1
AL GRAWANY
2 G. Hurst et al.
respiratory illness in humans. These illnesses virus has not been identified. It is possible that
range from mild upper respiratory illness (the the SARS-CoV-2 spillover event occurred at the
common cold) to more severe outbreaks of ill- market. However, it is also possible a human
nesses, such as severe acute respiratory syn- already infected with SARS-CoV-2 introduced
drome (SARS-CoV-1) and Middle East the virus to the market and it subsequently served
respiratory syndrome (MERS-CoV) [3]. Many as an amplification center. More research is
coronavirus s pecies can infect both humans and needed to determine the exact origin of the pre-
animal species. A virus transmitted from an ani- sumed spillover event.
mal to a human is called a zoonotic virus. The SARS-CoV-2 has subsequently been identi-
transmission from animal to human is termed fied in persons on every continent across the
the spillover event. Both SARS-CoV-1 and globe, excluding Antarctica. The genomic
MERS-CoV were identified as zoonotic viruses sequence of SARS-CoV-2 is similar from sam-
arising from various wildlife and dromedary ples across the globe suggesting a single spillover
camels, respectively [6]. Upon investigation, it event from animal to human followed by rapid
appears SARS-CoV-2 is closely genetically person-to-person spread [5].
related to coronaviruses isolated from some bat
species; therefore, it is believed that they are the
ecological reservoir for SARS-CoV-2 [4]. It is Virology
not known exactly how SARS-CoV-2 was trans-
mitted from its presumed ecological reservoir in Coronaviruses are the largest group of viruses
bats eventually to humans. As human interac- under the order of Nidovirales, with further sub-
tion with bats is relatively rare, it is hypothe- classification into four genera: Alphacoronavirus,
sized the SARS-CoV-2 may have had an Betacoronavirus, Deltacoronavirus, and
intermediate animal host prior to transmission Gammacoronavirus. Alpha- and betacoronavi-
to humans. This hypothesis is derived from ruses are the subclassifications known to infect
experience with SARS-CoV-1 which had its humans, while the gamma- and deltacoronavi-
ecological reservoir in horseshoe bats and then ruses primarily infect birds. SARS-CoV-2, the
infected masked palm civets before being trans- virus that causes COVID-19, is an enveloped
mitted to humans [3]. betacoronavirus with a similar genetic sequence
The investigation of the spillover event lead- to SARS-CoV-1 (80%) and bat coronavirus
ing to transmission of SARS-CoV-2 began in RaTG13 (96.2%) [7]. Two betacoronaviruses
Wuhan City, China, where a large proportion of have been previously known to be associated
the initial cases of COVID-19 were identified. with severe disease along with significant trans-
These cases were linked to the Huanan Seafood mission: severe acute respiratory syndrome
Wholesale Market, a location where various liv- coronavirus (SARS-CoV-1) and Middle East
ing wild animals were being sold [1]. Many of respiratory syndrome coronavirus (MERS-
the index cases were stall owners, employees, or CoV). The SARS outbreak was a worldwide
visitors of the market [1]. According to the pandemic in 2002–2003 with over 8000 cases
Chinese Center for Disease Control and and 774 deaths reported. MERS was responsible
Prevention (Chinese CDC), several environmen- for over 2000 cases and 780 deaths reported in
tal samples from the market tested positive for 2012. SARS-CoV-2 is the seventh coronavirus
SARS-CoV-2. There was suspicion of zoonotic identified to infect humans [8, 9]. The emergence
transmission as SARS-CoV-2 was shown to be and impact of these viruses on the human popu-
related to a coronavirus derived from chrysanthe- lation have reshaped our view of the virus previ-
mum bats (Rhinolophus ferrumequinum). ously associated, most often, with the common
However, a specific animal associated with the cold [10].
1 Overview of the COVID-19 Infection 3
Virion Structure and Host Cell Entry through the mechanism of binding and fusion
using the S′ protein. The virus acts by binding to
The Coronaviridae family of viruses are envel- the target cell and initiating fusion with the host
oped, single-stranded positive-sense RNA cell membrane. The S protein is made up of two
viruses. The virions are spherical with diame- domains S1 and S2. S1 is further classified into
ters of approximately 125 nm evidenced by three subdomains A, B, and C. Subdomain A of
cryo-electron tomography and cryo-electron S1 is primarily responsible for binding with host
microscopy [11]. Coronavirus particles contain receptors. It contains the receptor binding domain
four main structural proteins. They have club- and engages with the host receptor, while S2
shaped trimeric surface spike (S) glycoproteins mediates subsequent membrane fusion and ulti-
that give the virions the appearance of a crown, mate release of the viral genome into the host
hence the Latin name corona meaning “crown” cytoplasm. The S proteins of SARS-CoV-2 use
[12]. The three additional major structural pro- host ACE2 as their receptor [13]. The SARS-
teins are the membrane (M), envelope (E), and CoV-2 S protein binds to the host ACE2 receptor
the nucleocapsid (N) protein located in the and is then cleaved at S1/S2 and S2’ sites by a
core (Fig. 1.1). protease. This lysis leads to an irreversible con-
The M protein is critical for incorporating formation change which increases the binding
essential viral components into the virions during affinity of the protein. This leads to activation of
morphogenesis and thought to give the virion its the S2 domain and drives the above-described
shape. The N protein is the only protein present fusion of the viral and host membranes. The
in the nucleocapsid. It associates with the viral ACE2 receptors are expressed in most organs
genome and M protein to direct genome packag- with higher concentrations found in the lung and
ing into new viral particles. The E protein is a small intestine [14]. The cleavage sites and S1
transmembrane protein that forms an ion channel receptor binding sites are thought to be the rea-
in the viral membrane and aids in viral assembly sons of increased rapidity of transmission, repli-
and release. The E protein is not required for viral cation, and infectivity of this virus [9]. A
replication but is necessary for pathogenesis. The considerable amount of research has been dedi-
S protein is essential component required for cated to investigating the SARS CoV-2 S protein
viral entry into target host cells. Coronaviruses given the role it plays during viral host cell entry;
enter host cell cytoplasm either by endocytosis or however, further investigation is needed to fully
Fig. 1.1 Schematic
representation of the
SARS-CoV-2 virus
showing all its
components, including a
single-strand RNA,
envelope protein,
nucleocapsid protein,
spike protein, and
membrane protein [38]
AL GRAWANY
4 G. Hurst et al.
understand the relationship between the S protein Viral Transmission

of SARS-CoV-2 and therapeutic interventions.
After a host is in contact with SARS-CoV-2, the
virus may enter cells such as nasal or bronchial
Viral Replication epithelial cells and pneumocytes [19]. This con-
tact is likely to occur during interactions where
In general, coronaviruses have one of the largest respiratory droplet exposure may occur such as
known genomes of RNA viruses, ranging from talking, sneezing, or coughing. This “droplet
26 to 32 kb in length. The genome contains a 5′ exposure” is a result of a direct spray of large
cap structure along with a 3′ poly (A) tail, allow- droplets containing viral particles [20]. The risk
ing it to act as an mRNA for translation of the of viral transmission from droplet exposure is
replicase polyproteins. Two-thirds of the genome dependent upon length of exposure, type of expo-
contain open reading frames (ORFs) that encode sure, and use of preventative measures (e.g.,
the replicase gene [15]. These ORFs get trans- masks).
lated into two large polyproteins, pp1a and pp1ab. It is also possible to spread SARS-CoV-2
Subsequently, two protease enzymes, namely, through contact with contaminated surfaces,
papain-like protease (PL pro) and 3C-like prote- albeit to a much lower degree than droplet spread.
ase (3CLpro), cleave these polyproteins into 16 The transmission from inanimate surfaces is
non-structural proteins (NSPs) [16]. These NSPs related to the viral load on the surface. Logically,
are involved in the replication and transcription one would presume that a higher viral load con-
process and are also referred to as replicase and tent on a surface would lead to a greater risk of
transcriptase proteins. The NSPs arrange them- infection in an exposed host. What remains
selves within the rough endoplasmic reticulum unclear is the quantity of viral particles required
and make the replicase-transcription complex to lead to an infection after a contaminated sur-
(RTC). The RTC create a stable environment for face exposure. The materials encountered by a
RNA synthesis and play a role in RNA replica- host have varying propensity to maintain a per-
tion and transcription of the sub-genomic RNAs. sistent viral load. SARS-CoV-2 appears to have a
The remaining one-third of the viral genome longer life on impermeable surfaces, with esti-
make up the structural and accessory proteins. mates up to 3 and 4 days, whereas on permeable
These are transcribed into antisense RNA using surfaces, the virus tends to have a more abbrevi-
RNA-dependent RNA polymerase [17]. The anti- ated life span. Although these viral particles may
sense is replicated and forms a full-length posi- remain on inanimate objects for a prolonged
tive strand of genomic RNA using replicase period, the particles degrade and reduce in infec-
activity of the viral RNA-dependent RNA poly- tious potential with time. They become unlikely
merase [18]. Antisense RNA also synthesizes dif- to cause infection within 48–72 hours [19, 22].
ferent small subgenomic mRNA via transcription Aerosol exposure is another source of disease
process. This gives rise to the viral structural pro- transmission. No conclusive studies have been
teins (M,N,E,S) discussed above. Structural pro- conducted on differentiating between the modes
teins E, M, and S are then inserted into the of transmission of viruses via droplets and aero-
endoplasmic reticulum or Golgi membrane. The sols [21]. There is some evidence suggesting that
viral genomic RNA subsequently combines with smaller virus containing aerosols can become air-
protein N to form nucleocapsids and mature viri- borne and may travel beyond the usual 6 feet esti-
ons. The mature viruses containing vesicles are mated for respiratory droplet spread and remain
released from the cell by exocytosis or fusion in the air for several hours [22]. These events
with the plasma membrane. The virions may then appear less common than respiratory droplet
continue this process by entering neighboring exposure and have typically involved the pres-
host cells and increasing the viral burden within a ence of an infectious person producing respira-
host (Fig. 1.2). tory droplets for an extended time (>30 minutes
Fig. 1.2 Replication of the virus in host cell. SARS- replicated and formed into a full-length positive strand of
CoV-2 enters the host cell by binding with specific cell genomic RNA utilizing the replicase activity of RNA
surface receptors (ACE receptor). S proteins facilitate the polymerase. Antisense RNA also synthesizes several dif-
process of entry between the host and the viral cell mem- ferent small subgenomic mRNAs and further translates
brane. Viral genomic mRNA then enters the host cell cyto- structural proteins like envelope protein (E), membrane
plasm. A two-third portion of the genomic RNA contains protein (M), nucleocapsid (N), and spike proteins (S).
ORFs which get translated into two polypeptides (pp1a, These structural proteins are assembled into the nucleo-
pp1ab). These further give rise to NSPs through proteoly- capsid and viral envelopes at the ER. This is followed by
sis. These NSP proteins are involved in the replication and release of the mature virus by exocytosis or membrane
transcription processes. The remaining one-third of the fusion [38]
viral genome is transcribed into antisense RNA which is
AL GRAWANY
6 G. Hurst et al.
to multiple hours) in an enclosed space [23, 24]. Lastly, the question of vertical transmission
While transmission of infectious material is pos- has been raised. It is the current observation
sible, the degree of risk for aerosol spread within that maternal COVID-19 is low risk for vertical
the community is unclear at the time of this transmission; however, this research is limited
authorship. [19, 27].
Within the medical field, aerosol-related
infectious transmission is of particular concern.
Medical procedures have the potential to create Viral Shedding
aerosols in addition to those that patients regu-
larly form from breathing, coughing, sneezing, or Early in the course of illness, SARS-CoV-2 car-
talking. These medical treatments and interven- ries the highest potential for transmission. The
tions are commonly referred to as aerosol- viral load present in the upper respiratory tract
generating medical procedures (AGMPs) [25]. peaks around the time of symptom onset, allow-
AGMPs such as intubation, mechanical ventila- ing SARS-CoV-2 its greatest potential for spread.
tion, nebulized medication administration (see The period of infectiousness is present for 7–10
Table 1.1), and other interventions increase the days, as viral shedding begins approximately 2–3
risk of nosocomial transmission of disease to days prior to symptom onset and extends for
healthcare workers [26]. Aerosol generation nearly a week after symptom onset [28]. The
occurs by procedures that mechanically create transmission of SARS-CoV-2 is possible from
and disperse aerosols and procedures that induce asymptomatic, pre-symptomatic, as well as
the patient to produce aerosols. Research on symptomatic individuals [29–31]. The pre-
SARS-CoV and MERS-CoV viruses confirmed symptomatic transmission is thought to be the
the potential for nosocomial transmission of most significant contributor to disease transmis-
Coronaviridae via AGMPs and has since been sion accounting for a presumed 48%–62% of
extrapolated to SARS-CoV-2 [25, 26]. transmitted infections [32]. The rate of transmis-
sion from asymptomatic infections seems to be
much lower than pre-symptomatic or symptom-
Table 1.1 Potential aerosol-generating medical proce-
dures involved in nosocomial virus transmission [26] atic individuals. It is difficult, however, to inter-
pret literature reporting asymptomatic infections,
How/where aerosols may be
AGMP generated as it is unclear if these cases are truly lacking
Bronchoscopy Induced cough, respiratory symptoms. It is possible that mild symptoms
tract went unrecognized or individuals had not yet
Cardiopulmonary Induced cough, mechanical developed symptoms and would have more
resuscitation dispersal of aerosols, appropriately been labeled as pre-symptomatic.
respiratory tract
Noninvasive Possible mechanical dispersal
This lack of certainty poses a challenge in deter-
ventilation of aerosols, respiratory tract mining the significance of an asymptomatic indi-
Endotracheal Induced cough, respiratory vidual as a source of transmission.
intubation tract
Manual ventilation Possible mechanical dispersal
of aerosols, respiratory tract
Sputum induction Induced cough, respiratory
COVID19 Clinical Presentations
tract
Nebulizer treatment Possible mechanical dispersal The disease caused by SARS-CoV-2 is referred
of aerosols, respiratory tract to as COVID-19, which primarily presents as a
Laser plume Mechanical dispersal of respiratory infection and may manifest with other
aerosols
Surgery Cutting bone and tendon,
organ involvements. Severity of disease varies,
irrigation and aerosolized with risk for hospitalization and need for respira-
blood tory support being higher in certain populations.
Suctioning Possible mechanical dispersal Early data from the initial outbreak in Wuhan,
of aerosols, respiratory tract
China, identified elderly patients and those with range of illness spectrum, the disease is divided
underlying cardiac disease as highest risk [33]. into categories based on severity: asymptomatic,
Now that there have been over 85 million cases pre-symptomatic, mild illness, moderate illness,
globally, more information regarding disease severe illness, and critical illness [35].
manifestation and presentation is known.
The clinical spectrum of COVID-19 patient Asymptomatic or Pre-symptomatic
presentations varies widely, ranging from asymp- Infection Individuals who test positive for
tomatic infection to severe acute respiratory fail- SARS-Cov-2 using a virologic test but who have
ure with multisystem organ dysfunction. The no symptoms that are consistent with
average incubation period of COVID-19 is 5 COVID-19.
days, such that the time from exposure to symp-
tom onset will typically occur within 1 week. The Mild Illness Patients experience fatigue, muscle
most common symptoms associated with aches, cough, nasal congestion, sore throat, and
COVID-19 are fever (most common), cough with headache. Occasionally nausea, vomiting, and
or without sputum, dyspnea, headache, myalgias, diarrhea have been observed. These patients do
fatigue, anosmia, ageusia, and diarrhea (see not present with dyspnea, or abnormal imaging.
Table 1.2). Less common, but other observed, Mild illness accounts for the majority of symp-
symptoms include abdominal pain and hemopty- tomatic patients.
sis [19].
The earliest days of infection tend to possess Moderate Illness In addition to symptoms of
constitutional symptoms of fever, fatigue, head- mild illness, imaging or clinical assessment sug-
ache, and muscles aches, beginning as soon as 2 gests lower respiratory disease; SpO2 will be
days from exposure to virus. The vast majority ≥94% on room air.
(80%) of those afflicted with COVID-19 will
have mild symptoms and recover without conse- Severe Illness Individuals will have dyspnea,
quence. For others, the disease progresses in respiratory rate >30 breaths/minute, SpO2 < 94%
severity, and symptoms of dyspnea may appear on room air, a PaO2/FiO2 ratio <300 mmHg, or
within 5–8 days after illness onset. Respiratory chest x-ray with >50% lung infiltrates.
failure may follow, associated with worsening
oxygenation and a median time to mechanical Critical Illness Individuals with respiratory fail-
ventilation between 9 and 12 days. In cases of ure, most often acute respiratory distress syn-
severe illness, presentation could extend beyond drome (ARDS), and septic shock (virus-induced
this window, with some observational studies distributive shock) with multiple organ dysfunc-
noting time from onset of illness to respiratory tion. Multifocal pneumonia on x-ray or CT
failure as late as 14 days [34]. Given the wide imaging.
While these classifications are plotted along a
Table 1.2 Common symptoms of hospitalized patients spectrum, the illness categories are useful for
with COVID-19 determining therapeutic interventions, prognosis,
Symptom Frequency and research. Furthermore, these illness catego-
Fever 70–90% ries are helpful in identifying which patient
Cough 60–86% should be hospitalized. Patients with severe and
Dyspnea 53–80% critical illness have features that necessitate hos-
Anosmia or ageusia 33–80%
pitalization, whereas those with moderate illness
Fatigue 38%
Myalgias 15–44%
require a discerning evaluation. Consideration of
Nausea, vomiting, or diarrhea 15–39% risk factors for the development of severe illness
Sore throat 18% (Table 1.3) can lead to early identification and
Headache 16% hospitalization, or appropriate monitoring with
Chest pain 15% anticipatory guidance.
AL GRAWANY
8 G. Hurst et al.
Extrapulmonary manifestations of COVID-19 nary and extrapulmonary organ systems of

have been observed, affecting all organ systems. COVID-19.
Symptoms vary based on severity of illness and
degree of organ involvement. This may include Critical Points
abnormalities such as myocarditis, liver failure, • SARS-CoV-2 is a betacoronavirus responsible
gastrointestinal distress, hypercoagulable states, for a novel respiratory illness referred to as
cutaneous rashes, and encephalitis. COVID-19 COVID-19.
has the propensity to have substantial effect on • The virology of SAR-CoV-2 has a structure
other organ systems, which will be examined in which lends itself to easy spread and provides
detail throughout this textbook. a pathophysiological underpinning to the
respiratory and multi-organ involvement of
the COVID-19 infection.
Conclusion • COVID-19 is commonly transmitted from
person-person contact via respiratory
SARS-CoV-2, a novel severe acute respiratory droplets.
syndrome coronavirus, is the culprit virus leading • SARS-CoV-2 has its greatest potential for
to COVID-19. This virus was initially identified transmission in early infection when viral load
as the source of a respiratory illness in Wuhan, is highest, often before an individual has
China, and later as a global pandemic in early symptoms.
2020. This betacoronavirus is transmitted by • The majority of COVID-19 infections will be
exposure to droplets, contaminated surfaces, and classified as mild illness with upper respira-
aerosols. Transmission is likely to occur in earlier tory symptoms or flu-like illness.
stages of infection when the host has a high viral • Severe and critical COVID-19 infections
load. COVID-19 typically presents with fever, cause ARDS and multi-organ dysfunction.
cough, and dyspnea. This illness has a spectrum
of severity ranging from mild upper respiratory
symptoms to cytokine storm, ARDS, and multi- References
ple organ failure. This infection has the propen-
sity to affect multiple organ systems in a unique 1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang
L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y,
manner due to its pro-inflammatory traits. This Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H,
textbook will continue to explore the diagnosis, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang
management strategies, and impact on pulmo- J, Cao B. Clinical features of patients infected with
2019 novel coronavirus in Wuhan, China. Lancet.
2020;395(10223):497–506. https://doi.org/10.1016/
S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum
Table 1.3 Risk factors for severe COVID-19 in: Lancet. 2020 Jan 30;: PMID: 31986264; PMCID:
PMC7159299.
Risk factors for the development of severe 2. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y,
COVID-19 Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X,
Age ≥ 65 Zhang L. Epidemiological and clinical characteris-
Male sex tics of 99 cases of 2019 novel coronavirus pneumo-
Obesity (BMI >30) nia in Wuhan, China: a descriptive study. Lancet.
Pregnancy 2020;395(10223):507–13. https://doi.org/10.1016/
Heart disease S0140-6736(20)30211-7. Epub 2020 Jan 30. PMID:
Diabetes mellitus 32007143; PMCID: PMC7135076.
Smoking 3. Paules CI, Marston HD, Fauci AS. Coronavirus
Chronic lung disease infections-more than just the common cold. JAMA.
Chronic kidney disease
jama.2020.0757. PMID: 31971553.
Sickle cell disease 4. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W,
Cancer Song H, Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang
Immunosuppression L, Hu T, Zhou H, Hu Z, Zhou W, Zhao L, Chen J,
Meng Y, Wang J, Lin Y, Yuan J, Xie Z, Ma J, Liu WJ, 19. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ,
Wang D, Xu W, Holmes EC, Gao GF, Wu G, Chen Prescott HC. Pathophysiology, transmission, diag-
W, Shi W, Tan W. Genomic characterisation and nosis, and treatment of coronavirus disease 2019
epidemiology of 2019 novel coronavirus: implica- (COVID-19): a review. JAMA. 2020;324(8):782–93.
tions for virus origins and receptor binding. Lancet. 20. Nicas M, Nazaroff WW, Hubbard A. Toward under-
2020;395(10224):565–74. https://doi.org/10.1016/ standing the risk of secondary airborne infection:
S0140-6736(20)30251-8. Epub 2020 Jan 30. PMID: emission of respirable pathogens. J Occup Environ
32007145; PMCID: PMC7159086. Hyg. 2005;2(3):143–54.
5. Andersen KG, Rambaut A, Lipkin WI, et al. The prox- 21. Jayaweera M, Perera H, Gunawardana B, Manatunge
imal origin of SARS-CoV-2. Nat Med. 2020;26:450– J. Transmission of COVID-19 virus by droplets and
2. https://doi.org/10.1038/s41591-020-0820-9. aerosols: a critical review on the unresolved dichot-
6. Petersen E, Koopmans M, Go U, Hamer DH, omy. Environ Res. 2020;188:109819.
Petrosillo N, Castelli F, Storgaard M, Al Khalili S, 22. van Doremalen N, Bushmaker T, Morris DH,

Simonsen L. Comparing SARS-CoV-2 with SARS- Holbrook MG, Gamble A, Williamson BN, Tamin A,
CoV and influenza pandemics. Lancet Infect Dis. Harcourt JL, Thornburg NJ, Gerber SI, Lloyd-Smith
2020;20(9):e238–44. https://doi.org/10.1016/S1473- JO, de Wit E, Munster VJ. Aerosol and surface stabil-
3099(20)30484-9. Epub 2020 Jul 3. PMID: 32628905; ity of SARS-CoV-2 as compared with SARS-CoV-1.
PMCID: PMC7333991. N Engl J Med. 2020;382(16):1564–7.
7. Yan R, et al. Structural basis for the recognition of 23. Balachandar S, Zaleski S, Soldati A, Ahmadi G,

SARS-CoV-2 by full-length human ACE2. Science. Bourouiba L. Host-to-host airborne transmis-
2020;367:1444–8. https://doi.org/10.1126/science. sion as a multiphase flow problem for science-
abb2762. PMID: 32132184. based social distance guidelines. Int J Multiphase
8. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang Flow. 2020;132:103439. https://doi.org/10.1016/j.
W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen ijmultiphaseflow.2020.103439.
J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen 24. CDC. Scientific brief: SARS-CoV-2 and poten-

XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng tial airborne transmission. https://www.cdc.gov/
F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, coronavirus/2019-ncov/more/scientific-brief-sars-
Shi ZL. A pneumonia outbreak associated with a cov-2.html.
new coronavirus of probable bat origin. Nature. 25. Davies A, Thomson G, Walker J, Bennett A. A review
2020;579(7798):270–3. of the risks and disease transmission associated with
9. Paules C, et al. Coronavirus infections-more than just aerosol generating medical procedures. J Infect Prev.
the common cold. JAMA. https://doi.org/10.1001/ 2009;10:122–6.
jama.2020.1097. 26. Judson SD, Munster VJ. Nosocomial transmission of
10. Paules C, et al. Coronavirus infections-more than just emerging viruses via aerosol-generating medical pro-
the common cold. JAMA. https://doi.org/10.1001/ cedures. Viruses. 2019;11(10):940. Published 2019
jama.2020.1097. Oct 12. https://doi.org/10.3390/v11100940.
11. Barcena M, et al. Cryo-electron tomography of mouse 27. Zaigham M, Andersson O. Maternal and perina-

hepatitis virus: insights into the structure of the corona tal outcomes with COVID-19: a systematic review
virion. Proc Natl Acad Sci U S A. 2009;106:582–7. of 108 pregnancies. Acta Obstet Gynecol Scand.
12. Perlman S. Another decade, another coronavirus. N 2020;99(7):823–9.
Engl J Med. 2020;382(8):760–2. 28. He X, Lau EHY, Wu P, Deng X, Wang J, Hao X, Lau
13. Li WH, et al. Angiotensin-converting enzyme 2 is a YC, Wong JY, Guan Y, Tan X, Mo X, Chen Y, Liao
functional receptor for the SARS coronavirus. Nature. B, Chen W, Hu F, Zhang Q, Zhong M, Wu Y, Zhao
426:450–4. https://doi.org/10.1038/nautre02145. L, Zhang F, Cowling BJ, Li F, Leung GM. Temporal
14. Hamming I, et al. Tissue distribution of ACE2 protein, dynamics in viral shedding and transmissibility of
the functional receptor for SARS coronavirus: a first COVID-19. Nat Med. 2020;26(5):672–5.
step in understanding SARS pathogenesis. J Pathol. 29. Wang Y, He Y, Tong J, Qin Y, Xie T, Li J, Li J, Xiang
2004;203:631–7. J, Cui Y, Higgs ES, Xiang J. Characterization of an
15. Cowling BJ, Leung GM. Epidemiological research asymptomatic cohort of severe acute respiratory
priorities for public health control of the ongoing syndrome coronavirus 2 (SARS-CoV-2) infected

global novel coronavirus (2019-nCoV) outbreak. Euro individuals outside of Wuhan, China. Clin Infect Dis.
Surveill. 2020;25(6):2000110. PMID: 32046814. 2020;71(16):2132–8.
16. Schoeman D, Fielding BC. Coronavirus envelope pro- 30. Bai Y, Yao L, Wei T, Tian F, Jin DY, Chen L, Wang
tein: current knowledge. Virol J. 2019;16(1):69. M. Presumed asymptomatic carrier transmission of
17. Fehr AR, Perlman S. Coronaviruses: an overview of COVID-19. JAMA. 2020;323(14):1406–7.
their replication and pathogenesis. Methods Mol Biol. 31. Buitrago-Garcia D, Egli-Gany D, Counotte MJ,

2015;1282:1–23. Hossmann S, Imeri H, Ipekci AM, Salanti G, Low
18. Sawicki S. Coronavirus transcription: a perspective. N. Occurrence and transmission potential of asymp-
Curr Top Microbiol Immunol. 2005;287:31–55. tomatic and presymptomatic SARS-CoV-2 infections:
AL GRAWANY
10 G. Hurst et al.
a living systematic review and meta-analysis. PLoS Emergency Medicine Multidisciplinary COVID-19
Med. 2020;17(9):e1003346. Working Group consensus paper. J Global Infect Dis.
32. Ganyani T, Kremer C, Chen D, Torneri A, Faes C, 2020;12(2):47–93.
Wallinga J, Hens N. Estimating the generation inter- 35. CDC treatment guidelines. Clinical spectrum of

val for coronavirus disease (COVID-19) based on SARS-CoV-2 infection. https://www.covid19treat-
symptom onset data, March 2020. Euro Surveill. mentguidelines.nih.gov/overview/clinical-spectrum/.
2020;25(17):2000257. 36. Kakodkar P, Kaka N, Baig MN. A comprehensive lit-
33. Wu Z, McGoogan JM. Characteristics of and impor- erature review on the clinical presentation, and man-
tant lessons from the coronavirus disease 2019 agement of the pandemic coronavirus disease 2019
(COVID-19) outbreak in China: summary of a report (COVID-19). Cureus. 2020;12(4):e7560. https://doi.
of 72 314 cases from the Chinese Center for Disease org/10.7759/cureus.7560. PMID: 32269893; PMCID:
Control and Prevention. JAMA. 2020;323(13):1239– PMC7138423.
42. https://doi.org/10.1001/jama.2020.2648. 37. Pascarella G, Strumia A, Piliego C, Bruno F, Del
34. Stawicki SP, Jeanmonod R, Miller AC, Paladino
Buono R, Costa F, Scarlata S, Agrò FE. COVID-19
L, Gaieski DF, Yaffee AQ, De Wulf A, Grover J, diagnosis and management: a comprehensive review.
Papadimos TJ, Bloem C, Galwankar SC, Chauhan J Intern Med. 2020;288(2):192–206. https://doi.
V, Firstenberg MS, Di Somma S, Jeanmonod org/10.1111/joim.13091. Epub 2020 May 13. PMID:
D, Garg SM, Tucci V, Anderson HL, Fatimah L, 32348588; PMCID: PMC7267177.
Worlton TJ, et al. The 2019-2020 novel coronavirus 38. Samudrala PK, Kumar P, Choudhary K, et al. Virology,
(severe acute respiratory syndrome coronavirus 2) pathogenesis, diagnosis and in-line treatment of
pandemic: aA oint American College of Academic COVID-19. Eur J Pharmacol. 2020;883:173375.
International Medicine-World Academic Council of https://doi.org/10.1016/j.ejphar.2020.173375.
Management of Undifferentiated
Critically Ill COVID-19 Patients
2
Quincy K. Tran
Critical Points HTN, DM, CAD, CHF, chronic lung disease,

• Patients with early COVID-19 disease com- ESRD, obesity, pregnancy, and cancer.
monly present with fever, myalgias, and GI
symptoms and may not show signs of hypox-
emia or respiratory distress. Background
• Early proning for hypoxic COVID-19 patients
is feasible and beneficial. However, awake Severe acute respiratory syndrome-coronavirus-2
proning should not delay intubation if patients (SARS-CoV-2), which causes COVID-19, has
require mechanical ventilation. affected global health and its practice. Toward the
• Patients with COVID-19 have coagulopathy; end of November 2020, COVID-19 has affected
PT/PTT may not accurately predict risk of approximately 60 million worldwide and caused
major bleeding in these patients. Emergency 1.4 million deaths. The United States is the lead-
clinicians should use thromboelastography ing country with both infection (13 million) and
(TEG) to guide anticoagulation medication. death (260 thousand). As a result of this pan-
• Airway management to reduce viral transmis- demic, emergency medicine is at the forefront of
sion should include video laryngoscopy with this public health crisis.
apneic oxygenation during deep sedation and The illness severity among patients with
paralysis but avoid bagging. COVID-19 infection can range from mild to
• Consider early treatment with remdesivir critical. The median time interval from symp-
(200 mg intravenously for 1 day and then tom onset to development of acute respiratory
100 mg IV for 4 days) and dexamethasone distress syndrome (ARDS) was approximately
(6 mg daily for up to 10 days) for hypoxic 5–8 days [1]. The median time from onset of ill-
COVID-19 patients. ness to ICU admission was 10–12 days [1].
• Risk factors for ICU admission, mechanical However, some patients with COVID-19 also
ventilation, and mortality risk: men, age >60, deteriorate quickly within 1 week from symp-
tom onset. As a result, it is helpful for the emer-
Q. K. Tran (*) gency clinicians to know where the patients are
Department of Emergency Medicine, University of during their disease progress so we can manage
Maryland School of Medicine, Baltimore, MD, USA these critically ill patients more effectively and
The Critical Care Resuscitation Unit, The R Adams promptly. Managing these critically ill patients
Cowley Shock Trauma Center, University of with COVID-19 may be different from other
disease states. However, for emergency clini-
e-mail: [email protected]

12 Q. K. Tran
cians, the initial management of these undiffer- Furthermore, the clinicians who are most
entiated critically ill patients still involves their experienced with endotracheal intubation should
ABCs, and it is still essential. perform the procedure, to maximize first-pass
In this chapter, we highlight certain recom- success rate [5]. Although there was low-quality
mendations and managements that are specific evidence, it is recommended that clinicians
for the critically ill COVID-19 patients. should use video laryngoscopy over direct laryn-
goscopy [5].
For patients with significant hypoxia, 5 min-
Initial Management utes of preoxygenation and RSI may help to
of Undifferentiated Critically Ill avoid manual ventilation of patients’ lungs and
COVID-19 Patients prevent aerosolization of viral particles. In
patients with hypoxia, “apneic oxygenation” can
Airway be considered in addition to preoxygenation,
prior to endotracheal intubation:
COVID-19 is a highly contagious ribonucleic
acid (RNA) virus which spreads through droplets • Provide 15 liters/minute of oxygen flow via
or small particles between people within 6 feet nasal cannula.
(1.8 meter) of each other [2]. Emergency clini- • Administer the induction medication.
cians are at high risk of contracting the illness • Maintain patent airway with either nasopha-
during intubation procedure, which generates ryngeal airway or oropharyngeal airway.
aerosols. Emergency clinicians will need to make • Proceed with endotracheal intubation.
the clinical decision of whether the patients
would need intubation. The clinical decision to
intubate COVID-19 patients should be similar to Breathing
the indications for other disease states. The emer-
gency clinicians should consider the clinical pic- Although the Center for Disease Control (CDC)
tures prior to making the decision to intubate, lists a number of symptoms of COVID-19 [2],
such as hemodynamic parameters, mental status patients will mostly present to the emergency
and the capacity to protect airway, work of departments with respiratory symptoms. A meta-
breathing and impending respiratory collapse, analysis of 148 studies and 24,410 adults [6]
etc. For the COVID-19 patients, hypoxia should reported that 57% [95% confidence interval (CI)
not be the only factor for intubation (as explained 54%–60%] of patients would present with cough-
further in the next section). ing, while 23% (95% CI 19%–28%) of patients
However, once the emergency clinicians would have shortness of breath.
decide that patients will need intubation and inva- Furthermore, some authors noticed that during
sive mechanical ventilation, there are a few the early stage of the pandemic in New York City
marked differences for intubating COVID-19 (New York, USA), a group of patients presented
patients [3]. The recommendations from the with low oxygen saturation [pulse oximetry
Diffult Airway Society’s consensus guidelines (SpO2) < 90%], but they were not in respiratory
suggested emergency physicians, first of all, to distress. This group of patients were informally
wear full personal protective equipment (PPE) referred to as “happy hypoxemics” [7]. Multiple
during the entire procedure [3]. Additionally, the different mechanisms may be responsible for
consensus guidelines also suggested clinicians to these “happy hypoxemics.” COVID-19 patients
refrain from using bag-valve-mask ventilation may experience significant changes in the oxyhe-
unless it is absolutely necessary [3]. As a result, moglobin dissociation curve [8, 9], intrapulmo-
consensus of expert panels recommended rapid nary shunting, intravascular thrombi, and
sequencing induction (RSI) [3, 4] and to avoid impaired diffusion capacity [8, 9], while their
delayed sequence intubation. lungs’ mechanics, such as lung compliance, are
2 Management of Undifferentiated Critically Ill COVID-19 Patients 13
still preserved. As a result, these patients did not pared with patients not undergoing awake pron-
show increase of their work of breathing. ing [15]. The authors suggested that the number
Additionally, certain authors suggested that needed to treat (NNT) for awake proning was 5
the shortage of ventilators and critical care (95% CI, 3–8).
resources during the early stage of the pandemic When considering awake proning for
in New York City could have been caused by COVID-19 patients, emergency clinicians should
early intubation of hypoxic COVID-19 patients encourage patients to avoid any one particular
[7], to avoid aerosol generation. Clinicians should position for extended periods of time, to avoid
assess patient’s clinical status and decide the the risk of skin breakdown. Patients can rotate
need for invasive mechanical ventilation. While their positions every 1–2 hours as tolerated. If
there should not be delay of invasive mechanical patients cannot tolerate total proning, they can
ventilation when the patients need it [10], emer- rotate between either right or left lateral decubital
gency clinicians should consider delaying the positions and upright in chair and then supine for
need for noninvasive mechanical ventilation in rest.
mild or moderately hypoxic patients as delay of
intubation after 8 hours of presentation was not
associated with higher mortality in COVID-19 Circulation
patients [11].
Shock
omputed Tomography (CT) of Chest
C The prevalence of COVID-19 patients who
as Diagnostic and Prognostic Tools develop shock may occur in up to 12% among all
Findings of chest CT in patients with COVID-19 hospitalized COVID-19 patients and can be up to
pneumonia have been shown to correlate with 35% among ICU patients [5]. The treatment for
patients’ outcomes [12]. The presence of opaci- the COVID-19 patients who develop shock is
ties and the higher degree of lung involvements similar to the treatment for non-COVID-19
would correlate with patients’ mortality with a patients. Emergency clinicians should consider a
sensitivity of 84% (95% CI, 71.7%–92.4%) and conservative therapy of crystalloids with norepi-
specificity of 66% (59.1%–72.5%) [12]. nephrine as the first-line therapy [5, 16]. To avoid
liberal fluid therapy, emergency clinicians may
wake Proning to Prevent Intubation
A consider early initiation of norepinephrine.
Prone positioning is used for patients with severe Starting norepinephrine early has been shown to
acute respiratory distress syndrome (ARDS) improve mortality of non-COVID-19 patients
because prone positioning improves the ratio of with septic shock in a meta-analysis [17]. To
partial pressure of oxygen (PaO2) to fraction of avoid delay of vasopressor initiation, emergency
inspired oxygen (FiO2) (P/F ratio), oxygen clinicians may not need to wait until central
requirement, and ventilator-dependent days [13]. venous catheters are placed because norepineph-
The efficacy for proning positioning in intubated rine can be initiated safely through good and reli-
COVID-19 patients had led many authors to rec- able peripheral venous catheters in the ED
ommend awake proning in COVID-19 patients settings [18].
who are admitted to the hospital [5, 14]. Although
there has been limited evidence about the effi- Coagulopathy
cacy of awake proning in hypoxic COVID-19 Patients with COVID-19 are at higher risk for
patients, early evidence suggested that the tech- cardiovascular-related conditions. In a meta-
nique was feasible to carry out even in emergency analysis, myocardial injury occurred in 33%
departments [7]. In another small study, awake (95% CI 24%–43%) of patients admitted to an
proning in COVID-19 patients was associated intensive care unit [19]. Furthermore, patients
with lower likelihood of intubation (hazard ratio with COVID-19 are at increased risk for coagu-
0.30, 95% CI 0.09–0.96; p = 0.043) when com- lopathy [20]. Besides cardiac biomarkers,
14 Q. K. Tran
emergency clinicians should consider ordering thrombolytics, if there are no contraindications,

or assaying coagulopathic markers such as if patients are not candidates for surgical
d-dimer, fibrin degradation product (FDP), and interventions.
fibrinogen. These markers not only provide
diagnostic values but also potential prognostic Ischemic Stroke
information [21]. However, patients with In the critically ill COVID-19 patients who have
COVID-19 infection are at high risk for coagu- any neurologic symptoms, emergency clinicians
lopathy, and their risks for major bleeding should have low threshold for stroke workup
ranged from 11% to 21% [22] so TEG is also since these patients are at high risk of coagulopa-
helpful to correct any coagulopathy. A prospec- thy and ischemic stroke. Critically ill COVID-19
tive, single-center study involving 21 COVID- patients with ischemic stroke from large vessel
19 patients reported that after using TEG-guided occlusion were reported to be younger (mean age
anticoagulation protocol without initial boluses, from 53 to 60 years of age) when compared with
patients were 20-fold less likely to have major historical patients with stroke requiring mechani-
bleeding [22]. cal thrombectomy [30]. Previous studies esti-
mated that ischemic stroke may occur up to 5%
ulmonary Embolism (PE) Among
P of patients with COVID-19 patients [31].
Patients with COVID-19 CT scan without contrast and CT angiogram
Due to increased risk of coagulopathy, patients of the brain should be performed as quickly as
with COVID-19 patients are at higher risk for possible to identify the source of ischemia.
pulmonary embolism. The prevalence of PE Thrombolysis within the recommended window
was estimated to range between 26% [23] and of treatment should be carried out with consulta-
38% [24] among ICU-admitted COVID-19 tion from a neurologist. The treatment of the
patients. critically ill COVID-19 patients with ischemic
Similar to patients without COVID-19, thera- stroke from large vessel occlusion is also mechan-
peutic anticoagulation is the treatment of choice ical thrombectomy, and it can be performed
for the critically ill patients with PE. An expert within 24 hours from when patients were last
consensus recommended low molecular weight known to be normal [32]. Emergency clinicians
heparin (LMWH) as first-line treatment (subcuta- should consider transferring patients to the near-
neous enoxaparin 1 mg/kg twice daily or 1.5 mg/ est comprehensive stroke center with thrombec-
kg once daily) for critically ill COVID-19 patients tomy capability.
with PE and normal renal function [25]. For
patients with PE and severe renal impairment,
infusion of unfractionated heparin (UFH) is Other Considerations
recommended.
Emergency clinicians should be familiar with I n-Hospital Cardiac Arrest Among
common disease severity score for pulmonary Critically Ill COVID-19 Patients
embolism. One of the common scores is the Bova
score [26, 27], which takes into account systolic In a multicenter observational study of 5019 criti-
blood pressure, heart rate, signs of right ventricu- cally ill adult patients with COVID-19, 14%
lar strain, and serum lactate. Patients with high (701/5019) had in-hospital cardiac arrest. The
Bova score is considered as having massive PE common presenting rhythm (49.8%, 199/400)
and may need consultation for catheter-directed was non-shockable rhythm [33]. As a result,
thrombolysis or extracorporeal membrane oxy- these patients were hypothesized to have cardio-
genation (ECMO) as early interventions in these pulmonary arrest from non-cardiac causes. Most
patients were associated with improved outcomes notably, patients who were admitted to hospitals
[28, 29]. In patients who have massive PE, emer- with small number of ICU beds (≤ 50 beds) were
gency clinicians can also consider systemic 5.6-times (OR 5.6, 95% CI 4.4–7.1) more likely
AL GRAWANY
of having cardiac arrests than patients being critical COVID-19 infection. The recommended
admitted to hospitals with larger number of ICU dose for dexamethasone among COVID-19
beds (≥100 beds). This data would enable patients where indicated was 6 mg daily for up to
clinicians at small to mid-size hospitals to pay 10 days [16]. Additionally, critically ill
close attention to the critically ill COVID-19 COVID-19 patients, who are also in refractory
patients. shock, can continue to receive dexamethasone
and do not have to switch to hydrocortisone [5].
Quality of Cardiopulmonary
Resuscitation During the Pandemic Risk Factors and Prediction Scores
A meta-analysis involving five simulation studies Recognized risk factors for severe COVID-19 ill-
showed that wearing personal protective equip- ness include older age (>60 years), male sex, dia-
ment would compromise the quality of CPR [34]. betes, hypertension, coronary artery disease,
The authors reported that wearing PPE was asso- congestive heart failure, end-stage renal disease,
ciated with 60% of cases having adequate chest obesity, pregnancy, cancer, and immunosuppres-
compression rate, when compared with 74% of sion [37–39]. Laboratory results that have been
cases when providers did not have PPE. Similarly, found to predict need for ICU admission and
adequate chest compression depth was achieved mechanical ventilation include elevated
in only 55% of cases, when compared with 78% C-reactive protein, D-dimer, IL-6, lymphocyte
(p = 0.001) of cases when providers did not have counts, and BUN. Although traditional scoring
PPE [34]. Therefore, emergency clinicians should systems such as APACHE II or SOFA can be
pay close attention to the quality of chest com- applied, there are some novel scoring systems
pression to ensure patients’ best chances of developed specially for COVID-19 that predict
survival. inpatient mortality. They have identified the addi-
tional items as independent predictors of mortal-
ity: hemoptysis, abnormal level of consciousness,
Therapeutic Treatments for COVID-19 dyspnea, lowest SaO2 during initial 4 hours of
care, chest radiograph abnormality, neutrophil-
Remdesivir to-lymphocyte ratio, lactate dehydrogenase, and
On October 15, 2020, the Solidarity trial, which direct bilirubin [37, 38, 40, 41].
was sponsored by the World Health Organization
(WHO), suggested that remdesivir had no effect
on mortality and hospital length of stay in References
COVID-19 patients [35]. In contrast, the US
Food and Drug Administration (FDA) approved 1. Centers for Disease Control and Prevention. Interim
clinical guidance for management of patients with con-
remdesivir for treatment of COVID-19 patients firmed coronavirus disease (COVID-19). Published 8
[36]. As a result of this controversy, emergency Dec 2020. https://www.cdc.gov/coronavirus/2019-
clinicians should refer to their hospitals’ policies ncov/hcp/clinical-guidance-managementpatients.
for the use of remdesivir in critically ill html.
2. (CDC) C for DC and P. Coronavirus disease 2019
COVID-19 patients. However, the recommended (COIVD-19). Published 2020. https://www.cdc.gov/
treatment would be 200 mg intravenously (IV) coronavirus/2019-nCoV/index.html. Accessed 1 Nov
for 1 day and then remdesivir 100 mg IV for 4 2020.
days or until hospital discharge [16]. 3. Cook TM, El-Boghdadly K, McGuire B, McNarry AF,
Patel A, Higgs A. Consensus guidelines for manag-
ing the airway in patients with COVID-19: guidelines
Corticosteroids from the Difficult Airway Society, the Association of
The Solidarity trial showed that only corticoste- Anaesthetists the Intensive Care Society, the Faculty
roids were effective in patients with severe and of Intensive Care Medicine and the Royal College
16 Q. K. Tran
of Anaesthetist. Anaesthesia. 2020;75(6):785–99. 16.

NIH. NIH COVID-19 treatment guidelines.
https://doi.org/10.1111/anae.15054. Published 28 Nov 2020. https://www.covid19treat-
4. Orser BA. Recommendations for endotracheal mentguidelines.nih.gov/whatsnew/. Accessed 11 Jan
intubation of COVID-19 patients. Anesth Analg. 2020.
2020;130(5):1109–10. https://doi.org/10.1213/ 17. Li Y, Li H, Zhang D. Timing of norepinephrine initia-
ANE.0000000000004803. tion in patients with septic shock: a systematic review
5. Alhazzani W, Møller MH, Arabi YM, et al. Surviving and meta-analysis. Crit Care. 2020;24(1):1–9. https://
sepsis campaign: guidelines on the management of doi.org/10.1186/s13054-020-03204-x.
critically ill adults with Coronavirus Disease 2019 18. Tran QK, Mester G, Bzhilyanskaya V, et al.

(COVID-19). Intensive Care Med. 2020;46(5):854– Complication of vasopressor infusion through periph-
87. https://doi.org/10.1007/s00134-020-06022-5. eral venous catheter: a systematic review and meta-
6. Grant MC, Geoghegan L, Arbyn M, et al. The preva- analysis. Am J Emerg Med. 2020;38(11):2434–43.
lence of symptoms in 24,410 adults infected by the https://doi.org/10.1016/j.ajem.2020.09.047.
novel coronavirus (SARS-CoV-2; COVID-19): a sys- 19. Hessami A, Shamshirian A, Heydari K, et al.

tematic review and meta-analysis of 148 studies from Cardiovascular diseases burden in COVID-19: sys-
9 countries. PLoS One. 2020;15(6 June) https://doi. tematic review and meta-analysis. Am J Emerg
org/10.1371/journal.pone.0234765. Med. 2021;46:382–91. https://doi.org/10.1016/j.
7. Caputo ND, Strayer RJ, Levitan R. Early self- ajem.2020.10.022.
proning in awake, non-intubated patients in the 20. AlSamman M, Caggiula A, Ganguli S, Misak M,

emergency department: a single ED’s experience Pourmand A. Non-respiratory presentations of
during the COVID-19 pandemic. Acad Emerg COVID-19, a clinical review. Am J Emerg Med.
Med. 2020;27(5):375–8. https://doi.org/10.1111/ 2020;38(11):2444–54. https://doi.org/10.1016/j.
acem.13994. ajem.2020.09.054.
8. Dhont S, Derom E, Van Braeckel E, Depuydt P, 21. Tang N, Li D, Wang X, Sun Z. Abnormal coagula-
Lambrecht BN. Conceptions of the pathophysiol- tion parameters are associated with poor prognosis in
ogy of happy hypoxemia in COVID-19. Respir patients with novel coronavirus pneumonia. J Thromb
Res. 2021;22(1):1–9. https://doi.org/10.1186/ Haemost. 2020;18(4):844–7. https://doi.org/10.1111/
s12931-021-01614-1. jth.14768.
9. Tobin MJ, Laghi F, Jubran A. Why COVID-19 silent 22.
Stillson JE, Bunch CM, Gillespie L, et al.
hypoxemia is baffling to physicians. Am J Respir Thromboelastography-guided management of antico-
Crit Care Med. 2020;202(3):356–60. https://doi. agulated COVID-19 patients to prevent hemorrhage.
org/10.1164/rccm.202006-2157CP. Semin Thromb Hemost. 2021;47(4):442–6. https://
10. SCCM. COVID-19 resources. SCCM COVID-19
doi.org/10.1055/s-0041-1723754.
Rapid Resource Center. https://doi.org/10.1097/01. 23. Sakr Y, Giovini M, Leone M, et al. Pulmonary

NURSE.0000694848.23939.02. embolism in patients with coronavirus disease-2019
11. Hernandez-Romieu AC, Adelman MW, Hockstein
(COVID-19) pneumonia: a narrative review. Ann
MA, et al. Timing of intubation and mortal- Intensive Care. 2020;10(124):1–13. https://doi.
ity among critically ill coronavirus disease 2019 org/10.1186/s13613-020-00741-0.
patients: a single-center cohort study. Crit Care 24. Bompard F, Monnier H, Saab I, et al. Pulmonary
Med. 2020;48:E1045–53. https://doi.org/10.1097/ embolism in patients with COVID-19 pneumo-
CCM.0000000000004600. nia. Eur Respir J. 2020;56(1):17–20. https://doi.
12. Abbasi B, Akhavan R, Ghamari Khameneh A, et
org/10.1183/13993003.01365-2020.
al. Evaluation of the relationship between inpatient 25. Zhai Z, Li C, Chen Y, et al. Prevention and treatment of
COVID-19 mortality and chest CT severity score. venous thromboembolism associated with coronavirus
Am J Emerg Med. 2020; https://doi.org/10.1016/j. disease 2019 infection: a consensus statement before
ajem.2020.09.056. guidelines. Thromb Haemost. 2020;120(6):937–48.
13. Bloomfield RNDSA. Prone position for acute respira- https://doi.org/10.1055/s-0040-1710019.
tory failure in adults. Cochrane Database Syst Rev. 26. Jimenez D, Lobo JL, Fernandez-Golfin C, et al.

2015; https://doi.org/10.1002/14651858.CD008095. Effectiveness of prognosticating pulmonary embo-
pub2. lism using the ESC algorithm and the Bova score.
14. Bentley SK, Iavicoli L, Cherkas D, et al. Guidance Thromb Haemost. 2016;115(04):827–34. https://doi.
and patient instructions for proning and reposition- org/10.1160/th15-09-0761.
ing of awake, nonintubated COVID-19 patients. 27. Bova C, Vanni S, Prandoni P, et al. A prospective
Acad Emerg Med. 2020; https://doi.org/10.1111/ validation of the Bova score in normotensive patients
acem.14067. with acute pulmonary embolism. Thromb Res.
15. Jagan N, Morrow LE, Walters RW, et al. The
2018;165(January):107–11. https://doi.org/10.1016/j.
POSITIONED study: prone positioning in nonventi- thromres.2018.04.002.
lated coronavirus disease 2019 patients—a retrospec- 28. Aymard T, Kadner A, Widmer A, et al. Massive pul-
tive analysis. Crit Care Explor. 2020;2(10):e0229. monary embolism: surgical embolectomy versus
https://doi.org/10.1097/cce.0000000000000229. thrombolytic therapy--should surgical indications be
revisited? Eur J Cardiothorac Surg. 2013;43(1):90–4; 35.

World Health Organization. “Solidarity” clini-
discussion 94. https://doi.org/10.1093/ejcts/ezs123. cal trial for COVID-19 treatments. Published
29. Yavuz S, Toktas F, Goncu T, et al. Surgical embolec- Nov 2020. https://www.who.int/emergen-
tomy for acute massive pulmonary embolism. Int J cies/diseases/novel-coronavirus-2019/global-
Clin Exp Med. 2014;7(12):5362–75. r e s e a r c h - o n - n ove l - c o r o n av i r u s - 2 0 1 9 - n c ov /
30. Fifi JT, Mocco J. COVID-19 related stroke in young solidarityclinical-trial-for-covid-19-treatments.
individuals. Lancet Neurol. 2020;19(9):713–5. https:// 36. NIH. NIH COVID-19 treatment guidelines. Published
doi.org/10.1016/S1474-4422(20)30272-6. 28 Nov 2020. https://www.covid19treatmentguide-
31. Avila J, Long B, Holladay D, Gottlieb M. Thrombotic lines.nih.gov/whatsnew/.
complications of COVID-19. Am J Emerg 37. Altschul DJ, Unda SR, Benton J, et al. A novel sever-
Med. 2021;39:213–8. https://doi.org/10.1016/j. ity score to predict inpatient mortality in COVID-19
ajem.2020.09.065. patients. Nat Sci Rep. 2020;10:16726.
32.
Nogueira RG, Jadhav AP, Haussen 38. Shang Y, Liu T, Wei Y, et al. Scoring systems for pre-
DCDTI. Thrombectomy 6 to 24 hours after stroke dicting mortality for severe patients with COVID-19.
with a mismatch between deficit and infarct. N Engl EClin Med. 2020;24:1000426.
J Med. 2018;378(1):11–21. https://doi.org/10.1056/ 39. Zhang C, Qin L, Li K, et al. A novel scoring sytem
NEJMoa1706442. for prediction of disease severity in COVID-19. Front
33. Hayek SS, Brenner SK, Azam TU, et al. In-hospital Cell Infect Microbiol. 2020;10:318.
cardiac arrest in critically ill patients with covid-19: 40. Liang W, Liang H, Ou L, et al. Development and
multicenter cohort study. BMJ. 371:m3513. https:// validation of a clinical risk score to predict the occur-
doi.org/10.1136/bmj.m3513. rence of critical illness in hopsitalized patients with
34. Sahu AK, Suresh S, Mathew R, Aggarwal P, Nayer COVID-19. JAMA Intern Med. 2020;180:1–9.
J. Impact of personal protective equipment on the effec- 41. Haimovish AD, Ravindra NG, Stoytcho S, et al.

tiveness of chest compression – a systematic review Development and validation of the quick COVID-19
and meta-analysis. Am J Emerg Med. 2021;39:190–6. severity index: a prognostic tool for early clinical
https://doi.org/10.1016/j.ajem.2020.09.058. decompensation. Ann Emerg Med. 2020;76:442–53.
Personal Protection During Patient
Care and Procedures
3
Mark Sutherland, David Gordon,
and Michael Winters
Critical Points pathogens (e.g., PUIs, possible influenza, etc.)

• As of now the exact mechanism of transmis- should not be co-located.
sion of SARS-CoV-2 remains uncertain. There • Depending on local prevalence, strong consid-
is evidence to support contact, droplet, and eration should be given to restricted visitor
aerosol transmission, and healthcare workers policies and mask mandates for employees,
are at high risk. patients, and visitors.
• Proper PPE is essential. Proper aerosol masks • Aerosol-generating procedures are associated
should have an appropriate fit and should ide- with increased risk of healthcare worker infec-
ally be single use, but if this isn’t possible tion; full airborne PPE should be worn in these
should at least be changed when damaged, procedures.
contaminated, or after five donnings.
• Donning and doffing are high-risk times for
contamination and require proper space, train- Introduction
ing, and equipment/supplies to minimize this
risk. At the time of this writing, more than 113 million
• Optimal rooming practices are unknown, but patients across the globe have been infected with
it is believed that patients with the same patho- the SARS-CoV-2 virus. Sadly, over 2.5 million of
gen can be safely housed on the same unit or these patients have lost their lives to COVID-19
room, but patients with unknown or different infection. Healthcare workers account for a sig-
nificant percentage of COVID-19 patients who
require hospitalization and admission to the
intensive care unit. Given the continued exposure
M. Sutherland to patients with COVID-19 infection, it is imper-
University of Maryland School of Medicine, ative for the healthcare worker to be knowledge-
Baltimore, MD, USA
e-mail: [email protected] able on personal protective equipment (PPE) and
current recommendations for proper PPE use.
D. Gordon
Department of Medicine, University of Maryland The chapter discusses important information on
School of Medicine, Baltimore, MD, USA PPE, including various types of PPE, appropriate
e-mail: [email protected] donning and doffing, appropriate rooming and
M. Winters (*) isolation precautions, and select clinical proce-
Department of Emergency Medicine, University of dures such as intubation and CPR. Armed with
Maryland School of Medicine, Baltimore, MD, USA this information, it is our hope that the healthcare

20 M. Sutherland et al.
provider can remain safe and prevent additional Personal Protection Equipment
transmission of SARS-CoV-2.
Current PPE recommendations from the Society
of Critical Care Medicine (SCCM) and the WHO
Particle Dynamics are listed in Table 3.1.
Proper PPE is essential to prevent the spread
In order to assess the effectiveness of various of SARS-CoV-2. Improper PPE is associated
types of PPE, it is important to discuss how virus with a significant increased risk of acquiring
particles are spread. There are three primary COVID-19 infection [19]. PPE has two compo-
routes of transmission: contact, droplet, and air- nents: contact precautions (i.e., gown, gloves,
borne. Contact transmission can occur via direct shoe covers) and mucous membrane precau-
or indirect contact. Droplet transmission can tions (i.e., masks, eye protection). Early studies
occur when respiratory droplets contact mucosal on the use of PPE to prevent COVID-19 infec-
surfaces. Droplet spread is generally thought to tion illustrate the precautions taken in China.
occur with particles greater than 5 microns in size Liu and colleagues published a cross-sectional
and when the reservoir is within 6 feet of the study of over 400 healthcare workers in Wuhan,
host. The droplet route of transmission is consid- China, who cared for critically ill patients with
ered the primary mode of transmission for most COVID-19 for more than 16 hours per week for
viruses [1, 2]. Airborne transmission generally 6–8 weeks [20]. All healthcare workers in this
occurs when particles less than 5 microns in size study performed at least one aerosol-generating
are inhaled. Higher degrees of respiratory protec- procedure (AGP) and used numerous PPE pre-
tion are required to prevent airborne transmission cautions that included protective suits, gowns,
of virus particles. gloves, masks (N95 and surgical masks), gog-
At present, the primary route of transmission gles, and face shields. All healthcare workers
of the SARS-CoV-2 virus remains controversial.
Early reports from the Centers for Disease Table 3.1 PPE recommendations
Control (CDC) and World Health Organization SCCM WHO
(WHO) suggested that both droplet and contact PPE in AGP Use fitted Airborne
routes were responsible for disease transmission respiratory mask in protection
addition to gloves,
[3–5]. This was based on several reports that gowns, eye
demonstrated widespread contamination of inpa- protection
tient hospital rooms (floor, ventilation system, Location for Negative pressure
bed) for patients infected with the SARS-CoV-2 AGP room
virus [6–10]. More recent literature has impli- PPE for Surgical/medical
non-AGP on mask plus gloves,
cated aerosol transmission of SARS-CoV-2. Case mechanical gowns, eye
series from the United States and abroad detail ventilation protection, face
“super spreader” events that cannot be com- shield
pletely explained by either contact or droplet For all patients Contact +
with probable or droplet
transmission of the virus [11–16]. In addition to
confirmed precautions
these case series, experimental studies have dem- COVID
onstrated that aerosolized virus particles may PPE reuse Does not
maintain viability anywhere from 3 to 16 hours in recommend
aerosols and up to 72 hours on contact surfaces Mask over Does not
respirator recommend
[11, 12]. As a result, the CDC and WHO have
Surgical/medical Does not
expanded the route of SARS-CoV-2 transmission mask instead of recommend
to include contact, droplet, and aerosol routes respirator
[17, 18]. Adapted from Refs. [40, 98]
3 Personal Protection During Patient Care and Procedures 21
were tested upon return home, and all tested The ideal isolation gown combines a high
negative for SARS- CoV-2 infection [20]. A water repellency, to avoid spread and diffusion of
meta-analysis performed prior to SARS-CoV2 droplet nuclei, with high water vapor and air per-
demonstrated several PPE measures to be effec- meability for better provider comfort. Gowns
tive in reducing the spread of respiratory viruses with high water repellency keep both the top and
[21]. These included masks, gloves, and gowns bottom layers dry, whereas those with less water
with numbers needed to prevent spread of 6, 7, repellency (“wettable”) can serve as a conduit for
and 5, respectively [21]. The number needed to infection. Another important factor to consider is
use to prevent infection with an N95 mask was the amount of hydrostatic force it takes for a liq-
just 3 [21]. uid to penetrate the material, as gowns vary in
Several studies have evaluated the safety of their penetration pressures. The traditional surgi-
PPE. In many of these studies, substitutes for cal gown has lower water repellency, lower pen-
actual contamination (i.e., fluorescent dye) are etration pressure, and average permeability,
used to simulate potential virus spread. Hall and thereby making this gown less suitable for ideal
colleagues evaluated a variety of PPE ensembles PPE [24]. Gowns that have good water repel-
that included surgical masks, foot attire, gloves lency, good air permeability, and high penetration
of varying lengths, surgical caps, visors, and resistance are considered the most usable and
gowns at different lengths [22]. In this simulation effective for prevention of infection and virus
study, the authors found the most commonly con- spread [27].
taminated areas were the forearms and hands As stated, there are several sites of high-risk
[22]. In another simulation study that evaluated exposure to infection for the provider. The fore-
emergency department personnel in intubation arms and hands are among the most commonly
and peripheral intravenous line insertion scenar- contaminated areas when caring for COVID-19
ios, authors found a high potential for droplet patients. Thumb loops on the isolation gown are
spread to exposed areas of the skin, neck, hair, recommended to minimize the risk of infection to
and shoes [23]. These and other similar studies the provider [24]. If thumb loops are not avail-
provide valuable information on the effectiveness able, the provider or an assistant can circumfer-
of various types of PPE to prevent spread of entially place tape at the gown-glove interface
SARS-CoV-2. [22]. In addition to the forearm and hands,
another area at high risk of contamination and
exposure to infection is the neck [22]. It is impor-
Gowns tant to pay close attention to these locations when
donning and doffing isolation gowns.
Isolation gowns have been mandated as part of Unfortunately, there is very limited literature
universal precautions by the US Occupation on the utility of isolation gowns for the preven-
Safety and Health Administration (OSHA) since tion of infection and spread of SARS-CoV-2.
1991 [24]. The American National Standards Much of the current literature is based on retro-
Institute/American Association for the spective survey data. Thus far, the use of isolation
Advancement of Medical Instrumentation grades gowns has not been shown to significantly
isolation gowns on a scale of 1 to 4 based on their decrease the rate of seroprevalence of SARS-
resistance to water, blood, and viral particles CoV- 2 in healthcare workers [28].
[25]. Isolation gowns are made from a variety of Notwithstanding, their use is recommended when
materials and can either be reusable or single-use caring for patients with COVID-19 infection.
garments [26]. Repellency, pore size, thickness, Importantly, isolation gowns should be dispos-
and wicking are the main determinants that effect able, single-use gowns, as reusable gowns have
the protective nature of an isolation gown. Of been associated with an increased risk of sero-
these, repellency is the most important [24]. conversion for SARS-CoV-2 [29].
Masks mask is the FFP3, which has a filtering efficiency

for aerosols of approximately 99% [32, 33].
Masks have been used by healthcare workers to Several studies have reported the efficacy of
prevent infection since the early 1900s. Masks masks in the healthcare setting for prevention of
have significantly evolved since the original COVID-19 infection. Similar to the studies on
cloth and gauze masks used to prevent the 1918 isolation gowns, the majority of the current liter-
Spanish Flu to modern-day masks to prevent ature is based on retrospective and survey-based
COVID-19 infection. Importantly, masks help to data. Overall, the current literature demonstrates
protect the wearer from the environment, rather a lower risk of infection with SARS-CoV-2 with
than protect the environment from the wearer. At proper mask use [28, 29, 36–39]. In the largest
present, there are several types of masks that study to date, Sims and colleagues demonstrated
have been worn to prevent infection with that healthcare workers who wore masks were
SARS-CoV-2. less likely to be seropositive and that providers
Standard surgical masks are frequently worn who wore a N95 mask or a powered air-purifying
by patients and healthcare workers to protect respiratory (PAPR) had the lowest seropositivity
from droplet secretions. Surgical masks have when compared with other types of masks [38].
been shown to decrease both droplet and aerosol- During the course of the COVID-19 pan-
sized particles spread through cough in patients demic, there has been significant concern about
with a respiratory viral infection [30]. There are PPE shortage. This has raised many questions,
currently three grades of surgical masks: Type I, including whether masks can be reused or decon-
Type II, and Type IIR [31]. Type IIR surgical taminated. While not in accordance with current
masks are splash resistant, used to protect against standards, masks can be used past their expira-
both contact and droplet transmission, and are the tion date if needed and as long as they are in good
preferred type of surgical mask [1]. condition [40, 41]. Importantly, the CDC recom-
Filtering facepiece (FFP) masks or particulate mends that FFP masks be only single use, but can
respirator masks (i.e., elastomeric masks) can be reused if a crisis situation arises. A fit check
either be disposable or reusable. These type of should be performed each time a mask is worn.
masks are ranked on filtering efficiency and regu- To protect an N95 or FFP mask, a face shield or
lated by varying standards across countries [32]. surgical masks can be worn over it. Any contami-
In the United States, appropriate fit testing of nated or damaged mask should be discarded. In
these masks is regulated by OSHA standards. addition, masks should be discarded if used dur-
The filtering efficiency of FFP1 masks is approx- ing an AGP or the provider feels it is difficult to
imately 80%, whereas the efficiency of FFP2 and breathe through [41, 42]. In a crisis situation, an
N95 masks approach 95% [33]. In simulation extended use strategy, whereby there is a single
studies, N95 masks are excellent at blocking donning for use with multiple patients, can be
droplet dispersion [34]. In these studies, the used. In this circumstance, the CDC recommends
greatest risk of droplet dispersion with cough no more than five donnings, as an increasing
with an N95 was located around the bridge of the number of N95 models have been shown to fail a
nose [34]. It may be possible to decrease this risk fit test after this number [43].
with the use of a nose wire or a mask brace or Ideal decontamination of N95 masks theoreti-
knotting and tucking the ear loops of the masks cally inactivates microbes while not affecting the
[35]. N95 and FFP2 graded masks are currently fit or filtration of the device, or having negative
recommended for healthcare workers who per- impacts on the wearer [43]. Though decontami-
form aerosol-generating procedures (AGPs) [31– nation is not permitted by OSHA standards, the
33]. Importantly, N95 masks with an exhalation US Food and Drug Administration (FDA) has
port have been shown to allow for significant provided emergency use authorization for sev-
droplet dispersion [34]. The highest-grade FFP eral different decontamination technologies
[44]. The most promising technologies are of the PAPR provides splash and eye protection
vaporized hydrogen peroxide and ultraviolet and has been shown to decrease healthcare
germicidal radiation. In addition, technologies worker infection with SARS-CoV-2 during intu-
that use both moist and dry heat have also been bation. While beneficial for decreasing infection,
evaluated [42, 44]. Unfortunately, most of these PAPRs require cleaning and appropriate storage
decontamination technologies and methods have and can be difficult to communicate in with
not assessed the effect on the fit of the mask to patients and colleagues.
the provider [45].
Side Effects and Barriers to Use

Eye Protection
It is important to understand some of the chal-
Eye protection and face shields have become a lenges with PPE. PPE can be uncomfortable to
prominent piece of PPE during the COVID-19 wear; can cause difficulty hearing, seeing, and
pandemic. It is thought that face shields may speaking; and can significantly impact work
limit the spread of infection to healthcare work- performance [50, 51]. Lan and colleagues found
ers by decreasing droplet exposure and protect- that approximately 97% of healthcare workers
ing masks. To date, the literature on eye protection reported skin breakdown with PPE use [52].
and face shields has been mixed. In a large data- N95 masks may alter scalp and cerebral blood
base study, Akinbami and colleagues demon- flow and have been associated with headaches
strated that continuous use of eye protection was [50, 53]. Headaches were more common when
not associated with a decreased rate of seroposi- eye wear was worn with an N95 mask, when
tivity for SARS-CoV-2 [28]. Ye and colleagues combined PPE was worn for longer than 4 con-
demonstrated that less than 2% of eye protection tinuous hours, and in those with a pre-existing
and face shields were contaminated by SARS- history of headaches [50]. In addition to head-
CoV-2 [46]. In contrast, a cross-sectional study aches, redness of the cheeks, nose, and ears and
by Khalil and colleagues demonstrated that use mouth dryness have also been associated with
of a face shield and goggles was helpful in pre- N95 mask use [54].
venting infection of healthcare workers during Another significant issue with PPE is dehu-
routine clinical care [29]. Though firm recom- manization, which has been reported in previous
mendations on the use of eye protection and face pandemics. The anonymizing effect of PPE can
shields cannot be made at this time, the authors make it difficult to identify persons and their spe-
support the use of these PPE. If reusable eye pro- cific roles in patient care. In many locations,
tection and face shields are used, they should be placement of a provider picture (“PPE Portrait”)
properly cleaned between patients [47]. on their PPE has been helpful to identify mem-
bers of the healthcare team [55]. In a survey of
healthcare workers, Reidy and colleagues
Powered Air-Purifying Respirator reported improved staff interactions, improved
connections with patients and families, and
The highest level of respiratory PPE is the improved staff well-being with the use of PPE
PAPR. A PAPR is a battery-operated air purifier Portraits [56].
that provides positive air flow through a high-
efficiency particulate filter to a head or face piece.
PAPRs have been shown to filter 99.7% of parti- Donning and Doffing
cles that are 0.3 microns or larger and are equiva-
lent to FFP3 level PPE [48, 49]. PAPRs are PPE use during patient care occurs in three
generally considered more comfortable for the phases: donning (putting on the PPE), providing
provider and do not require fit testing. The hood care to the patient, and doffing (removing PPE)
AL GRAWANY
[57]. Improper donning and doffing has been shown to improve donning and doffing fidelity
identified as a high-risk portion of the patient and to reduce cognitive load during the process,
care process, and contamination and exposure and this approach may be a consideration for
can occur in any of these three phases. For high-risk or high-utilization providers such as
instance, the doffing process, which requires par- the EDor intensive care unit staff [63]. At many
ticular flexibility, balance, and vigilance, has institutions, however, there are not enough train-
been demonstrated to result in self-contamination ers and spotters to ensure proper infection con-
rates ranging from 13% to 90% [57]. Studies vid- trol practices by direct observation or for
eotaping donning and doffing processes have in-person training of all staff. Christensen and
reported protocol violations in up to 39% of par- colleagues examined the effectiveness of video
ticipants during donning and 84% of participants training as compared to live instructor-led train-
during doffing [58]. During the 2014 Ebola epi- ing [64]. They found no significant difference in
demic, it was reported that approximately 10% of donning or doffing error rates among partici-
healthcare workers contracted Ebola despite pants trained by the two methods and suggest
wearing PPE [59–62]. Fortunately, there is an that asynchronous methods may augment in-
extensive literature base, both pre-COVID and person training approaches.
during the pandemic, examining best practices Much of the existing literature base regarding
for donning and doffing to minimize likelihood best practices for donning and doffing was devel-
of staff exposure. oped during the Ebola crisis. It is not completely
A study by Wundavalli and colleagues utilized known how applicable these studies are to
rigorous quality improvement methods at an COVID transmission, but they provide useful
acute cancer hospital that was converted into a general information on optimal donning/doffing
COVID care facility to determine optimal con- methods and risk of self-contamination.
figuration for donning and doffing spaces [57]. Chughtai and colleagues examined 10 donning
This study recommends a minimum area of 16 m2 and doffing protocols recommended by health
each for donning and doffing area. The authors organizations during the Ebola crisis and had
utilized existing literature to identify nine dis- participants carry this process out using fluores-
crete, sequential steps to donning and provided cent lotion and spray with ultraviolet light after-
individual stations for each step with a corre- wards to detect contamination [61]. The overall
sponding poster describing the process. A similar contamination rate was 13%, and protocols
workflow was performed for 11 discrete, sequen- involving coveralls were noted to have the high-
tial doffing steps. A list of supplies and diagram est risk of contamination as compared to gowns.
showing the flow and setup of the areas is pro- All participants using N95s reported breathing
vided in the article. The authors also observed problems, feelings of suffocation, or heat stress.
and cataloged errors in the process and noted that PAPRs were more comfortable for participants
touching the front of the mask to adjust its posi- but were occasionally associated with difficulty
tioning was the most common error. in donning and doffing or hearing difficulty.
Unfortunately, most emergency departments Both this and other studies support lower con-
(ED) do not have enough additional physical tamination rates and improved user satisfaction
space to accommodate these large donning and with PAPRs [65–67].
doffing areas, and best practices for modifying
these approaches to fit more crowded units are
not known. Rooming and Isolation Procedures
With the rapid expansion in the number of
healthcare workers who will be regularly per- The COVID pandemic has created a confluence
forming donning and doffing procedures, one of events that threaten to exacerbate existing
major challenge has been providing proper capacity shortfalls in healthcare. These shortfalls
training. Use of simulation exercises has been include the increased demand for healthcare ser-
vices with the simultaneous need for distancing, for PUI and COVID-positive patients, but are not
isolation, and other practices that limit overall mandatory, and when limited should be priori-
capacity. Lax infection control practices can tized to patients undergoing aerosol-generating
worsen the spread of the virus to patients, visi- procedures. Where possible, facilities may con-
tors, and staff, further exacerbating capacity sider constructing dedicated COVID units to
shortages and causing harm. On the other hand, reduce transmission via staff and to conserve
approaches that include elimination of semi- PPE [70]. OSHA guidelines state that “if possi-
private rooms, expansion of ED waiting areas, ble, isolating suspected cases separately from
and other infection control practices themselves confirmed cases may also help prevent transmis-
lead to a reduction in total capacity at a time sion” but do not clarify whether PUIs or COVID-
when more beds are needed. Unfortunately, there pending patients may be roomed with each other
are very few evidence-based guidelines to direct [72]. Our hospital’s policy states that patients
hospitals on how to balance these competing with COVID tests pending can be placed in semi-
interests to keep their patients and staff safe while private rooms if they (a) can comply with mask-
also promoting patient flow. ing, (b) do not have symptoms of COVID, (c) do
One clear recommendation from the CDC is not refuse testing, (d) are not high risk by expo-
that facilities should minimize in-person care sure history, and (e) do not have other exclusions
where possible through the use of telehealth and to semi-private rooming. However, to our knowl-
deferral of elective care [68]. Unfortunately, edge, there are no existing guidelines or literature
these suggestions are of limited utility in the ED describing patient placement practices such as
and ICU, although many institutions have suc- appropriateness of semi-private rooms for low-
cessfully adopted approaches such as symptom suspicion patients during the pandemic, and this
hotlines, ED teletriage, e-consultation, and dis- likely depends on several factors such as patient
charge from triage for appropriate patients to volumes, availability of rooms of various types,
reduce total ED volume. Federal and state gov- and an assessment of how policies will affect
ernments in the United States have put forth poli- patient flow. As discussed above, suboptimal
cies, recommended changes to reimbursement patient placement practices in either the overly
practices, and established legal protections to aggressive or conservative direction will increase
encourage the use of telehealth and allow other risk of infectious spread, worsen ED crowding,
modifications to standard care [69]. and hamper ED to inpatient flow. As facilities
continue to struggle with rapid turnaround testing
availability, this will affect access to care not only
Rooming Practices and Guidelines for PUI and COVID-positive patients but also for
low-risk or asymptomatic patients awaiting
For hospitals heavily reliant on semi-private screening results.
rooms, COVID may present severe capacity chal- These challenges increase the importance of
lenges. It is recommended that suspected and rapidly turning around rooms once they are emp-
positive patients be placed in single patient rooms tied, but it is also necessary to do so safely. OSHA
with the door closed [70, 71]. Guidelines state guidelines state that “routine cleaning and disin-
that in scenarios where other respiratory viral fection procedures are appropriate for SARS-
pathogens, such as influenza, are present, it is CoV- 2 in healthcare settings” [72]. They
reasonable to house patients with different patho- specifically indicate that disinfectant contact
gens (or unclear pathogen) in the same unit, but times as indicated on product labels and would-
patients with different pathogens should not be be standard for routine cleaning are appropriate
housed in the same room. Similarly, Persons [72]. However, practices seem to vary between
Under Investigation (PUIs) should not share a facilities, with many requiring extended dwell
room with COVID-positive patients. Airborne time for the cleaning of rooms that housed
Infection Isolation Rooms (AIIRs) are preferred COVID-positive or PUI patients, and this prac-
tice may increase waiting room crowding and ntry to Healthcare Facility
E
increase risk of exposure in common areas. and Waiting Rooms
CDC and other guidelines recommend routine

niversal Enhanced Precautions
U screening for symptoms of COVID-19 at first
and Testing contact with the healthcare system and segrega-
tion of patients based on risk level, and they pro-
In addition to standard precautions, the CDC rec- vide suggested questionnaires and an algorithm
ommends what are often referred to as universal for how to disposition patients based on their
enhanced precautions, elevated precautions, or responses [68, 74]. Visual alerts should be posted
universal source control measures [70, 71]. These in entrances and waiting rooms to encourage
include requiring all persons, including employ- mask use and hand hygiene [70, 75]. The CDC
ees, patients, and visitors, who are over 2 years guidelines provide options for screening meth-
old and can tolerate it, to wear a mask while in ods, such as mandatory temperature checks,
the hospital, encouraging physical distancing by symptom questionnaire, exposure history, or
modifying seating, and limiting visitation. There electronic monitoring systems, but do not endorse
is no specific endpoint on these recommenda- a specific approach.
tions, but they do specify that this is recom- It is suggested, where feasible, that a separate
mended for healthcare personnel working in waiting room be established for patients with
facilities located in areas with “moderate to sub- confirmed or suspected infection [70, 71]. This
stantial community transmission.” Additionally, waiting room, especially if PUIs are included,
healthcare personnel should wear an N95, equiv- should be a well-ventilated space which allows
alent, or higher-level respirator instead of a stan- patients to remain 6 or more feet apart. Where
dard facemask during AGPs or surgical possible, it is also suggested that encouraging
procedures with risk of transmission [70]. patients to wait outside or in personal vehicles
With regard to universal testing, the CDC may help reduce the risk of infectious spread in
guidelines largely defer to state and local health waiting rooms [70].
department recommendations, as well as facility
specific factors such as testing availability and
turnaround time.(70)They do note that false neg- Clinical Considerations
atives may be encountered and represent a limita-
tion of this approach. During the pandemic, many Aerosol-Generating Procedures
hospitals have enacted policies requiring testing
of all patients upon admission. We are not aware Aerosols can be generated by numerous medical
of any data specifically demonstrating patient and non-medically related activities, including
flow or outcome improvements with this prac- intubation, bronchoscopy, cardiopulmonary
tice, but it is intuitive as an effort to improve resuscitation (CPR), open suctioning of the air-
accurate patient cohorting, especially where test- way, running water, speaking, coughing, sneez-
ing is readily available. ing, and even flushing toilets [2, 3]. The actual
In patients who experienced severe illness or amount of aerosols that are produced varies by
are immunocompromised, the CDC guidelines person, time, procedure, and particle size [76,
recommend maintenance of isolation precautions 77]. Larger particle sizes theoretically drop in the
for at least 10 days and up to 20 days after symp- air within 6 feet of the reservoir, whereas smaller
tom onset [73]. The change to a symptom-based particles remain suspended in the air for longer
strategy discussed in these guidelines reflects a periods of time. AGPs have been associated with
shift from the testing-based clearance of patients an increased risk of infection in healthcare work-
from enhanced precautions that many facilities ers [78]. Akinbami and colleagues demonstrated
utilized in the initial COVID surge. increased seropositivity for SARS-CoV-2 in
healthcare workers who performed AGPs, with 80]. Unfortunately, the use of these boxes in the
the greatest rate among workers who performed clinical setting has proved technically challeng-
more than 25 AGPs per shift [28]. At present, ing, and they have largely fallen out of favor [88,
aerosol PPE is recommended during intubation, 89]. In addition to airway boxes, others have rec-
bronchoscopy, CPR, open suctioning of the air- ommended a clear sheet or drape be placed over
way, delivery of high-flow nasal cannula oxygen, the patient during intubation [90, 91]. The effect
and nebulization of medications [76]. of these sheets on disease transmission, however,
is uncertain at this time.
Intubation
Cardiopulmonary Resuscitation
Intubation is a high-risk AGP and is associated
with increased disease transmission [78]. In sim- There is conflicting literature and debate as to
ulation studies, droplet contamination has been whether CPR is an AGP [92, 93]. Various ani-
found on the neck, ear, shoes, gown, gloves, face- mal, simulation, and cadaver studies have dem-
mask, eye shield, chest, and abdomen and even in onstrated variable rates of aerosol generation
the hair of healthcare workers who perform the during CPR [93–96]. In studies that demon-
intubation [23, 79, 80]. In addition, bag-valve strate increased aerosol generation during CPR,
mask ventilation, tube insertion, and cuff infla- it is unclear if this is due to compressions, defi-
tion have also been associated with increased brillation, intubation, or a combination of all
aerosol concentrations of droplet particles [81]. three procedures [94]. The effect on disease
In a large international survey of over 5100 intu- transmission and aerosol generation with a
bations performed by 1718 healthcare workers, supraglottic airway used during CPR is uncer-
El-Boghdadly and colleagues demonstrated an tain [97]. These uncertainties remain important
infection rate with SARS-CoV-2 of 8.9% [82]. In questions and considerations, as delays in ini-
approximately 88% of these intubations, health- tiation of CPR and resuscitative measures for
care workers reported meeting the minimum patients in cardiac arrest often lead to worse
WHO requirements for PPE (N95, PAPR, or patient outcomes. Notwithstanding the limita-
equivalent) [82]. Additional studies of intubations of the current literature, full aerosol PPE
tions performed in the setting of COVID-19 have is recommended for patients who sustain car-
demonstrated variable infection rates among pro- diac arrest and require CPR.
viders. In many cases, those that have demon-
strated higher infection rates have been attributed
to lower levels of PPE worn by the provider [83– Recommendations
87]. As a result, SCCM and the WHO recom-
mend full PPE for any healthcare worker –– Masks and eye protection should be worn for
performing intubation. This includes gown, all interactions with all COVID patients.
gloves, eye protection, and an N95 mask or –– Hand hygiene should be performed before and
PAPR. In addition to full PPE, intubations should after interacting with every individual patient.
be performed, when possible, in negative pres- –– When performing AGPs, full aerosol PPE
sure rooms. including N95 or equivalent that is properly
During the initial months of the COVID-19 fitted and checked, eye protection, gown, and
pandemic, many developed an “airway box” to gloves should be donned.
limit the spread of infection and decrease risk to
the provider team. Simulation studies on these Conflict of Interest The authors do not have any finan-
cial conflicts of interest.
airway boxes have demonstrated variable effect
on droplet spread based on overall design [79, Funding None
References Jan 19];11(1) Available from: https://www.ncbi.nlm.

nih.gov/pmc/articles/PMC7260225/?report=abstract.
10. Lednicky JA, Lauzard M, Fan ZH, Jutla A, Tilly TB,
1. Cook TM. Personal protective equipment during the
Gangwar M, et al. Viable SARS-CoV-2 in the air of
coronavirus disease (COVID) 2019 pandemic – a
a hospital room with COVID-19 patients. Int J Infect
narrative review [Internet]. Anaesthesia. Blackwell
Dis [Internet]. 2020 [cited 2021 Jan 19];100:476–82.
Publishing Ltd; 2020 [cited 2021 Jan 18]. 75:920–7.
Available from: https://www.ncbi.nlm.nih.gov/pmc/
Available from: https://associationofanaesthetists-
articles/PMC7493737/?report=abstract.
p u b l i c a t i o n s . o n l i n e l i b r a r y. w i l e y. c o m / d o i /
11. van Doremalen N, Bushmaker T, Morris DH,

full/10.1111/anae.15071.
Holbrook MG, Gamble A, Williamson BN, et al.
2. Shiu EYC, Leung NHL, Cowling BJ. Controversy
Aerosol and surface stability of SARS-CoV-2 as com-
around airborne versus droplet transmission
pared with SARS-CoV-1. N Engl J Med [Internet].
of respiratory viruses. Curr Opin Infect Dis
2020 [cited 2021 Jan 19];382(16):1564–7. Available
[Internet]. 2019 [cited 2021 Jan 18];32(4):372–
from: https://www.ncbi.nlm.nih.gov/pmc/articles/
9. Available from: http://journals.lww.
PMC7121658/.
com/00001432-201908000-00012.
12. Fears AC, Klimstra WB, Duprex P, Hartman A,

3. Jayaweera M, Perera H, Gunawardana B, Manatunge
Weaver SC, Plante KS, et al. Persistence of severe
J. Transmission of COVID-19 virus by droplets and
acute respiratory syndrome coronavirus 2 in aerosol
aerosols: a critical review on the unresolved dichot-
suspensions. Emerg Infect Dis [Internet]. 2020 [cited
omy [Internet]. Environ Res. Academic Press Inc.;
2021 Jan 19];26(9):2168. Available from: https://
2020 [cited 2021 Jan 18]. 188:109819. Available
www.ncbi.nlm.nih.gov/pmc/articles/PMC7454081/?r
eport=abstract.
PMC7293495/?report=abstract.
13. Hamner L, Dubbel P, Capron I, Ross A, Jordan A, Lee
4. World Health Organization. Modes of transmission of
J, et al. High SARS-CoV-2 attack rate following expo-
virus causing COVID-19: implications for IPC pre-
sure at a choir practice — Skagit County, Washington,
caution recommendations. 2020 [cited 2021 Jan 18].;
March 2020. MMWR Morb Mortal Wkly Rep
Available from: https://www.gov.uk/government/
[Internet]. 2020 [cited 2021 Jan 19];69(19):606–10.
publications/wuhan-.
Available from: http://www.cdc.gov/mmwr/vol-
5. How coronavirus spreads | CDC [Internet]. [cited
umes/69/wr/mm6919e6.htm?s_cid=mm6919e6_w.
2021 Jan 18]. Available from: https://www.cdc.gov/
14. Asadi S, Wexler AS, Cappa CD, Barreda S, Bouvier
coronavirus/2019-n cov/prevent-g etting-sick/how-
NM, Ristenpart WD. Aerosol emission and superemis-
c ovid-s preads.html?CDC_AA_refVal=https%3
sion during human speech increase with voice loud-
A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-
ness. Sci Rep. 2019;9(1):2348.
ncov%2Fprepare%2Ftransmission.html#edn1.
15. Gaeckle NT, Lee J, Park Y, Kreykes G, Evans MD,
6. Fennelly KP. Particle sizes of infectious aerosols:
Hogan CJ. Aerosol generation from the respiratory
implications for infection control [Internet]. Lancet
tract with various modes of oxygen delivery. Am J
Respir Med. Lancet Publishing Group; 2020 [cited
Respir Crit Care Med [Internet]. 2020 [cited 2021 Feb
2021 Jan 27]. 8:914–24. Available from: https://www.
7];208(8):1115–24. Available from: https://www.ats-
ncbi.nlm.nih.gov/pmc/articles/PMC7380927/?report
journals.org/doi/10.1164/rccm.202006-2309OC.
=abstract.
16. Lu J, Gu J, Gu J, Li K, Xu C, Su W, et al. COVID-19
7. Tang JW, Bahnfleth WP, Bluyssen PM, Buonanno
outbreak associated with air conditioning in restau-
G, Jimenez JL, Kurnitski J, et al. Dismantling myths
rant, Guangzhou, China, 2020. Emerg Infect Dis
on the airborne transmission of severe acute respira-
[Internet]. 2020 [cited 2021 Jan 20];26(7):1628–31.
tory syndrome coronavirus (SARS-CoV-2). J Hosp
Available from: https://doi.org/10.1155/2013/493960.
Infect [Internet]. 2021 [cited 2021 Jan 20]; Available
17. Transmission of SARS-CoV-2: implications for

from: https://linkinghub.elsevier.com/retrieve/pii/
infection prevention precautions [Internet]. [cited
S0195670121000074.
2021 Jan 20]. Available from: https://www.who.int/
8. Ong SWX, Tan YK, Chia PY, Lee TH, Ng OT, Wong
publications/i/item/modes-of-transmission-of-virus-
MSY, et al. Air, surface environmental, and per-
causing-covid-19-implications-for-ipc-precaution-
sonal protective equipment contamination by severe
recommendations.
acute respiratory syndrome coronavirus 2 (SARS-
18.
Scientific Brief: SARS-CoV-2 and Potential
CoV- 2) from a symptomatic patient [Internet].
Airborne Transmission | CDC [Internet]. [cited
JAMA. American Medical Association; 2020 [cited
2021 Jan 20]. Available from: https://www.cdc.gov/
2021 Jan 19]. 323:1610–2. Available from: https://
coronavirus/2019-n cov/more/scientific-b rief-s ars-
www.ncbi.nlm.nih.gov/pmc/articles/PMC7057172/?r
cov-2.html.
eport=abstract.
19. Ran L, Chen X, Wang Y, Wu W, Zhang L, Tan X. Risk
9. Chia PY, Coleman KK, Tan YK, Ong SWX, Gum M,
factors of healthcare workers with coronavirus dis-
Lau SK, et al. Detection of air and surface contami-
ease 2019: a retrospective cohort study in a desig-
nation by SARS-CoV-2 in hospital rooms of infected
nated hospital of Wuhan in China. Clin Infect Dis
patients. Nat Commun [Internet]. 2020 [cited 2021
[Internet]. 2020 [cited 2021 Feb 22];71(16):2218–21.
Available from: https://academic.oup.com/cid/ 29. Khalil MM, Alam MM, Arefin MK, Chowdhury MR,
article/71/16/2218/5808788. Huq MR, Chowdhury JA, et al. Role of personal pro-
20. Liu M, Cheng SZ, Xu KW, Yang Y, Zhu QT, Zhang tective measures in prevention of COVID-19 spread
H, et al. Use of personal protective equipment against among physicians in Bangladesh: a multicenter cross-
coronavirus disease 2019 by healthcare profession- sectional comparative study. SN Compr Clin Med
als in Wuhan, China: cross sectional study. BMJ [Internet]. 2020 [cited 2021 Jan 31];2(10):1733–9.
[Internet]. 2020 [cited 2020 Oct 30];369: m2195. Available from: https://www.ncbi.nlm.nih.gov/pmc/
Available from: https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC7454131/?report=abstract.
articles/PMC7284314/?report=abstract. 30. Leung NHL, Chu DKW, Shiu EYC, Chan KH,

