Analytic Review

Journal of Intensive Care Medicine

2021, Vol. 36(1) 18-41
Evidence-Based Management of the Critically ª The Author(s) 2020
Article reuse guidelines:
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Ill Adult With SARS-CoV-2 Infection DOI: 10.1177/0885066620969132
journals.sagepub.com/home/jic

Raghu R. Chivukula, MD, PhD1,2, Jason H. Maley, MD1,

David M. Dudzinski, MD3,4 , Kathryn Hibbert, MD1,
and C. Corey Hardin, MD, PhD1

Abstract
Human infection by the novel viral pathogen SARS-CoV-2 results in a clinical syndrome termed Coronavirus Disease 2019
(COVID-19). Although the majority of COVID-19 cases are self-limiting, a substantial minority of patients develop disease severe
enough to require intensive care. Features of critical illness associated with COVID-19 include hypoxemic respiratory failure,
acute respiratory distress syndrome (ARDS), shock, and multiple organ dysfunction syndrome (MODS). In most (but not all)
respects critically ill patients with COVID-19 resemble critically ill patients with ARDS due to other causes and are optimally
managed with standard, evidence-based critical care protocols. However, there is naturally an intense interest in developing
specific therapies for severe COVID-19. Here we synthesize the rapidly expanding literature around the pathophysiology, clinical
presentation, and management of COVID-19 with a focus on those points most relevant for intensivists tasked with caring for
these patients. We specifically highlight evidence-based approaches that we believe should guide the identification, triage,
respiratory support, and general ICU care of critically ill patients infected with SARS-CoV-2. In addition, in light of the pressing
need and growing enthusiasm for targeted COVID-19 therapies, we review the biological basis, plausibility, and clinical evidence
underlying these novel treatment approaches.

Keywords
coronavirus, SARS-CoV-2, COVID-19, pandemic, critical care, acute respiratory failure, acute respiratory distress syndrome
(ARDS), hypoxemia

Since the first reports of a novel viral respiratory illness
emerged in December 2019 in Hubei Province, China,1 the
illness has spread to pandemic proportions—infecting tens of
millions of individuals on all populated continents and respon-
sible for over a million deaths.2 Both professional society
guidelines3 and individual approaches4-7 for the care of patients
with what became known as Coronavirus Disease 2019
(COVID-19) were rapidly promulgated. These early efforts
naturally preceded the wealth of clinical and basic science
data8 which have since become available regarding the patho-
physiology and clinical management of COVID-19. In this
review, we synthesize what is now known about COVID-19
critical illness into a consensus, evidence-based approach
informed by the pre-existing critical care literature, emerging
basic biology,9-11 multiple observational reports,12-18 and
recently published randomized controlled trial data.19,20
Bronchoalveolar lavage samples from 3 affected patients with
pneumonia revealed the presence of a previously unidentified
viral sequence, “2019-nCoV,” aligning to lineage B of the
betacoronavirus (Beta-CoV) family and highly homologous
to a bat coronavirus, CoV ZXC21.9 Existing Beta-CoV family
members, namely SARS-CoV and MERS-CoV, had previously
been linked to epidemic respiratory viral infections (SARS and
MERS, respectively), strongly suggesting a causal role for this
novel agent in disease pathophysiology. Further sequence
1
Division of Pulmonary and Critical Care Medicine, Department of Medicine,
Massachusetts General Hospital, Boston, MA, USA
2
Whitehead Institute for Biomedical Research, Cambridge, MA, USA
3
Corrigan Minehan Heart Center, Division of Cardiology, Department
of Medicine, Massachusetts General Hospital, Boston, MA, USA
4
Cardiac Intensive Care Unit, Division of Cardiology, Department of Medicine,
Massachusetts General, Hospital, Boston, MA, USA

Epidemiology, and Pathophysiology Received April 10, 2020. Received revised September 14, 2020. Accepted
of SARS-CoV-2 October 07, 2020.

Epidemiology and Transmission Corresponding Author:

C. Corey Hardin, MD, PhD, Massachusetts General Hospital, Division of Pul-
Reports of a respiratory illness among individuals linked to an monary and Critical Care Medicine, 55 Fruit Street, Boston, MA 02114, USA.
indoor seafood market in Wuhan first arose in late 2019.1 Email: charles.hardin@mgh.harvard.edu
Chivukula et al
analysis established 2019-nCoV as most similar to SARS-CoV
among previously identified coronaviruses; it was therefore
renamed “SARS-CoV-2” and the disease that it causes in
humans was termed Coronavirus Disease 2019, abbreviated
COVID-19.1
Early analyses of disease transmission estimated the
SARS-CoV-2 basic reproductive number (R0) between 2.0 and
2.5, indicating that an average infected individual would infect
*2 others and thereby propagate disease.21,22 Given a modest
case fatality rate under 5%23 (versus, for example, MERS’ of
>25%24) these data raised concern for the possibility of wide-
spread dissemination within and outside of China. In the
approximately 7 months following the initial report and char-
acterization of COVID-19, the illness has indeed spread to
pandemic proportions.25 Given the challenges in case identifi-
cation these data are almost certainly substantial underesti-
mates, highlighting the pressing need for physical distancing
and other public health responses in curbing COVID-19
spread.26 Even if such efforts are successful, however, the bur-
den of disease already present worldwide guarantees a surge in
intensive care utilization—a phenomenon already experienced
in areas with high infection burden27 and which demands
familiarity among intensivists with identifying and managing
this infection and its sequelae.