21. Jefferson T, Del Mar CB, Dooley L, Ferroni E,
McDevitt JJ, Hau BJP, et al. Respiratory virus shed-
Al-Ansary LA, Bawazeer GA, et al. Physical inter- ding in exhaled breath and efficacy of face masks. Nat
ventions to interrupt or reduce the spread of respira- Med [Internet]. 2020 [cited 2020 Oct 29];26(5):676–
tory viruses. Cochrane Database Syst Rev [Internet]. 80. Available from: https://pubmed.ncbi.nlm.nih.
2011 [cited 2020 Oct 30];2011(7) Available from: gov/32371934/.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC699 31. Lepelletier D, Grandbastien B, Romano-Bertrand

3921/?report=abstract. S, Aho S, Chidiac C, Géhanno JF, et al. What face
22. Hall S, Poller B, Bailey C, Gregory S, Clark R,
mask for what use in the context of the COVID-19
Roberts P, et al. Use of ultraviolet-fluorescence- pandemic? The French guidelines. J Hosp Infect
based simulation in evaluation of personal protective [Internet]. 2020 [cited 2021 Jan 29];105(3):414–8.
equipment worn for first assessment and care of a Available from: https://www.ncbi.nlm.nih.gov/pmc/
patient with suspected high-consequence infectious articles/PMC7194956/?report=abstract.
disease. J Hosp Infect [Internet]. 2018 [cited 2021 32. 3M technical report respiratory protection for air-

Jan 22];99(2):218–28. Available from: https://doi. borne exposures to biohazards. 2020.
org/10.1016/j.jhin.2018.01.002. 33. CDC, Niosh, NPPTL. Understanding the difference
23. Feldman O, Meir M, Shavit D, Idelman R, Shavit (surgical masks, N95 FFRs, and Elastomerics) info-
I. Exposure to a surrogate measure of contamination graphic [Internet]. [cited 2021 Jan 29]. Available
from simulated patients by emergency department from: https://www.jointcommission.org/assets/1/18/
personnel wearing personal protective equipment Implementing_Hospital_RPP_2-19-15.pdf.
[Internet]. JAMA. American Medical Association; 34. Verma S, Dhanak M, Frankenfield J. Visualizing drop-
2020 [cited 2020 Nov 1]. 323:2091–3. Available let dispersal for face shields and masks with exhala-
from: https://www.cdc.gov/coronavirus/2019-ncov/ tion valves articles you may be interested in. Phys
infection-control/control-. Fluids [Internet]. 2020 [cited 2021 Jan 24];32:91701.
24. Kilinc FS. A review of isolation gowns in healthcare: Available from: https://doi.org/10.1063/5.0022968.
fabric and gown properties. J Eng Fiber Fabr [Internet]. 35. Improve the fit and filtration of your mask to reduce
2015 [cited 2021 Jan 22];10(3):155892501501000. the spread of COVID-19 | CDC [Internet]. 2021 [cited
Available from: https://www.ncbi.nlm.nih.gov/pmc/ 2021 Feb 22]. Available from: https://www.cdc.gov/
articles/PMC4791533/?report=abstract. coronavirus/2019-ncov/prevent-getting-sick/mask-
25. PPE-Info - Standard Details [Internet]. [cited 2021 fit-and-filtration.html.
Jan 22]. Available from: https://wwwn.cdc.gov/ 36. Wang X, Pan Z, Cheng Z. Association between 2019-
PPEInfo/Standards/Info/ANSI/AAMIPB70Class3. nCoV transmission and N95 respirator use. J Hosp
26. McQuerry M, Easter E, Cao A. Disposable versus Infect [Internet]. 2020 [cited 2021 Jan 31];105(1):104.
reusable medical gowns: a performance comparison. Available from: https://www.ncbi.nlm.nih.gov/pmc/
Am J Infect Control [Internet]. 2020 [cited 2021 Feb articles/PMC7134426/.
22];0(0) Available from: https://doi.org/10.1016/j. 37. Piapan L, De Michieli P, Ronchese F, Rui F, Mauro
ajic.2020.10.013. M, Peresson M, et al. COVID-19 outbreak in health-
27. Wong TKS, Chung JWY, Li Y, Chan WF, Ching PTY, care workers in hospitals in Trieste, North-east
Lam CHS, et al. Effective personal protective clothing Italy [Internet]. J Hosp Infect. W.B. Saunders Ltd;
for health care workers attending patients with severe 2020 [cited 2021 Jan 31]. 106:626–8. Available
acute respiratory syndrome. Am J Infect Control from: https://www.ncbi.nlm.nih.gov/pmc/articles/
[Internet]. 2004 [cited 2021 Jan 21];32(2):90–6. PMC7427613/.
Available from: https://www.ncbi.nlm.nih.gov/pmc/ 38. Sims MD, Maine GN, Childers KL, Podolsky RH,
articles/PMC7137615/?report=abstract. Voss DR, Berkiw-Scenna N, et al. Coronavirus Disease
28. Akinbami LJ, Vuong N, Petersen LR, Sami S, Patel A, 2019 (COVID-19) Seropositivity and Asymptomatic
Lukacs SL, et al. SARS-CoV-2 seroprevalence among Rates in Healthcare Workers Are Associated with Job
healthcare, first response, and public safety person- Function and Masking. Clin Infect Dis [Internet].
nel, detroit metropolitan area, Michigan, USA, May- 2020 [cited 2021 Jan 31]; Available from: https://
June 2020. Emerg Infect Dis [Internet]. 2020 [cited www.ncbi.nlm.nih.gov/pmc/articles/PMC7665441/?r
2021 Jan 31];26(12):2863–71. Available from: https:// eport=abstract.
www.ncbi.nlm.nih.gov/pmc/articles/PMC7706918/?r 39. Chatterjee P, Anand T, Singh K, Rasaily R, Singh
eport=abstract. R, Das S, et al. Healthcare workers & SARS-
CoV-2 infection in India: a case-control investiga- protective equipment – a cross-sectional study among
tion in the time of COVID-19. Indian J Med Res. frontline healthcare workers during COVID- 19.
2020;151(5):459–67. Headache J Head Face Pain [Internet]. 2020 [cited
40. Rational use of personal protective equipment for coro- 2021 Feb 12];60(5):864–77. Available from: https://
navirus disease (COVID-19) and considerations during onlinelibrary.wiley.com/doi/abs/10.1111/head.13811.
severe shortages [Internet]. 2020 [cited 2021 Feb 25]. 51. Parush A, Wacht O, Gomes R, Frenkel A. Human
Available from: https://www.who.int/publications/i/ factor considerations in using personal protective
i t e m / r a t i o n a l -u s e -o f -p e r s o n a l -p r o t e c t i v e - equipment in the COVID-19 pandemic context: bina-
equipment-for-coronavirus-disease-(covid-19)-and- tional survey study [Internet]. J Med Internet Res.
considerations-during-severe-shortages. JMIR Publications Inc. 2020 [cited 2021 Feb 12];22.
41. Strategies for optimizing the supply of N95 res-
Available from: https://www.ncbi.nlm.nih.gov/pmc/
pirators: COVID-19 | CDC [Internet]. [cited 2021 articles/PMC7301688/.
Feb 17]. Available from: https://www.cdc.gov/ 52. Lan J, Song ZB, Miao X, Li H, Li Y, Dong L, et al.
coronavirus/2019-n cov/hcp/respirators-s trategy/ Skin damage among health care workers manag-
index.html. ing coronavirus disease-2019. 2020 [cited 2021
42. ECDC. Options for the decontamination and reuse of Feb 12]; Available from: https://doi.org/10.1016/j.
respirators in the context of the COVID-19 pandemic. jaad.2020.03.014.
2020. 53. Bharatendu C, Ong JJY, Goh Y, Tan BYQ, Chan ACY,
43. COVID-19 decontamination and reuse of filter-
Tang JZY, et al. Powered air purifying respirator
ing facepiece respirators | CDC [Internet]. [cited (PAPR) restores the N95 face mask induced cerebral
2021 Feb 3]. Available from: https://www.cdc. hemodynamic alterations among healthcare workers
gov/coronavirus/2019-n cov/hcp/ppe-s trategy/ during COVID-19 outbreak. J Neurol Sci [Internet].
decontamination-reuse-respirators.html. 2020 [cited 2021 Feb 8];417:117078. Available
44. Emergency use authorization | FDA [Internet].
[cited 2021 Feb 4]. Available from: https://www. PMC7398036/.
fda.gov/emergency-p reparedness-a nd-r esponse/ 54. Atay S, Cura ŞÜ. Problems encountered by nurses
mcm-l egal-r egulatory-a nd-p olicy-f ramework/ due to the use of personal protective equipment during
emergency-use-authorization#covidppe. the coronavirus pandemic: results of a survey. Wound
45. Toomey EC, Conway Y, Burton C, Smith S, Smalle Manag Prev. 2020;66(10):12–6.
M, Chan XHS, et al. Extended use or reuse of single- 55. Brown-Johnson C, Vilendrer S, Heffernan MB, Winter
use surgical masks and filtering face-piece respirators S, Khong T, Reidy J, et al. PPE portraits—a way to
during the coronavirus disease 2019 (COVID-19) humanize personal protective equipment [Internet].
pandemic: a rapid systematic review [Internet]. Infect J Gen Intern Med. Springer; 2020 [cited 2021 Feb
Control Hosp Epidemiol. Cambridge University 13];35:2240–2. Available from: https://www.ncbi.
Press; 2021 [cited 2021 Feb 17]. 42:75–83. Available nlm.nih.gov/pmc/articles/PMC7224350/.
from: https://www.ncbi.nlm.nih.gov/pmc/articles/ 56. Reidy J, Brown-Johnson C, McCool N, Steadman
PMC7588721/. S, Heffernan MB, Nagpal V. Provider percep-
46. Ye G, Lin H, Chen S, Wang S, Zeng Z, Wang W, et al. tions of a humanizing intervention for health care
Environmental contamination of SARS-CoV-2 in workers—a survey study of PPE portraits. J Pain
healthcare premises. J Infect [Internet]. 2020 [cited Symptom Manage [Internet]. 2020 [cited 2021 Feb
2020 Nov 1];81(2):e1–5. Available from: https://doi. 13];60(5):e7–10. Available from: https://www.ncbi.
org/10.1016/j.jinf.2020.04.034. nlm.nih.gov/pmc/articles/PMC7476604/.
47. Strategies for optimizing the supply of eye pro-
57. Wundavalli LT, Singh S, Singh AR, Satpathy S. How
tection: COVID-19 | CDC [Internet]. [cited 2021 to rapidly design and operationalise PPE donning and
Feb 25]. Available from: https://www.cdc.gov/ doffing areas for a COVID-19 care facility: quality
coronavirus/2019-n cov/hcp/ppe-s trategy/eye- improvement initiative. BMJ Open Qual [Internet].
protection.html. 2020 [cited 2020 Nov 28];9(3) Available from: https://
48. Roberts V. To PAPR or not to PAPR? [Internet].
pubmed.ncbi.nlm.nih.gov/32978176/.
Can J Respir Ther. Canadian Society of Respiratory 58. Kwon JH, Burnham CAD, Reske KA, Liang

Therapists; 2014 [cited 2021 Jan 31];50:87–90. SY, Hink T, Wallace MA, et al. Assessment of
Available from: www.phac-aspc.gc.ca/id-mi/vhf-fvh/. healthcare worker protocol deviations and self-
49. Licina A, Silvers A. Use of powered air-purifying contamination during personal protective equip-
respirator(PAPR) as part of protective equipment ment donning and doffing. Infect Control Hosp
against SARS-CoV-2-a narrative review and critical Epidemiol [Internet]. 2017 [cited 2020 Nov
appraisal of evidence [Internet]. Am J Infect Control. 28];38(9):1077–83. Available from: https://
Mosby Inc. 2020 [cited 2021 Jan 31]; Available from: pubmed.ncbi.nlm.nih.gov/28606192/.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC765 59. MacIntyre CR, Chughtai AA, Seale H, Richards GA,
4369/?report=abstract. Davidson PM. Uncertainty, risk analysis and change
50. Ong JJY, Bharatendu C, Goh Y, Tang JZY, Sooi KWX, for Ebola personal protective equipment guidelines
Tan YL, et al. Headaches associated with personal [Internet]. Int J Nurs Stud. Elsevier Ltd; 2015 [cited
2020 Nov 29]. 52:899–903. Available from: https:// gov/coronavirus/2019-ncov/hcp/infection-control-

www.ncbi.nlm.nih.gov/pmc/articles/PMC7130314/. recommendations.html.
60. Edmond MB, Diekema DJ, Perencevich EN. Ebola 71. Coronavirus disease 2019 (COVID-19): infection

virus disease and the need for new personal protec- control in health care and home settings - UpToDate
tive equipment [Internet]. JAMA. American Medical [Internet]. [cited 2020 Oct 29]. Available from: https://
Association; 2014 [cited 2020 Nov 29]. 312:2495–6. www.uptodate.com/contents/coronavirus-d isease-
Available from: https://jamanetwork.com/journals/ 2019-covid-19-infection-control-in-health-care-and--
jama/fullarticle/1920943. home-settings.
61. Chughtai AA, Chen X, Macintyre CR. Risk of self- 72. COVID-19 - Control and Prevention | Healthcare

contamination during doffing of personal protec- Workers and Employers | Occupational Safety and
tive equipment. Am J Infect Control [Internet]. 2018 Health Administration [Internet]. [cited 2020 Oct 29].
[cited 2020 Nov 28];46(12):1329–34. Available from: Available from: https://www.osha.gov/SLTC/covid-
https://pubmed.ncbi.nlm.nih.gov/30029796/. 19/healthcare-workers.html.
62. Ebola: doctors and nurses at the front line need thanks 73. Discontinuation of transmission-based precautions

and protection, not punishment and blame. [Internet]. and disposition of patients with COVID-19 in health-
[cited 2020 Nov 29]. Available from: https://sphcm. care settings (Interim Guidance) | CDC [Internet].
med.unsw.edu.au/infectious-d iseases-b log/ebola- [cited 2020 Nov 8]. Available from: https://www.
doctors-a nd-n urses-f ront-l ine-n eed-t hanks-a nd- cdc.gov/coronavirus/2019-n cov/hcp/disposition-
protection-not. hospitalized-patients.html.
63. Díaz-Guio DA, Ricardo-Zapata A, Ospina-Velez J, 74. Telephone response guide for clinics | CDC [Internet].
Gómez-Candamil G, Mora-Martinez S, Rodriguez- [cited 2020 Nov 8]. Available from: https://www.cdc.
Morales AJ. Cognitive load and performance of health gov/coronavirus/2019-ncov/hcp/phone-guide/index.
care professionals in donning and doffing PPE before html.
and after a simulation-based educational intervention 75. Lentz RJ, Colt H. Summarizing societal guidelines
and its implications during the covid-19 pandemic regarding bronchoscopy during the COVID-19 pan-
for biosafety. Infez Med [Internet]. 2020 [cited 2020 demic [Internet]. Respirology. Blackwell Publishing;
Nov 28];28(suppl 1):111–7. Available from: https:// 2020 [cited 2020 Oct 29]. 25: 574–7. Available
pubmed.ncbi.nlm.nih.gov/32532947/. from: https://www.ncbi.nlm.nih.gov/pmc/articles/
64. Christensen L, Rasmussen CS, Benfield T, Franc
PMC7262091/.
JM. A randomized trial of instructor-led training 76. Klompas M, Baker M, Rhee C. What is an aerosol-
versus video lesson in training health care providers generating procedure? [Internet]. JAMA Surg.
in proper donning and doffing of personal protec- American Medical Association; 2020 [cited 2021
tive equipment. Disaster Med Public Health Prep Jan 23]. Available from: https://www.cdc.gov/
[Internet]. 2020 [cited 2020 Nov 28]; Available from: coronavirus/.
https://pubmed.ncbi.nlm.nih.gov/32223776/. 77. Hamilton F, Gregson F, Arnold D, Sheikh S, Ward K,
65. Zellmer C, Van Hoof S, Safdar N. Variation in health Brown J, et al. Aerosol emission from the respiratory
care worker removal of personal protective equip- tract: an analysis of relative risks from oxygen deliv-
ment. Am J Infect Control. 2015;43(7):750–1. ery systems. North Bristol NHS Trust [Internet]. cited
66. Tomas ME, Kundrapu S, Thota P, Sunkesula VCK, 2021 Feb 7;8. Available from: https://doi.org/10.1101
Cadnum JL, Mana TSC, et al. Contamination of /2021.01.29.21250552.
health care personnel during removal of personal 78. Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly
protective equipment. JAMA Intern Med [Internet]. J. Aerosol generating procedures and risk of trans-
2015 [cited 2020 Nov 29];175(12):1904–10. mission of acute respiratory infections to healthcare
Available from: https://jamanetwork.com/journals/ workers: a systematic review [Internet]. PLoS One.
jamainternalmedicine/fullarticle/2457400. 2012 [cited 2020 Nov 21];7. Available from: https://
67. Wong TKS, Chung JWY, Li Y, Chan WF, Ching PTY, pubmed.ncbi.nlm.nih.gov/22563403/.
Lam CHS, et al. Effective personal protective clothing 79. Canelli R, Connor CW, Gonzalez M, Nozari A,

for health care workers attending patients with severe Ortega R. Barrier enclosure during endotracheal intu-
acute respiratory syndrome. Am J Infect Control. bation. N Engl J Med [Internet]. 2020 [cited 2020 Oct
2004;32(2):90–6. 29];382(20):1957–8. Available from: https://www.
68. Healthcare facilities: managing operations during
ncbi.nlm.nih.gov/pmc/articles/PMC7151333/.
the COVID-19 pandemic | CDC [Internet]. [cited 80. Laosuwan P, Earsakul A, Pannangpetch P, Sereeyotin
2020 Nov 8]. Available from: https://www.cdc.gov/ J. Acrylic box versus plastic sheet covering on drop-
coronavirus/2019-ncov/hcp/guidance-hcf.html. let dispersal during extubation in COVID-19 patients
69. For providers | Telehealth.HHS.gov [Internet]. [cited [Internet]. Anesth Analg. Lippincott Williams and
2020 Nov 8]. Available from: https://telehealth.hhs. Wilkins. 2020 [cited 2021 Feb 21]:E106–8. Available
gov/providers/. from: https://www.ncbi.nlm.nih.gov/pmc/articles/
70. Infection control: severe acute respiratory syndrome PMC7219829/.
coronavirus 2 (SARS-CoV-2) | CDC [Internet]. 81. Dhillon RS, Rowin WA, Humphries RS, Kevin K,
[cited 2020 Nov 8]. Available from: https://www.cdc. Ward JD, Phan TD, et al. Aerosolisation during tra-
cheal intubation and extubation in an operating the- 90. Rehm M, Eichler J, Meidert AS, Briegel J. Protecting
atre setting. Anaesthesia [Internet]. 2021 [cited 2021 health care workers: use of a body covering trans-
Feb 22];76(2):182–8. Available from: https://www. parent sheet during and after intubation of patients
ncbi.nlm.nih.gov/pmc/articles/PMC7675280/. with COVID-19 [Internet]. Anesth Analg. Lippincott
82. El-Boghdadly K, Wong DJN, Owen R, Neuman MD, Williams and Wilkins. 2020 [cited 2020 Oct
Pocock S, Carlisle JB, et al. Risks to healthcare work- 29]:E111–2. Available from: https://www.ncbi.nlm.
ers following tracheal intubation of patients with nih.gov/pmc/articles/PMC7219839/
COVID-19: a prospective international multicentre 91. Giampalmo M, Pasquesi R, Solinas E. Easy and

cohort study. Anaesthesia. 2020;75(11):1437–47. accessible protection against aerosol contagion dur-
83. Aziz MF. The COVID-19 intubation experience
ing airway management [Internet]. Anesthesiology.
in Wuhan [Internet]. Br J Anaesth. Elsevier Ltd; Lippincott Williams and Wilkins; 2020 [cited 2021
2020 [cited 2020 Oct 29]. 125: e25–7. Available Feb 21]. 133:686–7. Available from: https://www.
from: https://www.ncbi.nlm.nih.gov/pmc/articles/ ncbi.nlm.nih.gov/pmc/articles/PMC7288759/.
PMC7183995/. 92. Hassan ZA. Covid-19: are chest compressions an

84. Yao W, Wang T, Jiang B, Gao F, Wang L, Zheng H, aerosol generating procedure or not? [Internet]. BMJ
et al. Emergency tracheal intubation in 202 patients (Clin Res Ed.). NLM (Medline); 2020 [cited 2021
with COVID-19 in Wuhan, China: lessons learnt and Feb 21]. 369:m1825. Available from: https://app.box.
international expert recommendations. Br J Anaesth com/s/.
[Internet]. 2020 [cited 2020 Oct 30];125(1):e28–37. 93. Brown E, Chan LM. Should chest compressions be
Available from: https://www.ncbi.nlm.nih.gov/pmc/ considered an aerosol-generating procedure? A litera-
articles/PMC7151238/?report=abstract. ture review in response to recent guidelines on per-
85. Cai SJ, Wu LL, Chen DF, Li YX, Liu YJ, Fan YQ, sonal protective equipment for patients with suspected
et al. [Analysis of bronchoscope-guided tracheal intu- COVID-19. Clin Med J R Coll Physicians London
bation in 12 cases with COVID-19 under the personal [Internet]. 2020 [cited 2021 Feb 22];20(5):E154–9.
protective equipment with positive pressure protective Available from: https://www.ncbi.nlm.nih.gov/pmc/
hood]. Zhonghua Jie He He Hu Xi Za Zhi [Internet]. articles/PMC7539717/.
2020 [cited 2021 Feb 21];43(0):E033. Available from: 94. Couper K, Taylor-Phillips S, Grove A, Freeman K,
http://www.ncbi.nlm.nih.gov/pubmed/32133829. Osokogu O, Court R, et al. COVID-19 in cardiac
86. Raboud J, Shigayeva A, McGeer A, Bontovics E,
arrest and infection risk to rescuers: a systematic
Chapman M, Gravel D, et al. Risk factors for SARS review. 2020 [cited 2021 Feb 22]; Available from:
transmission from patients requiring intubation: a mul- https://doi.org/10.1016/j.resuscitation.2020.04.022.
ticentre investigation in Toronto, Canada [Internet]. 95. Hsu CH, Tiba MH, Boehman AL, McCracken BM,
PLoS One. 2010 [cited 2020 Nov 21];5. Available Leander DC, Francalancia SC, et al. Aerosol gen-
from: https://pubmed.ncbi.nlm.nih.gov/20502660/. eration during chest compression and defibrilla-
87. Liu Z, Wu Z, Zhao H, Zuo M. Personal protective tion in a swine cardiac arrest model. Resuscitation.
equipment during tracheal intubation in patients with 2021;159:28–34.
COVID-19 in China: a cross-sectional survey. Br J 96. Ott M, Milazzo A, Liebau S, Jaki C, Schilling T,
Anaesth. Elsevier Ltd. 2020;125:e420–2. Krohn A, et al. Exploration of strategies to reduce
88. Gould CL, Alexander PDG, Allen CN, McGrath
aerosol-spread during chest compressions: a simu-
BA, Shelton CL. Protecting staff and patients dur- lation and cadaver model. Resuscitation [Internet].
ing airway management in the COVID-19 pandemic: 2020 [cited 2021 Feb 22];152:192–8. Available from:
are intubation boxes safe? [Internet]. Br J Anaesth. https://pubmed.ncbi.nlm.nih.gov/32437780/.
Elsevier Ltd; 2020 [cited 2021 Feb 21]. 125:e292–3. 97. Somri M, Gaitini L, Gat M, Sonallah M, Paz A,

Available from: https://www.ncbi.nlm.nih.gov/pmc/ Gómez-Ríos MÁ. Cardiopulmonary resuscitation
articles/PMC7218390/. during the COVID-19 pandemic. Do supraglottic air-
89. Clariot S, Dumain G, Gauci E, Langeron O, Levesque ways protect against aerosol-generation? [Internet].
É. Minimising COVID-19 exposure during tracheal Resuscitation. Elsevier Ireland Ltd; 2020 [cited
intubation by using a transparent plastic box: a ran- 2021 Jan 22]. 157:123–5. Available from: https://doi.
domised prospective simulation study [Internet]. org/10.1016/j.resuscitation.2020.10.013.
Anaesth Crit Care Pain Med. Elsevier Masson SAS; 98. Alhazzani W, Evans L, Alshamsi F, Møller MH,

2020 [cited 2021 Feb 21]. 39: 461–3. Available Ostermann M, Prescott HC, et al. Surviving Sepsis
from: https://www.ncbi.nlm.nih.gov/pmc/articles/ Campaign guidelines on the management of adults
PMC7834731/. With Coronavirus Disease 2019 (COVID-19) in the
ICU: first update. Crit Care Med. 2021;49(3):e219–34.
Evaluation and Diagnosis of COVID
Illness
4
Danny VanValkinburgh and Brian T. Wessman
Introduction and the flexibility of the ED to adapt to novel

roles. This chapter will highlight core concepts
The colloquial “front line” of any hospital is its regarding the evaluation and diagnosis of patients
emergency department (ED). The ED serves as in the ED setting during the COVID-19
the front door, the receiving bay, and the emer- pandemic.
gency arrival location for a multitude of patients
seeking medical care. Some healthcare systems
report greater than 70% of all admissions present Community
through the ED. The emergency physician (EP)
takes on the role of triaging, investigating, diag- If you are calling regarding a medical emergency,
please hang up and call 911 or visit your local
nosing, treating, and dispositioning patients in emergency department…
this realm. In this role, the EP also becomes a
bedside public health educator for their local Most medical offices or physician help lines
community. With the advent of a novel disease end with some variation of the above message.
process, the EP becomes the “watchperson on the The ED is open 24/7 and becomes the safety net
tower” to identify and alarm regarding novel pub- for any and all disease processes. The COVID-19
lic health risks. A novel coronavirus called pandemic continues to highlight the dependence
SARS-CoV-2 was discovered in 2019 and on emergency medical care as patients present to
declared a pandemic by the World Health the ED. Community spread has become prevalent
Organization (WHO) in March of 2020. Its dis- due to asymptomatic carriers and a prolonged
ease, named coronavirus disease 19 (COVID-19), incubation period of this viral disease. Current
and the ensuing worldwide pandemic has high- teaching is that symptoms may appear 2–14 days
lighted the strengths and weaknesses of the emer- after exposure to the virus [1–3]. Infected patients
gency healthcare system, the training of the EP, may actively shed virus throughout this period
making this disease highly communicable in the
community setting, specifically in the asymptom-
D. VanValkinburgh
Critical Care Medicine Fellow, Washington atic carrier [1]. COVID-19 impacts all age ranges,
University in Saint Louis School of Medicine, demographics, and geographic locations. Anyone
Barnes-Jewish Hospital, St. Louis, MO, USA can have mild to severe symptoms. Most public
B. T. Wessman (*) health messaging regarding COVID-19 directs
Washington University in Saint Louis, School of patients to the ED if they have trouble breathing,
Medicine, St. Louis, MO, USA persistent chest pain, new confusion, increased

34 D. VanValkinburgh and B. T. Wessman
somnolence, or cyanosis. This message will Healthcare Setting

impact both typical patient presentation and over-
all ED volume. At the onset of the pandemic, most hospitals
Several important community healthcare adapted the practice of creating “clean” and
concepts will impact how this increase in ED “dirty” areas of their ED as well as their inpatient
volume will affect the work-up of all ED units. However, the combination of non-specific
patients during this current pandemic. The ED symptoms and asymptomatic patients created
provider needs to be cognizant of community difficulties in deciding which patients needed
prevalence, incidence, rolling day positivity further testing or isolation upon arrival to the ED
rate, community susceptibility, and the repro- setting. Even patients presenting with constitu-
duction number. tional symptoms of a viral illness could not reli-
ably be ruled in or out for COVID-19. Hospital
• Prevalence: the proportion of a population limitations on bed availability while continuing
who have a specific characteristic or disease in to provide care for non-COVID-19 emergent
a given time period patients impacted the ability to maintain these
• Incidence: a measure of the number of new distinctions. Air flow, ventilation systems, and
cases of a characteristic or disease that develop access to negative pressure rooms also impacted
in a population in a specified time period many decisions on patient flow and bed place-
• Rolling day positivity rate: how prevalent pos- ment. All of these considerations impact nosoco-
itive cases of the disease are, when compared mial disease spread.
to the number of tests, being done (typically Our local healthcare system still has shared
presented as a 7-day or 14-day rolling inpatient rooms. Initially, we also had issues with
average) personal protection equipment and supply deliv-
• Susceptibility: tendency of a host population eries. Early in the pandemic, we adopted the
to be infected by a disease. Typically based practice of screening all patients being admitted
on community factors such as nutritional sta- from the ED regardless of clinical symptoms.
tus of the population, comorbidities, and This was done due to isolation needs on shared
environment (demographics, socioeconomic, patient rooms as well as screening due to poten-
climate factors, population density). It also tial need for procedural areas (endoscopy, cathe-
depends on vaccination rates, potential terization lab, operating room, interventional
immunity due to prior exposure, and other radiology, etc.). For patients deemed higher risk,
healthcare measures (masking, distancing, we employed the designation of “patient under
group gathering, etc.). investigation” (PUI) while awaiting laboratory
• Reproduction number (“R naught” or Ro): testing confirmation. We adopted the local prac-
used to describe the intensity of an infec- tice of closing all doors/curtains/glass sliding
tious disease outbreak. The number of cases, doors on all patients to help with isolation.
on average, that an infected person will Specific isolation signage was prominently dis-
cause during their infectious period. If the played outside of rooms. Our healthcare provid-
Ro is greater than 1, the disease will con- ers adapted the practice of wearing eye protection
tinue to spread. The current Ro estimation and N95 masks in all patient care areas (please
for SARS-CoV-2 is thought to be between see the personal protection chapter for further
1.5 and 3.5. details and guidance).
The decision to test asymptomatic patients in
Understanding these concepts will impact ED your region will depend on the prevalence in the
clinical work-up (in combination with access to community, access to personal protection equip-
COVID-19 testing platforms: type and rapidity), ment, inpatient hospital resources, availability of
isolation strategies, and community healthcare testing capacity, and the exposure history of the
education. patient while following institutional guidelines.
4 Evaluation and Diagnosis of COVID Illness 35
Patient Presentation infection due to a reported range of 47–73% of

patients complaining of this symptom. Sore
Patients present to the ED with a spectrum of dis- throat, myalgia, and diarrhea have been reported
eases and complaints, and any patient (trauma but had lower incidences in COVID-19 positive
evaluation, stroke activation, dental complaint, patients [4–6].
myocardial infarction, etc.) may be infected with Appropriate consideration should be given to
the virus. As with any patient evaluation, a thor- past/current medical history and social history/
ough patient history from both the patient and exposures. Specific risk factors include:
potential corroborators will provide nuanced
Residence/work/travel in Residency in a long-term
information to guide the ED work-up. A range of region with high risk of care facility
symptoms have been reported to be associated transmission
with COVID-19, and the astute clinician should Contact with probable or Male sex
explore these specifically during the current pan- confirmed case
Older age (>65) Ethnicity (Black, Asian,
demic. As a reminder, some patients are also
minority ethnic groups)
asymptomatic so a high level of suspicion should Hypertension Malignancy
remain. Sickle cell disease Smoking
Diabetes Pregnancy
Fever or chills Confusion/delirium Dysphagia Chronic respiratory Immunosuppression
Cough Headache Nasal congestion disease
Dyspnea Anosmia Nausea Cardiovascular disease Autoimmune disease
Fatigue Hyposmia Emesis Obesity Developmental/intellectual
Myalgias Hypogeusia Diarrhea disability
The virus SARS-CoV-2 may present as a viral A physical exam should be performed on all
syndrome with symptoms of cough, coryza, patients per usual ED evaluation. Specific atten-
headache, fever, and other non-specific symp- tion should be given to the following:
toms. Typically, this constellation of symptoms
would point to a viral illness without the need for Delirium Fever
further testing, and a patient would be disposi- Hypoxia Cyanosis
Cough Nasal congestion
tioned appropriately. However, due to the poten-
Bronchial breath sounds Oropharynx erythema
tial severity of disease caused by COVID-19 and Hemoptysis Ocular discharge
the widespread pandemic, it has become impera- Tachypnea Cutaneous symptoms
tive that physicians accurately diagnose patients. Tachycardia Signs of thrombosis
Carpenter et al. examined 87 studies in a scop-
ing review of diagnosing COVID-19 in the emer- Ultimately, low threshold should be had to
gency department. Fever is the most commonly move forward with laboratory evaluation, imag-
reported symptom of COVID-19 infections ing, and formal SARS-CoV-2 testing if suspicion
reported in 84–87% of patients. Cough was found of COVID-19 remains high and it will impact
to have about 58% frequency in COVID-19 posi- disposition.
tive patients [4, 5]. Hyposmia (decreased sense of
smell) and hypogeusia (decreased sense of taste)
were both symptoms noted to be common in Testing: Laboratory
COVID-19 infections early in the pandemic.
They found positive likelihood ratios to be 5.3 The ideal diagnostic test, resource utilization,
and 7.1 for hyposmia and hypogeusia, respec- and testing strategy have been in flux through the
tively. The negative likelihood ratios were much initial stages of the pandemic. Prior to wide-
less significant at 0.61 and 0.38. The more spread availability of reliable polymerase chain
extreme symptom of anosmia (total lack of smell) reaction (PCR) testing, other supplemental labo-
also lacked reliability in determining COVID-19 ratory and radiological tests were implemented in
the hospital system. Routine laboratory samples, evaluating the temporal relationship with rising
inflammatory markers, coagulation markers, and hepatic enzyme levels in patients with COVID-19
imaging studies have all been used to help diag- show that aspartate aminotransferase (AST) is
nose and predict the course of COVID-19. the first enzyme to show elevation followed by
Specific tests include: alanine aminotransferase (ALT). Elevated AST to
ALT ratios were noted in patients that developed
Complete blood count with Ferritin
more severe disease and predicted higher mortal-
differential
Comprehensive metabolic panel C-reactive protein ity [12]. The pattern and time frame of AST ele-
(CRP) vations differ from other hepatitis-induced liver
Coagulation markers D-dimer injury such as hepatitis B virus and severe acute
Lactate dehydrogenase (LDH) respiratory syndrome (SARS-CoV-1) [12]. In
severe COVID-19 cases, AST elevation around
Lymphopenia Leukopenia, and specifically the tenth day of the disease was associated with
lymphopenia, is associated with infection by higher mortality. Alkaline phosphatase does not
SARS-CoV-2. Around 50% of patients with seem to have direct correlation with COVID-19.
COVID-19 have been found to be lymphopenic Bilirubin levels fluctuate depending on severity
with a range of 40–70% reported in the literature of overall clinical picture and do not predict
[6]. The majority of viral infections cause a tem- infection or risk of clinical decompensation.
porary leukopenia and lymphopenia, minimizing Overall, the pattern of liver enzyme elevation
the utility of these markers when used in isolation most closely resembles immune-mediated
[7, 8]. However, for COVID-19 in particular, inflammation as opposed to direct liver injury
there are strong associations with lymphopenia from the virus [12].
as a potential predictor of disease severity [9].
Ferritin Ferritin is an intracellular storage pro-
Lactate dehydrogenase LDH has been described tein for iron in a nontoxic form. During cases of
in the literature to have elevations in COVID-19. infection and inflammation, the body reduces
The incidence of elevated values ranges from free iron in the blood by increasing storage with
30% to 70% of positive patients. A pooled analy- ferritin. Ferritin may also be actively secreted
sis of published literature found that elevated by macrophages or damaged cells. Ferritin ele-
LDH was associated with a six-fold increase in vation is typically associated with viral infec-
odds of developing severe disease and a 16-fold tions and correlates with IL-16 levels. This has
increase in odds of mortality [10]. Although this also been observed in other viral infections such
may be true in SARS-CoV-2 infections, it is also as Epstein-Barr virus (EBV), human immuno-
true for severely ill patients in general. Non- deficiency virus (HIV), and dengue [13]. Studies
COVID-19 studies show that elevated LDH lev- have attempted to assess the feasibility of using
els predict severe disease in cases of metastatic ferritin as a marker of COVID-19 disease. One
cancer, hematological malignancies, and infec- large study performed a retrospective review
tion. Elevated LDH level is also an independent assessing ferritin as a predictive lab value for
predictor of mortality in admitted medical worsening disease. Unfortunately, ferritin levels
patients [11]. had poor positive and negative predictive values
for clinical deterioration. When assessing mor-
Hepatic enzymes Elevation in hepatic enzyme tality, the presenting ferritin level had a positive
levels is associated with acute COVID-19 infec- predictive value (PPV) of 0.356 and negative
tion. Large studies show that elevated levels not predictive value (NPV) of 0.776 at a cutoff of
only show correlation with infection but predict a 799 ng/mL. For predicting mechanical ventila-
more severe clinical trajectory. Lab values greater tion, the presenting PPV and NPV values were
than three times the upper limit of normal were 0.371 and 0.813 at a cutoff of 619 ng/mL [14].
considered significant in most studies. Studies Ferritin does appear to be elevated in patients
with COVID-19 and is more elevated in patients mL). Patients with elevated d-dimer levels were
that will progress to more severe disease; how- associated with an increased risk of progressing
ever, the ability to predict severe disease is not to critical illness, requiring mechanical ventila-
sufficient enough to reliably predict these tion, and developing acute kidney injury (AKI).
changes alone. The rate of those outcomes increased as the level
of d-dimer increased. D-dimer levels >2000 ng/
C-reactive protein CRP is an acute-phase pro- mL had the highest risk of critical illness, throm-
tein found in very low levels in healthy individu- bosis, and AKI. Adjusted odds ratios showed sig-
als. After an inflammatory stimulus, levels can nificantly higher odds of death in patients with
rise 1000-fold and may remain elevated due to a elevated D-dimer than those without elevations.
half-life of about 20 hours. Since levels are Patients found to have normal D-dimer levels at
reduced through a predictable half-life presentation were more likely to be discharged
degradation, CRP is commonly used to trend
without developing critical illness. These patients
inflammation states [13]. Bacterial infections were also noted to have a low mortality rate of
typically increase CRP levels as opposed to viral 10.7% (significantly lower than the 30.3% mor-
infections that have relatively low levels of CRP tality for patients with d-dimer elevations). If the
[15]. However, COVID-19 appears to have higher presenting d-dimer level was >2000 ng/mL,
prevalence of CRP elevation. One meta-analysis patients had the highest risk of all-cause mortal-
found about 58% of patients had a CRP eleva- ity at 48.3% [17].
tion; however, there was a wide confidence inter-
val that spanned 21.8–94.7% [16]. Other case
series have noted that CRP may be used as a pre- Testing: Imaging
dictor of impending deterioration. One study
found that patients who were admitted without Early in the pandemic, a significant number of the
severe symptoms but with marked CRP eleva- patients were found to have bilateral diffuse infil-
tions all (100%) progressed to severe disease trates on imaging. Prior to widespread availability
(however it should be noted that the patients with of testing for the virus, chest radiography (CXR)
CRP elevations were also a group of patients and computerized tomography (CT) frequently
expected to do worse due to other comorbidities were employed for diagnosing COVID-19. The
like older age [15]). CRP should not be used as a World Health Organization (WHO) released a
screening test but can help predict patient pro- rapid advice guide in the summer of 2020 for
gression to severe disease. imaging patients with suspected COVID-19 [19].
Of the six recommendations in which provid-
D-dimer D-dimer is a breakdown product of ers should consider diagnostic imaging, only a
fibrin and is commonly used for evaluating fibrin few apply to the initial evaluation and diagnosis
formation and degradation. Healthy individuals in the ED. The WHO recommends against using
have low levels of d-dimer, while elevations are chest imaging for diagnosing COVID-19 if
seen in thrombotic events, acutely ill patients, or reverse transcription-polymerase chain reaction
chronically ill patients [17]. COVID-19-infected (RT-PCR) is readily available with a timely turn-
individuals have elevated d-dimer levels propor- around. However, the WHO recommends chest
tionally related to microvascular thrombosis. imaging if RT-PCR is not available or has delayed
Studies have evaluated the level of d-dimer eleva- results or test result is negative with a high clini-
tion at ED presentation for predicting progres- cal suspicion of COVID-19. Imaging in this sce-
sion to severe disease or death in patients with nario should be in addition to other clinical and
COVID-19 [18]. In one large cohort, it was found laboratory work-up to provide an accurate diag-
that around 76% of patients presented with ele- nosis. For the patient with mild symptoms that is
vated d-dimer levels. The average level observed not hospitalized, the WHO recommends chest
was 767 ng/mL (upper limit of normal is 230 ng/ imaging in addition to clinical and laboratory
assessment to help determine dispositioning. For these findings are non-specific across the spec-
patients with suspected or confirmed COVID-19 trum of pulmonary pathology. CT scanning is an
experiencing moderate to severe symptoms, chest expensive test for widespread screening of all
imaging is recommended to determine admission patients suspected of SARS-CoV-2 in the
to an intensive care unit or medical floor. Imaging ED. The logistics of using a CT scanner as a
patients with moderate to severe symptoms can screening test also poses problems for most
help predict which patients will decompensate EDs. It takes around 30 minutes to clean the
prior to clinical deterioration. It should be noted scanner effectively after suspected patients have
that all of the WHO recommendations are either been tested [5]. Not only would it be difficult
based on expert opinion or conditional recom- logistically, but the testing characteristics of
mendations with low-quality evidence [19]. diagnosing COVID-19 by CT scan have mixed
results. From some reviews, the sensitivity of
Chest radiography Symptomatic COVID-19 CT scans was 72–94% with a specificity of
patients may have abnormal CXR findings [20]. 24–100% [5]. When used in combination with
However, studies have shown that radiographs RT-PCR, the sensitivity of screening for
may be normal in up to 63% of patients with COVID-19 reaches about 97% [5].
COVID-19 pneumonia [20]. As a screening test
on admission, radiographs may have a sensitivity Ultrasound Point-of-care ultrasound (POCUS)
of only 33%–60% [5]. Abnormal findings include has expanded significantly over the past several
ground-glass appearance in over half of patients, years. Ultrasound machines are small, portable,
horizontal linear opacities, and consolidation. safe, and easy to clean, especially when com-
These abnormal findings may be seen in all parts pared to CT scanners or portable CXR machines
of the lung but preferentially occur at the bases [21]. Logistically, POCUS is the ideal diagnostic
and most commonly are bilateral [20]. These imaging study for a pandemic. In previous pan-
findings are non-specific to COVID-19 pneumo- demics like H1N1 influenza, patients would rap-
nia and are neither sensitive nor specific enough idly decline before changes in chest radiography
to be the only diagnostic test in the disease’s ini- [22]. Several studies from 2009 evaluated the use
tial evaluation. Additionally, the early phase of of POCUS for earlier detection of viral pneumo-
the disease may not have observable findings on nia in symptomatic patients. At the time, POCUS
CXR. Around 30% may have normal radiographs characteristics included a sensitivity of 94%, a
on admission, while at least a third of those specificity of 89%, a PPV of 86%, and a NPV of
patients will progress to abnormal films [20]. 96%. These studies paved the way for the use of
Peak radiograph severity may be delayed, with POCUS in COVID-19 [22]. Symptomatic
the worst appearing around days 10–12 after the patients admitted to the hospital overwhelmingly
onset of symptoms [20]. The most significant have positive findings on ultrasound. One retro-
benefit of CXR resides in the serial imaging of spective study assessing the feasibility of POCUS
admitted patients to assess the disease’s progres- found that compared to RT-PCR, POCUS per-
sion. Chest radiographs can be easily obtained on formed better. The sensitivity and NPV were
admitted patients with portable machines, thus 93.3% and 94.1%. On the other hand, other test
limiting the amount of time infected patients characteristics were inadequate—the specificity,
would travel out of isolation [19]. PPV, and accuracy were 21.3%, 19.2%, and
33.3%, respectively [23]. This data suggests that
Computed tomography Prior to the availability POCUS may be a quick, efficient, and safe
of RT-PCR tests, some protocols used CT imag- screening test to use in the ED for patients pre-
ing to diagnose COVID-19 [5]. Common find- senting with respiratory symptoms concerning
ings on CT scan include bilateral and peripheral for infection with SARS-CoV-2. In comparison,
ground-glass opacities without pleural effusions CT scans in this study had a lower sensitivity and
or mediastinal adenopathy [4, 5]. Unfortunately, a NPV but higher specificity [23].
Testing: Diagnostic Testing Unfortunately, RT-PCR in the COVID-19

of SARS-CoV-2 pandemic has not been perfect. The poor sensitiv-
ity limits its use as an exclusive screening test,
Direct testing for the SARS-CoV-2 virus comes even though a high specificity allows it to rule in
in many forms. The most common test is the the disease with near certainty. A single RT-PCR
reverse transcription-polymerase chain reaction test’s sensitivity is reported to be about 78%,
(RT-PCR) test that uses small amounts of viral meaning only 78% of patients infected with the
RNA to be reverse transcribed into DNA. This virus will actually test positive. Repeating the test
DNA then has genetic markers added to the solu- two times reaches a sensitivity of 86% and repeat-
tion that attaches to specific sequences of the ing five times reaches 98% [5, 24]. Although
DNA. The marked DNA is then amplified expo- repeating the test five times is not practical when
nentially through a protein replication process supplies are limited, several institutions required
and identified by the PCR machine. Once the a minimum of two tests to rule out admitted
sample reaches a specific threshold that the patients.
device can measure, the test is determined posi- Other factors influencing the test dynamics
tive. The number of cycles it takes to achieve the include the viral load for each patient. The higher
threshold is relative to the amount of RNA in the the viral load, the higher amounts of RNA are
patient’s sample. The time it takes to complete a amplified, meaning the more likely a test will be
PCR test varies on the manufacturer but usually positive. These patients with higher viral loads
is on the order of hours. For SARS-CoV-2, two have more severe disease, have higher mortality,
nucleocapsid genes N1 and N2 are commonly and are more likely to test positive on the first
used in tests in the United States [5, 16]. If both RT-PCR evaluation [24]. Another confounding
of the genes are detected, the sample is deter- factor to the accuracy of these tests is the timing
mined to be positive. If only one of the genes from initial infection or exposure. One large
tests positive, the test is inconclusive. A sample study found the lowest false-negative rate around
must be negative for both genes to be considered day 8 after exposure and day 3 after symptom
a negative result. onset [25]. False-negative rates were significantly
Limitations for RT-PCR in a pandemic higher in the 5 days prior to symptom onset. The
include the lag time of testing results from when NPV also increased over time and at day 21 after
the sample is taken [5]. The quicker a result can probable exposure, the false-negative rate was
be determined, the quicker treatment or isola- over 60% [25]. This lag time between likely
tion can be initiated. Specifically, for this pan- exposure and high rates of false-negative tests is
demic, the supply of reagents became a limiting concerning since patients will frequently present
factor. Manufactures quickly depleted stores of prior to or at the onset of symptoms— exactly
reagents, causing delays in the ability to test. when the false-negative rate is the highest. How
One solution to this problem was the batching of long patients continue to test positive also varies,
samples. Multiple samples are batched together with older patients testing positive longer after
by mixing them into one testing machine. symptom resolution. Other patients with immune-
Reagents are preserved in this fashion if the compromised states may have prolonged viral
batched test was negative since only one test RNA shedding compared to healthier individu-
was performed instead of several. However, als. Medical treatments, such as steroid usage,
each sample would require evaluation indepen- may also impact the length of viral shedding.
dently if the batched test returns positive. Data There is a variety of testing sites and body flu-
of the current COVID-19 pandemic demon- ids used for RT-PCR. Nasopharyngeal (NP) are
strates that when the community prevalence is the most common; however, oropharyngeal (OP),
<10%, four individual samples in each batch is saliva, sputum, stool, blood, and urine may be
the ideal number in order to reduce overall chosen. Several of these testing sites are easily
reagent use by 69% [5]. performed, but others require specific training
[26]. NP and OP swabs require training on col- esting: Summary of Strategies

T
lection techniques as well as safety precautions. in the ED Setting
Both of these methods put testers at risk due to
close encounters and frequent coughing during Being able to quickly rule in or rule out a patient for
the tests. Saliva testing can be done quickly and COVID-19 is crucial for limiting community and
safely [26, 27]. Testers do not need to be in close nosocomial spread of the disease. This is also para-
contact during a saliva test, and patients can even mount for patient education regarding quarantine
self-perform this test while in isolation or during and inpatient bed assignments. The ideal evaluation
a telemedicine examination. The test method is not known yet; however, the comprehen-
characteristics of saliva on symptomatic patients sive strategy would consider the prevalence in the
are comparable to that of NP or OP swabs. When community, known exposure risk, symptoms and
compared to the reference standard of NP or OP signs on patient presentation, physical exam, rou-
swab, one study found saliva testing 84% sensi- tine lab work, SARS-CoV-2 specific testing, and
tive and 99% specific, with a 97.5% agreement imaging studies to determine the likelihood of an
between the tests. Saliva tests can be considered acute infection [5, 30]. Physicians will be poised to
to have similar testing characteristics while being make the most accurate diagnosis by incorporating
potentially safer for the administering staff [27]. the entire patient work-up and evaluation with the
Other testing methods include antigen testing. pretest probability. Studies have shown that a multi-
These tests directly assess the presence of spe- modal testing strategy improves the sensitivity and
cific antigens as opposed to RNA material. These accuracy of tests. Procedures or workflows may
tests are less common than RT-PCR at this time. vary depending on the specific hospital or emer-
The advantages of these tests are in the rapid gency department, and developing a plan is para-
turnaround time [28]. These antigen tests would mount for accurate testing.
ideally be used in triaging patients, especially in
the ED, to seclude positive patients to COVID-19 Critical Points
specific units. The antigen tests have unclear • Quick and accurate testing of individuals sus-
diagnostic accuracy at this time. They, like the pected of COVID-19 is required for initiating
RT-PCR, are highly specific and have low false- treatment and isolating individuals.
positive tests. However, the sensitivities appear to • Presenting signs and symptoms are insuffi-
be less than that of RT-PCR [5]. cient for ruling are insufficient for ruling in or
Serology testing using lateral-flow assays out the disease.
(LFA) or enzyme-linked immunosorbent assay • Routine lab work is not sufficient to rule in or
(ELISA) tests measure antibodies in a patient’s rule out the disease; however, many lab tests
serum or plasma. One review of 12 different LFA are used to help predict disease severity and
and ELISA tests found a wide range of test per- risk of decompensation.
formances. Test specificity ranged from 84 to • Routine lab work may be requested for prog-
100%, with the time from symptom onset to posi- nostication depending on the inpatient ser-
tivity playing a large role in the characteristics. vice’s requests.
The highest rate of positive tests came in the • Chest radiography is insufficient for diagnos-
16–20-day and > 20-day intervals when IgM and ing COVID-19 but may help in trending the
IgG testing were combined [29]. This late time disease.
frame may improve the overall testing of a popu- • Chest CT and lung ultrasound can be used as a
lation but does little for evaluating patients in the screening test, as a diagnostic test, or for
acute phase of illness. If long-term immunity trending disease severity.
occurs after an infection, serology testing could • A single RT-PCR testing can be insufficient
be beneficial. However, current data do not sup- for ruling out disease.
port serology testing as a screening test for • Combining RT-PCR with disease prevalence,
patients in the acute phase of work-up or illness. signs and symptoms, routine lab work, imag-
AL GRAWANY
ing, and SARS-CoV-2 testing is the most org/10.1016/j.tmaid.2020.101623. Epub 2020 Mar
accurate strategy for effectively diagnosing 13. PMID: 32179124; PMCID: PMC7102608.
7. Pascutti MF, Erkelens MN, Nolte MA. Impact of
COVID-19. viral infections on hematopoiesis: from beneficial
• Protocols for rapid testing and isolation are to detrimental effects on bone marrow output. Front
crucial for limiting community, nosocomial, Immunol. 2016;7:364. https://doi.org/10.3389/
and healthcare worker spread of the disease. fimmu.2016.00364. PMID: 27695457; PMCID:
PMC5025449.
• Develop a plan with local and hospital 8. Fathi N, Rezaei N. Lymphopenia in COVID-19: ther-
resources on the preferred method of work-up apeutic opportunities. Cell Biol Int. 2020;44(9):1792–
and disposition of positive patients as well as 7. https://doi.org/10.1002/cbin.11403.
suspected patients. 9. Huang I, Pranata R. Lymphopenia in severe coronavi-
rus disease-2019 (COVID-19): systematic review and
meta-analysis. J Intensive Care. 2020;8:36. https://
doi.org/10.1186/s40560-020-00453-4.
References 10. Henry BM, Aggarwal G, Wong J, et al. Lactate dehy-
drogenase levels predict coronavirus disease 2019
1. Huff HV, Singh A. Asymptomatic transmission during (COVID-19) severity and mortality: a pooled analy-
the COVID-19 pandemic and implications for pub- sis. Am J Emerg Med. 2020;38(9):1722–6. https://doi.
lic health strategies. Clin Infect Dis. 2020:ciaa654. org/10.1016/j.ajem.2020.05.073.
https://doi.org/10.1093/cid/ciaa654. Epub ahead of 11. Erez A, Shental O, Tchebiner JZ, Laufer-Perl M,
print. PMID: 32463076; PMCID: PMC7314132. Wasserman A, Sella T, Guzner-Gur H. Diagnostic and
2. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, prognostic value of very high serum lactate dehydro-
Prescott HC. Pathophysiology, transmission, diag- genase in admitted medical patients. Isr Med Assoc J.
nosis, and treatment of coronavirus disease 2019 2014;16(7):439–43. PMID: 25167691.
(COVID-19): a review. JAMA. 2020;324(8):782–93. 12. Lei F, Liu YM, Zhou F, Qin JJ, Zhang P, Zhu L, Zhang
https://doi.org/10.1001/jama.2020.12839. PMID: XJ, Cai J, Lin L, Ouyang S, Wang X, Yang C, Cheng
32648899. X, Liu W, Li H, Xie J, Wu B, Luo H, Xiao F, Chen
3. Zhou R, Li F, Chen F, Liu H, Zheng J, Lei C, Wu J, Tao L, Cheng G, She ZG, Zhou J, Wang H, Lin J,
X. Viral dynamics in asymptomatic patients with Luo P, Fu S, Zhou J, Ye P, Xiao B, Mao W, Liu L,
COVID-19. Int J Infect Dis. 2020;96:288–90. https:// Yan Y, Liu L, Chen G, Li H, Huang X, Zhang BH,
doi.org/10.1016/j.ijid.2020.05.030. Epub 2020 May Yuan Y. Longitudinal association between mark-
11. PMID: 32437933; PMCID: PMC7211726. ers of liver injury and mortality in COVID-19 in
4. Cao Y, Liu X, Xiong L, Cai K. Imaging and clini- China. Hepatology. 2020;72(2):389–98. https://doi.
cal features of patients with 2019 novel coronavirus org/10.1002/hep.31301. PMID: 32359177; PMCID:
SARS-CoV-2: a systematic review and meta-analysis. PMC7267515.
J Med Virol. 2020:10.1002/jmv.25822. https://doi. 13. Slaats J, Ten Oever J, van de Veerdonk FL, Netea
org/10.1002/jmv.25822. Epub ahead of print. PMID: MG. IL-1β/IL-6/CRP and IL-18/ferritin: distinct
32242947; PMCID: PMC7228215. inflammatory programs in infections. PLoS Pathog.
5. Carpenter CR, Mudd PA, West CP, Wilber E, Wilber 2016;12(12):e1005973. https://doi.org/10.1371/
ST. Diagnosing COVID-19 in the emergency depart- journal.ppat.1005973. PMID: 27977798; PMCID:
ment: a scoping review of clinical examinations, PMC5158075.
laboratory tests, imaging accuracy, and biases. Acad 14. Feld J, Tremblay D, Thibaud S, Kessler A,
Emerg Med. 2020:10.1111/acem.14048. https:// Naymagon L. Ferritin levels in patients with
doi.org/10.1111/acem.14048. Epub ahead of print. COVID-19: a poor predictor of mortality and hemo-
PMID: 32542934; PMCID: PMC7323136. phagocytic lymphohistiocytosis. Int J Lab Hematol.
6. Rodriguez-Morales AJ, Cardona-Ospina JA, 2020;42(6):773–9. https://doi.org/10.1111/
Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin- ijlh.13309. Epub 2020 Aug 13. PMID: 32790918;
Rivera Y, Escalera-Antezana JP, Alvarado-Arnez PMCID: PMC7436675.
LE, Bonilla-Aldana DK, Franco-Paredes C, Henao- 15. Wang G, Wu C, Zhang Q, et al. C reactive protein
Martinez AF, Paniz-Mondolfi A, Lagos-Grisales level may predict the risk of COVID-19 aggravation.
GJ, Ramírez-Vallejo E, Suárez JA, Zambrano LI, Open Forum Infect Dis. https://doi.org/10.1093/ofid/
Villamil-Gómez WE, Balbin-Ramon GJ, Rabaan ofaa153. [published online April 29, 2020].
AA, Harapan H, Dhama K, Nishiura H, Kataoka 16. Cheng MP, Papenburg J, Desjardins M, Kanjilal
H, Ahmad T, Sah R, Latin American Network of S, Quach C, Libman M, Dittrich S, Yansouni
Coronavirus Disease 2019-COVID-19 Research CP. Diagnostic testing for severe acute respiratory
(LANCOVID-19). Electronic address: https://www. syndrome-related coronavirus 2: a narrative review.
lancovid.org. Clinical, laboratory and imaging features Ann Intern Med. 2020;172(11):726–34. https://doi.
of COVID-19: a systematic review and meta-analysis. org/10.7326/M20-1301. Epub 2020 Apr 13. PMID:
Travel Med Infect Dis. 2020;34:101623. https://doi. 32282894; PMCID: PMC7170415.
17. Berger JS, Kunichoff D, Adhikari S, Ahuja T,

https://doi.org/10.1001/jama.2020.3786. PMID:
Amoroso N, Aphinyanaphongs Y, Cao M, Goldenberg 32159775; PMCID: PMC7066521.
R, Hindenburg A, Horowitz J, Parnia S, Petrilli C, 27. Pasomsub E, Watcharananan SP, Boonyawat K,

Reynolds H, Simon E, Slater J, Yaghi S, Yuriditsky Suksuwan W, Sungkanuparph S, Phuphuakrat
E, Hochman J, Horwitz LI. Prevalence and out- A. Saliva sample as a non-invasive specimen for
comes of D-dimer elevation in hospitalized patients the diagnosis of coronavirus disease 2019: a cross-
with COVID-19. Arterioscler Thromb Vasc Biol. sectional study. Clin Microbiol Infect. 2021;27(2):285.
2020;40(10):2539–47. https://doi.org/10.1161/ e1–4. https://doi.org/10.1016/j.cmi.2020.05.001.
ATVBAHA.120.314872. Epub 2020 Aug 25. PMID: Published: 15 May 2020.
32840379; PMCID: PMC7505147. 28. Scohy A, Anantharajah A, Bodéus M, Kabamba-

18. Yao Y, Cao J, Wang Q, et al. D-dimer as a biomarker Mukadi B, Verroken A, Rodriguez-Villalobos
for disease severity and mortality in COVID-19 H. Low performance of rapid antigen detection test
patients: a case control study. J Intensive Care. as frontline testing for COVID-19 diagnosis. J Clin
2020;8:49. https://doi.org/10.1186/s40560-020- Virol. 2020;129:104455. https://doi.org/10.1016/j.
00466-zphohistiocytosis. Int J Lab Hematol. 2020; jcv.2020.104455. Epub 2020 May 21. PMID:
00:1–7. https://doi.org/10.1111/ijlh.13309. 32485618; PMCID: PMC7240272.
19. World Health Organization. Use of chest imaging
29. Whitman JD, Hiatt J, Mowery CT, Shy BR, Yu R,
in COVID-19: a rapid advice guide. Geneva: World Yamamoto TN, Rathore U, Goldgof GM, Whitty
Health Organization; 2020. (WHO/2019-nCoV/ C, Woo JM, Gallman AE, Miller TE, Levine AG,
Clinical/Radiology_imaging/2020.1). Licence: CC Nguyen DN, Bapat SP, Balcerek J, Bylsma SA, Lyons
BY-NC-SA 3.0 IGO. AM, Li S, Wong AW, Gillis-Buck EM, Steinhart
20. Cleverley J, Piper J, Jones MM. The role of chest ZB, Lee Y, Apathy R, Lipke MJ, Smith JA, Zheng T,
radiography in confirming covid-19 pneumonia. Boothby IC, Isaza E, Chan J, Acenas DD 2nd, Lee J,
BMJ. 2020;370:m2426. https://doi.org/10.1136/bmj. Macrae TA, Kyaw TS, Wu D, Ng DL, Gu W, York VA,
m2426. PMID: 32675083. Eskandarian HA, Callaway PC, Warrier L, Moreno
21. Zhang Y, Xue H, Wang M, He N, Lv Z, Cui L. Lung ME, Levan J, Torres L, Farrington LA, Loudermilk
ultrasound findings in patients with coronavirus dis- RP, Koshal K, Zorn KC, Garcia-Beltran WF, Yang D,
ease (COVID-19). AJR Am J Roentgenol. 2020:1–5. Astudillo MG, Bernstein BE, Gelfand JA, Ryan ET,
https://doi.org/10.2214/AJR.20.23513. Epub ahead of Charles RC, Iafrate AJ, Lennerz JK, Miller S, Chiu
print. PMID: 32755198. CY, Stramer SL, Wilson MR, Manglik A, Ye CJ,
22. Convissar DL, Gibson LE, Berra L, Bittner EA,
Krogan NJ, Anderson MS, Cyster JG, Ernst JD, AHB
Chang MG. Application of lung ultrasound during W, Lynch KL, Bern C, Hsu PD, Marson A. Evaluation
the COVID-19 pandemic: a narrative review. Anesth of SARS-CoV-2 serology assays reveals a range of
Analg. 2020;131(2):345–50. https://doi.org/10.1213/ test performance. Nat Biotechnol. 2020;38(10):1174–
ANE.0000000000004929. PMID: 32366774; 83. https://doi.org/10.1038/s41587-020-0659-0. Epub
PMCID: PMC7202122. 2020 Aug 27. PMID: 32855547.
23. Narinx N, Smismans A, Symons R, et al. Feasibility 30. Ren X, Liu Y, Chen H, et al. Application and optimi-
of using point-of-care lung ultrasound for early tri- zation of RT-PCR in diagnosis of SARS-CoV-2 infec-
age of COVID-19 patients in the emergency room. tion. medRxiv 2020.
Emerg Radiol. 2020; https://doi.org/10.1007/
s10140-020-01849-3.
24. Zhang JJ, Cao YY, Dong X, Wang BC, Liao MY,
Lin J, Yan YQ, Akdis CA, Gao YD. Distinct char- Further Reading
acteristics of COVID-19 patients with initial rRT-
PCR- positive and rRT-PCR-negative results for Bestpractice.bmj.com. Coronavirus Disease 2019
SARS-CoV-2. Allergy. 2020;75(7):1809–12. https:// (COVID-19) – symptoms, diagnosis and treatment
doi.org/10.1111/all.14316. Epub 2020 Apr 27. PMID: | BMJ Best Practice. 2020. [online] Available at:
32281110; PMCID: PMC7262033. https://bestpractice.bmj.com/topics/en-gb/3000201.
25. Kucirka LM, Lauer SA, Laeyendecker O, Boon D, Accessed 29 Nov 2020.
Lessler J. Variation in false-negative rate of reverse Centers for Disease Control and Prevention. Coronavirus
transcriptase polymerase chain reaction-based SARS- Disease 2019 (COVID-19). 2020. [online] Available
CoV- 2 tests by time since exposure. Ann Intern at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/
Med. 2020;173(4):262–7. https://doi.org/10.7326/ index.html. Accessed 29 Nov 2020.
M20-1495. New England Journal of Medicine. Coronavirus (Covid-
26. Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, Tan 19) — NEJM. 2020. [online] Available at: https://
W. Detection of SARS-CoV-2 in different types of www.nejm.org/coronavirus. Accessed 29 Nov 2020.
clinical specimens. JAMA. 2020;323(18):1843–4.
Noninvasive Respiratory Support
for COVID-19
5
Josiah Smith, Nicholas Goodmanson,
and Matthew Niehaus
Introduction and Background greater than or equal to 90% and PaO2 greater

than 65 mmhg [1].
COVID-19 initially causes respiratory failure Supplemental oxygen can be delivered by
through a combination of endothelial disruption both invasive and noninvasive means. Invasive
and an inflammatory cascade culminating severe therapy relies on the placement of an advanced
hypoxemia due to alveolar damage, with the airway and is beyond the scope of this chapter.
potential to progress to acute respiratory distress Noninvasive therapy provides supplemental oxy-
syndrome (ARDS) [8]. The initial treatment gen through external methods without the place-
strategy for these patients is to implement thera- ment of an advanced airway. In many cases,
pies aimed at improving oxygenation [1, 8]. hypoxemia can be managed effectively with non-
Notably for COVID-19, clinicians have noted invasive methods of oxygen delivery, avoiding
that patients with hypoxemia may not display the complications associated with mechanical
common outward signs of respiratory distress ventilation. This is particularly true in COVID-19,
despite low oxygen saturations. This has led to as there is documented evidence of equivalent
the development of the term “happy hypoxemic” patient outcomes for early versus late intubation
[9]. Some clinicians have considered tolerating [2–7]. Clinicians should become well-versed in
lower SpO2 and PaO2 values than previously the various methods of noninvasive oxygen deliv-
accepted; however, at this time there is no con- ery to best treat patients suffering from COVID-19
sensus on specific targets beyond those which are infection.
accepted for other forms of respiratory failure.
Most commonly this includes pulse oximetry
Low to Moderate Flow Devices
There are a variety of external applications of

J. Smith (*) · M. Niehaus supplemental oxygen. This section will review
University Hospitals Cleveland Medical Center/Case
Western Reserve University, Cleveland, OH, USA
those options in a stepwise fashion. For patients
e-mail: [email protected]; who are in mild respiratory distress or who are
[email protected] noted to have low saturations on room air without
N. Goodmanson clinical signs concerning for acute decompensa-
Advocate Christ Medical Center and Advocate tion, there are several modalities used to provide
Lutheran General Hospital/University of Illinois at supplemental oxygen. Basic application of sup-
Chicago, Chicago, IL, USA
plemental oxygen occurs most commonly

44 J. Smith et al.
through the nasal cannula. The cannula is capable way inflammation and promote secretion clear-
of delivering up to 5–6 L/min of flow and roughly ance. There are no contraindications to the use of
around 45% FiO2 to a patient [1]. There are no HFNC, and this device is well tolerated by
specific contraindications to nasal cannula use; patients. Unlike full face masks, patients can
however, intranasal blockage such as nasal pack- continue to easily talk, mobilize, and eat. HFNC
ing may alter effectiveness. A basic face mask has been successful in treating the hypoxia sec-
can also be used to apply external oxygen to ondary to COVID while preventing some of the
patients. These face masks typically allow for risks associated with mechanical ventilation.
5–10 L of flow. However, FiO2 is not titratable This is the current recommended intervention
when using this modality, and the actual amount for COVID-19 patients presenting in moderate
of oxygen received by an individual patient is to severe hypoxic respiratory failure from a vari-
highly dependent on a variety of factors, such as ety of international societies including the World
respiratory rate, tidal volume, and lung pathology Health Organization (WHO) and the Society of
[1]. The Venturi mask allows users to titrate the Critical Care Medicine (SCCM) [1]. A non-
flow and percent FiO2, with approximately rebreather mask set at 15 L/minute can be added
between 2 and 15 L of flow and 24 and 60% to a patient already using HFNC as it will supply
FiO2. The actual amount the patient receives, additional oxygen and PEEP.
again, depends on individual patient factors [1,
9]. Non-heated high-flow nasal cannula is similar
to the previously mentioned nasal cannula; how- ositive Pressure Noninvasive
P
ever, due to low resistance, tubing is able to reach Ventilation
flow rates up to 15 L/min. The non-rebreather
face mask utilizes a reservoir of oxygen to Noninvasive positive pressure ventilation
increase inhaled FiO2. It is capable of providing (NIPPV) is another modality considered for the
roughly 90% FiO2 when fully inflated at 15 L/ treatment of moderate to severe respiratory dis-
min of flow. In order to be effective, the reservoir tress. This is most commonly administered as
bag needs to remain inflated at all times which either continuous positive airway pressure
typically requires at least 8–10 L/min of flow [1]. (CPAP) or bilevel positive airway pressure
(BiPap) through a variety of masks. FiO2 is titrat-
able, though there is some variation in delivery
Heated High-Flow Nasal Cannula based on mask fit and seal. Commonly utilized
masks typically cover the nose and mouth. Other
Heated high-flow nasal cannula (HFNC) is a sys- varieties include nasal masks, full face masks
tem that delivers high levels of air flow, up to (sometimes referred to as face shields), and hel-
60 L/min, which allows for more accurate titra- mets [1].
tion and delivery of a specific FiO2 up to 100%. While NIPPV has been widely successful in
There was concern previously that the high-flow treating rapidly reversible causes of respiratory
rates would lead to increased aerosolization, failure such as an acute exacerbation of chronic
although it has been shown that aerosolization is obstructive pulmonary disease or flash pulmo-
not increased with these devices [7, 10]. The nary edema secondary to congestive heart failure,
higher flows provided by this specialized device worse outcomes have been seen in patients with
wash out the oropharyngeal dead space which pneumonia [11]. This outcome may be attributed
can improve oxygenation and CO2 clearance. to a phenomenon known as self-induced lung
Additionally, the higher flows can, in theory, injury with the use of these devices. In theory,
provide a modest amount of positive end-expira- augmented inspiratory pressures coupled with a
tory pressure (PEEP) which can improve oxy- high respiratory rate and drive may cause patients
genation and the work of breathing. Finally, the to draw larger than normal tidal volumes leading
humidification and higher flows can reduce air- to self-induced volutrauma. Of course, it is the
5 Noninvasive Respiratory Support for COVID-19 45
underlying lung pathology that is truly the cause Venturi masks, and nasal cannulas generate
of lung injury since when exercising vigorously, aerosols roughly around 40 cm at their highest
such as playing basketball or running a 10 K race, respective flow rates. NIPPV can lead to genera-
participants with normal/uninjured lungs breathe tion of aerosolized viral particles as far as 90 cm
with huge tidal volumes (well over 1 L) and high depending on mask fit, which has contributed to
respiratory rates but suffer no acute lung injury. the conflicting recommendations regarding its
NPPV is recognized to dry secretions and inhibit use in COVID-19 [1].
mucociliary clearance which is detrimental in
pneumonia.
There is currently conflict among various Awake Prone Positioning
international societies regarding the use of
NIPPV in COVID-19 patients. This is due both Prone positioning is a proven therapy for improv-
to the concern about increased risk of aerosol- ing hypoxemia in respiratory failure and particu-
ization and the mixed data regarding patient larly ARDS [15, 16]. These benefits are believed
outcomes. SCCM recommends against the use to be due to the redistribution of pressure gradi-
of NIPPV if HFNC is readily available; how- ents within the lung and prevention of overdisten-
ever, this is a weak recommendation and differs tion of the non-dependent areas. The reversal of
among individual societies [1, 12]. Based on the dependent sides allows for recruitment of the pre-
current evidence, we recommend prioritization vious atelectatic areas, while continued PEEP
of HFNC when available over NIPPV unless cli- maintains the already appropriately function and
nicians believe the primary cause of respiratory open alveoli in the anterior lung fields. This miti-
failure is secondary to a known etiology respon- gates the effects of ventilator-associated lung
sive to NIPPV with comorbid COVID-19 infec- injury and aids in maximizing the viable lung for
tion [1, 12]. gas exchange. As the COVID-19 pandemic has
progressed, prone positioning was proposed as a
method to combat hypoxia in awake, cooperative
Aerosol Generation patients requiring supplemental oxygen support.
Previously, contraindications to prone position-
The application of external supplemental oxy- ing included ECMO cannulation, chest tube
gen through the abovementioned modalities for placement, spinal instability, and recent abdomi-
COVID-19 respiratory failure was initially con- nal or chest surgery. Concerning complications
troversial due to the concern for aerosolization included accidental extubation, device or access
of viral particles and increased spread [1, 2, 7]. disruption, and pressure injuries to the face, eyes,
When these modalities are appropriately applied or brachial plexus [17–19]. These complications
in negative pressure rooms with HEPA filtering are much less common in awake, non-cannulated,
systems present, while patients wear masks, and non-intubated patients. While possibly less sig-
with the correct personal protective equipment nificant, the benefits of atelectasis redistribution
(PPE) for healthcare workers, they have been are still present in awake, noninvasively venti-
found to be safe and effective. On review of the lated patients. Several studies have now shown
current evidence, the least aerosol-generating both the beneficial effects and feasibility of
forms of supplemental oxygen include the non- awake prone positioning in COVID-19 patients
rebreather mask and HFNC1 [13, 14]. Even at with moderate respiratory distress. Important
the highest flow rates, aerosol dispersion does relative contraindications continue to include
not exceed 10 cm for non-rebreather masks, fractures, spinal instability, chest tube placement,
while HFNC was equal to or less than 17 cm inability to cooperate with prone positioning,
based on high fidelity mannequin simulations altered mental status, or signs of rapid decom-
[1, 15]. Comparatively, basic face masks, pensation requiring intubation [18, 19].
46 J. Smith et al.
Therapeutic Progression Open. 2020;1(2):95–101. https://doi.org/10.1002/

emp2.12071.
2. Tobin MJ, Laghi F, Jubran A. Caution about early
Based on the current evidence, we recommend all intubation and mechanical ventilation in COVID-19.
COVID-19 patients should be masked, preferably Ann Intensive Care. 2020;10(1):78. https://doi.
placed in a negative pressure room with HEPA fil- org/10.1186/s13613-020-00692-6.
3. Rola P, Farkas J, Spiegel R, et al. Rethinking the early
ter present, and that healthcare workers should be intubation paradigm of COVID-19: time to change
wearing appropriate PPE. All suspected or con- gears? Clin Exp Emerg Med. 2020;7(2):78–80.
firmed COVID-19 patients who present with mild https://doi.org/10.15441/ceem.20.043.
to moderate signs of hypoxic respiratory failure 4. Hernandez-Romieu AC, Adelman MW, Hockstein
MA, et al. Timing of intubation and mortal-
should be placed on supplemental oxygen [1, 12– ity among critically ill coronavirus disease 2019
14]. For patients with mild symptoms, begin with patients: a single-center cohort study. Crit Care Med.
nasal cannula [13]. For those in moderate distress, 2020;48(11):e1045–53. https://doi.org/10.1097/
apply a non-rebreather face mask or consider a CCM.0000000000004600.
5. Matta A, Chaudhary S, Bryan Lo K, et al. Timing of
transition to HFNC. If these patients are not able to intubation and its implications on outcomes in criti-
maintain SpO2 greater than or equal to 90% while cally ill patients with coronavirus disease 2019 infec-
on any of the previous therapies, they should transition. Crit Care Explor. 2020;2(10):e0262. https://doi.
tion to HFNC [1, 7, 12–14]. For patients on HFNC, org/10.1097/CCE.0000000000000262.
6. Lee YH, Choi KJ, Choi SH, et al. Clinical signifi-
consider awake prone positioning while keeping in cance of timing of intubation in critically ill patients
mind the relative contraindications [18, 19]. NIPPV with COVID-19: a multi-center retrospective study. J
should be deferred unless there is a strong suspi- Clin Med. 2020;9(9):2847. https://doi.org/10.3390/
cion for contributing comorbid pathology known to jcm9092847.
7. Frat JP, Thille AW, Mercat A, et al. High-flow oxygen
benefit from this therapy, or if HFNC is unavail- through nasal cannula in acute hypoxemic respiratory
able, at which time it can be utilized as a second- failure. N Engl J Med. 2015;372(23):2185–96. https://
line therapy [1, 14]. Patients who have failed to doi.org/10.1056/NEJMoa1503326.
achieve an SpO2 greater than or equal to 90% and 8. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ,
Prescott HC. Pathophysiology, transmission, diag-
PaO2 greater to or equal than 65 despite the above nosis, and treatment of coronavirus disease 2019
therapies, or who show other findings consistent (COVID-19): a review. JAMA. 2020;324(8):782–93.
with rapid respiratory decompensation, should be https://doi.org/10.1001/jama.2020.12839.
considered to have failed noninvasive management 9. Tobin MJ, Laghi F, Jubran A. Why COVID-19 silent
hypoxemia is baffling to physicians. Am J Respir
and may need to be considered for invasive ventila- Crit Care Med. 2020;202(3):356–60. https://doi.
tory support [12–14]. org/10.1164/rccm.202006-2157CP.
10. Kotoda M, Hishiyama S, Mitsui K, et al. Assessment
Critical Points of the potential for pathogen dispersal during high-
flow nasal therapy. J Hosp Infect. 2020;104(4):534–7.
• Hypoxemia is a common problem in moderate https://doi.org/10.1016/j.jhin.2019.11.010.
and severe COVID-19 illness. 11. Valley TS, Walkey AJ, Lindenauer PK, Wiener RS,
• Although these patients may not display respi- Cooke CR. Association between noninvasive ventila-
ratory distress, it is still necessary to target an tion and mortality among older patients with pneumo-
nia. Crit Care Med. 2017;45(3):e246–54. https://doi.
SaO2 of ≥90% to prevent tissue hypoxia. org/10.1097/CCM.0000000000002076.
• HFNC offers high O2 supply with modest 12. Alhazzani W, Møller MH, Arabi YM, et al. Surviving
PEEP but promotes secretion clearance. sepsis campaign: guidelines on the management of
• NPPV offers more PEEP but may worsen critically ill adults with coronavirus disease 2019
(COVID-19). Intensive Care Med. 2020;46(5):854–
secretion clearance. 87. https://doi.org/10.1007/s00134-020-06022-5.
13. WHO. Clinical management of severe acute respira-
tory infection when Novel coronavirus (2019-nCoV)
References infection is suspected: interim guidance. WHO/nCoV/
Clinical/2020.3. 28 Jan 2020.
14. ANZICS. COVID-19 guidelines. Australian and New
1. Whittle JS, Pavlov I, Sacchetti AD, Atwood C,
Zealand Intensive Care Society. ANZICS: Melbourne;
Rosenberg MS. Respiratory support for adult patients
2020.
with COVID-19. J Am Coll Emerg Physicians
5 Noninvasive Respiratory Support for COVID-19 47
15. Gattinoni L, Busana M, Giosa L, Macrì MM, Quintel Emerg Surg. 2020:1–6. https://doi.org/10.1007/
M. Prone positioning in acute respiratory distress syn- s00068-020-01542-7.
drome. Semin Respir Crit Care Med. 2019;40(1):94– 18. Scaravilli V, Grasselli G, Castagna L, et al. Prone
100. https://doi.org/10.1055/s-0039-1685180. positioning improves oxygenation in spontaneously
16. Guérin C, Reignier J, Richard JC, et al. Prone posi- breathing nonintubated patients with hypoxemic
tioning in severe acute respiratory distress syndrome. acute respiratory failure: a retrospective study. J Crit
N Engl J Med. 2013;368(23):2159–68. https://doi. Care. 2015;30(6):1390–4.
org/10.1056/NEJMoa1214103. 19. Dubosh NM, Wong ML, Grossestreuer AV, et al. Early,
17. Petrone P, Brathwaite CEM, Joseph DK. Prone
awake proning in emergency department patients
ventilation as treatment of acute respiratory dis- with COVID-19. Am J Emerg Med. 2021;46:640–5.
tress syndrome related to COVID-19. Eur J Trauma https://doi.org/10.1016/j.ajem.2020.11.074.
Mechanical Ventilation
in the COVID-19 Patient
6
Katelin Morrissette, Skyler Lentz,
and Jarrod Mosier
Introduction as to the pathogenic mechanism of the virus and

mechanisms of hypoxia, as well as concerns over
COVID-19 quickly spread across the globe in aerosolization and potential transmission to
late 2019 and early 2020, straining or overwhelm- healthcare workers [1–4]. However, as the dis-
ing healthcare systems along the way with a large ease prevalence increased, clinical, pathological,
influx of patients presenting with acute respira- physiological, and histological data from
tory failure. The situation naturally sparked spec- cohorts, trials, and autopsy studies shed light
ulation about pathophysiology, ideal treatment, onto what is unique and what is not unique about
and how best to meet the competing needs of COVID-19-associated respiratory failure [5, 6].
patients and strained hospitals. Debate over opti- There is an increasing body of evidence suggest-
mal invasive and noninvasive respiratory support ing that, while some aspects of the primary
strategies and recommendations for utilization in mechanism for hypoxemia may be unique, the
an emerging pathogen stemmed from uncertainty spectrum of acute lung injury is similar to that of
acute respiratory distress syndrome (ARDS)
K. Morrissette with which healthcare providers are already
Department of Medicine, Division of Pulmonary and experienced [7–9].
Critical Care Medicine, University of Vermont ARDS, currently operationally defined clini-
Medical Center, Burlington, VT, USA cally by the Berlin criteria (Table 6.1), is a syn-
drome which exists along a spectrum of severity,
S. Lentz making phenotyping ARDS an attractive
Department of Medicine, Division of Pulmonary and
Critical Care Medicine, University of Vermont endeavor even before COVID-19 [10–13]. ARDS
Medical Center, Burlington, VT, USA is histologically characterized by diffuse alveolar
Department of Surgery, Division of Emergency damage, hyaline membrane and cellular infiltra-
Medicine, University of Vermont Larner College of tion, and microvascular thrombosis [14, 15].
Medicine, Burlington, VT, USA Many patients with COVID-19 will meet criteria
e-mail: [email protected] for ARDS, and autopsy findings demonstrate dif-
J. Mosier (*) fuse alveolar damage [15]. Several mechanisms
Department of Emergency Medicine, University of for the profound hypoxemia in COVID-19 have
Arizona College of Medicine, Tucson, AZ, USA
been hypothesized including dysregulated
Division of Pulmonary, Allergy, Critical Care and hypoxic vasoconstriction mediated by a hyperin-
Sleep, Department of Medicine, University of
Arizona College of Medicine, Tucson, AZ, USA flammatory state and downstream effects of the
e-mail: [email protected] renin-angiotensin-aldosterone system (RAAS)

50 K. Morrissette et al.
Table 6.1 The Berlin definition of the acute respiratory nasal oxygen), or (3) invasive mechanical venti-
distress syndrome [83] lation. If conventional oxygen therapy does not
Clinical improve hypoxemia and reduce work of breath-
feature Definition ing, then a trial of a noninvasive strategy is rea-
Timing Develops within 1 week of clinical
sonable [20, 21].
insult or new or worsening respiratory
symptoms The purpose of noninvasive strategies is to
Chest Bilateral opacities not fully explained by improve oxygenation and reduce work of breath-
imaging pleural effusions, lobar collapse, or ing while avoiding the undesirable consequences
nodules of mechanical ventilation and iatrogenic injury.
Origin of Non-cardiogenic pulmonary edema;
edema edema not suspected to be from an
High-flow nasal cannulas (HFNC) have been
elevated left atrial pressure or cardiac used successfully in other forms of pneumonia
failure; an echocardiogram may be and ARDS [22] and may reduce the need for
needed in unclear cases invasive mechanical ventilation [23]. NIPPV has
Oxygenation Mild: PaO2/FiO2 of >200 mm Hg to
also been used successfully in hypoxemic failure
≤300 mm Hg with PEEP ≥5 cm H2O
Moderate: PaO2/FiO2 of >100 mm Hg to and is associated with a lower risk of mortality
≤200 mm Hg with PEEP ≥5 cm H2O and intubation [24]. A helmet interface, where
Severe: PaO2/FiO2 ≤ 100 with PEEP available, may offer particular benefit [25]. Those
≥5 cm H2O
that improve in response to HFNC or NIPPV
may avoid intubation. While noninvasive strate-
[16], endothelial damage leading to micro- gies can improve outcomes compared to conven-
thrombi [17], and impaired surfactant function tional oxygen therapy [24], failure of noninvasive
leading to atelectasis [18]. Clinically, patients strategies can be detrimentally out of proportion
present with profound ventilation-perfusion mis- to just worsening disease. The risk, especially
match and shunt and along a spectrum of lung with NIPPV, is patient self-induced lung injury
compliance [19]. Most of these features are com- (P-SILI).
mon to all ARDS patients and do not necessitate P-SILI is a risk due to excessive, spontaneous
new definitions or obviate the prior investigations respiratory effort with large tidal volumes and
of optimal mechanical ventilation strategies. This changes in transpulmonary pressures during
chapter will focus on the pathophysiology of spontaneous breathing, particularly when breath-
acute hypoxemic respiratory failure, ARDS, and ing spontaneously on positive pressure [26]. The
mechanical ventilation strategies to best optimize respiratory drive, and thus transpulmonary pres-
lung mechanics and avoid ventilator-induced sure swings, can be limited in some cases with
lung injury. higher positive end-expiratory pressure (PEEP),
most commonly delivered by helmet [27–29].
However, regional amplification of transpulmo-
hen to Initiate Mechanical
W nary pressures results in excessive regional strain
Ventilation and overall high tidal volumes that propagate lung
injury [30, 31]. The decision to intubate depends
As in other forms of hypoxemic respiratory fail- on a bedside assessment of early response to ther-
ure, the decision to intubate patients with apy and clinical trajectory. Waiting until failure of
COVID-19 is based partially on the clinical noninvasive support is associated with worse pro-
response to noninvasive respiratory support and cedural outcomes during intubation [32] and
the anticipated clinical course. There are only patient-centered outcomes [33]. In general, those
three options available for providing respiratory with distress from increased respiratory drive and
support: (1) conventional oxygen therapy, (2) work of breathing with large spontaneous tidal
noninvasive respiratory support (noninvasive volumes, despite optimized NIPPV or HFNC,
positive pressure ventilation (NIPPV), high-flow should be intubated.
6 Mechanical Ventilation in the COVID-19 Patient 51
Mechanical Ventilation Principles absorbed and dissipated, and that process exposes
the lung to potential injury. This risk of mechani-
In the most simplistic sense, a mechanical ventila- cal ventilation is ventilator-induced lung injury
tor works by opening an inspiratory valve and (VILI) and why we attempt to optimize “lung
delivering a titratable flow and mixture of gas until protective ventilation.” The concept of lung pro-
it reaches a goal—either a volume or a pressure— tective ventilation is currently operationalized by
and then an expiratory valve opens to allow efflux limiting tidal volumes to the height-based ideal
of exhaled gas until the airway opening pressure bodyweight (6–8 ml/kgIBW), limiting plateau
reaches a set end-expiratory pressure (i.e., PEEP). pressures to <30 cmH2O, and using PEEP to
The ventilator goes through this cycle every time avoid injurious oxygen concentrations (>60%).
the inspiratory valve is triggered, either by a time While, in reality, lung protective ventilation is
interval with a set rate, or it senses spontaneous likely more complex, in practicality these princi-
effort that exceeds the threshold to trigger a breath. ples will improve outcomes in most patients most
Thus, mechanical ventilation requires energy, of the time. As such, we will focus this chapter on
and energy (work per breath) x time (respiratory achieving these goals, and the recommendations
rate) = power. This kinetic energy must be are summarized in Table 6.2.
Table 6.2 Lung protective strategy [40, 43]

Variable Target Comments
Lung protective strategy ventilator settings
Tidal volume 6 ml/kg predicted body weight (PBW) PBW from height and gender
Range: 4–8 ml/kg Tidal volume reduced to as low as 4 ml/kg if
plateau pressure remains >30 cm H2O
Respiratory rate Up to 35/min Target pH 7.30 but tolerate hypercapnia to pH >
7.15 in severe cases
Plateau pressure ≤30 cm H2O A higher plateau pressure may be acceptable in
cases of suspected elevated pleural pressure
(e.g., abdominal compartment syndrome, morbid
obesity)
Positive end- 5 cm H2O–24 cm H2O Titrate based on PEEP FiO2 table or
expiratory pressure individualized. Consider higher PEEP/FiO2
(PEEP) table in those with a PaO2:FiO2 ratio < 200
mmHg [44].
Oxygenation PaO2 80–105 mm Hg LOCO2 suggests liberal oxygen strategy
Saturation 92–96% favorable to conservative [46]
Driving pressure Target driving pressure < 15 cm H2O Reduce Vt or adjust PEEP if the driving pressure
(plateau is>15 cm H2O [41]
pressure-PEEP)
Non-ventilator ARDS interventions
Prone positioning Consider if PaO2:FiO2 < 150 mmHg Caution in the ED. Risk of pressure injury, nerve
despite optimization of ventilator settings injury, and other complications if done
over the first 12–24 hours incorrectly. Mortality benefit demonstrated with
16 hrs/day of prone positioning after a 12–24 hr.
stabilization period in those with a PaO2:FiO2 <
150 mmHg [84]
Fluid balance Avoid aggressive fluid administration Improvement in lung function has been
demonstrated with conservative fluid
administration over the hospitalization [85]
Neuromuscular Consider bolus dosing followed by
blockade continuous infusion when unable to
maintain a safe plateau pressure and tidal
volume, in refractory hypoxemia, or with
significant ventilator dyssynchrony
AL GRAWANY
Compliance and Ventilator-Induced and thus transpulmonary pressure is not easily