Virology and Pathophysiology
An appreciation of SARS-CoV-2 life cycle and pathobiology is
worthwhile for the practicing clinician, particularly in under-
standing the basis for therapies currently in development and
trials. Like other betacoronaviruses, SARS-CoV-2 is an envel-
oped, positive-strand RNA virus28,29 and, as for SARS-CoV
and MERS-CoV, is transmitted primarily through respiratory
droplets harboring intact virions.30 Unlike SARS, however,
multiple reports indicate the potential for viral transmission
from currently asymptomatic individuals and even those in
whom symptoms never develop.31,32 In addition to respiratory
droplets, SARS-CoV-2 exhibits laboratory stability in aerosols
(half-life *1 hour) and on a wide variety of inorganic sur-
faces.33,34 Epidemiologic investigations to date indicate that
droplet and contact transmission are the major routes of trans-
mission of SARS-CoV-2,30,35 in line with the longstanding
recognition that persistence in aerosols is but one parameter
required for airborne transmission.36 Accordingly, true air-
borne transmission is rare, having been firmly established for
only a very small number of pathogens.36 Nevertheless, it
remains possible that special circumstances may allow
droplet-transmitted pathogens such as SARS-CoV-2 to traverse
larger times and distances as in airborne transmission.37 Some
reports during the SARS outbreak indicated that such permis-
sive airborne transmission may have occurred,38 while others
suggested transmission was exclusively by the droplet route.39
As discussed in following sections, the precise contribution of
droplets, direct contact, aerosols, and fomites40 in driving
SARS-CoV-2 spread remains a topic of intense debate, with
attendant implications for contact and respiratory precautions
19
among care providers: droplet-transmitted pathogens spread
via close, relatively extended contact with an infected person
whereas airborne-transmitted pathogens can remain in the
environment for hours36 and are far more easily transmissible.
Although potent, specific therapies against SARS-CoV-2
remain elusive to date, a large number of candidate drug thera-
pies targeting the viral life cycle are under investigation in
pre-clinical and clinical studies and one agent (remdesivir) has
been approved for clinical use.41 Here we briefly review key
steps in viral pathophysiology (Figure 1) in order to place these
therapies (addressed later) in context.
Whether encountered directly in respiratory secretions or
via an intermediate fomite, SARS-CoV-2 enters cells of the
host respiratory tract by way of a viral envelope protein (spike
protein, “S”) that engages cell-surface receptors. 1 The
receptor-binding region of SARS-CoV-2 S protein is nearly
identical to SARS-CoV,10 which has previously been estab-
lished to engage at least 2 cell surface transmembrane pro-
teins—angiotensin-converting enzyme 2 (ACE2) 42 and
CD209 L (L-SIGN).43 Recent work has definitively established
that ACE2 can engage the SARS-CoV-2 S protein as well11 but
whether this is the only relevant receptor in vivo remains
unclear and the observed pattern of affected tissues44 is not
entirely consistent with the known ACE2 expression domain.45
Following receptor binding, coronaviruses may enter host
cells through either of 2 mechanisms: (1) direct fusion or
(2) receptor-mediated endocytosis46 (Figure 1). In the former
case, one or more host cell surface proteases cleave the S protein,
driving fusion of the viral envelope with host cell membrane and
delivering the naked virus to the cytoplasm.11 In the latter case,
the entire virion is internalized into an “endosome” from which
it must escape in a lysosome-dependent process.47
Once in the cell, SARS-CoV-2 replicates its genome using a
virally-encoded RNA-dependent RNA polymerase (RdRp) and
hijacks host cell translation machinery to produce viral poly-
proteins required for virion assembly.48 These polyproteins are
cleaved by a virally encoded protease (CoV Mpro),49 after
which viral assembly can occur. Infected cells transport assem-
bled virions to the cell surface, where they are released through
exocytosis to infect other host cells. As for SARS-CoV before
it, the specific mechanisms that account for the ability of
SARS-CoV-2 to cause severe disease in humans remain poorly
understood. Early lung pathology reports50-53 from biopsy and
autopsy specimens indicate (as for SARS54 and MERS55) dif-
fuse alveolar damage (DAD) with alveolar desquamation, hya-
line membranes, and variable degrees of viral cytopathic
changes—overall consistent with viral-induced acute respira-
tory distress syndrome (ARDS). In patients who recover, a
polyclonal humoral (antibody) and cellular immune response
typically develops with evidence of neutralizing antibodies.9,56-58
The duration and quality of immunity provided by those antibo-
dies against re-infection remains to be comprehensively charac-
terized, though analogous responses in nonhuman primates
confer protection against SARS-CoV-2 re-challenge.59 As dis-
cussed in detail below, specific targeted therapies intended to
block S protein binding, S protein cleavage, endo-lysosomal
20 Journal of Intensive Care Medicine 36(1)

Figure 1. Life cycle of SARS-CoV-2 and targets of investigational therapies. SARS-CoV-2 enters cells by fusion (1a) or by endocytosis (1b), the
latter of which requires escape from acidified endolysosomal compartments. Following entry, viral RNA (2) and protein synthesis (3) occur in
order to produce new virions which are assembled and packaged (4) prior to release from the cell (5). Therapies targeting the viral life cycle are
depicted according to their proposed mechanism of action as detailed in the text. Figure created with BioRender.com.

escape, RdRp activity, and Mpro activity are in active develop-
ment and testing, as are approaches aimed at vaccination
and adoptive transfer of neutralizing antibodies from convales-
cent sera.
Clinical Presentation, Diagnostic Testing,
and Triage
Clinical Features
The initial presentation of COVID-19 is non-specific and may
include fever, malaise, sore throat, cough, and myalgias—
though no single symptom is present in a majority of cases.
Fever is the most common presenting symptom but is present
on presentation in less than half of cases.60 “Atypical” respira-
tory viral symptoms including anosmia61 and gastrointestinal
complaints62 have also been reported, sometimes as the domi-
nant or sole early symptoms. In published case series, the med-
ian incubation period is approximately 4 days and the median
time to ICU transfer from symptom onset is approximately
10 days.63
Data from Wuhan, China63 and Lombardy, Italy27 indicate
that a minority (7% and *16%, respectively) of patients prog-
ress to require ICU admission, almost universally for hypoxe-
mic respiratory failure. While initial reports indicated that ICU
mortality was quite high,63 subsequent cohorts 12-15 have
reported substantially lower mortality rates in line with
pre-COVID-19 mortalities in moderate to severe ARDS.64
Patient characteristics associated with need for critical care
include age >60 years, male sex, active or historical smoking,
and presence of comorbidities including cardiac disease, dia-
betes, and chronic pulmonary disease.65 Laboratory abnormal-
ities significantly associated with risk of severe disease include
lymphopenia, elevated troponin, elevated creatine phosphoki-
nase (CPK), elevated creatinine, elevated lactate dehydrogen-
ase (LDH), elevated d-dimer, prolonged international
normalized ratio of prothrombin time (PT/INR), and increased
C-reactive protein (CRP); procalcitonin and total leukocyte
count are often normal.66-69 The vast majority of patients exhi-
bit abnormalities on chest imaging—typically bilateral patchy
opacities and/or consolidation.12-16,63 CT imaging does not
reliably distinguish COVID-19 from other causes of infectious
Chivukula et al
Table 1. Clinical Characteristics and Preliminary Outcomes of COVID-19 Respiratory Failure.a
Cohort Location Number of patients Patient population
Schenck et al15 New York City, NY, USA
Ziehr et al12 Boston, MA, USA
Auld et al13 Atlanta, GA, USA
Mitra et al14 Vancouver, BC, Canada
Bhatraju et al16 Seattle, WA, USA
Cummings et al17 New York City, NY, USA
a
The table summarizes physiologic variables and outcomes of patients with severe (requiring ICU admission) COVID-19 in North America. Mortality figures
include outcomes for all patients at the time of data censoring, including those still hospitalized, in the ICU or one mechanical ventilation. P: F refers to the ration
of partial pressure of arterial oxygen to fraction of inspired oxygen. Reported values are medians. Respiratory system compliance values are also reported as
medians.
pneumonitis, but SARS-CoV-2 has been associated with a
preferentially peripheral distribution of opacities, absence of
pleural effusions, and absence of lymphadenopathy.70 The
most common severe manifestation of COVID-19 in the ICU
is ARDS, defined clinically by acute onset of hypoxemia, bilat-
eral opacities not clearly caused by heart failure, and hypox-
emia that persists on at least 5 cm H 2 O of positive
end-expiratory pressure (PEEP).71
Controversies Regarding Clinical Features
of Severe COVID-19
Some controversy as to the nature of COVID-19 ARDS has
arisen following early anecdotal reports suggesting that, as
compared with patients suffering from comparable degrees of
hypoxemia from alternate causes, COVID-19 patients exhibit
lower driving pressures (plateau pressure—PEEP), lower
“recruitability,” and higher respiratory system compliance.5 It
was suggested from such reports that COVID-19 uniquely pre-
sents with a novel phenotype characterized by preserved com-
pliance in the face of severely impaired oxygenation. Some
went further to propose that COVID-19 respiratory failure rep-
resents a state analogous to high-altitude pulmonary edema
(HAPE)72,73 and should be treated accordingly. It was not
immediately clear from these reports why (or even how)
organ-level mechanical consequences of biopsy-proven DAD
might systematically differ by inciting pathogen, and such
speculation has not been supported by subsequent investiga-
tions. Instead, multiple reports12-17 demonstrate that critically
ill patients with COVID-19 have, on average, both low respira-
tory system compliance and arterial oxygenation (as measured
by the ratio of partial pressure of arterial oxygen to fraction of
inspired oxygen, P: F, Table 1). Indeed, reported data on gas
exchange and pulmonary mechanics in COVID-19 are entirely
in line with published series on ARDS in the pre-COVID-19
era64,74,75 and are inconsistent with HAPE.76 These findings
have important implications for therapy and strongly support
the application of evidence-based ARDS therapeutic strategies
in this disease, as discussed below.