Lung Injury measured in clinical practice. One must esti-
mate a safe inflation pressure using plateau
Lung compliance, defined as the change in lung pressure ≤30 cm H2O or driving pressure (PPlat-
volume over the change in the transpulmonary PEEP) < 15 cm H2O [40, 41]. Atelectrauma
pressure, underpins the idea that positive pres- refers to the cyclic opening and closing of alve-
sure breaths are delivered to the lung tissues oli leading to injury. Related is strain or shear-
which then stretch to permit inflation and recoil ing forces on neighboring open alveoli and
passively during exhalation. This can be thought closed alveoli from interdependence [38]. PEEP
of as the strain, or the volume distortion, during may help reduce these forms of injury by main-
inhalation and the stress force per region of lung taining lung recruitment and homogeneity and
tissue imposed by the positive pressure breath. stability of the alveolar units [39]. Biotrauma
Healthy lung tissue has a normal compliance of refers to the inflammatory insult—potentially
approximately 200 ml/cm H2O [34]. The lung causing remote organ injury—from VILI [38]. It
compliance of ARDS patients, and specifically has been suggested that the frequency (i.e.,
those with COVID-19, can vary but has been respiratory rate) of alveolar stretching also plays
documented at approximately 25–36 ml per cm a role in VILI [38].
H2O [1, 35, 36]. As the functional residual capac-
ity decreases from any cause, the lung strain
(tidal volume/functional residual capacity) chieving Lung Protective
A
becomes more likely to be injurious. Additionally, Ventilation
spontaneous breathing, especially vigorous spon-
taneous breathing, contributes to injury by Set the Tidal Volume
increasing lung stress (transpulmonary pressure), and Respiratory Rate
which is amplified regionally in heterogeneously
affected lungs through stress risers. ARDS- The cornerstone of evidence-based ARDS man-
affected lungs have decreased compliance; how- agement from any cause—including ARDS from
ever, within that range there is a spectrum of lung COVID-19—is a lung protective strategy with
pathology in both the COVID-19 and “tradi- low tidal volume ventilation [40]. Outcomes data
tional” ARDS patients. Heterogeneous patterns and specialty guidelines specific to COVID-19-
of pathologic lung compliance result in increased related ARDS support this evidence-based strat-
susceptibility to ventilator-induced lung injury egy of mechanical ventilation [8, 20, 21]. The
(VILI) in diseased lungs [37]. low tidal volume is necessary because of the
The most commonly described types of VILI reduced functional residual capacity seen in
are barotrauma, volutrauma, atelectrauma, and ARDS, which decreases in direct proportion to
biotrauma [38]. Barotrauma is from excessive the severity. The seminal clinical trial in ARDS
airway pressure, whereas volutrauma is from used a volume-targeted mode of ventilation;
alveolar overdistension (i.e., stretch). These two however, the superiority of volume-targeted
can be more easily described by the concept of modes over pressure controlled modes has not
transpulmonary pressure (alveolar pressure- been demonstrated [42]. The importance, despite
pleural pressure) [38]. The regional overdisten- the mode of ventilation, is to maintain a lung pro-
sion from an elevated transpulmonary pressure tective tidal volume. The respiratory rate can be
in a heterogeneously injured lung is a major increased to maintain the minute ventilation
driver of VILI [39]. Using this concept it is the required for acid-base status, but respiratory rate
difference in pressure across the alveoli induced also contributes to mechanical power, and thus
by a change in volume that causes heteroge- permissive hypercapnia should be allowed when
neous injury. Unfortunately, pleural pressure necessary.
Key Point#1 for lacking individualization; it is likely there are

We recommend setting the tidal volume at 6 ml/kg cases of ARDS when higher or lower PEEP may
IBW either directly with volume control ventila- be beneficial [45], which has been a central com-
tion or with the driving pressure if using pressure ponent in the debate surrounding the character-
control ventilation to start. The IBW is based on ization of COVID-19 pneumonia.
the patient’s height and gender. Set the respira- PEEP may also be set by the driving pressure.
tory rate based on the underlying acid-base sta- The driving pressure (∆P) is related to static
tus and pre-intubation respiratory rate, and allow respiratory system compliance (CRS) by the for-
permissive hypercapnia when necessary. mula CRS=VT/∆P. The ∆P represents the amount
of pressure and cyclical strain applied to the alve-
oli with each breath. If an increase in PEEP
Set PEEP and FiO2 causes a drop in ∆P, for a constant VT, this sug-
gests an improvement in compliance from lung
Common to nearly all ventilation strategies is recruitment [41]. If the increase in PEEP causes
using PEEP to reduce the amount of non-aerated an increase in ∆P, overdistension is suggested. A
lung, reduce VILI from cyclic opening and clos- retrospective study showed an increase in mortal-
ing of alveoli, and improve oxygenation through ity with a ∆P > 15 cm H2O [41].
lung recruitment and ventilation-perfusion mis-
matching. The major risks of PEEP are the poten-
tially injurious effects of overdistension and of Oxygenation Targets
hemodynamic deterioration. The ARDS clinical
trials PEEP/FiO2 tables (Table 6.3) may guide The goal of oxygenation is to avoid tissue hypoxia
PEEP titration with a stepwise increase in PEEP while avoiding the potential harmful effects of
based on the FiO2 requirement [40]. The step- hyperoxia. The original ARDS clinical trials sug-
wise increase in PEEP with worsening oxygen- gested a PaO2 target of 55–80 mmHg or SpO2 of
ation is based on the physiological principle that 88–95% [40]. A recent multicenter, randomized
more severe hypoxemia suggests diffuse lung trial suggests a conservative oxygenation strategy
injury, surfactant dysfunction, atelectasis, and (target PaO2 55–70 mm Hg and SpO2 88–92%)
more potential benefit from higher levels of in ARDS may be harmful [46], and a liberal oxy-
PEEP. The ARDS clinical trial network examined genation target SpO2 of 92–96% or PaO2 of
outcomes using the high and low PEEP/FIO2 80–105 mm Hg is now recommended [21]. It
table [43]. This trial showed no difference in out- should be noted hyperoxia may also be harmful
comes [43], though a later meta-analysis showed and should be equally avoided [47, 48].
improvement in mortality in the group with
ARDS and a PaO2/FiO2 ratio of <200 mmHg Key Point#2 We recommend setting the PEEP
[44]. The PEEP/FiO2 tables have been criticized using the ARDS net high or low PEEP tables to
allow a safe FiO2 <60% as a starting point.
Table 6.3 PEEP/FiO2 combinations from ARDS clinical Target a SpO2 of 92–96% or a PaO2 of
trials network [43] 80–105 mm Hg.
Lower PEEP/FiO2 combination
FiO2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
PEEP 5 5–8 8–10 10 10– 14 14– 18– Limit Airway Pressures
(cm 14 18 24
H2O)
In addition to limiting tidal volume to avoid volu-
Higher PEEP/FiO2 combination
FiO2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 trauma, airway pressures need to be managed to
PEEP 5–14 14– 16– 20 20 20– 22 22– avoid barotrauma. When using a volume-targeted
(cm 16 20 22 24 mode, closing the inspiratory valve at end-
H2O) inspiration—an end inspiratory hold—gives an
approximation of the pressure at the alveolar “fine tune” the ventilator settings in the following
level, called the plateau pressure. In pressure- way.
targeted modes, the total pressure is considered
the plateau pressure. A plateau pressure of tep 1: Evaluate the stress index [50]
S
≤30 cm H2O is generally considered safe and Figure 6.1 illustrates the stress index as deter-
thus is targeted in any mode of ventilation uti- mined by the pressure-time waveform on the ven-
lized [49], except in patients with a very high tilator. If your ventilator settings avoid
pleural pressure from external compression: mor- atelectrauma and volutrauma, you should be in
bidly obese, large volume ascites, and third tri- the linear portion of a pressure-volume curve—
mester pregnancy. The plateau pressure may need where you want to be. If that is the case, then the
to be much higher just to lift the chest wall. linear variable “time” can substitute for the
The plateau pressure minus the PEEP is the assumed linear variable “volume,” and you have
driving pressure (∆P), or the distending pressure, a pressure-time curve, which all ventilators give
and can offer a second safety target. ∆P is related you on a breath-to-breath basis. Turning down
to static respiratory system compliance (CRS) by the inspiratory flow to 20 lpm will remove the
the formula CRS=VT/∆P. Thus ∆P represents the effect of airway resistance on the airway pres-
amount of pressure and cyclical strain applied to sures such that the pressure-time waveform will
the alveoli with each breath. A ∆P > 15 cm H2O generally reflect alveolar distention. If your infla-
was demonstrated to be independently associated tion pressure is linear, your ventilator settings are
with mortality, even in patients receiving “protec- in your target range (Fig. 6.1a). If you have an
tive” tidal volumes and plateau pressures [41]. At increased pressure at the beginning of a breath,
the bedside, evaluation of ∆P is the difference you are opening atelectatic lung units and the
between the plateau pressure and the PEEP in a solution is to increase PEEP (stress index <1)
passively breathing patient. Titration of ventilator (Fig. 6.1b). If you have increased pressure at the
settings targeted toward minimal driving pressure end of a breath, you are overdistending lung units
is achieved by adjusting PEEP, allowing time for and you need to decrease tidal volume (stress
recruitment, and then calculating ∆P. If the ∆P is index >1) (Fig. 6.1c). Change PEEP and tidal
>15 cm H2O, further decreases in tidal volume or volume until you have a linear inflation, and then
adjustment in PEEP are recommended. Driving increase the flow back to the original settings
pressure is also amplified by spontaneous breath- (usually 40–50LPM). You can then check your
ing. Please refer to the section of this paper on plateau and driving pressures again to see if there
neuromuscular blockade for details of this is an improvement.
component.
tep 2: Recruit what is recruitable
S
Key Point#3 If the plateau pressure is at goal but the driving
We recommend starting with a volume-targeted pressure is still high despite a 6 ml/kg VT or
mode. Set the PEEP and the tidal volume as lower, i.e., poor lung compliance, this can poten-
above, and measure the plateau pressure; the tially be improved with increased PEEP or per-
goal is less than 30 cm H2O. Next, note the driv- forming a recruitment maneuver. There are
ing pressure, and adjust ventilator settings as several ways to do a recruitment maneuver (e.g.,
necessary to achieve the goal of <15 cm H2O. 35–40 cmH2O for 30–40s), which do likely
improve oxygenation and may reduce the need
for rescue therapies [51] but have not been shown
Fine-Tune PEEP and Tidal Volume to improve outcomes and may even cause harm
in some cases [52, 53]. Most likely because you
Setting the ventilator based on the above recom- recruit available lung briefly but then go immedi-
mendations will get you most of the way in most ately back to the same MV strategy that let the
patients. To take things a step further, one can lung collapse in the first place, so of course it
Stress index=1 Stress index >1 Stress index <1
Problem: Atelectasis Problem: Over-distension

Solution: Increase PEEP Solution: Decrease VT
Pressure
PEEP
(a) (b) (c)
Time
Fig. 6.1 Inspiratory pressure curves for mechanical ventilation in variable lung compliance examples
does again. It progresses lung injury to repeat- energy required to deliver the desired volume or
edly open and then let injured, unstable alveoli pressure in joules per minute. In addition to the
collapse. The risks include barotrauma and strain and stress of mechanical ventilation, other
hemodynamic deterioration from overdistension, factors such as respiratory rate and flow rate are
but rates of adverse events are overall low [51]. included in the calculation of total energy deliv-
Recruitment maneuvers should be considered to ered to the respiratory system during mechanical
improve oxygenation if the clinician suspects ventilation. If the lung has low compliance, as in
there is recruitable (i.e., atelectatic) lung. Caution edematous or fibrotic lung tissue, more work will
should be used when using a combination of be required to open the viable alveoli resulting in
recruitment maneuvers followed by PEEP titra- higher power requirements in the less complaint
tion to the best respiratory system compliance. (i.e., more elastic) lung parenchyma. The effect
This strategy recently demonstrated an increase of mechanical power on VILI has been studied in
in mortality as compared to using the low PEEP/ the context of ARDS as predictive of develop-
FIO2 table in one study [54]. A conservative ment of VILI [55, 56]. As in prior lung protective
approach is to increase PEEP while noting the strategies, the recommendations for mechani-
effect on plateau and driving pressures. If there is cally ventilated patients with COVID-19 lung
recruitability, an increase in PEEP should result disease are to improve lung compliance by
in either no change or even decreased driving recruiting viable airspace overtime while limiting
pressure. If the increase in PEEP results in mechanical power delivered to the lung through
increased driving pressure, then there is overdis- volume-limited and pressure-limited mechanical
tension and the lung is either not recruitable or ventilation strategies.
the tidal volume should be reduced (which can be
evaluated by the stress index). tep 1: Reduce respiratory rate
S
Respiratory rate contributes as much to mechani-
cal power as tidal volume and driving pressure
Limit Mechanical Power [57]. Thus, low tidal volume with high respira-
tory rates to maintain a neutral pH is counterpro-
These concepts can be combined into the unify- ductive. Permissive hypercapnia should be
ing concept of mechanical power of the lung. allowed as much as possible, especially given the
Mechanical power is measured as the amount of high dead space fractions seen in some ARDS
and COVID-19 patients [58]. The only contrain- ering the effect of spontaneous breathing (i.e., a
dications to permissive hypercapnia include high negative pleural pressure during inspiration
patients with intracranial catastrophes, pulmo- generating an elevated, injurious transpulmonary
nary hypertension, or late pregnancy, where pressure). For this reason, early on in the ARDS
eucapnia must be maintained. In some patients, course, eliminating spontaneous breathing is
we will allow a pH as low as 7.15 as long as it is important. Many patients with ARDS have a high
hemodynamically tolerated. respiratory drive, and thus eliminating spontane-
ous breathing with deep sedation alone is insuf-
tep 2: Reduce VQ mismatch and shunt
S ficient, and patients require a period of
with prone positioning neuromuscular blockade by continuous infusion.
The physiologic rationale for the prone position The physiology supporting the use of neuro-
in ARDS, including COVID-19, is multifaceted muscular blockade (NMB) to improve mechani-
but in general can be summarized as an increase cal ventilation is somewhat poorly understood,
in recruitable lung volume and improved though data is fairly robust that NMB does have a
ventilation-
perfusion matching. In the prone role to play in safely maximizing the benefits of
position, the weight of the abdomen can be sup- mechanical ventilation in patients refractory to
ported by the bed. The weight of the abdominal previously described therapies. Possible mecha-
contents in the supine position typically limits nisms include improved ventilator compliance,
the caudal movement of the diaphragm, and in decreased transpleural pressures, and mitigation
the prone position, the posterior portion of the of VILI. For patients with plateau pressures
diaphragm should have increased excursion to greater than 32 cm H2O, despite deep sedation
improve lung expansion [59]. By this mechanism and optimized ventilator settings, the use of cisa-
the posterior lung fields subject to atelectasis and tracurium for NMB was shown to reduce ICU
compression in the supine position can be and hospital mortality without significant
recruited over time to improve available gas increases in complications including ICU-related
transfer volume [60]. Perfusion is also redistrib- weakness [69]. A more recent study did not dem-
uted in the prone position, and Gattinoni and col- onstrate a mortality benefit [70] suggesting NMB
leagues [61, 62] have demonstrated that the should be used only selectively in those with per-
expected change in perfusion due to gravity alone sistent dyssynchrony, elevated plateau pressure,
is not completely observed in the proned patient, inability to tolerate low tidal volume ventilation,
allowing the now aerated, posterior fields to or refractory hypoxemia.
maintain higher levels of blood flow. This may be
due to anatomic structures facilitating increased Key Point #4
flows [63, 64]. For COVID-19 patients, prone We recommend neuromuscular blockade, along
positioning has demonstrated to improve oxy- with prone positioning (16 hours prone, 8 hours
genation in both awake, non-intubated patients, supine), and permissive hypercapnia for the first
including those in the emergency department, 48 hours and then re-evaluate for patients with
and has continued to be utilized in those requir- moderate to severe ARDS despite ventilation
ing mechanical ventilation [65–68]. strategies described above.
tep 3: Eliminate injurious

S
spontaneous breathing Alternate Ventilator Strategies
Transpulmonary pressure (alveolar pressure-
pleural pressure) leads to lung stress and is Alternate ventilator modes, such as airway pres-
regionally amplified through stress risers in sure release ventilation (APRV) or pressure regu-
regions of variable compliance. Thus, airway lated volume control (PRVC), have been tried
pressures that you think are safe based on the either as first-line or salvage modes for refractory
steps above may be quite injurious when consid- hypoxemia. The intent of PRVC is to limit baro-
trauma and volutrauma. Data has previously Outcomes and Complications

demonstrated that PRVC often leads to tidal vol-
umes significantly larger than targeted by the cli- Overall, mechanical ventilation outcomes for
nician, and thus not in line with prevention of COVID-19 patients reflect those of the general
volutrauma [71]. PRVC has not been shown to ARDS population, and strategies for improving
improve mortality or hospital days in ARDS [72]. oxygenation are similar to previously utilized
APRV can be thought of as a recruitment mode, strategies [74]. Due to the heterogeneity of
designed to have long periods of “inflation pres- reporting, local standard practice, and the evolv-
sures” for oxygenation and recruitment and short ing nature of this pandemic, there is a wide range
periods of “release pressures” for CO2 exchange of reported outcomes, summarized in Table 6.4.
with the added benefit that a patient may “over Based on these reports of hospitalized COVID-19
breathe” this setting to spontaneously ventilate patients, there is approximately a median of 30%
and theoretically improve comfort. A single ran- of patients who require mechanical ventilation.
domized trial [73] demonstrated an improvement Reported mortality in mechanically ventilated
in ICU length of stay and respiratory mechanics. patients ranges widely from 1.4% [75] to 47%
However, there is limited additional evidence for [76] and the spectrum in between. This disparity
improved outcomes, and there are potential likely reflects variation in patient selection,
harmful effects including decreased venous resource availability, local ventilator practices,
return and CO2 retention if not monitored closely. and possibly local viral mutations. A single
Overall, the use of these alternate modes of ven- cohort of COVID-19 patients on invasive
tilation is poorly supported by literature and mechanical ventilation had a survival rate of
requires close monitoring by providers skilled in 77%, and 88.7% of COVID-19 patients requiring
the titration parameters. tracheostomy survived [77, 78]. Fifty-four per-
Table 6.4 Summary of reported outcomes in mechanically ventilated COVID-19 patients published in peer reviewed
publications through Oct 2020
Survived to
Total Invasive extubation/end of
patients ventilation Percent study (out of those
(n) (n) ventilated Prone ECMO requiring MV) Location First author
28,585 8861 31.00% 2% International VIRUS
COVID-19
Registry Data
[86]
10,021 1318 13.15% 47% Germany Karagiannidis
[76]
5700 320 5.61% 11.80% New York City, Richardson [87]
USA
742 742 100.00% 76% 2.80% Spain/Andorra Ferrando [74]
733 307 41.9% Wuhan Xie [88]
522 97 18.6% 32.9% Georgia, USA Shah [89]
344 100 29.07% 4.8% 1.40% Wuhan, China Wang [75]
323 34 10.50% 2.9% Wuhan, China Hu [90]
221 26 11.76% 4.50% Wuhan, China Zhang [91]
191 32 16.75% 3% Wuhan, China Zhou [92]
73 73 100.00% 76.40% 6.80% 77% Milan, Italy Zangrillo [77]
53 53 100.00% 64.15% 13.20% 88.68% University of Chao [78]
Pennsylvania,
USA
24 18 75.00% 28% 33% Seattle, USA Bhatraju [35]
21 15 71.43% 8% Washington Arentz [93]
State, USA
cent of intubated patients were reported dis- 45% mortality (65% chance of survival) for each
charged from the ICU alive [74]. Acknowledging of them. The probability both will survive if both
the imprecision of specific outcomes, it does are getting lung protective ventilation is P(both) =
appear that early reports of near-guaranteed fatal- P(A) * P(B) = P(0.65) * P(0.65) = 42%. If neither
ity of intubation in COVID-19 patients were gets lung protective ventilation, which carries a
likely overly grim. roughly 30% increased relative risk of mortality,
or roughly 65% mortality, the probability both
survive is P(0.35) * (0.35) = 13%. If one received
Mechanical Ventilation in Limited standard lung protective ventilation while the
Resources other does not, this is represented by P(both) =
P(0.65) * P(0.35) = 23%. The ventilator sharing
Early in the pandemic, when it was becoming model has the lowest predicted survival of any
increasingly clear that health systems were going combination. While the ethical concern of triag-
to be overwhelmed, specifically with the avail- ing resources is well considered, we fail to con-
ability of mechanical ventilators, the idea of ven- sider the ethical concern of reducing the odds of
tilator sharing spread like wildfire. The idea was survival of one patient, to share the ventilator
first posed as a video on YouTube and projected with another patient, without their consent.
as a successful solution to the shortage encoun- Ventilator sharing would fail to deliver the
tered during the mass shooting in Las Vegas. This same ventilator settings to both patients unless
gained traction and as New York City became they had matched respiratory compliance, airway
overwhelmed, groups were convened to deter- resistance, respiratory drive, etc. Thus, even
mine how it could be done, even publishing the keeping both patients deeply sedated and para-
successful application for 48 hours a small case lyzed, there would need to be an endless repair-
series of 6 patients [79]. The FDA even granted ing of patients over the course of their disease.
an emergency use authorization for ventilator Instead of focusing on sharing ventilators, we
sharing, and a protocol was developed at one should focus on who would most benefit from
New York Hospital, while a multi-society press mechanical ventilation, how best to manage the
release strongly advocated against the practice other patients off of a ventilator, expanding venti-
[80, 81]. lator capacity, expanding capacity with high-flow
Ventilator sharing can technically be done, nasal cannulas [82], and developing well-
especially in patients intubated for airway protec- designed crisis standards of care triage
tion but without any lung injury. However, in protocols.
patients with ARDS, pneumonia, acute lung
injury, etc., it should be apparent by now that
ventilator sharing safely is infeasible. The ethical Conclusion
sentiment that it is the way to save the most lives
rather than triage resources is understandable, COVID-19 is a serious respiratory illness that
especially given the discomfort with triaging causes severe ARDS in many patients and has
resources in a crisis situation. However, rather imposed unprecedented demands on our health-
than save the most lives, it is most likely the way care system. Healthcare providers of all kinds are
to lose the most lives. You are more likely to lose being asked to perform duties outside their com-
both patients than save one of them if you share fort zone or expertise. It is quite possible that an
ventilators. emergency physician could be in a position to
Regardless of exact survival outcomes specific manage a ventilator for a critically ill patient for
to COVID-19, we have established that lung pro- longer durations than experienced in training or
tective ventilation improves overall survival in standard practice. Thus, it is imperative that the
ARDS in general. Given this, consider two emergency physician have an understanding of
patients, both with severe ARDS, which carries a the principals guiding lung protective ventilation
(Table 6.2), therapies for refractory hypoxemia, ysis of randomised controlled trials. Lancet Respir
and insights to additional therapies and strategies Med. 2020;8(3):247–57.
13. Sinha P, Calfee CS. Phenotypes in acute respiratory
to optimize outcomes in patients with distress syndrome: moving towards precision medi-
COVID-19. cine. Curr Opin Crit Care. 2019;25(1):12–20.
14. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C,
et al. Pathological findings of COVID-19 associated
with acute respiratory distress syndrome. Lancet
References Respir Med. 2020;8(4):420–2.
15. Calabrese F, Pezzuto F, Fortarezza F, Hofman P,

1. Fan E, Beitler JR, Brochard L, Calfee CS, Ferguson Kern I, Panizo A, et al. Pulmonary pathology and
ND, Slutsky AS, et al. COVID-19-associated acute COVID-19: lessons from autopsy. The experience of
respiratory distress syndrome: is a different approach European Pulmonary Pathologists. Virchows Arch.
to management warranted? Lancet Respir Med. 2020;477(3):359–72.
2020;8(8):816–21. 16. Lanza K, Perez LG, Costa LB, Cordeiro TM,

2. Bahl P, Doolan C, de Silva C, Chughtai AA, Bourouiba Palmeira VA, Ribeiro VT, et al. Covid-19: the renin-
L, MacIntyre CR. Airborne or droplet precautions angiotensin system imbalance hypothesis. Clin Sci
for health workers treating COVID-19? J Infect Dis. (Lond). 2020;134(11):1259–64.
2020. https://doi.org/10.1093/infdis/jiaa189. 17. Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S,
3. Xu K, Cai H, Shen Y, Ni Q, Chen Y, Hu S, et al. Harp J, et al. Complement associated microvascular
[Management of corona virus disease-19 (COVID-19): injury and thrombosis in the pathogenesis of severe
the Zhejiang experience]. Zhejiang Da Xue Xue Bao COVID-19 infection: A report of five cases. Transl
Yi Xue Ban. 2020;49(1):147–57. Res. 2020;220:1–13.
4. Gattinoni L, Chiumello D, Rossi S. COVID-19 pneu- 18. Takano H. Pulmonary surfactant itself must be a strong
monia: ARDS or not? Crit Care. 2020;24(1):154. defender against SARS-CoV-2. Med Hypotheses.
5. Polak SB, Van Gool IC, Cohen D, von der Thusen JH, 2020;144:110020.
van Paassen J. A systematic review of pathological 19. Grasselli G, Tonetti T, Protti A, Langer T, Girardis
findings in COVID-19: a pathophysiological timeline M, Bellani G, et al. Pathophysiology of COVID-19-
and possible mechanisms of disease progression. Mod associated acute respiratory distress syndrome: a
Pathol. 2020;33:2128–38. multicentre prospective observational study. Lancet
6. Bohn MK, Hall A, Sepiashvili L, Jung B, Steele S, Respir Med. 2020;8(12):1201–8.
Adeli K. Pathophysiology of COVID-19: mecha- 20. Janz DR, Mackey S, Patel N, Saccoccia BP, St

nisms underlying disease severity and progression. Romain M, Busack B, et al. Critically ill adults with
Physiology (Bethesda). 2020;35(5):288–301. COVID-19 in New Orleans and care with an evidence-
7. Grieco DL, Bongiovanni F, Chen L, Menga LS, Cutuli based protocol. Chest. 2021;159(1):196–204.
SL, Pintaudi G, et al. Respiratory physiology of 21. Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong
COVID-19-induced respiratory failure compared to MN, Fan E, et al. Surviving Sepsis Campaign: guide-
ARDS of other etiologies. Crit Care. 2020;24(1):529. lines on the management of critically ill adults with
8. Ziehr DR, Alladina J, Petri CR, Maley JH, Moskowitz Coronavirus Disease 2019 (COVID-19). Intensive
A, Medoff BD, et al. Respiratory pathophysiology Care Med. 2020;46(5):854–87.
of mechanically ventilated patients with COVID-19: 22. Frat JP, Thille AW, Mercat A, Girault C, Ragot S,
a cohort study. Am J Respir Crit Care Med. Perbet S, et al. High-flow oxygen through nasal can-
2020;201(12):1560–4. nula in acute hypoxemic respiratory failure. N Engl J
9. Bos LDJ. COVID-19-related acute respiratory dis- Med. 2015;372(23):2185–96.
tress syndrome: not so atypical. Am J Respir Crit Care 23. Agarwal A, Basmaji J, Muttalib F, Granton D,

Med. 2020;202(4):622–4. Chaudhuri D, Chetan D, et al. High-flow nasal can-
10. Sinha P, Calfee CS, Cherian S, Brealey D, Cutler S, nula for acute hypoxemic respiratory failure in
King C, et al. Prevalence of phenotypes of acute respi- patients with COVID-19: systematic reviews of
ratory distress syndrome in critically ill patients with effectiveness and its risks of aerosolization, disper-
COVID-19: a prospective observational study. Lancet sion, and infection transmission. Can J Anaesth.
Respir Med. 2020;8(12):1209–18. 2020;67(9):1217–48.
11. Sinha P, Churpek MM, Calfee CS. Machine learn- 24. Ferreyro BL, Angriman F, Munshi L, Del Sorbo L,
ing classifier models can identify acute respira- Ferguson ND, Rochwerg B, et al. Association of
tory distress syndrome phenotypes using readily noninvasive oxygenation strategies with all-cause
available clinical data. Am J Respir Crit Care Med. mortality in adults with acute hypoxemic respira-
2020;202(7):996–1004. tory failure: a systematic review and meta-analysis.
12. Sinha P, Delucchi KL, McAuley DF, O'Kane CM, JAMA. 2020;324(1):57–67.
Matthay MA, Calfee CS. Development and validation 25. Patel BK, Wolfe KS, Pohlman AS, Hall JB, Kress
of parsimonious algorithms to classify acute respira- JP. Effect of noninvasive ventilation delivered by
tory distress syndrome phenotypes: a secondary anal- helmet vs face mask on the rate of endotracheal
intubation in patients with acute respiratory dis- acute lung injury and the acute respiratory distress
tress syndrome: a randomized clinical trial. JAMA. syndrome. N Engl J Med. 2000;342(18):1301–8.
2016;315(22):2435–41. 41. Amato MB, Meade MO, Slutsky AS, Brochard L,
26. Brochard L, Slutsky A, Pesenti A. Mechanical ven- Costa EL, Schoenfeld DA, et al. Driving pressure and
tilation to minimize progression of lung injury in survival in the acute respiratory distress syndrome. N
acute respiratory failure. Am J Respir Crit Care Med. Engl J Med. 2015;372(8):747–55.
2017;195(4):438–42. 42. Chacko B, Peter JV, Tharyan P, John G, Jeyaseelan
27. Tonelli R, Fantini R, Tabbi L, Castaniere I, Pisani L. Pressure-controlled versus volume-controlled
L, Pellegrino MR, et al. Early inspiratory effort ventilation for acute respiratory failure due to acute
assessment by esophageal manometry predicts non- lung injury (ALI) or acute respiratory distress syn-
invasive ventilation outcome in de novo respiratory drome (ARDS). Cochrane Database Syst Rev.
failure. a pilot study. Am J Respir Crit Care Med. 2015;1:CD008807.
2020;202(4):558–67. 43. Brower RG, Lanken PN, MacIntyre N, Matthay MA,
28. Grieco DL, Menga LS, Raggi V, Bongiovanni F, Morris A, Ancukiewicz M, et al. Higher versus lower
Anzellotti GM, Tanzarella ES, et al. Physiological com- positive end-expiratory pressures in patients with the
parison of high-flow nasal cannula and helmet noninva- acute respiratory distress syndrome. N Engl J Med.
sive ventilation in acute hypoxemic respiratory failure. 2004;351(4):327–36.
Am J Respir Crit Care Med. 2020;201(3):303–12. 44. Briel M, Meade M, Mercat A, Brower RG, Talmor
29. Morais CCA, Koyama Y, Yoshida T, Plens GM, Gomes D, Walter SD, et al. Higher vs lower positive end-
S, Lima CAS, et al. High positive end-expiratory pres- expiratory pressure in patients with acute lung
sure renders spontaneous effort noninjurious. Am J injury and acute respiratory distress syndrome:
Respir Crit Care Med. 2018;197(10):1285–96. systematic review and meta-analysis. JAMA.
30. Carteaux G, Millan-Guilarte T, De Prost N, Razazi 2010;303(9):865–73.
K, Abid S, Thille AW, et al. Failure of noninvasive 45. Kallet RH, Branson RD. Do the NIH ARDS

ventilation for de novo acute hypoxemic respira- Clinical Trials Network PEEP/FIO2 tables pro-
tory failure: role of tidal volume. Crit Care Med. vide the best evidence-based guide to balancing
2016;44(2):282–90. PEEP and FIO2 settings in adults? Respir Care.
31. Gattinoni L, Tonetti T, Quintel M. Regional physiol- 2007;52(4):461–77.
ogy of ARDS. Crit Care. 2017;21(Suppl 3):312. 46. Barrot L, Asfar P, Mauny F, Winiszewski H, Montini
32. Mosier JM, Sakles JC, Whitmore SP, Hypes CD,
F, Badie J, et al. Liberal or conservative oxygen ther-
Hallett DK, Hawbaker KE, et al. Failed noninvasive apy for acute respiratory distress syndrome. N Engl J
positive-pressure ventilation is associated with an Med. 2020;382(11):999–1008.
increased risk of intubation-related complications. 47. Chu DK, Kim LH, Young PJ, Zamiri N, Almenawer
Ann Intensive Care. 2015;5:4. SA, Jaeschke R, et al. Mortality and morbidity in
33. Kang BJ, Koh Y, Lim CM, Huh JW, Baek S, Han M, acutely ill adults treated with liberal versus conserva-
et al. Failure of high-flow nasal cannula therapy may tive oxygen therapy (IOTA): a systematic review and
delay intubation and increase mortality. Intensive meta-analysis. Lancet. 2018;391(10131):1693–705.
Care Med. 2015;41(4):623–32. 48. Page D, Ablordeppey E, Wessman BT, Mohr NM,
34. Lu Q, Rouby JJ. Measurement of pressure-volume Trzeciak S, Kollef MH, et al. Emergency department
curves in patients on mechanical ventilation: methods hyperoxia is associated with increased mortality in
and significance. Crit Care. 2000;4(2):91–100. mechanically ventilated patients: a cohort study. Crit
35. Bhatraju PK, Ghassemieh BJ, Nichols M, Kim R, Care. 2018;22(1):9.
Jerome KR, Nalla AK, et al. Covid-19 in critically ill 49.
Slutsky AS. Mechanical ventilation. American
patients in the Seattle region – case series. N Engl J College of Chest Physicians’ consensus conference.
Med. 2020;382(21):2012–22. Chest. 1993;104(6):1833–59.
36. Lechin AE, Varon J. Adult respiratory distress
50. Grasso S, Terragni P, Mascia L, Fanelli V, Quintel M,
syndrome (ARDS): the basics. J Emerg Med. Herrmann P, et al. Airway pressure-time curve profile
1994;12(1):63–8. (stress index) detects tidal recruitment/hyperinflation
37. Gattinoni L, Meissner K, Marini JJ. The baby
in experimental acute lung injury. Crit Care Med.
lung and the COVID-19 era. Intensive Care Med. 2004;32(4):1018–27.
2020;46(7):1438–40. 51. Suzumura EA, Figueiro M, Normilio-Silva K,

38. Beitler JR, Malhotra A, Thompson BT. Ventilator- Laranjeira L, Oliveira C, Buehler AM, et al. Effects of
induced Lung Injury. Clin Chest Med. alveolar recruitment maneuvers on clinical outcomes
2016;37(4):633–46. in patients with acute respiratory distress syndrome: a
39. Slutsky AS, Ranieri VM. Ventilator-induced lung
systematic review and meta-analysis. Intensive Care
injury. N Engl J Med. 2013;369(22):2126–36. Med. 2014;40(9):1227–40.
40. Acute Respiratory Distress Syndrome Network,
52. Santos RS, Silva PL, Pelosi P, Rocco PR. Recruitment
Brower RG, Matthay MA, Morris A, Schoenfeld D, maneuvers in acute respiratory distress syndrome:
Thompson BT, et al. Ventilation with lower tidal vol- The safe way is the best way. World J Crit Care Med.
umes as compared with traditional tidal volumes for 2015;4(4):278–86.
53. Goligher EC, Hodgson CL, Adhikari NKJ, Meade 66. Coppo A, Bellani G, Winterton D, Di Pierro M, Soria
MO, Wunsch H, Uleryk E, et al. Lung recruit- A, Faverio P, et al. Feasibility and physiological
ment maneuvers for adult patients with acute effects of prone positioning in non-intubated patients
respiratory distress syndrome. A systematic with acute respiratory failure due to COVID-19
review and meta-analysis. Ann Am Thorac Soc. (PRON-COVID): a prospective cohort study. Lancet
2017;14(Supplement_4):S304–S11. Respir Med. 2020;8(8):765–74.
54. Writing Group for the Alveolar Recruitment for Acute 67. Zarantonello F, Andreatta G, Sella N, Navalesi P. Prone
Respiratory Distress Syndrome Trial I, Cavalcanti position and lung ventilation and perfusion matching
AB, Suzumura EA, Laranjeira LN, Paisani DM, in acute respiratory failure due to COVID-19. Am J
Damiani LP, et al. Effect of lung recruitment and Respir Crit Care Med. 2020;202(2):278–9.
titrated positive end-expiratory pressure (PEEP) vs 68. Carsetti A, Damia Paciarini A, Marini B, Pantanetti S,
low PEEP on mortality in patients with acute respi- Adrario E, Donati A. Prolonged prone position venti-
ratory distress syndrome: a randomized clinical trial. lation for SARS-CoV-2 patients is feasible and effec-
JAMA. 2017;318(14):1335–45. tive. Crit Care. 2020;24(1):225.
55. Marini JJ, Rocco PRM, Gattinoni L. Static and
69. Alhazzani W, Alshahrani M, Jaeschke R, Forel JM,
dynamic contributors to ventilator-induced lung injury Papazian L, Sevransky J, et al. Neuromuscular block-
in clinical practice. Pressure, energy, and power. Am J ing agents in acute respiratory distress syndrome: a
Respir Crit Care Med. 2020;201(7):767–74. systematic review and meta-analysis of randomized
56. Cressoni M, Gotti M, Chiurazzi C, Massari D, Algieri controlled trials. Crit Care. 2013;17(2):R43.
I, Amini M, et al. Mechanical power and development 70. National Heart, Lung, and Blood Institute PETAL
of ventilator-induced lung injury. Anesthesiology. Clinical Trials Network, Moss M, Huang DT, Brower
2016;124(5):1100–8. RG, Ferguson ND, et al. Early Neuromuscular
57. Gattinoni L, Tonetti T, Cressoni M, Cadringher P, Blockade in the Acute Respiratory Distress Syndrome.
Herrmann P, Moerer O, et al. Ventilator-related causes N Engl J Med. 2019;380(21):1997–2008.
of lung injury: the mechanical power. Intensive Care 71. Matusov Y, Li J, Resuello D, Mathers H, Fried JC.
Med. 2016;42(10):1567–75. Use of pressure-regulated volume control in the
58. Mauri T, Spinelli E, Scotti E, Colussi G, Basile MC, first 48 hours of hospitalization of mechanically
Crotti S, et al. Potential for lung recruitment and ventilated patients with sepsis or septic shock, with
ventilation-perfusion mismatch in patients with the or without ARDS. Journal of the Intensive Care
acute respiratory distress syndrome from Coronavirus Society. 2019.
Disease 2019. Crit Care Med. 2020;48(8):1129–34. 72. Guldager H, Nielsen SL, Carl P, Soerensen MB. A
59. Paiva KCA, Beppu OS. Posição prona %J Jornal
comparison of volume control and pressure-regulated
Brasileiro de. Pneumologia. 2005;31:332–40. volume control ventilation in acute respiratory failure.
60. Pan C, Chen L, Lu C, Zhang W, Xia JA, Sklar MC, Crit Care. 1997;1(2):75–7.
et al. Lung recruitability in COVID-19-associated 73. Zhou Y, Jin X, Lv Y, Wang P, Yang Y, Liang G, et al.
acute respiratory distress syndrome: a single-center Early application of airway pressure release ventila-
observational study. Am J Respir Crit Care Med. tion may reduce the duration of mechanical ventila-
2020;201(10):1294–7. tion in acute respiratory distress syndrome. Intensive
61. Gattinoni L, Pelosi P, Vitale G, Pesenti A, D’Andrea Care Med. 2017;43(11):1648–59.
L, Mascheroni D. Body position changes redistrib- 74. Ferrando C, Suarez-Sipmann F, Mellado-Artigas R,
ute lung computed-tomographic density in patients Hernandez M, Gea A, Arruti E, et al. Clinical features,
with acute respiratory failure. Anesthesiology. ventilatory management, and outcome of ARDS
1991;74(1):15–23. caused by COVID-19 are similar to other causes of
62. Gattinoni L, Taccone P, Carlesso E, Marini JJ. Prone ARDS.Intensive Care Med. 2020.
position in acute respiratory distress syndrome. 75. Wang Y, Lu X, Li Y, Chen H, Chen T, Su N, et al.
Rationale, indications, and limits. Am J Respir Crit Clinical Course and Outcomes of 344 Intensive Care
Care Med. 2013;188(11):1286–93. Patients with COVID-19. Am J Respir Crit Care Med.
63. Wiener CM, Kirk W, Albert RK. Prone position
2020;201(11):1430–4.
reverses gravitational distribution of perfusion in dog 76. Karagiannidis C, Mostert C, Hentschker C, Voshaar
lungs with oleic acid-induced injury. J Appl Physiol T, Malzahn J, Schillinger G, et al. Case characteris-
(1985). 1990;68(4):1386–92. tics, resource use, and outcomes of 10 021 patients
64. Mure M, Domino KB, Lindahl SG, Hlastala MP,
with COVID-19 admitted to 920 German hospi-
Altemeier WA, Glenny RW. Regional ventilation- tals: an observational study. Lancet Respir Med.
perfusion distribution is more uniform in the prone 2020;8(9):853–62.
position. J Appl Physiol (1985). 2000;88(3):1076–83. 77. Zangrillo A, Beretta L, Scandroglio AM, Monti G,
65. Caputo ND, Strayer RJ, Levitan R. Early self-
Fominskiy E, Colombo S, et al. Characteristics,
proning in awake, non-intubated patients in the treatment, outcomes and cause of death of invasively
emergency department: a single ED’s experience ventilated patients with COVID-19 ARDS in Milan,
during the COVID-19 pandemic. Acad Emerg Med. Italy. Crit Care Resusc. 2020.
2020;27(5):375–8.
AL GRAWANY
78. Chao TN, Harbison SP, Braslow BM, Hutchinson

ratory illness universal study (VIRUS): an interna-
CT, Rajasekaran K, Go BC, et al. Outcomes after tional registry of coronavirus 2019-related critical
Tracheostomy in COVID-19 Patients. Ann Surg. illness. Crit Care Explor. 2020;2(4):e0113.
2020. 87. Richardson S, Hirsch JS, Narasimhan M, Crawford
79. Beitler JR, Mittel AM, Kallet R, Kacmarek R, Hess JM, McGinn T, Davidson KW, et al. Presenting char-
D, Branson R, et al. Ventilator sharing during an acute acteristics, comorbidities, and outcomes among 5700
shortage caused by the COVID-19 pandemic. Am J patients hospitalized with COVID-19 in the New York
Respir Crit Care Med. 2020;202(4):600–4. City Area. JAMA. 2020;323(20):2052–9.
80. FDA emergency use authorization 2020. Available
88. Xie J, Wu W, Li S, Hu Y, Hu M, Li J, et al. Clinical
from: https://www.fda.gov/media/136423/download. characteristics and outcomes of critically ill patients
81. Anesthesiology ASo. Joint Statement on Multiple Patients with novel coronavirus infectious disease (COVID-19)
Per Ventilator 2020. Available from: https://www.asahq. in China: a retrospective multicenter study. Intensive
org/about-a sa/newsroom/news-r eleases/2020/03/ Care Med. 2020;46(10):1863–72.
joint-statement-on-multiple-patients-per-ventilator. 89. Shah P, Owens J, Franklin J, Mehta A, Heymann W,
82. Gershengorn HB, Hu Y, Chen JT, Hsieh SJ, Dong Sewell W, et al. Demographics, comorbidities and
J, Gong MN, et al. The Impact of High-Flow Nasal outcomes in hospitalized Covid-19 patients in rural
Cannula Use on Patient Mortality and the Availability southwest Georgia. Ann Med. 2020;52(7):354–60.
of Mechanical Ventilators in COVID-19. Ann Am 90. Hu L, Chen S, Fu Y, Gao Z, Long H, Wang JM, et
Thorac Soc. 2020. al. Risk Factors Associated with Clinical Outcomes
83. Force ADT, Ranieri VM, Rubenfeld GD, Thompson in 323 COVID-19 Hospitalized Patients in Wuhan,
BT, Ferguson ND, Caldwell E, et al. Acute respira- China. Clin Infect Dis. 2020.
tory distress syndrome: the Berlin Definition. JAMA. 91. Zhang G, Hu C, Luo L, Fang F, Chen Y, Li J, et al.
2012;307(23):2526–33. Clinical features and short-term outcomes of 221
84. Guerin C, Reignier J, Richard JC, Beuret P, Gacouin patients with COVID-19 in Wuhan, China. J Clin
A, Boulain T, et al. Prone positioning in severe Virol. 2020;127:104364.
acute respiratory distress syndrome. N Engl J Med. 92. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al.
2013;368(23):2159–68. Clinical course and risk factors for mortality
85. National Heart L, Blood Institute Acute Respiratory of adult inpatients with COVID-19 in Wuhan,
Distress Syndrome Clinical Trials N, Wiedemann China: a retrospective cohort study. Lancet.
HP, Wheeler AP, Bernard GR, Thompson BT, et 2020;395(10229):1054–62.
al. Comparison of two fluid-management strate- 93. Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX,
gies in acute lung injury. N Engl J Med. 2006; Chong M, et al. Characteristics and outcomes of 21
354(24):2564–75. critically ill patients with COVID-19 in Washington
86. Walkey AJ, Kumar VK, Harhay MO, Bolesta S,
State. JAMA. 2020;323(16):1612–4.
Bansal V, Gajic O, et al. The viral infection and respi-
ECMO and Rescue Therapies
for Severe Hypoxemia
7
Emily Ball, Keith Azevedo, and Jonathan Marinaro
Critical Points • Generally, ECMO may be indicated be when

• VV ECMO provides pulmonary support, the risk of death from the underlying disease
while VA ECMO provides cardiac and pulmo- process outweighs the risk of death due to
nary support. complications associated with ECMO.
• COVID-19 patients typically require VV
ECMO for severe hypoxemic respiratory
failure. Introduction
• eCPR (initiation of VA ECMO while in car-
diac arrest) is not currently indicated for Infection with COVID-19 can result in severe
COVID-19 patients due to poor results and refractory hypoxemia in a subset of patients, and
high risk of exposure. despite maximally supportive ventilatory strate-
gies, certain patients are unable to maintain ade-
quate arterial oxygenation to support vital
functions. Extracorporeal membrane oxygen-
ation (ECMO) is a life-sustaining therapy that
E. Ball (*) has been used as a means of rescue treatment for
Surgical Critical Care Fellow at the University of severe hypoxemia due to COVID-19. In the fol-
New Mexico, Departments of Surgery and lowing chapter, we will explore a brief history,
Emergency Medicine, Albuquerque, NM, USA
e-mail: [email protected] basic principle and circuitry, indications, contra-
indication, fundamental management, complica-
K. Azevedo
Critical Care and Emergency Medicine at the tions, and considerations of providing ECMO as
University of New Mexico, Departments of a means of rescue therapy. It should be noted that
Emergency and Internal Medicine, as with most writings specific to COVID-19,
Albuquerque, NM, USA
there exists limited literature, and therefore the
following represents expert and personal opinion
J. Marinaro
as well as currently available data. The intent of
University of New Mexico Center for Adult Critical
Care, University of New Mexico ECMO Program, this chapter is to provide a clinically relevant and
Department of Emergency Medicine, comprehensive approach to understanding the
Albuquerque, NM, USA role of ECMO in the context of severe hypox-
Department of Emergency Medicine and Critical emia due to COVID-19.
Care, University of New Mexico,
Albuquerque, NM, USA

64 E. Ball et al.
rief History of ECMO and Use

B (ELSO), the World Health Organization (WHO),
in Treatment of ARDS and the Surviving Sepsis Campaign COVID-19
panel [6–8]. At present, just over 4000 confirmed
The ECMO circuit has been adapted from stan- COVID-19-positive patients have been treated
dard cardiopulmonary bypass (CPB) to serve as with ECMO according to the ELSO registry data-
longer-acting support for lung and heart function. base, 95% of them received VV ECMO, and the
ECMO as we know it today stems from the devel- group overall has an in-hospital mortality rate of
opment of a heart-lung bypass machine by Dr. 48% [9]. Barbaro et al. published an analysis of
John Gibbon, which he used in the operating patients from the ELSO registry treated early in
room for the first time in 1953. In concert with the pandemic, which offered a report of estimated
other innovations, such as anticoagulation for survivability for patients with COVID-19 treated
prolonged periods of time and silicone for mem- at experienced ECMO centers [10]. Among the
branes, the use of ECMO was able to be extended 1035 patients included in the analysis, estimated
from periods of several hours to days [1]. In the survival at 90 days post-cannulation was close to
early 1970s, ECMO was successfully used in the 40% [10]. In a retrospective cohort study of 83
treatment of several patients. Dr. Robert Bartlett patients with COVID-19 placed on ECMO pub-
used the machine for 72 hours in the neonatal lished in the Lancet, Schmidt et al. found compa-
intensive care unit. Dr. J. Donald Hill used rable survival rates for patients placed on ECMO
ECMO in an adult patient with acute respiratory for COVID-19 compared to those placed on
distress syndrome (ARDS). In the 1990s ECMO ECMO for other etiologies of ARDS; 98% of the
was being used in adults with respiratory failure, patients received VV ECMO. They also found
and Morris published a trial in 1994 showing a that once patients with COVID-19-associated
lack of demonstrated benefit from the use of respiratory failure were cannulated, ECMO
veno-venous (VV) ECMO. As a result, the use of allowed for reduced ventilator support and rapid
ECMO for ARDS was slow to advance. It was normalization of arterial blood gas with the
not until the 2000s that the widespread use of median duration of ECMO support being 20 days
ECMO for a variety of indications has gained [6]. Treatment of COVID-19 is rapidly evolving,
more prominent favor [2]. In 2009 the conven- and additional publications are anticipated to
tional ventilatory support versus extracorporeal continue to inform use of ECMO.
membrane oxygenation for severe adult respira-
tory failure (CESAR) trial, a landmark random-
ized control trial that compared ECMO to Principles and Circuitry
mechanical ventilation, demonstrated survival
benefit attributed to ECMO [3]. In 2018 the An exhaustive discussion of the intricacies of
ECMO to rescue lung injury in severe ARDS ECMO is out of the scope of this chapter.
(EOLIA) trial further defined the parameters of However, it is important to understand the basic
mechanical ventilation in the control group and principles and circuitry, such that consultation
formalized indications for initiation of ECMO and referral can be completed appropriately. The
[4]. Survival benefit has also been demonstrated overall goal of the ECMO components is to meet
with the use of ECMO for ARDS related to infec- the physiologic demands of the patient by oxy-
tions with influenza H1N1, H7N9, as well as genating blood, removing CO2, and providing
Middle East respiratory syndrome coronavirus circulatory support. Components of the circuit
(MERS-CoV) [5]. Currently, use of ECMO has include the pump, membrane oxygenator, and
expanded to many indications, following cardiac heat exchanger. The pump is the mechanism by
arrest, for example, and the use of VV ECMO is which blood is circulated throughout the ECMO
recommended for COVID-19-associated respira- system and returned to the body. There are two
tory failure by organizations including the varieties of pumps commonly used: occlusive
Extracorporeal Life Support Organization and non-occlusive or centrifugal pumps. There
7 ECMO and Rescue Therapies for Severe Hypoxemia 65
has been an overall trend toward increased use of ECMO deployment: veno-venous (VV) and
centrifugal pumps, as these pumps can generate veno-arterial (VA).
higher pressures with lower revolutions per min- VV ECMO, VA ECMO, or combinations of
ute, allowing for clamping or occlusion of the the two represent ways to describe the location
circuit without compromising circuit integrity. and arrangement of the cannulas that circulate
This feature enables changing of circuit compo- the patient’s deoxygenated and oxygenated
nents more easily. One consideration to centrifu- blood. Cannula placement is fundamentally
gal pumps is the dependence on preload and patient and circumstance dependent. When the
afterload. If adequate preload and afterload are primary indication for placing a patient on
experienced by the pump, a constant flow of ECMO is pulmonary failure, VV ECMO can-
blood is able to be moved through the gas nula arrangement is typically used. In this
exchanging membrane, often referred to as the arrangement blood is shunted to the circuit
oxygenator, which provides both oxygenation from a vein and returned to the body via another
and removal of CO2 [1]. vein. In contrast, VA ECMO is employed in the
The oxygenator allows for diffusion of oxy- context of cardiac failure, acute obstructive
gen and CO2 in a manner similar to the native shock, often secondary to pulmonary embo-
lung. Within the oxygenator, hollow fibers com- lism, or severe hypothermia. Blood is returned
posed of polymethylpentene or polyolefin com- to the patient via an artery in VA ECMO. Given
prise the gas exchange membrane. The fibers are that the majority of patients with COVID-19
highly permeable to gas, allowing maximal sur- require VV ECMO support for hypoxemic
face area for gas exchange. The gas, typically respiratory failure, the majority of the discus-
100% oxygen, is entrained within the hollow sions in this chapter will focus on VV ECMO.
fibers as blood flows around the fibers allowing VV ECMO can be deployed as a rescue inter-
for robust gas exchange through the mem- vention in the setting of severe gas exchange
brane walls of the fibers. The rate of flow of gas impairment refractory to maximal ventilator set-
through these fibers can be titrated to achieve tings, recruitment maneuvers, pulmonary vasodi-
the desired CO2 clearance and is referred to as lators, or prone positioning or when ongoing
the sweep gas or simply sweep, in liters per mechanical ventilation is thought likely to induce
minute. Finally, the temperature of the circulat- lung injury. As such, respiratory function is
ing blood can be adjusted using a heat exchanger. replaced by the oxygenator, with the intent of
A water bath on one side of a membrane is used unburdening the respiratory system and allowing
to warm or cool blood by convection [1, 2]. for pulmonary recovery. VV ECMO cannulation
To summarize the circuit components: blood typically begins with a drainage cannula inserted
is transported by cannulas from the patient’s percutaneously using Seldinger technique into a
body, propelled by a pump. The pump brings large central vein which draws blood out of the
blood to an oxygenator that allows for CO2 and body, via the pump, and toward the oxygenator,
oxygen exchange. Throughout the process, the the location of CO2 and O2 exchange. After gas
temperature of the blood is controlled and exchange has occurred, this blood which is now
brought back into the body. Aside from this basic rich in oxygen and low in CO2 travels back into
circuitry, additional elements can be added, such the venous circulation via a return cannula placed
as renal replacement therapy, hemofiltration, in a large central vein which returns blood to the
additional oxygenators, and monitoring catheters right atrium. In contrast to using two separate
which can further contribute to the complexity of cannulas placed in two separate large veins, a
the system. No matter the degree of complexity, dual lumen single cannula system can be
the overall intent is the same, to provide an extra- deployed into a single venous vessel, typically
corporeal means of gas exchange to be delivered the right internal jugular vein, in which both
to the venous or arterial system. The following drainage and return can be accomplished by a
section will explore the two configurations of solitary dual lumen cannula. Typically, cannulas
66 E. Ball et al.
are advanced under fluoroscopy or transesopha- inserted to verify blood pressure, pulsatility, and
geal echocardiography to establish adequate oxygenation of the blood delivered presumably to
positioning of the catheter tip [1]. the most distal point from the mixing cloud, which
Numerous variations of cannula arrangements should correlate to heart and brain perfusion.
exist for the establishment of the VV ECMO cir- Partial occlusion of the femoral artery due to the
cuit, with patient anatomy, stability, indication, cannula position may result in inadequate perfu-
experience and training of the cannulator, and sion of the lower extremity distally, for which an
local practice informing cannula insertion site additional reperfusion cannula can be inserted. In
selection and positioning. Once established on addition, pressure from the return cannula in the
VV ECMO, ventilatory settings can be decreased opposite direction of native circulation can create
with the goal of maximizing lung protective strat- increased afterload for the left ventricle. The left
egies [6]. In the setting of isolated hypercarbic ventricle may require venting, or assistance with
respiratory failure, much lower blood flow rates maintaining ejection fraction; typically this is
are needed for CO2 clearance. This situation is accomplished with a left ventricular assist device
often encountered when weaning COVID-19 [1, 2].
patients from ECMO. In certain patients with
cardiac dysfunction, reversal of hypoxia with VV
ECMO allows for cardiac recovery and reduces Indications
pulmonary artery resistance [1]. In patients that
have continued or develop worsening cardiac Indications for ECMO have expanded in recent
function, transitioning from VV to VA ECMO years; for the sake of this discussion, the use of
may be necessary. VV and VA ECMO in the treatment of COVID-19
VA ECMO is used to provide oxygenated blood will be considered here. Identification of patients
under pressure sufficient for end-organ perfusion, with severe acute respiratory failure secondary to
typically in the setting of cardiogenic or obstruc- COVID-19 with the greatest need for ECMO
tive shock. A drainage cannula is positioned in a support, as well as the highest likelihood for sur-
large central vein, typically the femoral vein; the vival with good functional status, continues to be
cannula carries blood to the ECMO circuit. Blood an enormous challenge. The vast majority of
then passes through the circuit for gas exchange patients with ARDS secondary to COVID-19,
and warming, just as in VV ECMO. However, like ARDS secondary to other etiologies, should
unlike VV ECMO in which the oxygenated blood be considered primarily for VV
is returned to the venous system, in VA ECMO, ECMO. Indications for VV ECMO for
oxygenated blood is returned to the arterial circu- COVID-19, therefore, are related to severity of
lation via a cannula placed in the artery. The most respiratory failure. Due to the rapidly evolving
common return site for blood is the common fem- pandemic landscape, published data includes a
oral artery, with the catheter terminating near the heterogeneous patient population regarding crite-
bifurcation of the aorta. Blood pumped into the ria for initiation of ECMO. Prior to the COVID
aorta from the ECMO circuit mixes with the blood pandemic, many centers had used criteria pub-
volume supplied by native cardiac output, creating lished in the EOLIA study to assist in determin-
what is described as a “mixing cloud,” a mixture of ing which patients should be cannulated (see
relatively deoxygenated blood from the left ven- Table 7.1) [4]. Since the onset of the pandemic,
tricle and arterialized blood from the ECMO cir- ELSO has published and continues to update
cuit. The combination of these two circulations guidelines to aid in the process of patient selec-
should allow for adequate oxygen delivery to the tion taking into consideration evolving health-
brain. The oxygenation of the mixed blood is care system capacity (see Table 7.2) [8].
dependent on the proportion of blood diverted In general, the principal behind the use
through the ECMO circuit, which is controlled by of ECMO is that it can afford time to the patient,
flow. A right radial artery monitoring catheter is allowing other treatments and recovery to take
Table 7.1 EOLIA criteria [4] more nuanced than previously as systems are
Intubated and receiving mechanical ventilation <7 days overwhelmed. The crux of employing ECMO for
PaO2/FI O2 <50 for >3 hours COVID-19 lies within identifying those patients
PaO2/FI O2 <80 for >6 hours who will benefit from the therapy, separating
Arterial pH <7.25 with Pa CO2 ≥60 for >6 hours
them from those who will survive without it and
from those who will succumb to the illness
Table 7.2 COVID-19 specific ELSO criteria [8] despite the use of ECMO, and considering ethical
In the absence of contraindications, ECMO is decision-making in the setting of high demand on
recommended if the healthcare system. ECMO requires invest-
PaO2/FI O2 <60 mmHg for >6 hours ment of significant resources, and the allocation
PaO2/FI O2 <50 for >3 hours of these resources is a vital consideration during
pH <7.20 + Pa CO2 >80 or >6 hours
a pandemic. Therefore, clinicians must ultimately
use their best judgment to assess the risk of mor-
effect. Deployment should be considered when tality without use of ECMO and decide to can-
the morbidity and mortality of the underlying nulate patients if chances of survival are thought
conditions outweigh the anticipated morbidity or to be improved with ECMO, with these decisions
mortality associated with ECMO. Treatment of being made within the context of resource avail-
COVID-19 is rapidly evolving, and in the setting ability and demand for ECMO.
of use of ECMO for COVID-19, the require- With regard to indications for VA ECMO for
ments for ECMO candidacy vary by center, bur- patients with COVID-19, the recommendation is
den placed on healthcare systems, and local adherence to pre-existing guidelines. Acute myo-
experience. Patients with COVID-19-related car- cardial infarction, myocarditis, and pulmonary
diopulmonary failure who are thought to be good embolism have been associated with COVID-19
candidates for ECMO and have fully exhausted and may result in cardiogenic shock necessitating
treatment options including varied ventilatory VA ECMO support in these patients. Data sug-
strategies, recruitment maneuvers, pulmonary gests the small subset of patients who require VA
vasodilators, neuromuscular blockade, and prone ECMO in the setting of COVID-19 have
positioning should be cannulated. Much of the extremely poor outcomes [5, 8, 11, 12]. Patients
discussion surrounding indications for cannula- that are candidates for ventricular assist devices
tion centers on the threshold of hypoxia that or other support for biventricular failure are bet-
should be tolerated. The ratio of arterial oxygen ter served if ECMO can be avoided. VA ECMO is
partial pressure (PaO2 in mmHg) to fractional indicated for refractory cardiogenic shock,
inspired oxygen (FiO2), referred to commonly as defined by ELSO as persistent tissue hypo-
the P/F or PaO2:FiO2, is used as a way of moni- perfusion, systolic blood pressure <90 mmHg,
toring hypoxemia. The EOLIA trial inclusion cri- and cardiac index <2.2 L/min/m2 while receiving
teria include this marker, as do the ELSO norepinephrine >0.5 mcg/kg/min, dobutamine
guidelines on use of ECMO for COVID (see >20 mcg/kg/min, or equivalent [1, 2, 8]. Prior to
Tables 7.1 and 7.2) [4, 8]. the COVID-19 pandemic, VA ECMO was being
Patients meeting criteria for hypoxia, hyper- increasingly used to support patients suffering
carbia, or acidosis as outlined in the tables above cardiac arrest (E-CPR). Though it has been
should be considered. In addition, barotrauma is shown to benefit patients in cardiac arrest, par-
also taken into consideration, as presence of ticularly when occurring secondary to arrhyth-
pneumomediastinum, pneumothorax, or subcuta- mias, this subgroup of patients suffer a high
neous emphysema suggests spontaneous or mortality rate. In an effort to allocate resources to
mechanical ventilation is inducing lung injury those most likely to benefit, temporary cessation
and is a factor in the decision to cannulate. of E-CPR has been recommended by ELSO and
Although ELSO guidelines are available, others as a way to divert resources and reduce
patient selection in the time of COVID-19 is provider risk of exposure [8, 13].
68 E. Ball et al.
Contraindications Table 7.4 ELSO COVID guidelines [8]

Relative contraindications:
Conditions expected to shorten life expectancy Age ≥65 years
would generally exclude patients from consider- Obesity BMI ≥40
ation. Existence of degenerative or progressive Immunocompromised status
No legal medical decision maker available
illnesses including chronic liver, kidney, cardiac,
Advanced chronic underlying systolic heart failure
or lung disease, immunosuppressive conditions, High-dose vasopressor requirement (and not under
malignancy, and other pre-existing conditions are consideration for VA or VVA ECMO)
often relative or absolute contraindications for Absolute contraindications:
many ECMO centers. Tables 7.3 and 7.4 from Advanced age
both EOLIA and ELSO identify relative and Clinical Frailty Scale category ≥3
Mechanical ventilation >10 days
absolute contraindications [8].
Significant underlying comorbidities: CKD ≥ III,
cirrhosis, dementia, or baseline neurologic disease
which would preclude rehabilitation potential,
Fundamental Management disseminated malignancy, advanced lung disease,
uncontrolled DM with chronic end-organ
dysfunction, severe deconditioning, protein-calorie
Once placed on ECMO, patients with COVID-19 malnutrition, severe peripheral vascular disease,
should continue to receive supportive care as they non-ambulatory or unable to perform activities, and
did prior to cannulation with continued medical other pre-existing life-limiting medical condition.
treatment. Maximal lung protective ventilation, Severe multiple organ failure
with low tidal volumes (4–8 cc/kg of predicted Severe acute neurologic injury e.g. anoxic injury,
stroke
body weight) and plateau pressures (<30 cm Uncontrolled bleeding
H20), should be initiated to minimize further Contraindications to anticoagulation
ventilator-induced lung injury [5]. Tight control Inability to accept blood products
of driving pressures and use of airway pressure- Ongoing CPR
release ventilation modes may be beneficial [5,
14]. Reduced ventilatory pressures may also
allow for reduction in sedation and improved
hemodynamics as a result of decreased intratho- tion of intubation. A large proportion of patients
racic pressures [5]. However, in certain patients, with COVID-19 have been noted to require
adequate oxygenation cannot be obtained with- higher doses of sedation and analgesia to tolerate
out some ongoing use of the native lungs, which mechanical ventilation; some of this may be
can result in persistent barotrauma. Tracheostomy attributed to patients being intubated who were
insertion is routinely performed due to the dura- previously younger and healthier than typically
ARDS patients, or high respiratory drive due to
Table 7.3 EOLIA Contraindications [4] hypoxia [15]. ECMO patients may require even
Mechanical ventilation ≥7 days deeper sedation as hemodynamic shifts associ-
Age <18 years ated with vent desynchrony can result in severe
Pregnancy and rapid drops in blood pressure. Prone posi-
BMI >45 kg/m2 tioning continues to play a role in management in
Chronic respiratory insufficiency treated with long the absence of contraindications including pro-
duration oxygen or respiratory assistance
found hemodynamic instability, massive hemop-
Previous history of HIT
Malignancy with fatal prognosis within 5 years tysis, DVT being treated for less than 2 days, or
Patient moribund single anterior chest tube with an air leak [6, 16].
SAPS II >90 Paralysis, either intermittent or continuous infu-
Non-drug-induced coma following cardiac arrest sion, may be necessary in the setting of desyn-
Irreversible neurological pathology chrony to reduce work of breathing as it is used in
ECMO cannulation not possible patients prior to cannulation. While on ECMO,
paralytics may serve as an adjunct when flows are dures, such as tube thoracostomy, tracheostomy,
inadequate due to coughing or for refractory and intracranial hemorrhage [5]. Intracranial
hypoxia. Inhaled nitric oxide should also be con- hemorrhage can be devastating [21–23]. Epistaxis
sidered as an adjunct therapy as it is a potent pul- and oral mucosal bleeding may be severe enough
monary vasodilator, which can improve right to require transfusion or ENT consult for inter-
heart function and potentially reduce ventilation vention [24]. Prolonged tracheostomy depen-
perfusion mismatch, thereby theoretically dence may result in associated tissue breakdown or
improving oxygenation [12, 17]. Superimposed erosion into surrounding structures, resulting in
bacterial infections, fevers, vasodilatory shock, need for further interventions, such as tracheal
and other physiologic derangements can increase reconstruction. Renal failure is common; 44% of
native cardiac output and, in a patient on VV patients in the ELSO cohort received renal
ECMO, can result in increased circulation of replacement therapy [10]. Persistent pneumotho-
deoxygenated blood as the proportion of total cir- rax attributed to bronchopleural fistula formation
culation running through the ECMO circuit complicates the hospital courses of many ECMO
decreases. Beta-blockers can be used to reduce patients and requires endobronchial blockers,
native cardiac output resulting in increased oxy- lobectomy, and other interventions.
genation [18]. The remainder of management and Pneumothorax, subcutaneous emphysema, and
weaning of ECMO is similar to use in patients other complications of barotrauma have been seen
with other etiologies of organ failure. at higher rates in patients with COVID-19.
Lemmers et al. reported a sevenfold increased rate
of pneumomediastinum/subcutaneous emphy-
Complications sema and attribute it to high transpulmonary pres-
sures. The study includes patients who were
As an invasive treatment strategy with high risk of intubated, but not on ECMO [25]. A study in press
injury at cannulation and throughout the ECMO out of NYULH found 15% of patients with
course, complications are anticipated. Little data COVID-19 suffered a complication attributed to
is available on differing rates of complications barotrauma, pneumothorax occurred in 9%, and
and causes of death for patients with COVID-19 pneumomediastinum occurred in 10%, being the
on ECMO. Complications associated with bleed- most common event. Persistent pneumothorax
ing and clotting are anticipated in ECMO patients, attributed to bronchopleural fistula formation
but COVID-19-associated coagulopathy has complicates the hospital courses of many ECMO
resulted in frequent thromboembolic events. patients and requires endobronchial blockers,
Despite higher doses of anticoagulation, studies lobectomy, and other interventions. Morbidity
have demonstrated higher rates of clot formation associated with these complications should be
while on ECMO. Clotting complications have considered and information provided to patients
driven some centers to target higher anticoagula- and their families as part of an informed consent
tion targets. Schmidt et al. used unfractionated process [26].
heparin with goal-activated partial thromboplastin
time of 60–75 s, or anti-Xa 0.3–0.5 IU/mL [6].
Heparin resistance, which is the failure to achieve Considerations
adequate anticoagulation effects despite the use of
>35,000 units per day of heparin, has increasingly As of January 2021, over 90,000,000 confirmed
been reported in the setting of COVID-19 [19]. cases and 1,900,000 deaths have been reported
Bivalirudin has been used in settings of heparin by the WHO [14]. Overwhelming numbers of
resistance or if heparin-induced thrombocytope- patients infected with COVID-19 are presenting
nia is diagnosed [20]. Bleeding represents a con- in extremis, and resource use and system capac-
trasting concern for many patients on ECMO, ity must be carefully considered when determin-
with significant bleeding associated with proce- ing how to equitably provide care. As we have
70 E. Ball et al.
discussed, ECMO is an extremely resource- support patients suffering cardiac arrest often
intensive strategy, and in the setting of the current referred to as E-CPR. In an effort to allocate
pandemic, its use has been questioned on the resources to those most likely to benefit, tempo-
basis of disproportionate resource allocation to a rary cessation of E-CPR has been recommended
select few with high anticipated morbidity and by ELSO and others as a way to divert efforts in
mortality. ECMO requires investment of special- this unprecedented time of limited resources [8,
ized equipment, ECMO technicians, qualified 10]. ELSO strongly recommends against creation
nurses, ancillary service providers, palliative care of new ECMO centers. Capacity should not be
practitioners, and intensivist, who will spend a expanded to new sites but resources and expertise
large proportion of their available time caring for maintained in specialized centers in order to
ECMO patients. The ethics of using ECMO at all maximize quality [8]. Once a system reaches cri-
in the treatment of COVID-19 has been called sis capacity, ECMO will no longer be feasible for
into question. ELSO strongly recommends both COVID-19 and non-COVID-19 patients,
against creation of new ECMO centers. Capacity and all futile care should be minimized [8].
should not be expanded to new sites but resources Although resource utilization should be exam-
and expertise maintained in specialized centers in ined in the context of medical utility and progno-
order to maximize quality. Adaptation of mobile sis, as discussed, it is extremely challenging to
units for assistance with cannulation and patient accurately assess prognosis as robust COVID-19
transfer may be necessary [8]. A method of data is lacking. Only recently has outcome data
patient retrieval used in Paris has been described on COVID-19 patients become available to aid
by Schmidt et al. If patients are unable to be can- in prognostication, both for selection of patients
nulated outside of an ECMO center, it is reason- and survival once cannulated. Imamura proposed
able to develop a referral system for young, a creation of a scoring system for use once
previously healthy patients with single organ patients are on ECMO to assist clinicians with
involvement in anticipation of possible need for prognostication [18]. Discussions about expecta-
ECMO [6]. tions for recovery should be discussed prior to
ECMO timeframes can be considerable and cannulation as part of the consent process, and
should be expected to continue for several re-addressed frequently with consideration of
weeks. Barbaro et al. reported mean ECMO run early involvement of palliative care. The estab-
durations of 13.9 days for patients included from lishment of expectations has become increas-
the ELSO database, which is comparable to the ingly more complicated by the media, which has
duration reported by Combes et al. in EOLIA, portrayed the use of ECMO for COVID-19 with
mean 14 days [4, 10]. Other sources have cited biased focus on patients that experienced favor-
average runs of 20 days and 29 days, and our able outcomes. A review of 605 news reports
experience has been that patients require longer from 31 countries found a reported survival at
duration of ECMO for COVID-19 than with 92.2%, and 88% of patients reported no disabil-
other etiologies of respiratory failure, upward of ity. This information potentially biases the expec-
60 days, several have been referred for lung tations of patients, families, and potentially
transplantation [6, 27]. medical providers [28].
In the setting of long timeframes and varying
numbers of COVID-19 cases, the draw on avail-
able resources may be at the detriment of the care Conclusion
of other patients; therefore, thoughtful consider-
ation must be given toward the decision to initiate Although ECMO may provide hope to patients
ECMO, and as such, ELSO recommends the use on the verge of death, there are many consider-
of ECMO only in circumstances in which sys- ations that must be weighed prior to pursuing
tems are not overwhelmed. Prior to the COVID-19 deployment. Among these considerations it is
pandemic, ECMO was being increasingly used to important to keep in mind that ECMO is used to
support respiratory and cardiac function while 8. Shekar K, Badulak J, Peek G, Boeken U, Dalton
HJ, Arora L, et al. Extracorporeal Life Support
allowing for the treatment of underlying disease Organization Coronavirus Disease 2019 interim guide-
processes. ECMO does not directly ameliorate lines: a consensus document from an International
illness, but instead affords time to allow other Group of Interdisciplinary Extracorporeal Membrane
treatment modalities to take effect. ECMO Oxygenation Providers. ASAIO J. 2020;66(7):707–21.
9. Extracorporeal Life Support Organization –
therefore should be a consideration when the
ECMO and ECLS > Registry > Full COVID-19
totality of a patient’s clinical setting to include Registry Dashboard [Internet]. [cited 2020 Sep 12].
resources and expected and inherent morbidity Available from: https://www.elso.org/Registry/
and mortality have been weighed. Local practices FullCOVID19RegistryDashboard.aspx.
10. Barbaro RP, MacLaren G, Boonstra PS, Iwashyna
may vary, and as such, providers in the commu- TJ, Slutsky AS, Fan E, et al. Extracorporeal mem-
nity should contact regional ECMO centers to brane oxygenation support in COVID-19: an
discuss referral for ECMO and refer to guidelines international cohort study of the Extracorporeal
provided by ELSO and other organizations as Life Support Organization registry. Lancet.
2020;396(10257):1071–8.
they continue to evolve. 11. Shao F, Xu S, Ma X, Xu Z, Lyu J, Ng M, et al.
In-hospital cardiac arrest outcomes among patients
with COVID-19 pneumonia in Wuhan, China.
References Resuscitation. 2020;151:18–23.
12. Ferrari M, Santini A, Protti A, Andreis DT, Iapichino
G, Castellani G, et al. Inhaled nitric oxide in mechani-
1. Brogan TV. Extracorporeal Life Support
cally ventilated patients with COVID-19. J Crit Care.
Organization – Extracorporeal Life Support: the
2020;60:159–60.
ELSO red book 5th edition [Internet]. 5th ed. Ann
13. Kandori K, Narumiya H, Iizuka R. Extracorporeal
Arbor: Extracorporeal Life Support Organization;
cardiopulmonary resuscitation should not be per-
2017. [cited 2020 Nov 14]. Available from: https://
formed on confirmed or suspected COVID-19
www.elso.org/Publications/RedBook5thEdition.
patients. Resuscitation. 2020;153:6–7.
aspx.
14. Coronavirus disease (COVID-19) – World Health

2. Sangalli F, Patroniti N, Pesenti A, editors. ECMO-
Organization [Internet]. [cited 2020 Sep 6]. Available
Extracorporeal Life Support in adults [Internet].
from: https://www.who.int/emergencies/diseases/
Mailand: Springer-Verlag; 2014. [cited 2021 Feb
novel-coronavirus-2019.
27]. Available from: https://www.springer.com/gp/
15. Hanidziar D, Bittner EA. Sedation of mechanically
book/9788847054264.
ventilated COVID-19 patients: challenges and special
3. Peek GJ, Mugford M, Tiruvoipati R, Wilson A,
considerations. Anesth Analg [Internet]. 2020; [cited
Allen E, Thalanany MM, et al. Efficacy and eco-
2021 Feb 27]; Available from: https://www.ncbi.nlm.
nomic assessment of conventional ventilatory sup-
nih.gov/pmc/articles/PMC7179055/.
port versus extracorporeal membrane oxygenation
16. Garcia B, Cousin N, Bourel C, Jourdain M, Poissy J,
for severe adult respiratory failure (CESAR): a
Duburcq T, et al. Prone positioning under VV-ECMO
multicentre randomised controlled trial. Lancet.
in SARS-CoV-2-induced acute respiratory distress
2009;374(9698):1351–63.
syndrome. Crit Care. 2020;24(1):428.
4. Combes A, Hajage D, Capellier G, Demoule A,
17. Alvarez RA, Berra L, Gladwin MT. Home nitric oxide
Lavoué S, Guervilly C, et al. Extracorporeal mem-
therapy for COVID-19. Am J Respir Crit Care Med.
brane oxygenation for severe acute respiratory distress
2020;202(1):16–20.
syndrome. N Engl J Med. 2018;378(21):1965–75.
18. Imamura T, Nikhil N. Optimal therapeutic strat-

5. Sanford Z, Madathil RJ, Deatrick KB, Tabatabai
egy using extracorporeal membrane oxygen-
A, Menaker J, Galvagno SM, et al. Extracorporeal
ation in patients with COVID-19. J Card Surg.
membrane oxygenation for COVID-19. Innovations.
2020;35(10):2872–3.
2020;15(4):306–13.
19. White D, MacDonald S, Bull T, Hayman M, de

6. Schmidt M, Hajage D, Lebreton G, Monsel A, Voiriot
Monteverde-Robb R, Sapsford D, et al. Heparin resis-
G, Levy D, et al. Extracorporeal membrane oxygen-
tance in COVID-19 patients in the intensive care unit.
ation for severe acute respiratory distress syndrome
J Thromb Thrombolysis. 2020;50(2):287–91.
associated with COVID-19: a retrospective cohort
20. Seelhammer TG, Rowse P, Yalamuri S. Bivalirudin
study. Lancet Respir Med. 2020;8(11):1121–31.
for maintenance anticoagulation during venovenous
7. Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong
extracorporeal membrane oxygenation for COVID-19.
MN, Fan E, et al. Surviving Sepsis Campaign: guide-
J Cardiothorac Vasc Anesth. 2021;35(4):1149–53.
lines on the management of critically ill adults with
21. Usman AA, Han J, Acker A, Olia SE, Bermudez

Coronavirus Disease 2019 (COVID-19). Intensive
C, Cucchiara B, et al. A case series of devastating
Care Med. 2020;28:1–34.
intracranial hemorrhage during venovenous extra-
AL GRAWANY
72 E. Ball et al.
corporeal membrane oxygenation for COVID-19. J subcutaneous emphysema in COVID-19: barotrauma

Cardiothorac Vasc Anesth. 2020;34(11):3006–12. or lung frailty? ERJ Open Res [Internet]. 2020 [cited
22. Masur J, Freeman CW, Mohan S. A double-edged 2021 Feb 27];6(4). Available from: https://openres.
sword: neurologic complications and mortality in ersjournals.com/content/6/4/00385-2020.
extracorporeal membrane oxygenation therapy for 26. McGuinness G, Zhan C, Rosenberg N, Azour L,

COVID-19–related severe acute respiratory distress Wickstrom M, Mason DM, et al. High incidence of
syndrome at a tertiary care center. Am J Neuroradiol. barotrauma in patients with COVID-19 infection on
2020;41(11):2009–11. invasive mechanical ventilation. Radiology [Internet].
23. Heman-Ackah SM, Su YS, Spadola M, Petrov D, 2020 [cited 2021 Feb 27]; Available from: https://
Chen HI, Schuster J, et al. Neurologically devastating www.ncbi.nlm.nih.gov/pmc/articles/PMC7336751/.
intraparenchymal hemorrhage in COVID-19 patients 27. Mustafa AK, Alexander PJ, Joshi DJ, Tabachnick DR,
on extracorporeal membrane oxygenation: a case Cross CA, Pappas PS, et al. Extracorporeal membrane
series. Neurosurgery. 2020;87(2):E147–51. oxygenation for patients with COVID-19 in severe
24. LoSavio PS, Patel T, Urban MJ, Tajudeen B,
respiratory failure. JAMA Surg. 2020;155(10):990.
Papagiannopoulos P, Revenaugh PC, et al. 28. Fernando SM, Mathew R, Slutsky AS, Rochwerg B,
Management of upper airway bleeding in COVID-19 Kyeremanteng K, Combes A, et al. Media portrayals
patients on extracorporeal membrane oxygenation. of outcomes after extracorporeal membrane oxygen-
Laryngoscope. 2020;130(11):2558–60. ation. JAMA Intern Med [Internet]. 2021; [cited 2021
25. Lemmers DHL, Hilal MA, Bnà C, Prezioso C,
Jan 13]; Available from: https://jamanetwork.com/
Cavallo E, Nencini N, et al. Pneumomediastinum and journals/jamainternalmedicine/fullarticle/2774726.
COVID-19: Cardiac Arrest
Management
8
Casey T. Carr and Torben K. Becker
Prehospital Considerations We will note that this literature is found in criti-

cally ill patients with known COVID-19 respira-
Sudden cardiac arrest remains a leading cause of tory failure and associated acute respiratory
death in the United States and world [1]. During distress syndrome (ARDS), where almost all
the initial wave of SARS-CoV-2 (COVID-19), in deaths were due to respiratory causes – which
which public life restrictions were implemented, may not be the case in patients with COVID-19
out-of-hospital cardiac arrest (OHCA) cases who suffer OHCA. COVID-19 has been shown to
rose – in some counties and municipalities, the cause acute cardiovascular pathology, and we
rate of OHCA doubled [2–4]. In one US retro- simply do not know yet how this influences rate
spective emergency medical system descriptive of cardiac arrest and prognosis [7, 8].
review, pandemic era OHCA was 2.2-fold greater This poor survivability combined with a high
than historic control – and this excess OHCA was healthcare worker infectivity rate raises impor-
greater than the number of patients who died with tant ethical and policy questions. Healthcare
a COVID-19 diagnosis [4]. In the midst of the workers faced a 12-fold increase in COVID-19
early COVID-19 pandemic, the prevalence of infections [9] and high infection-related mortal-
SARS-CoV-2 positivity was high – ranging ity [10]. While wearing personal protective
between 5% and 10% [5]. This early literature equipment (PPE) decreases the likelihood of
points towards an increasing burden of cardiac healthcare worker infection [9], it does not elimi-
arrest during COVID-19 surges and may even nate that risk. Chest compressions are considered
suggest the rise in OHCA may outweigh the aerosol generating, and possibly defibrillation as
impact of COVID-19 infection itself. well – though the evidence on this topic is poor
While survival from cardiac arrest continues [11]. The highest documented infectivity rate
to have significant variability, patients with from performing chest compressions on a
severe COVID-19 infections have very poor out- coronavirus- infected patient is 33% (threefold
comes. While most literature is based on inpa- increase compared to baseline infection rate) [12]
tient data, survival with acceptable neurologic though rates in alternative studies are much lower
outcome has been recorded as low as <1% [6]. [11].
An additional component to consider is that
C. T. Carr · T. K. Becker (*) the donning of PPE by rescuers reduces
Division of Critical Care Medicine, Department of response time to patients with cardiac arrest
Emergency Medicine, University of Florida – Health, [11] and reduces bystander response rate [2] by
Gainesville, FL, USA
a significant margin. PPE has been shown to be