21
Respiratory system
P:F ratio (median) compliance (median) Mortality
267 Mechanical 101 28 18.3%
Ventilation
66 Mechanical 182 35 16.7%
Ventilation
217 ICU 132 34 25.8%
117 ICU 180 35 15.4%
24 ICU 142 37 50%
257 ICU 129 27 39%
A second controversial topic surrounds the possibility of a
pathologically hyperinflammatory state in severe COVID-19,77
colloquially described as “cytokine storm.” Similar pathophysiol-
ogy has been proposed in SARS and influenza as well,78,79 though
definitive evidence of a causative role for immune dysfunction in
driving mortality remains lacking. The majority of data support-
ing a role for “cytokine storm” in SARS-CoV-2 infection have
focused on interleukin-6 (IL-6) and ferritin, secreted factors
previously associated with immunotherapy-related cytokine
release syndrome (CRS) and hemophagocytic lymphohistiocyto-
sis (HLH). For example, Ruan and colleagues65 reported *2-fold
higher IL-6, ferritin, and CRP levels in COVID-19 non-survivors
than survivors while Zhu et al. identified IL-6 elevation as highly
predictive of outcome.80 However, the mere presence of particu-
lar laboratory abnormalities in a heterogeneous disease (or in
severe cases of the disease) does not imply an etiologic role for
the analyte in question. Accordingly, hemophagocytosis and
hypercytokinemia have long been recognized as relatively com-
mon findings in patients who die with ARDS or sepsis.81,82 On
average, levels of pro-inflammatory cytokines such as IL-6, IL-8,
and TNFa do not differ between patients with severe COVID-19,
non-COVID-19 ARDS, and sepsis.83 There has, however, been a
longstanding interest in defining subtypes or endotypes84 of
ARDS which are characterized by hyperinflammation. Hyperin-
flammatory sub-types of ARDS have previously been linked with
poor outcome85 and differential treatment responses86 but were
associated with significantly higher levels of cytokines than have
been reported in COVID-19. Indeed, IL-6 levels reported in
severe COVID-1968 would actually have been classified as
hypo-inflammatory by previous subtyping schemes.87 In 2 large
(>200 patient) independent cohorts of severe COVID-19, for
example, median IL-6 levels of 25pg/ml88 and 26pg/ml17 were
reported; by contrast, Calfee and colleagues have previously
described hyper- and hypo-inflammatory subtypes of ARDS85
wherein the hypo-inflammatory subtype was characterized by
mean IL-6 levels of 282 pg/ml and the hyper-inflammatory by
mean levels of 1618 pg/ml.87,89 Another study examined levels of
TNFa, IL-6, and IL-8 in COVID-19 ARDS patients and again
found lower concentrations of these cytokines in critically-ill
22
COVID-19 patients than in matched cases of ARDS due to bac-
terial septic shock.90 Thus, while a fascinating hypothesis, it is far
from clear whether immune activation in COVID-19 represents a
causal event in disease progression (ie, “hyperinflammation”) or
instead identifies critically ill patients with robust and possibly
appropriate immune response. As discussed below, these data
have important implications for the use of targeted immunomo-
dulators in the treatment of COVID-19 patients admitted to the
ICU.
Initial Diagnostic Testing, ICU Triage, and Care
Delivery Considerations
A detailed technical discussion of various SARS-CoV-2 diag-
nostic assays is well beyond the scope of this critical
care-focused article, but treating physicians should be familiar
with the strengths and limitations of current tests. The most
sensitive assay for lower respiratory tract infection is likely
bronchoalveolar fluid (BAL) reverse transcription polymerase
chain reaction (RT-PCR) but is rarely performed owing to inva-
siveness and aerosol exposure risk to healthcare providers.91 By
far the most commonly used diagnostic test for SARS-CoV-2
infection is RT-PCR from nasal or nasopharyngeal swab sam-
ples, which recent data suggest perform comparably.92 Notably,
and in contrast with SARS-CoV, SARS-CoV-2 RNA is detect-
able early in the course of (if not prior to) symptoms.93 It has
been suggested, based in large part on a study indicating high
sensitivity of imaging compared to RT-PCR, that computed
tomography (CT) of the chest may be used to diagnose
COVID-19.94 This study, however, has been criticized for the
quality of the PCR assay used and the American College of
Radiology95 recommends against the routine use of CT in the
diagnosis of COVID-19, concluding that imaging findings are
neither adequately sensitive nor specific for ruling in or ruling
out the disease. As such, imaging does not significantly add to
the diagnostic yield in an RT-PCRþ COVID-19 patient and
should be reserved for situations where alternate diagnoses need
to be evaluated (ex. pulmonary embolism, pleural effusion) or to
identify high risk PCR-negative patients for further work-up. In
at least a subset of such patients, a definitive diagnosis could
change management, particularly as targeted SARS-CoV-2
therapies become more available. Some evidence does indicate
that lower respiratory tract sampling is likely to enhance diag-
nostic sensitivity for SARS-CoV-291,96 and a recent ACCP/
AABIP consensus statement suggests non-bronchoscopic endo-
tracheal sampling as a reasonable next diagnostic step.97
While no direct clinical data can yet support this practice
as changing outcomes, endotracheal sampling would likely
be performed regardless to evaluate for other infectious causes
of respiratory failure in an intubated patient and is therefore a
reasonable strategy. Importantly, any sampling associated with
opening the ventilator circuit to room air should be considered an
aerosol-generating procedure (implications discussed further
below).
The vast majority of patients in whom a critical care con-
sultation is sought will have already undergone targeted
Journal of Intensive Care Medicine 36(1)
SARS-CoV-2 testing but may not have had the full comple-
ment of ancillary laboratory evaluation useful for risk stratifi-
cation and triage. As lymphopenia and elevations in CPK,
d-dimer and LDH have been associated with poor prognosis
in COVID-19,66 we suggest obtaining CBC with differential,
complete metabolic panel, CPK, d-dimer, and LDH. ARDS is
associated with an increase in the risk of renal failure98 and
elevated indices of liver function have been associated with
poor outcome.99 For these reasons we recommend a compre-
hensive metabolic panel including liver function tests. Routine
echocardiography is discouraged by the American Society for
Echocardiography100 but may be of use for patients in whom
initial cardiac biomarkers are markedly elevated or if there
exists suspicion for a component of cardiogenic shock. The
greatest utility of these data may be in adding to clinical para-
meters for risk stratification and ICU triage decisions which
should, as always, be guided by clinical assessment, trajectory,
laboratory evaluation, and resource availability.6 There are few
evidence-based criteria for triggering ICU transfer in critical
illness generally, and certainly not in COVID-19 specifically,
so the decision to escalate care setting remains a function of
physician and nursing assessment, institutional resources, and
clinical trajectory.