74 C. T. Carr and T. K. Becker
less effective when performing chest compres- created a policy that stopped any transport of
sions, likely due to movement of the rescuer’s patients in persistent OHCA (NYC REMAC
facemask [11]. Policy 2020-8). Additional international poli-
Various professional societies have released cies have varied – in some instances utilizing
guidelines outlining the care of patients with cardiac arrest prognostic features, like type of
cardiac arrest and suspected COVID-19 infec- rhythm, as a decision point to determine when
tions [13, 14]. These guidelines recognize the to perform cardiopulmonary resuscitation
challenges of providing care during a coronavi- (CPR) [15]. Other advocates have attempted to
rus outbreak, quantify the risk to healthcare calculate the overall public health risk of pre-
workers, and revise arrest management recom- hospital OHCA management – their “back of
mendations. The American Heart Association the envelope” math would suggest a mortality
Advance Life Support modified recommenda- rate of 1 rescuer for every 10,000 CPR events
tions as it pertains to prehospital care are sum- [5]. However, this logic may be flawed. If we
marized below [13]: suppose that the healthcare worker infection
risk of performing CPR is 10% – though in fact
1. Don PPE prior to patient contact. it may be higher – for every 100 CPR events,
2. Consult local EMS system regarding recom- one rescuer will be infected. While the cumula-
mended PPE standards. tive mortality of COVID-19 is low, the hospi-
3. Limit to three personnel on scene. talization rate and ICU admission rate are
4. Replace manual chest compressions with relatively high: 20% and 5%, respectively [16].
mechanical chest compressions, when Additionally, likely due to the large viral inoc-
available. ulum associated with severe respiratory fail-
5. Attach high-efficiency particulate air (HEPA) ure, the mortality of healthcare workers who
filter to all ventilation devices. are infected during airway manipulation is
6. Intubate at the earliest opportunity. higher than the general population [17]. This
7. During intubation, use video laryngoscopy, would mean frontline healthcare workers
when available. would be exposed to a significant risk of hospi-
8. During intubation attempt, pause chest talization and ICU admission – which is not a
compressions. risk to be taken lightly. At a time when resource
9. Establish local policies for guidance regard- management is being challenged, this loss of
ing termination of cardiac arrest care by healthcare workers and addition of infectious
frontline providers. load need to be carefully weighed and mea-
10. Layperson bystanders are encouraged to per- sured. Patients who suffer cardiac arrest who
form hands-only chest compressions with a survive to hospital admission may also occupy
face covering over the patient’s mouth – hospital beds at a time of hospital bed scar-
especially if the bystander is in the patient’s city – and this bed requirement may be lengthy
household. despite relatively poor neurologic outcomes.
By limiting rescue efforts to only patients
With the high infectivity of COVID-19, and whose cardiac arrest was witnessed by EMS
uncertainty of the prevalence of the virus in personnel or first rhythm is shockable, one ret-
communities, consistent EMS policies regard- rospective study showed an additional 12,000
ing cardiac arrest are critical. The balance beds would be made available nationally –
between protecting prehospital providers and though 2000 patients would die from OHCA
optimally treating cardiac arrest is a difficult that would otherwise be saved [18]. A sum-
one – New York City ignited significant con- mary of our recommendations can be found in
troversy when their regional EMS committee Table 8.1.
8 COVID-19: Cardiac Arrest Management 75
Table 8.1 Recommendations for prehospital cardiac arrest care in areas of high COVID-19 positivity rate
Personal All prehospital providers should wear personal protective equipment (PPE) during all patient
protective encounters
equipment Mask: N95 (or greater particle filtration capability) that is a foldable type mask. All masks
should be fit tested prior to use
Filter: For all ventilation maneuvers, high-efficiency particulate air (HEPA) filters should be
used in line with the bag valve mask system
Additional: Hair covering and eye covering should be used on all patient encounters, regardless
of complaint
Decision to For all patients with out-of-hospital cardiac arrest (OHCA) during high community COVID-19
initiate/ prevalence, we recommend:
discontinue 1 initial cycle of CPR, regardless of age, comorbidity, or type of cardiac arrest
CPR For patients who are greater than age 80 with a non-shockable rhythm [19–21]:
1 additional cycle of CPR (total of 2 cycles)
Ventilation with bag valve mask
No intubation attempt
No transportation if ongoing resuscitation is required
For patients who are less than age 80 with a non-shockable rhythm:
2 additional cycles of CPR (total of 3 cycles)
Intubation after first cycle
Additional resuscitation to be guided by local policy and discussion with medical command
For patients who have a shockable rhythm:
Defibrillation as indicated
Intubation after first cycle
Transport patient with facial covering if ongoing resuscitation required
Airway Early intubation should be attempted in patients where invasive ventilation is recommended. We
management recommend after the first cycle of CPR
and ventilation All ventilation, whether invasive or noninvasive, should be performed with in-line HEPA filter.
When transporting patients, facial covering should be used to reduce spread of infected aerosols
Laryngoscopy should be performed with a video-assisted laryngoscope, if available
We recommend against initial rescue ventilation
For patients who require sedation and paralysis for intubation, we recommend rapid sequence
intubation (RSI) without ventilation prior to laryngoscopy
Chest For patient who require transportation for on-going resuscitation, we recommend mechanical
compressions chest compressions, if available.
Bystander CPR For bystander CPR during high community COVID-19 prevalence, we recommend:
For bystanders who are relatives or live in close proximity to patient:
Chest compressions and ventilation in 30:2 ratio
Application of AED, if available
Cover patient’s face with cloth or mask
For bystanders who are not relatives of patient:
Chest compressions without ventilation
Cover patient’s face with cloth or mask
For bystanders who are not relatives of patient and who themselves are immunosuppressed:
No chest compressions or ventilation
Miscellaneous For patients with ongoing CPR, we recommend allowing family presence during resuscitation,
with the additional recommendation that on-scene relatives self-quarantine for 2 weeks [22]
Intra-arrest Management aerosols generated during chest compressions

and defibrillation, and poor data to support either
ersonal Protective Equipment
P conclusion, the fact that healthcare workers
and Filtration Use remain a vulnerable population is of utmost
importance. In one randomized crossover trial,
While there is discordance among government different N95 mask types were measured against
bodies and professional societies regarding the each other during chest compressions, with the
primary outcome being adequate protection rate severe hypoxia – a common etiology in patients
[23]. The foldable subtype of N95 had the highest with severe COVID-19 [30]. When performing
adequate protection rate, as compared to the cup bag valve mask ventilation (BVM), we recom-
and valve type. Notably, all N95 types had a mend a two-person technique, in order to allow
lower adequate protection rate during chest com- one rescuer to create a mask seal with two hands.
pressions, regardless of type. While N95 masks We recommend intubation as early as possible as
provide better protection in laboratory condi- true rapid sequence intubation with BVM use.
tions, controversy exists whether N95 respirators We recommend continuing chest compressions
are more effective at reducing respiratory viral during the intubation attempt. While this may
infection than standard surgical masks in usual increase aerosols, the interruption in chest com-
clinical practice where best PPE practices may pression fraction may lead to a decrease in the
not always be feasible or followed [24, 25]. chance of return of spontaneous circulation
Transmission of COVID-19 is predominantly (ROSC). If available, video laryngoscopy should
thought to be due to respiratory droplets, yet con- be used as the primary method for intubation [31,
tact transmission can occur via skin or mucous 32]. While robust data for this does not exist,
membranes. Therefore all clinicians caring for secretion contamination is less likely when using
patients in cardiac arrest in communities with video laryngoscopy over direct intubation, and
high COVID-19 prevalence should wear imper- guidelines support this practice [33]. Single-use
meable gowns, gloves, eye wear, and hair cover- blades for laryngoscopy should also be used, to
ing – in accordance with CDC and WHO reduce clinician-to-clinician transmission. The
guidelines [26, 27]. most experienced airway operator should per-
High-efficiency particulate air (HEPA) filters form the intubation, and additional personnel
are critical for use in areas of high COVID-19 presence should be minimized. Contrary to con-
prevalence. While the Center for Disease Control temporary cardiac arrest management, we rec-
(CDC) recommends isolating COVID-19-ommend pausing chest compressions during
infected patients in single negative pressure laryngoscopy.
rooms, this is simply not sustainable from the We recommend early intubation. This serves
perspective of undifferentiated cardiac arrest dual purposes: having a closed circuit for posi-
resuscitation. A recent assessment of acute care tive pressure ventilation reduces aerosolization
hospitals in the United States showed that only when compared to noninvasive positive pres-
6% of hospital beds met criteria for isolation beds sure, lowering infection risk to rescuers as well
[28]. To qualify as HEPA grade, the filters must as providing a direct intervention for patients
remove at least 99% of particles that are 0.15–0.2 who are prone to hypoxemic cardiac arrest.
micrometers [29]. Therefore, during aerosol- During ongoing cardiac arrest management,
generating procedures such as positive pressure FiO2 should be 1.0.
ventilation, intubation, bronchoscopy, or chest A large number of barrier practices during
compression, in-line HEPA filters should be used aerosol-generating procedures have become
during bag valve mask ventilation and ventilation widespread – such as rigid plastic boxes or plas-
of the intubated patients. tic sheet coverings. There is very little to no lit-
erature to support this practice [34] – it may or
may not reduce viral transmission, but it also may
Airway Management reduce successful intubation and increase the
likelihood of having to utilize rescue noninvasive
Contrary to prior intra-arrest airway management ventilation and thus increase risk of aerosoliza-
principles, intubation should occur early in in- tion. One simulation-based study showed that
hospital resuscitation. This primarily serves as a barrier practices may disrupt or damage PPE
method to reduce aerosolization during bag valve [35]. We do not recommend patient barrier utili-
mask ventilation, but additionally may address zation during airway procedures.
There is significant heterogeneity among soci- diac arrest in a COVID-19-positive patient is

eties regarding supraglottic airway (SGA) use unclear. It has been demonstrated that patients
recommendations – though some groups are with COVID-19 infection are at high risk for
using SGA with HEPA filters as first line for car- thromboembolic disease [41]. Empiric sys-
diac arrest airway management [36]. This is not temic thrombolysis has not shown clear benefit
without risk, as incompetent seal of a SGA will in contemporary cardiac arrest management
create risk for aerosolization, much more so than [46] though whether this applies to patients
tracheal intubation [37]. In the in-hospital setting with COVID-19 infections is unclear, espe-
with an experienced intubator performing the cially in light of their high rate of thrombosis.
procedure, we recommend use of SGA as a res- If point-of- care echocardiography suggests
cue intervention only if endotracheal intubation right heart strain or failure, and there is a high
is unsuccessful, rather than continued facemask suspicion for COVID-19 infection, it may be
ventilation and repeated attempts at laryngos- reasonable to administer systemic thromboly-
copy. When using SGA, we recommend second- sis in patients with refractory cardiac arrest.
generation devices that promote occlusive sealing For reasons likely related to worsening lung
and recommend SGA devices that allow for sec- compliance, patients with COVID-19 seem to be
ondary bronchoscopic intubation [31, 38, 39]. more prone to developing pneumothorax –
While performing ventilation with SGA, we rec- though the data for this is limited, and specific to
ommend in-line HEPA filter and prioritizing ven- patients with a known diagnosis of COVID-19 in
tilation with low tidal volumes and low airway the inpatient setting who are frequently on
pressures to reduce the risk of SGA dislodgement mechanical ventilation [43]. Therefore, it is an
and generation of aerosols [37]. important consideration during the management
of refractory cardiac arrest, and this diagnosis
must be considered in all patients with
Etiologies of Cardiac Arrest COVID-19.
Lastly, another important consideration is
Contemporary management of cardiac arrest the possibility of drug-induced cardiac arrhyth-
includes the consideration of the cause of the mia and death. This is of important concern,
arrest, along with targeted interventions, often given the rapidly changing and emerging novel
taught as the “H’s and T’s.” This philosophy and medications used in patients with COVID-19.
practice is no different during periods of high Arrhythmia remains an important cardiac toxic-
COVID-19 prevalence. However, there are several ity associated with the drugs used in the treat-
factors to consider when evaluating patients with ment of COVID, likely both as a result of the
COVID-19 infections who are in cardiac arrest. medication itself and the increased incidence of
While data continues to accumulate regarding arrhythmias in infected patients [47]. In patients
arrest etiology, observational and retrospective with COVID-19, the disease may produce cor
trial data suggest that COVID-19 infection pulmonale, heart failure, myocarditis, and
increases the rate of hypoxemic cardiac arrest [6, hypokalemia from gastrointestinal loss – all of
40], thrombosis [41], arrythmia [42], and pneumo- which propagate malignant arrhythmia.
thorax [43]. There additionally are case reports of Additionally, infected patients were shown to
COVID-19 also resulting in cardiac tamponade – have a prolonged QTc, regardless of drug usage
likely a sequela of myocarditis [44] – and evidence or electrolyte state, thought to be secondary to
that up to 20% of patients with severe COVID-19 the intense inflammatory state these patients
have myocardial dysfunction [45]. reside in [48]. Both hydroxychloroquine and
The appropriate management of suspected azithromycin are arrhythmogenic and addition-
acute cardiac or pulmonary thrombosis in car- ally prolong the QTc.
Duration of Resuscitation continue chest compressions if able to do so

safely [13]. Hand positioning should be between
In-hospital data for the survivability of patients in the angles of the scapula. These data reflect
with severe COVID-19 infections after cardiac almost entirely patients who are receiving sur-
arrest is dismal – in one retrospective study, only gery in the prone position and therefore already
50% achieved ROSC, and 100% died [49]. What have an advanced airway and advanced monitor-
one must consider, however, is that these were ing placed. We recommend initiating chest com-
severely ill patients who almost all had refractory pressions in the prone position and, upon first
hypoxemia and shock as a cause of their cardiac available opportunity, to roll the patient into the
arrest – 90% had PEA as their initial rhythm. supine position.
Accordingly, one cannot entirely extrapolate this An interesting area of potential exposure
data to all cardiac arrests during COVID-19 out- reduction is the use of mechanical CPR. Replacing
breaks. What could be inferred, however, is that a rescuer who would otherwise be performing
various cardiac arrest features can predict likeli- chest compressions with a mechanical device
hood of survival, with a high accuracy [21]. would potentially reduce occupational exposure.
During COVID-19 surges, when healthcare This recommendation is in line with interim
workers are both vulnerable and essential, we guidelines put forth by the American Heart
recommend implementing decision rules for ter- Association [13]. In some institutions, this may
mination of resuscitative efforts. While this require the investment in purchasing a mechani-
should be decided on at the local and institutional cal CPR device and training on its use. Literature
level, we level ending resuscitation if the cardiac comparing manual versus mechanical chest com-
arrest is unwitnessed and non-shockable and the pressions is overall equivocal and fraught with
patient’s age is greater than 80. We additionally challenges to interpretation. Our recommenda-
recommend the use of cardiac ultrasound to tion is to transition to mechanical chest compres-
determine the presence of cardiac activity, with sions as soon as possible during cardiac arrest
the consideration of early resuscitation cessation resuscitation. We recommend institutions and
if there is a non-shockable rhythm and no cardiac municipalities invest in these devices and train
activity [50]. personnel accordingly.
A summary of our recommendations can be
found in Table 8.2.
Special Considerations
While obviously less common, patients may suf- Post-Cardiac Arrest Management
fer cardiac arrest while in the prone position.
Prone positioning is a cornerstone of manage- Airway Management
ment of acute respiratory distress syndrome
(ARDS), a common sequela of severe COVID-19 In patients who have achieved ROSC after car-
infection. There is essentially no data on per- diac arrest who do not have a definitive advanced
forming CPR in the prone position, and how airway, we recommend early intubation in
likely this is to occur in the COVID-19 popula- patients with poor mentation, evidence of hypox-
tion. Various simulation-based studies, cadaver emia, and inadequate ventilation. It is likely that
studies, and case reports have noted that circula- the majority of these patients will already have
tory support may be adequate when chest com- been orotracheally intubated. In the event that
pression is given to the thoracic spine on a hard patients achieve ROSC without an advanced air-
surface [51, 52] – however no guidelines have way, having a low threshold for intubation is
commented on recommendations in the past appropriate. Specifically, in patients who are
10 years, though interim guidelines recommend infected with COVID-19, timing of intubation is
changing the patient to the supine position to controversial [53] and ultimately lies in the judg-
Table 8.2 Recommendations for intra-arrest cardiac arrest care in areas of high COVID-19 positivity rate
Personal protectiveAll staff providing care for patients in cardiac arrest should wear personal protective
equipment equipment (PPE) during all patient encounters, prior to initiating care for patients
Mask: N95 (or greater particle filtration capability) that is a foldable type mask. All masks
should be fit tested prior to use
Filter: For all ventilation maneuvers, high-efficiency particulate air (HEPA) filters should be
used in line with the bag valve mask system
Additional: Hair covering and eye covering should be used on all patient encounters,
regardless of complaint
Duration of CPR For all patients with cardiac arrest (OHCA) with high community COVID-19 prevalence, we
recommend:
For patients who are greater than age 80 with an unwitnessed cardiac arrest and a
non-shockable rhythm [19–21]:
Cessation of CPR
No intubation attempts
For patients who are less than age 80 and/or with a non-shockable rhythm:
Utilization of cardiac ultrasound to identify potentially reversible causes and presence of
meaningful cardiac motion for detection of ROSC
Airway management Orotracheal intubation should be performed immediately
and ventilation Chest compressions should be paused during the intubation attempt
All ventilation, whether invasive or noninvasive, should be performed with in-line HEPA filter
If initial intubation attempt is not successful, a second-generation supraglottic airway should
be placed
Laryngoscopy should be performed with a video-assisted laryngoscope
Chest compressions Transition to mechanical chest compressions as soon as possible
If the patient is in the prone position: Begin chest compressions immediately by placing
hands between the inferior scapula. Ensure a hard surface is under the patient. When timing
and resources allow, transition to the supine position
Additional Consider pneumothorax early, and strongly consider empiric chest tube placement in patients
considerations with persistent pulseless electrical activity
Utilize cardiac ultrasound to identify presence of right ventricular pathology. If present, and
cardiac arrest is refractory, strongly consider empiric systemic thrombolysis
If a patient is being prescribed COVID-19-directed treatment, empirically administer
magnesium. Test for hypokalemia early in the arrest stage
Miscellaneous For patients with ongoing CPR, we recommend allowing family presence during
resuscitation, with the additional recommendation that these relatives must preferably wear a
N95 mask and eye protection, but a surgical mask at a minimum, and remain outside the
immediate vicinity of the patient while CPR is in progress; relatives should then self-
quarantine for 2 weeks [22]
ment of the clinician. During the early period of mate concern regarding whether this method
the COVID-19 pandemic, early mechanical ven- could create aerosols [55], the failure to pre-
tilation was advocated; that philosophy has been oxygenate will increase the likelihood of requir-
challenged however [53]. Early intubation in the ing rescue maneuvers, such as facemask
post-cardiac arrest state however can prove use- ventilation with bag valve mask, which would
ful: for facilitation of testing, protection against almost certainly create more aerosolization. We
rapid decline of airway reflexes, and strict venti- recommend apneic oxygenation for the same rea-
lation control, among other reasons. For intuba- son, by utilizing simple nasal cannula at 15 L/
tion, we recommend rapid sequence intubation. min. Bag valve mask ventilation should be
Pre-oxygenation should be performed with avoided if possible, unless critical hypoxemia
non-
rebreather with concurrent nasal cannula; develops. Intubation must be performed by an
non-rebreather should be at flush rate and nasal experienced intubator to maximize first-pass suc-
cannula at 15 L/min [54]. While there is legiti- cess and reduce the risk of desaturation requiring
rescue bagging. Once intubated, ventilation to reduce ventilator-induced lung injury. We rec-
should only be performed with in-line HEPA fil- ommend an initial 6 ml/kg tidal volume, in line
ter. When transitioning the patient to the ventila- with current ARDS guidelines. Lower tidal vol-
tor, or during any manipulation that requires umes – as low as 4 ml/kg – may be necessary in
breaking the closed circuit system, the endotra- order to meet the goal of plateau pressure less
cheal tube should be clamped. All airway opera- than 30 cm H2O. The optimal target PaCO2 in
tors should be in full airborne personal protective the post-cardiac arrest setting is still controver-
equipment – eye and hair protection, sial – with physiological considerations and clin-
non-permeable gown, and N95 mask (or greater ical biomarker studies suggesting that targeting a
filtration-capable respirator). slightly higher PaCO2 may be beneficial [60].
While there is no randomized clinical data, nor
any true patient-oriented outcome data, there
Ventilator Management seems to be a consistent signal in neurologic bio-
marker studies, as well as biologic plausibility,
In the post-cardiac arrest setting, a careful bal- that targeting a high-normal to slightly elevated
ance between hyperoxia and hypoxia must be PaCO2 improves neurologic outcome. We there-
struck. While it is critical to avoid hypoxia, expo- fore recommend targeting a PaCO2 of 40–45 mm
sure to hyperoxia can also be associated with Hg in patients after cardiac arrest who are
worse neurologic outcomes [56] – even early in mechanically ventilated.
the clinical course of the patient. However, in
patients with ARDS, recent literature suggests
improved outcomes with increased oxygenation Hemodynamics
[57] – beyond typical oxygenation goals as
defined by standard ARDSnet protocol [45]. Both patients after cardiac arrest and patients
What additionally complicates ventilator man- with severe COVID-19 infection are at high risk
agement is the theory that subtypes of COVID-19 for progression to multiple organ dysfunction
exist – with significantly differing lung compli- and significant hemodynamic perturbance. Data
ance [58] being the defining characteristic has emerged that positive fluid balance seems to
between phenotypes. While this phenotype con- be particularly harmful during the ICU course of
cept is not without controversy [59], contempo- patients with severe COVID-19 infection – which
rary ventilator management may not be is consistent with emerging data in patients with
sufficiently personalized in the era of COVID-19. ARDS and early sepsis [61, 62]. We therefore
Therefore, in post-cardiac arrest patients who recommend a conservative fluid strategy [32],
have either confirmed COVID-19 or high clinical using dynamic tests for fluid responsiveness,
probability, we recommend a target SpO2 of such as transthoracic echocardiography or pas-
>96% and a PaO2 between 90 and 105, with sive leg raise, as guidance for additional fluid
rapid decrease in FiO2 for sustained SpO2 >99%. resuscitation. Optimal mean arterial blood pres-
We recommend utilizing a high PEEP strategy sure goals remain a debate in the post-cardiac
[32] to obtain these goals, in order to reduce arrest setting. Prior retrospective studies have
exposure to hyperoxygenation and promote alve- shown a benefit targeting a higher MAP (>75 mm
olar recruitment. Hg) [63, 64] while randomized clinical trials
have not corroborated this finding, though these
trials were not powered to detect meaningful
Ventilation Goals patient-oriented outcomes [65, 66]. Given the
equivocal nature of these findings, and with prior
Patients with COVID-19 have a high incidence of data showing the neurologic vulnerability in the
ARDS, as do patients who have suffered cardiac immediate post-cardiac arrest period, we recom-
arrest. Lung protective ventilation is therefore mend targeting a MAP of 80 mm Hg. We addi-
critical in the post-cardiac arrest setting, in order tionally recommend utilizing norepinephrine
with a conservative fluid strategy to achieve this to empiric antibiotics in the post-cardiac arrest
hemodynamic goal. However, this approach setting, though the significance and magnitude of
should obviously be tailored to the individual these benefits are questionable [68]. We recom-
patient, who may need additional fluid adminis- mend a low threshold for the use of empiric
tration or an alternative vasoactive agent. This broad-spectrum antibiotics, with narrowing or
includes balancing the desire to achieve a higher discontinuation guided by both infectious bio-
than usual MAP goal with the potential detrimen- markers and radiographic and culture data.
tal effects of high-dose vasopressor therapy. At a Thrombotic risk is great in patients with
minimum, clinicians should make it a priority to COVID-19 [69]. This is important to note, since
avoid hypotension (MAP <65 mm Hg) for post- this guides the search for the etiology of arrest,
cardiac arrest patients to minimize secondary but clinicians should also consider empiric thera-
brain injury from hypoperfusion. peutic anticoagulation in severe COVID-19 dis-
ease – in fact, many patients with COVID-19 will
develop venous thromboembolic disease despite
Neurologic Prognosis prophylactic anticoagulation. One must weigh
this risk against the risk of occult but clinically
Patients with severe COVID-19 infection who significant bleeding. In patients after cardiac
have suffered an inpatient cardiac arrest have a arrest management, chest compression-related
dismal survival rate – the current data suggests trauma is not uncommon, and intracranial hemor-
that few if not none will survive to hospital dis- rhage can present initially with cardiac arrest as
charge. However, these patients almost entirely well. We therefore recommend liberal use of
have hypoxic etiologies or relentlessly progres- imaging in the post-cardiac arrest state, and if
sive circulatory collapse, which is likely much there is no evidence of significant trauma or
different than patients who suffer out-of-hospital bleeding, we recommend empiric therapeutic
cardiac arrest. The etiology and survivability of anticoagulation in patients with confirmed and
out-of-hospital cardiac arrest in COVID-19 “hot severe COVID-19 disease.
spots” remain to be elucidated, though early, ret- Many experimental interventions have
rospective data suggests a much lower ROSC rate emerged as possible treatment for COVID-19,
when compared to non-pandemic time periods in with the evidence supporting them often being
similar locations. Therefore, despite inpatient controversial, complex, and evolving. Of specific
arrest data suggesting a universally poor neuro- note are therapies targeting the SARS-CoV-2 life
logic and mortality outcome, we recommend cycle, such a chloroquine, hydroxychloroquine,
against extending this assumption to the emer- and remdesivir, as well as immunomodulating
gency department, where the vast majority of car- therapies, such as tocilizumab and steroids. A spe-
diac arrests will be out of hospital in nature. Early cific concern is the arrhythmogenic potential
neurologic prognosis is fraught with challenges among these agents. Malignant arrhythmias have
and pitfalls, and an extensive discussion of the a higher incidence in patients infected with
topic is beyond the scope of this review. We rec- COVID-19, and therefore agents that compound
ommend an interdisciplinary and guideline-based this risk need to be noted. The greatest risk occurs
approach to the assessment of neurologic prog- with QT prolongation with hydroxychloroquine
nosis in the post-cardiac arrest setting [67]. and azithromycin. These will not only indepen-
dently increase the risk for ventricular arrhythmia
but will increase the risk of hypokalemia – another
COVID-19 Specific Therapeutics source for arrhythmogenic potential. Of addi-
and Special Circumstances tional note, both azithromycin and hydroxychlo-
roquine have not been shown to be beneficial in
The prevalence of superimposed bacterial infec- randomized control trials and should be avoided,
tion is unclear in patients infected with given the potentially serious side effects.
COVID-19. However, there may be some benefit Remdesivir, an inhibitor of viral RNA polymer-
AL GRAWANY
ases, has been associated with diarrhea – again supported by randomized control trial data are
raising the possibility for electrolyte abnormal- remdesivir [72] and dexamethasone, with dexa-
ity – but also multiple organ dysfunction [70]. methasone being the only therapy that has shown
Tocilizumab, a monoclonal antibody acting as a reduction in mortality [73].
IL-6 inhibitor, has been reported to shorten Another notable medication that requires dis-
QT. While this may carry less risk than agents that cussion is angiotensin-converting enzyme inhibi-
prolong the QT, agents that shorten the QT inter- tor (ACEi) and angiotensin-receptor blocker
val have also been shown to be high risk for caus- (ARB). Many comorbidities, such as hyperten-
ing ventricular arrhythmias [71]. Convalescent sion, stroke, and diabetes, are associated with an
plasma, theorized to improve patient outcome by increase in mortality in COVID-19-related dis-
providing additional graft provided antibodies, ease, and an early hypothesis was that utilizing
has yet to be shown to be beneficial. Plasma trans- ACEi/ARB led to that increase in mortality and
fusion carries the risk of most blood products, severity in disease. Literature regarding this has
such as infection and allergic and hematologic yet to definitively conclude the risk of these med-
reactions. Of specific concern in the post-cardiac ications, though early data suggest that there is
arrest setting is the additional intravascular vol- no link between ACEi/ARB and increased dis-
ume that is required when giving convalescent ease burden. However, even in the absence of
plasma, which may be consequential in patients COVID-19, ACEi/ARB have been linked to
who may have stunned myocardium after cardiac higher incidence of acute kidney injury in the set-
arrest. Similar in mechanism is the development ting of critical illness [74, 75]. Therefore, given
of antibody infusion and hyperimmune globulin. the lack of clarity, and possible link to acute kid-
These agents are currently under trial, with a side ney injury regardless of COVID-19 infection, we
effect profile and clinical benefit that has yet to be recommend utilizing alternative agents for con-
elucidated. While further discussion of novel ther- trol of hypertension, in the absence of specific
apies is outside of the scope of this chapter, the indication. A collective summary of our recom-
current literature suggests that the only therapies mendations can be found in Table 8.3.
Table 8.3 Recommendations for post-cardiac arrest care in areas of high COVID-19 positivity rate
Airway We recommend rapid sequence intubation as the method for endotracheal intubation
management We recommend early intubation in the post-cardiac arrest period
Video laryngoscopy should be first line, if available
Facemask ventilation should not be performed prior to intubation, unless patients develop
hypoxemia or clinical instability
An in-line HEPA filter should be used in all ventilation devices
We recommend pre-oxygenation using non-rebreather mask at flush rate flow with concurrent
simple nasal cannula
We recommend apneic oxygenation with simple nasal cannula
Oxygenation For patients with confirmed, or highly suspected, severe COVID-19 infections in the post-cardiac
goals arrest state:
We recommend targeting an SpO2 of 96%–99%. Additionally, we recommend a target PaO2 of
90–105 mm Hg
Ventilation For patients with confirmed, or highly suspected, severe COVID-19 infections in the post-cardiac
goals arrest state:
We recommend lung protective ventilation strategies, with an initial target tidal volume of
6–8 cc/kg, with titration to a plateau pressure <30 cc H2O
We recommend targeting a mild hypercarbia, PaCO2 of 45–50 mm Hg, as long as this does not
create an intolerable acidemia
Hemodynamic For patients with confirmed, or highly suspected, severe COVID-19 infections in the post-cardiac
goals arrest state:
We recommend targeting a MAP of 80–90 mm Hg, utilizing a fluid restrictive strategy
Neurologic We recommend utilizing a guideline-based and multidisciplinary approach to neurologic
prognosis prognosis in the post-cardiac arrest setting
Table 8.3 (continued)
Additional For patients with confirmed, or highly suspected, severe COVID-19 infections in the post-cardiac
considerations arrest state:
We recommend early initiation of broad-spectrum, empiric antibiotics
We recommend low threshold use of advanced imaging, such as CT, to identify occult
CPR-related injury
We recommend therapeutic anticoagulation, once occult injury and risk for acute bleeding have
been assessed
References Pract. 2020;70(696):327–8. https://doi.org/10.3399/

bjgp20X710837.
11. Couper K, Taylor-Phillips S, Grove A, et al.

1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart
COVID- 19 in cardiac arrest and infection risk
disease and stroke statistics--2012 update: a report
to rescuers: a systematic review. Resuscitation.
from the American Heart Association. Circulation.
2020;151:59–66. https://doi.org/10.1016/j.
2012;125(1):e2–e220. https://doi.org/10.1161/
resuscitation.2020.04.022.
CIR.0b013e31823ac046.
12. Wei MT, de Vlas SJ, Yang Z, et al. The SARS out-
2. Baldi E, Sechi GM, Mare C, et al. Out-of-hospital
break in a general hospital in Tianjin, China: clinical
cardiac arrest during the Covid-19 outbreak in Italy.
aspects and risk factors for disease outcome. Tropical
N Engl J Med. 2020;383(5):496–8. https://doi.
Med Int Health. 2009;14(Suppl 1):60–70. https://doi.
org/10.1056/NEJMc2010418.
org/10.1111/j.1365-3156.2009.02347.x.
3. Baldi E, Sechi GM, Mare C, et al. COVID-19 kills
13. Edelson DP, Sasson C, Chan PS, et al. Interim

at home: the close relationship between the epidemic
guidance for basic and advanced life support in
and the increase of out-of-hospital cardiac arrests.
adults, children, and neonates with suspected or
Eur Heart J. 2020; https://doi.org/10.1093/eurheartj/
confirmed COVID-19: from the emergency cardio-
ehaa508.
vascular care committee and get with the guidelines-
4. Holland M, Burke J, Hulac S, et al. Excess cardiac
resuscitation adult and pediatric task forces of
arrest in the community during the COVID-19 pan-
the American Heart Association. Circulation.
demic. JACC Cardiovasc Interv. 2020;13(16):1968–9.
2020;141(25):e933–43. https://doi.org/10.1161/
https://doi.org/10.1016/j.jcin.2020.06.022.
CIRCULATIONAHA.120.047463.
5. Sayre MR, Barnard LM, Counts CR, et al. Prevalence
14. Craig S, Cubitt M, Jaison A, et al. Management of
of COVID-19 in out-of-hospital cardiac arrest: impli-
adult cardiac arrest in the COVID-19 era: consen-
cations for bystander CPR. Circulation. 2020; https://
sus statement from the Australasian College for
doi.org/10.1161/CIRCULATIONAHA.120.048951.
Emergency Medicine. Med J Aust. 2020;213(3):126–
6. Shao F, Xu S, Ma X, et al. In-hospital cardiac arrest
33. https://doi.org/10.5694/mja2.50699.
outcomes among patients with COVID-19 pneumo-
15. Mahase E, Kmietowicz Z. Covid-19: doctors are told
nia in Wuhan, China. Resuscitation. 2020;151:18–23.
not to perform CPR on patients in cardiac arrest.
https://doi.org/10.1016/j.resuscitation.2020.04.005.
BMJ. 2020;368:m1282. https://doi.org/10.1136/bmj.
7. Mottola FF, Verde N, Ricciolino R, et al.
m1282.
Cardiovascular system in COVID-19: simply a viewer
16. Girotra S, Tang Y, Chan PS, Nallamothu BK,

or a leading actor? Life (Basel). 2020;10(9) https://
Investigators AHAGWTGR. Survival after In-hospital
doi.org/10.3390/life10090165.
cardiac arrest in critically ill patients: implica-
8. Boriani G, Palmisano P, Guerra F, et al. Impact
tions for COVID-19 outbreak? Circ Cardiovasc
of COVID-19 pandemic on the clinical activities
Qual Outcomes. 2020;13(7):e006837. https://doi.
related to arrhythmias and electrophysiology in
org/10.1161/CIRCOUTCOMES.120.006837.
Italy: results of a survey promoted by AIAC (Italian
17. Ran L, Chen X, Wang Y, Wu W, Zhang L, Tan X.
Association of Arrhythmology and Cardiac Pacing).
Risk factors of healthcare workers with Corona Virus
Intern Emerg Med. 2020; https://doi.org/10.1007/
Disease 2019: a retrospective cohort study in a des-
s11739-020-02487-w.
ignated hospital of Wuhan in China. Clin Infect Dis.
9. Nguyen LH, Drew DA, Graham MS, et al. Risk of
2020; https://doi.org/10.1093/cid/ciaa287.
COVID-19 among front-line health-care workers and
18. Natalzia P, Murk W, Thompson JJ, et al. Evidence-
the general community: a prospective cohort study.
based crisis standards of care for out-of-hospital
Lancet Public Health. 2020;5(9):e475–83. https://doi.
cardiac arrests in a pandemic. Resuscitation. 2020;
org/10.1016/S2468-2667(20)30164-X.
https://doi.org/10.1016/j.resuscitation.2020.07.021.
10. Levene LS, Coles B, Davies MJ, Hanif W, Zaccardi
19. Glober NK, Tainter CR, Abramson TM, Staats

F, Khunti K. COVID-19 cumulative mortality rates
K, Gilbert G, Kim D. A simple decision rule pre-
for frontline healthcare staff in England. Br J Gen
dicts futile resuscitation of out-of-hospital cardiac
arrest. Resuscitation. 2019;142:8–13. https://doi. 31. Cook TM, El-Boghdadly K, McGuire B, McNarry AF,
org/10.1016/j.resuscitation.2019.06.011. Patel A, Higgs A. Consensus guidelines for manag-
20. Grunau B, Scheuermeyer F, Kawano T, et al. North ing the airway in patients with COVID-19: guidelines
American validation of the Bokutoh criteria for with- from the Difficult Airway Society, the Association of
holding professional resuscitation in non- traumatic Anaesthetists the Intensive Care Society, the Faculty
out-of-hospital cardiac arrest. Resuscitation. of Intensive Care Medicine and the Royal College
2019;135:51–6. https://doi.org/10.1016/j. of Anaesthetists. Anaesthesia. 2020;75(6):785–99.
resuscitation.2019.01.008. https://doi.org/10.1111/anae.15054.
21. Glober NK, Lardaro T, Christopher S, Tainter CR, 32. Alhazzani W, Møller MH, Arabi YM, et al. Surviving
Weinstein E, Kim D. Validation of the NUE rule to sepsis campaign: guidelines on the management of
predict futile resuscitation of out-of-hospital cardiac critically ill Adults with coronavirus disease 2019
arrest. Prehosp Emerg Care. 2020:1–8. https://doi.org (COVID-19). Crit Care Med. 2020;48(6):e440–69.
/10.1080/10903127.2020.1831666. https://doi.org/10.1097/CCM.0000000000004363.
22. Lederman Z. Family presence during cardiopulmo- 33. De Jong A, Pardo E, Rolle A, Bodin-Lario S,

nary resuscitation in the Covid-19 era. Resuscitation. Pouzeratte Y, Jaber S. Airway management for
2020;151:137–8. https://doi.org/10.1016/j. COVID-19: a move towards universal videolaryngo-
resuscitation.2020.04.028. scope? Lancet Respir Med. 2020;8(6):555. https://
23. Shin H, Oh J, Lim TH, Kang H, Song Y, Lee
doi.org/10.1016/S2213-2600(20)30221-6.
S. Comparing the protective performances of 3 34. Sorbello M, Rosenblatt W, Hofmeyr R, Greif

types of N95 filtering facepiece respirators during R, Urdaneta F. Aerosol boxes and barrier enclo-
chest compressions: a randomized simulation study. sures for airway management in COVID-19
Medicine (Baltimore). 2017;96(42):e8308. https:// patients: a scoping review and narrative synthe-
doi.org/10.1097/MD.0000000000008308. sis. Br J Anaesth. 2020; https://doi.org/10.1016/j.
24. Bartoszko JJ, Farooqi MAM, Alhazzani W, Loeb
bja.2020.08.038.
M. Medical masks vs N95 respirators for preventing 35. Begley JL, Lavery KE, Nickson CP, Brewster DJ. The
COVID-19 in healthcare workers: a systematic review aerosol box for intubation in coronavirus disease
and meta-analysis of randomized trials. Influenza 2019 patients: an in-situ simulation crossover study.
Other Respir Viruses. 2020;14(4):365–73. https://doi. Anaesthesia. 2020;75(8):1014–21. https://doi.
org/10.1111/irv.12745. org/10.1111/anae.15115.
25.
Offeddu V, Yung CF, Low MSF, Tam 36. Yang WS, Hou SW, Lee BC, et al. Taipei Azalea –
CC. Effectiveness of masks and respirators against Supraglottic airways (SGA) preassembled with
respiratory infections in healthcare workers: a sys- high-efficiency particulate air (HEPA) filters to sim-
tematic review and meta-analysis. Clin Infect Dis. plify prehospital airway management for patients
2017;65(11):1934–42. https://doi.org/10.1093/cid/ with out-of-hospital cardiac arrests (OHCA) dur-
cix681. ing Coronavirus Disease 2019 (COVID-19) pan-
26. Holland M, Zaloga DJ, Friderici CS. COVID-19 per- demic. Resuscitation. 2020;151:3–5. https://doi.
sonal protective equipment (PPE) for the emergency org/10.1016/j.resuscitation.2020.03.021.
physician. Vis J Emerg Med. 2020;19:100740. https:// 37. Lim WY, Wong P. Supraglottic airways in the manage-
doi.org/10.1016/j.visj.2020.100740. ment of COVID-19 patients. Anaesth Crit Care Pain
27. Chu DK, Akl EA, Duda S, et al. Physical distancing, Med. 2020;39(5):589–90. https://doi.org/10.1016/j.
face masks, and eye protection to prevent person-to- accpm.2020.06.012.
person transmission of SARS-CoV-2 and COVID-19: 38. Brewster DJ, Chrimes N, Do TB, et al. Consensus
a systematic review and meta-analysis. Lancet. statement: Safe Airway Society principles of air-
2020;395(10242):1973–87. https://doi.org/10.1016/ way management and tracheal intubation specific
S0140-6736(20)31142-9. to the COVID-19 adult patient group. Med J Aust.
28. Mousavi ES, Godri Pollitt KJ, Sherman J, Martinello 2020;212(10):472–81. https://doi.org/10.5694/
RA. Performance analysis of portable HEPA filters mja2.50598.
and temporary plastic anterooms on the spread of sur- 39. Sorbello M, El-Boghdadly K, Di Giacinto I, et al.
rogate coronavirus. Build Environ. 2020;183:107186. The Italian coronavirus disease 2019 outbreak: rec-
https://doi.org/10.1016/j.buildenv.2020.107186. ommendations from clinical practice. Anaesthesia.
29. Christopherson DA, Yao WC, Lu M, Vijayakumar 2020;75(6):724–32. https://doi.org/10.1111/
R, Sedaghat AR. High-efficiency particulate air fil- anae.15049.
ters in the era of COVID-19: function and efficacy. 40. Chen N, Zhou M, Dong X, et al. Epidemiological
Otolaryngol Head Neck Surg. 2020;163(6):1153–5. and clinical characteristics of 99 cases of 2019 novel
https://doi.org/10.1177/0194599820941838. coronavirus pneumonia in Wuhan, China: a descrip-
30. Perkins GD, Morley PT, Nolan JP, et al. International tive study. Lancet. 2020;395(10223):507–13. https://
Liaison Committee on Resuscitation: COVID-19 con- doi.org/10.1016/S0140-6736(20)30211-7.
sensus on science, treatment recommendations and 41. Watchmaker JM, Goldman DT, Lee JY, et al. Increased
task force insights. Resuscitation. 2020;151:145–7. incidence of acute pulmonary embolism in emergency
https://doi.org/10.1016/j.resuscitation.2020.04.035. department patients during the COVID-19 pandemic.
Acad Emerg Med. 2020; https://doi.org/10.1111/ for infection control research. Am J Infect Control.
acem.14148. 2007;35(10):684–9. https://doi.org/10.1016/j.
42. Turagam MK, Musikantow D, Goldman ME, et al. ajic.2007.05.007.
Malignant arrhythmias in patients with COVID-19: 56. Roberts BW, Kilgannon JH, Hunter BR, et al.

incidence, mechanisms and outcomes. Circ Arrhythm Association between early hyperoxia exposure
Electrophysiol. 2020; https://doi.org/10.1161/ after resuscitation from cardiac arrest and neu-
CIRCEP.120.008920. rological disability: prospective multicenter
43. Martinelli AW, Ingle T, Newman J, et al. COVID- protocol-directed cohort study. Circulation.
19 and pneumothorax: a multicentre retrospec- 2018;137(20):2114–24. https://doi.org/10.1161/
tive case series. Eur Respir J. 2020; https://doi. CIRCULATIONAHA.117.032054.
org/10.1183/13993003.02697-2020. 57. Barrot L, Asfar P, Mauny F, et al. Liberal or conser-
44. Ruiz-Rodríguez JC, Chiscano-Camon L, Ruiz D, et al. vative oxygen therapy for acute respiratory distress
Cardiac tamponade as a cause of cardiac arrest in severe syndrome. N Engl J Med. 2020;382(11):999–1008.
COVID-19 pneumonia. Resuscitation. 2020;155:1–2. https://doi.org/10.1056/NEJMoa1916431.
https://doi.org/10.1016/j.resuscitation.2020.07.008. 58. Marini JJ, Gattinoni L. Management of COVID-19
45. Coronavirus Disease 2019 (COVID-19) treatment
respiratory distress. JAMA. 2020;323(22):2329–30.
guidelines: care of critically ill patients with COVID- https://doi.org/10.1001/jama.2020.6825.
19. 2020. 59.
Gattinoni L, Camporota L, Marini JJ.
46. Böttiger BW, Arntz HR, Chamberlain DA, et al.
COVID-19 phenotypes: leading or mislead-
Thrombolysis during resuscitation for out-of-hospital ing? Eur Respir J. 2020;56(2) https://doi.
cardiac arrest. N Engl J Med. 2008;359(25):2651–62. org/10.1183/13993003.02195-2020.
https://doi.org/10.1056/NEJMoa070570. 60. Kang C, In YN, Park JS, et al. Impact of low and
47. Mavraganis G, Aivalioti E, Chatzidou S, et al.
high partial pressure of carbon dioxide on neuron-
Cardiac arrest and drug-related cardiac toxicity in the specific enolase derived from serum and cerebro-
Covid- 19 era. Epidemiology, pathophysiology and spinal fluid in patients who underwent targeted
management. Food Chem Toxicol. 2020;145:111742. temperature management after out-of-hospital
https://doi.org/10.1016/j.fct.2020.111742. cardiac arrest: a retrospective study. Resuscitation.
48. Akhmerov A, Marbán E. COVID-19 and the heart. 2020;153:79–87. https://doi.org/10.1016/j.
Circ Res. 2020;126(10):1443–55. https://doi. resuscitation.2020.05.050.
org/10.1161/CIRCRESAHA.120.317055. 61. Woodward CW, Lambert J, Ortiz-Soriano V, et al.
49. Thapa SB, Kakar TS, Mayer C, Khanal D. Clinical Fluid overload associates with major adverse kid-
outcomes of In-hospital cardiac arrest in COVID-19. ney events in critically ill patients with acute kidney
JAMA Intern Med. 2020; https://doi.org/10.1001/ injury requiring continuous renal replacement ther-
jamainternmed.2020.4796. apy. Crit Care Med. 2019;47(9):e753–60. https://doi.
50. Gaspari R, Weekes A, Adhikari S, et al. Emergency org/10.1097/CCM.0000000000003862.
department point-of-care ultrasound in out-of-hospital 62. Lee J, de Louw E, Niemi M, et al. Association

and in-ED cardiac arrest. Resuscitation. 2016;109:33– between fluid balance and survival in critically ill
9. https://doi.org/10.1016/j.resuscitation.2016.09.018. patients. J Intern Med. 2015;277(4):468–77. https://
51. Bhatnagar V, Jinjil K, Dwivedi D, Verma R, Tandon doi.org/10.1111/joim.12274.
U. Cardiopulmonary resuscitation: unusual tech- 63. Kilgannon JH, Roberts BW, Jones AE, et al.

niques for unusual situations. J Emerg Trauma Shock. Arterial blood pressure and neurologic outcome
2018;11(1):31–7. https://doi.org/10.4103/JETS. after resuscitation from cardiac arrest*. Crit Care
JETS_58_17. Med. 2014;42(9):2083–91. https://doi.org/10.1097/
52. Douma MJ, MacKenzie E, Loch T, et al. Prone car- CCM.0000000000000406.
diopulmonary resuscitation: a scoping and expanded 64. Roberts BW, Kilgannon JH, Hunter BR, et al.

grey literature review for the COVID-19 pan- Association between elevated mean arterial blood
demic. Resuscitation. 2020;155:103–11. https://doi. pressure and neurologic outcome after resuscitation
org/10.1016/j.resuscitation.2020.07.010. from cardiac arrest: results from a multicenter prospec-
53. Chivukula RR, Maley JH, Dudzinski DM, Hibbert tive cohort study. Crit Care Med. 2019;47(1):93–100.
K, Hardin CC. Evidence-based Management of the https://doi.org/10.1097/CCM.0000000000003474.
critically ill Adult with SARS-CoV-2 infection. J 65. Jakkula P, Pettilä V, Skrifvars MB, et al. Targeting
Intensive Care Med. 2021;36(1):18–41. https://doi. low-normal or high-normal mean arterial pressure
org/10.1177/0885066620969132. after cardiac arrest and resuscitation: a randomised
54. Driver BE, Prekker ME, Kornas RL, Cales EK,
pilot trial. Intensive Care Med. 2018;44(12):2091–
Reardon RF. Flush rate oxygen for emergency airway 101. https://doi.org/10.1007/s00134-018-5446-8.
preoxygenation. Ann Emerg Med. 2017;69(1):1–6. 66. Ameloot K, De Deyne C, Eertmans W, et al. Early
https://doi.org/10.1016/j.annemergmed.2016.06.018. goal-directed haemodynamic optimization of cere-
55. Ip M, Tang JW, Hui DS, et al. Airflow and droplet bral oxygenation in comatose survivors after car-
spreading around oxygen masks: a simulation model diac arrest: the Neuroprotect post-cardiac arrest
trial. Eur Heart J. 2019;40(22):1804–14. https://doi. implications. Eur Heart J. 2006;27(20):2440–7.

org/10.1093/eurheartj/ehz120. https://doi.org/10.1093/eurheartj/ehl185.
67. Sandroni C, D'Arrigo S, Nolan JP. Prognostication 72. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir
after cardiac arrest. Crit Care. 2018;22(1):150. https:// for the treatment of Covid-19 - final report. N Engl J
doi.org/10.1186/s13054-018-2060-7. Med. 2020; https://doi.org/10.1056/NEJMoa2007764.
68. François B, Cariou A, Clere-Jehl R, et al. Prevention 73. Horby P, Lim WS, Emberson JR, et al. Dexamethasone
of early ventilator-associated pneumonia after cardiac in hospitalized patients with Covid-19 – preliminary
arrest. N Engl J Med. 2019;381(19):1831–42. https:// report. N Engl J Med. 2020; https://doi.org/10.1056/
doi.org/10.1056/NEJMoa1812379. NEJMoa2021436.
69. Hasan SS, Radford S, Kow CS, Zaidi STR. Venous 74. Mansfield KE, Nitsch D, Smeeth L, Bhaskaran K,
thromboembolism in critically ill COVID-19 patients Tomlinson LA. Prescription of renin-angiotensin
receiving prophylactic or therapeutic anticoagulation: system blockers and risk of acute kidney injury:
a systematic review and meta-analysis. J Thromb a population-based cohort study. BMJ Open.
Thrombolysis. 2020;50(4):814–21. https://doi. 2016;6(12):e012690. https://doi.org/10.1136/
org/10.1007/s11239-020-02235-z. bmjopen-2016-012690.
70. Grein J, Ohmagari N, Shin D, et al. Compassionate 75. Palevsky PM, Zhang JH, Seliger SL, Emanuele

use of remdesivir for patients with severe Covid-19. N, Fried LF, Study VN-D. Incidence, severity,
N Engl J Med. 2020;382(24):2327–36. https://doi. and outcomes of AKI associated with dual renin-
org/10.1056/NEJMoa2007016. angiotensin system blockade. Clin J Am Soc Nephrol.
71. Giustetto C, Di Monte F, Wolpert C, et al. Short QT 2016;11(11):1944–53. https://doi.org/10.2215/
syndrome: clinical findings and diagnostic-therapeutic CJN.03470316.
COVID-19-Related Cardiac Illness
9
Christopher J. Hogan
Introduction The exact mechanism of cardiac injury in

COVID-19 is not clear [6, 43]. The COVID-19
Although the effects of the severe acute respira- virus can directly infect myocytes [50, 61].
tory syndrome coronavirus 2 (COVID-19) are Additionally, pericytes, cells that surround endo-
primarily pulmonary, its effects on other organ thelial cells in the cardiac capillaries, have been
systems became evident as larger numbers of found to contain the virus, which may cause capil-
patients were infected. Early in the pandemic, lary endothelial cell or microvascular dysfunction
cardiac involvement was observed in COVID-19 leading to thrombosis [7, 10]. Myocardial biopsies
patients with a higher risk of mortality [43]. on a limited number of COVID-19 patients show
These effects range from arrhythmias to cardiac varying degrees of myocardial inflammation but
injury (defined by elevated cardiac enzymes) to limited myocardial necrosis [10], so direct myo-
heart failure. cardial viral damage is less likely [10].
Instead, the myocardial manifestations of
COVID may be from an uncontrolled and dys-
Pathophysiology functional immune response. The virus induces
proinflammatory mediators that impact multiple
COVID-19 belongs to the same virus family as organ systems, cardiovascular included [21], and
severe acute respiratory syndrome-coronavirus there is a positive correlation between inflamma-
(SARS-CoV) and Middle East respiratory tory markers and myocardial damage that would
syndrome-coronavirus (MERS-CoV). Much of be consistent with the role of hyperinflammation
the initial assumptions about COVID-19 car- as a cause of cardiac injury [35, 52]. Other poten-
diac effects came from previous virus out- tial contributors include hypoxic myocardial
breaks that preceded the current pandemic, oxygen supply versus demand mismatch, coro-
such as SARS-CoV, MERS-CoV, and H1N1 nary spasm, and dysregulation of the renin-
influenza syndromes, in which there was a sig- angiotensin- aldosterone system [3]. But these
nificant association between underlying car- most likely only contribute to the “cytokine
diovascular disease, myocardial injury, and storm” that results in a subclinical autoimmune
worse outcomes [21]. myocarditis followed sometime later by myocar-
dial damage and/or molecular mimicry that initi-
ate a de novo autoimmune reaction [17].
C. J. Hogan (*) Another potential mechanism behind COVID-
VCU School of Medicine, Richmond, VA, USA
19-mediated myocardial damage worthy of men-

88 C. J. Hogan
tion is the angiotensin-2 (ACE-2) receptor, which discharge. Lastly, a reversible cardiomegaly was
is widely expressed not only in the lungs but also also reported in 10% with no clinical evidence
throughout the cardiovascular system. COVID-19 of heart failure [63].
binds to and downregulates the ACE2 receptors
that can result in myocardial inflammation and
lung edema [52]. COVID-19 Specific Study Data
The COVID-19 patient’s vital signs are similar to

Presentation any other viral illness. Sinus tachycardia is a fre-
quent finding even in healthy patients with no
Early Studies cardiac involvement [64]. Hypertension was
more prevalent in patients requiring the ICU than
As early as 2002, animal data demonstrated that in those not requiring the ICU [64].
coronaviruses can cause cardiomyopathy and Whereas the cardiac complications in SARS
systolic function impairment [21]. Even the influ- were self-limiting, COVID-19 patients have
enza virus has been associated with myocarditis, more pronounced cardiac involvement reflected
myocardial infarction, and HF exacerbation [32], by elevated cardiac enzymes (see Fig. 9.1). Early
although these are not frequent occurrences. studies suggested that a significant percentage of
First reported in 2002, SARS in particular COVID-19 patients had cardiac injury and major
was associated with hypotension, cardiac adverse clinical outcomes [38, 43], but as larger
arrhythmias, and sudden cardiac death [21, 60]. numbers of patients were studied, these initial
Other cardiovascular complications were fre- dire cardiac complication estimates have
quent: hypertension (>50%), persistent tachy- decreased.
cardia (40%), bradycardia (15%), and left Still, 10–20 percent of COVID-19 patients
ventricular impairment, but these were not asso- have elevated cardiac markers, usually high-
ciated with an increased risk of death. Sinus sensitivity troponin I, troponin T, or creatinine
tachycardia was the most common cardiovascu- kinase [27]. In the first studies describing general
lar SARS-CoV finding (72%) [63] that could COVID-19 patients, common cardiac issues were
persist in 40% of patients weeks after hospital arrhythmias (16.7%) and acute cardiac injury
Fig. 9.1 Cardiovascular effects of COVID-19 (with permission from [21])

9 COVID-19-Related Cardiac Illness 89
(7.2%) [57]. What constituted an “arrhythmia” Table 9.1 Frequent cardiac issues encountered in
was not fully described, but this subgroup had COVID-19 infection [20, 42, 45]
higher rates of ICU level of care and death. Cardiac issue Frequency
Guo et al. [16] looked specifically at car- Elevated troponins 17–44%
diac issues by stratifying patients with Heart failure 8%
Shock 8–17%
COVID-19 by troponin levels, which were
Arrhythmias:
elevated in 27% of their population. These All types 14–26%
patients had a higher incidence of malignant Atrial fibrillation 7%
ventricular arrhythmias (11.5% vs. 5.2%) and Ventricular tachycardia/fibrillation 5.9%
mortality (59.6% vs. 8.9%) when compared Pericardial effusion (may take days to 1–5%
with those with normal troponin levels. develop)
Subsequent studies have found similar rates of
myocardial injury [43, 58]. sion, and 1% sustained tachycardia (>125 bpm)
Pericardial effusions, which may take some [16]. Atrial fibrillation, conduction block, ven-
time to develop, occur in 1 to 5% of COVID-19 tricular tachycardia, and ventricular fibrillation
cases [29]. Most are not clinically relevant. also have been reported [17]. Hospitalized
COVID-19 infection can lead to type 2 myo- patients with COVID-19 who died experienced
cardial infarctions, the most common subtype in malignant cardiac arrhythmias more often than
viral conditions. This is because the infection and those surviving to discharge, but these are prob-
subsequent immune response causes microvascu- ably associated with severe metabolic derange-
lar dysfunction, contributing to myocardial ments and not the virus itself [53]. See Table 9.1
infarction in non-obstructed coronary arteries for a synopsis.
[17]. In COVID-19 patients found with A later study querying an international collec-
ST-elevation myocardial infarction, only 60% tion of electrophysiologists reported that 21%
had an identifiable atherosclerotic plaque rupture had clinically encountered COVID-19 patients
(Type 1 MI) leading to thrombotic obstructive with atrial fibrillation, 5.4% reported atrial flut-
coronary artery disease [3], suggesting nonob- ter, 3.5% reported sustained atrial tachycardia,
structive disease predominates in COVID-19 and 5.7% reported paroxysmal supraventricular
infection [48]. Among COVID-19 patients with tachycardia.
nonobstructive coronary disease, ST elevation Frequently reported ventricular arrhythmias
secondary to myocardial injury resulted in a include monomorphic premature ventricular con-
worse prognosis [3, 47]. Of interest, in the first tractions (5.3%), multimorphic premature ven-
studies, 85% of patients presented a STEMI as tricular contractions (3.5%), non-sustained
their initial COVID-19 presentation [47]. ventricular tachycardia (6.3%), sustained mono-
Some patients can later develop stress car- morphic VT (3.8%), polymorphic VT/torsade de
diomyopathy, left ventricular systolic dysfunc- pointes (3.5%), VT/ventricular fibrillation (VF)
tion, circulatory collapse with shock, cardiac arrest (4.8%), and pulseless electrical activity
arrhythmia, and, rarely, sudden myocardial rup- (5.6%).
ture [27]. They also reported bradycardic rhythms,
albeit less frequently: 8% reported significant
sinus bradycardia, 8% complete heart block,
Arrhythmias 5.9% first- or second-degree AV block, and 3.9%
bundle branch block or intraventricular conduc-
The definition of “cardiac arrhythmias” was not tion delay. This data is the percent of electrophys-
fully defined in the early COVID-19 literature, iologists who encountered these conditions, not
but was delineated in later studies [28]. The individual patients, and does not take into account
first studies reported a 5.9% incidence of ven- the hypoxia and multi-organ failure known to
tricular fibrillation/tachycardia, 1% hypoten- occur with COVID-19 infection [15].
90 C. J. Hogan
Cardiomyopathy can develop in COVID-19 Pre-existing conditions that should raise con-
with mild or absent respiratory symptoms [19] cern [43, 58] are male gender, age greater than 60
and in severe disease. It can occur from acute years, pre-existing pulmonary disease, hyperten-
coronary syndrome and sepsis or be stress sion [60], heart failure [62], and coronary artery
induced [46]. One early case series study showed disease. These patients are more likely to require
that 33% developed cardiomyopathy [2] that in ICU admission, mechanical ventilation, and
retrospect was most likely sepsis-related cardio- treatment with vasoactive agents and have a
myopathy. The three cardinal signs of sepsis- higher mortality [7, 16, 35, 60, 65].
related cardiomyopathy are left ventricular Heart failure deserves special mention in the
dilation, impaired ejection fraction, and revers- setting of COVID-19 infection because these
ibility in 7–10 days [46]. patients may have a combination of pre-existing
Cardiac COVID-19 effects can last after the left ventricular hypertrophy and diastolic dys-
acute phase of the illness by cardiac damage function that is exacerbated by COVID-19 infec-
induced by COVID-19 infection through formation and the resulting critical illness. They
tion of cardiac fibrotic tissue [54]. This is most subsequently are at high risk of worsening failure
likely a consequence of the cytokine storm and and poor outcomes [52]. Additionally therapeutic
release of proinflammatory mediators. Over time, interventions utilized to treat COVID-19 infec-
this leads to structural abnormalities and impaired tion such as intravenous (IV) fluids, steroids, and
cardiac function as well as arrhythmias. A fulmi- nonsteroidal anti-inflammatory agents can alter
nant myocarditis can also occur some weeks after salt and water balance, which further aggravates
the initial COVID-19 infection. the incidence of the disease [27].
Myocarditis COVID-19 Workup from a Cardiac

Perspective
Myocarditis is a controversial diagnosis in
COVID-19 population [8, 55]. Early in the pan- Physical Exam
demic, studies suggested up to 7% of COVID-19-
related deaths were attributable to myocarditis, Physical exam findings are not straightforward
but this most likely was an overestimation [14, in COVID-19 patients with multiple comor-
46]. COVID-19-induced acute myocarditis is not bidities. Early detection can be confounded in
common, but it manifests later in the course of patients with chronic cardiac conditions which
COVID-19 infection (up to 10–15 days). appear similar to COVID-19 symptoms,
including fatigue (51%), dyspnea (30%), and
dry cough (67%) [65]. Patients later found
Pre-existing Conditions with cardiac injury from COVID-19 infection
do not present with higher incidence of chest
It was hypothesized early in the pandemic [43] distress, chest pain, palpitations, or arrhyth-
that pre-existing cardiovascular diseases might mias [35].
facilitate COVID-19-induced cardiac injury and
mortality. Multiple international reports fol-
lowed, linking pre-existing comorbidities to Cardiac Enzymes
worsened COVID-19 severity and outcomes [2,
12, 16]. Inciardi et al. [19] found that mortality Myocardial injury, defined as the elevation of
was higher in patients with cardiac disease com- high-sensitivity cardiac troponin above the 99th
pared with the others (36% vs. 15%), as were percentile of its upper limit of normal or new
rates of thrombo-embolic events and septic ECG/echocardiographic abnormalities, should
shock. be evaluated in every COVID-19 confirmed or
suspected patient. While some critically ill disease, an inflammatory multisystem syndrome
patients may have troponins within normal limits temporally associated with COVID-19. They
[12], the top 20 percent of COVID-19 patients present with fever, evidence of inflammation
will have elevated troponin levels, even when (neutrophilia, elevated CRP, and lymphopenia),
they have no overt cardiac symptoms. This does and single- or multi-organ dysfunction in con-
not generally represent type 1 myocardial infarc- junction with an existing or previous COVID-19
tion (from acute occlusion), but may be a result infection [9]. Since untreated KD can lead to
of critical illness, sepsis, an exacerbation of the coronary aneurysms in 25% of patients, this
patient’s subclinical coronary artery disease by diagnosis is important to entertain in the pediat-
sepsis [46], stress cardiomyopathy, acute heart ric population.
failure, or pulmonary embolism [39].
Elevated cardiac enzymes and ventricular
arrhythmias are independent predictors of mor- Cardiac Ultrasound
tality [24, 31]. Presenting troponin levels were
not significantly associated with outcomes and Bedside and/or formal ultrasound can offer a
did not completely rule out the risk for mechani- glimpse into global cardiac function. In one
cal ventilation or death [35]. study, the most frequent abnormality was right
Serial measurement of cardiac biomarkers ventricular dilation or dysfunction, followed by
helps detect myocardial injury, as increasing tro- left ventricle systolic (10%) and diastolic dys-
ponin levels correlate with disease severity and function (16%) [49]. In COVID-19 patients with
mortality, even after controlling for other comor- severe disease, only one third have a normal TTE
bidities [20, 22, 24, 33, 41, 42, 47, 56]. For [13, 49]. While global hypokinesis suggests sep-
instance, Si et al. [45] found that mortality was tic shock, more focal dysfunction is found in
markedly higher in patients with cardiac injury myocarditis or stress-induced cardiomyopathy
(71.2% vs. 6.6%, p < 0.001) and that both the [46]. More importantly, TTE can assess RV dila-
initial and peak troponins were associated with tion and/or decreased right ventricular function
poor survival and the need for invasive suggestive of advanced circulatory failure or
ventilation. venous thromboembolism [5]. There are rare
Later studies found that non-survivors had a cases of cardiac tamponade reported that bedside
higher level of troponin elevation which contin- US can also identify.
ued to rise until death, while levels for survivors
remained unchanged [20, 39]. The risk of death
increases with higher troponin concentrations ECG
even after a multivariate regression controlling
for comorbid conditions, inflammatory markers, Depending on the progression of disease, ECG
acute kidney injury, and acute respiratory distress abnormalities include diffuse ST and/or ischemic
syndrome (Raad 2020), and increased levels T-wave abnormalities in up to 60% of COVID-19
beyond day 3 suggest a worse prognosis [23]. patients with myocardial injury [17]. ECG find-
BNP also is reflective of cardiac dysfunction ings that should be concerning are ones that dem-
in the setting of COVID-19 infection [47] and is onstrate both left- and right-sided pathology:
a good screen for heart failure. atrial premature contractions (odds ratio (OR) for
The bulk of COVID-19 cardiac data revolves death 2.57), a right bundle branch block or intra-
around adults. Children can have elevated car- ventricular block (OR 2.61), ischemic T-wave
diac markers with COVID-19 infection, and inversion (OR 3.49), and nonspecific repolariza-
those with underlying cardiac issues such as tion (OR 2.31). Focal ST elevation on ECG in the
structural defects may be at risk of more severe setting of COVID-19 is rare (0.7%) [26], so this
cardiac complications [40]. Previously healthy finding should prompt further investigation for
children can present with atypical Kawasaki ischemia or infarct.
AL GRAWANY
92 C. J. Hogan
The diagnosis of myocarditis is controversial hydroxychloroquine and azithromycin) that pro-

in the COVID-19 population, but this diagnosis long QT interval with potential development of
should be considered if a patient presents 2–3 polymorphic ventricular tachycardia [14].
weeks after the COVID-19 infection. These COVID-19 patients may present with gastroin-
patients are important to identify because a sig- testinal losses that may cause electrolyte
nificant number deteriorate, with acute-onset abnormalities.
heart failure with cardiogenic shock. They can be COVID-19-induced ARDS with hypoxia
difficult to identify, presenting with relatively increases the risk of atrial dysrhythmias includ-
mild symptoms, such as fatigue, dyspnea, chest ing atrial fibrillation and flutter [4]. While brady-
pain, or chest tightness on exertion [46]. In severe arrhythmias may require temporary cardiac
cases, patients may present with signs of right- pacing, tachyarrhythmias may respond to anti-
sided heart failure, including elevated jugular arrhythmic drugs (such as lidocaine) and over-
venous pressure, peripheral edema, and right drive pacing. This is particularly true if
upper quadrant pain. Fulminant myocarditis can antimalarials or macrolides, known to prolong
present like sepsis: fever, hypotension (in partic- the QTc interval, are involved (see Table 9.2).
ular, low pulse pressure), cold or mottled extrem- Torsades de pointes, a form of polymorphic
ities, and sinus tachycardia. As 78% of ventricular tachycardia associated with QT pro-
myocarditis patients exhibited some form of ven- longation, can be triggered by antiviral agents
tricular arrhythmia, consider this diagnosis if the used in combination with cardiac medications.
ECG has concerning ventricular ectopy. Other After magnesium sulfate administration, all QT
ECG abnormalities to look for include ST eleva- prolonging drugs should be withdrawn and elec-
tion and PR depression (similar to pericarditis trolyte levels corrected. If this fails, consider IV
morphology) [46], bundle branch block, QT pro- isoproterenol or an overdriving temporary pace-
longation, premature ventricular complexes, and maker [27, 51].
bradyarrhythmia with advanced atrioventricular Goals of therapy for supraventricular and ven-
nodal block. tricular arrhythmias include rate and rhythm con-
trol. In hemodynamically unstable patients with
atrial fibrillation/flutter or ventricular tachycar-
Treatment dia, electrical cardioversion is the best option. In
hemodynamically stable patients with atrial
In acute COVID-19 infection, hemodynamic fibrillation/flutter or ventricular tachycardia, IV
instability and arrhythmias are rarely a primary amiodarone can be used (but pay attention to the
cardiac issue, rather they are the secondary result QT interval). Initiation of rate control therapy
of the hypoxia and immune response to the infec- with calcium channel or beta-blockers should be
tion. Consequently, initiation of treatment (ste- avoided because of the negative inotropy. That
roids, antivirals) and correction of the hypoxia
are the best way to address cardiac issues.
Table 9.2 Medications that might be used in COVID-19
Cardiac monitoring allows identification and treatment that cause QT issues
treatment of brady- and tachyarrhythmias, which
Chloroquine/hydroxychloroquine
can include atrioventricular block, ventricular Macrolides (azithromycin)
tachycardia, or fibrillation. Patients with more Antibiotics Quinolones
severe COVID-19 infection tend to have more Antivirals Lopinavir/ritonavir
arrhythmias [59], so those with atrial or ventricu- Favipiravir
Tocilizumab
lar ectopy should be watched for progression of
Class 1A Quinidine and procainamide
disease. anti-arrhythmics
Correction of electrolytes, particularly potas- Class III Dofetilide, amiodarone, and sotalol
sium, is important as this can potentiate the anti-arrhythmics
adverse effects of therapies (e.g., chloroquine/ Anesthetics Propofol
being said, in cases of recurrent VT with increased If patients have a diagnosis of COVID-19 or
adrenergic surge, the addition of a short-acting COVID-19-like history that is over a week old,
sympathetic blockade (esmolol) can be consid- specifically consider myositis. Failure to respond
ered despite its negative inotropy and can always to resuscitation and pressors should prompt the
be discontinued if hypotension develops. consideration of mechanical circulatory support
A limited bedside ultrasound is very useful in such as extracorporeal membrane oxygenation,
the unstable COVID-19 patient – it can d etermine ventricular assist device, or intra-aortic balloon
fluid status, rule out pericardial effusion, and give pump [11].
insight to the right side of the heart. Cardiac arrest in the COVID-19 patient is a
Pressor management does not differ much terminal event, with reported inpatient survival
from other critically ill patients. For hypoperfu- rates ranging from 11% to 13%. These are
sion that does not respond to fluid, a vasopressor nearly all nonshockable rhythms such as pulse-
such as norepinephrine is a good first-line agent, less electrical activity or asystole [4]. Clinical
although dopamine can be used as well especially outcomes are poor in COVID-19 patients who
if there is an inappropriately low heart rate. A get this sick as an inpatient [44] and as outpa-
good second-line agent is vasopressin, particu- tients [18, 25, 34, 36].
larly in the elderly population who may already
have an elevated adrenergic response. If signifi-
cant cardiac involvement is suspected (a climb- COVID-19 Drug Issues
ing troponin, progressing ECG ischemic
changes), then add an inotrope such as dobuta- Although not currently recommended, chloro-
mine [11]. A good starting goal for mean arterial quine and hydroxychloroquine have been impli-
pressure is 60–65 mmHg [1], but this may need cated in cardiac dysrhythmias and prolonged QT
to be higher in patients with pre-existing intervals based limited to case reports [21].
hypertension. Patients may self-treat themselves with these
Failure to stabilize once fully resuscitated and drugs, so it is worth asking about medications
on multiple pressors portends a poor outcome. they are currently using. Both have anti-
Artificial cardiopulmonary support such as arrhythmic and proarrhythmic properties, and the
ECMO is not widely available and is a scarce American Heart Association has listed chloro-
resource in the COVID-19 environment. When quine and hydroxychloroquine as agents which
considering artificial cardiopulmonary support, can cause direct myocardial toxicity [30] as well.
the main question centers on if the failure is only They can cause syncope precipitated by fascicu-
right sided (consider V-V ECMO plus catheter- lar block and rarely atrioventricular blocks.
mounted right ventricular assist device) or if both Si et al. [45] found that although patients who
sides of the heart involved (V-A ECMO) [27]. received QT-prolonging drugs did have longer
This will be a multi-team decision [37], but QTc intervals than those who did not receive
ECMO works better when initiated sooner rather them, this was not independently associated with
than later, so an early transfer or ECLS team con- mortality.
sultation should be considered. If there is a possibility of heart failure or car-
The timing of hemodynamic instability plays diomyopathy, avoid nonsteroidal anti-
a role in the determining the cause of the patient’s inflammatories that cause sodium retention and
critical illness. If a suspected or confirmed impaired renal function [46].
COVID-19 patient is within the first week of Remdesivir is a nucleotide-analog inhibitor of
symptoms and is hypotensive and tachycardic, RNA polymerases, and there is some data sug-
consider septic shock and treat with administra- gesting it can cause hypotension, arrhythmias
tion of inotropes and/or vasopressors and [25], and elevated LFTs.
mechanical ventilation. It may take a few days Contrary to earlier suggestions, there is no
for troponin to climb, so repeat these lab studies. evidence of an increased COVID-19 susceptibil-
94 C. J. Hogan
ity or severity in patients receiving ACEi or https://doi.org/10.1111/echo.14779. Epub 2020 Jul

ARBs. These agents should not be discontinued 12. PMID: 32654210; PMCID: PMC7404652.
6. Chen L, Li X, Chen M, Feng Y, Xiong C. The
during the COVID-19 pandemic, as they may ACE2 expression in human heart indicates new
have a protective role for angiotensin II-mediated potential mechanism of heart injury among patients
organ damage during COVID-19 [52]. infected with SARS-CoV-2. Cardiovasc Res.
cvr/cvaa078. Erratum in: Cardiovasc Res. 2020
Critical Points Oct 1;116(12):1994. PMID: 32227090; PMCID:
1. Check serial ECGs and troponins. Further PMC7184507.
cardiac workup should depend on patient 7. Chen Q, Xu L, Dai Y, Ling Y, Mao J, Qian J, Zhu W,
Di W, Ge J. Cardiovascular manifestations in severe
comorbidities and presentation. and critical patients with COVID-19. Clin Cardiol.
2. Optimize electrolytes to prevent arrhythmias. 2020;43(7):796–802. https://doi.org/10.1002/
3. Correct underlying hypoxia. clc.23384. Epub 2020 Jun 20. PMID: 32562427;
4. ICU level of care in patients with underlying PMCID: PMC7323347.
8. Deng Q, Hu B, Zhang Y, Wang H, Zhou X, Hu W,
comorbidities (DM, COPD, CAD, HF of any Cheng Y, Yan J, Ping H, Zhou Q. Suspected myocar-
etiology). dial injury in patients with COVID-19: evidence from
5. Consider myocarditis in patients presenting front-line clinical observation in Wuhan, China. Int J
with vague symptoms 2 to 3 weeks after a Cardiol. 2020;311:116–21. https://doi.org/10.1016/j.
ijcard.2020.03.087. Epub 2020 Apr 8. PMID:
COVID-19 infection. 32291207; PMCID: PMC7141178.
9. Dou Q, Wei X, Zhou K, Yang S, Jia P. Cardiovascular
manifestations and mechanisms in patients
with COVID-19. Trends Endocrinol Metab.
References 2020;31(12):893–904. https://doi.org/10.1016/j.
tem.2020.10.001. Epub 2020 Oct 16. PMID:
1. American College of Cardiology. Key ques- 33172748; PMCID: PMC7566786.
tions on COVID-19 and cardiovascular disease. 10. Fox SE, Li G, Akmatbekov A, Harbert JL, Lameira
2020. Available at: https://www.acc.org/~/media/ FS, Brown JQ, Vander Heide RS. Unexpected fea-
N o n - C l i n i c a l / F i l e s - P D F s - E x c e l - M S - Wo r d - tures of cardiac pathology in COVID-19 infec-
etc/2020/04/30/S20057-Key-Questions-COVID-19- tion. Circulation. 2020;142(11):1123–5. https://doi.
CVDisease-FINAL-UPLOADED-April-30-2020.pdf. org/10.1161/CIRCULATIONAHA.120.049465.
Accessed 10 Jan 2021. Epub 2020 Jul 21. PMID: 32689809.
2. Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, 11. Ganatra S, Dani SS, Shah S, Asnani A, Neilan TG,
Chong M, Lee M. Characteristics and outcomes of 21 Lenihan D, Ky B, Barac A, Hayek SS, Leja M,
critically ill patients with COVID-19 in Washington Herrmann J, Thavendiranathan P, Fradley M, Bang V,
State. JAMA. 2020;323:1612. Shreyder K, Parikh R, Patel R, Singh A, Brar S, Guha
3. Bangalore S, Sharma A, Slotwiner A, Yatskar A, Gupta D, Mascari P, Patten RD, Venesy DM, Nohria
L, Harari R, Shah B, Ibrahim H, Friedman GH, A, Resnic FS. Management of cardiovascular disease
Thompson C, Alviar CL, Chadow HL, Fishman GI, during coronavirus disease (COVID-19) pandemic.
Reynolds HR, Keller N, Hochman JS. ST-segment Trends Cardiovasc Med. 2020;30(6):315–25. https://
elevation in patients with Covid-19— a case series. N doi.org/10.1016/j.tcm.2020.05.004. Epub 2020 May
Engl J Med. 2020;382:2478–80. 28. PMID: 32474135; PMCID: PMC7255720.
4. Bhatla A, Mayer MM, Adusumalli S, Hyman MC, 12. Ghio S, Baldi E, Vicentini A, Lenti MV, Di Sabatino
Oh E, Tierney A, Moss J, Chahal AA, Anesi G, A, Di Matteo A, Zuccaro V, Piloni D, Corsico A,
Denduluri S, Domenico CM, Arkles J, Abella BS, Gnecchi M, Speciale F, Sabena A, Oltrona Visconti
Bullinga JR, Callans DJ, Dixit S, Epstein AE, Frankel L, Perlini S, San Matteo COVID Cardiac Injury
DS, Garcia FC, Kumareswaram R, Nazarian S, Riley Task Force. Cardiac involvement at presentation in
MP, Santangeli P, Schaller RD, Supple GE, Lin D, patients hospitalized with COVID-19 and their out-
Marchlinski F, Deo R. COVID-19 and cardiac arrhyth- come in a tertiary referral hospital in Northern Italy.
mias. Heart Rhythm. 2020;17(9):1439–44. https://doi. Intern Emerg Med. 2020;15(8):1457–65. https://doi.
org/10.1016/j.hrthm.2020.06.016. Epub 2020 Jun 22. org/10.1007/s11739-020-02493-y. Epub 2020 Sep 22.
PMID: 32585191; PMCID: PMC7307518. PMID: 32960429; PMCID: PMC7505942.
5. Cameli M, Pastore MC, Soliman Aboumarie H, 13. Giustino G, Croft LB, Stefanini GG, Bragato R,

Mandoli GE, D'Ascenzi F, Cameli P, Bigio E, Franchi Silbiger JJ, Vicenzi M, Danilov T, Kukar N, Shaban N,
F, Mondillo S, Valente S. Usefulness of echocardiog- Kini A, Camaj A, Bienstock SW, Rashed ER, Rahman
raphy to detect cardiac involvement in COVID-19 K, Oates CP, Buckley S, Elbaum LS, Arkonac D, Fiter
patients. Echocardiography. 2020;37(8):1278–86. R, Singh R, Li E, Razuk V, Robinson SE, Miller M,
Bier B, Donghi V, Pisaniello M, Mantovani R, Pinto J. 2020;41(48):4591. PMID: 32383763; PMCID:

G, Rota I, Baggio S, Chiarito M, Fazzari F, Cusmano PMC7239204.
I, Curzi M, Ro R, Malick W, Kamran M, Kohli-Seth 20. Kang Y, Chen T, Mui D, Ferrari V, Jagasia D,

R, Bassily-Marcus AM, Neibart E, Serrao G, Perk G, Scherrer-Crosbie M, Chen Y, Han Y. Cardiovascular
Mancini D, Reddy VY, Pinney SP, Dangas G, Blasi manifestations and treatment considerations in
F, Sharma SK, Mehran R, Condorelli G, Stone GW, COVID-19. Heart. 2020;106(15):1132–41. https://
Fuster V, Lerakis S, Goldman ME. Characterization doi.org/10.1136/heartjnl-2020-317056. Epub 2020
of myocardial injury in patients with COVID-19. J Apr 30. PMID: 32354800; PMCID: PMC7211105.
Am Coll Cardiol. 2020;76(18):2043–55. https://doi. 21. Kochi AN, Tagliari AP, Forleo GB, Fassini GM,

org/10.1016/j.jacc.2020.08.069. PMID: 33121710; Tondo C. Cardiac and arrhythmic complications in
PMCID: PMC7588179. patients with COVID-19. J Cardiovasc Electrophysiol.
14. Goha A, Mezue K, Edwards P, Nunura F, Baugh D, 2020;31(5):1003–8. https://doi.org/10.1111/
Madu E. COVID-19 and the heart: an update for cli- jce.14479. Epub 2020 Apr 13. PMID: 32270559;
nicians. Clin Cardiol. 2020;43(11):1216–22. https:// PMCID: PMC7262150.
doi.org/10.1002/clc.23406. Epub 2020 Jun 12. PMID: 22. Lombardi CM, Carubelli V, Iorio A, Inciardi RM,
32533585; PMCID: PMC7323229. Bellasi A, Canale C, Camporotondo R, Catagnano
15. Gopinathannair R, Merchant FM, Lakkireddy DR, F, Dalla Vecchia LA, Giovinazzo S, Maccagni
Etheridge SP, Feigofsky S, Han JK, Kabra R, Natale G, Mapelli M, Margonato D, Monzo L, Nuzzi
A, Poe S, Saha SA, Russo AM. COVID-19 and car- V, Oriecuia C, Peveri G, Pozzi A, Provenzale
diac arrhythmias: a global perspective on arrhythmia G, Sarullo F, Tomasoni D, Ameri P, Gnecchi M,
characteristics and management strategies. J Interv Leonardi S, Merlo M, Agostoni P, Carugo S, Danzi
Card Electrophysiol. 2020;59(2):329–36. https://doi. GB, Guazzi M, La Rovere MT, Mortara A, Piepoli
org/10.1007/s10840-020-00789-9. Epub 2020 Jun 3. M, Porto I, Sinagra G, Volterrani M, Specchia C,
PMID: 32494896; PMCID: PMC7268965. Metra M, Liu Y, Li J, Liu D, et al. Clinical features
16. Guo T, Fan Y, Chen M, et al. Cardiovascular impli- and outcomes of 2019 novel coronavirus-infected
cations of fatal outcomes of patients with corona- patients with cardiac injury. medRxiv. 2020;
virus disease 2019 (COVID-19). JAMA Cardiol. 2020.2003.2011.20030957.
2020; https://doi.org/10.1001/jamacardio.2020.1017. 23. Li C, Jiang J, Wang F, Zhou N, Veronese G, Moslehi
E201017. JJ, Ammirati E, Wang DW. Longitudinal correlation
17. Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis of biomarkers of cardiac injury, inflammation, and
K, Marelli-Berg FM, Madhur MS, Tomaszewski M, coagulation to outcome in hospitalized COVID-19
Maffia P, D'Acquisto F, Nicklin SA, Marian AJ, patients. J Mol Cell Cardiol. 2020;147:74–87. https://
Nosalski R, Murray EC, Guzik B, Berry C, Touyz doi.org/10.1016/j.yjmcc.2020.08.008. Epub 2020
RM, Kreutz R, Wang DW, Bhella D, Sagliocco Aug 20. PMID: 32827510; PMCID: PMC7438272.
O, Crea F, Thomson EC, McInnes IB. COVID-19 24. Li X, Guan B, Su T, Liu W, Chen M, Bin Waleed K,
and the cardiovascular system: implications for Guan X, Gary T, Zhu Z. Impact of cardiovascular
risk assessment, diagnosis, and treatment options. disease and cardiac injury on in-hospital mortality
Cardiovasc Res. 2020;116(10):1666–87. https:// in patients with COVID-19: a systematic review and
doi.org/10.1093/cvr/cvaa106. PMID: 32352535; meta-analysis. Heart. 2020;106(15):1142–7. https://
PMCID: PMC7197627. doi.org/10.1136/heartjnl-2020-317062. Epub 2020
18. Hayek SS, Brenner SK, Azam TU, Shadid HR,
May 27. PMID: 32461330; PMCID: PMC7295861.
Anderson E, Berlin H, Pan M, Meloche C, Feroz R, 25.
Long B, Brady WJ, Koyfman A, Gottlieb
O'Hayer P, Kaakati R, Bitar A, Padalia K, Perry D, M. Cardiovascular complications in COVID-19.
Blakely P, Gupta S, Shaefi S, Srivastava A, Charytan Am J Emerg Med. 2020;38(7):1504–7. https://doi.
DM, Bansal A, Mallappallil M, Melamed ML, org/10.1016/j.ajem.2020.04.048. Epub 2020 Apr 18.
Shehata AM, Sunderram J, Mathews KS, Sutherland PMID: 32317203; PMCID: PMC7165109.
AK, Nallamothu BK, Leaf DE, STOP-COVID 26. McCullough SA, Goyal P, Krishnan U, Choi JJ,

Investigators. In-hospital cardiac arrest in critically Safford MM, Okin PM. Electrocardiographic find-
ill patients with covid-19: multicenter cohort study. ings in coronavirus disease-19: insights on mortal-
BMJ. 2020;371:m3513. https://doi.org/10.1136/bmj. ity and underlying myocardial processes. J Card
m3513. PMID: 32998872; PMCID: PMC7525342. Fail. 2020;26(7):626–32. https://doi.org/10.1016/j.
19. Inciardi RM, Adamo M, Lupi L, Cani DS, Di
cardfail.2020.06.005. Epub 2020 Jun 13. PMID:
Pasquale M, Tomasoni D, Italia L, Zaccone G, Tedino 32544622; PMCID: PMC7293518.
C, Fabbricatore D, Curnis A, Faggiano P, Gorga E, 27. Mahenthiran AK, Mahenthiran AK, Mahenthiran

Lombardi CM, Milesi G, Vizzardi E, Volpini M, J. Cardiovascular system and COVID-19: mani-
Nodari S, Specchia C, Maroldi R, Bezzi M, Metra festations and therapeutics. Rev Cardiovasc Med.
M. Characteristics and outcomes of patients hospital- 2020;21(3):399–409. https://doi.org/10.31083/j.
ized for COVID-19 and cardiac disease in Northern rcm.2020.03.124. PMID: 33070544.
Italy. Eur Heart J. 2020;41(19):1821–9. https://doi. 28.
Manolis AS, Manolis AA, Manolis TA,
org/10.1093/eurheartj/ehaa388. Erratum in: Eur Heart Apostolopoulos EJ, Papatheou D, Melita
96 C. J. Hogan
H. COVID- 19 infection and cardiac arrhythmias. pulmonary and cardiac support of COVID-19 patients:
Trends Cardiovasc Med. 2020;30(8):451–60. https:// emerging recommendations from ASAIO-A "living
doi.org/10.1016/j.tcm.2020.08.002. Epub 2020 Aug working document". ASAIO J. 2020;66(6):588–98.
16. PMID: 32814095; PMCID: PMC7429078. https://doi.org/10.1097/MAT.0000000000001180.
29. Mishra AK, Sahu KK, George AA, Lal A. A review PMID: 32358232; PMCID: PMC7217129.
of cardiac manifestations and predictors of out- 38. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical
come in patients with COVID - 19. Heart Lung. predictors of mortality due to COVID-19 based on an
2020;49(6):848–52. https://doi.org/10.1016/j. analysis of data of 150 patients from Wuhan, China.
hrtlng.2020.04.019. Epub 2020 May 3. PMID: Intensive Care Med. 2020;46(5):846–8. https://doi.
32593418; PMCID: PMC7196397. org/10.1007/s00134-020-05991-x. Epub 2020 Mar
30. Naksuk N, Lazar S, Peeraphatdit TB. Cardiac safety 3. Erratum in: Intensive Care Med. 2020; PMID:
of off-label COVID-19 drug therapy: a review and 32125452; PMCID: PMC7080116.
proposed monitoring protocol. Eur Heart J Acute 39. Sandoval Y, Januzzi JL Jr, Jaffe AS. Cardiac troponin
Cardiovasc Care. 2020;9(3):215–21. https://doi. for assessment of myocardial injury in COVID-19:
org/10.1177/2048872620922784. Epub 2020 May 6. JACC review topic of the week. J Am Coll Cardiol.
PMID: 32372695; PMCID: PMC7235441. 2020;76(10):1244–58. https://doi.org/10.1016/j.
31. Nie SF, Yu M, Xie T, Yang F, Wang HB, Wang ZH, jacc.2020.06.068. Epub 2020 Jul 8. PMID:
Li M, Gao XL, Lv BJ, Wang SJ, Zhang XB, He SL, 32652195.
Qiu ZH, Liao YH, Zhou ZH, Cheng X. Cardiac tro- 40. Sanna G, Serrau G, Bassareo PP, Neroni P, Fanos V,
ponin I is an independent predictor for mortality in Marcialis MA. Children's heart and COVID-19: up-
hospitalized patients with COVID-19. Circulation. to-date evidence in the form of a systematic review.
2020;142(6):608–10. https://doi.org/10.1161/ Eur J Pediatr. 2020;179(7):1079–87. https://doi.
CIRCULATIONAHA.120.048789. Epub 2020 Jun org/10.1007/s00431-020-03699-0. Epub 2020 May
15. PMID: 32539541; PMCID: PMC7418761. 30. PMID: 32474800; PMCID: PMC7261213.
32. Nguyen JL, Yang W, Ito K, Matte TD, Shaman
41. Senni M. Association of troponin levels with mor-
J, Kinney PL. Seasonal influenza infections and tality in Italian patients hospitalized with corona-
cardiovascular disease mortality. JAMA Cardiol. virus disease 2019: results of a multicenter study.
2016;1(3):274–81. https://doi.org/10.1001/ JAMA Cardiol. 2020;5(11):1274–80. https://
jamacardio.2016.0433. doi.org/10.1001/jamacardio.2020.3538. PMID:
33. Parohan M, Yaghoubi S, Seraji A. Cardiac injury
32845276; PMCID: PMC7450398.
is associated with severe outcome and death in 42. Shafi AMA, Shaikh SA, Shirke MM, Iddawela S,
patients with coronavirus disease 2019 (COVID-19) Harky A. Cardiac manifestations in COVID- 19
infection: a systematic review and meta- analysis patients – a systematic review. J Card Surg.
of observational studies. Eur Heart J Acute 2020;35(8):1988–2008. https://doi.org/10.1111/
Cardiovasc Care. 2020;9(6):665–77. https://doi. jocs.14808. Epub 2020 Jul 11. PMID: 32652713;
org/10.1177/2048872620937165. Epub 2020 Jun 21. PMCID: PMC7404674.
PMID: 32567326; PMCID: PMC7678334. 43. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W,
34. Pranata R, Lim MA, Yonas E, Siswanto BB, Meyer Liu X, Liang J, Zhao Q, Huang H, Yang B, Huang
M. Out-of-hospital cardiac arrest prognosis dur- C. Association of cardiac injury with mortality in
ing the COVID-19 pandemic. Intern Emerg Med. hospitalized patients with COVID-19 in Wuhan,
2020;15(5):875–7. https://doi.org/10.1007/s11739- China. JAMA Cardiol. 2020;5(7):802–10. https://
020-02428-7. Epub 2020 Jul 9. PMID: 32647947; doi.org/10.1001/jamacardio.2020.0950. PMID:
PMCID: PMC7345450. 32211816; PMCID: PMC7097841.
35. Raad M, Dabbagh M, Gorgis S, Yan J, Chehab O, 44. Shao F, Xu S, Ma X, Xu Z, Lyu J, Ng M, Cui H, Yu
Dagher C, Jamoor K, Hussein IH, Cook B, Van Harn C, Zhang Q, Sun P, Tang Z. In-hospital cardiac arrest
M, Singh G, McCord J, Parikh S. Cardiac injury pat- outcomes among patients with COVID-19 pneumo-
terns and inpatient outcomes among patients admit- nia in Wuhan, China. Resuscitation. 2020;151:18–23.
ted with COVID-19. Am J Cardiol. 2020;133:154–61. https://doi.org/10.1016/j.resuscitation.2020.04.005.
https://doi.org/10.1016/j.amjcard.2020.07.040. Epub 2020 Apr 10. PMID: 32283117; PMCID:
Epub 2020 Jul 24. PMID: 32829913; PMCID: PMC7151543.
PMC7378523. 45. Si D, Du B, Ni L, Yang B, Sun H, Jiang N, Liu G,
36. Ramzy M, Montrief T, Gottlieb M, Brady WJ, Singh Massé S, Jin L, Nanthakumar J, Bhaskaran A, Yang
M, Long B. COVID-19 cardiac arrest management: a P, Nanthakumar K. Death, discharge and arrhyth-
review for emergency clinicians. Am J Emerg Med. mias among patients with COVID-19 and cardiac
2020;38(12):2693–702. https://doi.org/10.1016/j. injury. CMAJ. 2020;192(28):E791–8. https://doi.
ajem.2020.08.011. Epub 2020 Aug 17. PMID: org/10.1503/cmaj.200879. Epub 2020 Jun 24. PMID:
33041141; PMCID: PMC7430285. 32586839.
37. Rajagopal K, Keller SP, Akkanti B, Bime C, Loyalka 46. Siripanthong B, Nazarian S, Muser D, Deo R,

P, Cheema FH, Zwischenberger JB, El Banayosy A, Santangeli P, Khanji MY, Cooper LT Jr, Chahal
Pappalardo F, Slaughter MS, Slepian MJ. Advanced CAA. Recognizing COVID-19-related myocarditis:
the possible pathophysiology and proposed guide- Kawamura I, Bokhari M, Whang W, Bier BA, Malick
line for diagnosis and management. Heart Rhythm. W, Hashemi H, Miller MA, Choudry S, Pumill C,
2020;17(9):1463–71. https://doi.org/10.1016/j. Ruiz-Maya T, Hadley M, Giustino G, Koruth JS,
hrthm.2020.05.001. Epub 2020 May 5. PMID: Langan N, Sofi A, Dukkipati SR, Halperin JL, Fuster
32387246; PMCID: PMC7199677. V, Kohli-Seth R, Reddy VY. Malignant arrhythmias
47. Stefanini GG, Chiarito M, Ferrante G, Cannata F, in patients with COVID-19: incidence, mecha-
Azzolini E, Viggiani G, De Marco A, Briani M, nisms, and outcomes. Circ Arrhythm Electrophysiol.
Bocciolone M, Bragato R, Corrada E, Gasparini GL, 2020;13(11):e008920. https://doi.org/10.1161/
Marconi M, Monti L, Pagnotta PA, Panico C, Pini CIRCEP.120.008920. Epub 2020 Oct 7. PMID:
D, Regazzoli D, My I, Kallikourdis M, Ciccarelli M, 33026892; PMCID: PMC7668347.
Badalamenti S, Aghemo A, Reimers B, Condorelli 54. Vitiello A, Ferrara F. Pharmacological agents to

G, Humanitas COVID-19 Task Force. Early detec- therapeutic treatment of cardiac injury caused by
tion of elevated cardiac biomarkers to optimise risk Covid-19. Life Sci. 2020;262:118510. https://doi.
stratification in patients with COVID-19. Heart. org/10.1016/j.lfs.2020.118510. Epub 2020 Sep 28.
2020;106(19):1512–8. https://doi.org/10.1136/ PMID: 32991879; PMCID: PMC7521881.
heartjnl-2020-317322. Epub 2020 Aug 14. PMID: 55. Verma V, Sondhi S, Sharma R, Mahajan K. COVID-19
32817312. associated viral myocarditis: does it exist? Monaldi
48. Stefanini GG, Montorfano M, Trabattoni D, Andreini Arch Chest Dis. 2020;90(4) https://doi.org/10.4081/
D, Ferrante G, Ancona M, Metra M, Curello S, monaldi.2020.1382. PMID: 32945641.
Maffeo D, Pero G, Cacucci M, Assanelli E, Bellini 56. Walker C, Deb S, Ling H, Wang Z. Assessing the
B, Russo F, Ielasi A, Tespili M, Danzi GB, Vandoni elevation of cardiac biomarkers and the severity of
P, Bollati M, Barbieri L, Oreglia J, Lettieri C, COVID-19 infection: a meta-analysis. J Pharm Pharm
Cremonesi A, Carugo S, Reimers B, Condorelli G, Sci. 2020;23:396–405. https://doi.org/10.18433/
Chieffo A. ST-elevation myocardial infarction in jpps31501. PMID: 33086028.
patients with COVID-19: clinical and angiographic 57. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang
outcomes. Circulation. 2020;141(25):2113–6. https:// B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang
doi.org/10.1161/CIRCULATIONAHA.120.047525. X, Peng Z. Clinical characteristics of 138 hospitalized
Epub 2020 Apr 30. PMID: 32352306; PMCID: patients with 2019 novel coronavirus-infected pneu-
PMC7302062. monia in Wuhan, China. JAMA. 2020;323(11):1061–
49. Szekely Y, Lichter Y, Taieb P, Banai A, Hochstadt A, 9. https://doi.org/10.1001/jama.2020.1585. PMID:
Merdler I, Gal Oz A, Rothschild E, Baruch G, Peri Y, 32031570; PMCID: PMC7042881.
Arbel Y, Topilsky Y. Spectrum of cardiac manifesta- 58. Wei JF, Huang FY, Xiong TY, Liu Q, Chen H, Wang H,
tions in COVID-19: a systematic echocardiographic Huang H, Luo YC, Zhou X, Liu ZY, Peng Y, Xu YN,
study. Circulation. 2020;142(4):342–53. https://doi. Wang B, Yang YY, Liang ZA, Lei XZ, Ge Y, Yang M,
org/10.1161/CIRCULATIONAHA.120.047971. Zhang L, Zeng MQ, Yu H, Liu K, Jia YH, Prendergast
Epub 2020 May 29. PMID: 32469253; PMCID: BD, Li WM, Chen M. Acute myocardial injury is
PMC7382541. common in patients with COVID-19 and impairs their
50. Tavazzi G, Pellegrini C, Maurelli M, Belliato M, Sciutti prognosis. Heart. 2020;106(15):1154–9. https://doi.
F, Bottazzi A, Sepe PA, Resasco T, Camporotondo R, org/10.1136/heartjnl-2020-317007. Epub 2020 Apr
Bruno R, Baldanti F, Paolucci S, Pelenghi S, Iotti 30. PMID: 32354798; PMCID: PMC7398466.
GA, Mojoli F, Arbustini E. Myocardial localization 59. Wen W, Zhang H, Zhou M, Cheng Y, Ye L, Chen J,
of coronavirus in COVID-19 cardiogenic shock. Wang M, Feng Z. Arrhythmia in patients with severe
Eur J Heart Fail. 2020;22(5):911–5. https://doi. coronavirus disease (COVID-19): a meta-analysis.
org/10.1002/ejhf.1828. Epub 2020 Apr 11. PMID: Eur Rev Med Pharmacol Sci. 2020;24(21):11395–
32275347; PMCID: PMC7262276. 401. https://doi.org/10.26355/eurrev_202011_23632.
51. The European Society for Cardiology. ESC guid-
PMID: 33215461.
ance for the diagnosis and management of CV dis- 60. Xiong TY, Huang FY, Liu Q, Peng Y, Xu YN, Wei
ease during the COVID-19 pandemic. https://www. JF, Li N, Bai B, Li JH, Prendergast B, Li WM, Chen
escardio.org/Education/COVID-19-and-Cardiology/ M. Hypertension is a risk factor for adverse outcomes
ESCCOVID-19-Guidance. Last update: 10 June in patients with coronavirus disease 2019: a cohort
2020. study. Ann Med. 2020;52(7):361–6. https://doi.org/1
52. Tomasoni D, Italia L, Adamo M, Inciardi RM,
0.1080/07853890.2020.1802059. Epub 2020 Jul 31.
Lombardi CM, Solomon SD, Metra M. COVID-19 PMID: 32716217.
and heart failure: from infection to inflammation and 61. Yang J, Chen T, Zhou Y. Mediators of SARS-CoV-2
angiotensin II stimulation. Searching for evidence entry are preferentially enriched in cardiomyocytes.
from a new disease. Eur J Heart Fail. 2020;22(6):957– Hereditas. 2021;158(1):4. https://doi.org/10.1186/
66. https://doi.org/10.1002/ejhf.1871. Epub 2020 Jun s41065-020-00168-4. PMID: 33397514; PMCID:
24. PMID: 32412156; PMCID: PMC7273093. PMC7781406.
53.
Turagam MK, Musikantow D, Goldman ME, 62. Yonas E, Alwi I, Pranata R, Huang I, Lim MA,