In addition to level of care, it is important to conduct triage
in such a way as to minimize risk to staff and the possibility of
nosocomial transmission. Considerable debate continues to
exist regarding the most appropriate forms of personal protec-
tive equipment (PPE) for healthcare workers. The U.S. Centers
for Disease Control101 suggests a number of measures includ-
ing strict contact and droplet precautions and, where possible,
cohorting COVID-19 patients to dedicated units with staff
trained in donning and doffing PPE. Current CDC guidelines
recommend routine use of N95 respirators for healthcare work-
ers caring for COVID-19 patients (when possible), based
largely upon the theoretical possibility of airborne transmission
as discussed above. World Health Organization (WHO) guide-
lines instead specify standard surgical masks outside of specif-
ically aerosol-generating procedures (AGPs), in line with
multiple studies which have found such standard droplet pre-
cautions effective in protecting hospital staff.30,102 Further-
more, a meta-analysis examining RCTs which compared the
efficacy of standard masks to N95 respirators in preventing
transmission of viral pathogens (including coronaviruses) like-
wise found no clear benefit associated with N95 use during
standard care.103 Our conclusion from the available evidence
is that N95 respirators may be safely reserved for situations
with high risk of aerosol exposure, but in resource-rich envir-
onments may theoretically provide some small additional mar-
gin of protection in routine use. For patients undergoing
aerosol-generating procedures, staff use of N95 or more strin-
gent particle-restricting respirators should be compulsory.
Recent evidence also suggests that masks worn by patients may
further reduce the risk of droplet and aerosol-mediated infec-
tion of others.104
Beyond personal protective equipment for care providers,
efforts should be made to minimize the number of staff in and
Chivukula et al
out of all patient rooms, and examinations limited to the min-
imum necessary for care provision. In the intensive care unit,
one practical change in physician practice to facilitate this is
the “bundling” of procedures such as central venous catheter
placement, arterial line placement, and orogastric tube place-
ment to limit staff exposure and PPE use. Nursing interventions
such as patient assessment, medication administration, lab
draws, and turns may likewise be combined to reduce don-
ning/doffing and exposure. Finally, technological and practice
changes may allow adequately equipped ICUs to place infusion
pumps and ventilator control panels outside of patient rooms,
thereby allowing titration of continuous infusions and respira-
tory support without direct contact.
A further challenge in caring for critically ill COVID-19
patients surrounds the difficulties in adequately communicating
with patients and families while maintaining the aforemen-
tioned infection controls. As has been documented in prior epi-
demic infectious disease outbreaks requiring limitation of
physical visitation, such communication challenges can, in turn,
erode the therapeutic alliance as well as staff morale if unad-
dressed.105-107 Few data can inform a specific set of best prac-
tices to facilitate communication, but many ICUs have taken
advantage of the near universal access to smartphones capable
of video calling to supplement or supplant traditional visitation
and communication. No matter an institution’s individual tech-
nical and logistical chosen solutions, we would stress the impor-
tance of retaining principles of family-centered care in the ICU.
Management of Respiratory Failure
in SARS-CoV-2 Infection
As discussed above, hypoxemic respiratory failure caused by
SARS-CoV-2 represents a form of ARDS75 and should there-
fore be managed as such, drawing upon the decades of avail-
able basic, translational, and clinical evidence in this area.
Anecdotal reports4,5,7,108 from early in the COVID-19 pan-
demic suggesting an atypical or unique combination of high
compliance and severely impaired gas exchange which might
merit non-standard treatment have been conclusively refuted
by more comprehensive subsequent analyses.12,75,109 Since
evidence to date supporting significant deviation from
guideline-based care of ARDS in this illness is lacking, treat-
ment algorithms should codify the primacy of established, evi-
dence based principles (Figure 2). That said, there are some
specific ways in which care of COVID-19 does differ from
usual care. These differences stem from (1) infection control
issues associated with SARS-CoV-2, (2) the expectation that
ICU resources may be limited in the course of a pandemic, and
(3) the use of therapies specific to SARS-CoV-2.
Use of Non-Invasive Support Strategies:
HFNC and NIPPV
Oxygen delivery by humidified high-flow nasal cannula
(HFNC) circuits has become increasingly utilized in hypoxe-
mic inpatients. Meta-analyses suggest HFNC may reduce the
23
need for endotracheal intubation, though without altering mor-
tality risk.110 In a setting where ICU and ventilator resources
may be limited, this finding provides a potentially compelling
rationale for HFNC use. Potential benefits to HFNC must,
however, be weighed against potential harms both to the patient
and to caregivers. To the extent that hypoxemia in COVID-19
represents ARDS, HFNC presents a theoretical (but yet unpro-
ven111) risk of propagating lung injury by allowing uncon-
trolled tidal volumes and large pleural pressure
swings. 108,112-115 While the importance of such patient
self-induced lung injury112 remains highly controversial116 and
supported primarily by animal data(108,112-114) and limited clin-
ical studies115 it is also true that there is currently no direct trial
evidence demonstrating the superiority of HFNC to invasive
ventilation with regard to patient centered outcomes such as
mortality. Furthermore, HFNC is unlikely to provide any
meaningful alveolar recruitment and attendant mitigation of
shunt fraction.117,118 For caregivers, HFNC has been suggested
to increase the risk of aerosol generation. While plausible, the
risk of increased droplet dispersion or aerosol generation with
HFNC has been called into question by extensive experimental
data indicating the risk is similar to other forms of oxygen
support.119-121 Modeling studies, in addition, suggest that what-
ever droplet dispersion exists can be substantially mitigated by
placing a surgical mask on the patient while employing
HFNC.122 Non-invasive positive pressure ventilation suffers
from many of the same disadvantages as HFNC (potential for
lung injury and potential for aerosol generation) and has, in
previously published studies, underperformed HFNC.123,124
Furthermore, it is less comfortable for most patients and does
not represent a practical strategy for extended periods of sup-
port123 as is typically required in ARDS. “Helmet” based
NIPPV has recently been associated with reduction in need for
intubation and reduced mortality in hypoxemic respiratory fail-
ure,125 but this modality has yet to be established in large ARDS
cohorts. Published guidelines126 on the care of COVID-19
patients generally recommend a trial of HFNC (over NIPPV)
prior to intubation but the level of evidence for these recommen-
dations is graded as low. NIPPV, with appropriate aerosol safe-
guards, should still be offered to patients with primarily
hypercarbic respiratory failure (ex. known COPD), an indica-
tion for which there exist high quality data for benefit.127 The
available evidence does suggest that a trial of HFNC may reduce
intubations in COVID-19 associated hypoxemic respiratory
failure, but is unlikely to affect mortality.