Bassily-Marcus A, Chu E, Shivamurthy P, Lampert J, Gutierrez EJ, Yamin M, Siswanto BB, Virani SS. Effect
98 C. J. Hogan
of heart failure on the outcome of COVID-19 – a 64. Zeng L, Wang S, Cai J, Sun S, Wang S, Li J, Sun
meta analysis and systematic review. Am J Emerg L. Clinical characteristics of COVID-19 with car-
Med. 2020:S0735-6757(20)30602-1. https://doi. diac injury: a systematic review and meta-analysis.
org/10.1016/j.ajem.2020.07.009. Epub ahead of print. Epidemiol Infect. 2020;148:e266. https://doi.
PMID: 33071085; PMCID: PMC7347316. org/10.1017/S0950268820002587. PMID: 33092664;
63. Yu CM, Wong RS, Wu EB, Kong SL, Wong J, Yip PMCID: PMC7653493.
GW, Soo YO, Chiu ML, Chan YS, Hui D, Lee N, Wu 65. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19
A, Leung CB, Sung JJ. Cardiovascular complications and the cardiovascular system. Nat Rev Cardiol.
of severe acute respiratory syndrome. Postgrad Med 2020;17(5):259–60. https://doi.org/10.1038/
J. 2006;82(964):140–4. https://doi.org/10.1136/ s41569-020-0360-5. PMID: 32139904; PMCID:
pgmj.2005.037515. PMID: 16461478; PMCID: PMC7095524.
PMC2596695.
COVID Cardiovascular Illness
10
Timothy J. Ellender and Joseph R. Shiber
Part 1 Cardiovascular: Introduction asymptomatic early disease state [6–8]. Prior car-
diovascular disease has been linked to worse
Severe acute respiratory syndrome coronavirus 2 COVID-19 outcomes and increased risk of death
(SARS-CoV-2) and the associated coronavirus [7]. COVID-19 can directly invade and injure
disease 2019 (COVID-19) has become a global vascular endothelium and cardiac myocytes,
pandemic affecting billions of people. Though drive cytokine storm/inflammation, and create
COVID-19 morbidity is crucially tied to the supply-demand imbalance that can induce myo-
respiratory system, emerging data suggest that it cardial injury, arrhythmia, acute coronary syn-
also leads to hematological, hepatic, neurologi- drome, cerebrovascular insufficiency, and venous
cal, renal, and cardiac diseases [1–4]. SARS- thromboembolism [9]. In addition to direct viral
COV-2 uses a system of cell entry triggered by effects on tissues, potential drug interactions
binding of its viral spike protein to angiotensin- affecting patients with COVID-19 have become a
converting enzyme 2. This mechanism of activity significant cardiovascular concern. COVID car-
bound to angiotensin-converting enzyme 2 led to diovascular disease typically manifests as acute
a host of questions about the vascular effects of cardiac injury with potential for arrhythmia and
the virus, risks of patients with hypertension, and acute myocardial dysfunction with progression
the role of angiotensin-targeted medications in of acute heart failure, but does not appear to be
susceptibility and patient risk. Though many of associated with acute coronary events (plaque
the earliest concerns have been refuted by evi- rupture) that is common in the majority of car-
dence, studies have reported an association diac injury syndromes [10]. One emerging theory
between COVID-19 and cardiovascular (CV) for pathogenesis proposes that endothelial cells
disease [5, 6]. A surprising number of people in people with pre-existing cardiac disease
who contract SARS-COV-2 develop myocarditis, behave differently under a COVID immune
with delayed disability, even despite a relatively response and release inflammatory cytokines that
further exasperate the body’s inflammatory
response and lead to the formation of micro-
T. J. Ellender (*)
Department of Emergency Medicine, Indiana thrombi [11]. Yet there is increasing evidence that
University School of Medicine, Indianapolis, IN, USA SARS-COV-2 directly affects cardiomyocytes
e-mail: [email protected] using ACE2 protein entry and can cause cardiac
J. R. Shiber dysfunction by direct injury, not just indirectly
Departments of Emergency Medicine, Neurology and via demand hypoxemia, small vessel thrombosis,
Surgery, University of Florida Health Science Center,
and hemodynamic stress [5]. Understanding this

100 T. J. Ellender and J. R. Shiber
interplay between various systems and therapies COVID-19 patients, and pre-existing cardiovas-
that might mitigate cardio-cerebral compromise cular comorbidities (p < 0.001), older age
is essential. (p < 0.001), and the development of cardiovascu-
lar complications (Fig. 10.1) during the hospital-
ization (p = 0.038) had a significant trend towards
Risk Factors death [14].
Pre-existing cardiovascular disease and CV risk

factors heighten vulnerability to COVID-19 and Pathophysiology
are linked to disease severity and worsened out-
comes [12]. Early compiled data from China The vascular endothelium regulates barrier isola-
including 1527 patients with COVID-19 reported tion, hemodynamic homeostasis, immune com-
a 9.7%, 16.4%, and 17.1% prevalence of diabe- petence, inflammatory equilibrium, and
tes, cardio-cerebrovascular disease, and hyper- thrombotic/fibrinolytic balance [11].
tension [13, 14]. More importantly, the presence Accumulating evidence from basic science,
of diabetes, cardio-cerebrovascular disease, and imaging, and clinical observations suggests that
hypertension was associated with a twofold to vascular endothelial cells can be affected by
threefold increased risk of severe disease. Figures COVID-19 [15–18]. These data suggest endothe-
from the Chinese Center for Disease Control and lium can be directly infected by SARS-COV-2
Prevention suggest a global case fatality rate and also contribute to leukocyte recruitment
(CFR) of 2.3% for the entire cohort but signifi- which when activated leads to tissue damage and
cantly higher (6%, 7.3%, and 10.5%, respec- cytokine release that can trigger acute respiratory
tively) in patients with hypertension, diabetes, distress syndrome (ARDS), disseminated intra-
and cardiovascular disease [12, 14]. This data vascular coagulation, and cardiovascular compli-
analysis found that 20% of hospitalized cations in COVID-19 [16]. Cytokine storm and
COVID-19 patients developed heart disease and coagulopathy characterized by interleukin-6
31% of those in the ICU developed thromboem- derangements and elevated D-dimer and fibrino-
bolic events [13]. A meta-analysis of observa- gen concentrations have long been linked to a
tional studies evaluating cardiovascular (CV) prothrombotic state and venous thromboembolic
complications in hospitalized COVID-19 patients events [19]. SARS-CoV-2 uses the angiotensin-
and the impact of cardiovascular risk factors (RF) converting enzyme 2 (ACE2) to facilitate entry
identified 21 eligible studies (77,317 hospitalized into target cells and endothelial cells, and cardiac
patients) from different geographic areas, includ- pericytes express abundant ACE2, making them a
ing Asia, Europe, and the United States, that direct target of SARS-CoV-2 infection [20].
reported clinical outcomes of patients admitted to Data suggests direct endotheliopathy can be
the hospital and with a confirmed positivity to the measured via markers of endothelial cell and
SARS-CoV-2 virus [14]. 12.86% had cardiovas- platelet activation, including von Willebrand fac-
cular comorbidities; hypertension was present in tor (VWF) antigen, soluble thrombomodulin,
36.08% (95% CI = 20.25–53.64) of all patients. soluble P-selectin, and soluble CD40 ligand, as
19.45% of all patients suffered from diabetes, well as coagulation factors, endogenous antico-
10.74% of patients were smokers, chronic agulants, and fibrinolytic enzymes. Studies have
obstructive pulmonary disease (COPD) was pres- suggested that significant elevation of endothelial
ent for 5.30% of patients, and obesity was present biomarkers (von Willebrand factor, P-selectin,
in 33.78% of patients. A diagnosis of coronary and thrombomodulin) can be traced in compari-
artery disease (CAD) was already known at pre- son samples of patients with COVID critical ill-
sentation for 11.67% of patients, and heart failure ness, and higher serum concentrations directly
(HF) was present in 9.35% (95% CI = 6.19– correlate to severity of illness, likelihood of dis-
13.09) of patients. Cardiovascular complications charge, and survival [11, 21]. Additional pathol-
were frequently encountered (14.09%) among ogy data examining widespread thrombosis,
10 COVID Cardiovascular Illness 101
CV complications
Angina 10.15% (3.15-20.48)

Arrhythmias 18.40% (7.78-32.25)
Myocardial injury 10.34% (6.73-14.62)
Acute HF 1.96% (0.94-3.35)
Myocardial infarction 3.54% (2.11-5.32)
CV complications 14.09% (10.26-20.23)
0 10 20 30 40
Proportion (%)
Fig. 10.1 Cardiovascular complications. (From Sabatino meta-analysis for a single endpoint. The square represents
et al. [96].) Cardiovascular complications in hospitalized the summary effect size (proportion) and the horizontal
COVID-19 patients. Each line represents the result of the line the relative 95% confidence interval
Endothelium and
endotheliitis
- Pericytes infection
Myocardium - Vascular injury Imbalance of ACE2
- Endothelial cells infection, - ↑ in ACE1/ACE2 ratio
- Direct viral injury activation, and local inflammation
- Microvascular injury - ↑ Profibrotic
- Systemic hyperinflammactory response - ↑ Proinflammatory
- Acute Coronary Syndrome - ↑ Proapoptotic
- Oxygen supply & demand mismatch - ↑ Vasoconstriction
Coagulation and fibrinolytic Host cell death

system
- Secondary to virus infection with or
- ↑ Fibrin deposition SARS-CoV2 without virus cell entry
- ↑ D-Dimer levels
- Regulated cell death by pyroptosis
- DIC and fibrinolysis shutdown
in critically ill patients - Local release of IL1b and IL-18
Neutrophil extracellular traps Hyperinflammation

- Platelet and neutrophils interaction Platelets - Diffuse lung inflammation and
- Thrombin generation
- Inflammatory and thrombotic state - Platelet activation and granule release pulmonary intravascular coagulopathy
promotion at micro & macrovascular level - Inflammation and thrombosis state - Systemic effect of IL-1b, IL-6, and IL-18
amplification
- Circulating megakaryocytes
Fig. 10.2 Pathogenesis of vascular injury and hyperco- interleukin, and SARS-CoV-2 severe acute respiratory
agulability. ACE indicates angiotensin-converting syndrome coronavirus 2
enzyme, DIC disseminated intravascular coagulation, IL
microangiopathy, endothelial activation, and and even sudden cardiac death have been reported
angiogenesis establish the role of viral injury to [24, 25]. Electrocardiographic changes and tro-
the vascular system with resulting vascular dys- ponin elevation may signal underlying cardiac
function in COVID-19 patients [22, 23] injury (myocarditis) which can progress to dia-
(Fig. 10.2). stolic impairment or systolic impairment with
Clinically this vascular dysfunction can reduced ejection fraction [25]. One German
worsen cardiovascular disease and prompt unique study reported ongoing myocardial inflammation
cardiac complications [24]. Tachycardia, brady- in 60% of 100 recently recovered patients with
cardia, arrhythmia, hypotension, heart failure, COVID-19 even in patients with minor symp-
AL GRAWANY
toms that never required hospitalization (67% of cardiac dysfunction and persistent hypoperfusion
100 patient cohort) [7]. Beyond the heart, despite adequate fluid loading and the use of
COVID-19-induced endotheliopathy with associ- vasopressor agents, dobutamine can be added.
ated impaired microcirculatory function might For adults with COVID-19 and refractory septic
explain COVID-related injury in a host of organs shock who are not receiving corticosteroids to
(Fig. 10.3). treat their COVID-19, low-dose corticosteroid
therapy can be added for shock reversal. A typi-
cal corticosteroid regimen in septic shock is
Treatment intravenous hydrocortisone 200 mg per day
administered either as an infusion or in intermit-
Cardiovascular Management tent doses. Patients who are receiving corticoste-
No direct evidence addresses the optimal resusci- roids for COVID-19 are receiving sufficient
tation strategy for patients with COVID-19- replacement therapy such that they do not require
associated shock. Available guidelines do additional hydrocortisone [1].
recommend early vasopressors and inotropes to
enable a conservative fluid resuscitation/hydra- Venous-Thromboembolic Disease,
tion strategy to maintain a net negative fluid bal- Anticoagulation, and Antiplatelet
ance goal as a means to treat COVID-associated Therapy
shock [1, 26]. Early vasopressors/inotropes are Infection with the novel severe acute respira-
most rapidly initiated via a good quality periph- tory syndrome coronavirus (SARS-CoV-2) has
eral venous line (with regular monitoring of the been associated with inflammation and a pro-
intravenous line site) and can later be converted thrombotic state, with increases in fibrin, fibrin
to a central venous access, when appropriate degradation products, fibrinogen, and D-dimers
[26]. Ultimately, patients with COVID-19 who [33–35]. The following table includes the NIH
require fluid resuscitation or hemodynamic man- guidelines for the use of testing and adjunctive
agement of shock should be treated and managed therapies in the prevention and treatment of
identically to patients with septic shock in accor- COVID-related coagulation disorders
dance with other published guidelines. (Table 10.1).
Specifically, resuscitative efforts using buff-
ered/balanced crystalloids over unbalanced crys-
talloids and albumin should be targeted to Part 2 Vascular: Introduction
dynamic parameters, skin temperature, capillary
refilling time, and/or lactate levels, over static SARS-CoV-2 enters and infects cells by binding
parameters to assess fluid responsiveness [27– to the ACE2 receptor on alveolar epithelial cells
31]. Dynamic parameters might include stroke but which is also widely expressed in the cardio-
volume variation (SVV), pulse pressure variation vascular, GI, renal, and central nervous systems
(PPV), and stroke volume change with passive as well as in adipose tissue [36–38]. The vascular
leg raise or fluid challenge, though passive leg endothelium is the critical link in regulating the
raising, followed by PPV and SVV, appears to coagulation/anticoagulation and fibrinolysis sys-
predict fluid responsiveness with the highest tems; the endothelial cell damage from
accuracy [32]. For those with profound hypoten- COVID- 19 infection can cause microvascular
sion or who remain hypo-perfused despite fluid dysfunction, vasoplegia, vascular permeability,
therapy, norepinephrine remains the first-choice and thrombosis [36, 39].
vasopressor. In refractory hypotension, either D-Dimer and fibrin/fibrinogen degradation
vasopressin (up to 0.03 units/min) or epinephrine products are key biomarkers of coagulation and
can be added to norepinephrine to raise mean platelet activation in clinical care, while
arterial pressure to target or decrease norepineph- C-reactive protein, procalcitonin, and ferritin are
rine dosage. In patients who show evidence of the biomarkers of inflammation (see Table 10.2).
Fig. 10.3 Organ injury-COVID-19. (From Mokhtari glutamyl transferase, ALP alkaline phosphatase, Cr cre-
et al. [95]). The features of multiorgan failure were sum- atinine, eGFR estimated glomerular filtration rate, BUN
marized due to the laboratory and imaging findings. hs- blood urea nitrogen, DIC disseminated intravascular
cTnI sensitive cardiac troponin I, CK creatine kinase, coagulation, VTE venous thromboembolism, LDH lactate
α-HBDH α-hydroxybutyrate dehydrogenase, LV left ven- dehydrogenase, NLR neutrophil/lymphocyte ratio, PLR
tricular, ALT alanine aminotransferase, AST aspartate platelet/lymphocyte ratio, PT prothrombin time, aPTT
aminotransferase, TB total bilirubin, GGT gamma- activated partial thromboplastin time
Table 10.1 Summary recommendations on VTE prophylaxis and therapy

Testing and screening
In non-hospitalized patients with COVID-19, there are currently no data to support the measurement of coagulation
markers (e.g., D-dimers, prothrombin time, platelet count, fibrinogen) (AIII) as there is a lack of prospective data
demonstrating that they can be used to predict the risk of VTE in those who are asymptomatic or who have mild
SARS-CoV-2 infection
In hospitalized patients with COVID-19, hematologic and coagulation parameters are commonly measured;
however, there are currently insufficient data to recommend either for or against using such data to guide
management decisions
Patients who are receiving anticoagulant or antiplatelet therapies for underlying conditions should continue these
medications if they receive a diagnosis of COVID-19 (AIII)
There are currently insufficient data to recommend either for or against routine deep vein thrombosis screening in
COVID-19 patients without signs or symptoms of VTE, regardless of the status of their coagulation markers
Venous thromboembolism prophylaxis
For non-hospitalized patients, anticoagulants and antiplatelet therapy should not be initiated for the prevention of
venous thromboembolism (VTE) or arterial thrombosis unless the patient has other indications for the therapy or is
participating in a clinical trial (AIII)
Hospitalized (nonpregnant) adults with COVID-19 should receive prophylactic dose anticoagulation (AIII). There
are currently insufficient data to recommend for or against higher than prophylactic dose of anticoagulation for VTE
prophylaxis in hospitalized COVID-19 patients outside of a clinical trial. Hospitalized patients with COVID-19
should not routinely be discharged from the hospital with VTE prophylaxis (AIII). Continuing anticoagulation with
a Food and Drug Administration-approved regimen for extended VTE prophylaxis after hospital discharge can be
considered in patients who are at low risk for bleeding and high risk for VTE (BI)
Anticoagulant or antiplatelet therapy should not be used to prevent arterial thrombosis outside of the usual standard
of care for patients without COVID-19 (AIII)
Treatment
For hospitalized COVID-19 patients who experience rapid deterioration of pulmonary, cardiac, or neurological
function or sudden, localized loss of peripheral perfusion, the possibility of thromboembolic disease should be
evaluated (AIII). When diagnostic imaging is not possible, patients with COVID-19 who experience an incident
thromboembolic event or who are highly suspected to have thromboembolic disease should be managed with
therapeutic doses of anticoagulant therapy (AIII)
Rating of recommendations: A = strong; B = moderate; C = optional
Rating of evidence: I = one or more randomized trials with clinical outcomes and/or validated laboratory
endpoints; II = one or more well-designed, nonrandomized trials or observational cohort studies; III = expert
opinion
Accessed 1/31/21
Last Updated: December 17, 2020: https://www.covid19treatmentguidelines.nih.gov/critical-care/
Table 10.2 Markers of thrombosis in COVID-19 (PT), D-dimer, and fibrinogen but lower platelet
Coagulation: D-dimer, fibrin/fibrinogen degradation counts [45–50].
products, von Willebrand factor, PT/APTT, platelet
count
Platelet activation: Thromboxane B2, P-selectin,
soluble CD40 ligand, mean platelet volume
Pathophysiology
Inflammation: CRP, ESR, ferritin, procalcitonin
Manolis et al. [42] The vascular endothelium is the interface between
blood and tissue interactions and tightly regulates
Elevated D-dimer at admission (>2500 ng/mL) vasomotor, inflammatory, permeability, and host
was found to be associated with coagulation- defense functions. The cytokine storm seen with
induced complication, critical condition, and severe COVID illness furthers the endothelial
mortality [40, 41]. D-Dimer levels were higher in dysfunction [51–53]. The dysregulated endothe-
patients who developed VTE than in those lium also is subject to leukocyte activation and
patients who did not have any VTE [42–44]. A neutrophil extracellular trap formation (DNA
meta-analysis found in patients with severe matrix with neutrophil granule proteins such as
COVID-19 infection higher prothrombin time myeloperoxidase and elastase), platelet activa-
tion, complement deposition, and programmed incidence in COVID-19 patients has been reported
inflammatory cell death [42, 54]. Alterations in to be 10–35% but including autopsy data reaching
endothelial activity from COVID-19 infection almost 60% [42, 79].
have been seen to predispose thrombi formation
in the pulmonary circulation, peripheral veins
and arteries, and cerebral and coronary circula- Treatment
tion; the microvascular dysfunction has been
seen to commonly cause what has been called Current COVID-19 therapies utilize anti-
“COVID toes” [40, 41, 55, 56]. inflammatory actions such as glucocorticoids,
The glycocalyx is a complex layer of glyco- statins, IL-1 antagonists anakinra and
sylated lipoproteins including proteoglycans canakinumab, and possibly anti-IL-6 strategies
with glycosaminoglycan side chains (heparan [80–85]. Cytokine clearance therapies such as
and chondroitin sulfate) and hyaluronic acid. It plasma absorption, plasma exchange, and hemo-
protects the vascular endothelium from damage filtration are currently recommended for treating
due to excessive shear from blood flow [23, 57, severe COVID-19 illness in order to reduce
58]. Fragmented vascular endothelial glycocalyx inflammatory cytokines and improve the balance
(VEGLX), the extracellular matrix covering the in coagulation and fibrinolysis [86–88]. There are
vascular endothelial cell monolayer, is elevated ongoing trials to determine the potential benefi-
in ARDS, DIC, severe traumatic and septic shock, cial effects of the anti-inflammatory drug colchi-
preeclampsia, Kawasaki disease, post-cardiac cine in COVID-19 illness, as it has been found to
arrest syndrome, and COVID-19 patients and have cardioprotective benefits in non-COVID
may be a useful prognostic indicator [59–64]. patients [89, 90].
VEGLX damage has been found in patients with In COVID-19 ICU patients receiving throm-
cardiovascular disease (hypertension, diabetes, boprophylaxis, one study found a 31% cumula-
coronary and peripheral arterial disease) which tive incidence of thrombotic events (PE, DVT,
potentially allows increased viral infection and stroke, MI, and systemic arterial occlusion) [91,
hence worsened endothelial dysfunction and 92]. The optimal agent and dosing for the pro-
clinical COVID-19 severity [65–70]. phylaxis and treatment of COVID-19-induced
The enhanced coagulation and thrombosis thrombosis are still being studied [89, 93].
induced by COVID-19 infection are known to Hypoxia has been theorized as an additional
cause pulmonary embolism and pulmonary arte- trigger of thrombosis and provides a possible
rial thrombosis (in situ clots without peripheral explanation for the perceived resistance to throm-
venous thrombosis), as well as microthrombi in boprophylaxis with heparin [56, 97]. Aspirin
cardiac, renal, and hepatic portal vessels [71–76]. with its anti-inflammatory and antithrombotic
There are two mechanisms responsible for the properties also should be considered for the
induced hypercoagulability: enhanced coagula- endothelial dysfunction and microvascular
tion and attenuation of anticoagulant and fibrino- inflammation of COVID [94].
lysis. A reduction in tissue plasminogen activator
(t-PA) while an increase in plasminogen activator Conflicts of Interest The authors declare no financial
inhibitor-1 (PAI-1) causes a decrease in plasmin conflicts of interest.
and increase in fibrinogen levels [36, 38, 77, 78].
Pulmonary arterial thrombosis is the most com-
mon vascular disorder caused by the endothelial References
dysfunction and hypercoagulable state induced by
1. Centers for Disease Control and Prevention. Evidence
COVID-19 infection. This thrombotic occlusion used to update the list of underlying medical condi-
of small- and medium-sized arteries leads to pul- tions that increase a person’s risk of severe illness
monary parenchymal infraction, severe hypoxic from COVID-19. 2020. Available at: https://www.cdc.
respiratory failure with increased physiologic dead gov/coronavirus/2019-ncov/need-extra-precautions/
evidence-table.html. Accessed 8 Mar 2021.
space, and increased mortality (3:1,2,3). The VTE
2. Wu C, Chen X, Cai Y, et al. Risk factors associ- 2020;15(12):e0243471. https://doi.org/10.1371/jour-

ated with acute respiratory distress syndrome and nal.pone.0243471.
death in patients with coronavirus disease 2019 16. Evans PC, Rainger GD, Mason JC, et al. Endothelial
pneumonia in Wuhan, China. JAMA Intern Med. dysfunction in COVID-19: a position paper of the
2020;180(7):934–43. ESC Working Group for Atherosclerosis and Vascular
3. Arentz M, Yim E, Klaff L, et al. Characteristics and Biology, and the ESC Council of Basic Cardiovascular
outcomes of 21 critically ill patients with COVID-19 in Science. Cardiovas Res. 2020;116(14):2177–84.
Washington state. JAMA. 2020;323(16):1612–4. 17.
Ortega-Paz L, Capodanno D, Montalescot G,
4. Bhatraju PK, Ghassemieh BJ, Nichols M, Angiolillo DJ. Coronavirus disease 2019-associated
et al. COVID- 19 in critically ill patients in the thrombosis and coagulopathy: review of the patho-
Seattle region—case series. N Engl J Med. physiological characteristics and implications for
2020;382(21):2012–22. antithrombotic management. J Am Heart Assoc.
5. Pérez-Bermejo JA, Serah Kang SJ, Rockwood CR, 2021;10(3):e019650.
et al. SARS-CoV-2 infection of human iPSC-derived 18. Henry BM, Vikse J, Benoit S, Favaloro EJ, Lippi
cardiac cells predicts novel cytopathic features in G. Hyperinflammation and derangement of renin-
hearts of COVID-19 patients. bioRxiv. 2020. https:// angiotensin- aldosterone system in COVID-19: a
doi.org/10.1101/2020.08.25.265561. novel hypothesis for clinically suspected hypercoagu-
6. Bavishi C, Bonow RO, Trivedi V, Abbott JD, Messerli lopathy and microvascular immunothrombosis. Clin
FH, Bhatt DL. Special article – acute myocardial Chim Acta. 2020;507:167–73.
injury in patients hospitalized with COVID-19 infec- 19. Zhou F, Yu T, Du R, et al. Clinical course and

tion: a review. Prog Cardiovasc Dis. 2020;63(5):682– risk factors for mortality of adult inpatients with
9. https://doi.org/10.1016/j.pcad.2020.05.013. COVID-19 in Wuhan, China: a retrospective cohort
7. Shi S, Qin M, Shen B, et al. Association of car- study. Lancet. 2020;395(10229):1054–62.
diac Injury with mortality in hospitalized patients 20. Hamming I, Timens W, Bulthuis M, Lely A, Navis
with COVID-19 in Wuhan, China. JAMA Cardiol. G, van Goor H. Tissue distribution of ACE2 protein,
2020;5(7):802–10. https://doi.org/10.1001/ the functional receptor for SARS coronavirus. A first
jamacardio.2020.0950. step in understanding SARS pathogenesis. J Pathol.
8. Puntmann VO, Carerj ML, Wieters I, et al. Outcomes 2004;203(2):631–7.
of cardiovascular magnetic resonance imaging in 21.
Malas MB, et al. Thromboembolism risk of
patients recently recovered from coronavirus disease COVID-19 is high and associated with a higher risk
2019 (COVID-19). JAMA Cardiol. 2020;5(11):1265– of mortality: a systematic review and meta-analysis.
73. https://doi.org/10.1001/jamacardio.2020.3557. EClinicalMedicine. 2020;29:100639.
9. Dhar SK, Sachdeva K, Das M, et al. Inflammation and 22. Libby P, Lüscher T. COVID-19 is, in the end, an endo-
hypercoagulopathy are predominant risk factors of thelial disease. Eur Heart J. 2020 Aug;21:4.
severity in COVID-19 patients with diabetes mellitus: 23. Ackermann M, Verleden SE, Kuehnel M, et al.

summary of a meta-analysis. Diabetes Metab Syndr Pulmonary vascular endothelialitis, thrombo-
Clin Res Rev. 2021;15(2):639–41. sis, and angiogenesis in Covid-19. N Engl J Med.
10. Smilowitz NR, Jethani N, Chen J, et al. Myocardial 2020;383(2):120–8. https://doi.org/10.1056/
injury in adults hospitalized with COVID-19. NEJMoa2015432.
Circulation. 2020;142(24):2393–5. 24.
Xiong T-Y, Redwood S, Prendergast B, Mao
11. Goshua G, et al. Endotheliopathy in COVID-19-
C. Coronaviruses and the cardiovascular system:
associated coagulopathy: evidence from a single- acute and long-term implications. Eur Heart J.
centre, cross-sectional study. Lancet Haemat. 2020;41(19):1798–800.
2020;7(8):e575–82. 25. Yu CM, Wong RSM, Wu EB, et al. Cardiovascular
12. Wu Z, McGoogan JM. Characteristics of and
complications of severe acute respiratory syndrome.
Important Lessons From the Coronavirus Disease Postgrad Med J 2006;82(964):140–144.
2019 (COVID-19) Outbreak in China: Summary 26. Alhazzani W, Moller MH, Arabi YM, et al. Surviving
of a Report of 72 314 Cases From the Chinese sepsis campaign: guidelines on the management of
Center for Disease Control and Prevention. JAMA. critically ill adults with coronavirus disease 2019
2020;323(13):1239–1242. https://doi.org/10.1001/ (COVID-19). Crit Care Med. 2020;48(6):e440–69.
jama.2020.2648. PMID: 32091533. 27. Bentzer P, Griesdale DE, Boyd J, MacLean K,

13. Li B, Yang J, Zhao F, et al. Prevalence and impact of Sirounis D, Ayas NT. Will this hemodynamically
cardiovascular metabolic diseases on COVID-19 in unstable patient respond to a bolus of intravenous flu-
China. Clin Res Cardiol. 2020. ids? JAMA. 2016;316(12):1298–309.
14. Bansal M. Cardiovascular disease and COVID-19.
28. Pan J, Peng M, Liao C, Hu X, Wang A, Li

Diabetes Metab Syndr. 2020;14(3):247–50. https:// X. Relative efficacy and safety of early lactate
doi.org/10.1016/j.dsx.2020.03.013. clearance-guided therapy resuscitation in patients
15. Sabatino J, De Rosa S, Di Salvo G, Indolfi
with sepsis: a meta-analysis. Medicine (Baltimore).
C. Correction: impact of cardiovascular risk profile 2019;98(8):e14453.
on COVID-19 outcome. A meta-analysis. PLoS One.
29. Semler MW, Self WH, Wanderer JP, et al. Balanced 43. Hasan SS, Radford S, Kow CS, Zaidi STR. Venous
crystalloids versus saline in critically ill adults. N thromboembolism in critically ill COVID-19 patients
Engl J Med. 2018;378(9):829–39. receiving prophylactic or therapeutic anticoagulation:
30. Brown RM, Wang L, Coston TD, et al. Balanced crys- a systematic review and meta-analysis. J Thromb
talloids versus saline in sepsis. A secondary analysis Thrombolysis. 2020;1–8. https://doi.org/10.1007/
of the SMART clinical trial. Am J Respir Crit Care s11239-020-02235-z. Online ahead of print:1–8.
Med. 2019;200(12):1487–95. 44. Al-Samkari H, Karp Leaf RS, Dzik WH, et al.

31. Lewis SR, Pritchard MW, Evans DJ, et al. Colloids COVID-19 and coagulation: bleeding and thrombotic
versus crystalloids for fluid resuscitation in criti- manifestations of SARS-CoV-2 infection. Blood.
cally ill people. Cochrane Database Syst Rev. 2020;136(4):489–500.
2018;8:CD000567. 45. Di Minno MND, Calcaterra I, Lupoli R, et al.

32.
Bednarczyk JM, Fridfinnson JA, Kumar A, Hemostatic changes in patients with COVID-19: a
et al. Incorporating dynamic assessment of fluid meta-analysis with meta-regressions. J Clin Med.
responsiveness into goal-directed therapy: a sys-
2020;9(7):2244.
tematic review and meta-analysis. Crit Care Med. 46. Vidali S, Morosetti D, Cossu E, et al. D-dimer

2017;45(9):1538–45. as an indicator of prognosis in SARS-CoV-2
33. Nishiga M, Wang DW, Han Y, Lewis DB, Wu
infection: a systematic review. ERJ Open Res.
JC. COVID-19 and cardiovascular disease: from basic 2020;6(2):00260–2020.
mechanisms to clinical perspectives. Nat Rev Cardiol. 47. Nougier C, Benoit R, Simon M, et al. Hypofibrinolytic
2020;17(9):543–58. state and high thrombin generation may play a major
34. Helms J, Tacquard C, Severac F, et al. High risk of role in sars-cov2 associated thrombosis. J Thromb
thrombosis in patients in severe SARS-CoV-2 infec- Haemost. 2020. https://doi.org/10.1111/jth.15016.
tion: a multicenter prospective cohort study. Intensive Online ahead of print.
Care Med. 2020. Published online ahead of print. 48.
Creel-Bulos C, Auld SC, Caridi-Scheible M,
Available at: https://www.ncbi.nlm.nih.gov/pmc/ et al. Fibrinolysis shutdown and thrombosis in
articles/PMC7197634/. A COVID- 19 ICU. Shock. 2020. https://doi.
35. Klok FA, Kruip M, van der Meer NJM, et al.
org/10.1097/SHK.0000000000001635. Online ahead
Incidence of thrombotic complications in critically ill of print.
ICU patients with COVID-19. Thromb Res. 2020. 49. Coccheri S. COVID-19: the crucial role of blood coag-
36. Ma H. Pathogenesis and treatment strategies of
ulation and fibrinolysis. Intern Emerg Med. 2020:1–5.
COVID-19-related hypercoagulant and throm- 2020 August 3;1–5. https://doi.org/10.1007/s11739-
botic complications. Clin Appl Thromb Hemost. 020-02443-8. Online ahead of print.
2020;26:1–5. 50. Patel BV, Arachchillage DJ, Ridge CA, et al.

37. Guzik TJ, Mohiddin SA, Dimarco A, et al. COVID-19 Pulmonary angiopathy in severe COVID-19: physi-
and the cardiovascular system implications for ologic, imaging and hematologic observations. Am J
risk assessment, diagnosis, and treatment options. Respir Crit Care Med. 2020;202(5):690–9.
Cardiovasc Res. 2020. https://doi.org/10.1093/cvr/ 51. Libby P, Luscher T. COVID-19 is, in the end, an endo-
cvaa106. thelial disease. Eur Heart J. 2020;41:3038–44.
38. Magrone T, Magrone M, Jirillo E. Focus on receptors 52. Libby P. The vascular biology of atherosclerosis. In:
for coronaviruses with special reference to ACE-2 as Zipes DP, Libby P, Bonow RO, Mann DL, Tomaselli
a potential drug target- a perspective. Endocr Metab GF, editors. Braunwald’s heart disease. 11th ed.
Immune Discord Drug Targets. 2020. Philadelphia: Elsevier; 2018. p. 859–75.
39. Spiezia L, Boscolo A, Poletto F, et al. COVID-19- 53. Pober JS, Sessa WC. Evolving functions of endo-
related severe hypercoagulability in patients admit- thelial cells in inflammation. Nat Rev Immunol.
ted to intensive care unit for acute respiratory failure. 2007;7:803–15.
Thromb Haemost. 2020;120(6):998–100. 54. Kipshidze N, Dangas G, White CJ, et al. Viral

40. McFadyen JD, Stevens H, Peter K. The emerging coagulopathy in patients with COVID-19: treat-
threat of (Micro)thrombosis in COVID-19 and its ther- ment and care. Clin Appl Thromb Hemost.
apeutic implications. Circ Res. 2020;127(4):571–87. 2020;26:1076029620936776.
41. Nagashima S, Mendes MC, Camargo Martins AP,
55. Connors JM, Levy JH. COVID-19 and its implica-
et al. Endothelial dysfunction and thrombosis in tions for thrombosis and anticoagulation. Blood.
patients with COVID-19. Arterioscler Thromb 2020;135(23):2033–40.
Vasc Biol. 2020. 402404. https://doi.org/10.1161/ 56. Thachil J. Hypoxia—an overlooked trigger for throm-
Atvbaha120314860. bosis in COVID-19 and other critically ill patients.
42. Manolis AS, Manolis TA, Manolis AA, et al.
J Thromb Haemost 2020. https://doi.org/10.1111/
COVID-19 infection: viral macro and micro-vascular jth.15029. Online ahead of print.
coagulopathy and thromboembolism/prophylactic 57. Yamaoka-Tojo M. Vascular endothelial glycocalyx

and therapeutic management. J Cardiovasc Pharmacol damage in COVID-19. Int J Mol Sci. 2020;21:9712.
Ther. 2021;26:12–24. 58. Rovas A., Osiaevi I., Buscher K., et al. Microvascular
dysfunction in COVID-19: the MYSTIC study.
Angiogenesis. 2020. https://doi.org/10.1007/ high-dose heparin for thromboprophylaxis justi-

s10456-020-09753-7. fied? [published online ahead of print April 29,
59. Rubio-Gayosso I, Platts SH, Duling BR. Reactive
2020]. Thromb Haemost. 2020. doi:https://doi.
oxygen species mediate modification of glycocalyx org/10.1055/s-0040-1712097.
during ischemia-reperfusion injury. Am J Physiol 73. Whyte CS, Morrow GB, Mitchell JL, Chowdary

Heart Circ Physiol. 2006;290:H2247–56. https://doi. P, Mutch NJ. Fibrinolytic abnormalities in acute
org/10.1152/ajpheart.00796.2005. respiratory distress syndrome (ARDS) and ver-
60. Nieuwdorp M, Meuwese MC, Vink H, Hoekstra JB, satility of thrombolytic drugs to treat COVID-19
Kastelein JJ, Stroes ES. The endothelial glycocalyx: [published online ahead of print April 23, 2020]. J
a potential barrier between health and vascular dis- Thromb Haemost. 2020;18(7):1548–55. https://doi.
ease. Curr Opin Lipidol. 2005;16:507–11. https://doi. org/10.1111/jth.14872.
org/10.1097/01.mol.0000181325.08926.9c. 74. Tang N, Li D, Wang X, Sun Z. Abnormal coagula-
61. Ostrowski SR, Gaini S, Pedersen C, Johansson
tion parameters are associated with poor prognosis in
PI. Sympathoadrenal activation and endothelial patients with novel coronavirus pneumonia. J Thromb
damage in patients with varying degrees of acute
Haemost. 2020;18(4):844–7.
infectious disease: an observational study. J Crit Care. 75. Klok FA, Kruip MJHA, van der Meer NJM, et al.
2015;30:90–6. Incidence of thrombotic complications in criti-
62. Steppan J, Hofer S, Funke B, et al. Sepsis and major cally ill ICU patients with COVID-19 [published
abdominal surgery lead to flaking of the endothelial online ahead of print April 10, 2020]. Thromb Res.
glycocalix. J Surg Res. 2011;165:136–41. 2020;191:145–7.
63.
Chignalia AZ, Yetimakman F, Christiaans SC, 76. Tian S, Hu W, Niu L, Liu H, Xu H, Xiao

et al. The glycocalyx and trauma: a review. Shock. SY. Pulmonary pathology of early-phase 2019
2016;45:338–48. novel coronavirus (COVID-19) pneumonia in
64. Johansson PI, Stensballe J, Ostrowski SR. Shock
two patients with lung cancer. J Thorac Oncol.
induced endotheliopathy (SHINE) in acute critical ill- 2020;15(5):700–4.
ness—a unifying pathophysiologic mechanism. Crit 77. Cheng Y, Liu J, Su Y, et al. Clinical impact of coagu-
Care. 2017;21:25. lation and fibrinolysis markers for predicting post-
65. Yamaoka-Tojo M. A note on systemic inflammatory- operative venous thromboembolism in total joint
reactive microvascular endotheliopathy (SIRME): arthroplasty patients. Clin Appl Thromb Hemost.
prevention of cardiovascular disease and COVID-19. 2019;25:1076029619877458.
JJCDP. 2020;55:1–14. 78. Lillicrap D. Disseminated intravascular coagulation
66. Butler PJ, Bhatnagar A. Mechanobiology of the ablu- inpatients with 2019-nCoV pneumonia. J Thromb
minal glycocalyx. Biorheology. 2019;56:101–12. Haemost. 2020;18(4):786–7.
https://doi.org/10.3233/BIR-190212. 79. Potere N, Valeriani E, Candeloro M, et al. Acute
67. Betteridge KB, Arkill KP, Neal CR, et al. Sialic acids complications and mortality in hospitalized patients
regulate microvessel permeability, revealed by novel with coronavirus disease 2019: a systematic review
in vivo studies of endothelial glycocalyx structure and and meta-analysis. Crit Care. 2020;24(1):389.
function. J Physiol. 2017;595:5015–35. 80. Horby P, Lim WS, Emberson J, et al. Effect of dexa-
68. Curry FE. Layer upon layer: the functional conse- methasone in hospitalized patients with COVID-19:
quences of disrupting the glycocalyx- endothelial preliminary report. medRxiv. 2020. https://doi.org/10.
barrier in vivo and in vitro. Cardiovasc Res. 1101/2020.06.22.20137273.
2017;113:559–61. 81. Deftereos SG, Giannopoulos G, Vrachatis DA, et al.
69. Ueda A, Shimomura M, Ikeda M, Yamaguchi R,
for GRECCO-19 Investigators. Effect of colchicine
Tanishita K. Effect of glycocalyx on shear-dependent vs standard care on cardiac and inflammatory bio-
albumin uptake in endothelial cells. Am J Physiol markers and clinical outcomes in patients hospital-
Heart Circ Physiol. 2004;287:H2287–94. ized with coronavirus disease 2019: the GRECCO-19
70. Bar A, Targosz-Korecka M, Suraj J, et al. Degradation randomized clinical trial. JAMA Netw Open.
of glycocalyx and multiple manifestations of endo- 2020;3:e2013136.
thelial dysfunction coincide in the early phase of 82. Zhang X-J, Qin J-J, Cheng X, et al. In-hospital use
endothelial dysfunction before atherosclerotic plaque of statins is associated with a reduced risk of mortal-
development in apolipoprotein E/low-density lipo- ity among individuals with COVID-19. Cell Metab.
protein receptor-deficient mice. J Am Heart Assoc. 2020. https://doi.org/10.1016/j.cmet.2020.06.015.
2019;8:e011171. 83. Cavalli G, De Luca G, Campochiaro C, et al.

71. Zhai Z, Li C, Chen Y, et al. Prevention and treatment of Interleukin-1 blockade with high-dose anakinra in
venous thromboembolism associated with coronavirus patients with COVID-19, acute respiratory distress
disease 2019 infection: a consensus statement before syndrome, and hyperinflammation: a retrospective
guidelines. Thromb Haemost. 2020;120(6):937–48. cohort study. Lancet Rheumatol. 2020;2:e325–31.
72. Cattaneo M, Bertinato EM, Birocchi S, et al.
84. Huet T, Beaussier H, Voisin O, et al. Anakinra for
Pulmonary embolism or pulmonary thrombo- severe forms of COVID-19: a cohort study. Lancet
sis in COVID-19? Is the recommendation to use Rheumatol. 2020;2:e393–400.
85. Xu X, Han M, Li T, et al. Effective treatment of severe monary disease: letter to the editor. Virchows Arch.
COVID-19 patients with tocilizumab. Proc Natl Acad 2020;477(3):467–8.
Sci U S A. 2020;117:10970–5. 93. CRICS TRIGGERSEP Group (Clinical Research

86. Violi F, Pastori D, Cangemi R, Pignatelli P, Loffredo in Intensive Care and Sepsis Trial Group for Global
L. Hypercoagulation and antithrombotic treatment in Evaluation and Research in Sepsis), Helms J,
coronavirus 2019: a new challenge [published online Tacquard C, Severac F, Leonard-Lorant I, Ohana
ahead of print April 29, 2020]. Thromb Haemost. M. High risk of thrombosis in patients with severe
2020;120(6):949–56. SARS-CoV-2 infection: a multicenter prospective
87. Liu X, Zhang Y, Xu X, et al. Evaluation of plasma cohort study. Intens Care Med. 2020;46(6):1089–98.
exchange and continuous veno-venous hemofil- 94. National Institutes of Health. Accelerating COVID-19
tration for the treatment of severe avian influenza Therapeutic Interventions and Vaccines (ACTIV)
a (H7N9): a cohort study. Ther Apheresis Dial. [Internet]. 2020 [cited 2020 Aug 27]. Available
2015;19(2):178–84. from: https://www.nih.gov/research-training/
88. Zhang Y, Yu L, Tang L, et al. A promising anti-cytokine- medical-research-initiatives/activ.
storm targeted therapy for COVID-19: the artificial- 95. Mokhtari T, Hassani F, Ghaffari N, Ebrahimi B,

liver blood-purification system [published online ahead Yarahmadi A, Hassanzadeh G. COVID-19 and mul-
of print March 20, 2020]. Engineering (Beijing). 2020; tiorgan failure: a narrative review on potential mecha-
https://doi.org/10.1016/j.eng.2020.03.006. nisms. J Mol Histol. 2020;51(6):613–28. https://doi.
89. Siddiqi HK, Libby P, RIdker PM. COVID-19 – a vas- org/10.1007/s10735-020-09915-3. Epub 2020 Oct 4.
cular disease. Trends Cardiovasc Med. 2021;31:1–5. PMID: 33011887; PMCID: PMC7533045.
90. Buckley LF, Wohlford GF, Ting C, Alahmed A, Van 96. Sabatino J, De Rosa S, Di Salvo G, Indolfi C. Impact
Tassell BW, Abbate A. Role for anti-cytokine thera- of cardiovascular risk profile on COVID-19 outcome.
pies in severe coronavirus disease 2019. Crit Care A meta-analysis. PLOS ONE. 2020;15(12):e0237131.
Exp. 2020;2(8):e0178. 97. Llitjos JF, Leclerc M, Chochois C, et al. High inci-
91. Lax SF, Skok K, Zechner P, et al. Pulmonary arterial dence of venous thromboembolic events in anticoagu-
thrombosis in COVID-19 with fatal outcome: results lated severe COVID-19 patients. J Thromb Haemost.
from a prospective, single-center, clinicopathologic 2020. Available at: https://www.ncbi.nlm.nih.gov/
case series. Ann Intern Med. 2020;173(5):350–61. pubmed/32320517.
92. Lax SF, Skok K, Trauner M. Pulmonary arterial throm-
bosis as an important complication of COVID-19 pul-
COVID-19 Renal Illnesses
11
Marie-Carmelle Elie-Turenne and Kruti Shah
Epidemiology strated advanced stages of injury correlated with

higher mortality. Of the patients with AKI, mild
Among hospitalized patients, acute kidney injury AKI was noted in 47%, moderate AKI was
(AKI) is a prevalent comorbidity of COVID-19 noted in 22%, and severe AKI was noted in 31%
illness. In a large meta-analysis of mostly hospi- of patients. Figure 11.2 shows the overall out-
talized patients, 17% had AKI at some point dur- come of all patients with AKI. Among patients
ing their hospital course [1]. The incidence of who required renal replacement therapy (RRT),
AKI between included studies varied widely, 55% died [2]. Factors associated with the onset
largely as a result of heterogeneity in the repre- of AKI among COVID-19 patients included
sentation of critically ill and nonhospitalized comorbid conditions of hypertension (HTN)
patients. Approximately 5% of patients with and obesity; demographics of male sex; African-
COVID-19 required renal replacement therapy American heritage; and clinical interventions
during the clinical course. The mortality experi- including mechanical ventilation and the utili-
enced by patients with AKI is reportedly high in zation of vasoactive medication [2]. Another
hospitalized patients, especially when stratified more recent study of 9657 admitted patients
by critical illness and ICU admission. In the across multiple sites in New York showed an
meta-analysis, nine studies with survival data overall incidence of AKI of 39.9%, with mild
demonstrated a 52% death rate (7–100%) with an AKI noted in 33.3%, moderate AKI noted in
OR of 15.27 (Fig. 11.1). Even when outlying 8%, and severe AKI noted in 14.2% of patients
studies with the highest mortality rates were [3]. 46.6% of patients required RRT in that
excluded, the OR was 6.2 [1]. study and 79.3% of those patients died, showing
A single study of 5449 patients that moni- an even higher mortality.
tored and stratified the degree of AKI of COVID- Importantly, patients with a preexisting his-
19 patients by Kidney Disease: Improving tory of end-stage renal disease exhibit high mor-
Global Outcomes (KDIGO) criteria demon- tality rates. The presence of coexisting
comorbidities, such as hypertension, diabetes,
M.-C. Elie-Turenne (*) and older age, likely compounds risk. Although
Department of Emergency Medicine, University of large epidemiological data have yet to be pub-
Alabama at Birmingham, Birmingham, AL, USA lished, early small studies of ESRD patients esti-
e-mail: [email protected] mate one half to one third of hospitalized patients
K. Shah with COVID-19 experience a death [4, 5].
Department of Emergency Medicine, University of
Florida, Gainesville, FL, USA
112 M.-C. Elie-Turenne and K. Shah
AKI No AKI OR Weight

Study Dead Alive Dead Alive with 95% CI (%)
China
Pei et al., JASN 19 3 10 301 190.63 [ 48.39, 750.94] 11.37
Wang et al., Crit Care 14 0 5 88 466.64 [ 24.48, 8896.20] 7.19
Zhou et al., Lancet 27 1 27 136 136.00 [ 17.72, 1044.04] 9.52
Zhang et al., Clin Micr Inf 5 63 20 575 2.28 [ 0.83, 6.29] 12.26
Xiao et al., preprint 12 43 7 225 8.97 [ 3.34, 24.08] 12.32
Heterogeneity: W= 4.37, I2 = 89.69%, H2 = 9.70 39.00 [ 5.34, 284.97]
Test of Ti= Tj Q(4) = 37.21, p = 0.00
Europe
Brill et al., preprint 54 31 119 246 3.60 [ 2.20, 5.90] 13.22
Rubin et al., preprint 4 53 0 14 2.44 [ 0.12, 47.97] 7.12
Test of Ti= Tj Q(1) = 0.06, p = 0.80
U.S
Hirsch et al., KI 694 1,299 194 3,262 8.98 [ 7.57, 10.67] 13.51
Chan et al., preprint 638 768 133 1,696 10.59 [ 8.63, 13.01] 13.49
Test of Ti= Tj Q(1) = 1.46, p = 0.23
Overall 15.27 [ 4.82, 48.36]

Heterogeneity: W= 2.55, I2 = 97.90%, H2 = 47.61
Test of Ti= Tj Q(8) = 56.13, p = 0.00
Test of group differences: Qb(2) = 16.72, p = 0.00
0.1 1 10 100 10000

Random-effects REML model
Fig. 11.1 Meta-analysis of multiple studies correlating AKI and mortality [1]
Fig. 11.2 Correlation 100%

between severity of AKI
and clinical outcome [2]
75%
Percentage of patients
Disposition
Admitted
50%
Discharged
Expired
25%
0%
No AKI AKI 1 AKI 2 AKI 3
Severity of acute kidney injury and outcome
11 COVID-19 Renal Illnesses 113
Pathophysiology of Kidney A key host receptor for the SARS-CoV-2 virus

Dysfunction is the angiotensin-converting enzyme 2 (ACE2)
receptor, though this does not appear to be an
The mechanism underlying the onset of kidney important mechanism for kidney injury [8].
injury associated with COVID-19 remains ACE2 is widely expressed in multiple organ sys-
unclear. Proposed etiologies include direct paren- tems, but the distribution of injury in disease does
chymal damage by the virus to the kidneys, not correlate with ACE2 expression, implying
hemodynamic changes, with the most evidence that other mechanisms are also involved in the
suggesting cytokine-mediated injury (Fig. 11.3). pathophysiology of cellular damage by
Microvascular thrombosis may also play a small COVID-19. Angiotensin-converting enzyme
role [6, 7]. inhibitors (ACEIs) and angiotensin receptor
SARS-CoV-2 infection
Endothelial damage
No symptoms
Podocyte localisation
Proximal tubule localisation
Hypovolaemia Mild symptoms
Mitochondrial dysfunction
Acute tubular necrosis
Cytokine storm Pneumonia Hypercoagulability

TNFD IL-6
Monocyte
IL-10 IL-8 Endothelial damage

Microthrombi
Rhabdomyolysis
ARDS Microembolism
Kidney infarction
Hyper-
volaemia
Mechanical
DAMPS Endothelial ventilation Myocardial
dysfunction ECMO dysfunction
Arterial
underfilling
Venous
congestion
Acute kidney injury
Fig. 11.3 Proposed mechanisms of AKI in patients with COVID-19 [10]

blockers (ARBs) have not been shown to have respectively [2]. Urine sodium was <35 mEq/l in
beneficial or detrimental effects on kidney func- 65.6% of patients, consistent with a prerenal eti-
tion in COVID-19 patients [2, 9]. ology of AKI but can also be seen with acute
In the large study of 5449 COVID-19 patients tubular necrosis (ATN) and glomerulonephritis.
in New York, the onset of AKI frequently coin- In an autopsy series of 42 patients with
cided with respiratory failure and the require- COVID-19 and AKI, 62% of patients demon-
ment of invasive mechanical ventilation. In that strated pathology consistent with ATN [6]. One
study, 89.7% of those patients who required had focal segmental glomerulosclerosis (FSGS)
mechanical ventilation had AKI, compared to and others had sequelae of their preexisting med-
21.7% of the patients that did not require mechanical comorbidities, such as diabetic glomerulo-
ical ventilation [2]. This suggests that the over- sclerosis. In this particular study, 14% of the
whelming inflammatory response that induces patients had some fibrin in the glomeruli or vas-
acute respiratory distress syndrome (ARDS) in culature, although it was noted in <5% of glom-
COVID-19 may play a role in the onset of kidney eruli sampled. The authors did note that the stage
damage. Another smaller study from China did of AKI witnessed clinically was worse than the
show that higher IL-6 levels were also correlated degree of ATN noted on histology, with 71% of
with AKI [11]. those with stage 2 or 3 AKI exhibiting absent or
Among a subset of 646 patients who devel- mild ATN by histology. See Figs. 11.4 and 11.5.
oped AKI and had available urine studies, Other smaller histologic studies have demon-
hematuria and proteinuria were the most com- strated similar ATN patterns in patients with AKI,
mon abnormalities noted in 46.1 and 42.1%, with a minority displaying a collapsing FSGS pat-
a b c
d e f
Fig. 11.4 Histology of kidneys in patients with AKI and glomerulus displays red blood cell congestion and an
COVID-19 [6]. Autopsy kidneys demonstrated arterio- intracapillary fibrin thrombus (hematoxylin and eosin,
sclerosis, variable degrees of autolysis, and, rarely, fibrin ×400). (d) A fibrin thrombus is seen in the lumen of an
thrombi. (a) A low-magnification view reveals complete artery (hematoxylin and eosin, ×400). (e) In this area of
autolysis in an autopsy with a prolonged PMI. Tubular microscopic infarction, tubules exhibit coagulative-type
nuclei are not visible, and tubular injury cannot be necrosis, and there is prominent neutrophil infiltration
assessed. In contrast, chronic changes of glomerulosclero- with neutrophilic debris (hematoxylin and eosin, ×200).
sis, arteriosclerosis, and TA/IF are still visualized (hema- (f) In this patient with hypertensive arterionephrosclero-
toxylin and eosin, ×100). (b) A glomerulus exhibits mild sis, an artery exhibits severe intimal sclerosis, compromis-
changes of NDGS (hematoxylin and eosin, ×400). (c) A ing >50% of the lumen (hematoxylin and eosin, ×400)
a b
c d
Fig. 11.5 Further histology of kidneys in patients with AKI stage 3 with an increase in creatinine from 0.94 to
COVID-19 and AKI [6]. ATI is the main finding in autopsy 6.83 mg/dl requiring CRRT, only mild ATI is noted, char-
kidneys from patients with COVID-19 and AKI. (a) A acterized by luminal ectasia and mild vacuolization
low-magnification view reveals intact renal cortex, with- (hematoxylin and eosin, ×200). (d) In this patient with
out evidence of ATI (hematoxylin and eosin, ×40). (b) In AKI stage 3 with an increase in creatinine from 0.67 to
this patient with AKI stage 1 with an increase in creatinine 3.48 mg/dl, the kidneys exhibit severe ATI, with more
from 1.09 to 1.6 mg/dl, the histologic evaluation revealed prominent luminal ectasia, cytoplasmic simplification,
mild ATI characterized by mild luminal ectasia, irregular vacuolization, and loss of brush border (hematoxylin and
luminal contours, and vacuolization. Prominent cytoplas- eosin, ×200). (e) In this patient with AKI stage 3 requiring
mic simplification and loss of brush border are not appar- CRRT, severe ATI is also apparent (hematoxylin and
ent (hematoxylin and eosin, ×100). (c) In this patient with eosin, ×100)
tern [11–22]. This FSGS pattern is associated A few studies have shown what appear to be
with nephrotic range proteinuria [14–17, 19, 21]. viral particles in the kidneys when studied with
An APOL1 gene mutation was found in many of electron microscopy [20, 22–24]. These results
these patients (many did not test for gene muta- are contested and thought to be clathrin-coated
tions) with an increased likelihood of African- multivesicles that are naturally occurring and not
Americans in this group [13, 14, 16]. Other viral related to viral infection, as in situ hybridization
infections have also been shown to cause collaps- has failed to demonstrate viral particles in kidney
ing FSGS in patients with APOL1 gene mutations cells [6, 18, 25–28].
[21]. It is unclear if this will have any treatment
implications in patients with FSGS due to
COVID-19 as further research needs to be done to Clinical Manifestations
determine if immunomodulatory treatments could
be used in this patient population (Fig. 11.6). In the clinical setting, a reduction in creatinine
There were also cases of other renal diseases clearance and decreasing urine output are hall-
identified as a consequence of COVID-19 infec- marks of AKI. KDIGO guidelines for staging
tion, such as minimal change disease, anti-GBM AKI are shown below in Table 11.1. As noted
nephritis, and membranous glomerulopathy [13]. above, in patients with AKI, hematuria and pro-
It is unclear if COVID-19 represents a second-hit teinuria were the most common manifestations
phenomenon inducing the onset of AKI in certain seen on urinalysis. Nephrotic range proteinuria in
predisposed populations. A minority of patients a patient who is likely to have APOL1 gene muta-
have evidence of fibrin deposits; however, this tions (those of African descent) may prompt
does not appear to be widespread among the glom- additional studies [21].
eruli sampled, with the exception of patients who
had other reasons to have thrombotic microangi-
opathy [6, 18]. There were also a couple of patients Treatment Approach
with noted pigment injury from rhabdomyolysis
[20]. Most of these studies found no viral particles Thus far, novel treatments have not emerged in
in any of the glomeruli sampled, arguing against the management of AKI in COVID-19 patients
direct viral infection as a major contributor to AKI that are distinct from other patients with
in COVID-19 [6, 12–14, 16, 18–20]. AKI. Special attention to fluid balance and cau-
Fig. 11.6 Proposed mechanism for FSGS in patients with APOL1 variant [21]
Table 11.1 KDIGO definition of stages of AKI [29] namic profile. Of note, studies in septic patients
Urine have not consistently shown benefit over conven-
Stage Serum creatinine output tional intermittent hemodialysis (iHD). In
1 1.5–1.9 times baseline or ≥0.3 <0.5 ml/kg/
patients with severe sepsis and hypercatabolic
mg/dl (≥26.5 μmol/l) increase hour for
6–12 hours states, CRRT with a high flow rate has been pos-
2 2.0–2.9 times baseline <0.5 ml/kg/ ited as a strategy for enhanced clearance of
hour for inflammatory cytokines, although again no study
≥12 hours has demonstrated a mortality benefit. A practical
3 3.0 times baseline or increase in <0.3 ml/kg/
consideration during the pandemic era of
serum creatinine to ≥4.0 mg/dl hour for
(≥353.6 μmol/l) or initiation of ≥24 hours COVID-19 supporting the preferential use of
renal replacement therapy or in or anuria CRRT over iHD is in the reduction in provider
patients < 18 years a decrease in for ≥ 12 exposure in a given timeframe and reducing the
eGFR to <35 ml/minute per 1.732 hours
amount of PPE required by the staff. Specifically,
eGFR estimated glomerular filtration rate if an additional dialysis nurse is not required for
iHD, the resource may be shifted to other patients.
tious fluid administration is recommended in For patients who require ECMO for treatment of
patients who appear to have prerenal AKI; how- their ARDS, CRRT can easily be added to the cir-
ever excessive fluid administration can result in cuit without the need for additional venous access
worsening pulmonary and renal status and should and can be managed by the bedside nurse or
be avoided [7, 10]. Patients with septic shock ECMO technician.
should be treated similar to non-COVID-19 A limitation of CRRT is the number of devices
patients with septic shock, with initial fluid in a given institution and the need for increased
administration and pressors to maintain perfu- nurse staffing ratio. If the number of patients
sion. Repetitive ultrasounds or other objective requiring CRRT outpaces the number of machines
measurements may guide fluid administration available at an institution, the CRRT machines
regardless of shock status. Rhabdomyolysis has can be used for prolonged intermittent sessions
been observed in COVID-19 patients, which may (such as 8–12 hours) at higher flow rates and then
require aggressive fluid administration to prevent be available for use for another patient. This form
the need for dialysis, but consideration could be has been called slow low-efficiency dialysis
made for early dialysis to prevent pulmonary (SLED), sustained low-efficiency daily dialysis
injury with excessive fluid. In patients with (SLEDD), or prolonged intermittent renal
COVID-19 myocarditis, the cardiac output replacement therapy (PIRRT). Not all CRRT or
should be optimized, with inotropes if necessary, iHD machines are capable of this as this would
to maintain renal perfusion. require an adaptation of flow rates and the device
The indications for renal replacement therapy manual and/or institutional protocols should be
(RRT) are similar to other patients with consulted to determine if this is a possibility at
AKI. Refractory hypervolemia, acidosis, hyper- individual institutions. Staff familiarity with this
kalemia, and uremia are among the most com- method should also be taken into consideration as
mon reasons to initiate dialysis. Consideration many institutions do not regularly use this method
may be given to the early initiation of CRRT and it may lead to increased errors. SLED gener-
dialysis in patients with hypervolemia associated ally results in less clotting and does not usually
with ARDS to assist with pulmonary mechanics require anticoagulation. It has also shown in
and to minimize further volume expansion in the small studies to have a similar hemodynamic pro-
setting of AKI. file to CRRT and has been well-tolerated in
The preferred method of renal replacement hemodynamically unstable patients. SLED does
therapy is CRRT [7, 30]. In the critically ill, require a dialysis nurse, but this nurse can man-
patients experience fewer episodes of wide varia- age multiple patients on SLED at the same time.
tions in blood pressure and have a better hemody- Another method to increase the number of
patients that can be treated with a limited number Peritoneal dialysis (PD) may also be consid-
of CRRT machines is to switch the CRRT ered in institutions where the capacity for CRRT
machines from one patient to another when the or iHD has been exceeded; however, it does
filter clots, which will minimize the use of new require surgery, nephrology, or interventional
filter sets. However, this method may not be fea- radiology for placement of a peritoneal catheter.
sible for all patients. An important consideration is PD is infrequently
Dialysate and replacement fluid may need to utilized in many critical care environments, mak-
be manually prepared by institutional pharmacies ing it less likely to be employed. Urgent start PD,
if supplies of commercially prepared solutions as it has been called, consists of urgently placing
are exhausted (Table 11.2). a peritoneal access catheter and initiating PD
iHD can be used in hemodynamically sta- emergently. Urgent start PD has not been shown
ble patients with COVID-19. However, most to have increased mortality, kidney function
patients with severe AKI from COVID-19 are recovery, or infectious complications in all
hemodynamically unstable due to the accom- patients with AKI, but this has not been studied in
panying sepsis. Some patients with preexisting COVID-19. However, it should be noted that the
chronic kidney disease (CKD) may be prone to instillation of fluid into the peritoneal cavity may
develop AKI requiring HD while infected with decrease diaphragmatic excursion and worsen
COVID-19. Regardless, if patients are hemody- respiratory mechanics. The interval distension of
namically stable but requiring dialysis, iHD can the abdominal cavity may be poorly tolerated in
be used, especially on floors where nursing care patients with severe respiratory compromise due
precludes the use of CRRT. To maximally utilize to ARDS. As prone positioning emerges as a
resources, the minimal amount of dialysis nec- potential key treatment intervention in the man-
essary to achieve fluid balance and correction of agement of ARDS, PD may be a less desirable
electrolytes should be used. This will also mini- option, with limited access to the anterior surface
mize the exposure of the dialysis nurses. of the abdomen. Notably, ultrafiltration with PD
is unpredictable and solute clearance may be
Table 11.2 Potential alternatives for CRRT when compromised in hypercatabolic states. The ben-
resources are limited [7] efits include that it can be done bedside with an
Alternatives in case of limited RRT resources auto-cycle, does not require a dialysis nurse, does
Potential alternatives (in combination not require anticoagulation, and requires less
Resource with optimal management of AKI to infrastructure than iHD or CRRT. There have
limitation avoid RRT)
been case studies published in areas where the
CRRT 6–8 hour sessions of PIRRT with CRRT
machines machines (2–3 patients per machine) capacity for iHD and CRRT was exceeded, and
Alternative RRT modalities (SLED, urgent start PD proved a generally effective strat-
IHD, peritoneal dialysis) egy [31–35]. A caveat was that in critically ill
Medical management of AKI to prolong patients, adequate solute clearance and ultrafil-
periods off-RRT
tration was challenging resulting in volume over-
Fluids IHD (online preparation of dialysis fluid,
reverse osmosis unit) load. With those limitations, it may be more
Aseptic manual preparation of dialysis or reasonable to use PD in non-ICU patients with
replacement fluid COVID-19 and AKI requiring dialysis, conserv-
Circuits Peritoneal dialysis ing CRRT machines for patients requiring ICU
catheters Strategies to prolong circuit and filter life level of care.
(optimal access, anticoagulation,
filtration fraction <30%)
Patients with ESRD should be dialyzed as per
their normal schedule while hospitalized.
Abbreviations: AKI acute kidney injury, CRRT continuous
renal replacement therapy, IHD intermittent hemodialy- However, they may require transition to CRRT if
sis, PIRRT prolonged intermittent hemodialysis, RRT they develop hemodynamic instability, similar to
renal replacement therapy, SLED sustained low efficiency non-COVID-19 patients with sepsis and ESRD.
dialysis
Anticoagulation obstruction when it accumulates; however, this

was at doses 50–100-fold from what a patient
Patients with COVID-19 are known to be hyper- would receive for a 5–10-day course of remde-
coagulable and anecdotally appear to require sivir. Voriconazole also uses this formulation as
anticoagulation while on CRRT at a higher fre- a carrier in previous studies. Short courses of
quency, although this has yet to be sufficiently voriconazole administration have been demon-
investigated. The other indications for systemic strated to be well tolerated without renal toxic-
anticoagulation are discussed elsewhere in this ity [36]. Moreover, SBECD is removed through
text; however if clotting of the CRRT machine is dialysis. Therefore, remdesivir is likely to be safe
the only indication, we would recommend in patients with ESRD or severe AKI necessitat-
regional anticoagulation with citrate, barring any ing dialysis. A thorough and informed discussion
contraindications, such as liver failure, severe with patients or their surrogates should be con-
hemodynamic instability, or severe lactic acido- ducted prior to the administration of remdesivir
sis. If the patient develops signs of citrate toxicity in patients with or at increased risk for renal fail-
or will not tolerate citrate, systemic anticoagula- ure. The potential benefits of resolution of symp-
tion may be necessary to prevent circuit thrombo- toms and disease will likely outweigh the risks
sis. This can be achieved with unfractionated in most patients, given the high baseline mor-
heparin, low molecular weight heparin, or direct tality in patients with severe AKI or ESRD and
thrombin inhibitors, based on individual patient COVID-19.
characteristics and individual hospital protocols.
Given the risks of regional anticoagulation with Critical Points
citrate when not administered correctly, we rec- • AKI is common in hospitalized COVID-19
ommend the use of systemic heparin in institu- patients and 5% will require RRT.
tions where citrate is not commonly used and if • It increases the mortality risk.
no protocol exists for its administration. • HD or CRRT may be useful in volume removal
for acute hypoxemic respiratory failure if
there is positive fluid status.
Remdesivir • Anticoagulation may be required during
CRRT due to hypercoagulable state.
Remdesivir has emerged as a major treatment for • CRRT may need to be modified to higher-
COVID-19; however, it was not formally studied intensity intermittent treatments based on pan-
in patients with eGFR <30 mL/min. No pharma- demic demand.
cokinetic data is available for these patients, and
the manufacturer’s labeling does not recommend
use in patients with GFR < 30 mL/min. However,
References
toxicology in rhesus monkeys only showed
adverse effects at higher doses than are used in 1. Robbins-Juarez SY, Qian L, King KL, Stevens JS,
humans, and large clinical trials have failed to Husain SA, Radhakrishnan J, et al. Outcomes for
show any increased kidney damage with remde- patients with COVID-19 and acute kidney injury: a
systematic review and meta-analysis. Kidney Int Rep.
sivir [36]. In 1 small observational study of 46 2020;5(8):1149–60.
patients with AKI or CKD who received remde- 2. Hirsch JS, Ng JH, Ross DW, Sharma P, Shah
sivir, there was no increase in LFTs or decrease HH, Barnett RL, et al. Acute kidney injury in
in kidney function attributable to the drug [37]. patients hospitalized with COVID-19. Kidney Int.
2020;98(1):209–18.
The IV formulation uses sulfobutylether-β- 3. Ng JH, Hirsch JS, Hazzan A, Wanchoo R, Shah HH,
cyclodextrin (SBECD) as a carrier to make the Malieckal DA, et al. Outcomes among patients hospi-
drug more water-soluble, and this molecule has talized with COVID-19 and acute kidney injury. Am J
been shown to have liver toxicity and renal tubule Kidney Dis. 2020;77(2):204–15.e1.
4. Valeri AM, Robbins-Juarez SY, Stevens JS, Ahn W, ing focal segmental glomerulosclerosis: a report of 2
Rao MK, Radhakrishnan J, et al. Presentation and out- cases. Kidney Med. 2020;2(4):493–7.
comes of patients with ESKD and COVID-19. J Am 20. Su H, Yang M, Wan C, Yi LX, Tang F, Zhu HY, et al.
Soc Nephrol. 2020;31(7):1409–15. Renal histopathological analysis of 26 postmortem
5. Flythe JE, Assimon MM, Tugman MJ, Chang EH, findings of patients with COVID-19 in China. Kidney
Gupta S, Shah J, et al. Characteristics and outcomes Int. 2020;98(1):219–27.
of individuals with pre-existing kidney disease and 21. Velez JCQ, Caza T, Larsen CP. COVAN is the

COVID-19 admitted to intensive care units in the new HIVAN: the re-emergence of collapsing glo-
United States. Am J Kidney Dis. 2020;77:190. merulopathy with COVID-19. Nat Rev Nephrol.
6. Santoriello D, Khairallah P, Bomback AS, Xu K, 2020;16(10):565–7.
Kudose S, Batal I, et al. Postmortem kidney pathol- 22. Werion A, Belkhir L, Perrot M, Schmit G, Aydin S,
ogy findings in patients with COVID-19. J Am Soc Chen Z, et al. SARS-CoV-2 causes a specific dys-
Nephrol. 2020;31(9):2158–67. function of the kidney proximal tubule. Kidney Int.
7. Ostermann M, Lumlertgul N, Forni LG, Hoste E. What 2020;98(5):1296–307.
every intensivist should know about COVID-19 asso- 23. Farkash EA, Wilson AM, Jentzen JM. Ultrastructural
ciated acute kidney injury. J Crit Care. 2020;60:91–5. evidence for direct renal infection with SARS-CoV-2.
8. Bourgonje AR, Abdulle AE, Timens W, Hillebrands J Am Soc Nephrol. 2020;31(8):1683–7.
JL, Navis GJ, Gordijn SJ, et al. Angiotensin- 24. Braun F, Lütgehetmann M, Pfefferle S, Wong MN,
converting enzyme 2 (ACE2), SARS-CoV-2 and Carsten A, Lindenmeyer MT, et al. SARS-CoV-2
the pathophysiology of coronavirus disease 2019 renal tropism associates with acute kidney injury.
(COVID-19). J Pathol. 2020;251(3):228–48. Lancet. 2020;396(10251):597–8.
9. Vaduganathan M, Vardeny O, Michel T, McMurray 25. Calomeni E, Satoskar A, Ayoub I, Brodsky S, Rovin
JJV, Pfeffer MA, Solomon SD. Renin-angiotensin- BH, Nadasdy T. Multivesicular bodies mimicking
aldosterone system inhibitors in patients with SARS-CoV-2 in patients without COVID-19. Kidney
Covid-19. N Engl J Med. 2020;382(17):1653–9. Int. 2020;98(1):233–4.
10. Ronco C, Reis T, Husain-Syed F. Management of 26. Goldsmith CS, Miller SE, Martines RB, Bullock HA,
acute kidney injury in patients with COVID-19. Zaki SR. Electron microscopy of SARS-CoV-2: a
Lancet Respir Med. 2020;8(7):738–42. challenging task. Lancet. 2020;395(10238):e99.
11. Xia P, Wen Y, Duan Y, Su H, Cao W, Xiao M, et al. 27. Goldsmith CS, Tatti KM, Ksiazek TG, Rollin PE,
Clinicopathological features and outcomes of acute Comer JA, Lee WW, et al. Ultrastructural charac-
kidney injury in critically ill COVID-19 with pro- terization of SARS coronavirus. Emerg Infect Dis.
longed disease course: a retrospective cohort. J Am 2004;10(2):320–6.
Soc Nephrol. 2020;31(9):2205–21. 28. Miller SE, Goldsmith CS. Caution in identifying coro-
12. Golmai P, Larsen CP, DeVita MV, Wahl SJ, Weins A, naviruses by electron microscopy. J Am Soc Nephrol.
Rennke HG, et al. Histopathologic and ultrastructural 2020;31(9):2223–4.
findings in postmortem kidney biopsy material in 12 29. Kellum JA, Lameire N, Group KAGW. Diagnosis,
patients with AKI and COVID-19. J Am Soc Nephrol. evaluation, and management of acute kidney injury: a
2020;31(9):1944–7. KDIGO summary (part 1). Crit Care. 2013;17(1):204.
13. Kudose S, Batal I, Santoriello D, Xu K, Barasch J, 30. Adapa S, Aeddula NR, Konala VM, Chenna A,

Peleg Y, et al. Kidney biopsy findings in patients with Naramala S, Madhira BR, et al. COVID-19 and renal
COVID-19. J Am Soc Nephrol. 2020;31(9):1959–68. failure: challenges in the delivery of renal replace-
14. Kissling S, Rotman S, Gerber C, Halfon M, Lamoth ment therapy. J Clin Med Res. 2020;12(5):276–85.
F, Comte D, et al. Collapsing glomerulopathy in a 31. Goldfarb DS, Benstein JA, Zhdanova O, Hammer E,
COVID-19 patient. Kidney Int. 2020;98(1):228–31. Block CA, Caplin NJ, et al. Impending shortages of
15. Larsen CP, Bourne TD, Wilson JD, Saqqa O, Sharshir kidney replacement therapy for COVID-19 patients.
MA. Collapsing glomerulopathy in a patient with Clin J Am Soc Nephrol. 2020;15(6):880–2.
COVID-19. Kidney Int Rep. 2020;5(6):935–9. 32. El Shamy O, Patel N, Abdelbaset MH, Chenet L,
16. Peleg Y, Kudose S, D’Agati V, Siddall E, Ahmad S, Tokita J, Lookstein R, et al. Acute start peritoneal
Kisselev S, et al. Acute kidney injury due to collaps- dialysis during the COVID-19 pandemic: outcomes
ing glomerulopathy following COVID-19 infection. and experiences. J Am Soc Nephrol. 2020;31(8):
Kidney Int Rep. 2020;5(6):940–5. 1680–2.
17. Nasr SH, Kopp JB. COVID-19-associated collapsing 33. El Shamy O, Vassalotti JA, Sharma S, Aydillo-Gomez
glomerulopathy: an emerging entity. Kidney Int Rep. T, Marjanovic N, Ramos I, et al. Coronavirus disease
2020;5(6):759–61. 2019 (COVID-19) hospitalized patients with acute
18. Sharma P, Uppal NN, Wanchoo R, Shah HH, Yang Y, kidney injury treated with acute peritoneal dialysis
Parikh R, et al. COVID-19-associated kidney injury: do not have infectious peritoneal dialysis effluent.
a case series of kidney biopsy findings. J Am Soc Kidney Int. 2020;98(3):782.
Nephrol. 2020;31(9):1948–58. 34. Parapiboon W, Ponce D, Cullis B. Acute peri-

19. Sharma Y, Nasr SH, Larsen CP, Kemper A, Ormsby toneal dialysis in COVID-19. Perit Dial Int.
AH, Williamson SR. COVID-19-associated collaps- 2020;40(4):359–62.
35. Sourial MY, Sourial MH, Dalsan R, Graham J,

in patients with acute or chronic kidney disease and
Ross M, Chen W, et al. Urgent peritoneal dialysis COVID-19. J Am Soc Nephrol. 2020;31(7):1384–6.
in patients with COVID-19 and acute kidney injury: 37. Thakare S, Gandhi C, Modi T, Bose S, Deb S, Saxena
a single-center experience in a time of crisis in the N, et al. Safety of remdesivir in patients with acute or
United States. Am J Kidney Dis. 2020;76(3):401–6. chronic kidney disease. Kidney Int Rep. 2020;6:206.
36. Adamsick ML, Gandhi RG, Bidell MR, Elshaboury
RH, Bhattacharyya RP, Kim AY, et al. Remdesivir
COVID-19 Hepatic Illness
12
Kimberly Boswell
Critical Points (SARS-CoV-2) which is known to cause the dis-

• Severity of liver enzyme elevation appears mild ease, COVID-19. Science has made extensive
in most cases, but patients with severe COVID-19 strides in the understanding of communicability,
infections are also observed to have more prevention, and treatment and, of course, the
marked increases in aminotransferase levels. development of a vaccine to induce immunity in
• While nonalcoholic fatty liver disease and a remarkably short period of time. The more we
decompensated cirrhosis appear to portend an learn about COVID-19, the more we understand
increased mortality, other preexisting liver that it appears to affect every organ system of the
diseases (hepatitis B and C and autoimmune body. But, despite the impressive advancements,
hepatitis) do not appear to be risk factors for we still do not understand a significant amount
increased mortality. about the manifestations and long-term effects of
• Many of the medications used to treat COVID-19 on the body. This chapter will focus
COVID- 19 are associated with increased on the virus’s effect on the liver, what we know
aminotransferase levels and possibly about the effects of COVID-19 in patients with
hepatotoxicity. underlying liver disease, current treatments, and
• Effects of the pandemic are not just related to what we still have to learn.
preexisting liver disease or acute effects of At the time this author is writing this chapter,
COVID-19; some will be a result of increased globally we have seen more than 100,000,000
substance use related to prolonged isolation cases of COVID-19. There have been more than
and economic hardships. 2.4 million deaths worldwide. In the United
States, more than 400,000 fatalities are attributed
to COVID-19 (JH Website). While overall mor-
Overview/Introduction tality was initially thought to be as high as 2.5%
[12], those numbers are decreasing as more cases
The world has encountered many challenges in are diagnosed, our treatment options improve,
the year following the identification of the severe and vaccines are distributed. Since the develop-
acute respiratory syndrome coronavirus 2 ment and granting of Emergency Use
Authorization (EUA) by the Food and Drug
K. Boswell (*) Administration (FDA), both the Moderna and
R Adams Cowley Shock Trauma Center, University Pfizer vaccines have been given to more than 71
of Maryland School of Medicine, million people worldwide. While the mortality
Baltimore, MD, USA numbers are startling, they are likely to continue
124 K. Boswell
to rise until herd immunity has been achieved or but also macrovesicular steatosis and sinusoidal
an adequate number of vaccinations have been dilation. Lymphocytic infiltration has also been
given. appreciated. Despite a higher concentration of
ACE2 receptors within cholangiocytes, little his-
tologic damage has been noted to the biliary tis-
Pathophysiology sue [26].
The virus is a novel single-stranded RNA beta-

coronavirus which gains access to the host cell by Laboratory Findings
attaching itself at the host’s angiotensin-
converting enzyme 2 (ACE2) receptor site [3]. Since the beginning of the pandemic, there have
The virus’s spike proteins are believed to have been characteristic patterns of lab abnormalities
several cleavage points which increase its recep- appreciated in patients with moderate to severe
tor binding affinity. This is believed to render it a SARS-CoV-2 infections. Some patients who
more pathogenic virus than when compared to develop the severe inflammatory response have
other, similar coronaviruses. One study demon- elevated inflammatory markers including IL-6
strated a 10–20-fold higher binding affinity of and ferritin, reminiscent of abnormalities seen in
SARS-CoV-2 compared to the SARS-CoV that the disease process hemophagocytic lymphohis-
was responsible for the pandemic in 2003 [7]. tiocytosis (HLH).
ACE2 receptors are found in many parts of the While the severe inflammatory response likely
body including the lungs, heart, vasculature, kid- affects all organs of the body, COVID-19 is really
neys, as well as within the gastrointestinal tract. only known to cause mild elevations in liver
It is believed the organs with the highest expres- transaminases. The incidence of transaminase
sion of ACE2 receptors are the most commonly elevation in patients infected with SARS-CoV-2
and severely affected organs by SARS-CoV-2. ranges dramatically between 14% and 53% of the
Within the liver and biliary system, cholangio- population [12]. In particular, aspartate amino-
cytes appear to have an increased expression of transferase (AST) and alanine aminotransferase
ACE2 receptors when compared to hepatocytes. (ALT) are frequently elevated in moderate to
This difference is quite significant with upwards severe infections, usually seeing their peak eleva-
of 30 times more ACE2 receptor expression in tion in the second to third week of illness [44].
cholangiocytes than in hepatocytes [8]. The fre- Transaminase elevations are usually only around
quency of expression within cholangiocytes is twice the normal values of AST and ALT, but
similar to that of expression within the alveolar more marked elevations, indicating liver injury or
cells in the lungs. The density of ACE2 receptor hepatitis, do occur and are usually associated
expression within the cholangiocytes could with more severe COVID-19 infection [20].
explain some of the cholestasis picture that can Occasionally elevations in the total bilirubin are
be seen with COVID-19, but does not adequately also seen, but increases in gamma-
explain the elevations in transaminases that we glutamyltransferase (GGT) and alkaline phos-
often see [6]. There has been no ACE2 receptor phatase (AP), two markers of biliary tree injury,
expression found within Kupffer cells. are uncommon. This differentiation is interesting
Histologic evaluation of liver biopsies from as it suggests that the liver injury related to
patients with severe COVID-19 infection demon- SARS-CoV-2 infection may not be a direct effect
strated microvesicular steatosis as well as mild of the virus, but possibly more related to the
lobular and portal activity. These findings suggest inflammatory response to the virus as there are
damage that has occurred as a result of the virus far more ACE2 receptors found in cholangiocytes
directly or possibly due to drug-induced liver than in hepatocytes. Patients who demonstrated
injury [24]. Additional biopsies have shown not elevated LFTs at the time of admission are at sig-
only the microvesicular changes previously noted nificantly higher risk of developing severe
12 COVID-19 Hepatic Illness 125
COVID-19 disease and have an association with It is unclear if preexisting liver disease is a
poorer outcome [25]. predisposing factor to the development of more
The true etiology of COVID-19-associated severe COVID-19 infection at this time. It has
transaminitis is not well understood. As men- been cited that rates of COVID-19 infection in
tioned above, the elevation could be related to the patients with preexisting liver conditions have
inflammatory response, but there are several ranged anywhere from 2% to 11% [17]. Several
other plausible explanations. We know that societies including the American Association for
SARS-CoV-2 is associated with a hypercoagula- the Study of Liver Diseases [19] have made rec-
ble state and many patients have had pulmonary ommendations regarding the management of
embolism, DVT, and other thrombotic events as a patients with preexisting liver disease during the
presenting feature or complication of their pandemic. These recommendations have included
COVID-19 infection [5, 31]. This hypercoagula- things such as encouraging telehealth visits for
ble state and increased risk of thrombosis can all those with liver disease (except those with
result in ischemic injury to tissue distally and hepatocellular carcinoma (HCC)), delaying non-
possible resultant rise in liver enzymes. urgent procedures and imaging, and continuing
Alternatively, congestive hepatopathy associated to meet preexisting standards of care in patients
with the known association between right heart with HCC, liver transplant, or decompensated
dilation and dysfunction and SARS-CoV-2 infec- cirrhosis. [19].
tion could also explain the mild transaminitis [2]. There have been various and somewhat incon-
Elevated liver enzymes can be seen in patients sistent findings regarding mortality risk associ-
with sepsis and septic shock as well and in this ated with COVID-19 infection in patients with
population reflect basic end-organ dysfunction preexisting liver disease. A study by Bangash
associated with shock. et al. suggests that the mortality rate for those
with underlying liver disease is somewhere
between 0% and 2% which is consistent, or only
reexisting Liver Disease
P slightly higher, than with our current rates of
and COVID-19 mortality in all comers with COVID-19 infection
[11]. Differing results from a study by Luo report
It is well known that patients with underlying mortality rates of 30–36% early in the pandemic
liver disease are at higher risk for the develop- in patients with preexisting liver disease [29].
ment of recurrent bacterial infections, including Another study suggests a markedly increased
infections like community-acquired pneumonia relative risk of mortality specifically in patients
and bacterial peritonitis, than in individuals with with underlying cirrhosis compared to those with
normal liver function [28]. Preexisting liver dis- other forms of preexisting liver disease [18]. As
ease is known to result in an acquired immune more studies are completed and more is learned
deficiency. This deficiency is a result of abnor- about the SARS-CoV-2, a more accurate picture
malities of nearly every type of systemically cir- of the mortality risk for those with preexisting
culating immune cell population. Some liver disease, and the general population, will
etiologies of liver disease are also associated become more clear.
with a systemic inflammatory activation with
circulating cytokines and an induced upregula-
tion of the cell activation markers [43]. The com- Hepatitis
bination of a persistently upregulated systemic
inflammatory activation and a generalized degree Data is limited in patients with COVID-19 and
of immunosuppression, in theory, makes patients hepatitis. As a result, current recommendations
with underlying liver disease a high-risk popula- are made conservatively and suggest that treat-
tion for the development of severe COVID-19 ment for underlying hepatitis diagnosis should
infection. not be routinely instituted in patients who develop
126 K. Boswell
COVID-19. Patients undergoing treatment for courses and worse outcomes in COVID-19
hepatitis B and C should continue their current infection.
regimen without interruption throughout the pan- Interestingly, a retrospective study demon-
demic, and those receiving immunosuppressive strated a prolonged period of viral shedding
therapies for autoimmune hepatitis should con- among 202 patients with NAFLD when com-
tinue. Practitioners should have a high index of pared to patients without underlying liver disease
suspicion to consider COVID-19 as an etiology at 17 days vs. 12 days, respectively
for an otherwise unexpected hepatitis flare [19]. (17.5 ± 5.2 days vs. 12.1 ± 4.4 days p < 0.0001)
A recent study of veterans suggests no difference [13].
in ICU admission and mortality in those with and
without hepatitis C, but did identify that patients
with hepatitis C are more frequently admitted to Cirrhosis
the hospital [38].
Similar data has been published in the autoim- The data in patients with known cirrhosis who
mune hepatitis (AIH) population, noting no develop COVID-19 has been relatively support-
increased risk of mortality when compared to ive of an increased risk of severe disease and
those without AIH even in the setting of immuno- mortality, especially when presenting with
suppression, but an increased risk of hospital decompensated cirrhosis at the time of their
admission with COVID-19 when compared to COVID-19 infection. Not surprisingly, they also
those without chronic liver disease [39]. tend to have a clinical course that is associated
with more complications [14, 15]. High Model
for End-Stage Liver Disease (MELD) scores at
onalcoholic Fatty Liver Disease
N the time of admission are also associated with a
and Nonalcoholic Steatohepatitis higher 30-day mortality [16]. We know that cir-
rhosis and chronic liver disease are associated
Nonalcoholic fatty liver disease (NAFLD) is with immune dysfunction and dysregulation
cited as the most common liver disease in indus- which likely play a role in the severity of their
trialized nations, including the United States disease process. Practitioners should have a low
[27]. Several studies have looked at NAFLD and threshold to test and treat patients with underly-
nonalcoholic steatohepatitis (NASH) to deter- ing cirrhosis for COVID-19.
mine if the existence of these conditions portends
a higher risk of contraction of COVID-19, a more
severe course of the disease process, or is poten- Liver Transplantation
tially associated with a higher mortality risk. Two
Chinese studies have shown a statistically signifi- The Centers for Medicare & Medicaid Services
cant increased risk for severe disease in patients (CMS) has established guidelines for the contin-
with NAFLD. Specifically noted was a substan- uation of surgical procedures during the pan-
tially increased risk of severe disease in patients demic where they recommend limiting “all
with NAFLD who are also obese [40] as well as a non-essential planned surgeries and procedures
higher risk associated with elevated liver fibrosis until further notice.” This recommendation spe-
scores [41]. cifically excludes transplantation procedures and
While these studies do suggest the possibility suggests not postponing these interventions [22].
of increased severity of COVID-19 infection in The AASLD has published similar recommenda-
those with underlying NAFLD or NASH, it is tions that all liver transplantation, unless urgent,
important to acknowledge that both of these dis- should be postponed. They define urgent liver
ease states are strongly associated with other transplantation as transplantation of a patient
components of metabolic syndrome, namely, who has a high MELD score or those at risk for
obesity and hypertension. Both obesity and being removed from the waiting list or progres-
hypertension are risk factors for more severe sion of disease. Testing of both the donor and
recipient for the SAR-CoV-2 with RT-PCR test- virus and require only supportive care. Yet, it is
ing as well as initial screening for exposure and crucial to ensure there isn’t another etiology to
symptom risk factors is required. Donors who are explain the laboratory abnormalities. Critically
positive for COVID-19 are rejected. The recom- ill patients are known to have increased instances
mendation against transplanting a potential recip- of acalculous cholecystitis. Additionally, the
ient who is COVID-19 positive is supported by hypercoagulable state associated with COVID-19
nearly all major liver and transplant societies. infection potentially presents a risk of portal
Following COVID-19 infection, recipients can be venous thrombosis. Ultrasound imaging with
transplanted once they are symptom-free for duplex studies are worthy of consideration to
21 days and have a negative RT-PCR test. evaluate the appearance of the gallbladder, bili-
For those patients who have previously under- ary tree, and portal venous blood flow. As noted
gone a liver transplant and are currently on immu- previously, right heart dilation and dysfunction is
nosuppressive therapies, it is encouraged that their associated with increased mortality in COVID-19
regimens should be continued throughout the pan- and also can lead to congestive hepatopathy. The
demic. It is believed that much of the severity of liberal use of transthoracic echocardiogram or
COVID-19 infection is mediated by the over- routine point of care ultrasound to examine right
whelming immune response and that immunosup- ventricular (or biventricular) size and function
pression may, in fact, be protective in the setting of should be considered. Routine evaluation of a
COVID-19 infection. It is unclear if that is the patient’s medications to elicit any potential phar-
case, but in prior pandemics, immunosuppression macologic contribution to abnormal LFTs is also
has not been a risk factor for more severe disease. suggested.
Interestingly in a small study from Lombardy,
Italy, which looked at a single transplant center’s
experience with COVID-19, higher-dose immuno- Current Therapies
suppression was associated with survival. The
transplanted patients who died from COVID-19 A remarkable number of medications and various
were considered “long-term” transplant patients therapies have been studied since SARS-CoV-2
being maintained on low-dose immunosuppres- was discovered. Many of the therapies we are
sion. None of the center’s recently transplanted currently using were not what we were initially
patients, on high-dose immunosuppression, who using earlier in the pandemic. Both dangerous
contracted COVID-19 died. While more research side effects and our gained understanding of
needs to be done to elucidate this association, the some of these medications lacking effectiveness
suggestion is that immunosuppression may, in have removed them from our armamentarium.
fact, be protective in COVID-19 [30]. There are a significant number of prospective
Additionally, elevated liver enzymes in a studies looking at many promising pharmaceuti-
COVID-19-positive patient should not be consid- cals in the prevention and treatment of the virus.
ered evidence of acute rejection without confir- The following information is not an exhaustive
mation based on biopsy. list of therapies, but is specifically focused on the
therapies that have the potential to be
hepatotoxic.
urrent Management and Therapies
C Use of antivirals at the beginning of the pan-
and Their Hepatic Effects demic, including the drug lopinavir-ritonavir,
was used with hopes that it would slow or stop
anagement of Liver Function
M viral replication in the SARS-CoV-2. Lopinavir-
Abnormalities ritonavir is a medication traditionally used in the
treatment of HIV infection, and in that popula-
The majority of patients who demonstrate ele- tion the medication has a well-known risk of
vated liver enzymes in the setting of COVID-19 hepatotoxicity. Patients who have both HIV and
infection can be attributed to the effects of the hepatitis C are potentially at higher risk for
128 K. Boswell
hepatic side effects when taking lopinavir- being treated for RA, and while this isn’t specific
ritonavir. Underlying liver disease in patients to the COVID-19 population, it warrants aware-
with COVID-19, especially hepatitis C, should ness prior to its use [37].
be monitored closely for evidence of hepatotox- The use of remdesivir, another antiviral, is
icity in the setting of treatment with lopinavir- ongoing in this pandemic. Remdesivir received
ritonavir [21]. FDA approval for compassionate use in the
Lopinavir-ritonavir use in the COVID-19 pan- United States early on in the pandemic and was
demic has unfortunately not been observed to officially approved as the first COVID-19 treat-
make a difference in any outcome measure ment by the FDA in the fall of 2020. It continues
including mortality, time to discharge, or need for to be a mainstay of treatment for people older
mechanical ventilation in several studies when than 12 years who require hospitalization for
compared to usual care [4, 32]. Several other COVID-19. There are a limited number of stud-
studies have found that the use of lopinavir-rito- ies regarding the efficacy of remdesivir; how-
navir leads to increased rates of transaminase ever, Beigel et al. published a multinational,
elevation suggestive of a possible component of double- blind, randomized controlled trial of
drug-related liver injury [9, 23]. Caution should remdesivir in more than 1000 patients, the
be used when treating patients with liver disease majority of which were categorized as having
and when considering the typical therapies given severe disease. Patients who received remdesi-
to patients with COVID-19. Several of the antivi- vir were found to have a statistically significant
ral medications mentioned in this chapter are shorter time to recovery, by about 5 days. There
metabolized by the liver making them potentially were no adverse effects to the liver associated
hepatotoxic, especially to patients with known with the use of remdesivir [10]. Conversely, few
liver disease, and therefore should be used with studies have found transaminase elevation as an
caution. adverse effect while studying remdesivir, but it
Tocilizumab is a monoclonal antibody that remains unclear if the LFT elevation is a direct
acts as an interleukin-6 (IL-6) receptor antagonist effect of the medication or a symptom of the
and is FDA approved for the treatment of rheu- disease severity. One of these studies, by Grein
matoid arthritis (RA) and juvenile idiopathic et al., discontinued treatment in 2 of their 53
arthritis. There are similar medications (siltux- study subjects due to rising aminotransferase
imab and sarilumab) that have also been used in levels attributed to remdesivir [42].
the treatment of COVID-19, but tocilizumab is Hydroxychloroquine is an antimalarial medi-
the most frequently used and studied of this fam- cation that was widely used at the onset of the
ily. Similar to lopinavir-ritonavir, the use of pandemic for its believed immunomodulatory
tocilizumab has been shown in the majority of and possible anti-inflammatory effects. However,
studies to be ineffective at improving survival or since then, a reasonable number of studies have
decreasing symptom duration or severity, or pre- demonstrated that hydroxychloroquine and chlo-
venting intubation [34, 35]. One study did dem- roquine are not effective in the treatment of
onstrate a 30-day mortality benefit when COVID-19 and more so can potentially cause
tocilizumab is given within 2 days of intensive harm. Notably, the Infectious Disease Society of
care admission [36]. It is important to note that America (IDSA) recommends against the use of
this study was a retrospective cohort study and these medications [33].
the results should be further examined with a ran-
domized control trial. These medications can be
associated with hepatotoxicity and therefore Conclusion
should be administered with caution in patients
with underlying liver disease. Additionally, Other important factors to consider when con-
tocilizumab has been associated with an increased templating the effects of the pandemic are not
risk of serious bacterial infection in patients just related to infection with COVID-19. The
social and economic effects of a pandemic on 8. Chai X, Hu L, Zhang Y, Han W, Lu Z, Ke A. Specific

individuals will result in more liver-related ACE2 expression in cholangiocytes may cause liver
damage after 2019-nCoV infection. BioRxiv. 2020.
deaths, as we have seen an increase in the use of 9. Fan Z, Chen L, Li J, Tian C, Zhang Y, Huang S, et al.
drugs and alcohol during prolonged periods of Clinical features of COVID-19 related liver damage.
quarantine and social isolation. Additionally, medRxiv. 2020.
patients with underlying liver conditions, 10. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir
for the treatment of COVID-19 – final report. N Engl J
including cirrhosis, liver cancers, and liver trans- Med. 2020;383:1813–26.
plants, have all been impacted as a result of their 11. Bangash MN, Patel J, Parekh D. COVID-19 and the
inability to have routine, safe, and reliable fol- liver: little cause for concern. Lancet Gastroenterol
low-up with primary and subspecialty care as a Hepatol. 2020;5(6):529–30.
12. Guan W, Ni Z, Liang C, et al. Clinical characteristics
result of the pandemic. We have yet to fully of coronavirus disease 2019 in China. NEJM. 2020.
understand the impact that SARS-CoV-2 will 13. Ji D, Qin E, Xu J, Zhang D, Cheng G, Wang

have on our global society. Y. Non- alcoholic fatty liver diseases in patients
The worldwide scientific community has with COVID- 19: a retrospective study. J Hepatol.
2020;73:451–3.
demonstrated a remarkable sense of collegiality 14. Qi X, Liu Y, Wang J, et al. For the COVID-

and collaboration that has been both compelling Cirrhosis- CHESS Group. Clinical course and risk
and inspiring since the identification of the factors for mortality of COVID-19 patients with pre-
SARS-CoV-2. While the amount we have learned existing cirrhosis: a multicentre cohort study. Gut.
2021;70:433–6.
as a scientific and medical community is aston- 15. Richardson S, Hirsch JS, Narasimhan M, et al.

ishing, there is still an immense amount to learn Presenting characteristics, comorbidities, and out-
about COVID-19. Undoubtedly, our understand- comes among 5700 patients hospitalized with
ing will continue to grow, and our practice will COVID-19 in the New York City area. JAMA.
2020;323:2052–9.
evolve as a result of our continued efforts to learn 16. Iavarone M, D’Ambrosio R, Soria A, et al. High rates
about the novel SARS-CoV-2. of 30-day mortality in patients with cirrhosis and
COVID-19. J Hepatol. 2020;73:1063–71.
17. Zhang C, Shi L, Wang F-S. Liver injury in COVID-19:
management and challenges. Lancet Gastroenterol
References Hepatol. 2020;5:428–30.
18. Singh S, Khan A. Clinical characteristics and out-
1. Coronavirus Resource Center. Johns Hopkins comes of coronavirus disease 2019 among patients
University & Medicine. Accessed January 2021. with preexisting liver disease in the United States: a
https://coronavirus.jhu.edu/. multicenter research network study. Gastroenterology.
2. Argulian E, Sud K, Vogel B, et al. Right ven- 2020;159:768–71.
tricular dilation in hospitalized patients with 19. AASLD. Clinical insights for hepatology and liver
COVID-19 infection. J Am Coll Cardiovasc Imag. transplant providers during the COVID-19 pandemic.
2020;13(11):2459–61. 2020: 1–28.
3. del Rio C, Malani PN. COVID-19—new 20. Wander P, Epstein M, Bernstein D. COVID-19
insights on a rapidly changing epidemic. JAMA. presenting as acute hepatitis. Am J Gastroenterol.
2020;323(14):1339–40. 2020;115(6):941–2.
4. Cao B, Wang Y, Wen D, et al. Atrial of lopinavir- 21. Sulton S, Altaya O, Siddique SM, et al. AGA insti-
ritonavir in adults hospitalized with severe Covid-19. tute rapid review of the gastrointestinal and liver
N Engl J Med. 2020;382:1787–99. manifestations of COVID-19, meta-analysis of inter-
5. Connors JM, Levy JH. Thromboinflammation and the national data, and recommendations for the con-
hypercoagulability of COVID-19. J Thromb Haemost. sultative management of patients with COVID-19.
2020;18:1559–61. Gastroenterology. 2020;159:320–34.
6. Chau TN, Lee KC, Yao H, et al. SARS-associated 22. Centers for Medicare and Medicaid Services. Non-
viral hepatitis caused by a novel coronavirus: report emergent, elective medical services, and treat-
of three cases. Hepatology. 2004;39:302–10. ment recommendations. https://www.cms.gov/files/
7. Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD, document/31820-c ms-a dult-e lective-s urgery-a nd-
Jin HJ, et al. The origin, transmission and clinical procedures-recommendations.pdf. Accessed Jan
therapies on coronavirus disease 2019 (COVID-19) 2021.
outbreak – an update on the status. Mil Med Res. 23. Cai Q, Huang D, Yu H, et al. COVID-19: abnormal
2020;7(1):11. liver function tests. J Hepatol. 2020;73(3):566–74.
130 K. Boswell
24. Xu Z, Shi L, Wang Y, et al. Pathological findings of 35. Salama C, Han J, Yau L, et al. Tocilizumab in patients
COVID-19 associated with acute respiratory distress hospitalized with Covid-19 pneumonia. N Engl J
syndrome. Lancet Respir Med. 2020;8(4):420–2. Med. 2021;384(1):20–30.
25.
Jothimani D, Venugopal R, Abdein MF, 36. Gupta S, Wang W, Hayek SS, et al. Association

et al. COVID- 19 and the liver. J Hepatol. between early treatment with tocilizumab and mor-
2020;73(5):1231–40. tality among critically ill patients with COVID-19.
26. Tian S, Xiong Y, Liu H, et al. Pathological study of JAMA Intern Med. 2021;181(1):41–51.
the 2019 novel coronavirus disease (COVID-19) 37. Pawar A, Desai RJ, Solomon DH, et al. Risk of serious
through postmortem core biopsies. Mod Pathol. infections in tocilizumab versus other biologic drugs
2020;33(6):1007–14. in patients with rheumatoid arthritis: a multidatabase
27. Ando Y, Jou JH. Nonalcoholic fatty liver disease and cohort study. Ann Rheum Dis. 2019;78(4):456–64.
recent guideline updates. Clin Liver Dis (Hoboken). 38. Butt AA, Yan P, Chotani RA, et al. Mortality is not
2021;17(1):23–8. increased in SARS-CoV-2 infected persons with
28. Nseir W, Taha H, Khateeb J, et al. Fatty liver is associ- hepatitis C virus infection. Liver Int. 2021. https://doi.
ated with recurrent bacterial infections independent of org/10.1111/liv.14804. Epub ahead of print
metabolic syndrome. Dig Dis Sci. 2011;56:3328–34. 39. Marjot T, Buescher G, Sebode M, et al. Contributing
29. Luo XM, Zhou W, Xia H, Yang W, Yan X, Wang Members and Collaborators of ERN RARE-
B, Guo T, Ye L, Xiong J, Jiang Z, Liu Y, Zhang LIVER/COVID-Hep/SECURE-Cirrhosis, Moon
B. Characteristics of SARS-CoV-2 infected patients AM, Webb GJ, Lohse AW. SARS-CoV-2 infec-
with clinical outcome during epidemic ongoing out- tion in patients with autoimmune hepatitis. J
break in Wuhan, China, SSRN Electron J. 2020. Hepatol. 2021:S0168-8278(21)00033-7. https://doi.
30. Bhoori S, Rossi RE, Citterio D, et al. COVID-19 in org/10.1016/j.jhep.2021.01.021. Epub ahead of print.
long term liver transplant patients: preliminary expe- PMID: 33508378; PMCID: PMC7835076.
rience from an Italian transplant centre in Lombardy. 40. Zheng KI, Gao F, Wang X-B, et al. Letter to the edi-
Lancet Gastroenterol Hepatol. 2020;5(6):532–3. tor: obesity as a risk factor for greater severity of
31.
Bilaloglu S, Aphinyanaphongs Y, Jones S, COVID-19 in patients with metabolic associated fatty
et al. Thrombosis in hospitalized patients with liver disease. Metabolism. 2020;108:154244.
COVID- 19 in a New York City Health System. 41. Targher G, Mantovani A, Byrne CD, et al. Risk of
JAMA. 2020;324(8):799–801. severe illness from COVID-19 in patients with meta-
32.
RECOVERY Collaborative Group. Lopinavir- bolic dysfunction-associated fatty liver disease and
ritonavir in patients admitted to hospital with increased fibrosis scores. Gut. 2020;69:1545–7.
COVID-19 (RECOVERY): a randomised, con- 42. Grein J, Ohmagari N, Shin D, et al. Compassionate
trolled, open-label, platform trial. Lancet. use of remdesivir for patients with severe COVID-19.
2020;396(10259):1345–52. N Engl J Med. 2020;382:2327–36.
33. Tang W, Cao Z, Han M, et al. Hydroxychloroquine 43. Albillos A, Lario M, Alvarez-Mon M. Cirrhosis-

in patients with mainly mild to moderate coronavirus associated immune dysfunction: Distinctive
disease 2019: open label, randomised controlled trial. features and clinical relevance. J Hepatol.
BMJ. 2020;369:m1849. 2014;61(6):1385–396.
34. Stone JH, Frigault MJ, Serling-Boyd NJ, et al.
44. Sahin T, Akbulut S, Yilmaz S. COVID-19 pandemic:
Efficacy of tocilizumab in patients hospitalized with It’s impact on liver disease and liver transplantation.
Covid-19. N Engl J Med. 2020;383(24):2333–44. World J Gastroenerol. 2020;26(22):2987–999.
Hematologic Emergencies
in Patients with Covid-19
13
Jessica Waters, Rory Spiegel,
and Michael T. McCurdy
Introduction cations likely contributes to the morbidity and

mortality associated with Covid-19 illness [1, 2].
While coronavirus disease 2019 (Covid-19) is Microvascular thrombi have been observed pre-
considered a disease that primarily affects the dominantly in the lungs and with much lower fre-
respiratory system, a growing body of literature quency in other capillary beds [3–5]. Pulmonary
suggests that its wide-ranging effects on the vasculature may be particularly predisposed to
hematologic system are clinically significant. In this phenomenon as the respiratory system is a
this chapter, we discuss the effects of severe acute major site of viral entry in coronavirus infections
respiratory syndrome coronavirus 2 (SARS- [6] and histopathology studies confirmed an
CoV-2) on coagulation and other hematological increased prevalence of ACE2 receptor-positive
manifestations, as well as their impact on diag- cells, the cellular target of SARS-CoV-2 [7], in
nostic and therapeutic decisions. lung vasculature in Covid-19 patients [8].
Although microthrombi have previously been
described in severe ARDS and with other corona-
Defining Hematologic virus infections, the prevalence of microthrombi
Abnormalities in Covid-19 in Covid-19 is nine times more common than in
patients with influenza [8]. Additional histologic
Covid-19-associated coagulopathy (CAC) refers analyses of lung tissue of Covid-19 patients have
to the unique hematologic laboratory abnormali- found both platelet-rich and fibrin microthrombi
ties and hemorrhagic and thrombotic complica- in up to 90% of cases [9, 10]. The frequency of
tions resulting from SARS-CoV-2 infection. The both large vessel thrombosis and microthrombi
unusually high incidence of thrombotic compli- was not associated with anticoagulation therapy,
occurring despite prophylactic and sometimes
J. Waters
therapeutic anticoagulation [1, 11, 12].
Department of Emergency Medicine, MedStar Interestingly, large vessel pulmonary thrombi
Washington Hospital Center, Washington, DC, USA were more frequently found in segmental or sub-
R. Spiegel (*) segmental vasculature, suggesting that at least
Departments of Emergency Medicine and Critical some of the pulmonary thrombi seen in Covid-19
Care, MedStar Washington Hospital Center, may be in situ thromboses rather than embolic
Washington, DC, USA
phenomena [13].
M. T. McCurdy Based on its unique biomarker and histopatho-
University of Maryland School of Medicine,
Baltimore, MD, USA
logical patterns, CAC is thought to be distinct
132 J. Waters et al.
from disseminated intravascular coagulation myocardial infarction (STEMI) [25–28] but also
(DIC) and sepsis-induced coagulopathy (SIC) [2, as non-STEMI, and unstable angina have also
12]. SARS-CoV-2 infects cells via vascular endo- been reported [16]. Hemorrhagic complications
thelial ACE2 receptors, leading to direct endothe- occur less frequently, with major bleeding events
lial injury and subsequent thrombosis. Due to the occurring in 2.3% of patients in one retrospective
injury, the endothelium is unable to secrete tissue study [16].
plasminogen activator (tPA), which inhibits
platelet binding and coagulation cascade activa-
tion. This endothelial dysfunction may contribute Thrombotic Events in Covid-19
to excess clotting risk. In addition to SARS-CoV-
2-induced cytokine and leukocyte activation, Although SARS-CoV-2 infection has yet to be
endothelial dysfunction itself amplifies existing definitively established as an independent risk
inflammation by releasing interleukin-5 (IL-5) factor for VTE, the increased incidence of VTE
[1]. Thrombogenic proinflammatory cytokines in hospitalized patients with Covid-19 has been
further exacerbate endothelial damage and described in many observational studies. A sys-
unchecked coagulation activation [14]. tematic review and meta-analysis of 28,173
The coagulopathy most often seen in non- patients in 66 studies found a VTE prevalence of
Covid-19 sepsis is consumptive and marked by 14% overall and 23% in ICU patients [29]. While
profound thrombocytopenia and an increased these mostly retrospective reports must be inter-
prothrombin time (PT). In contrast, significant preted cautiously, one particular prospective
derangements of these coagulation biomarkers cohort study in patients with Covid-19 ARDS
are infrequently observed in CAC, which exhibits suggests an increased risk of thrombotic events.
only moderately reduced platelet counts and a In this study, the authors report an increased inci-
mildly prolonged PT. [15] In addition, Covid-19 dence of pulmonary embolism (PE) in Covid-19
patients appear to be at a significantly lower risk ARDS as compared with a matched non-
of developing DIC when compared to patients Covid-19 ARDS cohort (11.7 vs 2.1%) [12].
with sepsis [12, 16]. Elevated D-dimer levels in Due to many hospitals’ infection protocols or
CAC may result from upregulation of local alve- shortages of personal protective equipment
olar fibrinolysis [2] and may correlate with dis- (PPE), especially in early stages of the pandemic,
ease severity [17–19]. obtaining radiologic confirmation of VTE was
The coagulopathy associated with Covid-19 occasionally limited and may have underesti-
illness appears to be primarily hemostatic, with a mated the number of thrombotic events [30]. In
far greater incidence of thrombotic events than one study utilizing systematic Doppler ultraso-
hemorrhagic complications. Venous thromboses nography in all patients with Covid-19, VTE was
heavily predominate, comprising 90% of all diagnosed in 69% of cases [11]. These findings
thrombotic complications in one Dutch study are corroborated by a review of the literature in
[20]. A recent literature review describes an over- which the incidence of VTE in those with
all venous thromboembolism (VTE) frequency Covid- 19 was fourfold higher in studies with
of 20% [21]. Recurrent clotting of extracorporeal screening strategies than in those without [29].
circuits (e.g., CVVH, ECMO) has also been Autopsy studies of 12 Covid-19 patients in
reported despite standard anticoagulation strate- Germany identified previously undiagnosed and
gies [12, 16]. Arterial thrombosis, primarily cere- unsuspected DVT in 58% of cases [31], further
brovascular thrombosis causing acute ischemic suggesting underdiagnosis of VTE in this
stroke [20, 22, 23], is not an uncommon compli- population.
cation. For example, retrospective data from Although obtaining high-quality prospective
Wuhan, China, and elsewhere report an occur- data regarding the incidence of VTE in critically
rence rate of ischemic stroke between 2.7% and ill and hospitalized patients with Covid-19 has
3.8% [21, 24]. Covid-19-associated cardiovascu- been challenging, the high likelihood of increased
lar ischemia, primarily presenting as ST-elevation VTE risk is generally accepted. More challeng-
13 Hematologic Emergencies in Patients with Covid-19 133
ing, however, is deciphering from sparse outpa- symptoms of Covid-19 pneumonia. Moreover,
tient data about whether SARS-CoV-2 is a risk traditional markers and scoring systems of proco-
factor for VTE in mild or asymptomatic agulant states previously used to diagnose SIC
infections. Case reports detailing diagnoses of and DIC have proven unreliable in patients with
VTE in minimally symptomatic patients raise the Covid-19 [12].
issue [32], though few studies have looked at the
incidence of VTE in emergency department (ED)
patients. A recent multinational review [33] of Decision Tools
ED patients with Covid-19 undergoing computed
tomography pulmonary angiography (CTPA) for Given the difficulty in obtaining radiologic con-
suspected PE found that the incidence of PE, as firmation of suspected VTE in many patients with
compared to both historical and contemporane- Covid-19, either due to risk management and
ous non-Covid-19 controls, was equal in patients infection prevention or hemodynamic instability
with and without Covid-19 infection. While ill- preventing transfer [37], significant effort has
ness severity and rate of subsequent hospitaliza- been made to identify tools to risk stratify these
tion were not described in this report, these patients according to their likelihood of having a
findings suggest that Covid-19 may not be an VTE. Though no traditional scoring systems
independent risk factor for PE in ED patients, have been validated in patients with Covid-19,
though further study is needed. the modified Wells score has been used in hospi-
With regard to timing of VTE occurrence, the talized patients to evaluate the risk of PE [38] and
data examining the period in which Covid-19 may be a viable option in patients with Covid-19
patients are at highest risk is inconclusive. One [37]. One study applied the Wells score retro-
small retrospective study of 92 patients admitted spectively and found the incidence of DVT in
to a Covid-19 ICU in France found that the patients with a moderate risk Wells score of 1–2
median number of days between ICU admission was 49%, significantly lower than in patients
and diagnosis of VTE was 9, with a median of with a Wells score of ≥3 (88%) [36]. Similarly,
17 days from onset of first Covid-19 symptoms only case reports have described a PE diagnosis
[34]. Other retrospective inpatient studies have in patients with Covid-19 who were categorized
found similar timeframes [35, 36], though in one as low risk by the Pulmonary Embolism Rule-out
Italian study over half of diagnosed arterial and Criteria (PERC) tool [32]. Given the paucity of
venous thromboembolism were found within data, the ability of the PERC to safely rule out PE
24 hours of hospital admission [25]. The current in patients with Covid-19 remains unknown.
literature has reported on VTE occurrence pri- For hospitalized medical patients, the Padua
marily in hospitalized patients and the critically and IMPROVE scores were designed to assist cli-
ill [30, 31, 33, 34]. Given the variability in the nicians in weighing the risks and benefits of VTE
time period of highest risk and the scarcity of and thromboprophylaxis [39, 40]. Small retro-
studies utilizing systematic VTE screening in spective studies examining the application of
both inpatient and outpatient settings, the timing these scores in patients with Covid-19 have
of VTE with respect to onset of symptoms, ED yielded mixed results [36, 41, 42]. One study
presentation, and hospital admission is unknown. found an increased incidence of DVT in patients
with Padua score ≥ 4, whereas none of those with
a Padua score of <4 had a DVT [36]. Conversely,
TE Diagnostic Considerations
V Trimaille et al. determined that a Padua score ≥ 4
in Patients with Covid-19 was not associated with risk of VTE [41]. Both of
these small retrospective cohort studies found
Diagnosing VTE, and particularly PE, in patients that higher IMPROVE scores were associated
with SARS-CoV-2 presents a considerable chal- with higher incidence of VTE [36, 41]. However,
lenge, as symptoms of PE may overlap with neither the Padua nor IMPROVE scores are vali-
dated in ICU or ED patient populations, limiting such as YEARS criteria and age-adjusted
wide application of these tools. Given the incon- D-dimer, have not been validated in patients with
sistency of data, the recent American College of SARS-CoV-2 and should be avoided until better
Chest Physicians (ACCP) guidelines recommend data are available.
avoiding such individualized VTE risk assess-
ment altogether [43].
Imaging
Laboratory Markers Given reports of increased incidence of PE (81%

of diagnosed VTE) compared to DVT (10%) [20]
The data examining individual inflammatory in Covid-19 and the possibility of non-embolic
markers’ ability to predict VTE are inconclu- pulmonary thrombosis [13], clinicians should
sive [44]. While some studies have found eleva- favor chest imaging over lower extremity Doppler
tions in inflammatory and coagulation in cases where PE is suspected. A French case
biomarkers, such as D-dimer, platelet count, series found a twofold increased prevalence of
C-reactive protein (CRP), and erythrocyte sedi- PE compared to DVT [50], and meta-analyses
mentation rate (ESR), at initial presentation to identified a pooled incidence of PE of 15.3%
be predictive of downstream thrombotic com- [51]. However, DVT incidence is much higher in
plications [16, 45], others have found no asso- studies utilizing systematic screening techniques
ciation between some of these biomarkers and [11, 52] than in those where imaging was obtained
thrombotic events [13, 45, 46]. Elevated for clinical suspicion [50], suggesting an under-
D-dimer has not only been associated with diagnosis of DVT. In fact, one study utilizing sys-
thrombotic risk but also mortality. [15, 17, 18, tematic DVT screening in ICU patients found a
47, 48] Observational studies have found prevalence of 85.4% [52]. Given the heterogene-
D-dimer to increase with disease severity [15, ity in study design and reported incidence, even
17], likely confounding the relationship estimated pooled prevalences of DVT (16%) [53]
between D-dimer values, severe Covid-19 or PE are unlikely to provide an accurate assess-
pneumonia, critical illness, and VTE risk. ment of risk reliable enough to guide diagnostic
Citing such variability in biomarker associa- imaging strategies.
tions and diagnostic strategies employed by Until better data are published, CTPA should
studies attempting to establish the predictive be sought in patients with hemodynamic instabil-
values of individual markers, the recent ACCP ity or persistent hypoxemia out of proportion to
guidelines recommend against using biomark- pulmonary disease burden, even without clini-
ers for the diagnostic evaluation of VTE [43]. cally evident DVT. In patients for whom CTPA is
In those patients in whom a D-dimer is contraindicated, ventilation and perfusion (VQ)
obtained, multiple optimal cutoff points for VTE imaging remains an alternative, albeit somewhat
exclusion have been identified, though none have controversial, tool. The American College of
been validated in the Covid-19 population. Radiology released a statement suggesting that
Artifoni et al. found that the negative predictive perfusion-only imaging may be obtained to
value (NPV) of D-dimer <1.0 μg/ml was 90% for reduce aerosolization associated with ventilation
VTE and 98% for PE [45]. Other studies have scans [54]. However, given the decreased diag-
found varying optimal thresholds for cutoff for nostic accuracy of perfusion-only imaging and
diagnosing VTE [35, 46, 49]. Given the limita- the considerable discussion surrounding clini-
tions of retrospective data and the absence of reli- cians’ ability to risk stratify patients with SARS-
ably established cutoff thresholds, if D-dimer is CoV-2, perfusion-only imaging is a substandard
used as a diagnostic marker, the previously estab- alternative [55, 56]. Duplex ultrasonography
lished threshold of <0.5 μg/ml should be applied. remains the most common imaging modality for
Adjusted D-dimer risk stratification strategies, diagnosis of DVT, though DVT imaging is not a
surrogate diagnostic tool for PE, given its poor therapeutic anticoagulation. These guidelines
sensitivity in this setting, with a NPV of only recommend systemic fibrinolysis in patients with
77% [37]. confirmed PE who become acutely hypotensive
or exhibit signs of obstructive shock and in those
who fail therapeutic anticoagulation and exhibit
Diagnostic Strategy persistent hemodynamic instability. However, in
those patients with recurrent VTE but no hemo-
Currently no appropriately validated schema dynamic instability, the recommendation is to
exists to evaluate VTE in patients with SARS- adjust dosing rather than to proceed with sys-
CoV-2. Without a validated tool to confidently temic thrombolytic therapy [43]. Thrombolytic
incorporate into clinical care, diagnostic strate- therapy dosed according to institutional protocol
gies in patients with SARSCoV-2 should be simi- in patients with imminent or ongoing hemody-
lar to typical practices used to diagnose VTE in namic instability or worsening RV function with
ED patients. As for patients without SARS- confirmed PE is likewise supported by the PERT
CoV-2, the primary step in any diagnostic algo- Consortium’s recent position paper [57].
rithm is to determine which patients require Regarding procedural therapy, both the PERT
further evaluation. Much like patients without Consortium and ACCP recommend against pro-
SARS-CoV-2, this decision should be based on cedural intervention unless patients exhibit
the patient’s presentation and a clinician’s assess- hemodynamic instability with contraindications
ment that the current symptoms are not due to to medical therapy [43, 57]. In patients in whom
Covid-19 alone. Once the decision to pursue the PE is not confirmed and who are too unstable to
diagnosis of VTE is made, patients should be risk proceed with further imaging, the ACCP guide-
stratified according to their likelihood of having lines recommend against empiric thrombolytic
VTE, and the PERC rule and D-dimer assays therapy except in the case of cardiac arrest and a
should be used in low-risk patients. For those that high index of suspicion for PE [43].
are at high enough risk to forego PERC or
D-dimer testing or who have failed this initial
step, CTPA is the imaging test of choice. In Anticoagulation in the Absence
patients who cannot receive CTPA, VQ and of Macrothrombi
perfusion-only scanning are possible but insuffi-
cient to adequately rule out PE in high-risk Although anticoagulation in patients with SARS-
patients due to its poor sensitivity. In such cases CoV- 2 and radiographic evidence of macro-
clinicians should assess the risk of hemorrhagic thrombi is not controversial, it is unclear whether
complications and consider if empiric anticoagu- a more aggressive anticoagulation strategy in
lation is justified. patients with severe Covid-19 without evidence
of macrothrombi lessens the microthrombotic
burden.
Treatment of Macrothrombi Despite a paucity of high-quality randomized
control trial data, many observational studies
Current ACCP guidelines regarding treatment of suggest that patients may benefit from more
VTE in hospitalized patients indicate that thera- aggressive anticoagulation strategies than tradi-
peutic low molecular weight heparin (LMWH) or tional prophylactic dosing. Many observational
unfractionated heparin (UFH) is favored over studies have demonstrated that VTE rates in
oral anticoagulants due to risk of clinical deterio- patients with Covid-19 exceed what is typically
ration in this patient population [43]. observed in ICU patients despite standard pro-
In hemodynamically stable patients with con- phylactic dosing strategies [12, 20].
firmed VTE, ACCP guidelines recommend Additionally, retrospective cohorts have
against systemic thrombolytic therapy, favoring reported improved mortality in patients given a
VTE category Dose of anticoagulation Dose adjustments

for CrCl > 30
High risk: confirmed or CrCl 15-30: 0.5 mg/kg SubQ Q12h
suspected: 1. LMWH 1 mg/kg SubQ hours or UFH gtt anti Xa goal 0.3
• Know indication for Q12h to 0.7
anticoagulation or CrCl < 15: Do not use LMWH
• Newly Diagnosed VTE 2. UFH att Anti Xa goal Known or suspected HIT:
• High Clinical Suspicion for 0.3 to 0.7 [Preferred Argatroban gtt or
VTE in ECMO or CRRT] Fondaparinux SubQ Q24h if
• On ECMO or CRRT CrCI > 30 and low bleeding risk
and clinically stable
Moderate risk: 1. LMWH 0.5 mg/kg CrCl < 30 or CRRT: UFH 7500 u
• Hypercoagulable risk SubQ Q12h SubQ Q8h
(clinical or lab -e.g. TEG) or Remote HIT:
• Moderate clinical 2. LMW 1mg/kg SubQ Consult Hematology
Suspicion for VTE Q24h Consider Fondaparinux 5mg SC
Unproven Or Q24 if CrCl >30
• Clotting of central line 3. UFH gtt Anti Xa goal
0.1 to 0.3
Average risk: 1. LMWH 40mg SubQ CrCl 15-30: LMWH 30mg SubQ
• No know or suspected Q24h if BMI < 40 Q24h
VTE 2. LMW 40 mg SubQ CrCl < 15: UFH 5000 u SubQ Q8h
Q12h if BMI t40 BMI > 40 and CrCl <30: UFH 7500
u SubQ Q8h
Remote HIT:
CrCl > 30: Fondaparinux
2.5mg SubQ Q24h
CrCl t30: SCDs and
consult Heme
Fig. 13.1 Example of anticoagulation strategies in Covid-19 patients*. *Anticoagulation protocol used for patients
with Covid-19 at MedStar Washington Hospital Center as of June 2020
more aggressive anticoagulation protocol when ied widely across institutions. Many have contin-
compared to standard prophylactic dosing [12, ued to use standard prophylactic dosing, while
15, 58]. A small single-center phase 2 trial ran- others have turned to intermediate dosing or even
domized 20 patients with severe Covid-19 requir- full therapeutic strategies in critically ill patients
ing mechanical ventilation to standard admitted to the ICU. See Fig. 13.1 for an example
prophylactic dosing or full therapeutic doses of of such a protocol.
enoxaparin [59]. The authors found that patients The ACTIV-4 trial [60], a randomized con-
receiving full-dose anticoagulation experienced a trolled trial examining the use of full dose antico-
larger improvement in the ratio of the partial agulation compared to standard prophylactic
pressure of arterial oxygen (PaO2) to the fraction dosing, prematurely halted the critically ill arm
of inspired oxygen (FiO2) (PaO2-FiO2 ratio), of the trial due to futility. Though not yet pub-
were liberated from the ventilator more fre- lished at the time of drafting this chapter, these
quently, and had more ventilator-free days, as results call into question administering a more
compared to patients who received standard pro- aggressive dosing strategy.
phylactic dosing. The recommendations made by various guide-
Without definitive data clearly supporting a lines regarding the ideal anticoagulation strategy
single anticoagulant strategy, practices have var- in patients with severe Covid-19 infections vary.
The ACCP guidelines recommend against the use of the effects of SARS-CoV-2 on the coagulation
of more aggressive anticoagulation strategy in system. Moreover, incorporating new informa-
favor of standard prophylactic dosing [43]. In tion into the diagnosis and management of these
contrast, the guidelines from the International complex patients and continuing to adapt prac-
Society on Thrombosis and Haemostasis [61] tice according to emerging data will be essential
recommend using an intermediate dosing to optimize patient clinical outcomes.
strategy.
References
Antiplatelet Agents
1. Ahmed S, Zimba O, Gasparyan AY. Thrombosis
Because platelet dysfunction seems to be a com- in coronavirus disease 2019 (COVID-19) through
ponent of CAC, antiplatelet agents such as aspi- the prism of Virchow’s triad. Clin Rheumatol.
2020;39(9):2529–43.
rin may potentially benefit these patients. 2. Iba T, Levy JH, Connors JM, Warkentin TE, Thachil
Unfortunately, the evidence supporting this prac- J, Levi M. The unique characteristics of COVID-19
tice is even more scarce than the data regarding coagulopathy. Crit Care. 2020;24(1):360.
anticoagulation [62]. In one multicenter retro- 3. Menter T, Haslbauer JD, Nienhold R, et al.
Postmortem examination of COVID-19 patients
spective study, the authors examined all patients reveals diffuse alveolar damage with severe capillary
with Covid-19. After controlling for potential congestion and variegated findings in lungs and other
confounding variables, the authors reported an organs suggesting vascular dysfunction [Internet].
association with the use of only a median dose of Histopathology. 2020;77(2):198–209. Available from:
https://doi.org/10.1111/his.14134.
81 mg of aspirin and a decrease in the risk of 4. Magro C, Mulvey JJ, Berlin D, Nuovo G. Complement
mechanical ventilation, ICU admission, and associated microvascular injury and thrombosis in the
inpatient mortality. Despite these positive find- pathogenesis of severe COVID-19 infection: a report
ings, due to the retrospective nature of this study, of five cases. Translational [Internet] 2020. Available
from: https://www.sciencedirect.com/science/article/
more high-quality data are required. pii/S1931524420300700.
5. Duarte-Neto AN, Monteiro RAA, Silva LFF, et al.
Pulmonary and systemic involvement in COVID-19
Fibrinolytic Therapy patients assessed with ultrasound-guided mini-
mally invasive autopsy [Internet]. Histopathology.
2020;77(2):186–97. Available from: https://doi.
The use of fibrinolytic therapy in patients without org/10.1111/his.14160.
diagnosed macrothrombi is controversial and not 6. Jonsdottir HR, Dijkman R. Coronaviruses and the
supported by current guidelines. Case reports human airway: a universal system for virus-host inter-
action studies. Virol J. 2016;13:24.
describe varying levels of clinical improvement 7. Walls AC, Park Y-J, Tortorici MA, Wall A, McGuire
in patients given systemic thrombolytic therapy AT, Veesler D. Structure, function, and antigenic-
[63–65]. Studies evaluating these interventions ity of the SARS-CoV-2 spike glycoprotein. Cell.
are ongoing [66, 67], but currently limited evi- 2020;183(6):1735.
8. Ackermann M, Verleden SE, Kuehnel M, et al.
dence suggests this as a viable treatment option. Pulmonary vascular endothelialitis, thrombo-
sis, and angiogenesis in Covid-19. N Engl J Med.
2020;383(2):120–8.
Conclusion 9. Borczuk AC, Salvatore SP, Seshan SV, et al.
COVID- 19 pulmonary pathology: a multi-
institutional autopsy cohort from Italy and New York
Many details of CAC have yet to be fully under- City. Mod Pathol. 2020;33(11):2156–68.
stood. However, patients with SARS-CoV-2 10. Carsana L, Sonzogni A, Nasr A, et al. Pulmonary
often have a hypercoagulable state that increases post-mortem findings in a series of COVID-19 cases
from northern Italy: a two-centre descriptive study.
their risk of thrombotic events. The optimal treat- Lancet Infect Dis. 2020;20(10):1135–40.
ment strategy to combat this coagulopathy 11. Llitjos J-F, Leclerc M, Chochois C, et al. High inci-
remains unclear, but clinicians should be aware dence of venous thromboembolic events in anticoagu-
lated severe COVID-19 patients. J Thromb Haemost. 27. Dominguez-Erquicia P, Dobarro D, Raposeiras-

2020;18(7):1743–6. Roubín S, Bastos-Fernandez G, Iñiguez-Romo
12. Helms J, Tacquard C, Severac F, et al. High risk of A. Multivessel coronary thrombosis in a patient
thrombosis in patients with severe SARS-CoV-2 with COVID-19 pneumonia. Eur Heart J.
infection: a multicenter prospective cohort study. 2020;41(22):2132.
Intensive Care Med. 2020;46(6):1089–98. 28. Shams A, Ata F, Mushtaq K, Munir W, Yousaf

13. Desborough MJR, Doyle AJ, Griffiths A, Retter A, Z. Coronary thrombosis in a young male with
Breen KA, Hunt BJ. Image-proven thromboembo- COVID-19. IDCases. 2020;21:e00923.
lism in patients with severe COVID-19 in a tertiary 29. Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Risk
critical care unit in the United Kingdom. Thromb Res. of venous thromboembolism in patients with
2020;193:1–4. COVID-19: a systematic review and meta-analysis.
14. Colling ME, Kanthi Y. COVID–19-associated coagu- Res Pract Thromb Haemost [Internet] 2020. Available
lopathy: an exploration of mechanisms. Vasc Med. from: https://doi.org/10.1002/rth2.12439.
2020;25(5):471–8. 30. Nopp S, Janata-Schwatczek K, Prosch H, et al.

15. Tang N, Bai H, Chen X, Gong J, Li D, Sun
Pulmonary embolism during the COVID-19 pan-
Z. Anticoagulant treatment is associated with demic: decline in diagnostic procedures and incidence
decreased mortality in severe coronavirus disease at a university hospital. Res Pract Thromb Haemost.
2019 patients with coagulopathy. J Thromb Haemost. 2020;4(5):835–41.
2020;18(5):1094–9. 31. Wichmann D, Sperhake J-P, Lütgehetmann M, et al.
16. Al-Samkari H, Karp Leaf RS, Dzik WH, et al.
Autopsy findings and venous thromboembolism in
COVID-19 and coagulation: bleeding and thrombotic patients with COVID-19: a prospective cohort study.
manifestations of SARS-CoV-2 infection. Blood. Ann Intern Med. 2020;173(4):268–77.
2020;136(4):489–500. 32. Joseph JW, Roberts JC, Weaver CN, Anderson

17. Wang D, Hu B, Hu C, et al. Clinical characteristics JS, Wong ML. Patients with mild COVID-19
of 138 hospitalized patients with 2019 novel corona- symptoms and coincident pulmonary embo-
virus–infected pneumonia in Wuhan, China. JAMA. lism: a case series. Clin Pract Cases Emerg Med.
2020;323(11):1061–9. 2020;4(3):295–8.
18. Zhou F, Yu T, Du R, et al. Clinical course and
33. Freund Y, Drogrey M, Miró Ò, et al. Association

risk factors for mortality of adult inpatients with between pulmonary embolism and COVID-19 in
COVID-19 in Wuhan, China: a retrospective cohort emergency department patients undergoing computed
study. Lancet. 2020;395(10229):1054–62. tomography pulmonary angiogram: the PEPCOV
19. Tang N, Li D, Wang X, Sun Z. Abnormal coagula- international retrospective study. Acad Emerg Med.
tion parameters are associated with poor prognosis in 2020;27(9):811–20.
patients with novel coronavirus pneumonia [internet]. 34. Fraissé M, Logre E, Pajot O, Mentec H, Plantefève
J Thromb Haemost. 2020;18(4):844–7. Available G, Contou D. Thrombotic and hemorrhagic events in
from: https://doi.org/10.1111/jth.14768 critically ill COVID-19 patients: a French monocenter
20. Klok FA, Kruip MJHA, van der Meer NJM, et al. retrospective study. Crit Care. 2020;24(1):275.
Incidence of thrombotic complications in criti- 35. Creel-Bulos C, Liu M, Auld SC, et al. Trends and
cally ill ICU patients with COVID-19. Thromb Res. diagnostic value of D-dimer levels in patients hos-
2020;191:145–7. pitalized with coronavirus disease 2019. Medicine.
21. Al-Ani F, Chehade S, Lazo-Langner A. Thrombosis 2020;99(46):e23186.
risk associated with COVID-19 infection. A scoping 36. Chen S, Zhang D, Zheng T, Yu Y, Jiang J. DVT

review. Thromb Res. 2020;192:152–60. incidence and risk factors in critically ill patients
22. Kihira S, Schefflein J, Chung M, et al. Incidental with COVID-19. J Thromb Thrombolysis [Internet]
COVID-19 related lung apical findings on stroke CTA 2020. Available from: https://doi.org/10.1007/
during the COVID-19 pandemic. J Neurointerv Surg. s11239-020-02181-w.
2020;12(7):669–72. 37. Obi AT, Barnes GD, Wakefield TW, et al. Practical
23. Yaghi S, Ishida K, Torres J, et al. SARS-CoV-2 and diagnosis and treatment of suspected venous throm-
stroke in a New York healthcare system. Stroke. boembolism during COVID-19 pandemic. J Vasc
2020;51(7):2002–11. Surg Venous Lymphat Disord. 2020;8(4):526–34.
24. Mao L, Jin H, Wang M, et al. Neurologic mani-
38. Bahia A, Albert RK. The modified Wells score accu-
festations of hospitalized patients with coronavi- rately excludes pulmonary embolus in hospitalized
rus disease 2019 in Wuhan, China. JAMA Neurol. patients receiving heparin prophylaxis. J Hosp Med.
2020;77(6):683–90. 2011;6(4):190–4.
25. Lodigiani C, Iapichino G, Carenzo L, et al. Venous and 39. Barbar S, Noventa F, Rossetto V, et al. A risk assess-
arterial thromboembolic complications in COVID-19 ment model for the identification of hospitalized
patients admitted to an academic hospital in Milan, medical patients at risk for venous thromboembo-
Italy. Thromb Res. 2020;191:9–14. lism: the Padua prediction score [internet]. J Thromb
26. Kurdi H, Obaid DR, UlHaq Z, Ionescu A, Sekar
Haemost. 2010;8(11):2450–7. Available from: https://
B. Multiple spontaneous coronary thrombosis causing doi.org/10.1111/j.1538-7836.2010.04044.x
ST-elevation myocardial infarction in a patient with 40. Spyropoulos AC, Anderson FA Jr, FitzGerald G,

COVID-19. Br J Hosp Med. 2020;81(7):1–6. et al. Predictive and associative models to identify
hospitalized medical patients at risk for VTE. Chest. current methods and interpretation criteria in clinical
2011;140(3):706–14. practice. Radiol Oncol. 2014;48(2):113–9.
41. Trimaille A, Curtiaud A, Marchandot B, et al. Venous 56. Fielding PA, Morley NCD, Bradley KM. Beware

thromboembolism in non-critically ill patients with COVID-19 on VQ scans (Ventilation/Perfusion
COVID-19 infection. Thromb Res. 2020;193:166–9. Scintigraphy). QJM [Internet] 2020. Available from:
42. Yu B, Li X, Chen J, et al. Evaluation of variation https://doi.org/10.1093/qjmed/hcaa274.
in D-dimer levels among COVID-19 and bacte- 57. Rosovsky RP, Grodzin C, Channick R, et al. Diagnosis
rial pneumonia: a retrospective analysis. J Thromb and treatment of pulmonary embolism during the
Thrombolysis. 2020;50(3):548–57. coronavirus disease 2019 pandemic [internet]. Chest
43. Moores LK, Tritschler T, Brosnahan S, et al.
2020;158(6):2590–2601 . Available from: https://doi.
Prevention, diagnosis, and treatment of VTE in patients org/10.1016/j.chest.2020.08.2064.
with coronavirus disease 2019: CHEST guideline and 58. Paranjpe I, Fuster V, Lala A, et al. Association of treat-
expert panel report. Chest. 2020;158(3):1143–63. ment dose anticoagulation with in-hospital survival
44. Moll M, Zon RL, Sylvester KW, et al. VTE in ICU among hospitalized patients with COVID-19 [inter-
patients with COVID-19. Chest. 2020;158(5):2130–5. net]. J Am Coll Cardiol. 2020;76(1):122–4. Available
45. Artifoni M, Danic G, Gautier G, et al. Systematic from: https://doi.org/10.1016/j.jacc.2020.05.001
assessment of venous thromboembolism in 59. Lemos ACB, do Espírito Santo DA, Salvetti MC,

COVID- 19 patients receiving thromboprophylaxis: et al. Therapeutic versus prophylactic anticoagulation
incidence and role of D-dimer as predictive factors. J for severe COVID-19: a randomized phase II clinical
Thromb Thrombolysis. 2020;50(1):211–6. trial (HESACOVID). Thromb Res. 2020;196:359–66.
46. Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of 60.
Anti-thrombotics for adults hospitalized with
venous thromboembolism in patients with severe COVID-19 (ACTIV-4) [Internet]. [cited 2020 Dec
novel coronavirus pneumonia. J Thromb Haemost. 23]. Available from: https://clinicaltrials.gov/ct2/
2020;18(6):1421–4. show/NCT04505774.
47. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical 61. Spyropoulos AC, Levy JH, Ageno W, et al. Scientific
predictors of mortality due to COVID-19 based on an and standardization committee communication:
analysis of data of 150 patients from Wuhan, China. clinical guidance on the diagnosis, prevention, and
Intensive Care Med. 2020;46(5):846–8. treatment of venous thromboembolism in hospital-
48.
Ruan Q, Yang K, Wang W, Jiang L, Song ized patients with COVID-19. J Thromb Haemost.
J. Correction to: clinical predictors of mortality due 2020;18(8):1859–65.
to COVID-19 based on an analysis of data of 150 62. Chow JH, Khanna AK, Kethireddy S, et al. Aspirin
patients from Wuhan, China. Intensive Care Med. use is associated with decreased mechanical ven-
2020;46(6):1294–7. tilation, ICU admission, and in-hospital mortality
49.
Léonard-Lorant I, Delabranche X, Séverac F, in hospitalized patients with COVID-19. Anesth
et al. Acute pulmonary embolism in patients with Analg [Internet] 2020. Available from: https://doi.
COVID- 19 at CT angiography and relationship to org/10.1213/ANE.0000000000005292.
d-dimer levels. Radiology. 2020;296(3):E189–91. 63. Goyal A, Saigal S, Niwariya Y, Sharma J, Singh

50. Poissy J, Goutay J, Caplan M, et al. Pulmonary
P. Successful use of tPA for thrombolysis in COVID
embolism in patients with COVID-19: aware- related ARDS: a case series. J Thromb Thrombolysis
ness of an increased prevalence. Circulation. [Internet] 2020. Available from: https://doi.
2020;142(2):184–6. org/10.1007/s11239-020-02208-2.
51. Liao S-C, Shao S-C, Chen Y-T, Chen Y-C, Hung
64. Poor HD, Ventetuolo CE, Tolbert T, et al. COVID-19
M-J. Incidence and mortality of pulmonary embolism critical illness pathophysiology driven by diffuse pul-
in COVID-19: a systematic review and meta-analysis. monary thrombi and pulmonary endothelial dysfunc-
Crit Care. 2020;24(1):464. tion responsive to thrombolysis. Clin Transl Med.
52. Ren B, Yan F, Deng Z, et al. Extremely high inci- 2020;10(2):e44.
dence of lower extremity deep venous thrombosis 65. Wang J, Hajizadeh N, Moore EE, et al. Tissue plas-
in 48 patients with severe COVID-19 in Wuhan. minogen activator (tPA) treatment for COVID- 19
Circulation. 2020;142(2):181–3. associated acute respiratory distress syndrome
53. Wang Y, Shi L, Yang H, Duan G, Wang Y. Pooled (ARDS): a case series [internet]. J Thromb Haemost.
prevalence of deep vein thrombosis among 2020;18(7):1752–5. Available from: https://doi.
coronavirus disease 2019 patients. Crit Care. org/10.1111/jth.14828
2020;24(1):466. 66. Fibrinolytic Therapy to Treat ARDS in the Setting
54. COVID-19: ACR statement on nuclear medicine
of COVID-19 Infection [Internet]. [cited 2020 Dec
ventilation scans [Internet]. [cited 2020 Dec 20]. 23];Available from: https://clinicaltrials.gov/ct2/
Available from: https://www.acr.org/Advocacy- show/NCT04357730.
a n d -E c o n o m i c s / AC R -P o s i t i o n -S t a t e m e n t s / 67. Nebulised Rt-PA for ARDS Due to COVID-19 – Full
COVID19-Nuclear-Medicine-Ventilation-Scans. Text View – ClinicalTrials.Gov [Internet]. [cited 2020
55. Skarlovnik A, Hrastnik D, Fettich J, Grmek M. Lung Dec 23];Available from: https://clinicaltrials.gov/ct2/
scintigraphy in the diagnosis of pulmonary embolism: show/NCT04356833.
COVID-19 Neurologic Illnesses
14
David Poliner and Wan-Tsu Wendy Chang
Introduction disease. Similar findings have been found in

other cohorts with reports of delirium, clonus,
COVID-19 has proven to have variable neuro- and frontal symptoms of inattention and disorien-
logic symptoms and outcomes with 30–40% of tation most evident at the time of hospital dis-
affected patients showing signs of serious central charge [3]. This was regardless of radiographic or
nervous system complications or neuroradio- cerebrospinal fluid (CSF) findings.
graphic changes [1]. In the initial retrospective, Comparatively, in the Wuhan study, periph-
observational cohort from Wuhan, China, 36.4% eral nervous system (PNS) complaints con-
of the 214 cases were found to have some form of sisted mostly of impaired sense of smell (5.1%)
neurologic sequelae [2]. These included both and taste (5.6%) without similar associations to
central (24.8%) and peripheral (8.9%) nervous illness severity. In a European cohort, 80%
system manifestations. The most commonly were found to have anosmia despite an absence
reported central nervous system (CNS) symp- of associated nasal symptoms with incidence
toms were dizziness (16.8%), headache (13%), increasing as chemosensitive impairment has
and impaired consciousness (7.5%). Symptoms become more recognized [4–7]. There have
were more prominent in more severe disease as also been reports of Guillain-Barré syndrome,
suggested by higher inflammatory markers and transverse myelitis, and other inflammatory and
increased incidence of organ failure. Much has immune-mediated polyneuropathies associated
also been made regarding the 2.8% incidence of with or immediately anteceding viral infection
acute cerebrovascular events which were princi- [5, 6].
pally noted on hospital days 8–9 and in those Despite the novelty of COVID-19, there is
considered to have severe manifestations of the precedence for these neurologic manifestations.
Coronaviruses have been linked with a myriad of
para-infectious complications related to macro-
D. Poliner and microcirculatory dysfunction, metabolic
Section of Neurocritical Care and Emergency
derangements, and local prothrombotic states [8,
Neurology, Department of Neurology, University of
Maryland Medical Center, Baltimore, MD, USA 9]. SARS-CoV-1 was found in the CSF of SARS
e-mail: [email protected] patients with associated encephalitis, seizures,
W.-T. W. Chang (*) and optic neuritis [7]. Cerebral large vessel occlu-
Departments of Emergency Medicine and Neurology, sion rates were reported at 2.4% [8]. It was also
Program in Trauma, University of Maryland School associated with peripheral neuropathy, myopa-
of Medicine, Baltimore, MD, USA
thy, vasculopathy, as well as olfactory d ysfunction
142 D. Poliner and W.-T. W. Chang
up to 3 weeks postinfection [8–10]. Similarly, inflammatory cascade which causes perivascular

MERS-CoV (MERS) was found to afflict both breakdown within the CNS or PNS contributing
the central and peripheral nervous systems with to a plethora of neurodegenerative and neuropsy-
reported cases of seizure, delirium, and encepha- chiatric presentations [1, 9, 13, 14].
lopathy [8–10]. The two viruses demonstrate
similar histopathology, disease course, as well as
neurotropism [9, 10]. Endotheliopathy
ACE2 receptor is also found in abundance

Pathophysiology throughout the vascular endothelium allowing for
possible hematogenous spread [9, 11, 12, 14].
The precise nature by which COVID-19 gener- Increasing clinical evidence shows that common
ates its neurologic presentation is likely comorbidities associated with poor outcomes
multifactorial. observed in COVID-19 patients, such as hyper-
tension and diabetes, are predisposed to endothe-
lial dysfunction [15, 16]. Pulmonary, myocardial,
Neurotropism and gastrointestinal tissue samples on autopsy
have demonstrated distinctive vascular features,
There is a neurotropic predilection and neuroin- though similar findings have been variable on
vasive potential for coronaviruses. In those pre- neuropathology, possibly as a result of the lower
senting with anosmia, areas of gliosis have been prevalence of ACE2 receptors within the cerebro-
found within the olfactory bulb suggestive of a vascular endothelium [17–19].
local reaction to a pathogen and neuronal inflam- The fundamental question is whether the
mation [4, 7]. SARS-CoV-2 has demonstrated observed neuropathological lesions are the result
affinity for angiotensin-converting enzyme 2 of primary cerebrovascular disease with second-
(ACE2) receptors which are found in abundance ary white matter injury, para-infectious demye-
throughout the oro- and nasopharynx allowing lination, or a combination [20]. The preservation
for direct cellular entry [11, 12]. Virus present in of deep gray matter structures would suggest a
the upper respiratory tract mucosa can directly vascular origin with secondary myelin loss [15,
infect olfactory sensory neurons and then spread 20, 21]. Given the absence of gross vasculitis on
via anterograde axonal transport into the olfac- cerebral angiogram or autopsy, it is likely a peri-
tory bulb. Transsynaptic spread allows for virus vascular inflammatory process [1, 19, 21–24].
migration along the olfactory tract to other areas Additionally, there is evidence of increased vas-
in the brain [11]. It is also possible that SARS- cular permeability contributing to the develop-
CoV-2’s predisposition for the ACE2 receptor- ment of vasogenic edema and susceptibility to
mediated pathway corresponds to a retrograde vessel rupture [25–27].
axonal transport along the vagus nerve in those
with lower respiratory illnesses [11, 12].
This neurotropic pathway may partially Immunothrombosis
explain the delay between alteration of smell and Coagulopathy
within the first 5 days of illness and development
of other sequelae [5, 11, 12]. The degree of olfac- In addition to extrinsic vascular phenomena,
tory dysfunction may provide insight into the much attention has been on underlying intravas-
clinical course as affected patients have been cular features as they pertain to neurologic
found to generate a more pronounced innate sequelae with COVID-19. Early studies reported
immune response [9]. It has also been proposed the presence of anticardiolipin and anti-beta-2
that even without direct axonal spread, direct glycoprotein 1 antibodies in patients with bilat-
viral invasion or local exposure activates an eral cerebral infarctions in multiple vascular
14 COVID-19 Neurologic Illnesses 143
territories [28]. Higher levels of antiphospholipid following seizure, acute cerebrovascular event to
antibodies have been found to be associated with hyperinflammatory state resulting in acute hem-
lower SpO2/FiO2 ratios and the development of orrhagic necrotizing encephalopathy (AHNE)
multisystem organ failure in COVID-19 patients [14, 25, 33–35]. There are also autopsy reports of
[29]. While clinically suggestive of the presence encephalitis and meningitis in the absence of
of microthrombi, there were only 2 arterial (1%) CSF pleocytosis suggestive of a reactive process
and 8 (5%) venous thrombi in this 172-person as opposed to true meningeal viral invasion [19,
cohort. The presence or transient increase of 22, 24, 33, 36–38].
these antibodies has been previously investigated The majority of neuroimaging studies did not
in the general critical illness population and reveal any radiographic abnormalities directly
found to be likely reflective of an acute phase attributed to COVID-19 [1, 26]. The most com-
reactant as opposed to true pathology [15]. mon finding in affected cases is nonspecific white
The interplay of neutrophil extracellular traps matter changes, seen as hypodensities on CT or
(NETs) with platelets may contribute to a T2 hyperintensities on MRI [39]. Punctate hem-
thrombo-inflammatory cascade leading to the orrhages on non-contrast head CT have been
clinically observed hypercoagulability and reported though these are not unique to
thrombosis [30–32]. Observed as web-like struc- COVID-19 and have been seen in viral infections
tures of DNA and proteins expelled from the neu- such as influenza and herpes [1, 12, 25, 26]. It is
trophil that ensnare intravascular pathogens, possible that early neurological symptoms, which
NETs have been found in the pulmonary capil- were the reason for brain imaging, may precede
lary beds of postmortem COVID-19 lungs [30]. detectable changes on imaging or that COVID-19
Higher circulating levels were associated with may not have a specific neuroimaging finding [1].
mortality in those with severe COVID-19 inde- A subset of patients may have been too ill to
pendent of other markers of thrombosis such as undergo diagnostic imaging despite distinct neu-
D-dimer and von Willebrand factor [31]. Levels rological deficits, thus not described by these
returned to normal upon convalescence. studies.
Clinically, NETs may also account for the vari- Management of COVID-19 patients with
able response to mechanical thrombectomy and a alterations of consciousness is analogous to any
higher than anticipated mortality in COVID-19- other patient with the focus on time-sensitive
related strokes [30, 32]. and reversible causes. A detailed neurological
exam is essential to narrow the broad differen-
tial diagnosis and tailor the diagnostic evalua-
Clinical Syndromes tion, which may reduce unnecessary
neuroimaging and potential risks associated
Central Nervous System with transporting the patient. Reduction of seda-
tion in mechanically ventilated patients should
Alteration of Consciousness be coordinated with neurology consultation to
Decreased level of consciousness and encepha- optimize the bedside clinical assessment. In
lopathy were reported in 7.5–31% of patients cases where high dose sedation and neuromus-
with COVID-19 and appear indicative of a worse cular blockade are needed for management of
prognosis [2, 7, 26, 32]. Early alteration of con- acute respiratory distress syndrome and the
sciousness occurred significantly more often in severity of the patient’s illness precludes trans-
non-survivors (22%) compared to survivors (1%) port for neuroimaging, alternative neuromoni-
[32]. Multiple etiologies have been identified toring modalities such as automated
likely due to the multifactorial pathogenesis of pupillometry, continuous electroencephalogra-
the virus. They range from metabolic encepha- phy (EEG), transcranial Doppler, and somato-
lopathy, hypoxic-ischemic injury, postictal state sensory evoked potential can be considered.
Seizure nytoin and valproate and can sequester drugs

Seizures have been associated with coronavirus then later released into the circulation resulting in
infections such as SARS and MERS, as well as unpredictable therapeutic effects [50, 51].
COVID-19 [2, 40, 41]. The underlying etiology
is not fully understood. Proposed mechanisms Ischemic Stroke
include CNS inflammatory cytokines causing There has also been a great deal of discussion
neuronal hyperexcitability, blood-brain barrier surrounding the incidence of acute cerebrovascu-
disruption, and oxidative stress [42]. COVID-19- lar disease and acute ischemic stroke (AIS) in
related stroke and multiorgan dysfunction may COVID-19 patients. In a subgroup analysis of the
also predispose patients to seizures. original Wuhan cohort, 11 patients (5%) devel-
While the incidence of clinical seizures is low oped new cerebrovascular disease [52, 53]. The
in the literature, only 0.5% in the original Wuhan overall incidence of AIS reported across multiple
cohort, seizure-like events accounted for nearly studies, however, is quite variable at 1–3% [26].
one-third of EEGs obtained in COVID-19 This discrepancy is likely multifactorial. While
patients [2, 43]. In a systematic review of 617 AIS in COVID-19 was most commonly crypto-
patients, 88% of EEGs were abnormal with the genic in origin compared to contemporary
most common abnormality being diffuse back- cohorts, these patients had underlying comorbid-
ground slowing, consistent with nonspecific ities which made them more susceptible to
encephalopathy [43]. Electrographic seizures thromboembolic events [54]. Elevated levels of
were identified in 5.5–10.5% of EEGs [43, 44]. pro-inflammatory cytokines have been associated
Focal EEG abnormalities were most common in with increased risk of atherosclerotic plaque rup-
the frontal region, seen in half of the patients with ture. Cardiac manifestations and arrhythmogenic
status epilepticus [43, 45]. This frontal predomi- complications of COVID-19 provide a cardioem-
nance suggests a localized injury, possibly infec- bolic mechanism. Furthermore, there is some
tious, para-infectious, or vascular in etiology. concern that the public health initiatives aimed at
Interestingly, SARS-CoV-2 has not been identi- reducing viral spread have led to individuals with
fied in CSF by real-time polymerase chain reac- mild AIS (NIHSS <5) and TIA to avoid present-
tion (PCR) analysis in reported cases of seizures ing to a hospital [55–58]. This may enrich the
and only rarely found in indeterminate levels in cohort of large vessel occlusions (LVO) in com-
patients with other neurological symptoms parison to the non-COVID-19 or general stroke
[46–49]. population [59].
Treatment of seizures in COVID-19 follows Despite the variable reporting of stroke inci-
the same approach as in non-COVID-19 patients. dence, the increased case fatality rate of 30–50%
Seizures longer than 5 minutes or without return in comparison to noninfected and contemporary
to baseline mental status should be treated with controls is striking [26, 60–62]. It should be
benzodiazepines expeditiously to abort status noted that these reflect sicker patients with ele-
epilepticus. Many antiepileptic drugs can have vated levels of inflammatory cytokines, more
interactions with COVID-19 therapies profound hypoxemia, and a higher arrhythmo-
(Table 14.1) in addition to known interactions genic potential [59, 63, 64]. There has also been
with other antiepileptics [50]. This is especially discussion around the incidence of younger
important to consider in patients with preexisting patients with AIS and LVO; however, this remains
epilepsy who develop COVID-19. Therapeutic conflicted depending upon the cohort sampled
drug monitoring is helpful in critically ill patients [59–61, 65]. The exact incidence of LVO versus
given that the bioavailability of antiepileptic non-LVO AIS is imprecise but appears to be sim-
drugs is affected by changes in volume of distri- ilar between COVID-19 and non-COVID-19
bution and hypoalbuminemia. Extracorporeal cohorts [65]. Regardless, there does appear to be
membrane oxygenation (ECMO) also affects an increased magnitude of disability among sur-
highly protein bound antiepileptics such as phe- vivors with 60% requiring discharge to a
Table 14.1 Antiepileptic drug interactions with COVID-19 therapies

COVID-19 therapies Antiepileptic drugs
Interactions that decrease antiepileptic plasma Hydroxychloroquine Carbamazepine
concentration Lacosamide
Lamotrigine
Oxcarbazepine
Phenobarbital
Phenytoin
Lopinavir-ritonavir Lamotrigine
Phenytoin
Valproate
Tocilizumab Carbamazepine
Lacosamide
Perampanel
Phenobarbital
Phenytoin
Interactions that increase antiepileptic plasma Ritonavir Carbamazepine
concentration Clonazepam
Lacosamide
Perampanel
Zonisamide
Therapies associated with cardiovascular adverse effects Hydroxychloroquine Carbamazepine
Lopinavir-ritonavir Lacosamide
Phenobarbital
Phenytoin
rehabilitation facility compared to 40% in non- COVID-19 patients who undergo EVT compared
COVID-19 AIS [61, 66]. This was irrespective of to those who do not [62]. Infected patients who
initial NIHSS likely owing to the heterogeneity do undergo attempted thrombectomy, however,
of this population and its propensity for critical do have a higher rate of favorable discharge ver-
illness. How this will translate to long-term cog- sus matched controls, and as such, EVT and
nitive and neurologic outcome remains to be thrombolytic therapy should still be offered to
investigated. this population. It is important to remember that
For those who do present with LVO, rates of the etiology of the occlusion is likely multifacto-
thrombolysis (33%) and endovascular thrombec- rial owing to the interplay of NETs, immu-
tomy (EVT) [66%] appear similar to the non- nothrombosis, endotheliitis, and microvascular
COVID- 19 population [59, 65]. However, inflammation, such that it may not respond to
last-known-well (530 vs. 406 minutes) and door- traditional AIS therapies [31, 32, 68]. The work-
to-needle times (average 16 minutes later) are flow for COVID-19 patients and patients under
longer than the pre-COVID-19 era [59, 66, 67]. investigation should also be considered, espe-
LVO was more likely to be found in multiple- cially pertaining to the choice of general anesthe-
vessel territories with higher infarct core vol- sia, conscious sedation, or local anesthesia for
umes, though the initial recanalization rates for EVT [69–72].
thrombolysis, EVT, and thrombolysis with EVT
were similar to non-COVID-19 patients [65, 68]. Intracranial Hemorrhage
The EVT procedure itself was much more com- Like AIS, the incidence of intracranial hemor-
plicated in the COVID-19 patients owing to the rhage is also variable. In the initial Wuhan cohort,
multiple-vessel territory and the higher than incidence was reported at 9.1%, occurring in 1 of
expected early occlusion rates despite initial the 11 patients with acute cerebrovascular dis-
recanalization [68]. This may account for the ease [52]. While this was not significantly differ-
lack of difference in the overall mortality in ent from the 8.6% incidence of stroke reported in
septic, non-COVID-19 patients, composite anal- Peripheral Nervous System

ysis of 13,741 COVID-19 patients found a lower
incidence of 0.3–1.2% [73, 74]. Intraparenchymal As mentioned, COVID-19 does appear to have
hemorrhage was the most common (63%), prin- predilection for antegrade and retrograde axonal
cipally in the cerebral hemispheres and basal movement along neuronal fibers. As such, cranial
ganglia. Hemorrhages involved multiple cranial nerve palsies should come as no surprise. Isolated
compartments in 9.5% of cases. The time interval cranial neuropathies, Miller Fisher syndrome,
from onset of COVID-19 to the diagnosis of and Guillain-Barré syndrome (GBS) have all
intracranial hemorrhage was between 2 and been reported [82–87]. The incidence of GBS
25 days. Approximately 70% were admitted for was 0.5% in an Italian cohort, with the first symp-
respiratory symptoms and then developed intra- toms of flaccid paralysis and facial diplegia
cranial hemorrhage versus 20% who presented occurring within 5–10 days from the onset of
with neurologic complaints and were subse- acute respiratory symptoms [86].
quently diagnosed with COVID-19. Of note, In general, CSF profiles were bland without
more than half of the patients were on therapeutic pleocytosis and SARS-CoV-2 has not been
anticoagulation at the time of diagnosis of the detected by PCR in these cases. In one case of
intracranial hemorrhage. Indications for antico- Miller Fisher syndrome, serum anti-GD1b IgG
agulation included treatment algorithm for antibody was found [85]. MRI has shown
COVID-19, elevated D-dimer, or ECMO in 84% enhancement of the facial nerve and caudal nerve
of cases [74]. roots in some patients, otherwise unremarkable
Cerebral microhemorrhages have been seen in others [82, 86]. Electromyography and nerve
on MRI and neuropathology in COVID-19 conduction studies revealed axonal and demye-
patients [27]. The risk of hemorrhagic transfor- linating patterns in the reported GBS cases [86,
mation in fully anticoagulated patients is 87]. The timing of symptoms and the fact that
approximately 5% with 50% mortality [27, 75, SARS-CoV-2 has not been detected in the CSF of
76]. Although occult thromboembolic events these patients suggest that this is potentially an
may be possible or even likely in critically ill inflammatory and immune-mediated pathology
COVID-19 patients, given the risk of intracra- rather than true viral tropism.
nial hemorrhage, empiric intensification of Treatment in these reported cases have ranged
anticoagulation beyond standard of care should from supportive care, antiviral therapies, steroids,
be pursued with caution especially given the IV immunoglobulin to plasma exchange.
reported fragility of the blood vessels in the Response to treatment has been variable. While
setting of apparent endotheliopathy [26, 27]. COVID-19 is presumed to be the cause of these
Hyperfibrinolysis has also been described in neuropathies, it is prudent to maintain a wide dif-
cardiovascular diseases and COVID-19 and ferential diagnosis and broad diagnostic evalua-
may contribute to the increased risk of bleed- tion [88]. And finally, it is also important to
ing [77]. remember the iatrogenic neuropathies that can
While a hypercoagulable state is more com- occur with prolonged immobility, prone position-
monly found in critically ill COVID-19 patients ing, and the therapies utilized to treat the virus.
despite near normal traditional measures of coag-
ulation, thromboelastography (TEG), rotational
thromboelastometry (ROTEM), and platelet Conclusion
mapping can be considered in intracranial hem-
orrhage to guide therapies [78–81]. Prolonged COVID-19 provides a myriad of neurologic chal-
reaction (R) time, elevated LY30, and thrombo- lenges, most of which are still not completely under-
cytopenia have been associated with hemorrhagic stood. Its pathophysiology, however, is not new in
complications and death [81]. the setting of viral pandemics or critical illness.
Central and peripheral nervous system sequelae can 7. Romero-Sánchez CM, Díaz-Maroto I, Fernández-
occur with diagnostic and therapeutic decisions Díaz E, et al. Neurologic manifestations in hospi-
talized patients with COVID-19: the ALBACOVID
comparable to non-COVID-19 patients. Robust clin- registry. Neurology. 2020;95(8):e1060–70.
ical data are needed before embarking upon practice 8. Valerio F, Whitehouse DP, Menon DK, Newcombe
changes from current standards of care. Long-term VF. The neurological sequelae of pandemics and epi-
follow-up should continue to determine the potential demics. J Neurol. 2020;268:2629.
9. Yachou Y, El Idrissi A, Belapasov V, Benali
lasting neurological effects of COVID-19. SA. Neuroinvasion, neurotropic, and neuroinflamma-
tory events of SARS-CoV-2: understanding the neuro-
Critical Points logical manifestations in COVID-19 patients. Neurol
• Central and peripheral nervous system Sci. 2020;41(10):2657–69.
10. Pleasure SJ, Green AJ, Josephs SA. The spectrum
involvement can occur with COVID-19 infec- of neurologic disease in the severe acute respiratory
tions as has been associated with other coro- syndrome coronavirus 2 pandemic infection. JAMA
naviruses (SARS and MERS). Neurol. 2020;77(6):679–80.
• Neurological symptoms are more common 11.
van den Brand JM, Smits SL, Haagmans
BL. Pathogenesis of Middle East respiratory syn-
with severe COVID-19 illnesses. drome coronavirus. J Pathol. 2015;235(2):175–84.
• Headache, dizziness, and alterations of con- 12. Ludlow M, Kortekaas J, Herden C, et al. Neurotropic
sciousness are the most common CNS virus infections as the cause of immediate and
symptoms. delayed neuropathology. Acta Neuropathol.
2016;131:159–84.
• Acute ischemic stroke in COVID-19 infection 13. Murta V, Villarreal A, Ramos AJ. Severe Acute

should be considered for thrombolytics or Respiratory Syndrome Coronavirus 2 impact on the
endovascular treatment if there is large vessel central nervous system: are astrocytes and microg-
occlusion. lia main players or merely bystanders? ASN Neuro.
2020;12:1759091420954960.
• Cerebral microhemorrhages reported in 14. Huang H, Eichelberger H, Chan M, et al. Pearls &
COVID-19 may increase the risk of hemor- oysters: leukoencephalopathy in critically ill patients
rhagic transformation with anticoagulation. with COVID-19. Neurology. 2020;95(16):753–7.
15. Huertas A, Montani D, Savale L, et al. Endothelial cell
dysfunction: a major player in SARS-CoV-2 infection
(COVID-19)? Eur Respir J. 2020;56(1):2001634.
References 16. Data Sciences Collaborative Group. Differences in
clinical deterioration among three sub-phenotypes of
1. Egbert AR, Cankurtaran S, Karpiak S. Brain abnor- COVID-19 patients at the time of first positive test:
malities in COVID-19 acute/subacute phase: a results from a clustering analysis. Intensive Care
rapid systematic review. Brain Behav Immun. Med. 2021;47(1):113–5.
2020;89:543–54. 17. Ackermann M, Verleden SE, Kuehnel M, et al.

2. Mao L, Jin H, Wang M, et al. Neurologic mani- Pulmonary vascular endothelialitis, thrombosis,
festations of hospitalized patients with coronavi- and angiogenesis in COVID-19. N Engl J Med.
rus disease 2019 in Wuhan, China. JAMA Neurol. 2020;383:120–8.
2020;77(6):683–90. 18. Varga Z, Flammer AJ, Steiger P, et al. Endothelial
3. Helms J, Kremer S, Merdji H, et al. Neurologic fea- cell infection and endotheliitis in COVID-19. Lancet.
tures in severe SARS-CoV-2 infection. N Engl J Med. 2020;395(10234):1417–8.
2020;382(23):2268–70. 19. Schaller T, Hirschbühl K, Burkhardt K, et al.

4. Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Postmortem examination of patients with COVID-19.
Olfactory and gustatory dysfunctions as a clinical pre- JAMA. 2020;323(24):2518–20.
sentation of mild-to-moderate forms of the coronavirus 20.
Reichard RR, Kashani KB, Boire NA,
disease (COVID-19): a multicenter European study. Constantopoulos E, Guo Y, Luccinetti
Eur Arch Otorhinolaryngol. 2020;277(8):2251–61. CF. Neuropathology of COVID- 19: a spectrum
5. Zhou Z, Kang H, Li S, Zhao X. Understanding of vascular and acute disseminated encephalomy-
the neurotropic characteristics of SARS-CoV-2: elitis (ADEM)-like pathology. Acta Neuropathol.
from neurological manifestations of COVID-19 2020;140(1):1–6.
to potential neurotropic mechanisms. J Neurol. 21. Fox SE, Akmatbekov A, Harbert JL, Li G, Brown JQ,
2020;267(8):2179–84. Vander Heide RS. Pulmonary and cardiac pathology
6. Puelles VG, Lütgehetmann M, Lindenmeyer MT, in African American patients with COVID-19: an
et al. Multiorgan and renal tropism of SARS-CoV-2. autopsy series from New Orleans. Lancet Respir Med.
N Engl J Med. 2020;383(6):590–2. 2020;8(7):681–6.
22. Solomon IH, Normandin E, Bhattacharyya S, et al. Germany: a post-mortem case series. Lancet Neurol.
Neuropathological features of Covid-19. N Engl J 2020;19(11):919–29.
Med. 2020;383(10):989–92. 38. Edler C, Schröder AS, Aepfelbacher M, et al. Dying
23. Wichmann D, Sperhake J-P, Lütgehetmann M, et al. with SARS-CoV-2 infection - an autopsy study of the
Autopsy findings and venous thromboembolism in first consecutive 80 cases in Hamberg, Germany. Int J
patients with COVID-19: a prospective cohort study. Legal Med. 2020;134(4):1275–84.
Ann Intern Med. 2020;173(4):268–77. 39. Radmanesh A, Raz E, Zan E, Derman A, Kaminetzky
24. Barton LM, Duval EJ, Stroberg E, Ghosh S,
M. Brain imaging use and findings in COVID-19:
Mukhopadhyay S. COVID-19 autopsies, Oklahoma, a single academic center experience in the epi-
USA. Am J Clin Pathol. 2020;153(6):725–33. center of disease in the United States. AJNR.
25.
Radmanesh A, Derman A, Lui YW, et al. 2020;41(7):1179–83.
COVID-19- associated diffuse leukoencepha- 40. Asadi-Pooya AA. Seizures associated with coronavi-
lopathy and microhemorrhages. Radiology. rus infections. Seizure. 2020;79:49–52.
2020;297(1):E223–7. 41. Moriguchi T, Harrii N, Goto J, et al. A first case
26. Sharifian-Dorche M, Huot P, Osherov M, et al.
of meningitis/encephalitis associated with SARS-
Neurological complications of coronavirus infec- Coronavirus-2. Int J Infect Dis. 2020;94:55–8.
tion; a comparative review and lessons learned 42. Nikbakht F, Mohammadkhanizadeh A, Mohammadi
during the COVID-19 pandemic. J Neurol Sci. E. How does the COVID-19 cause seizure and epi-
2020;417:117085. lepsy in patients? The potential mechanisms. Mult
27. Saitta L, Molin A, Villani F, et al. Brain microvascu- Scler Relat Disord. 2020;46:102535.
lar occlusive disorder in COVID-19: a case report. 43. Antony AR, Haneef Z. Systematic review of EEG
Neurol Sci. 2020;41(12):3401–4. findings in 617 patients diagnosed with COVID-19.
28. Zhang Y, Xiao M, Zhang S, et al. Coagulopathy and Seizure. 2020;83:234–41.
antiphospholipid antibodies in patients with Covid-19. 44. Louis S, Dhawan A, Newey C, et al. Continuous

N Engl J Med. 2020;382(17):e38. electroencephalography characteristics and acute
29. Zuo Y, Estes SK, Ali RA, et al. Prothrombotic
symptomatic seizures in COVID-19 patients. Clin
autoantibodies in serum for patients hos- Neurophysiol. 2020;131(11):2651–6.
pitalized with COVID-19. Sci Transl Med. 45. Vespignani H, Colas D, Lavin BS, et al. Report on elec-
2020;12(570):eabd3876. troencephalographic findings in critically ill patients
30.
Barnes BJ, Adrover JM, Bacter-Stoltzfus A, with COVID-19. Ann Neurol. 2020;88(3):626–30.
et al. Targeting potential drivers of COVID- 19: 46. Roberto KT, Espiritu AI, Fernandez MLL, Gutierrez
neutrophil extracellular traps. J Exp Med. JC. Electroencephalographic findings in COVID-19
2020;217(6):e20200652. patients: a systematic review. Seizure. 2020;82:17–22.
31. Middleton EA, He X-Y, Denorme F, et al. Neurotrophil 47. Neumann B, Schmidbauer ML, Dimitriadis K,

extracellular traps contribute to immunothrombosis et al. Cerebrospinal fluid findings in COVID-19
in COVID-19 acute respiratory distress syndrome. patients with neurological symptoms. J Neurol Sci.
Blood. 2020;136(10):1169–79. 2020;418:117090.
32. Mansour OY, Malik AM, Linfante I. Mechanical
48. Destras G, Bal A, Escuret V, et al. Systematic

thrombectomy of COVID-19 positive acute ischemic SARS-CoV-2 screening in cerebrospinal fluid dur-
stroke patient: a case report and call for preparedness. ing the COVID-19 pandemic. Lancet Microbe.
BMC Neurol. 2020;20(1):258. 2020;1(4):e149.
33. Román GC, Spencer PS, Reis J, et al. The neu-
49. Edén A, Kanberg N, Gostner J, et al. CSF biomark-
rology of COVID-19 revisited: a proposal from ers in patients with COVID-19 and neurologic symp-
the Environmental Neurology Specialty Group of toms: a case series. Neurology. 2021;96(2):e294–300.
the World Federation of Neurology to implement 50.
Asadi-Pooya AA, Attar A, Moghadami M,
international neurological registries. J Neurol Sci. Karimzadeh I. Management of COVID-19 in peo-
2020;414:116884. ple with epilepsy: drug considerations. Neurol Sci.
34. Morassi M, Bagatto D, Cobelli M, et al. Stroke in 2020;41(8):2005–11.
patients with SARS-CoV-2 infection: case series. J 51. Farrokh S, Tahsili-Fahadan P, Ritzl EK, Lewin JJ

Neurol. 2020;267(8):2185–92. 3rd, Mirski MA. Antiepileptic drugs in critically ill
35. Poyiadji N, Shahin G, Noujaim D, Stone M, Patel patients. Crit Care. 2018;22(1):153.
S, Griffith B. COVID-19-associated acute hemor- 52. Li Y, Li M, Wang M, et al. Acute cerebrovascular
rhagic necrotizing encephalopathy: imaging features. disease following COVID-19: a single center, retro-
Radiology. 2020;296(2):E119–20. spective, observational study. Stroke Vasc Neurol.
36. von Weyhern CH, Kaufmann I, Neff F, Kremer
2020;5(3):279–84.
M. Early evidence of pronounced brain involve- 53. Adams HP Jr, Bendixen BH, Kappelle LJ, et al.

ment in fatal COVID-19 outcomes. Lancet. Classification of subtype of acute ischemic stroke.
2020;395(10241):e109. Definitions for use in a multicenter clinical trial.
37. Matschke J, Lütgehetmann M, Hagel C, et al.
TOAST. Trial of Org 10172 in Acute Stroke
Neuropathology of patients with COVID-19 in Treatment. Stroke. 1993;24(1):35–41.
54. Yaghi S, Ishida K, Torres J, et al. SARS-CoV-2 and 69.

Powers CJ, Dornbos D, Mlynash M, et al.
stroke in a New York healthcare system. Stroke. Thrombectomy with conscious sedation compared
2020;51(7):2002–11. to general anesthesia: a DEFUSE 3 analysis. AJNR.
55. Morelli N, Rota E, Terracciano C, et al. The baffling 2019;40(6):1001–5.
case of ischemic stroke disappearance from the casu- 70. Schönenberger S, Hendén PL, Simonsen CZ, et al.
alty department in the COVID-19 era. Eur Neurol. Association of general anesthesia vs procedural
2020;83(2):213–5. sedation with functional outcome among patients
56. Ikenberg B, Hemmer B, Dommasch M, Kanz K-G, with acute ischemic stroke undergoing thrombec-
Wunderlich S, Knier B. Code stroke patient refer- tomy: a systematic review and meta-analysis. JAMA.
ral by emergency medical services during the public 2019;322(13):1283–93.
COVID-19 pandemic lockdown. J Stroke Cerebrovasc 71. Ren C, Xu G, Liu Y, Liu G, Wang J, Gao J. Effect of
Dis. 2020;29(11):105175. conscious sedation vs general anesthesia on outcomes
57. Jasne AS, Chojecka P, Maran I, et al. Stroke code in patients undergoing mechanical thrombectomy
presentations, interventions, and outcomes before for acute ischemic stroke: a prospective randomized
and during the COVID-19 pandemic. Stroke. clinical trial. Front Neurol. 2020;11:170.
2020;51(9):2664–73. 72. Cappellari M, Pracucci G, Forlivesi S, et al. General
58. Bekelis K, Missios S, Ahmad J, et al. Ischemic stroke anesthesia versus conscious sedation and local anes-
occurs less frequently in patients with COVID-19: thesia during thrombectomy for acute ischemic
a multicenter cross-sectional study. Stroke. stroke. Stroke. 2020;51(7):2036–44.
2020;51(12):3570–6. 73. Boehme AK, Ranawat P, Luna J, Kamel H, Elkind
59. Majidi S, Fifi JT, Ladner TR, et al. Emergent large MSV. Risk of acute stroke after hospitaliza-
vessel occlusion stroke during New York City’s tion for sepsis: a case-crossover study. Stroke.
COVID-19 outbreak: clinical characteristics and para- 2017;48(3):574–80.
clinical findings. Stroke. 2020;51(9):2656–63. 74. Cheruiyot I, Sehmi P, Ominde B, et al. Intracranial
60. Jain R, Young M, Dogra S, et al. COVID-19 related hemorrhage in coronavirus disease 2019 (COVID-19)
neuroimaging findings: a signal of thromboembolic patients. Neurol Sci. 2021;42(1):25–33.
complications and a strong prognostic marker of poor 75. Al-Samkari H, Karp Leaf RS, Dzik WH, et al.

patient outcome. J Neurol Sci. 2020;414:116923. COVID-19 and coagulation: bleeding and thrombotic
61.
Katz JM, Libman RB, Wang JJ, et al. manifestations of SARS-CoV-2 infection. Blood.
Cerebrovascular complications of COVID-19. Stroke. 2020;136(4):489–500.
2020;51(9):e227–31. 76. Ntaios G, Michel P, Georgiopoulos G, et al.

62. de Havenon A, Yaghi S, Mistry EA, et al. Endovascular Characteristics and outcomes in patients with
thrombectomy in acute ischemic stroke patients with COVID- 19 and acute ischemic stroke: the
COVID-19: prevalence, demographics, and outcomes. global COVID-19 stroke registry. Stroke.
J Neurointerv Surg. 2020;12(11):1045–8. 2020;51(9):e254–8.
63. Kaushik P, Kaushik M, Parveen S, Tabassum H,
77. Ji H-L, Zhao R, Matalon S, Matthay MA. Elevated
Parvez S. Cross-talk between key players in patients plasmin(ogen) as a common risk factor for COVID-19
with COVID-19 and ischemic stroke: a review on neu- susceptibility. Physiol Rev. 2020;100(3):1065–75.
robiological insight of the pandemic. Mol Neurobiol. 78.
Mortus JR, Manek SE, Brubaker LS, et al.
2020;57(12):4921–8. Thromboelastographic results and hypercoagula-
64. Abootalebi S, Aertker BM, Andalibi MS, et al.
bility syndrome in patients with coronavirus dis-
Call to action: SARS-CoV-2 and CerebrovAscular ease 2019 who are critically ill. JAMA Netw Open.
DisordErs (CASCADE). J Stroke Cerebrovasc Dis. 2020;3(6):e2011192.
2020;29(9):104938. 79. Yuriditsky E, Horowitz JM, Merchan C, et al.