Decision to Intubate
Specific triggers for intubation in hypoxemic respiratory fail-
ure remain controversial and largely in the realm of clinician
judgment; indications include increased work of breathing
(accessory muscle use, tachypnea), persistent hypoxemia
despite supplemental oxygen, agitation/altered mental status
precluding care, and trajectory of worsening hypoxe-
mia.6,108,111,112 In the presence of bilateral pneumonia (and
thus heterogeneous inflation), mechanical ventilation with low
24 Journal of Intensive Care Medicine 36(1)

Figure 2. Evaluation and management of critically ill adults with SARS-CoV-2. This single-page guideline outlines consensus recommendations
for the evaluation and the management of critically ill patients with COVID-19. The left panels describe clinical and laboratory diagnostics, the
middle panel provides a stepwise algorithm for respiratory failure management, and the right panel highlights COVID-19 specific aspects of
general critical care. URI, upper respiratory infection; HTN, hypertension; CBC, complete blood count; CMP, comprehensive metabolic panel;
PT, prothrombin time; PTT, partial thromboplastin time; EKG, electrocardiogram; LFTs, liver function tests; CPK, creatine phosphokinase; CRP,
C-reactive protein; FiO2, fraction of inspired oxygen; SaO2, arterial hemoglobin oxygen saturation; Vt, tidal volume; PEEP, positive end-
expiratory pressure; POCUS, point-of-care ultrasound; MDI, metered dose inhaler; CVO2, central venous hemoglobin oxygen saturation; SAT,
spontaneous awakening trial; SBT, spontaneous breathing trial; ABCDEF bundle, SCCM ICU liberation bundle; VTE, venous thromboembolism,
NMB, Neuromuscular blockade.

tidal volumes may theoretically be less injurious than contin-
ued vigorous spontaneous breathing with or without
non-invasive support112,128 but this theoretical benefit is
balanced by the risks of sedation and invasive procedures asso-
ciated with mechanical ventilation, particularly as sedation has
been independently associated with increased mortality129 in
ICU patients. In the particular case of COVID-19, mechanical
ventilation results in the patient breathing in a closed, filtered
circuit that may also reduce the risk of viral transmission.
Reports on the use of non-invasive ventilation in prior out-
breaks of MERS have indicated a high rate of failure and pro-
gression to mechanical ventilation130 and initial reports of
outcomes in COVID-19 from centers employing an “early
intubation” (ie. minimal use of HFNC/NIPPV) strategy sug-
gests favorable outcomes.12 Prior analyses of intubation com-
plications (particularly cardiac arrest) have also identified
pre-intubation hypoxemia and lack of pre-oxygenation as
major risk factors,131,132 arguing against delaying intubation
to the point of truly refractory hypoxemia. However, as for
other forms of respiratory failure, no specific objective cutoffs
to guide this decision are likely forthcoming and the decision to
intubate must be made based on individual provider clinical
judgment. In practice, one argument for erring on the side of
“early” intubation in COVID-19 may be logistical:
Chivukula et al
non-emergent intubation allows staff adequate time to don
appropriate PPE and prepare for the procedure.3
Initial Ventilator Settings
Management of ARDS in the setting of COVID-19 does not
meaningfully differ from standard ARDS management.3 Based
on extensive clinical trial data133,134 demonstrating mortality
benefits of a low-tidal volume strategy, patients should be ini-
tially placed on assist/control ventilation with tidal volume of
approximately 4-8cc/kg predicted body weight (PBW, calcu-
lated from height) and a set rate less than or equal to 35 breaths
per minute.133 A number of published approaches to setting
positive end-expiratory pressure (PEEP) level are available and
are discussed below. Median PEEP levels in most available
series of COVID-19 patients are in the range of 8-12 cm
H2O135,12-15 and moderate (8-10 cmH2O) initial PEEP is there-
fore suggested. Strategies employing higher or individualized
PEEP, despite strong physiologic rationale136,137 and promis-
ing results in retrospectively identified subsets of patients,138
have not been shown to be beneficial in prospective rando-
mized, controlled trials.139-141 Plateau airway pressure (Pplat,
airway pressure measured during an end-inspiratory pause)
should be maintained below 30 cmH2O, though more recent
evidence indicates that driving pressure (P plat —PEEP)
<15cmH2O better predicts mortality than either set tidal vol-
ume or plateau pressure.142 Hypercarbia is acceptable (permis-
sive hypercarbia) if there is no evidence of increased
intracranial pressure and arterial pH remains greater than
7.25. Initial tidal volume and PEEP should be adjusted (see
below) to maintain targeted driving pressures, oxygen saturation,
and plateau pressure. A discussion of alternative modes of venti-
lation is beyond the scope of this article, but pressure-cycled
modes143 such as pressure-assist control (PC), volume support
ventilation, 144 and airway pressure-release ventilation
(APRV)145 should be avoided insofar as these modes are incon-
sistent with the maintenance of low tidal volumes,146 may
respond inappropriately to increases in patients respiratory
demand, and have not conclusively been shown to improve out-
comes. In this context it is worth reiterating that the benefit of low
tidal volume ventilation is among the most robust results in the
critical literature. In a recent re-analysis147 of trials reporting an
effect on mortality in critical care, low tidal volume ventilation
and prone ventilation represented 2 of only 4 (out of 862 studied)
interventions with robust fragility index and positive effect on
mortality.