65. Escalard S, Chalumeau V, Escalard C, et al. Early Thromboelastography profiles of critically ill patients
brain imaging shows increased severity of acute isch- with coronavirus disease 2019. Crit Care Med.
emic strokes with large vessel occlusion in COVID-19 2020;48(9):1319–26.
patients. Stroke. 2020;51(11):3366–70. 80. Salem N, Atallah B, El Nekidy WS, Sadik ZG, Park
66. Ghoreishi A, Arsang-Jang S, Sabaa-Ayoun Z, et al. WM, Mallat J. Thromboelastography findings in
Stroke care trends during COVID-19 pandemic in critically ill COVID-19 patients. J Thromb Thrombol.
Zanjian province, Iran. From the CASCADE Initiative: 2020;51:961.
statistical analysis plan and preliminary results. J 81. Hranjec T, Estreicher M, Rogers B, et al. Integral
Stroke Cerebrovasc Dis. 2020;29(12):105321. use of thromboelastography with platelet mapping
67. Montaner J, Barragán-Prieto A, Pérez-Sánchez S,
to guide appropriate treatment, avoid complications,
et al. Break in the stroke chain of survival due to and improve survival of patients with coronavirus
COVID-19. Stroke. 2020;51(8):2307–14. disease 2019-related coagulopathy. Crit Care Explor.
68. Escalard S, Maïer B, Redjem H, et al. Treatment of 2020;2(12):e0287.
acute ischemic stroke due to large vessel occlusion 82. Goh Y, Beh DLL, Makmur A, Somani J, Chan

with COVID-19: experience from Paris. Stroke. ACY. Pearls & oysters: facial nerve palsy in
2020;51(8):2540–3. COVID-19 infection. Neurology. 2020;95(8):364–7.
83. Gogia B, Guevara AG, Rai PK, Fang X. A case of 86. Toscano G, Palmerini F, Ravaglia S, et al. Guillain-
COVID-19 with multiple cranial neuropathies. Int J Barré syndrome associated with SARS-CoV-2. N
Neurosci. 2020;Dec 30:1–3. Engl J Med. 2020;382(26):2574–6.
84. Dinkin M, Gao V, Kahan J, et al. COVID-19 present- 87. Sedaghat Z, Karimi N. Guillain Barre syndrome asso-
ing with ophthalmoparesis from cranial nerve palsy. ciated with COVID-19 infection: a case report. J Clin
Neurology. 2020;95(5):221–3. Neurosci. 2020;76:233–5.
85. Gutiérrez-Ortiz C, Méndez-Guerrero A, Rodrigo-Rey 88. Keane JR. Multiple cranial nerve palsies: analysis of
S, et al. Miller fisher syndrome and polyneuritis cra- 979 cases. Arch Neurol. 2025;62(11):1714–7.
nialis in COVID-19. Neurology. 2020;95(5):e601–5.
Pharmacological Agents
for COVID-19 Patients
15
Donald Johnson, Randi Searcy,
and Beranton Whisenant
Abbreviations a wide range of patients will present with these

varying degrees of COVID-19 infections. This
APAP Acetaminophen chapter will help guide providers, based on cur-
ECMO Extracorporeal membrane oxygen- rent recommendations, on the pharmacological
ation agents of most benefit from COVID-19 infec-
ED Emergency Department tions. As such, the treatment of patients will vary
EUA Emergency use authorization based on disease severity and consideration of
FDA Federal Drug Administration underlying medical conditions. Most of the cur-
mAbs Monoclonal antibodies rent evidence available is lacking and the major-
MDI Metered dose inhaler ity of the clinical data is considered investigational.
NIH National Institutes of Health Currently, dexamethasone, a corticosteroid, is the
PPE Personal protective equipment only agent shown to reduce mortality in patients
hospitalized with COVID-19 infection.
Remdesivir, an antiviral agent, is the only Food
and Drug Administration (FDA)-approved drug
Introduction for hospitalized COVID-19 patients. Remdesivir
has no mortality benefit but has shown to shorten
The clinical manifestations of COVID-19- time to recovery or may help prevent the progres-
infected individuals range from asymptomatic or sion to more severe disease in patients requiring
mild disease to critical illness with rapid deterio- low-flow oxygen. The monoclonal antibodies
ration, and death. In the Emergency Department, (mAbs) may show promise based on phase 1 and
2 studies, but finalized data is necessary to see the
role in management of COVID-19.
D. Johnson There has been a large volume of literature
UF Health Jacksonville: SICU,
Jacksonville, FL, USA published as randomized controlled trials, obser-
e-mail: [email protected] vational cohorts, and case series are emerging at
R. Searcy a very rapid pace, some in peer-reviewed jour-
UF Health North: North ICU, Jacksonville, FL, USA nals, others as manuscripts that have not yet been
e-mail: [email protected] peer-reviewed, and, in some cases, in press
B. Whisenant (*) releases. The abundance of information coming
UF Health Jacksonville, Departments of Emergency out and in such a rapid speed makes it difficult to
Medicine and Critical Care, Jacksonville, FL, USA keep up with the literature and applying these
152 D. Johnson et al.
therapies in an evidence-based practice. equipment (PPE), isolation rooms, non-vented

Currently, based on the available literature, the masks, viral expiratory filters, and low mist nebu-
following are no longer a recommended thera- lizers with one-way valve(s), the risk associated
peutic option for COVID-19: tocilizumab, with aerosol therapy via nebulization in con-
hydroxychloroquine ± azithromycin, lopinavir- firmed and suspected COVID-19 patients can be
ritonavir, and favipiravir; and these will not be significantly reduced [5].
discussed [1].
Therapeutic Review
Supportive Care
Remdesivir
When patients present to the healthcare system
with mild symptoms of COVID-19, it is recom- Remdesivir received FDA approval on October
mended to treat using supportive care. The most 22, 2020, for treatment of COVID-19 in adults
common reported symptoms associated with and pediatric patients ≥12 years of age weigh-
COVID-19 are fever, cough, loss of taste and ing at least 40 kg who are hospitalized and
smell, and shortness of breath. receiving supplemental oxygen therapy [6]
For a fever, take an antipyretic, stay hydrated, Remdesivir is a nucleoside ribonucleic acid
and rest [2] It is currently recommended to use (RNA) polymerase inhibitor. It is metabolized
acetaminophen. Although there is a lack of evi- intracellularly into an analog of adenosine tri-
dence supporting the potential risks of nonsteroi- phosphate that inhibits viral RNA polymerases.
dal anti-inflammatory drugs (NSAIDs) use in Remdesivir therefore incorporates into the viral
patients with COVID-19, it may be prudent to RNA chain resulting in premature chain termi-
use alternative antipyretic medications such as nation [4]. Safety and effectiveness have not
acetaminophen, until more concrete data is avail- been established in pediatric patients <12 years
able [3, 4]. of age or weighing <40 kg [6].
For a cough, it is recommended to sip on Remdesivir is only available as an intravenous
drinks throughout the day for comfort. These administration over 1 hour per 100 mg dose.
beverages may be cold or warm. These will help Remdesivir is dosed 200 mg on day 1 followed
patient stay hydrated and a warm drink may help by 100 mg once daily starting day 2 with total
break up mucus in the throat and upper airway. duration based on patient status [6] It is cur-
Patients may also benefit from cough medicines. rently recommended to complete a 5-day course
If patients present with a wet cough with lots of for patients not severely ill by COVID-19.
mucus, an expectorant (e.g., guaifenesin) may be Remdesivir may be given up to a total of
used to get the mucus out. If patients have a dry 10 days, if not improving clinically or for severe
cough, a cough suppressant with dextrometho- cases involving mechanical ventilation or extra-
rphan will help. And for pain associated with corporeal membrane oxygenation (ECMO), but
cough, acetaminophen is recommended [2]. benefit is less defined or elucidated in clinical
For shortness of breath, it is recommended to studies [2].
take slow deep breaths [2]. If patients need a Currently it is recommended to monitor renal
bronchodilator (e.g., albuterol or ipratropium), function (i.e., SCr), hepatic function (i.e., AST,
then a metered dose inhaler (MDI) is recom- ALT, AlkPhos, T. bilirubin), and prothrombin as
mended. In the hospital, with known or presump- clinically relevant. Additionally, daily hematol-
tive COVID-19 infection, it is recommended to ogy may be considered [2, 6, 7]. Consider dis-
use MDI as a way to decrease aerosolizing the continuing remdesivir if the patients’ ALT
virus. If the supply of MDIs is limited, nebulized reaches five times upper limit of normal.
products can be used. With proper precautions, Additionally, a short course of remdesivir appears
such as the use of appropriate personal protective to have minimal risk of toxicity from cyclodex-
15 Pharmacological Agents for COVID-19 Patients 153
trin accumulation in patients with creatinine Table 15.1 NIH recommendations for pharmacological
clearance ≤30 and/or patients on renal replace- management of patients with COVID-19 based on disease
severity
ment therapy (hemodialysis, peritoneal dialysis,
continuous renal replacement therapy, etc.) if Disease severity Panel recommendations
Not hospitalized or No specific antiviral or
benefits outweigh risks. A 5-day limit is encour-
hospitalized but does immunomodulatory therapy
aged in this population regardless of severity of not require recommended
COVID-19 infection [8]. supplemental oxygen The panel recommends
against the use of
dexamethasone
The panel leaves it up to
Remdesivir Literature clinical judgment for
initiating remdesivir in
The literature that will be reviewed in this chapter hospitalized patients with
moderate COVID-19
regarding remdesivir will highlight the patient
symptoms and at high risk
population that will exhibit the most clinical ben- for clinical deterioration
efit as well as duration of therapy. The National Hospitalized and Remdesivir 200 mg IV for
Institutes of Health (NIH) guidelines (Table 15.1) requires supplemental 1 day, followed by remdesivir
also have a recommendation for remdesivir in oxygen (but does not 100 mg IV once daily for
require oxygen delivery 4 days or until hospital
clinical practice. Overall, the majority of remde- through high-flow discharge, whichever comes
sivir therapy is investigational/salvage and based device, noninvasive first
on a small body of evidence with limited efficacy ventilation, invasive Or
and safety data. mechanical ventilation, Remdesivir (dose and
or ECMO) duration as above) plus
Adaptive COVID-19 Treatment Trial (ACTT- dexamethasone 6 mg IV or
1) evaluated remdesivir (200 mg IV on day 1, PO for up to 10 days or until
then 100 mg IV once daily on days 2–10 or until hospital discharge, whichever
hospital discharge or death) as compared to pla- comes first
If remdesivir cannot be used,
cebo in a double-blind, randomized trial in adult dexamethasone may be used
patients hospitalized with mild, moderate, and instead
severe COVID-19 for up to 10 days. Supportive Hospitalized and Dexamethasone plus
care was provided to all patents based on hospital requires oxygen remdesivir at doses and
delivery through a durations discussed above
trial site. The primary outcome was time to high-flow device or Or
recovery, defined as the first day within 28 days noninvasive ventilation Dexamethasone at dose and
after enrollment when clinical status met criteria duration discussed above
for category 1, 2, or 3 on an 8-category ordinal Hospitalized and Dexamethasone at dose and
requires invasive duration discussed above
scale (i.e., discharged from hospital with or with-
mechanical ventilation Or
out limitations on activities or requirement for or ECMO Dexamethasone plus
home oxygen, or hospitalized but not requiring remdesivir for patients who
supplemental oxygen and no longer requiring have recently been intubated
at the doses and durations
ongoing medical care). A total of 90.1% patients
discussed above
had severe disease (i.e., required mechanical ven-
tilation, required supplemental oxygen, had
SpO2 ≤ 94% on room air, or had tachypnea with data suggests that treatment with remdesivir may
respiratory rate ≥ 24 breaths/minute) at study have prevented the progression to more severe
enrollment, and the median time from symptom respiratory disease. There was no mortality dif-
onset to randomization was 9 days (range: ference seen at day 15 and 29. In a post hoc anal-
6–12 days). Patients in the remdesivir group had ysis, patients with a baseline ordinal score of 5
a shorter time to recovery than the placebo group (i.e., receiving low-flow oxygen) had a recovery
(median 10 days vs 15 days; rate ratio for recov- rate ratio of 1.45 (1.18–1.79), which was statisti-
ery 1.29; 95% CI 1.12–1.49; p < 0.0001). The cally significant. However, the authors caution
this may be due to the larger sample size for this The WHO SOLIDARITY trial evaluated mor-
category and interaction tests suggest greater tality rates associated with four repurposed anti-
benefit in lower ordinal score categories (i.e., not viral drugs in hospitalized COVID-19 patients.
receiving oxygen, receiving low-flow oxygen, or Study drugs were remdesivir, hydroxychloro-
high-flow oxygen/noninvasive mechanical venti- quine, lopinavir/ritonavir, and interferon beta-1a.
lation). Furthermore, the authors suggest the ben- Duration of remdesivir treatment was 10 days (or
efits of remdesivir are larger when given earlier until death or discharge). The primary objective
in the illness [7]. was to assess in-hospital mortality and whether
Although most studies look at 10-day courses any effects differed between moderate and severe
of remdesivir for hospitalized patient, there may disease. Death rate ratio (RR) for remdesivir
be growing evidence that 5 days of therapy may compared to its control was 0.95 (95% CI, 0.81–
be sufficient in patients not receiving mechanical 1.11; p = 0.5). It was determined no study drug
ventilation and ECMO [2, 9, 10]. Spinner et al. definitively reduced mortality in unventilated
conducted a randomized, open-label, phase 3 patients or any other subgroup. Furthermore,
trial that included patients with moderate there was no difference in the secondary out-
COVID-19 (i.e., hospitalized with evidence of comes of initiation of ventilation or hospital
pulmonary infiltrates and SpO2 > 94% on room duration. The between-group differences in the
air). The study initially was designed to evaluate use of corticosteroids and other non-study treat-
safety and antiviral activity of 5- and 10-day reg- ments were small. The WHO consortium addi-
imens of remdesivir (200 mg IV on day 1, fol- tionally performed a meta-analysis from the four
lowed by 100 mg IV once daily for total of 5 or above trials and concluded the death rate ratio
10 days) in conjunction with standard of care (RR) for remdesivir versus control is 0.91 (95%
compared with standard care. The change in pro- CI 0.79–1.05; p = 0.21) and not significant. The
tocol was secondary to the antiviral activity not subtotals for the lower-risk subgroup (with no
being measured. Thus, the protocol was modi- ventilation) suggest some benefit for remdesivir
fied to change the primary endpoint to clinical with a RR of 0.80 (95% CI 0.63–1.01) and some
status on day 11 based on a 7-point ordinal scale hazard in high-risk patients; however, the experts
and include patients 12 years of age or older and caution neither subtotal should be considered in
add an extension phase to include additional isolation from others based on the total confi-
patients. Patients randomized to a 10-day course dence interval [11, 12].
of remdesivir did not have a statistically signifi- The FDA recently approved the use of remde-
cant difference in clinical status compared with sivir in combination with baricitinib under an
standard of care on day 11 (p = 0.18). However, EUA. Baricitinib is a Janus kinase [JAK] inhibi-
patients randomized to a 5-day course had a sig- tor which blocks cytokine signaling reducing the
nificantly higher odds of a better clinical status inflammatory state. This phase 3 study compared
(odds ratio 1.65; 95% CI 1.09–2.48; p = 0.02). remdesivir (200 mg IV on day 1, then 100 mg IV
There were several noted limitations including once daily on days 2–10 or until hospital dis-
the open-label design and the 7-point ordinal charge or death) alone and the combination of
scale used to evaluate clinical status; thus the remdesivir and baricitinib (4 mg once daily for
effect size is of uncertain clinical importance [9]. the duration of hospitalization up to 14 days
Goldman et al. conducted a randomized, open- total) or placebo. The primary outcome was time
label, phase 3 trial evaluating remdesivir for to recovery through day 29 (defined as discharged
either 5 days or 10 days. Overall, the odds of a from the hospital with or without limitations on
subject’s symptoms improving were similar for activities or requiring home oxygen or still hospi-
those in both groups, and there were no statisti- talized but not requiring supplemental oxygen
cally significant differences in recovery rates or and no longer requiring ongoing medical care).
mortality rates [10]. Patients were enrolled if hospitalized with
COVID-19 at any illness duration and they had tion but most likely with little clinical efficacy.
one of the following abnormal imaging (chest There is still insufficient data to provide a broad
x-rays, CT scan, etc.) and SpO2 ≤ 94% on room recommendation either for or against the use of
air or required supplemental oxygen, mechanical remdesivir in hospitalized patients with
ventilation, or ECMO. Preliminary data suggests COVID-19 [12].
that the combination of remdesivir and barici-
tinib met primary outcome of time to recovery
(median time to recovery was 7 days in those Monoclonal Antibodies
receiving the combined regimen vs 8 days in
those receiving remdesivir alone). Preliminary Monoclonal antibodies (mAbs) directly neutral-
data also showed that mortality at 29 days was ize the spike protein on SARS-CoV-2, therefore
5.1% in the combination group versus 7.8% in blocking the receptor-binding domain to the
remdesivir alone. Reduction in mortality was human ACE2 receptor. The mAbs are intended to
more associated with supplemental oxygen [13]. prevent progression of disease and are likely to
The dose of baricitinib used in this study is higher be most effective when given early in infection,
than the recommended dose of 2 mg for rheuma- before antibody formation [15, 16]. Currently
toid arthritis. There is also a current study evalu- there are two mAbs authorized under emergency
ating baricitinib alone [13]. use authorization (EUA) by the FDA: bamla-
There is currently a phase 3 randomized, nivimab (Eli Lilly) and the combination of
double-blind, placebo-controlled trial ongoing to casirivimab and imdevimab (Regeneron)
evaluate a 3-day regimen of IV remdesivir in an (Table 15.2). Both mAbs are delivered via single
outpatient setting. Adults and pediatric patients administration (e.g., IV infusion). Early phase 1
≥12 years of age with early COVID-19 to deter- and 2 evidence suggest promise of mAb products
mine the efficacy for reducing the rate of hospi- in outpatient or ambulatory settings [17, 18].
talization or death [14]. Administration of mAbs in patients that are hos-
In conclusion, remdesivir is the first FDA- pitalized was associated with worse outcomes
approved treatment for COVID-19 in hospital- and those studies have been halted [19]. The
ized patients. ACTT-1 demonstrated that IDSA comments that mAbs hold promise but
remdesivir group had a shorter time to recovery cautions that more clinical trial data are neces-
in patients requiring low-flow oxygen supple- sary. A conversation between provider and patient
mentation; however, the largest trial to date is necessary to discuss the value of mAb benefits
found no benefit related to mortality, initiation may be low to the uncertain adverse events that
of ventilation, or hospital duration [7]. There is may occur.
uncertainty regarding whether starting remdesi- For both mAbs available under EUA by the
vir confers clinical benefit, especially in FDA, the recommendation is to administer to
patients who require oxygen delivery through a patients with mild-to-moderate symptoms of
high-flow device, noninvasive ventilation, inva- COVID-19 and at high risk of progressing to
sive mechanical ventilation, or ECMO [11, 12]. severe disease or hospitalization, age ≥ 12 years
The lack of benefit of remdesivir and progres- old, and weight ≥ 40 kg. (Table 15.3).
sion to more severe disease state are secondary In conclusion, the use of monoclonal antibod-
to later stages of the inflammatory process of ies (mAbs) should only be used in the ambulatory
COVID-19. A 5-day course of therapy may be setting for mild-to-moderate COVID-19 patients
adequate in patients not requiring mechanical at high risk to progress to severe disease or hospi-
ventilation or ECMO therapy [9, 10]. Therapy talization. In some circumstance the Emergency
may be extended up to 10 days in that popula- Department (ED) will help identify high-risk
Table 15.2 Available monoclonal antibodies (mAbs) available and dosing

Monoclonal antibody (mAbs)
Available agents Dose Monitoring Adverse effects
Bamlanivimab 700 mg in 200 mL 0.9% NaCl IVPB Monitor during Hypersensitivity reactions,
over at least 60 min infusion and for nausea, diarrhea, dizziness,
1 hour after headache, pruritus, vomiting
completion
No hepatic or renal
dose adjustments
necessary
Casirivimab and Casirivimab 1200 mg (10 mL) and Monitor during Infusion-related reactions,
imdevimab imdevimab 1200 mg (10 mL) from each infusion and for pneumonia, hyperglycemia,
respective vial using 2 separate syringes 1 hour after nausea, vomiting, intestinal
and dilute together in the infusion bag completion obstruction, dyspnea
containing 0.9% NaCl; withdraw and No hepatic or renal
discard 20 mL of 0.9% NaCl from dose adjustments
infusion bag before adding casirivimab necessary
and imdevimab solutions; infuse over
60 minutes
Table 15.3 Patient population to receive monoclonal Table 15.4 Positive COVID-19 infection and manage-
antibodies (mAbs) ment based on severity
High-risk: All patients who meet at least one of the Mild disease: Ambulatory and high risk:
following criteria No supplemental Monoclonal antibodies
BMI ≥ 35 oxygen (mAbs)
Chronic kidney disease No dyspnea Currently available by EUA
Diabetes No evidence of Hospitalized:
Immunosuppressive disease pneumonia Supportive care/
Receiving immunosuppressive treatment symptomatic treatment
Age ≥ 65 years Moderate disease: Ambulatory and high risk:
Age ≥ 55 years and have any of the following: Dyspnea Monoclonal antibodies
Cardiovascular disease O2 requirements (mAbs)
Hypertension (low-flow) Currently available by EUA
COPD/other chronic respiratory disease High-risk group Hospitalized:
Additional high-risk factors in patients aged No evidence of Supportive care/
12–17 years pneumonia symptomatic treatment
BMI ≥85th percentile for their age and sex based on Lung infiltrates Remdesivir if on low-flow
CDC growth charts ≤50% oxygen
Sickle cell disease May consider steroids
Congenital or acquired heart disease Severe disease: Hospitalized and requiring
Neurodevelopmental disorders (e.g., cerebral palsy) RR ≥30/min more advanced form of oxygen
Medical-related technological dependence (e.g., Blood O2 ≤ 94% delivery:
tracheostomy, gastrostomy, positive-pressure PaO2/FiO2 Supportive care/
ventilation [not related to COVID-19]) ratio < 300 symptomatic treatment
Asthma, reactive airway disease, or other chronic Lung infiltrates Steroids
respiratory disease requiring daily medication for >50% of lung Aggressive
control within 24–48 hours thromboprophylaxis
Consider remdesivir
Critically ill: Hospitalized and mechanical
ARDS ventilation or ECMO:
ambulatory patients. In this situation there need Sepsis Supportive care/
to be protocol and procedures in place to get Altered symptomatic treatment
high-risk patient to the appropriate place for the consciousness Steroids
Multiple organ Aggressive
early administration of mAbs. The Emergency failure thromboprophylaxis or
Department will have a major role of administer- treatment dose
ing mAbs to patients that are COVID-19 positive anticoagulation
(Table 15.4). Consider remdesivir
evelopment of Vaccine against

D Threshold = 1 – 1 / R0 .

SARS-CoV-2
For COVID-19, the Ro or infectivity rate is
Vaccines have had a major impact on human pub- 1.7–3 depending upon the population being stud-
lic health than any other medical intervention in ied, meaning that one infected individual can
history. Smallpox was the deadliest disease ever transmit the virus to one to three susceptible indi-
known to mankind. It was responsible for the viduals. In minority communities the mean Ro is 3
death and disability of 1 in 20 persons who have to as high as 5 due to environment factors: the
ever lived. In the last century, smallpox was nature and duration of the contact with infected
responsible for >500,000 million deaths, (5 mil- individuals in densely and heavily populated
lion per year globally). Mass immunization communities, medical risk factors, and employ-
against smallpox with modern vaccines during the ment as essential workers. For SARS-CoV-2, with
1950s through 1970s resulted the establishment a Ro of 3, more than 70–85% of the population
of population immunity. The World Health needs to be immunized to reach a threshold for
Organization, WHO, in 1979 declared the small- herd immunity. Once R is <1, further spread of the
pox eradiated. It is the only infectious disease that infection is unlikely and is manageable; Ro > 1
has been completely eradicated. This was accom- means rapid spread of the infectious virus and an
plished by mandatory mass immunization mea- epidemic/pandemic is anticipated [20–22, 23].
sures by governmental and international public Figure 15.1 This figure represents the infectiv-
health officials to institute herd (population) ity rate of susceptible individuals without herd
immunity [20]. immunity and those with herd immunity. Not
Herd immunity or population protection indi- included in this figure are the case fatality rate
cates the proportion of people who needs to be and the incidence of waning immunity and sus-
immune to prevent further spread of an infection. ceptibility to reinfection. Mutations of the virus
Ro refers to the reproduction rate or infectious can increase its infectivity rate leading to an ele-
rate of a pathogen described by the formula [21]: vated herd immunity threshold [20, 21].
Susceptible Infected Immuned Indirectly protected
No herd immunity With herd immunity
Fig. 15.1 Herd immunity. Population hierarchy

DISEASE SEVERITY PANEL’S RECOMMENDATIONS

(Recommendaions are listed in order of preference in each category
below; however, all options are considered acceptable.)
Not Hospitalized No Specific antiviral or Immunomodulatory therapy recommended

or The Panel recommends against the use of dexamethasone (AI)
Hospitalized but Does Not Require See the Remdesivir section for a discussion of the data on using
Supplemental Oxygen this drug in hospitalized patients with moderate COVID-19.a
Remdesivir 200 mg IV for one day, followed by remdesivir

Hospitalized and Requires 100 mg IV once daily for 4 days or untill hospital discharge,
whichever comes first (AI)b,c,d
Supplemental Oxygen
or
(but Does Not Require Oxygen Delivery Remdesivir (dose and duration as above) plus dexamethasonee
Through a High-Flow Device, 6mg IV or PO for up to 10 days or untill hospital discharge,
whichever comes first (BIII)f
Noninvasive Ventilation, invasive
Mechanical Ventilation, or ECMO) If remdesivir cannot be used, dexamethasonee may be used
instead (BIII)
Dexamethasoned plus remdesivir at the doses and durations

Hospitalized and Requires Oxygen discussed above (AIII)f
Delivery Through a High-Flow Device or
or Noninvasive Ventilation Dexamethasoned,e at the doses and duration discussed above (AI)
Dexamethasoned,e at the doses and duration discussed above (AI)

Hospitalized and Requires Invasive or
Mechanical Vantilation or ECMO Dexamethasonee plus remdesivir for patients who have recently
benn Intubated at the doses and durations discussed above (CIII)f
Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: 1= One or more randomized trials with clinical outcomes and/or valiated laboratory endpointsl II = One or more
well-designed, nonrandomized trials or observational cohort studies; III = Expert opinion
a
The Panel recongnizes that there may be situations in which a clinician judges that remdesivir is an appropriate treatment for a hospitalized patients with
moderate COVID-19 (e.g., a patient who is at a particularly high risk for clinical deterioration). However, the Panel finds the data insufficient to recommend
either for or against using remdesivir as routine treatment for all hospitalized patients with moderate COVID-19.
b
Treatment duration may be extended to up to 10 days if there is no substantial clinical improvement by Day 5.
c
The Panel recognizes there is a theoretical rationale for intiating remdesivir plus dexamethasone in patients with rapidly progressing COVID-19.
d
For patients who are receiving remdesivir but progress to requiring oxygen through a high-flow devices, nonivasive ventilation, invasive mechanical
ventilation, or ECMO, remdesivir should be continued until the treatment course is completed.
e
If dexamethasone is not available, equivalent doses of other corticosteroids, such as prednisone, methylprednisolone, or hydrocortisone, may be used.
see Corticosteroids for more information.
f
The combination of dexamethasone and remdesivir has not been studied in clinical trials; see text for the rationale for using this combination.
Key: ECMO = extracorporeal membrane oxygenation; IV =intravenously; PO =orally
The USA is in the midst of a global countries with limited economic means. The
COVID-19 pandemic that has disproportion- criteria for an ideal SARS-CoV-2 vaccine(s)
ately threatened the health, safety, and political are [22]:
and economic stability. A safe and effective
vaccine against SARS- CoV- 2 is urgently • Safe with few side effects.
needed to bring stability to the USA and glob- • Efficacy of at least 70%.
ally. The USA and the World Health • Low cost.
Organization in coordination with multiple • Able to be mass produced at a reasonable cost.
countries throughout the world in an effort to • Stable for storage at room temperature and
control the spread of COVID-19 pandemic transport.
have develop and manufactured billions of
doses of vacines or the widepread distribution Following the announcement of a new emerg-
to the world population [24]. These vaccines ing beta-coronavirus, Wuhan, China, scientists
must be suitable to provide immunization to published its genetic sequence [25]. The US
National Institute of Allergy and Infectious Antiviral vaccines are classified as gene-
Diseases and the Division of Vaccine Research based vaccines that deliver the genetic sequence
had identified the DNA sequence of the gene that encodes for the protein antigen of interest,
encoding the spike protein [24, 26, 27]. Prior pre- and it is produced by the host cellular machinery
clinical studies on SARS-CoV-1, MERS, and [31]. This method is superfast and cost-efficient
Zika had indicated that the spike protein was the and avoids the use of cell tissue culture the gen-
antigen that would be likely to generate the most eration of live viruses [24, 28–31]. The Other
robust immunogenic response [24–30]. A new methodologies for the development of COVID
era of genetic-structured, cryo-electron micros- vaccines involve the use of whole inactivated
copy with computational informatic analysis of viruses, viralproteins or subunits, and viral pro-
the structured protein provided epitopes on the tein assembled as empty shells. The DNA and
subunits, S1 and S2, and receptor-binding domain mRNA vaccine methods have generated efficacy
(RBD) would be the most suitable as targets for and safety during the preclinical evaluation stage
antibodies development [28, 30]. Antibodies [24, 28–33].
developed against the RBD would prevent the Figure 15.2 This figure represents the RNA-
virus from attaching to the ACE2 receptor of the based Nucleic Acid Biotechnology Platform used
host cell membrane and neutralize the virus. It by NIH, NIAID and other academic institute for
was demonstrated by cryo-EM that maintains the the emergency development of a SARS-CoV-2
spike protein in its prefusion mushroom shape vaccine. Accelerated Process for the develop-
would allow better exposure and antibodies gen- ment and rapid manufacturing of safe and effica-
eration against the RBD. Protein engineering of cious vaccine against COVID-19
the trimeric spike protein was performed with the This was a joint effort of the National
insertion of two proline amino acids in key posi- Institutes of Health, National Institute of Allergy
tions of the peptide chain to maintain the natural and Infectious Diseases (NIAID), and Centers
surface contour of the antigen. This resulted in for Disease Control and Prevention (CDC). Joint
better exposure of the receptor-binding domain efforts involving the National Institue of Health,
(RBD) for the development of tight binding anti- National Institute of Allergy and Infectious
bodies against the attachment site of the virus Diseases, Center for Disease Control, in associa-
[24–30]. Current Good manufacturing Practice tion with other governmental, academic and pri-
(GMP) platform was used to product mRNA/ vate companies were instrumental in establishing
nano-lipid particles that expressed the SP within the platform for vacine development and manu-
15 days. Preclinical evaluation of the mRNA was facturing [34]. There are multiple and different
initiated and completed in 42 days, and phase 1 technologies use in development of rapid, safe
clinical trial was initiated in 66 days following and effective COVID-19 vaccine that are capable
sequence of DNA genes that encoded the SP8. of generating large scale production of million
The mRNA-1273 was found to be a potent immu- of doses of vaccine against COVID-19. These
nogen that produced IgG neutralizing antibodies vaccine platforms using the new era technolo-
(Abs) levels that exceeded IgG titers of patients gies for the production of safe and efficacious
who had survived severe COVID-19 infections. vaccines are:
The vaccine was also evaluated for cellular-medi-
ated immune response, and it demonstrated a bal- • Nucleic acid-based platform (Moderna, etc.)
anced TH1/TH2 response in favor of CD4+ T-cell • Replication-defective live vector platform
activation favored antibodies formation vs TH2 (AstraZeneca, J&J).
that elicit enhanced T8 effector cells. Phases 1, 2, • Protein subunit adjuvant-based platform
and 3 showed that the vaccine was safe and effi- (Novavax).
cacious and could easily be produced in large • Attenuated replicating live vector platform
quantities [7–27]. (Covanix, PiCoVacc).
Current good manufacturing practice (cCMP)
15 Pre-
8 months Distribution
days clinical
Phase 1 Phase 3
DNA Vaccine
100 pts 40,000 pts
sequencing Production
SP purified
Vaccine Phase 2
developed 1,000 pts
Approval EUA
300
Vaccination
Beginning million
of human doses
clinical
trials
Fig. 15.2 Operation warp speed vaccine development for SARS-CoV-2
ucleic Acid (RNA and DNA

N delivered in cationic ionized pegylated lipopro-
Recombinant Vaccine tein nanoparticles intramuscularly [26, 27].
Development) [31–37] Pfizer requires a primer dose of 30 ug IM injec-
tion followed by a booster of the same injection
Prototypes of this method of vaccinology are 3 weeks afterward [32–35, 37]. Moderna’s vac-
Pfizer/BioNTech and Moderna-NIH vaccines cine dose is three times higher than the Pfizer
[31]. The clinical analysis of Moderna’s vaccine vaccine at 100 ug for both primer and booster
in nonhuman primate and mice showed that the dose [33–39]. Both vaccines require cold stor-
coronavirus is cleared from the lower respira- age: Pfizer at 97 C and Moderna at −20C [22–
tory tract and nasal turbinate at time of infection 31]. They should not be refrozen and discarded
and on rechallenge with the virus [24, 28]. after 6 hours.
Moderna’s clinical trials in phases 1 and 2 dem- The side effects are minimal for both vaccines
onstrated that the vaccine is safe and has a which include headache, pain at the site of injec-
94.5% efficacy in the neuralization against tion, muscle pain, fever, gastrointestinal discom-
COVID-19 with minimal known side effects fort, and rare allergic/anaphylaxis reactions. This
[28]. The immunological response has been is believed to be secondary to polyethylene gly-
showed in preclinical studies and in phase 1 and col ingredient used for formulation of lipid
2 clinical trials to elicit T follicular helper (TfH) nanoparticles [39].
regulatory cells that control the development Table 15.5 represents a brief summary of four
and maturation of naïve B cell toward plasma of the most likely vaccine candidates for advance-
cells for the secretion of target specific antibod- ment to emergency use authorization (EUA) for
ies with high binding capabilities [28, 29]. The SARS-CoV-2 which is outlined below. Australian
TfH cells also promote the maturation and regu- pharmaceutical company CSL lost their contract
late the clonal expansion of B cells to long-last- for $1 billion with the Australian Government
ing memory B cells within the germinal center due to faulty mutation of spike protein design.
of lymphoid tissue [8]. The mRNA vaccines are The design and protein modification of the
Table 15.5 Summary of likely vaccine candidates for US use

T-cell
Vaccine COVID-19 target response Advantages Disadvantages Side effects
Moderna 22 SP, RBD TH1 Designed Abs Cost per dose Minimal SE
mRNA-1273 Specific target Storage concerns
design
95% efficacy
Pfizer/BioNTech SP RBD TH2 Advanced tech Cost per dose Allergic Rx,
mRNA Storage minimal SE
AstraZeneca ChAdOx TH1 Genetic Storage acceptable Hemolytic
SP NP engineered anemia
Transverse
myelitis
Johnson & Prefusion SP TH1 CD4+ T Viral vector Moderate immune
Johnson [20] Adeno 26 cells Adenovirus response
nonreplicating Requires booters
SP N Storage 20 °C for
2 yrs
3 months at 8 °C
Novavax R protein TH1 or 2 Nano sub/Pr Matrix M1 adjuvant Inflammation
COVID-19 SP with the insertion of protein Viral Vaccines [33, 37, 40–42]
molecular clamps to keep the SP in a prefusion
conformation led to the development of antibod- Live Virus Vector Vaccines
ies to these molecular clamps that are similar to
HIV SP glycoproteins. It led to false positive The prototypical vaccine under this class of
HIV screening test in a number of participants in vaccine development is the chimpanzee adeno-
their phase 1 clinical trial (The Sydney Morning virus [42].
Herald). Viral vector vaccine referred to as ChAdOx/
DNA-Based Vaccines [33, 35, 39]. The bio- AZD1212 is a common cold virus that only
technology pharmaceutical company developed affects chimpanzees. Humans have never had
a DNA-based plasmid that utilized a sequence exposure to this virus. It is engineered to trans-
of a targeted antigen of SARS-CoV-2 and is port to express the COVID-19 spike proteins or
administered by IM injection. During injection other subunits of SARS-CoV-2. The advantage of
of the DNA plasmid, an electric charge is given this vaccine is that it is able to generate intense
to allow the DNA plasmid to penetrate the cel- immune response simulating a virus infection to
lular and nuclear membranes of the muscle our immune system. This vaccine induces an
cells by a process called electropolation. The intense humoral response with neutralizing IgG.
muscle cells then integrate the DNA sequence It has the following characteristics:
encoding for the viral spike protein into its
DNA and undergo transcription and translation • Efficacy of 90%.
for the production of SPs that are embedded in • Two doses 4 weeks apart.
the host cell plasma membranes and secreted. • Side effects: minor to moderate. There have
Antigen-presenting cells are thus generated for been three cases of transverse myelitis in a MS
the development of innate and adaptive immu- patient and in another patient hemolytic ane-
nity. For SARS-CoV-2, four different DNA mia. All recovered.
vaccines are currently in phase 2 clinical trial • Cost 2–3 dollars per dose.
[40–42]. • Storage in refrigerator for 6 months.
• Advantages: storage, low cost for low- and This precipitous drop in Novavax efficacy was
moderate-income countries. due to the finding of a new variant of SARS-
• Disadvantages: side effects developed. CoV-2, B1.351. The Novavax vaccine is highly
effective against the original and the UK variant
(B1.1.7) at 85.6% but not so with South African
J ohnson & Johnson’s Janssen variant E484K [44].
Pharmaceutical Company [41–43] Novavax is currently in the development of a
bivalent vaccine to address the lack of efficacy
Johnson & Johnson vaccine is a double-stranded against the B1.351 South African SARS mutant
DNA that encodes the COVID-19 spike protein (501Y.V2) [34].
in an incompetent recombinant. It has the
advance of using DNA which is less likely sus- Mucosal SARS-CoV-2 Vaccine [23, 45]
ceptible to degradation compared to the mRNA The oral and nasal mucosal surface of the human
platform. It produces an intense immunological body serves as a protective barrier to the portal of
response with neutralizing Abs and TH1 CD4+ T entrance for many pathogens similar to SARS-
lymphocyte predominance. The Johnson and CoV-2. A mucosal vaccine utilizing the nasal or oral
Johnson vaccine is a single-dose vaccine that route is in development to deliver the SARS-CoV-2
offers many advantages over other vaccines prefusion spike protein via lipid nanoparticle encap-
being a one-time dose and having routine refrig- sulated m-RNA, DNA plasmid, and viral vectors
eration at -20C for 2 years and 8C for 6 months. platforms. A single intranasal spray dose of SARS-
The Johnson and Johnson’s (J&J) vaccine was CoV-2 spike proteins and/or SARS-CoV-2 subunits
demonstrated in a clinical randomized control induces high levels of neutralizing antibodies of the
trial involving 44,000 participant to have an effi- IgA anti-SARS-CoV-2 idiotype and cellular immu-
cacy of 90% against severe disease following a nity. Virtually complete protection against COVID
single (low dose) of 5 × 1010 viral particles by 29 infection in the nasal, upper and lower respiratory
days and 100% at day 57. The J&J vaccine is cur- tract was accomplished without the development of
rently in phase 3 trial with 60,00 people enrolled pneumonia. There was signficantly protection
between the age of 18 and > 65 and anticipating against nasal innoculation and viral shedding. The
EUA approval. introduction of a mucosal COVID-19 vaccine may
offer better patient compliance in terms of comfort
measures and compatible for up scale industrial
Protein Subunit production for mass immunization. Vaccine admin-
istration using the intranasal or oral route can be
NVX-CoV2373 (Novavax) is the prototypical easily administered without the need for trained
representative of protein subunit vaccine plat- healthcare personnel particularly in less developed
form. It is a recombinant SARS-CoV-2 spike pro- countries and population.
tein, full-length nanoparticle with an adjuvant
M-matrix to enhance its immunogenicity with
the production of antibodies [41–43]. evelopment of Mutant SARS-CoV-2
D
In a South African clinical trial using Novavax Viruses [44, 46]
vaccine with the enrollment of 15,000 partici-
pants in which 3% in the placebo group had prior The development of multiple vaccines for SARS-
infection with SARS-CoV-2 before the study, Co-V-2 that are highly efficacious, safe, and able
they (prior infected placebo group) developed to be mass produced represents a new era in the
the same rate of infection and those who had biogenetic vaccinology. Globally, about seven
never been infected. It showed that Novavax vac- billion people will need vaccination against the
cine had an efficacy of 60% that dropped to COVID-19. There will be pressure for the SARS-
49.9% in immunocompromised individuals. CoV-2 to mutate at the spike protein epitopes to
escape the immune systems. The current plat- • Moderna and Pfizer vaccines have shown
forms for the rapid production of safe and effec- reduced neutralizing antidodies against the
tive vaccine can be repurposed to address changes B1.351 South African variant.
in the virus antigen determinants or the emer-
gence of new infectious pathogens. .1 (501Y.V3) Brazil/Japan [46]
P
Recently there has been the development of sev- This variant appears to have originated from
eral variants of the original SARS-CoV-2 that are of Manaus and Amazonian cities in Brazil. 75% of
clinical significance that results in increased trans- the population had acquired natural immunity
missibility of these mutation strains of the SARS- to the original SARS-CoV-2, herd immunity, but
CoV-2 with increased binding to the ACE2 receptor in the month of December 2020 developed a
site of the respiratory epithelial cells. These mutants surge and reinfection with this variant that over-
have been found in South Africa, the UK, and whelmed the Brazil’s healthcare system [52].
Manaus, Brazil. These three variants are of clinical
concern in that they developed independently and • Important mutations are E484K, K417K,
common genomic mutation, N501Y [44]. D614G, and N501Y that are associated with
increase transmissibility and reinfection.
.1.1.7 (501Y.V1) UK Variant [44, 47]
B • Virus can escape human antibodies neutraliza-
• The B.1.1.7, originally detected in the UK, is the tion and eradication. There is tenfold reduction
dominant SARS-CoV-2 in the UK and rapidly in the effectiveness of convalescent and mono-
spreading in the USA, in the states of California, clonal antibodies.
Texas, and Florida. It has key mutations:
• 69/70 deletion, N501Y, and K417N. These All three of these variants developed indepen-
key mutations allow increased transmissibility dently having the same mutational defects,
of the virus. mainly E484K, N501Y, and D614G. This indi-
• The 501Y cause 70% increased affinity of the cates that these mutants have survival advantages
RBD binding to the ACE2 target. for the virus adaptive evolution.
• There is no loss of efficacy of vaccines: The rapid administration of vaccines against
Moderna, Pfizer/BioNTech, and other vac- SARS is imperative to lessen the spread and
cines developed. generation of more pathogenic variants. There
• Novavax has 96% efficacy against original is consideration for the development of booster
SARS-CoV-2 and 85.6% against B.1.1.7 vaccines against selective spike mutational
mutant. changes to provide additional protection
against emerging variants in particular the
1.351 (501Y.V2) South Africa [44, 47]
B strain B.1.351.
This is the dominant strain in South Africa and
the mutation developed independently from the
UK variant. anagement of Vaccine Side
M
Effects [48]
• Important mutational defects are N501Y,
K417N, D614G, and E484K. The E484K The incidence is rare, occurring in less than 1 in
mutation of this strain allows the virus to 100,000 vaccinations, which is less than allergic
evade neutralizing antibodies. reactions to antibiotics and generally occurs in
• Novavax is less effective against this South individual with a history of documented severe
African strain with reduced efficacy of 60% allergic reactions: anaphylaxis, angioedema, urti-
down to 49% in immunocompromised people. caria, edema of oropharyngeal airway, and acute
• Convalescent serum from people who had bronchospasm. It may be due to an IgE-mediated
recovered from COVID-19 found to be less allergic reaction with mast cell degranulation and
effective. complement fixation.
If an allergic reaction develops to the first to infect immune cells and extend their tropism
dose, do not administer a second dose prior to to other cells (myocardial, hepatic, nervous sys-
receiving an allergy/immunology consultation tem cells) and tissues. This mechanism may
and evaluation. This is a new CDC recommenda- explain the clinical diversity of COVID-19 dis-
tion. Immediately post-management of allergic ease leading to mild symptoms to shock-like
and anaphylaxis reaction obtain serial measure- state and death [47–51].
ment of serum total tryptase at 15 minutes and 60 There is increased vigilance in genomic moni-
minutes.Serum tryptase levels have been found to toring of the SARS-CoV-2 to detecting signifi-
have a sensitivity and specificity of 73 and 98% cant mutation changes affecting Ab affinity and
respectively for anaphylaxis. Other labortory avidity of the RBD and S1/S2 epitope sites [53].
studies may include serum leukotrienes (LTE4) a
urine methyhistamine level but both are not as Critical Points
reliable as serum tryptase levels: CRP; ESR; • There are multiple vaccines available using a
tryptase; complement level for C1q, C3a, and C5 genetically engineered platform that have effi-
levels; urine for leukotrienes (LTE4) and methyl- cacy of 80% or greater.
histamine. Perform skin testing with PEG prior to • If a patient presents to the Emergency
giving second dose. Skin testing with COVID-19 Department with reactogenicity symptoms
vaccine(s) has not received FDA approval. persisting longer that 3 days post-COVID-19
vaccination, perform a COVID-19 test. The
likely cause of these reactogenic symptoms of
Antibody-Dependent Enhancement severe fatigue, myalgia, headaches and fever
(ADE) [49–51] is likely due to the inadvertent vaccination of
a COVID positive patient. This occurs in
Another theoretical potential serious problem approximately 8 to 10% of the population at
associated with the SARS-CoV-2 vaccine is large being vaccinated.
antibody- dependent enhancement. ADE is a • Natural herd immunity does not protect an
mechanism where non-neutralizing antibodies individual from reinfection with the P.1
might have the potential to allow the SARCoV-2 variant.
to gain entry and replicate in the viral target cells • Current Moderna and Pfizer vaccines provide
or macrophage/monocytes via the Fc receptors. It acceptable protection against the E484K
may also be related to the over-activation of the South Africa variant. Neutralizing Ab titers
TH2 T-8 effector killer pathway for adaptive are above 60% in immunocompetent
immunity [50, 51]. ADE has been hypothesized individuals.
to occur when there are antibodies generated • SARS-CoV-2 is undergoing evolutionary
against one virus that provides limited neutral- adaptation and thus requires urgent mass
ization against a second variant strain of same vaccinations.
virus that leads to paradoxical enhancement of
the replication of the second viral mutant variant
virus [51]. In COVID-19, this may occur and Conclusion
lead to severe SARS-CoV-2 disease where prior
heterotypic antibodies result in a sub-neutraliz- In conclusion COVID-19 has become one of the
ing titer of antibodies binding to the spike pro- most published disease states in history. This is in
tein that is critical for neutralizing Ab binding an attempt to reduce mortality and hospital
and elimination of the virus. The mutations of admissions. We should remind ourselves to con-
SARS-CoV-2 particularly if it occurs at the tinue using the most evidence-based approach for
RBD, S1/S2 subunits, may have low-affinity the treatment of COVID-19. As of writing this
binding of antibodies to the new variant strain. chapter, our best evidence lies, with limitations,
The virus is not neutralized and able to continue in utilizing corticosteroids, remdesivir in select
populations, and thromboprophylaxis. There is disease and COVID-19. J Am Soc Nephrol 2020;
also promise with mAbs in the ambulatory set- 31(7):1384. Epub 2020 Jun 8. PMID: 32513665.
https://doi.org/10.1681/ASN.2020050589 (remdesi-
ting. The ultimate cure of COVID-19 will be the vir and kidney).
worldwide distribution of highly effective vac- 9. Spinner CD, Gottlieb RL, Criner GJ et al. Effect of
cines. There are currently several vaccines that remdesivir vs standard care on clinical status at 11 days
are approved and currently being administered in in patients with moderate COVID-19: a randomized
clinical trial. JAMA 2020; 324:1048–1057. PMID:
the USA and around the world. COVID-19 32821939. https://doi.org/10.1001/jama.2020.16349.
immunization is the best means to establish herd (remdesivir duration).
immunity rapidly and crush this pandemic by 10. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir
providing protective long-term immune memory for 5 or 10 days in patients with severe covid-19.
N Engl J Med. 2020. PMID: 32459919. https://doi.
and preventing escape mutations and eradicating org/10.1056/NEJMoa2015301 (remdesivir duration).
the virus. Failure to dispense safe and efficacious 11. Pan H, Peto R, Karim QA et al. Repurposed antiviral
vaccines in a fair and impartial manner will risk drugs for COVID-19 – interim WHO SOLIDARITY
persistence and emergence of other evolving trial results. medRxiv. Posted Oct 15, 2020. Preprint
(not peer reviewed). (https://www.medrxiv.org/conten
COVID-19 variants. t/10.1101/2020.10.15.20209817v1). (WHO).
12.
World Health Organization. Therapeutics and
COVID-19: living guideline. https://www.who.int/
References publications/i/item/therapeutics-and-covid-19-living-
guideline. Accessed 20 Nov 2020. PMID: 32887691
(WHO).
1. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell 13. Fact sheet for healthcare providers: Emergency use
JB. Pharmacologic treatments for coronavi- authorization (EUA) of baricitinib. https://www.
rus disease 2019 (COVID-19): a review. JAMA. fda.gov/media/143823/download. Accessed 23 Nov
2020;323(18):1824–36. Available at: https://www. 2020).
ncbi.nlm.nih.gov/pubmed/32282022. (Review of 14. Study to evaluate the safety and efficacy of remdesi-
therapeutic agents). vir (GS-5734) treatment of coronavirus disease 2019
2. National Institutes of Health. Coronavirus disease (COVID-19) in an outpatient setting. NCT04501952.
2019 (COVID-19) treatment guidelines. Updated https://clinicaltrials.gov/ct2/show/NCT04501952.
2020 Oct 9. From NIH website https://www. (outpatient).
covid19treatmentguidelines.nih.gov/). Accessed 2020 15. Marovich M, Mascola JR, Cohen MS. Monoclonal
Nov 20. (Supportive care and remdesivir, duration). antibodies for prevention and treatment of COVID-19.
3. Jeong HE, Lee H, Shin HJ et al. Association between JAMA 2020; 324:131–132. PMID: 32539093. https://
NSAIDs use and adverse clinical outcomes among doi.org/10.1001/jama.2020.10245. (mAbs).
adults hospitalized with COVID-19 in South Korea: 16. Zost SJ, Gilchuk P, Case JB et al. Potently neutral-
a nationwide study. Clin Infect Dis 2020. PMID: izing and protective human antibodies against SARS-
32717066. https://doi.org/10.1093/cid/ciaa1056 CoV-2. Nature 2020; 584:443–449. PMID: 32668443.
(NSAIDs). https://doi.org/10.1038/s41586-020-2548-6 (mAbs).
4. Rinott E, Kozer E, Shapira Y, et al. Ibuprofen use and 17. Chen et al. SARS-CoV-2 neutralizing antibody

clinical outcomes in COVID-19 patients. Clin Infect LY-CoV555 in outpatients with COVID-19. N Engl
Dis 2020. PMID: 32535147. https://doi.org/10.1016/j. J Med. 2020 Oct 28 [epub ahead of print]. PMID:
cmi.2020.06.003 (NSAIDs). 33113295. https://doi.org/10.1056/NEJMoa2029849.
5. Ari A. Practical strategies for a safe and effective 18. A Study of LY3819253 (LY-CoV555) and LY3832479
delivery of aerosolized medications to patients with (LY-CoV016) in Participants Hospitalized with
COVID-19. Respir Med. 2020;167:105987. https:// Mild to Moderate COVID-19 Illness (BLAZE- 1).
doi.org/10.1016/j.rmed.2020.105987. (Safety of new NCT04427501. Update posted 2020 Sep 18.
drugs). https://www.clinicaltrials.gov/ct2/show/study/
6. Gilead Sciences. Veklury® (remdesivir) for injection NCT04427501.
and injection prescribing information. Foster City, 19. A Study of LY3819253 (LY-CoV555) in Participants
CA; 2020 Oct. (Remdesivir). Hospitalized for COVID-19. NCT04411628. Update
7. Beigel JH, Tomashek KM, Dodd LE et al. Remdesivir posted 2020 Oct 30. https://www.clinicaltrials.gov/
for the treatment of Covid-19 - final report. N Engl J ct2/show/study/NCT04411628.
Med 2020; 383(19):1813. Epub 2020 Oct 8. PMID: 20.
Desai A. What is herd immunity. JAMA.
32445440. https://doi.org/10.1056/NEJMoa2007764 2020;324(20):2118.
(Remdesivir). 21. Rubin, Rita Difficult to determine herd immunity

8. Adamsick ML, Gandhi RG, Bidell MR et al. threshold for COVID-19 JAMA. 2020;3248;732.
Remdesivir in patients with acute or chronic kidney
22. Ada GL. The ideal vaccine. World J Microbiol

38. Abbasi J. COVID-19 and mRNA vaccines—first large
Biotech. 1991;7(2):105–9. test for a new approach. JAMA. 2020;324(12):1125–
23. Hassan et al., 2020, Cell 183, 169–184 October 1, 7. https://doi.org/10.1001/jama.2020.16866.
2020 a 2020 Elsevier Inc. https://doi.org/10.1016/j. 39. COVID-19 Vaccine Candidate. MGH Nov 2020.

cell.2020.08.026. SARS-CoV-2 Vaccine.
24.
Graham BS, Corbett KS. Prototype pathogen 40.
Liu Y, Wang K, Massoud TF, Paulmurugan
approach for pandemic preparedness: world on R. Development: an overview and perspectives. ACS
fire. J Clin Invest. 2020. https://doi.org/10.1172/ Pharmaco Trans Sci. 2020;3(5):844–58. https://doi.
JCI139601. org/10.1021/acsptsci.0c00109.
25. Nature. 2020;579(7798):265–269. Published online
41. Johnson and Johnson study protocol for vaccine.
2020 Feb 3. 42. Safety and Efficacy of the BNT162b2 mRNA

26. Hassett KJ, et al. Optimization of lipid nanoparticles Covid-19 Vaccine NEJM 12/2020.
for intramuscular administration of mRNA vaccines. 43.
AstraZeneca/oxford covid-19 vaccine efficacy
Mol Ther Nucleic Acids. 2019;15:1–11. https://doi. 12/2020.
org/10.1016/j.omtn.2019.01.013. 44. CDC Government Mutant Variant of SAR-CoV-2 in
27. Nanotechnology for COVID-19: Therapeutics and
UK and South Africa.
Vaccine Research. 45. Mudgal R, et al. Prospects for mucosal vaccine:

28. Graham B, Rapid S. COVID-19 vaccine development. shutting the door on SARS-CoV-2. Human Vacc
Science. 2020;368:945–6. https://doi.org/10.1126/ Immunother. 2020. https://doi.org/10.1080/21645515
science.abb8923. .2020.1805992.
29. Walls AC, et al. Cryo-electron microscopy structure 46. Sara Reardon Scientific American Jan 29, 2021.
of a coronavirus spike glycoprotein trimer. Nature. 47.
CDC.GOV Understanding mRNA COVID-19
2016;531:114–7. https://doi.org/10.1038/nature16988. Vaccines.
30. Graham BS, Sullivan NJ. Emerging viral diseases
48. Campell R. Emergency department diagnosis and

from a vaccinology perspective: preparing for the treatment of anaphylaxis: a practice parameter. Ann
next pandemic. Nat Immunol. 2018;19:20–8. https:// Allergy Asthma Immunol. 2014;1139:599–608.
doi.org/10.1038/s41590-017-0007-9. 49.
Lee W. Yip: antibody-dependent enhancement
31. SARS-CoV-2 mRNA Vaccine Development Enabled and SARS-CoV-2 vaccines and therapeutics. Nat
by Prototype Pathogen Preparedness. Microbiol. 2020;5:1185–91.
32. Safety and Immunogenicity of Two RNA-Based
50. Tetro J. Is COVID-19 receiving ADE from other coro-
Covid-19 Vaccine Candidates Edward Walsh NEJM naviruses? Microbes Infection. 2020;22(2):72–3.
2020. 51. Zaichuk TA, Nechipurenko YD, Adzhubey AA,

33. Krammer F. SARS-CoV-2 vaccines in development. et al. The challenges of vaccine development against
Nature. 2020;586:516–27. https://doi.org/10.1038/ Betacoronaviruses: antibody dependent enhancement
s41586-020-2798-. and Sendai virus as a possible vaccine vector. Mol
34.
Kai Kupferschmidt Health coronavirus Science Biol. 2020.
do110:1126. 52. Al-Betar MA, Alyasseri ZAA, Awadallah MA, et al.
35. Dong Y, Dai T, Wei Y, et al. A systematic review of Coronavirus herd immunity optimizer (CHIO).
SARS-CoV-2 vaccine candidates. Sig Transduct Neural Comput & Applic. 2020.
Target Ther. 2020;5:237. https://doi.org/10.1038/ 53. Faria NR, Claro IM. Genomic characterisation

s41392-020-00352-y. of an emergent SARS-CoV-2 lineage in Manaus:
36. Amanai F, Krammer Floian SARS-CoV-2 Vaccines: preliminary findings. https://doi.org/10.1007/
Status. s00521-020-05296-6.
37. Gregory Poland Mayo Clinic Proceedings SARS

Vaccine Development: Current Status.
Point of Care Echocardiography
in the COVID-19 Patient
16
Daniel Haase, William A. Teeter, Jaskirat Gill,
and Adnan Javed
Introduction state which can cause venothromboembolism,

intracardiac thrombus, acute respiratory distress
COVID-19 is associated with significant cardiac syndrome (ARDS), and exacerbation of preexist-
and pulmonary pathology. Cardiopulmonary ing coronary artery disease. Critically ill patients
complications are due to direct and indirect viral may present to the emergency department or ICU
effects as well as exacerbation of underlying car- with the COVID-19, prompting rapid assess-
diopulmonary disease. In addition to toxic cyto- ment, diagnosis, and treatment.
kine storm, stress cardiomyopathy, direct lung POCUS can be used to assess the hemody-
injury, and pro-inflammatory state, patients may namically unstable patient. Whether suspected
experience a prothrombotic hypercoagulable of having an acute cardiac or pulmonary process,
POCUS allows a rapid screen for significant
pathology which can lead to more rapid progres-
sion to definitive therapy.
D. Haase While POCUS has been used for decades to
Departments of Emergency Medicine and Surgery,
Program in Trauma/Surgical Critical Care, R Adams evaluate cardiac pathology, the use of lung ultra-
Cowley Shock Trauma Center, University of sound is a somewhat more recent development
Maryland School of Medicine, Baltimore, MD, USA but is also used for years. Its use in the evalu-
e-mail: [email protected] ation and diagnosis of the COVID-19 patient
W. A. Teeter has proved of great use to the bedside clinician.
Departments of Emergency Medicine, Program in Further benefits of POCUS include intrepidity of
Trauma/Surgical Critical Care, R Adams Cowley
Shock Trauma Center, University of Maryland School deployment to the bedside, the lack of ionizing
of Medicine, Baltimore, MD, USA radiation, superiority to standard chest X-rays in
e-mail: [email protected] the evaluation of pneumonia and ARDS [1], and
J. Gill ease of use for serial measurements, especially in
Surgical Critical Care Fellow, Program in Trauma/ various therapies utilized in COVID-19 patients
Surgical Critical Care, R Adams Cowley Shock
such as prone positioning and extracorporeal
Trauma Center, University of Maryland School of
Medicine, Baltimore, MD, USA membrane therapy (ECMO) [2].
A. Javed (*)
University of Florida College of Medicine -
Jacksonville, Department of Emergency Medicine,
168 D. Haase et al.
Safety Considerations • In the doffing area, the US machine should

also be cleaned with CDC-approved wipes
Given the clinical instability of COVID-19 and stored away from the doffing area.
patients and its highly contagious nature, it has
been imperative to use an imaging modality that
provides the clinician with the most information Cardiac POCUS in COVID-19
in the safest way possible. POCUS affords us
ability through its portability, repeatability, and Indications [5]
relative ease of disinfection following exposure While POCUS is a readily available resource in
to the virus, as opposed to more traditional most emergency departments, its use should be
imaging methods including X-ray, CT, and MRI, guided by appropriate clinical questions to limit
which carry much higher resource utilization for the unnecessary exposure of both equipment and
disinfection of equipment, but also travel with a clinicians to patients with COVID-19. There are
COVID-19 patient to these modalities is fraught. several clinical scenarios in which cardiac
Prior to use, special attention must be paid POCUS could offer valuable information. These
to the cleaning and disinfection of the POCUS include:
equipment. A protocolized approach will allow
compliance across departments while ensuring 1. Hemodynamic assessment in the COVID-19
infectious disease standards are met. We recom- patient in shock.
mend that, similar to the donning and doffing 2. The COVID-19 patient with elevated and/or
process for personnel, there should be an ultra- rising cardiac biomarkers or EKG
sound monitor who ensures that the machine is abnormalities.
cleaned appropriately between rooms. 3. The COVID-19 patient in whom an acute car-
In accordance with various guidelines put diac process is suspected, e.g., PE, ACS, acute
forth by the American College of Emergency heart failure, or myocarditis.
Physicians (ACEP) [3] and American Institute
of Ultrasound in Medicine (AIUM) [4], here we Findings on Formal Transthoracic
present important points of consideration prior to Echocardiography Studies
entering the room to scan COVID-19 patients: Given the novelty of the disease, there is a rela-
tive paucity of echocardiographic findings in
• Ensure all nonessential items are removed COVID-19 patients. At a single quaternary care
from the machine. center in NYC, 72 COVID-19 patients underwent
• Ensure proper hand hygiene is performed by formal TTEs, demonstrating 35% had LVEF
staff touching the machine. <50%, 14% had moderately reduced RV func-
• Based on the exam being performed, preset tion, and 5% had wall motion abnormalities sug-
selection and patient information should be gestive of stress-induced cardiomyopathy [6]. In
entered prior to entering the room. a multicenter cohort in New Jersey, Vasudev et al.
• If possible, a two-person approach may be reported LV systolic dysfunction in 31% of
employed where one individual touches the patients and RV dilation or dysfunction in 24%
machine and other places the probe on the [7]. A case series of patients with severe
patient. COVID- 19 infection in Wuhan illustrated the
• If a handheld US machine is being used, then utility of early cardiac POCUS in the diagnosis of
we recommend using a plastic barrier severe LV systolic dysfunction causing acute
covering. heart failure, RV dysfunction suggesting acute
• During scanning plastic probe covers should pulmonary embolism, and wall motion abnor-
be used for one-time use. malities indicating acute myocardial injury [8].
16 Point of Care Echocardiography in the COVID-19 Patient 169
asic Cardiac POCUS Protocol

B A. Placement of probe for PLAX
The American Society of Echocardiography
recently published a statement in support of
POCUS in patients with COVID-19. The cardiac-
specific protocol includes basic cardiac views
that many emergency physicians will be familiar
with (see Table 16.1) [5].
Basic Technique [9]

Transthoracic echocardiography requires use of
the cardiac or phased-array transducer which has
a frequency of 2 Mhz–7.5 Mhz. This transducer
is well suited to fit into the intercostal spaces and
maximize scanning area.
Parasternal Long Axis (PLAX) B. PLAX in systole

Place the transducer at the left sternal border in the
3rd–4th intercostal space with probe indicator
pointed toward the patient’s right shoulder. The
goal is to visualize the heart along its long axis
plane with the probe indicator corresponding to the
superior aspect of the heart. Ideally the LV should
appear perpendicular to the ultrasound beam. The
LV, LA, RV, LVOT, and aortic and mitral valves
should be seen. Zooming in the PLAX view can
allow for accurate measurement of the LVOT
diameter which can be used for cardiac output cal-
culations in some ultrasound machines.
Table 16.1 Basic cardiac windows/views

View Structure imaged Assessment Disease associations
Parasternal LV, RV, AV, IVS, LA, LV/RV size and function, pericardial Myocarditis, pericarditis,
long (PLAX) LVOT, MV, effusion, gross AI or AS tamponade, PE, cardiomyopathy,
pericardium ACS
Parasternal Left ventricle LV/RV size and function, pericardial
short (PSAX) Right ventricle effusion
Pericardium
Apical 4 Left ventricle LV/RV size and function, pericardial
chamber (A4C) Right ventricle effusion, gross TV or MV
regurgitation or stenosis
Subcostal IVC, LV, RV, IVC diameter and collapsibility Possible correlation with CVP
pericardium and utility in assessing volume
status
AV aortic valve, IVS intraventricular septum, LV left ventricle, RV right ventricle, LVOT left ventricular outflow tract,
MV mitral valve, TV tricuspid valve, AI aortic insufficiency, AS aortic stenosis, PE pulmonary embolism, ACS acute
coronary syndrome
170 D. Haase et al.
C. PLAX in diastole B. PSAX aortic view
C. PSAX mid-papillary view

Parasternal Short Axis (PSAX)
With the transducer in the PLAX position, rotating
the probe 90 degrees in the same axis with the indi-
cator pointed toward the patient’s left shoulder
yields the PSAX view. In this short-axis plane, the
LV and RV are predominantly seen, although
depending on where the probe is in relation to the
mitral valve and apex, different parts of the ventri-
cles can be seen. Scanning in the PSAX at the level
of the mitral valve allows visualization of the ante-
rior and posterior leaflets. Moving the probe in
plane toward the apex will first allow one to see the
papillary muscles followed by the LV apex (at
which level the RV will usually no longer be visi-
ble). The view of the LV at the level of the papillary Apical 4 Chamber (A4C)
muscles is essential for assessing global LV func- The anatomical reference for the apical views is
tion as well as regional abnormalities. on the left side of the chest near the point of maxi-
mum impulse. Starting with the transducer at this
A. Placement of probe for PSAX location and angled toward the heart with indica-
tor pointed toward the patient’s left side, the view
should be optimized and patient repositioned if
necessary, so that all four chambers of the heart
can be seen. The left-sided structures will usually
be on the right side of the image display. In nor-
mal anatomy, the LV should be larger than the RV,
and the ventricles should occupy about two thirds
of the view of the long axis of the heart with the
rest consisting of atria. Capturing a full view of
each chamber including myocardium and valves
throughout the cardiac cycle can allow for a quali-
tative assessment of function as well as quantita-
tive measurements in addition to RV specific
measurements such as TAPSE.
A. Placement of probe for A4C A. Placement of the probe for subcostal view
B. Apical 4 chamber view B. Subcostal cardiac view
C. Subcostal IVC view

Subcostal
The transducer should be placed on the patient’s
abdomen just inferior to the xiphoid process and
pointed toward the patient’s left shoulder with the
indicator pointed toward the patient’s left side. In
addition to the four chambers, the interventricu-
lar septum and RV wall thickness can be better
evaluated. Rotating the transducer 90 degrees
toward the patient’s right (indicator now pointed
up) allows for the IVC to be seen in longitudinal
orientation. IVC diameter during the respiratory
cycle can thus be evaluated both qualitatively and
quantitatively. IVC diameter should be assessed
2 cm proximal to the cavoatrial junction.
172 D. Haase et al.
Left Ventricular Function B. Reduced TAPSE

The basic cardiac views as outlined in Table 16.1
can allow for a rapid global assessment of the
major contributors to cardiac function. A qualita-
tive visual assessment of left ventricular ejection
fraction (LVEF) is the most practical method for
estimating left ventricular systolic function, and
emergency physicians with training in echocar-
diography have been shown to accurately use this
method to estimate LVEF as normal, depressed,
or severely depressed [10]. This can accurately
guide subsequent resuscitation including initia-
tion of fluid, vasopressors, or inotropic support.
Right Ventricular Function

Use of bedside echocardiography to evaluate the Pulmonary POCUS in COVID-19
right ventricle in suspected pulmonary embolism
has been well studied, and most emergency physi- Indications [5]
cians will be familiar with the classic echocardio- Pulmonary POCUS can establish and elucidate
graphic findings consistent with right ventricular diagnostic information in the emergency depart-
dysfunction in the setting of PE. Ultrasound evi- ment, including:
dence of right heart strain even in normotensive
patients with PE can predict the development of 1. Serial assessment of the severity of COVID-
PE-related shock [11]. All cardiac windows allow 19 pneumonia in conjunction with oximetry
for assessment of RV enlargement or RV dysfunc- and physical exam.
tion. In the literature, echocardiographic indicators 2. Identification of ultrasonographic features
of RV dysfunction include a RV-LV ratio of ≥1, RV with distinct disease associations or
free wall hypokinesis, tricuspid annular plane sys- diagnoses.
tolic excursion (TAPSE) < 1.0 cm, mid-RV wall (a) ARDS: subpleural consolidation, pleural
hypokinesis with apical sparing (McConnell’s thickening, parenchymal consolidation,
sign), and septal bowing into the LV (D sign), air bronchograms.
among others. Determining RV-LV ratio may be (b) Pneumonia: B lines, pleural thickening,
best assessed in the apical 4CH or parasternal long parenchymal consolidation, air
axis. Assessing TAPSE requires the apical view. bronchograms.
McConnell’s sign is best visualized in the apical (c) CHF: B lines, effusion.
view and D sign is seen in the parasternal short axis.
Pulmonary Findings
A. Normal TAPSE CT imaging has described lung lesions seen in
COVID-19 patients as peripheral ground glass
opacities seen most frequently in the posterior
and inferior parts of the lung. These areas on CT
correspond to regions of inflammation seen on
US, and the most common findings are described
below.
1. Pleural lines: These are commonly seen as

discontinuous or heterogenous. While normal
pleura is about 0.2–0.5 mm in thickness, vari-
able thickening of the pleural line to about
1–2 mm is observed. Decreased aeration of Pleural thickening

subpleural lung segments creates scatter of
the ultrasound signal leading to roughness of
the pleural line. Also, focal regions of sub-
pleural effusions can also be observed.
2. B lines: These can be used as both a qualita-
tive and quantitative measure of inflamma-
tion. Fusing of B lines to create “waterfall
sign” or “white lung sign” was associated
with more advanced disease and worsening
ARDS. The change in the number of B lines
overtime also corresponded to disease
course. Unlike cardiogenic pulmonary
edema, B lines in COVID-19 were found in
non-gravity dependent areas of the lungs Waterfall sign
more frequently.
• An example of a scoring system based on
B lines is presented by Gargani et al [12].
–– Score 0: predominant A lines or < 3 sep-
arated B lines.
–– Score 1: at least three B lines or coales-
cent B lines occupying <50% of the
screen without a clearly irregular pleu-
ral line.
–– Score 2: coalescent B lines occupying
>50% of the screen without a clearly
irregular pleural line.
–– Score 3: large consolidations (at least
>1 cm). It is useful to characterize the
consolidation (hypoechoic, tissue-like, Critical Points
air or fluid bronchogram, etc.). • While thoroughness is important, in the midst
*Presence of pleural effusion should of a highly contagious disease, we recom-
always be reported as well. mend that institutions employ a protocol that
3. Consolidations: While POCUS was good at gives them the most information while also
visualizing both subpleural and large consoli- limiting operator time in the room.
dations, it missed lesions that were fully intra- • Multiple pulmonary findings are seen in
pulmonary or apical. There was a lack of COVID-19 and their progression can be used
blood flow seen within the consolidations, to track disease progression.
which is atypical when compared to consoli- • COVID-19 patients may present with several
dations caused by pneumonia and was thought cardiac manifestations of disease all of which
to be secondary to the thickened interstitium. are potentially detected by cardiac POCUS.
174 D. Haase et al.
• Findings on cardiac POCUS in the emergency raphy in COVID- 19. J Am Soc Echocardiogr.
2020;33(10):1278–84. https://doi.org/10.1016/j.
department can greatly influence emergency echo.2020.06.009.
department therapies and potentially patient 7. Vasudev R, Guragai N, Habib H, et al. The utility of
outcomes. bedside echocardiography in critically ill COVID-19
• Volume assessment in the critically ill patients: early observational findings from three
northern New Jersey hospitals. Echocardiography.
COVID-19 patient is complicated due to con- 2020;37(9):1362–5. https://doi.org/10.1111/
current cardiac, pulmonary, and renal dys- echo.14825.
function and requires a multifaceted POCUS 8. Zhang L, Wang B, Zhou J, Kirkpatrick J, Xie M,
approach. Johri AM. Bedside focused cardiac ultrasound in
COVID-19 from the Wuhan epicenter: the role of car-
diac point-of-care ultrasound, limited transthoracic
echocardiography, and critical care echocardiography.
References J Am Soc Echocardiogr. 2020;33(6):676–82. https://
doi.org/10.1016/j.echo.2020.04.004.
1. Mayo PH, Copetti R, Feller-Kopman D, et al. Thoracic 9. Mitchell C, Rahko PS, Blauwet LA, et al. Guidelines
ultrasonography: a narrative review. Intensive Care for performing a comprehensive transthoracic echo-
Med. 2019;45(9):1200–11. https://doi.org/10.1007/ cardiographic examination in adults: recommenda-
s00134-019-05725-8. tions from the American Society of Echocardiography.
2. Peng QY, Wang XT, Zhang LN. Chinese critical care J Am Soc Echocardiogr. 2019;32(1):1–64. https://doi.
ultrasound study G. findings of lung ultrasonography org/10.1016/j.echo.2018.06.004.
of novel corona virus pneumonia during the 2019- 10. Moore CL, Rose GA, Tayal VS, Sullivan DM,
2020 epidemic. Intensive Care Med. 2020;46(5):849– Arrowood JA, Kline JA. Determination of left ven-
50. https://doi.org/10.1007/s00134-020-05996-6. tricular function by emergency physician echocar-
3. ACEP COVID-19 field guide. American College diography of hypotensive patients. Acad Emerg Med.
of Emergency Physicians https://www.acep. 2002;9(3):186–93. https://doi.org/10.1111/j.1553-
org/corona/covid-1 9-f ield-g uide/work-s afety/ 2712.2002.tb00242.x.
ultrasound-cleaning/. 11. Grifoni S, Olivotto I, Cecchini P, et al. Short-term
4. Guidelines for cleaning and preparing external- and clinical outcome of patients with acute pulmonary
internal-use ultrasound transducers and equipment embolism, normal blood pressure, and echocardio-
between patients as well as safe handling and use graphic right ventricular dysfunction. Circulation.
of ultrasound coupling gel. https://www.aium.org/ 2000;101(24):2817–22. https://doi.org/10.1161/01.
officialStatements/57. cir.101.24.2817.
5. Johri AM, Galen B, Kirkpatrick JN, Lanspa M, 12. Gargani L, Soliman-Aboumarie H, Volpicelli G,
Mulvagh S, Thamman R. ASE statement on point- Corradi F, Pastore MC, Cameli M. Why, when, and
of-care ultrasound during the 2019 novel coronavirus how to use lung ultrasound during the COVID-19
pandemic. J Am Soc Echocardiogr. 2020;33(6):670– pandemic: enthusiasm and caution. Eur Heart J
3. https://doi.org/10.1016/j.echo.2020.04.017. Cardiovasc Imaging. 2020;21(9):941–8. https://doi.
6. Jain SS, Liu Q, Raikhelkar J, et al. Indications org/10.1093/ehjci/jeaa163.
for and findings on transthoracic echocardiog-
Inter-Hospital Transfer
of the Critically Ill COVID-19
17
Patient
Adam B. Schlichting, Zeid Kalarikkal,
and Nicholas M. Mohr
Introduction care unit, or overstressed local resources, many

COVID-19 patients presenting to an ED require
The COVID-19 pandemic has unmasked several transfer to another hospital for definitive higher-
truths about the infrastructure for the delivery level care.
of care to critically ill patients throughout the The Emergency Medical Treatment and
United States. In 2020, 11 million Americans live Active Labor Act (EMTALA) was introduced in
in a county with no hospital, and 18 million more 1986 and globally defines the requirements for a
live in a county with a hospital but no intensive federally compliant transfer; there is no excep-
care unit [1]. During the COVID-19 pandemic, tion to EMTALA for the transfer of COVID-19
even large hospitals are finding that the capac- patients [2].
ity to manage such a large volume of critically Management of the critically ill COVID-19
ill COVID-19 patients for prolonged periods of patients should be initiated in the ED. Emergency
time is exceeded by simple lack of availability of department therapies are described in previous
beds, equipment, and staffing. Much of this book chapters of this book but include time-sensitive
focuses on the initial resuscitation of a critically items such as testing for both SARS-CoV-2 and
ill COVID-19 patient presenting to the emergency other etiologies of respiratory failure, manage-
department (ED), and this care should be similar ment of hypoxic respiratory failure, and initiation
regardless of a hospital’s capabilities. Due to lack of specific, time-sensitive pharmacotherapies.
of specialty resources, local lack of an intensive Key to optimal resource utilization is appropriate
triage of patients, so testing of patients for SARS-
A. B. Schlichting (*) CoV-2 plays an important role in the decision-
Medical Respiratory Intensive Care Unit, Aurora making process; a patient who tests negative for
St. Luke’s Medical Center, Aurora Critical SARS-CoV-2 may not require transfer to a spe-
Care Service, Aurora Emergency Medicine Services, cialized tertiary COVID-19 unit.
Milwaukee, WI, USA
e-mail: [email protected] Time-sensitive therapies should not be delayed
for transfer, and the need for definitive therapy
Z. Kalarikkal
Aurora Critical Care Service, Aurora Emergency after transfer should be balanced carefully with
Medicine Services, Milwaukee, WI, USA the priorities of appropriate triage and early
N. M. Mohr resuscitation. Transitioning a critically ill patient
Department of Emergency Medicine, Division of from the relative safety of an ED to the transport
Critical Care, Department of Anesthesia, University environment can be daunting. In this context,
of Iowa Carver College of Medicine,
transferring a critically ill patient from one
Iowa City, IA, USA
176 A. B. Schlichting et al.
edical facility to another is perhaps one of the

m exception of perhaps extra corporeal membrane
most common and risky procedures an emer- oxygenation (ECMO), there is little as far as spe-
gency physician performs. cialized equipment needed for the care of criti-
At the time of writing, there is very little pub- cally ill patients with COVID-19. The need for
lished literature on inter-hospital transport of the transfer of patients with critical illness secondary
critically ill COVID-19 patient. All recommenda- to COVID-19 is often determined by the need for
tions in this chapter are extrapolations of in- expertise of critical care nurses, physicians, and
hospital management of COVID-19 patients, respiratory therapists.
transport of non-COVID-19 patients, and our
collective experience to date. Nonetheless, this
chapter will present considerations for inter- nowing the Capabilities of Your
K
hospital transfer of critically ill patients with Hospital
COVID-19, outline the legal issues and require-
ments for transfer of these patients, and provide aAs a clinician, knowing the technical capabilities
framework for facilitating inter-hospital transfer and human resources of your hospital is an essen-
while maintaining safety for both the transport tial component of the daily practice of emergency
crew and patient. medicine. The capabilities of a local hospital
environment can be broadly divided into five
domains for consideration: personnel, physical
Regionalization resources, specialized life-sustaining equipment,
specialized diagnostic equipment, and special-
The Institute of Medicine (IOM) has described ized therapeutics (Table 17.1).
regionalization as the coordination of resources With COVID-19, many of the previously
to optimize condition-specific care for patients established norms have been upended. Admission
across a geographic area [3, 4]. Citing multiple of a critically ill patient that requires a higher
examples of improved outcomes, the 2006 IOM level of care than a hospital can provide places
report on the Future of Emergency Care in the the patient at risk, but early experience with con-
United States Health System recommended that tinuation of pre-pandemic transfer patterns very
the United States further develop a “coordinated, quickly resulted in overwhelming conditions at
regionalized, accountable system” for emer- tertiary referral centers. As the COVID-19 pan-
gency medical care [4]. The evidence cited by the demic evolves, we recommend close and fre-
IOM focused on explicit, formalized networks quent discussions both within hospitals and
for transferring patients with conditions includ- across referral networks. These discussions
ing trauma, ST-elevation myocardial infarction should involve both the ED and inpatient units
(STEMI), post-cardiac arrest care, and acute and have representation from nursing, respiratory
ischemic stroke. Although not included in the therapy, and bedside physicians in addition to
IOM report, explicit transfer would also apply to hospital administration. As capacity of tertiary
referral to a regional burn center. referral centers is exceeded, capabilities of even
Extrapolating from the management of these small hospitals may be required to evolve. For
multiple non-COVID-19 conditions, the manage- example, small hospitals are implementing thera-
ment of critically ill patients with COVID-19 peutic modalities such as high-flow nasal cannula
relies more on the availability of physical beds and prone positioning that were not used before
and available staffing, and less on specialized the pandemic as these patients may have previ-
equipment. The structure for the management of ously been transferred to a referral center.
most therapies for COVID-19 includes heated- On the other end of the spectrum is implemen-
high flow oxygen, prone positioning, and tation of highly specialized care with extracorpo-
mechanical ventilators, which are available at real membrane oxygenation (ECMO). A small,
most hospitals in the United States. With the critical access hospital simply cannot support the
17 Inter-Hospital Transfer of the Critically Ill COVID-19 Patient 177
Table 17.1 Five areas of assessment for understanding patient with very advanced age, underlying
local hospital environment capabilities
malignancy, or cardiac arrest [5, 6]. Due to sev-
Category Description Examples eral depictions of ECMO in the popular media,
Personnel Number of Intensivists,
families may ask early about referral to an
physicians, neurosurgeons,
advanced interventional ECMO-capable center, so knowing absolute con-
practice radiologists, traindications for ECMO therapy in your region
providers, interventional may save significant time in discussion with
nurses, support cardiologists, hand
patients and families and help refocus discussion
staff with surgeons,
specialty gastroenterologists, on what therapies are possible.
training clinical pharmacists,
respiratory therapists
Physical Number of ED Cardiac catheterization Local Management Versus Transfer
resources beds, inpatient lab, interventional
floor beds, ICU radiology suite,
beds, operating endoscopy suite Due to the volume of patients being admitted
rooms, locally as well as requiring transfer, often patients
procedural may board for hours or days prior to arrival in
suites
Advanced airway
a destination intensive care unit. Time-sensitive
Specialized Advanced
life- equipment equipment, ventilators, therapies should not be delayed until admission.
sustaining necessary for transvenous Prone positioning of patients – intubated or
equipment managing pacemakers, renal non-intubated – can markedly improve oxygen-
specific critical replacement therapies,
illnesses intra-aortic balloon
ation [7, 8]. Even in remote hospitals, if equip-
pump, extracorporeal ment is available, interventions such as heated
membrane oxygenation high-flow nasal cannula can both improve patient
Specialized Advanced Magnetic resonance comfort compared to traditional noninvasive ven-
diagnostic radiologic and imaging, ventilation/ tilation and improve oxygenation [9, 10]. Even
equipment laboratory perfusion scanning,
testing blood gas analyzer, while awaiting transport, these therapies can be
modalities mass spectrometry instituted.
Specialized Rapid Antibiotics, vasoactive For patients with acute hypoxemic respiratory
therapeutics availability of medications, factor failure secondary to COVID-19 pneumonia, there
medications replacement therapies,
and products anti-dysrhythmic
is growing support for initiation of steroids [11,
necessary for agents, blood products 12]. If steroids provide benefit based on anti-
management of inflammatory mechanisms, earlier initiation of
critically ill steroids may provide additional benefit. Delaying
patients
this impacting therapy should be avoided while
awaiting inter-hospital transport. Emergency
infrastructure to maintain an ECMO program, so physicians frequently administer steroids to criti-
knowing regionally which centers can provide cally ill patients with asthma or COPD exacerba-
this therapy is vital. Prior to consideration of tions, so early administration of steroids for a
transfer to an ECMO-capable center, knowing patient with respiratory failure due to COVID-19
the inclusion criteria and absolute and relative pneumonia is certainly feasible.
exclusion criteria for ECMO consideration is of
immense value. Although these criteria may
change with strain on the available resources and Futility Decisions
with research on use of ECMO in COVID-19
respiratory failure, being aware of current As with the inter-hospital transport of any criti-
regional ECMO practice can help inform even cally ill patient, inter-facility transfer of a critically
early transfer decision-making. For example, few ill patient COVID-19 patient must be assessed
ECMO centers would consider cannulation of a for expected benefit versus futility. Transferring
a moribund patient potentially far from their of the physician to transfer the patient to a facil-
home and family may only cause additional stress ity capable of appropriately managing his condi-
among surviving family and friends. Furthermore, tion [15–17]. With passage of EMTALA, referral
many patients prefer to die near their home and centers were also required to accept transfers of
their family [13]. The potential for dying en-route patients with life-threatening conditions with-
between hospitals can be very hard to determine, out considering the patient’s ability to pay for
but is a distinct possibility for a patient with multi- services. The Centers for Medicare & Medicaid
organ system failure secondary to intractable, Services (CMS) that enforces EMTALA has spe-
critical hypoxia being transferred may not survive cifically stated that COVID-19 does not exempt
despite all possible aggressive measures. Although physicians or hospitals from complying with
little data exist, at the time of writing, survival to EMTALA [2].
hospital discharge of COVID-19 patients who EMTALA involves several very specific defi-
underwent cardiopulmonary resuscitation for in- nitions that influence the way clinicians inter-
hospital cardiac arrest is 12% [14]. pret the law. Emergency physicians are trained
The bedside treating clinician is the best indi- to recognize an “emergency medical condition,”
vidual to determine this risk-benefit relationship, but EMTALA specifically defines this term
and even after a transfer has been arranged, futil- (Table 17.2). EMTALA also defines an appro-
ity should be reassessed in the case of clinical priate, medically indicated transfer as a transfer
decompensation. Honestly addressing family to a facility that can provide a level of care nec-
expectations can be difficult, but if a patient essary to treat a medical condition that is
decompensates after acceptance for transfer to a unavailable at the transferring facility
referral center or if a referral center declines (Table 17.3). The transferring facility is required
transfer due to futility, ensuring patient comfort to provide appropriate stabilization and resusci-
should become a key point in discussions with tation prior to transfer. “To stabilize” is defined
patients and families. as providing “medical treatment of the condi-
tion as may be necessary to assure, within rea-
sonable medical probability, that no material
he Emergency Medical Treatment
T deterioration of the condition is likely to result
and Active Labor Act (EMTALA) from or occur during the transfer of the individ-
ual from a facility.” [15] This mandate does not
The inter-hospital transfer of critically ill patients preclude transferring unstable patients, pro-
is largely defined by the 1986 Emergency Medical vided that (a) benefits of transfer outweigh risks
Treatment and Active Labor Act (EMTALA). or (b) a patient or family request transfer. For
This legislative mandate became known as the
“anti-dumping” law, as it prohibited refusal of Table 17.2 EMTALA-defined emergency medical con-
service to any patient presenting to an ED that dition [20]
receives federal payment through the Medicare “A medical condition manifesting itself by acute
program, regardless of a patient’s ability to pay symptoms of sufficient severity (including severe pain)
for services. This legislation explicitly applies to such that the absence of immediate medical attention
could reasonably be expected to result in: (i) placing
patients both with and without Medicare, mak-
the health of the individual (or, with respect to a
ing EMTALA nearly universally applicable in pregnant woman, the health of the woman or her
the United States. All patients presenting to an unborn child) in serious jeopardy, (ii) serious
ED are legally entitled to a medical screening impairment to bodily functions, or (iii) serious
dysfunction of any bodily organ or part.”
examination for emergency medical conditions
“With respect to a pregnant woman who is having
and, should an emergency medical condition contractions: (i) that there is inadequate time to effect a
be identified, appropriate stabilizing therapy. safe transfer to another hospital before delivery, or (ii)
Furthermore, if a patient requires interventions or that transfer may pose a threat to the health or safety of
therapies are not available, it is the responsibility the woman or the unborn child.” [20]
Table 17.3 EMTALA-defined appropriate transfer [20] Timing of the Transfer Process

Transferring hospital provides stabilization of the
patient and treatment, within the capacity of the There are two primary time points of consider-
sending facility, to minimize morbidity and mortality
ation for inter-hospital transfer of a critically
Receiving hospital must have capacity and qualified
personnel to manage the patient and must agree to ill patient with COVID-19. First is the decision
accept the patient in transfer by the transferring facility to initiate transfer,
Transferring hospital must send all available, and second is the actual transfer of the patient.
appropriate records and test results pertaining to the
Outside of the initial decision to initiate transfer
emergency medical condition; it is understood
documentation may not be complete at the time of of a patient after evaluation for futility of trans-
transfer port, appropriate timing of conducting the inter-
hospital transfer of a critically ill patient has
Transferring facility must select qualified personnel and
appropriate equipment, capable of responding to been a long-standing subject of debate. Factors
foreseeable deterioration during transport
affecting this timing have become more complex
during the COVID-19 pandemic. Lack of capac-
facilities that do not have a physician present, ity at tertiary receiving facilities has resulted
transfer of unstable patients to a more appropri- in multiday delays in transfer of some patients
ate medical center can also be arranged after a after the initiation of the transfer process. Once
qualified provider has discussed the case with the decision to transfer a critically ill COVID-19
the supervising physician at the transferring patient has been made and a hospital has ten-
facility. The transferring clinician must arrange tatively accepted this patient in transfer while
for the receiving hospital to accept the patient in awaiting a bed, optimal care as defined in earlier
transfer and provide appropriate medical data chapters of this book needs to be continued at the
and records. Furthermore, the transferring clini- transferring facility. Interventions including opti-
cian must certify that the benefits to the patient mal management of mechanical ventilation and
outweigh the risks of the transfer, informed con- prone positioning may result in some patients
sent of the patient or their family has been improving to the point that transfer is no longer
obtained, if possible, and an appropriately necessary. Unfortunately, some patients may also
trained, qualified provider accompanies the decompensate to a point that transfer is no lon-
patient for transfer [15]. ger indicated. Either way, communication with
Some authors continue to oppose EMTALA the receiving center is vital to communicate such
as it is an unfunded mandate, but penalties for status changes.
violation are severe. Physicians violating If there is not an expected delay in facilitating
EMTALA may be fined up to $50,000 per occur- an inter-hospital transfer of a patient, a clear dis-
rence, and hospitals in violation of EMTALA can cussion between the transferring and receiving
be subject to fines in excess of $100,000 per medical teams with regard to additional interven-
occurrence. Legally, the transferring physician is tions or diagnostic studies to be performed prior
responsible for the well-being of the patient until to transfer should be included in the handoff.
arrival of the patient at the receiving facility, Outside of procedures that may help ensure
again reiterating the importance of following a safety of the patient during transport (e.g., intu-
well-defined institutional protocol for an bation, central venous access), discussion of
EMTALA-mediated transfer. Once again, there imaging such as CT scan of the chest may be
are no exceptions to EMTALA for the inter- more rapidly accomplished at the transferring
hospital transfer of patients with COVID-19; facility and can be interpreted during the trans-
however “In the event of any EMTALA com- port. This can be particularly helpful in large,
plaints alleging inappropriate transfers or refusal integrated health systems that share electronic
to accept appropriate transfers, CMS will take medical records or imaging software.
into consideration the public health guidance in Additional factors that need to be considered
effect at the time.” [15] in making the transfer timing decision include
the distance and time to the receiving facility, ties of local inpatient centers are elucidated.
mode of transportation, and the skill set of the Absent guidance from these two sources, experi-
transporting providers. enced emergency department staff can be a useful
resource in guiding selection of a transfer desti-
nation. There may be clearly established, long-
Transfer Procedures standing transfer arrangements for critically ill
patients that have now become strained by lack of
Transferring any critically ill patient can be a capacity at receiving facilities, so again under-
complicated procedure, but transfer itself should standing regional capabilities outside of the tradi-
not be an emergency. Inter-hospital transfer may tional transfer patterns is of vital importance.
require coordination of two healthcare systems, In selecting patients appropriate for an
several healthcare providers, and a transport- EMTALA-compliant transfer, providers must be
ing agency. The transfer should be conducted explicit about the indication for transfer. For
in accordance with guidance specified through instance, a hospital without access to an intensive
federal regulation and local custom. Most of the care unit must transfer patients requiring mechani-
transfer negotiation should be conducted prior to cal ventilation. In addition, patients or families may
a transfer event through transfer agreements and request inter-hospital transfer at any time, regard-
standardized transfer procedures. less of the capabilities of the transferring center –
these transfers are permissible outside of EMTALA
mandates. In such cases, we suggest consulting
I dentify Patient Appropriate perhaps one referral center on behalf of the family
for Transfer but placing much of the responsibility of arranging
a patient or family request transfer on their shoul-
The first step in initiating transfer of a critically ill ders. Transferring a patient for a service available at
patient is identifying a patient who would benefit the local hospital without this patient request, how-
from care at another institution. The ideal trans- ever, would be a violation of federal law.
fer patient is one for whom the transferring insti-
tution is incapable of offering a specific therapy,
procedure, specialized expertise, or other capa- I nitial Discussion with Patient/Family
bility that is necessary for expeditious standard Regarding Intention to Seek Transfer
care, especially as it relates to improved survival
free from disability. During the current COVID- Prior to initiating the transfer process for a patient
19 pandemic, added to this is hospital capacity. with COVID-19 who you feel would benefit from
The medical decision to initiate a transfer for a intra-hospital transfer, we suggest mentioning to
critically ill COVID-19 patient may be obvious, the patient or family your intention. Even with
but often these patients fall into a “gray area” very specific intended benefits of a potential
where the capability of your inpatient facility to transfer, a patient or family member may outright
care for a critically ill patient is in question. For refuse transfer for a variety of reasons, possibly
example, the patients who present to the ED with fear of dying far from home [13]. By discuss-
profound hypoxia, but demonstrate early, marked ing your intention to transfer early, you may
improvement in oxygenation using noninvasive save yourself considerable time in arranging for
techniques, the so-called happy hypoxemic or transfer if the patient or family outright refuses
silent hypoxemia patients [18]. transfer. If, on the other hand, the patient or fam-
In these scenarios, early consultation with ily member desires transfer to another facility for
local inpatient physicians can help to guide services available at your hospital, we suggest
appropriate disposition. It is also critically impor- offering to discuss with an accepting physician
tant when new clinicians begin working in an ED once the patient or family identifies this individ-
that the available inpatient services and capabili- ual at their hospital of choice.
I dentify Receiving Facility We also suggest disclosing challenging family

and Discuss Case with Accepting dynamics that may impact care at the receiving
Physician facility, as this type of discussion can prepare the
care team on both sides of the transfer for
Once a patient has been identified for consider- success.
ation for transfer, the next step is identifying a
receiving hospital and clinician. For providers
unfamiliar with regional transfer patterns, an Obtain Consent for Transfer
experienced colleague or nurse can greatly help
in identifying which center to contact for transfer. After establishing a receiving hospital and
Some centers accept transfers directly for admis- accepting physician, the next step in the transfer
sion to an ICU (preferable for a patient with a process is obtaining the consent of the patient or
clear diagnosis and treatment plan), while others family. As with any medical procedure, transfer
request transfer to an emergency department for offers a patient benefits, but it also places them
further evaluation and inpatient disposition. A at unique risks. These risks may be even higher
local transfer center should have a protocol that it in critically ill patients with COVID-19 and can
uses to guide the ultimate transfer recipient. include risks of clinical deterioration, a lack of
Most tertiary referral centers have a central adequate transfer medical resources, delays in
telephone number that connects referring provid- time-sensitive care, risks of transport itself, inad-
ers to tertiary accepting physicians. In some sys- equate handoff communication, and neglected
tems, ED nursing staff or unit clerks can initiate patient preferences. Patients who are unable to
the early steps of inter-hospital transfer (e.g., fax- make their own medical decisions (e.g., uncon-
ing patient information, requesting a specialty scious patients, intubated patients receiving
clinician, evaluating tertiary center bed availabil- sedation) rely on the experience and knowledge
ity). The goal of the initial contact with the of their medical providers to advocate on their
accepting hospital is to [1] screen for the capacity behalf. Such advocacy may require that you initi-
to care for your patient (e.g., available ICU beds, ate transfer without patient or family consent.
staffing, and equipment) and [2] request consul- It is during this discussion with the patient and
tation with the accepting physician. their family that the sending providers can impact
Once the capacity and capability of a center to the expectations of care delivered at a receiving
care for your patient is established, you will be facility. For example, if the family of a critically
connected with an accepting clinician. That clini- ill COVID-19 patient is assured a patient will
cian is talking with you to screen for [1] the abil- survive by transfer to another hospital or will be
ity of his institution to care for your patient’s cannulated for ECMO on arrival at a referral cen-
problem and [2] your compliance with EMTALA ter, the expectations of the family can be unreal-
mandates. Preparing well for the telephone inter- istic, thereby placing undue strain on the
action is one successful strategy for simplifying receiving hospital before the patient has even
the transfer process. Using a checklist to guide departed in transfer.
your oral presentation may provide additional Most hospitals have documentation that must
structure and help to ease the acceptance of your be completed for a patient who will be trans-
transfer patient (Table 17.4). ferred to another hospital. That documentation is
While it is always important to share informa- mostly required by federal regulation and
tion that will aid the accepting clinician in provid- includes a transfer consent document. Figure 17.1
ing ongoing care, it is prudent to avoid discussing is an example of an EMTALA-compliant transfer
your patient’s insurance status or ability to pay for consent form. Although this document is used to
care. Focusing on medical care alone avoids the illustrate a patient’s informed consent, the docu-
impression that your patient’s transfer is noncom- ment alone is insufficient – this is only the docu-
pliant with EMTALA mandates. mentation of a conversation between a provider
Table 17.4 Structured oral presentation for transfer consultation