Adjustment of Ventilator Settings in COVID-19 ARDS
Patients with ARDS may fail to respond to initial ventilator
settings, either through persistent high airway pressures
(Pplat > 30cmH20 and/or driving pressure > 15cmH2O) or per-
sistent hypoxemia (SaO2 <90% and/or persistently low PaO2 to
FiO2 (P: F) ratio. Although ideally oxygen saturation should be
maintained between 90 and 96%,148,149 trial data suggest opti-
mization of airway pressures is to be prioritized over correcting
25
moderate hypoxemia without evidence of end organ
hypoxia.150 While no single algorithmic approach to optimiz-
ing ventilator settings can be succinctly summarized, below we
outline a reasonable approach which incorporates physiologi-
cal and clinical trial evidence:
If Pplat exceeds 30 cmH2O and/or driving pressure exceeds
15 cmH2O, patients may be at risk of barotrauma despite low
tidal volume ventilation. One common situation in which high
plateau pressures do not necessarily indicate high transpulmon-
ary pressures (and thus risk for barotrauma) is in the obese, in
whom elevated plateau pressure may nevertheless be associ-
ated with low transpulmonary pressures (Ptp) due to elevated
pleural pressure (Ppl; Ptp ¼ Pairway opening—Ppl).151 In circum-
stances where persistent high plateau pressures and concern for
barotrauma persist, it may be beneficial to further reduce tidal
volume below 6cc/kg to as low as 4cc/kg PBW.133,142 The
lower limit on the ability to decrease tidal volume is deter-
mined by the associated decrease in minute ventilation and
resultant hypercarbia.133,142 Respiratory rate can be increased
as needed to compensate minute ventilation, as long this does
not result in significant auto-PEEP—a phenomenon in which
expiratory time is insufficient for complete exhalation.152
Patients with pre-existing obstructive lung disease (COPD,
asthma, or bronchiectasis) and subsequent flow limitation153
are at highest risk of auto-PEEP. Auto-PEEP can be recognized
by an expiratory flow curve that does not return to zero prior to
the initiation of the next inspiration.154 Auto-PEEP can be
mitigated or eliminated most effectively155 by decreasing
respiratory rate but also, potentially, by increasing inspiratory
flow rate (thereby decreasing I: E ratio) and by treating rever-
sible airflow obstruction with bronchodilators.
In the presence of persistent hypoxemia (SaO2 < 90%)
requiring high FiO2, attempts should be made to formally opti-
mize the PEEP.156 The physiological consequences of varying
PEEP are well-reviewed elsewhere157 but increased PEEP can
maintain in the open state alveoli at risk for collapse. This
results in decreased intrapulmonary shunt and augmented oxy-
genation. However, higher PEEP may also impair respiratory
system mechanics, paradoxically increase intrapulmonary
shunt, and precipitate hemodynamic instability (particularly
in the setting of hypovolemia or limited right ventricular
reserve). A physiological approach to PEEP titration attempts
to identify the end-expiratory pressure that maximizes the ben-
efits of PEEP and minimizes its potential harms. Despite
numerous clinical trials, however, no method of PEEP optimi-
zation in ARDS has been demonstrated as clearly superior to
any other and some titration protocols can cause harm.139-141 In
addition, physiological PEEP titration may be laborious and
require substantial time investments on the part of intensivists
and respiratory therapists—both likely in short supply in the
setting of a pandemic. Thus, it is our opinion that a reasonable
initial approach to persistent hypoxemia is to implement the
ARDSnet “low PEEP” algorithm140 in most circumstances.
In unusual circumstances (refractory hypoxemia, extreme
body habitus, unacceptable hemodynamic or respiratory
mechanical parameters) and if time and staffing allow, PEEP
26
may alternatively be set by best tidal compliance156 using a
decremental “best PEEP” trial.158 In a decremental best PEEP
trial, the optimal PEEP is the one that maximizes the compli-
ance (Crs ¼ Vt/driving pressure).159 When setting PEEP by best
tidal compliance, a sustained application of high airway pres-
sure (“recruitment maneuver”) is often performed first. How-
ever, the protocol of a recruitment maneuver followed by
decremental PEEP was specifically associated with harm in the
recent Alveolar Recruitment Trial (ART).141 This trial has been
criticized for applying recruitment maneuvers in an unselected
population and, in that context, it is notable that few of the
patients in ART demonstrated evidence of recruitment. This
leaves open the possibility that it may yet be possible to iden-
tify a subgroup of patients, such as those described above, in
whom recruitment is beneficial but it remains unknown
whether COVID-19 ARDS might be enriched or depleted for
such patients. Therefore, while there may be a role for such
maneuvers as a rescue for refractory hypoxemia, our opinion
based on the available data is that they are best used rarely.