Checklist Example presentation
1. Introduce yourself, your location, and your role 1. Good afternoon, I’m Dr. McGillicutty, an emergency
in your medical center. physician at St. Mary’s Hospital in Springfield.
2. Introduce your patient, with relevant identifiers. 2. I’m calling you about Bart Michaels. Would you like a birth
3. Explicitly state your request. date?
4. List the most important diagnosis and the 3. I would like to transfer him to your facility for ongoing ICU
reason for transfer, along with the service you care….
are unable to provide. 4. …because he has pneumonia and I have intubated him. I
5. Present a brief synopsis of the case, including don’t have an ICU that can care for an intubated patient.
relevant vital signs and laboratory data. Detail 5. He is a 74-year-old patient from a local nursing home with
interventions you have performed and the a history of diabetes mellitus who came in with a 5-day
patient’s current status. history of progressive cough and progressive altered mental
6. Summarize the proposed method of transport status. On arrival, he was febrile to 39.1 degrees and
and any additional information that will be sent hypoxic to 78%. I tried oxygen by facemask, but he
with your patient. continued to have a respiratory rate into the 40s and was
7. Invite questions or clarifications. altered, so I just finished intubating him. His laboratory
8. Thank the accepting clinician. tests are remarkable for a white blood cell count of 18,000
9. Record the name of the accepting physician (for and a creatinine of 3.1, but his lactate is normal at 1.4, and
the transfer document). the remainder of his labs are unremarkable. He has a right
lower lobe infiltrate on his chest X-ray, and he is doing well
on the ventilator with an FiO2 of 60%. I’ve given him 2
liters of normal saline and a dose of cefepime and
vancomycin. After intubation, his vital signs have
normalized, and he is stable for transfer.
6. I will plan to send his laboratory studies, his EKG, and a
summary of his ED care with him, and I will burn his two
chest X-rays to a CD for you, too. He’ll be coming by
ground ambulance, and I think he is ready for admission to
the ICU.
7. Is there any additional information that I can get for you?
8. Thank you for your time, and let me know if there is
anything else I can do!
9. Can I get your name please as the accepting clinician?
and a patient that the risks and benefits of transfer ment for transfer of your patient to their facility.
have been discussed and the patient agrees with For the majority of inter-hospital transfers, how-
transfer. A portion of the form typically allows ever, you are the physician making such determi-
the provider to indicate when patients are unable nations, and these decisions may have significant
to consent for themselves. impact on your patient’s outcome.
The crew training component of the inter-
facility transfer cannot be underestimated.
Identify Appropriate Transfer Crew Although there have been no reviews of the
safety of inter-hospital transfer of COVID-19
The next step in safely transporting a critically patients, retrospective cohort of more than 5000
ill patient to a receiving facility is identifying urgent ground transports of non-COVID-19
the appropriate level of training for the crew to patients revealed that a critical event associated
accompany the patient, which is often closely with mechanical ventilation, hemodynamic insta-
associated with the mode of transport. Some bility, or transport duration occurred in nearly
referral centers work with affiliated transfer 1 in 15 transports [19]. An important factor in
agencies, so the referral center may help deter- predicting decompensation was the level of train-
mine the appropriate mode and staffing compli- ing of the transport crew, with significantly
Fig. 17.1 Sample EMTALA-compliant transfer document. (Forms courtesy of University of Iowa Hospitals and
Clinics)
higher odds of decompensation among patients become certified as critical care paramedics,
transferred by paramedics as compared to critical which better prepares them to provide advanced
care paramedics (OR 1.6, 95% CI 1.1–2.2) [19]. critical care transport, mainly in the inter-hospital
The transferring clinician bears the obligation environment. Critical care paramedics have
to select the team appropriate for the transfer. In enhanced training in multiple areas including
order to properly evaluate the options available, it noninvasive ventilation, advanced airway and
is very important that one understand the capa- ventilation management, chest tube maintenance,
bilities and scope of practice of the various out- central venous line maintenance, expanded phar-
of-
hospital medical professionals. There is a macologic formulary usage, and invasive hemo-
wide degree of variation in title and capabilities dynamic monitoring.
of providers between countries, so practitioners Critical care transport nurses are not defined in
should familiarize themselves with local conven- the National EMS Scope of Practice Model but are
tions. Within the United States, the clinician may essential to the critical care transport team, espe-
refer to the National EMS Scope of Practice cially in the air medical environment. These nurses
Model, which is a component of the National often come from an emergency medicine and/or
Highway Traffic Safety Administration’s EMS critical care background and have focused their
Agenda for the Future [20]. The National EMS careers on out-of-hospital care. They are experi-
Scope of Practice Model defines four levels of enced and knowledgeable in the realm of advanced
EMS licensure for out-of-hospital providers: life support to include airway, ventilation, and
emergency medical responder, emergency medi- hemodynamic management as well as the delivery
cal technician (EMT), advanced emergency med- of basic and advanced pharmaceuticals.
ical technician (AEMT), and paramedic. Some In some cases, a specialty team may be
paramedics obtain additional education to employed to conduct the transport. Of very spe-
cific pertinence to the COVID-19 patient is an Traditionally, ground ambulance services

ECMO specialty transport team. Such a team (even with advanced training and protocols) may
must be dispatched from a referral center, which not possess the level of clinical experience and/or
will likely delay arrival of the team to the patient. scope of practice that air ambulance can provide.
A transferring clinician must balance the time This difference is a reflection of the very narrow
factors with training factors for a specialty trans- practice niche for air ambulances, which were
port team, but this decision is best informed by created to transport the most critical patients with
discussion with the receiving ECMO referral time-sensitive conditions. Air ambulances are
center. almost universally staffed with a combination of
critical care paramedics, critical care transport
nurses, and occasionally physicians. These crew
Identify Appropriate Transfer Mode members can therefore provide a higher level of
critical care intervention during transit and prior
Multiple factors must be taken into consideration to departure than typical paramedic crew,
when deciding how to transfer a critically ill although the specifics of training and crew
COVID-19 patient between hospitals. Selecting resources vary for each transport service. To spe-
the most appropriate mode of transport requires cifically address this challenge, in some regions,
consideration of the acuity of illness, expected specialized ground ambulances with the specific
clinical course and interventions that will be intent of inter-hospital transfer are staffed by crit-
required en route, local EMS resources, the ical care paramedics and transport nurses.
desired speed and distance of transit (time out The most common modality for air medical
of a hospital), and the prevailing weather con- transport is rotor wing aircraft (e.g., helicopters),
ditions. While patients may be transported by which allow for easy access to hospitals and can
aircraft (rotor wing or fixed wing), ambulance be deployed quickly and efficiently. Helicopters
(advanced life support or basic life support crew), range from single-engine, single-pilot helicopters
or private vehicle, this chapter will only focus on to multi-engine, two-pilot aircraft with the capa-
aircraft and ambulance in our treatment of trans- bility to fly in poor weather conditions. Fixed-
ferring critically ill patients. wing aircraft are also used for transfers, especially
Intimately related to mode of transfer is the in remote areas far from referral centers as this
level of training of the crew. Some ground ambu- allows for a rapid transfer over long distances.
lance systems operate with paramedics at all Because of the necessity for a runway, ground
times, while others adjust the crew makeup to ambulances are used to transport patients to and
include critical care paramedics or critical care from airports/airstrips.
transport nurses based on the patient’s condition An important consideration for use of a ground
and transfer request. It is important for the physi- ambulance, especially in the setting of a long-
cian transferring a critically ill patient to under- range transfer of a patient to a distant referral
stand local practice. Paramedic ground services center from a rural location, is the time the local
are highly capable of transporting the majority of community may be without an ambulance.
critically ill patients with COVID-19, but addi- Another limitation of ground ambulances is
tional experience with high-flow nasal cannula or speed, which equates to time out of the hospital.
invasive or noninvasive mechanical ventilation Ground ambulances are slower than air ambu-
may require critical care paramedic or critical lances, but they often are stationed near the point
care transport nurse training. This crew determi- of departure. Air ambulances can travel more
nation will be best informed by close discussion quickly than ground ambulances, but there will
with the dispatch center on initial request for the likely be a longer lead time before arrival of a
transport. helicopter to pick up a patient.
The largest limitation of either ground or air matching patient characteristics with an appropri-
transportation is weather. Ground ambulances are ate transport mode, optimally trained crew, and
susceptible to road conditions such as icy roads ensuring appropriate compliance with PPE.
or floods, while air ambulance transport can be
cancelled by fog or high winds.
Other limitations on helicopter transport “Package” Patient
include large patient size, as helicopter capabili- and Documentation for Transfer
ties may limit the weight of patients that can be
safely transported. Additionally, patients with a Once a patient has been accepted for transfer
small pneumothorax can safely be transported by and a mode of transport has been defined, the
air at non-mountainous altitudes, as tube thora- astute clinician should prepare or “package” the
costomy may not be routinely necessary [21]. patient for transit. This includes both clinical
Finally, the rate of fatal crashes for rotor wing stabilization and preparation of transfer docu-
air ambulances is higher than in all sectors of mentation. EMTALA and good medical practice
aviation, and 1993 to 2002 saw an increase in the dictate that patients being transferred are stabi-
number of accidents [22]. This risk is sobering lized within the transferring center’s capabili-
and should be considered when deciding on ties. This may require endotracheal intubation,
whether air medical transport is necessary. prone positioning, volume resuscitation, initia-
Despite seemingly significant advantages, the tion of vasopressor therapy, tube thoracostomy,
list of conditions for which air-based transport or other life-saving procedures tailored to your
has demonstrated improved patient outcome is COVID- 19 patient’s condition. One challenge
short. As of publication, there are no analyses of for a transferring clinician can be anticipating
over- or underutilization of air transport of the interventions that might be required prior to
patients with critical illness due to COVID-19. arrival in the accepting center, but one should
Some suggest that air ambulances are overuti- avoid delaying stabilizing interventions solely
lized, especially in patients who do not require for transfer.
specific time-sensitive interventions [23]. For In general, ED-based interventions are safer
many conditions (even for critically ill and than interventions during transit. For example,
injured patients), ground transport offers a level both the safety of the patient and the intubating
of care and time to destination that equals that of provider will be enhanced by intubation in the
air transport – especially for those with less time- ED instead of in the much more confined setting
sensitive conditions [24–26]. in the back of an ambulance or in a helicopter.
In addition to the personal protective equip- Many patients presenting to the hospital with
ment (PPE) and ambulance decontamination COVID-19 have had several days of nausea,
involved with ground transport of a critically ill vomiting, and diarrhea, so adequate venous
COVID-19 patient, particular flight equipment access for continued volume resuscitation should
may complicate air transport. For instance, per- be secured prior to departure. If the patient is
sonal protective equipment required for flight intubated and sedated, vasoactive medications
such as a flight helmet may preclude maintaining may be required, so central access may be pre-
a proper fit of respiratory protective equipment ferred by the transport crew. Again, knowledge of
such as an N95 respirator. Simultaneous use of a local practice and preferences can greatly impact
flight helmet and powered air-purifying respira- the management of these patients, even after
tor (PAPR) is not possible. acceptance at a referral center. A transferring cli-
Moving critically ill COVID-19 patients is not nician’s objective is to make transit itself as safe
without risk to both the patient and transport crew, as possible by anticipating clinical decompensa-
but dangers can be minimized through carefully tion and emergencies prior to departure. An expe-
rienced and knowledgeable transfer crew can raise their concerns for stability of the patient dur-
also help anticipate potential decompensation ing the transport, and collaborative discussions
and recommend or request pre-departure regarding measures to improve stability, such
interventions. as endotracheal intubation, may further prevent
Preparing documentation for transfer requires decompensation. Providing this comprehensive
completing the EMTALA-compliant transfer handoff is a respectful way to ensure continuity of
form, the patient’s consent for transfer, any certi- care during the inter-hospital transfer.
fications for ambulance transfer required by your
institution, and providing records to accepting
clinicians. Timing of Departure
Compiling records to accompany a patient is
often completed in concert with nursing and clerical Ultimately, the exact time of departure from the
staff. The transferring clinician should carefully transferring facility to the receiving hospital is a
consider the data that will be required to continue nuanced decision that should be discussed as a
caring for a patient. Often, the chart is not complete team, but it is the transferring clinician who is
at the time of transfer, so one should carefully select responsible for the care and safety of the patient
the documents that will enhance the care that a until arrival at the receiving hospital. Clear
patient will receive. In most locations it is accept- communication between hospital-based provid-
able to fax or send electronic records to the receiv- ers and out-of-hospital providers is essential to
ing facility. For example, awaiting final labratory successful transfer, as inappropriate timing or
study results before the patient leaves the sending preparation for the transfer of care can lead to
hospital will only delay transfer. disastrous consequences.
Handoff to Transfer Crew Conclusions
The final aspect to the transfer is the information Emergency medicine has a long history of sta-
provided to the transport personnel. The consci- bilizing the most critically ill patients presenting
entious provider will directly provide a verbal for emergency care. As laid out in other chap-
report to the crew assuming care of a critically ill ters of this book, emergency physicians are also
patient with COVID-19 prior to transfer. This task charged with stabilizing and managing critically
should not be delegated exclusively to nursing ill patients with COVID-19, but when hospital
staff, especially for critically ill patients. Ideally, capability or capacity is surpassed, inter-facil-
the sending clinician should be present during this ity transfer of critically ill COVID-19 patients
handoff to reassess the critically ill COVID-19 becomes necessary. Inter-hospital transfer of any
patient immediately prior to departure. Establish critically ill patient is one of the highest-risk pro-
clearly who is providing medical control for cedures any patient can undergo, but emergency
the patient en route (e.g., transferring provider, physicians have honed their skills at this proce-
accepting provider, EMS medical director), and dure through decades of trauma, STEMI, acute
your expectation for potential changes of condi- stroke, and pediatrics transfers. While inter-
tion during transit. Often medical providers can hospital transfer of COVID-19 patients presents
anticipate clinical decompensation, so discuss- some new challenges, adhering with the long-
ing expectations and potential solutions with the established EMTALA framework will help guar-
transport personnel can provide some additional antee the safest arrival of a critically ill patient to
guidance. The experienced transfer crew can also a receiving hospital.
References 13. Fischer S, Min SJ, Cervantes L, Kutner J. Where do you

want to spend your last days of life? Low concordance
between preferred and actual site of death among hospi-
1. Sflerjslh J. Millions of older Americans live in coun-
talized adults. J Hosp Med. 2013;8:178–83.
ties with no ICU beds as pandemic intensifies. Kaiser
14. Hayek SS, Brenner SK, Azam TU, et al. In-hospital
Health News 2020.
cardiac arrest in critically ill patients with covid-19:
2. Emergency Medical Treatment and Labor Act
multicenter cohort study. BMJ. 2020;371:m3513.
(EMTALA) Requirements and Implications Related
15. Office UGP. 1395DD – THE PUBLIC HEALTH

to Coronavirus Disease 2019 (COVID-19) (Revised).
AND WELFARE. . United States Code 2006;2006
In: Services CfMaM, ed.2020.
Edition, Supplement 4, Title 42.
3. National Academy of Sciences IoM, Committee on
16. Kindermann S, Mutter R, Pines J. Emergency

the Future of Emergency Care in the United States
Department Transfers to Acute Care Facilities, 2009.
Health System. Hospital-Based Emergency Care: At
HCUP statistical brief #155. Rockville: Agency for
the Breaking Point: National Academies Press; 2007.
Healthcare Research and Quality. p. 2013.
4. Regionalizing Emergency Care: Workshop Summary:
17. American College of Emergency P. EMTALA and
The National Academies Press; 2010.
on-call responsibility for emergency department
5. Shekar K, Badulak J, Peek G, et al. Extracorporeal
patients. Policy statement. Ann Emerg Med. 2013;62:
life support organization coronavirus disease
441–2.
2019 interim guidelines: a consensus document
18. Tobin MJ, Laghi F, Jubran A. Why COVID-19 silent
from an International Group of Interdisciplinary
hypoxemia is baffling to physicians. Am J Respir Crit
Extracorporeal Membrane Oxygenation Providers.
Care Med. 2020;202:356–60.
ASAIO J. 2020;66:707–21.
19. Singh JM, MacDonald RD, Ahghari M. Critical

6. Shekar K, Slutsky AS, Brodie D. ECMO for
events during land-based interfacility transport. Ann
severe ARDS associated with COVID-19: now we
Emerg Med. 2014;64:9–15 e2.
know we can, but should we? Lancet Respir Med.
20. Administration NHTS. The National EMS Scope of
2020;8:1066–8.
Practice Model. 1007;DOT HS 810 657.
7. Elharrar X, Trigui Y, Dols AM, et al. Use of prone
21. Braude D, Tutera D, Tawil I, Pirkl G. Air transport
positioning in nonintubated patients with COVID-19
of patients with pneumothorax: is tube thoracostomy
and hypoxemic acute respiratory failure. JAMA.
required before flight? Air Med J. 2014;33:152–6.
2020;323:2336–8.
22. Plevin RE, Evans HL. Helicopter transport: help or
8. Coppo A, Bellani G, Winterton D, et al. Feasibility
hindrance? Curr Opin Crit Care. 2011;17:596–600.
and physiological effects of prone positioning in non-
23. Wormer BA, Fleming GP, Christmas AB, Sing RF,
intubated patients with acute respiratory failure due
Thomason MH, Huynh T. Improving overtriage of
to COVID-19 (PRON-COVID): a prospective cohort
aeromedical transport in trauma: a regional process
study. Lancet Respir Med. 2020;8:765–74.
improvement initiative. J Trauma nd Acute Care Surg.
9. Calligaro GL, Lalla U, Audley G, et al. The utility of
2013;75:92–6; discussion 6
high-flow nasal oxygen for severe COVID-19 pneu-
24. Borst GM, Davies SW, Waibel BH, et al. When birds
monia in a resource-constrained setting: a multi-centre
can't fly: an analysis of interfacility ground transport
prospective observational study. EClinicalMedicine.
using advanced life support when helicopter emer-
2020;28:100570.
gency medical service is unavailable. J Trauma Acute
10. Agarwal A, Basmaji J, Muttalib F, et al. High-flow
Care Surg. 2014;77:331–6; discussion 6–7
nasal cannula for acute hypoxemic respiratory fail-
25. Munoz D, Roettig ML, Monk L, Al-Khalidi H, Jollis
ure in patients with COVID-19: systematic reviews
JG, Granger CB. Transport time and care processes
of effectiveness and its risks of aerosolization, dis-
for patients transferred with ST-segment-elevation
persion, and infection transmission. Can J Anaesth.
myocardial infarction: the reperfusion in acute myo-
2020;67:1217–48.
cardial infarction in Carolina emergency rooms expe-
11. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect
rience. Circ Cardiovasc Interv. 2012;5:555–62.
of dexamethasone on days alive and ventilator-free in
26. Hesselfeldt R, Gyllenborg J, Steinmetz J, Do HQ,
patients with moderate or severe acute respiratory dis-
Hejselbaek J, Rasmussen LS. Is air transport of stroke
tress syndrome and COVID-19: the CoDEX random-
patients faster than ground transport? A prospec-
ized clinical trial. JAMA. 2020;324:1307–16.
tive controlled observational study. Emerg Med J.
12. Group RC, Horby P, Lim WS, et al. Dexamethasone
2014;31:268–72.
in hospitalized patients with Covid-19 – preliminary
report. N Engl J Med. 2020;384:693.
Surge Planning
18
Daniel Eraso and Brian Wright
Critical Points paces the ability to supply routine standard of

• COVID-19 is a global pandemic utilizing care. Many previous disasters presented as dis-
healthcare resources worldwide. crete time- and location-sensitive events, like
• Hospital Incident Command System should natural disasters or mass casualty trauma events.
prepare for all types of surge events (natural The COVID-19 pandemic has differed in the vol-
disaster, mass trauma, pandemic, etc.). ume of disease, the extended timeline of disease
• Distinct markers should be determined to burden, and widespread involvement of the entire
escalate capacity from conventional, to con- healthcare system. This has required a prolonged
tingency, and then to crisis as well as when to disaster response and created difficulties in local,
de-escalate. national, and international response.
• The four Ss of surge capacity: system, space, As a subset of the disaster response, surge
staff, and supply. capacity dictates how an institution adjusts
• Awareness for the physical, psychological, resource supply to match the increased demand.
and emotional toll on healthcare workers is In response to prior disasters, major organiza-
vital to provide the best possible support tions have developed coordinated action plans to
systems. meet this need. The Centers for Disease Control
and Prevention (CDC), the World Health
The COVID-19 pandemic has globally strained Organization (WHO), the Society of Critical
medical infrastructure, with waves of critically ill Care Medicine (SCCM), and the American
patients continuing to burden the healthcare sys- College of Emergency Physicians (ACEP) have
tem. With resource demands vastly outstripping provided extensive resources for institutions to
available supply, institutions have mobilized utilize in order to protect and maintain adequate
disaster responses and starting rationing resources healthcare delivery under straining circumstances
in some instances. A disaster in the context of [1–3].
healthcare systems exists anytime demand out- The National Incident Management System
(NIMS) was developed after a series of poorly
D. Eraso (*) coordinated disasters with the goal of saving lives,
University of Florida Jacksonville, property, and the environment while stabilizing
Jacksonville, FL, USA any given incident [4]. The system is targeted
e-mail: [email protected] toward any stakeholder in incident management
B. Wright including emergency management systems, local
Stony Brook University, Stony Brook, NY, USA governmental officials, and NGOs among other
190 D. Eraso and B. Wright
invested groups. It was designed to be flexible, chain of command and division of labor. This
adaptable, and scalable to any event from antici- system facilitates clear lines of communication
pated local incidents to large multistate disasters. while using a common language among disparate
The components are standardized to maintain agencies and locales (Fig. 18.1).
interoperability and allow ease of communica- The general structure calls for a single inci-
tion through a common defined language. This dent commander with multiple section chiefs
allows coordinated action and delegation of charged with specific roles. The general staff
effort among multiple organizations while main- include chiefs of operations, planning, logistics,
taining both local and hierarchical responsibility and finance/administration, while the command
and authority. Organizationally, NIMS is divided staff include a public information officer, safety
into three major components: Command and officer, and liaison officer. Farcas et al. present an
Coordination, Communication and Information ED-focused command system based on this
Management, and Resource Management. For structure with site-specific additions including
a rapid introduction, these components can be research and education [5].
categorized into Organizational Operations and After the institutional organizational struc-
Resource Management. ture is established, a full review of preexisting
surge protocols is important, with subsequent
modifications implemented based on both pro-
Organizational Operations jected and real-time data as the pandemic pro-
gresses. Multiple models exist for disease
Command burden projections, and identification of local,
regional, and national trends is critical in main-
Once an increase in disease burden is recognized, taining situational awareness for local changes
hospital leadership should adapt a disaster struc- in protocols [6]. With multidisciplinary input
ture and activate the Hospital Incident Command the surge plan should be operationalized and run
System (HICS). The HICS is a component of through both tabletop and full-scale surge drills,
NIMS and provides a structured approach to with iterative feedback refining and improving
local incident management with a clearly defined the plan [7].
Hospital incident
EM Chair
Command
ED Forward
Command
Analytics Communications
External
Administration Operations Logistics Research Education Staff Affairs
Affairs
Credential Hospital Consultants Staff Wellness/Peer

Finances Supply Chain Food
Privileges Throughput Liaison Resources Support
Infection
Health System Community Social Respiratory
EMS Patient Care Informatics Home Health Staffing Control Pharmacy
Integration Education Services Therapy
Liaison
Airway Team Ethics COVID Tent Exposures
Fig. 18.1 An ED forward command, which falls under ED command sections report to the ED forward com-
command of the HICS operations section. The same over- mand, which is functioning as the departmental incident
all hospital command structure is duplicated for commander equivalent
ED-specific demands of each role. The section chiefs for
18 Surge Planning 191
Communication and Information Personnel

Management
The chronic nature of this pandemic has demon-
The rapidity of disease progression and resource strated the critical importance of staff protection
utilization need to be matched by the frequency in maintaining effective institutional operations.
of communication. With institutional decisions There are several mitigating processes to main-
on surge protocol activation made on a daily tain this operational workforce. As discussed
basis, information dissemination is critical to above, adequate PPE supply is critical, as well as
ensuring all stakeholders share the same mental staff education on proper use. Adjustments to
model of the current state of affairs. Built within workload, shift frequency, and shift length may
NIMS and HICS are several positions with com- be necessary with increasing staff shortages. This
mand of information dissemination, both inter- must be balanced by the increased physical, men-
nally and to the public at large. The public tal, and emotional demands of working within a
information officer can disseminate information disaster mode pandemic [10].
on local conditions as well as provide community An attempt should be made to protect high-
education targeted for risk mitigation. risk workers. The presence of advanced age,
comorbid medical conditions, and immunocom-
promised state all increase the risk of morbidity
Resource Management and mortality if infected with COVID-19.
Temporary leave, furlough, or reassignment to
Supply and Assets lower-risk working conditions may be required
depending on staffing shortages.
The unexpected rise in COVID-19 cases and A clear system to monitor healthcare workers
severity of disease overwhelmed the logistical with subsequent quarantine protocols should be
systems of institutions involved in the initial out- established for both COVID-19-positive workers
break. Information from those sites has rein- and workers with high-risk exposures [11, 12].
forced the need for immediate analysis of the Under crisis staffing conditions, asymptomatic
supply chain and procurement protocols [8]. The high-risk exposure workers, and potentially con-
logistics section chief of the HICS is charged firmed COVID-19-positive workers well enough
with ordering, receiving, and storing resources. to work, may be allowed back into the work pool
A detailed evaluation of current inventory is [13]. Screening and testing of high-risk workers
critical, with concurrent knowledge of local, can minimize nosocomial spread while maintain-
regional, and national supply shortages. With ing adequate staffing [14]. An additional benefit
supply chain disruptions, orders and acquisition of readily available testing for healthcare workers
may necessarily occur outside of normal venues would alleviate the mental stress of potentially
depending on availability. Personal protective transmitting infections to family members.
equipment, critical care medications, respiratory As this crisis continues, the psychological
support equipment (noninvasive and invasive impact is becoming more apparent. Working
mechanical ventilators), and testing supplies under crisis capacity (described in more detail
have all at least intermittently been in shortage below) where workers may feel they are provid-
status nationwide. Stockpiling these resources in ing suboptimal care compared to traditional stan-
anticipation of impending surges is reasonable. dards of care has introduced a sense of moral
Methods to decrease PPE consumption have injury. Originating from military experiences,
included purchasing reusable durable respirators moral injury manifests as psychological distress
and the use of telemedicine [9]. secondary to acting against one’s ethical or moral
compass, with the long-term consequence of within a hospital. Most institutions are readily
early burnout. Early education on the mental capable of facilitating daily surge capacity based
stress and recognition of symptoms as well as on expected fluctuations in resource utilization.
readily available access to mental health resources Contingency capacity may involve deviations
should be provided [15]. from standard operating procedure while main-
Finally, the recent availability of COVID-19 taining standard of care measures. Converting
vaccines had been effective in preventing severe postanesthesia care unit (PACU) beds into ICU
illness and death from COVID-19. Like many beds, reallocation of comparably trained staff to
resources in disaster scenarios, demand has out- other units, or conservation of equipment could
paced supply. Healthcare workers should receive all fall into contingency capacity protocols. Crisis
prioritization for vaccination as a workforce pres- capacity utilizes space, staff, and supplies in a
ervation strategy. manner not consistent with standard protocols or
necessarily the expected standard of care but
attempts to provide the best care possible with
Surge Capacity the available resources at the time. Medical
decision- making shifts from patient-centered
The ability of a healthcare system to meet the care to population-centered care. As this pan-
unanticipated extraordinary increase in demand demic progresses, waves of disease burden may
defines surge capacity. Obtaining and allocating shift a system through all three capacities multi-
additional resources during an emergency ple times (Fig. 18.2).
response can be divided into four essential and While the goal is to remain in conventional
interdependent components: system, space, staff, capacity mode for as long as possible, it is crucial
and supply (the “four Ss”). System resources are to identify clear and concise triggers for exten-
described above (NIMS, HICS, etc.) and lay the sion into contingency or crisis capacity protocols.
foundation for operationalizing efficient surge Conversely, triggers for regression to conven-
capacity protocols by coordinating the other three tional capacity protocols should be clearly out-
components. Surge capacity is also defined as a lined as well.
resilient system that can absorb stressors and
events, adapt to external forces, anticipate
changes in demand, and transform structures and Space
operations to achieve these goals [16].
An important conceptual distinction of surge A detailed assessment of current space capacity
capacity involves the degree of stress imposed on is critical. Under normal operating circumstances
any given system. The stress response can be cat- an institution should be capable of an immediate
egorized into conventional capacity, contingency increase of 20% in capacity, while under contin-
capacity, and crisis capacity [17]. Conventional gency circumstances capacity should be capable
capacity is consistent with the standard of care of a 100% increase, and under crisis conditions a
and relatively normal operating procedures 200% or more increase in capacity should be
Conventional capacity Contingency capacity Crisis capacity

Phase 1
Phase 2
Phase 3
Fig. 18.2 An institutional approach to phased adjust- Clear triggers should exist for progression into the next
ments in space, staff, or supplies. Each parameter may phase (i.e., when bed capacity is at 90%, additional bed-
exist in disparate phases (i.e., adequate supplies with space will open, accompanied by a defined increase in
insufficient staff); thus there can be overlap in phases. staffing)
anticipated [18]. An immediate strategy to Physical layout of the emergency department

increase space is to decrease resource demand. can be altered to expand space and to segregate
This can be accomplished by early discharge pro- at-risk populations. Early in the pandemic, some
tocols, early ICU downgrade criteria, deferment emergency departments were separated into so
of elective procedures that require an inpatient called dirty or clean zones based on probability
bed, and establishing telemedicine capabilities to of COVID-19 infection; however as the pan-
reduce exposure, among other actions [19–21]. demic has progressed and more asymptomati-
Despite aggressive measures to reduce cally infectious patients were identified, this
demand, it should be anticipated that demand strategy became less viable. There are still con-
will exceed institutional capacity at times. siderations to be made regarding segregation of a
Alternate care sites should be identified early and respiratory population that may require interven-
evaluated for transition to active medical areas. tions in the form of nebulized medications or
Multiple factors influence site suitability includ- noninvasive ventilation [8]. Regardless of pre-
ing power, HVAC and plumbing considerations, sumed infectivity, both patient and practitioner
access to medical gases, suction, hemodynamic should always be wearing appropriate PPE,
monitoring, IT considerations including connec- which will vary per local ordinances.
tivity, as well as access to ancillary services such One approach to minimize transmission
as radiology, pharmacy, and nutrition [16]. opportunities involved establishing a forward-
Multiple sites should be evaluated for suitability facing tent for the initial triage of lower acuity
and a phased response set in place for expected patients for rapid disposition [22, 23]. Once an
rollout of additional sites based on surge volume. EMTALA-appropriate medical screening exam
Converted outpatient facilities, long-term care has been completed, patients can be safely dis-
facilities, field tents, lobbies, and auditoriums are charged without invasive workup if they meet
all potential alternate care sites that can be retro- low-risk criteria [24].
fitted for a specific task. There should be clearly The flow of critically ill patients through the
defined criteria for triggering these responses. ED will be affected by ICU bed availability.
The alternate care sites can be utilized to cohort Unfortunately, these patients can remain criti-
similar patient populations to colocate required cally ill for a prolonged period and can occupy an
resources, developing de novo ICU pods or ICU bed with the associated resources during a
long-
term care facilities, as dictated by local protracted hospitalization. One representative
needs (Fig. 18.3). study found a mean duration of mechanical ven-

Decreased utilization
x Early transfer and discharge
x Reduced or canceled elective procedures
Early identification of alternate care sites
Existing structures with intact infrastructure
x PACU
x Endoscopy suites
Alternate sites with easily modifiable infrastructure (ie clinic
space)
Open flat structures (ie
auditoriums, lobbies)
Field tents
Long care term facilities
Fig. 18.3 Space utilization in relation to demand

tilation of 14 days in COVID-19 patients requir- supplement the preexisting staff with an influx of
ing intubation [25]. Appropriate selection of practitioners. An alternate model in the emer-
patients for ICU resources and development of gency department created specialty pods for spe-
additional institutional ICU capacity is critical cialty services (surgery, cardiology, etc.) with
for ED throughput and effective patient care. appropriate patients triaged to the respective sec-
tors [23]. A fast-track area staffed primarily by
Space Checklist internists or family medicine practitioners could
• Infrastructure safely manage lower acuity presentations.
–– Electricity with backup Institutional protocols for onboarding new or
–– HVAC transferred staff should be reviewed. This would
–– Water/plumbing include emergency credentialing, streamlined
–– Waste: solid and biohazard orientations, just-in-time training, and establish-
–– Isolation/negative pressure ment of a mentor or supervisor system. Resources
• Operations are readily available for surge-specific training
–– Patient monitoring including medical student curricula, surge man-
–– Medical gases and suction agement of mechanical ventilation, and complex
–– Communication and IT task simulation [27–31]. Academic centers with
–– Proximity to ancillary staff and supplies graduate medical education programs can reas-
(radiology, pharmacy, supply) sign trainees to high-demand units while remain-
–– PPE storage and waste ing attentive to the educational mandate of the
–– Evacuation and transfer protocols institution. [32, 33]
–– Patient privacy Crisis capacity staffing pertains when any
staff are performing duties outside the normal
scope of practice. This could also include recall-
Staff ing retired practitioners or allowing subspecialist
surgeons and outpatient family practice physi-
Perhaps the most fragile resource, staffing con- cians to provide inpatient care in their respective
siderations are the major driver of expansion fields. Utilization of telemedicine resources can
capability. The widespread nature of this pan- also be considered for appropriate low acuity
demic has strained the entire global skilled medi- patients or to assist with triage or patient follow-
cal pipeline, making importation of staff from up. Telemedicine has the added benefit of pro-
outside regions less feasible. However, with sig- tecting healthcare workers with high-risk
nificant regional variations in disease burden, comorbidities and also utilizing healthcare work-
certain hotspots have been commoditized with ers with asymptomatic COVID-19 infection or
lucrative contract work, allowing a small degree those that are in a convalescent phase (Table 18.1).
of skill transfer to heavily affected areas.
Understanding the limitations of a relatively con-
strained workforce, reallocation of existing staff Supplies
is more reasonable [26].
An institutional inventory of all available staff Personal protective equipment has become the
is the initial step. Identification of nursing staff focal point in the supply chain during this pan-
previously cross-trained in high-demand special- demic, but there are other equally critical supply
ties such as critical care or emergency medicine chain links requiring protection including dura-
can create a labor pool to be activated as needed. ble medical equipment and pharmaceuticals. The
With a reduction in elective procedures and evaluation of space and staff and a thorough anal-
outpatient visits, staff from surgical specialties, ysis of current supply inventory with rapid iden-
urgent care clinics, or medicine clinics can be tification of early supply shortages are of
phased into inpatient teams. One model would paramount importance.
Table 18.1 Distribution of skill and location for aug- cists to develop alternate medications and dosing
mented staff
regimens may mitigate anticipated shortages
Conventional Normal standards of care and [36]. Discussion with hospital leadership and eth-
capacity institutional workflow
Institutional staff in normal place of
ics committee will dictate triage of care in real-
work location scenarios such as ventilator allocation or
Contingency Redistribution of similarly trained provision of care based on crisis capacity that
capacity staff into alternate care locations falls outside of normal standards of care [37].
Standard of care and scope of
practice remain intact
Institutional or outside staff
performing similar work in new llocation of Scarce Medical
A
location Resources
Crisis capacity Staff are performing duties outside
the normal scope of practice
Institutional or outside staff The allocation of scarce medical resources, or
performing new work in new rationing of care, is a complex topic that should
location be addressed early in the pandemic phase prior to
Volunteers recruited for tasks crisis capacity protocols. The primary goal is not
requiring minimal training
to withhold care, but to save the most lives pos-
sible in a population-centered approach [38]. The
Supply shortages can occur from both underlying philosophy involves what is best for
increased demand and decreased supply. Supply the community, not necessarily for the
chain disruptions can occur anywhere along the individual.
chain based on workforce and transportation One commonly referenced protocol empha-
availability, material availability, or production. sizes the triage team, the criteria for ICU admis-
This is particularly exacerbated by overdepen- sion and/or mechanical ventilation, and the
dence on imported medical goods from areas reassessment of resource need [39]. Triage teams
similarly afflicted [34]. Increases in demand are a multidisciplinary collection of interested
occur from the surge of patients with prolonged parties that applies the allocation protocol in an
hospitalizations, as well as regional stockpiling unbiased, consistent, and transparent manner.
in anticipation of supply shortages. Close com- This separation of allocation from bedside care
munication with local and national supply chains can reduce biased subjectivity, and moral distress
is essential to minimize anticipated supply from the bedside clinician having to make these
shortages. National stockpiles of equipment exist decisions.
to augment regional crises. [35] The widespread The allocation criteria for ICU admission or
nature of the pandemic has created a ubiquitous mechanical ventilation should follow pre-
demand for national resources; therefore resource prescribed measures for determining both likeli-
sparing practices should be utilized when hood of survival to hospital discharge and
possible. likelihood of long-term survival [40]. A graded or
Under contingency and crisis capacity proto- ranked score can be composed of severity of dis-
cols, institutions can address supply shortages ease (e.g., as measured by SOFA scores) and con-
through substitution of equivalent items, adapta- ditions that reduce likelihood of long-term
tion of nontraditional items, conservation via survival such as comorbid conditions [41]. The
reduced dosing or utilization, reuse of appropri- use of a graded system negates the need for abso-
ately cleaned single-use items, or reallocation of lute exclusion criteria. Advanced age should not
resources to the greater good. Adjustments in be taken as exclusion criteria per se, acknowledg-
visitor policies can have an immediate effect on ing that age is associated with comorbid
PPE consumption, as allowing even one visitor conditions.
per patient can result in increased PPE utilization Reassessment for ongoing resource utilization
by over 100%. Early consultation with pharma- is an important facet that prevents prolonged
Substitution
Adaptation
Conservation
Reuse
Reallocation
Fig. 18.4 Gradient of supply augmentation. Reallocation of supplies under triage protocols of crisis capacity
resource utilization and allows fair distribution of Supply Checklist

resources throughout the course of a pandemic
x PPE
trajectory. This reassessment should occur at
defined intervals (i.e., every 48 hours, or at Masks
48 hours and again at 120 hours) with the inten-
Gloves
tion of reexamining the appropriateness of goals
of care and whether to continue or to deescalate Face shields
care and transition to palliative care [42].
Surgical caps
When patient preference or allocation of
scarce resources precludes ICU admission or Hand sanitizer
mechanical ventilation, systems for palliative
x Medications
care need to be in place to relieve physical, men-
tal, and emotional distress. Like other finite Respiratory medications
resources during a pandemic, palliative care pro- Antibiotics
grams need surge protocols to ensure adequate
availability. Priorities for surge planning include Sedatives
widespread and well-documented advance care Analgesics
planning, identification of alternate care sites for
palliative and hospice care, and expanding pallia- Paralytics
tive care access through telehealth [43]. Antivirals
Prioritizing palliative care access ensures clini-
cians are able to continue providing maximally Vasopressors
aggressive care, even in a palliative sense (Figs. x Patient care
18.4 and 18.5).
Ventilators
Intubation equipment
Summary
Hemodynamic monitors
COVID-19 has shown the ability to overwhelm IV pumps

healthcare systems around the world regardless
Oxygen
of size or resource availability. Excess demand
for PPE, medical equipment, staff, and space x Facilities
should be anticipated early and managed proac-
Cleaning solutions
tively. This occasionally will necessitate devia-
tion from conventional operating procedures and Linens and gowns
developing novel solutions to new problems.
Potable water
Best practices include stockpiling resources,
judicious use and preservation of PPE, protection Fig. 18.5 Common supplies and equipment with
of healthcare workers, minimizing iatrogenic expected limited supply.
transmission, redeployment of non-EM and the COVID- 19 pandemic. Lancet Infect Dis.
2020;20(10):e261–7. https://doi.org/10.1016/
CCM workforce to new roles, deferring elective S1473-3099(20)30458-8.
cases, and creation of new patient care spaces. 12. Larochelle MR. "Is it safe for me to go to work?" Risk
Coordination of care within the hospital as well stratification for workers during the Covid-19 pan-
as with other institutions in the healthcare system demic. N Engl J Med. 2020;(5):383, e28. https://doi.
org/10.1056/NEJMp2013413.
and local and federal government is important. 13. https://www.cdc.gov/coronavirus/2019-n cov/hcp/
Rationing of care should only be used in extreme mitigating-staff-shortages.html.
circumstances and should be done in an equitable 14. Black JRM, Bailey C, Przewrocka J, Dijkstra KK,
and just way. The hope is that proper preemptive Swanton C. COVID-19: the case for health-care
worker screening to prevent hospital transmission.
planning and management can relegate care Lancet. 2020;395(10234):1418–20. https://doi.
rationing to the most rare clinical and disaster org/10.1016/S0140-6736(20)30917-X.
circumstances. 15. Greenberg N, Docherty M, Gnanapragasam S,

Wessely S. Managing mental health challenges faced
by healthcare workers during covid-19 pandemic.
BMJ. 2020;368:m1211. Published 2020 Mar 26.
References https://doi.org/10.1136/bmj.m1211.
16. Paganini M, Conti A, Weinstein E, Della Corte F,
1. https://www.acep.org/globalassets/sites/acep/media/ Ragazzoni L. Translating COVID-19 pandemic surge
by-m edical-f ocus/covid-1 9-n ational-s trategic- theory to practice in the emergency department: how
plan_0320.pdf. to expand structure. Disaster Med Public Health
2. https://www.who.int/publications/i/item/WHO-2019- Prep. 2020;14(4):541–50. https://doi.org/10.1017/
nCoV-hospital-readiness-checklist-2020.1. dmp.2020.57.
3. https://www.cdc.gov/coronavirus/2019-ncov/down- 17. Hick JL, Barbera JA, Kelen GD. Refining surge

loads/HCW_Checklist_508.pdf. capacity: conventional, contingency, and cri-
4. https://www.fema.gov/sites/default/files/2020-0 7/ sis capacity. Disaster Med Public Health Prep.
fema_nims_doctrine-2017.pdf. 2009;3(2 Suppl):S59–67. https://doi.org/10.1097/
5. Farcas A, Ko J, Chan J, Malik S, Nono L, Chiampas DMP.0b013e31819f1ae2.
G. Use of incident command system for disaster 18. Hick JL, Einav S, Hanfling D, et al. Surge capacity
preparedness: a model for an emergency depart- principles: care of the critically ill and injured dur-
ment COVID-19 response. Disaster Med Public ing pandemics and disasters: CHEST consensus state-
Health Prep. 2020:1–6. https://doi.org/10.1017/ ment. Chest. 2014;146(4 Suppl):e1S–e16S. https://
dmp.2020.210. doi.org/10.1378/chest.14-0733.
6. Klein MG, Cheng CJ, Lii E, et al. COVID-19 mod- 19. Kelen GD, Kraus CK, McCarthy ML, et al. Inpatient
els for hospital surge capacity planning: a systematic disposition classification for the creation of hos-
review. Disaster Med Public Health Prep. 2020:1–8. pital surge capacity: a multiphase study. Lancet.
https://doi.org/10.1017/dmp.2020.332. 2006;368(9551):1984–90. https://doi.org/10.1016/
7. Schmidt AR, Pham PK, Liu DR, Goldberg BS. Surge S0140-6736(06)69808-5.
activation by the emergency department for 20. Ross SW, Lauer CW, Miles WS, et al. Max the

COVID-19. Am J Emerg Med. 2020;38(10):2130–3. calm before the storm: tiered surgical response
https://doi.org/10.1016/j.ajem.2020.07.024. plan for novel coronavirus (COVID-19). J Am Coll
8. Faccincani R, Pascucci F, Lennquist S. How to surge Surg. 2020;230(6):1080–1091.e3. doi:https://doi.
to face the SARS-CoV-2 outbreak: lessons learned org/10.1016/j.jamcollsurg.2020.03.019.
from Lombardy, Italy. Disaster Med Public Health 21. Hollander JE, Carr BG. Virtually perfect? Telemedicine
Prep. 2020;14(5):e39–41. https://doi.org/10.1017/ for Covid-19. N Engl J Med. 2020;382(18):1679–81.
dmp.2020.64. https://doi.org/10.1056/NEJMp2003539.
9. Heslin SM, Nappi M, Kelly G, et al. Rapid creation 22. Singer AJ, Morley EJ, Henry MC. Staying ahead of
of an emergency department telehealth program dur- the wave. N Engl J Med. 2020;382(18):e44. https://
ing the COVID-19 pandemic. J Telemed Telecare. doi.org/10.1056/NEJMc2009409.
2020;1357633X20952632. doi:https://doi.org/10.117 23. Schreyer KE, Del Portal DA, King LJL, et al.

7/1357633X20952632 Emergency Department Management of the Covid-19
10. Einav S, Hick JL, Hanfling D, et al. Surge capacity pandemic. J Emerg Med. 2020;59(6):946–51. https://
logistics: care of the critically ill and injured during doi.org/10.1016/j.jemermed.2020.07.022.
pandemics and disasters: CHEST consensus state- 24. Berdahl CT, Glennon NC, Henreid AJ, Torbati SS. The
ment. Chest. 2014;146(4 Suppl):e17S–43S. https:// safety of home discharge for low-risk emergency
doi.org/10.1378/chest.14-0734. department patients presenting with coronavirus-like
11. Bielicki JA, Duval X, Gobat N, et al. Monitoring symptoms during the COVID-19 pandemic: a retro-
approaches for health-care workers during spective cohort study. J Am Coll Emerg Physicians
Open. 2020;1(6):1380–5. https://doi.org/10.1002/ surge [published online ahead of print, 2020 Oct 10].
emp2.12230. Jt Comm J Qual Patient Saf. 2020;47(1):60–8. https://
25. Gamberini L, Tonetti T, Spadaro S, et al. Factors influ- doi.org/10.1016/j.jcjq.2020.09.007.
encing liberation from mechanical ventilation in coro- 34.
Francis JR. COVID-19: implications for sup-
navirus disease 2019: multicenter observational study ply chain management. Front Health Serv
in fifteen Italian ICUs [published correction appears Manag. 2020;37(1):33–8. https://doi.org/10.1097/
in J Intensive Care. 2020 Dec 17;8(1):96]. J Intensive HAP.0000000000000092.
Care 2020;8:80 Published 2020 Oct 15. https://doi. 35. http://www.centerforhealthsecurity.org/resources/
org/10.1186/s40560-020-00499-4. COVID-19/200214-VentilatorAvailability-factsheet.
26. Aznavorian R. Successfully deploying your valuable pdf.
resources: staffing implications and prioritization dur- 36. Burry LD, Barletta JF, Williamson D, et al. It takes
ing crisis. Nurse Lead. 2020;18(6):536–8. https://doi. a village…: contending with drug shortages during
org/10.1016/j.mnl.2020.08.014. disasters. Chest. 2020;158(6):2414–24. https://doi.
27. Ashcroft J, Byrne MHV, Brennan PA, Davies
org/10.1016/j.chest.2020.08.015.
RJ. Preparing medical students for a pandemic: 37. Maves RC, Downar J, Dichter JR, et al. Triage of
a systematic review of student disaster training scarce critical care resources in COVID-19 an imple-
programmes. Postgrad Med J. 2020; https://doi. mentation guide for regional allocation: an expert
org/10.1136/postgradmedj-2020-137906. panel report of the task force for mass critical care
28. Soled D, Goel S, Barry D, et al. Medical stu-
and the American College of Chest Physicians.
dent mobilization during a crisis: lessons from a Chest. 2020;158(1):212–25. https://doi.org/10.1016/j.
COVID-19 medical student response team. Acad chest.2020.03.063.
Med. 2020;95(9):1384–7. https://doi.org/10.1097/ 38. Emanuel EJ, Persad G, Upshur R, et al. Fair allocation
ACM.0000000000003401. of scarce medical resources in the time of Covid-19.
29. Hanley ME, Bogdan GM. Mechanical ventilation in N Engl J Med. 2020;382(21):2049–55. https://doi.
mass casualty scenarios. Augmenting staff: project org/10.1056/NEJMsb2005114.
XTREME. Respir Care. 2008;53(2):176–89. 39. https://ccm.pitt.edu/sites/default/files/Univ
30. Shrestha A, Shrestha A, Sonnenberg T, Shrestha
P i t t s bu rg h _ M o d e l H o s p i t a l R e s o u r c e P o l i cy _
R. COVID-19 emergency department protocols: 2020_04_15.pdf.
experience of protocol implementation through in-situ 40. White DB, Lo B. A framework for rationing venti-
simulation. Open Access Emerg Med. 2020;12:293– lators and critical care beds during the COVID-19
303. Published 2020 Oct 16. https://doi.org/10.2147/ pandemic. JAMA. 2020;323(18):1773–4. https://doi.
OAEM.S266702. org/10.1001/jama.2020.5046.
31. Carenzo L, Costantini E, Greco M, et al. Hospital 41. https://www.health.ny.gov/regulations/task_force/
surge capacity in a tertiary emergency referral Centre reports_publications/docs/ventilator_guidelines.pdf.
during the COVID-19 outbreak in Italy. Anaesthesia. 42. Swiss Academy Of Medical Sciences. COVID-19

2020;75(7):928–34. https://doi.org/10.1111/ pandemic: triage for intensive-care treatment under
anae.15072. resource scarcity (3rd, updated version). Swiss Med
32. Meo N, Kim CS, Ilgen JS, Choe JH, Singh N, Joyner Wkly. 2020;150:w20401. Published 2020 Nov 12.
B. Redeploying residents and fellows in response to https://doi.org/10.4414/smw.2020.20401.
COVID-19: tensions, guiding principles, and les- 43. Abbott J, Johnson D, Wynia M. Ensuring adequate
sons from the University of Washington. J Grad Med palliative and hospice care during COVID- 19
Educ. 2020;12(6):678–81. https://doi.org/10.4300/ surges. JAMA. 2020. https://doi.org/10.1001/
JGME-D-20-00430.1. jama.2020.16843.
33. Kim CS, Meo N, Little D, et al. Bracing for the storm:
one health care system's planning for the COVID-19
Surgical Emergencies
19
T. Shane Hester
Critical Points to these challenges. Surgeons around the world

• Surgical emergencies should proceed in have grappled with how to deliver the best care
patients with COVID-19 or if delay for testing to their patients during this time all while main-
may cause harm while appreciating there may taining a safe environment for the healthcare pro-
be increased perioperative risk and while viders. As we know, during a pandemic surgical
maintaining a safe environment for emergencies, including trauma, still exist and
personnel. need to be dealt with in a way that is both effec-
• In patient positive for COVID-19 with a surgi- tive and safe for the patients and the healthcare
cal issue, surgery should be delayed or man- team. Furthermore, there are specific surgi-
aged nonoperatively until recovered from cal issues related to COVID-19 and its systemic
COVID-19 if possible. effects. The factions of patients can broadly be
• Patients pending a COVID-19 test result, or grouped into three categories: (1) patients with
who are unable to be tested, should be treated COVID-19 presenting with a surgical emergency,
as if they are positive, and personnel should (2) patients with COVID-19 presenting with
have the proper PPE in place. symptoms as a result of the virus, and (3) patients
without COVID-19 presenting with a surgical
emergency.
Introduction
COVID-19 has brought with it a multitude of I mpact of COVID-19 on Patients

challenges – from the specific care related to Requiring Surgery
the patient with COVID-19 infection to how to
deliver care to patients with other medical condi- During the evolution of this pandemic, it has
tions during this time. Additionally, the dangers become clear that those patients positive for
to which healthcare workers are exposed has SARS-CoV-2 may develop acute issues, both
been brought to the forefront, along with both the related and unrelated to SARS-CoV-2, that
struggles and importance of personal protective require emergency evaluation. Many of these
equipment. The field of surgery is no exception patients will have a surgical issue and require
a consultation with a surgeon. It is important
T. Shane Hester (*) to appreciate that patients that are positive for
University of Florida College of Medicine – SARS-CoV-2 have an increased risk of postop-
Jacksonville, Jacksonville, FL, USA erative complications [1]. A majority of reported
200 T. Shane Hester
complications are related to pulmonary sequelae screened for symptoms and undergo testing for
and an overall increased risk of postoperative SARS-CoV-2 prior to surgery. Patients without
mortality [1]. symptoms of COVID-19 requiring emergent or
Postoperative pulmonary complications urgent surgery should undergo SARS-CoV-2
include a vast spectrum of diagnoses from atelec- testing as long as this can be expedited and the
tasis to severe ARDS. Prior to the pandemic, the delay will not cause harm to the patient. Patients,
incidence of postoperative pulmonary complica- in whom the surgeon has determined surgery can-
tions has been estimated to be between 6% and not be delayed for testing, should proceed with
60%, depending on the definitions used [2–4]. surgery, taking the appropriate precautions. The
When the more severe pulmonary complica- patient should be made aware of the increased
tions were explored, the estimated incidence was risk if there is an underlying SARS-CoV-2 infec-
about 2–4% [4]. There have been several factors tion [6, 7] (Table 19.1).
identified that can be used to predict postopera-
tive pulmonary complications including patients
older than 60 years of age, history of COPD, mergency Surgery in Patients
E
smoking, renal insufficiency, and low albumin with COVID-19
[4]. Additionally, the type of surgery, along with
the level of urgency, increases the risk of post- When considering emergency surgery for patients
operative complications [2, 4]. Based on our who have been infected with SARS-CoV-2, the
current knowledge of the physiologic effects of surgeon must carefully consider the risks and
the SARS-CoV-2 virus, it is easy to see how one benefits to the patient as well as the risk to the
might anticipate an increased risk of pulmonary healthcare team. One must carefully consider if
complications in this population. One interna- postponement of the surgical procedure is pos-
tional multicenter cohort study looking at patients sible, which would reduce the risk of exposure to
with a perioperative diagnosis of SARS-CoV-2 staff as well as reduce the significant risk of peri-
showed a rate of pulmonary complications of operative complications related to SARS-CoV-2
approximately 50% for patients who had either to the patient. If it is determined that emergency
elective or emergency surgery [5]. The types of surgery is necessary, the increased risk of peri-
pulmonary complications included pneumonia, operative complications should be discussed with
ARDS, and unexpected postoperative ventila- the patient or the patient’s healthcare surrogate.
tion. More concerning is the significant increase Additionally, the minimum number of healthcare
in mortality rate of 38% in those patients with staff needed to safely care for the patient should
a postoperative pulmonary complication, com- be involved, especially during the time of intuba-
pared to 9% in the patients without a postopera- tion or other aerosolizing procedures. The appro-
tive pulmonary complication [5]. priate PPE, summarized in Table 19.2, should be
worn by all staff caring for patients infected with
SARS-CoV-2 [6–8].
Patient Preparation for Surgery
Many patients with COVID-19 are asymptomatic trategy for Common Surgical

S
or have mild symptoms that may go unrecog- Issues During the Pandemic
nized; however, these patients continue to carry
an increased risk of postoperative complications Many patients presenting to the emergency
[1]. Patients with unrecognized infections also department with a surgical problem are treated
place the healthcare providers at significant risk with an urgent as opposed to emergent surgery.
for contracting the virus. In areas where there is These include common diagnoses such as acute
local or regional presence of SARS-CoV-2, all appendicitis, acute cholecystitis, and abscesses.
patients scheduled for elective surgery should be For these patients, in whom time allows, testing
19 Surgical Emergencies 201
Table 19.1 Recommendations based on surgical acuity
• Proceed to OR in compliance with guidelines for COVID-19 postive patients

Emergent surgery • Patient should be aware of increased perioperative risk if SARS-CoV-2 incfection present
• Obtain COVID-19 test prior to proceeding to OR (as long as this can be done in a time that does not
negatively impact the patient
Urgent surgery
• If unable to obtain test review imaging to evalute for signs of COVID-19 infection
• proceed to OR in complicance with guidelines for COVID-19 positive patient
• patient should be aware of increased risk if SARS-CoV-2 infection present
• Obtain COVID-19 test

• if negative proceed with surgery
Elective surgery • if positive delay surgery until the patient is no longer infectious and has demonstrated recovery from
COVID-19
Table 19.2 Recommended PPE during the treatment of complications in patients with COVID-19, care-
patients with suspected or confirmed COVID-19 [8] ful consideration should be given to nonoperative
N95 respirator or higher management [9]. Although antibiotic choice is
Eye protection – goggles or face shield not standardized, most trials used 1–3 days of IV
Clean, non-sterile gloves antibiotics followed by oral antibiotics for up to
Clean isolation gown
10 days. The antibiotic regimen should have activ-
ity against Streptococcus, Enterobacteriaceae,
for SARS-CoV-2 should be performed prior to and anaerobes [11–13].
determining the best plan of care. For patients Unstable patients with a free perforation of
who are positive for COVID-19, nonoperative the appendix and generalized peritonitis should
management is preferred if possible [9]. The plan undergo emergent surgery taking the precau-
of care must be made in conjunction with the tions as listed above. Stable patients infected
consulting surgeon, as there is no substitute for with SARS-CoV-2, with perforated appendici-
sound surgical judgment in determining the best tis, should be considered for nonoperative man-
plan of care for a surgical disease. agement. Nonoperative management includes
antibiotics, fluid resuscitation, bowel rest, and
percutaneous drainage of any accessible abscess.
Appendicitis Patients who fail a trial of nonoperative manage-
ment should proceed to surgery with the appro-
Laparoscopic appendectomy continues to be priate precautions in place.
the treatment of choice in patients with acute
uncomplicated appendicitis. There has been

increasing interest in nonoperative manage- Acute Cholecystitis
ment for uncomplicated appendicitis. There is
evidence to suggest that the majority of patients Laparoscopic cholecystectomy remains the treat-
with acute uncomplicated appendicitis can ini- ment for acute cholecystitis. Otherwise healthy
tially be treated successfully with nonoperative patients with acute cholecystitis should undergo
management, thus avoiding surgery during the surgery; however, in patients with COVID-19
initial admission. There is an increased risk of infection, the risk of surgery must be weighed
recurrent appendicitis especially in patients with carefully. A trial of nonoperative management
an appendicolith on initial imaging [10]. Due to with antibiotics may allow for a delay in surgery
the significantly increased risk of perioperative in patients who are deemed to be high risk for
202 T. Shane Hester
surgery [9]. Additionally, cholecystostomy tube urgical Issues as a Sequelae

S
placement has been used in critically ill patients of COVID-19
unfit for surgery. This can be considered as an
alternative to surgery, but it must be kept in mind Typically COVID-19 is characterized by respira-
that placement of a cholecystostomy tube carries tory symptoms, fevers, and body aches, but there
with it a high morbidity and mortality. Patients have been reports of gastrointestinal symptoms
with symptomatic cholelithiasis and COVID- as well [16–19]. These most often include nau-
19 should delay surgery until recovered from sea, vomiting, and diarrhea; however, in a small
COVID-19 [9]. number of patients, significant abdominal pain
may occur. The SARS-CoV-2 enters and repli-
cates into the cells by binding to its angiotensin-
Abscesses and Soft Tissue Infections converting enzyme 2 receptors, which are
expressed in type 2 alveolar cells. There is also
Often perianal abscesses are superficial, allow- a high level of expression in epithelial cells
ing for bedside drainage with local anesthesia. throughout the GI tract, which may account for
If adequate drainage cannot be completed with some of the symptoms [16]. Abdominal pain
beside drainage due to the location or depth of may be the only symptom related to a COVID-19
the abscess cavity, then the patient should pro- infection, but often with further inquiry, patients
ceed to the operating room for drainage. Careful will report some respiratory symptoms. It is
consideration should be given to alternatives to important to include a differential diagnosis of
general anesthesia which may avoid intubation, COVID-19 in patients that present to the emer-
such as sedation or regional anesthesia, so long gency department with GI symptoms because
as adequate drainage can be performed safely. they often appear early and may worsen during
Patients with a necrotizing soft tissue infection the course of disease. A meta-analysis of obser-
should proceed emergently to the operating room vational studies showed a pooled prevalence rate
for debridement. Delay in these patients leads to of 9% for all the GI symptoms including diar-
increased loss of tissue as well as increased mor- rhea, nausea/vomiting, and abdominal pain [16].
bidity and mortality [14, 15]. It is important to recognize GI symptoms as a
potential indicator of a patient with COVID-19 to
allow for the appropriate treatment plan as well
Bowel Obstruction as to ensure the safety of the healthcare workers
who could potentially be exposed if a diagnosis
Small bowel obstructions can often be treated of COVID-19 was not made.
with a trial of nonoperative management with As the virus infects the epithelial cells of the
bowel rest and decompression. Indications for GI tract, cytokines are released causing acute
proceeding directly to surgery include evidence intestinal inflammation characterized by the pres-
of compromised bowel, incarcerated/strangulated ence of neutrophils, macrophages, and T cells.
hernia as a cause of the obstruction, closed-loop This is thought to account for the majority of
obstruction, and volvulus. As always, the deci- GI-related symptoms. Often the abdominal pain
sion to proceed with nonoperative treatment must associated with COVID-19 is nonsurgical; how-
be made in conjunction with a surgeon. Patients ever, there have been patients who required emer-
with COVID-19 and a bowel obstruction requir- gency surgery as a result of complications from
ing surgery should proceed, but the increased COVID-19 [20]. Cross-sectional imaging is the
risk of perioperative complications should be modality of choice in further evaluating abdomi-
discussed with the patient or their caregiver. nal pain, and it also allows for partial visualiza-
tion of the lung fields. No acute abnormality is care may lead to an increase in the risk of adverse
predominantly seen on the cross-sectional imag- outcomes for the patient. As always, patients pre-
ing; however, additional findings have included senting with surgical conditions should be evalu-
bowel wall thickening, pancreatitis, appendicitis, ated by a surgeon to determine the best course
solid organ infarction, pneumatosis, and portal of action. When developing a plan of care, it is
venous gas [21, 22]. important to consider the risk and benefits of the
COVID-19 has been associated with a hyper- management options, risk to healthcare provid-
coagulable state, which has been presumed to ers, and resource utilization. In general, for aver-
lead to small-vessel thrombosis resulting in the age risk patients without COVID-19, presenting
related image findings. Pathology results from with an urgent or emergent surgical condition,
patients requiring emergency surgery for bowel the patient should undergo surgery if delaying
ischemia with COVID-19 have demonstrated the procedure is likely to prolong hospitalization,
fibrin thrombus formation in the arterioles increase the likelihood of readmission, or cause
[20, 23]. An early diagnosis of acute intestinal harm to the patient [9].
ischemia may allow for emergent laparotomy and
resection of ischemic bowel; however, a delay in
diagnosis can often be fatal. Additionally, acute Trauma
limb ischemia is an important consideration for
patients with COVID-19. There have been many The use of personal protective equipment has
reports of COVID-19 patients developing acute always played an important role in the care of
limb ischemia, many of whom have no prior his- trauma patients. These patients often arrive with
tory of peripheral vascular disease [24, 25]. a multitude of injuries, many requiring aerosol-
izing procedures, including intubation, chest
tube placement, and cricothyroidotomy. The
Emergency Surgery in Non- COVID- 19 status of the traumatically injured
COVID-19 Patients During patient is not immediately known; however, the
the Pandemic care cannot be delayed. Due to this uncertainty,
it is imperative for the healthcare team to have
As this pandemic has continued to worsen, so adequate personal protective equipment while
much of the medical focus surrounds SARS- caring for these patients. The appropriate PPE for
CoV-2. However, a plethora of patients without a trauma resuscitation has traditionally included
active SARS-CoV-2 infections are continuing to gown, gloves, and mask. Due to the unknown
present to the local emergency departments with viral status of these patients and the need to
other acute issues. It is extremely important to respond quickly to the injuries with which they
acknowledge that there may be new factors pres- present, healthcare providers should act as if
ent that may affect the care of these patients as all trauma patients are COVID-19 positive until
well as their outcomes, from direct and indirect proven otherwise, and therefore, don N95 masks
effects of this pandemic. For example, many and eye protection in addition to standard PPE
patients have delayed seeking medical attention [26]. Appropriate measures must also be taken
due to a fear of contracting the virus or as a result during the transportation of these patients to
of financial strain, which many people are facing other areas of the hospital such as the CT scanner,
during this pandemic. Additionally, many medical interventional radiology, the OR, etc. Movement
offices have decreased the number of in-person throughout the hospital should be limited for
visits significantly which has caused another bar- patients with a positive or unknown COVID-
rier to care for many people. This delay in seeking 19 status. When transportation is necessary, the
204 T. Shane Hester
patient should wear a face mask throughout the infection-control-recommendations.html. Accessed 2

Jan 21.
transport process, and intubated patients should 9. American College of Surgeons. COVID 19: elective
have a HEPA filter connected between the bag- case triage guidelines for surgical care. 2020. Available
valve-mask device and the patient [7, 27]. In the at: https://www.facs.org/covid-19/clinical-guidance/
event the patient’s condition warrants emergent elective-case/emergency-surgery.
10. Flum DR, Davidson GH, Monsell SE, Shapiro NI,
surgery, the trauma surgeon should initiate safe Odom SR, Sanchez SE, et al. A randomized trial com-
transfer to the operating room without delay [26]. paring antibiotics with appendectomy for appendici-
The operating room staff should be aware of the tis. N Engl J Med. 2020;383(20):1907–19.
patient’s unknown or positive status, and the 11. Di Saverio S, Sibilio A, Giorgini E, Biscardi A, Villani
S, Coccolini F, et al. The NOTA study (non operative
appropriate precautions should be taken. treatment for acute appendicitis): prospective study
on the efficacy and safety of antibiotics (amoxicillin
and clavulanic acid) for treating patients with right
References lower quadrant abdominal pain and long-term follow-
up of conservatively treated suspected appendicitis.
Ann Surg. 2014;260(1):109–17.
1. Knisely A, Zhou ZN, Wu J, Huang Y, Holcomb
12. Sippola S, Haijanen J, Grönroos J, Rautio T,

K, Melamed A, et al. Perioperative morbidity and
Nordström P, Rantanen T, et al. Effect of oral
mortality of patients with COVID-19 who undergo
moxifloxacin vs intravenous ertapenem plus oral
urgent and emergent surgical procedures. Ann Surg.
levofloxacin for treatment of uncomplicated acute
2021;273(1):34–40.
appendicitis: the APPAC II randomized clinical trial.
2. Smetana GW, Lawrence VA, Cornell JE, American
JAMA. 2021;325(4):353–62.
College of Physicians. Preoperative pulmonary risk
13. Harnoss JC, Zelienka I, Probst P, Grummich K,

stratification for noncardiothoracic surgery: system-
Müller-Lantzsch C, Harnoss JM, et al. Antibiotics
atic review for the American College of Physicians.
versus surgical therapy for uncomplicated appendici-
Ann Intern Med. 2006;144(8):581–95.
tis: systematic review and meta-analysis of controlled
3. Canet J, Gallart L, Gomar C, Paluzie G, Vallès J,
trials (PROSPERO 2015: CRD42015016882). Ann
Castillo J, et al. Prediction of postoperative pulmo-
Surg. 2017;265(5):889–900.
nary complications in a population-based surgical
14. Sartelli M, Malangoni MA, May AK, Viale P, Kao LS,
cohort. Anesthesiology. 2010;113(6):1338–50.
Catena F, et al. World Society of Emergency Surgery
4. Arozullah AM, Daley J, Henderson WG, Khuri
(WSES) guidelines for management of skin and soft
SF. Multifactorial risk index for predicting postop-
tissue infections. World journal of emergency surgery.
erative respiratory failure in men after major noncar-
2014;9(1):57.
diac surgery. The National Veterans Administration
15. Hadeed G, Smith J, O'Keeffe T, Kulvatunyou N,

Surgical Quality Improvement Program. Ann Surg.
Wynne J, Joseph B, et al. Early surgical intervention
2000;232(2):242–53.
and its impact on patients presenting with necrotizing
5. Nepogodiev D, Breen KA, Di Saverio S, Pata F,
soft tissue infections: a single academic center experi-
Ashoush FM, Babu BH, et al. Mortality and pulmo-
ence. J Emerg Trauma Shock. 2016;9(1):22–7.
nary complications in patients undergoing surgery
16.
Rokkas T. Gastrointestinal involvement in
with perioperative SARS-CoV-2 infection: an inter-
COVID-19: a systematic review and meta-analysis.
national cohort study. The Lancet (British edition)
Ann Gastroenterol. 2020;33(4):355–65.
2020;396(10243):27–38.
17. Suresh Kumar VC, Mukherjee S, Harne PS, Subedi
6. Moletta L, Pierobon ES, Capovilla G, Costantini
A, Ganapathy MK, Patthipati VS, et al. Novelty in
M, Salvador R, Merigliano S, et al. International
the gut: a systematic review and meta-analysis of the
guidelines and recommendations for surgery during
gastrointestinal manifestations of COVID-19. BMJ
Covid-19 pandemic: a systematic review. Int J Surg.
Open Gastroenterol. 2020;7(1):e000417. https://doi.
2020;79:180–8.
org/10.1136/bmjgast-000417.
7. Coimbra R, Edwards S, Kurihara H, Bass GA, Balogh
18. Hadi A, Werge M, Kristiansen KT, Pedersen UG,

ZJ, Tilsed J, et al. European Society of Trauma and
Karstensen JG, Novovic S, et al. Coronavirus dis-
Emergency Surgery (ESTES) recommendations for
ease-19 (COVID-19) associated with severe acute
trauma and emergency surgery preparation during
pancreatitis: case report on three family members.
times of COVID-19 infection. Eur J Trauma Emerg
Pancreatology. 2020;20(4):665–7.
Surg (Munich : 2007). 2020;46(3):505–10.
19. Ahmed AOE, Badawi M, Ahmed K, Mohamed

8. Center for Disease Control and Prevention. Interim
MFH. Case report: COVID-19 masquerading as
infection prevention and control recommendations
an acute surgical abdomen. Am J Trop Med Hyg.
for healthcare personnel during the coronavirus dis-
2020;103(2):841–3.
ease 2019 (COVID-19) pandemic. 2021; Available
20. Besutti G, Bonacini R, Iotti V, Marini G, Riva

at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/
N, Dolci G, et al. Abdominal visceral infarction
in 3 patients with COVID-19. Emerg Infect Dis. 2 5. Lari E, Lari A, AlQinai S, Abdulrasoul M, AlSafran
2020;26(8):1926–8. S, Ameer A, et al. Severe ischemic complications
21. Bhayana R, Som A, Li MD, Carey DE, Anderson in Covid-19—a case series. Int J Surg Case Rep.
MA, Blake MA, et al. Abdominal imaging findings 2020;75:131–5.
in COVID-19: preliminary observations. Radiology. 26.
American College of Surgeons Committee on
2020;297(1):E207–15. Trauma. Maintaining trauma center access and care
22. Shiralkar K, Chinapuvvula N, Ocazionez D. Cross- during the COVID-19 pandemic: guidance docu-
sectional abdominal imaging findings in patients with ment for trauma medical directors. 2020; Available
COVID-19. Cureus. 2020;12(8):e9538. at: https://www.facs.org/quality-programs/trauma/
23. Cheung S, Quiwa JC, Pillai A, Onwu C, Tharayil maintaining-access.
ZJ, Gupta R. Superior mesenteric artery throm- 27. Heffernan DS, Evans HL, Huston JM, Claridge JA,
bosis and acute intestinal ischemia as a conse- Blake DP, May AK, et al. Surgical Infection Society
quence of COVID- 19 infection. Am J Case Rep. Guidance for operative and peri-operative care of
2020;21:e925753. adult patients infected by the severe acute respiratory
24. Castro RA, Frishman WH. Thrombotic complica-
syndrome coronavirus-2 (SARS-CoV-2). Surg Infect.
tions of COVID-19 infection: a review. Cardiol Rev. 2020;21(4):31–308.
2021;29(1):43–7.
Index
A Corticosteroids, 15, 154

Acute ischemic stroke (AIS), 144 COVID-19, 1, 87, 111, 114
Acute kidney injury (AKI), 111 airway management, 12, 76, 79, 80
Acute respiratory distress syndrome (ARDS), 11, 49, 50, anticoagulation, 119
73, 78, 114, 131, 132 breathing, 12, 13
Aerosol, 4 cardiac arrest, 77
Aerosol generating medical procedures (AGMPs), 6, cardiac issues, 89
25, 27 cardiac perspective, 90–92
Airway management, 79, 82 cardiopulmonary resuscitation, 15
Airway pressure release ventilation (APRV), 56 circulation, 13, 14
Alanine aminotransferase (ALT), 36 clinical manifestations, 116
Ambulance, 184, 185 clinical presentations, 7
Angiotensin-receptor blocker (ARB), 82 critically ill, 14
Anosmia, 142 drug issues, 93, 94
Antibody dependent enhancement (ADE), 164 emergency clinicians, 13
Arrhythmias, 89, 90 emergency department, 12, 13, 33
Autoimmune disease, 35 community, 33, 34
healthcare setting, 34
imaging, 37, 38
B laboratory, 35–37
Bag-valve mask ventilation (BVM), 76 patient presentation, 35
Bilevel positive airway pressure (BiPAP), 44 SARS-CoV-2, 39, 40
Bowel obstruction, 202 epidemiology, 1, 2
Breathing, 12 hemodynamics, 80, 81
Bronchoscopy, 6 intra-arrest management, 75, 76
kidney dysfunction, 113, 114, 116
neurologic prognosis, 81, 82
C pathophysiology, 87, 88
Cardiopulmonary bypass (CPB), 64 pre-hospital considerations, 73, 74
Cardiovascular illness, 99 presentation, 88–90
management, 102 remdesivir, 119
pathophysiology, 100, 101 risk factors, 8, 15
risk factors, 100 symptoms, 7
Centers for disease control and prevention treatment, 92, 93, 117, 118
(CDC), 189 ventilation goals, 80
Chest compression, 75 ventilator management, 80
Chest radiography (CXR), 37 viral shedding, 6
Chronic kidney disease (CKD), 118 viral transmission, 4, 6
Chronic respiratory disease, 35 virology, 2–5
Cirrhosis, 126 Covid-19-associated coagulopathy (CAC), 131
Coagulopathy, 13 Cyanosis, 35
Coronavirus, 1–3 Cytokine storm, 87, 90
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature 207
Switzerland AG 2021
https://doi.org/10.1007/978-3-030-85636-6
208 Index
D liver transplantation, 126, 127

D-dimer, 132, 134 NAFLD, 126
Delirium, 35 pathophysiology, 124
Doffing, 24 preexisting liver disease, 125
Donning, 24 Hepatitis, 126
Hepatotoxicity, 127, 128
High efficiency particulate air (HEPA), 76
E High flow nasal cannulas (HFNC), 50
Ebstein-Barr Virus (EBV), 36 Human immunodeficiency virus (HIV), 36
Echocardiography, 167
left ventricular function, 172
POCUS, 168, 169 I
pulmonary findings, 172, 173 Immunosuppression, 35
right ventricular function, 172 Inflammation, 99, 102
safety considerations, 168 Inter-hospital transfer
subcostal, 171 COVID-19, 175, 176
Emergency clinicians, 12, 13 capabilities, 176, 177
Emergency medical treatment and active labor act EMTALA, 178, 179
(EMTALA), 175 futility decisions, 178
Encephalopathy, 143 local management versus transfer, 177
Endothelial cells, 99 regionalization, 176
Endotracheal intubation, 6 transfer procedures, 179–186
Extracorporeal membrane oxygenation (ECMO), 63, 176 Intracranial hemorrhage, 146
complications, 69 Isolation gowns, 21
considerations, 69, 70
contraindications, 68
fundamental management, 68, 69 L
history, 64 Lactate dehydrogenase (LDH), 36
indications, 66, 67 Lateral-flow assays (LFA), 40
principles, 64–66
M
F Mechanical ventilation
Focal segmental glomerulosclerosis (FSGS), 114 COVID-19, 49
complications, 57, 58
FiO2, 53
G HFNC, 50
Guillain-Barré syndrome (GBS), 141, 146 limit airway pressures, 54
limited resources, 58
mechanical power, 55, 56
H oxygenation targets, 53
Heated high-flow nasal cannula (HFNC), 44 PEEP, 53
Helicopter, 184, 185 principles, 51
Hematologic emergencies, 131, 132 P-SILI, 50
anticoagulation, 135–137 respiratory rate, 52
antiplatelet agents, 137 tidal volume, 54, 55
decision tools, 133, 134 ventilator-induced lung injury, 52
diagnostic strategy, 135 lung-protective strategy, 51
imaging, 134 Microthrombi, 131
laboratory markers, 134 Miller Fisher syndrome, 146
macrothrombi, 135 Monoclonal antibodies (mAbs), 151
thrombotic events, 132, 133 Mortality, 111, 117
Hemodynamic goals, 82 Myocarditis, 90
Hemoptysis, 35
Hepatic illness
COVID-19, 123 N
cirrhosis, 126 Neurologic illnesses, 141
current therapies, 127, 128 antiepileptic drugs, 145
laboratory findings, 124, 125 central nervous system, 143
liver function abnormalities, 127 endotheliopathy, 142
Index 209
immunothrombosis, 142, 143 Powered air purifying respiratory (PAPR), 22, 23

intracranial hemorrhage, 145, 146 Pressure regulated volume control (PRVC), 56
ischemic stroke, 144, 145 Protective equipment (PPE), 12
neurotropism, 142 Pulmonary embolism (PE), 14
peripheral nervous system, 146
seizures, 144
Neurologic prognosis, 82 R
Non-alcoholic fatty liver disease (NAFLD), 126 Remdesivir, 15, 119, 151, 152
Non-alcoholic steatohepatitis (NASH), 126 Renal replacement therapy (RRT), 117
Noninvasive positive pressure ventilation (NIPPV), 44, Renin-angiotensin system (RAS), 50
45, 50 Return of spontaneous circulation (ROSC), 76
Noninvasive respiratory support, 43 Reverse transcriptase-polymerase chain reaction
aerosol generation, 45 (RT-PCR), 39
heated high-flow nasal cannula, 44 Ribonucleic acid (RNA), 12
moderate flow devices, 43
prone positioning, 45
therapeutic progression, 46 S
SARS-CoV-2, 1, 2, 4, 5, 35, 41, 200
Seizure, 142, 144
O Severe acute respiratory syndrome coronavirus 2
Oropharynx erythema, 35 (SARS-CoV-2), 99
Slow low-efficiency dialysis (SLED), 117
Specialized diagnostic equipment, 177
P Specialized life-sustaining equipment, 177
Parasternal long axis (PLAX), 169 Specialized therapeutics, 177
Parasternal short axis (PSAX), 170 Sulfobutylether-β-cyclodextrin (SBECD), 119
Peritoneal dialysis (PD), 118 Surge planning, 190, 196
Personal protective equipment (PPE), 19–21, 73, capacity, 192
75, 185 command, 190
aerosol generating procedures, 27 personnel, 191, 192
air purifying respirator, 23 resource management, 191
cardiopulmonary resuscitation, 27 scarce medical resources, 195, 196
doffing, 24 space, 193–194
donning, 24 staff, 194
eye protection, 23 supplies, 194, 195
gowns, 21 Surgical emergencies, 199
isolation procedures, 25, 26 acute cholecystitis, 201
masks, 22 appendicitis, 201
particle dynamics, 20 bowel obstructions, 202
side effects, 23 COVID-19, 200
Pharmacological agents, 151, 152 pandemic, 203
antibody dependent enhancement, 164 patient preparation, 200
COVID-19, 153 SARS-CoV-2, 199, 200, 202, 203
Johnson & Johnson, 162 soft tissue infections, 202
monoclonal antibodies (mAbs), 155, 156 trauma, 203
nucleic acid RNA, 160, 161 Sustained low-efficiency daily dialysis (SLEDD), 117
protein subunit, 162
remdesivir, 152
remdesivir literature, 153–155 T
SARS-CoV-2, 157, 159, 160, 162, 163 Thrombosis, 104
side effects, 163 Tocilizumab, 128
supportive care, 152 Transfer consultation, 182
viral vaccines, 161 Transmission, 3, 4
Physical resources, 177 Transpulmonary pressure, 56
Point of care ultrasound (POCUS), 38 Troponin, 89
Polymerase chain reaction (PCR), 35
Positive end-expiratory pressure (PEEP), 44, 50
Positive predictive value (PPV), 36 U
Post cardiac arrest management, 78 Unfractionated heparin (UFH), 14
210 Index
V Ventilator-induced lung injury (VILI), 51, 52

Vascular, 102 Viral replication, 4
pathophysiology, 104, 105
treatment, 105
Venous thromboembolism, 104 W
Ventilation goals, 82 World Health Organization (WHO), 33

Critical Care of COVID-19 in The Emergency Department 2021

Uploaded by

Copyright:

Available Formats

Critical Care of COVID-19 in The Emergency Department 2021

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Critical Care of COVID-19 in The Emergency Department 2021

Uploaded by

Copyright:

Available Formats

Critical Care of

ISBN 978-3-030-85635-9 ISBN 978-3-030-85636-6 (eBook)

Prior to COVID-19, I would typically complete one or two death certificates

Jacksonville, FL, USA Joseph R. Shiber

1 Overview of the COVID-19 Infection�������������������������������������������� 1

15 Pharmacological Agents for COVID-19 Patients�������������������������� 151

Keith Azevedo Critical Care and Emergency Medicine at the University of

Daniel Haase Departments of Emergency Medicine and Surgery, Program

Randi Searcy UF Health North: North ICU, Jacksonville, FL, USA

Introduction well-being of our communities. This chapter will

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 1

understand the relationship between the S protein Viral Transmission

Extrapulmonary manifestations of COVID-19 nary and extrapulmonary organ systems of

Critical Points HTN, DM, CAD, CHF, chronic lung disease,

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 11

emergency clinicians should consider ordering thrombolytics, if there are no contraindications,

of Anaesthetist. Anaesthesia. 2020;75(6):785–99. 16.

revisited? Eur J Cardiothorac Surg. 2013;43(1):90–4; 35.

Critical Points pathogens (e.g., PUIs, possible influenza, etc.)

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 19

Masks mask is the FFP3, which has a filtering efficiency

Side Effects and Barriers to Use

CDC and other guidelines recommend routine

References Jan 19];11(1) Available from: https://www.ncbi.nlm.

2020 Nov 29]. 52:899–903. Available from: https:// gov/coronavirus/2019-­ncov/hcp/infection-­control-­

Introduction and the flexibility of the ED to adapt to novel

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 33

somnolence, or cyanosis. This message will Healthcare Setting

Patient Presentation infection due to a reported range of 47–73% of

Testing: Diagnostic Testing Unfortunately, RT-PCR in the COVID-19

[26]. NP and OP swabs require training on col-  esting: Summary of Strategies

17. Berger JS, Kunichoff D, Adhikari S, Ahuja T,

Introduction and Background greater than or equal to 90% and PaO2 greater

There are a variety of external applications of

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 43

Therapeutic Progression Open. 2020;1(2):95–101. https://doi.org/10.1002/

Introduction as to the pathogenic mechanism of the virus and

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 49

Table 6.2 Lung protective strategy [40, 43]

Compliance and Ventilator-Induced and thus transpulmonary pressure is not easily

Key Point#1 for lacking individualization; it is likely there are

Stress index=1 Stress index >1 Stress index <1

Problem: Atelectasis Problem: Over-distension

 tep 3: Eliminate injurious

trauma and volutrauma. Data has previously Outcomes and Complications

78. Chao TN, Harbison SP, Braslow BM, Hutchinson

Critical Points • Generally, ECMO may be indicated be when

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 63

 rief History of ECMO and Use

Contraindications Table 7.4 ELSO COVID guidelines [8]

corporeal membrane oxygenation for COVID-19. J subcutaneous emphysema in COVID-19: barotrauma

Prehospital Considerations We will note that this literature is found in criti-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 73

Intra-arrest Management aerosols generated during chest compressions

There is significant heterogeneity among soci- diac arrest in a COVID-19-positive patient is

Duration of Resuscitation continue chest compressions if able to do so

References Pract. 2020;70(696):327–8. https://doi.org/10.3399/

trial. Eur Heart J. 2019;40(22):1804–14. https://doi. implications. Eur Heart J. 2006;27(20):2440–7.

Introduction The exact mechanism of cardiac injury in

Jacksonville, FL, USA Joseph R. Shiber

1 Overview of the COVID-19 Infection�� 1

15 Pharmacological Agents for COVID-19 Patients�� 151

Introduction well-being of our communities. This chapter will

understand the relationship between the S protein Viral Transmission

Masks mask is the FFP3, which has a filtering efficiency

Side Effects and Barriers to Use

2020 Nov 29]. 52:899–903. Available from: https:// gov/coronavirus/2019-ncov/hcp/infection-control-

Introduction and the flexibility of the ED to adapt to novel

somnolence, or cyanosis. This message will Healthcare Setting

Patient Presentation infection due to a reported range of 47–73% of

Testing: Diagnostic Testing Unfortunately, RT-PCR in the COVID-19

[26]. NP and OP swabs require training on col- esting: Summary of Strategies

Introduction and Background greater than or equal to 90% and PaO2 greater

Therapeutic Progression Open. 2020;1(2):95–101. https://doi.org/10.1002/

Introduction as to the pathogenic mechanism of the virus and

Compliance and Ventilator-Induced and thus transpulmonary pressure is not easily

tep 3: Eliminate injurious

trauma and volutrauma. Data has previously Outcomes and Complications

rief History of ECMO and Use

Contraindications Table 7.4 ELSO COVID guidelines [8]

Prehospital Considerations We will note that this literature is found in criti-

Intra-arrest Management aerosols generated during chest compressions

Duration of Resuscitation continue chest compressions if able to do so

Introduction The exact mechanism of cardiac injury in

Myocarditis COVID-19 Workup from a Cardiac

Angiogenesis. 2020. https://doi.org/10.1007/ high-dose heparin for thromboprophylaxis justi-

Epidemiology strated advanced stages of injury correlated with

Pathophysiology of Kidney A key host receptor for the SARS-CoV-2 virus

Anticoagulation obstruction when it accumulates; however, this

Introduction cations likely contributes to the morbidity and

Laboratory Markers Given reports of increased incidence of PE (81%

Introduction disease. Similar findings have been found in

Seizure nytoin and valproate and can sequester drugs

septic, non-COVID-19 patients, composite anal- Peripheral Nervous System

evelopment of Vaccine against

ucleic Acid (RNA and DNA

Introduction state which can cause venothromboembolism,

Safety Considerations • In the doffing area, the US machine should

asic Cardiac POCUS Protocol

Basic Technique [9]

Left Ventricular Function B. Reduced TAPSE