A gentler approach, which attempts to reconcile the findings of
ART and other PEEP titration trials with physiologic reason-
ing, may be to simply increment PEEP in a stepwise fashion,
starting from current PEEP, with careful attention to driving
pressure to ensure it is not increasing at each step. This man-
euver can be followed by a decremental trial from some more
modestly increased PEEP than the 25-30 cmH2O traditionally
used in recruitment maneuvers. The best PEEP is again chosen
by best compliance as long as this coincides with hemody-
namic stability and acceptable oxygenation (arterial oxygen
saturation 90-96%).
Prone Ventilation
Prone ventilation for ARDS is strongly recommended in cur-
rent clinical practice guidelines160 and should be implemented
in intubated COVID-19 patients with persistent moderate to
severe ARDS. Physiological benefits associated with prone
positioning include improved recruitment, decreased inhomo-
geneity of ventilatory units, improved V/Q matching, and
decreased pulmonary vascular resistance.161 Evidence-based
indications162,163 for prone ventilation include a P:F ratio
<100-150 and FiO2 >0.6 following initial stabilization. How-
ever, since prone ventilation results in a host of improvements
to lung mechanics and is associated with low risk and low cost,
we feel it is reasonable to employ a relatively low threshold
(P:F *150) for considering prone positioning. Furthermore, as
many of the physiological benefits associated with prone posi-
tioning do not depend on positive pressure ventilation, it is not
unreasonable to consider employing this strategy even in spon-
taneously breathing COVID-19 patients (“self-proning”).
Mindful of the potential need to conserve ventilators, many
centers have employed such a strategy in the current outbreak
with evident benefit.164-168
Prone ventilation can be carried out in the patient’s existing
bed and requires minimal additional equipment, though it does
require additional staff for physically positioning the patient.
Journal of Intensive Care Medicine 36(1)
Anecdotally, several centers have established hospital-wide
“proning teams” to ease these resource needs and ensure expe-
rienced operators are available for positioning critically ill
patients. Contraindications to prone ventilation include an
inability to turn the neck (e.g. fixed or unstable c-spine) and
unstable sternum. Vascular access lines, thoracostomy tubes,
and hemodialysis lines are not absolute contraindications to
prone ventilation162 The patient should be maintained in the
prone position for at least 12169 hours, and potentially longer
(24þ hours)170 as patient care needs allow. One approach
which may also mitigate the additional needs for caregiver PPE
and exposure in COVID-19 patients is to supinate patients for
daily care needs in the morning, allowing an extended period
for prone positioning thereafter. The decision to discontinue
prone ventilation is driven by physiological parameters: if
P:F remains >150-200 and driving pressure <15 cmH2O at the
end of a 2 hour period of supine ventilation on PEEP
<10 cmH2O, we discontinue prone ventilation.162
Management of Ventilator Asynchrony
Patients with ARDS may have a high respiratory drive, so
attempts to reduce tidal volumes and airway pressures can result
in dyspnea and ventilator asynchrony.171 Asynchrony com-
monly manifests as “double triggering,” during which ongoing
inspiratory effort triggers a second ventilator-delivered breath
prior to expiration. Double triggering results in high tidal
volumes and airway pressures that can be injurious.172 Increas-
ing inspiratory flow may decrease dyspnea, but if asynchrony is
persistent then consider augmenting sedation and/or neuromus-
cular blockade (NMB). Effective sedation is a prerequisite for
neuromuscular blockade and may obviate its need altogether;
narcotics are particularly effective suppressors of respiratory
drive. The initiation of neuromuscular blockade should be only
undertaken in response to asynchrony or persistent high airway
pressures as recent high-quality RCTs do not indicate a benefit to
routine NMB173 in ARDS. Double triggering which increases
with deep sedation may indicate “reverse triggering” or entrain-
ment,174 a reflex breathing pattern which may abate with reduc-
ing sedation.
Pulmonary Vasodilators
In case of persistent hypoxemia despite optimization of venti-
lator settings, patients may be treated with inhaled pulmonary
vasodilators as temporizing or salvage therapy.175 These agents
work to match ventilation and perfusion by specifically redir-
ecting pulmonary arterial blood flow to those regions that are
best ventilated. The net effect is to decrease V/Q mismatch and
thereby augment oxygenation.176 Importantly, while inhaled
pulmonary vasodilators typically improve P:F ratios for
approximately 24 hours in ARDS, their use has never been
linked to reduced mortality or even liberation from mechanical
ventilation—underscoring the pathophysiology of ARDS as a
multi-organ system disorder of more than hypoxemia.177 While
physiologically equivalent, the use of inhaled nitric oxide
Chivukula et al
(iNO) over inhaled prostacyclin analogs in COVID-19 may be
preferred in practice, if available, as inhaled prostacyclin
requires the use of a filter in the ventilator circuit which has
to be changed periodically, thus creating an additional expo-
sure for staff. In addition, NO exerts anti-viral effects in vitro,
theoretically a useful if clinically unproven adjunctive property
in viral respiratory illness.178,179 A successful trial of iNO may
be defined by a 20% increase in PaO2 with administration of
40 ppm iNO; if a patient responds to iNO, its use should be
maintained and ventilator settings re-titrated to maximize lung
protection. There is, however, likely little benefit to prolonged
use of iNO.
Extracorporeal Membrane Oxygenation (ECMO)
Patients with persistent hypoxemia or unacceptable airway
pressures despite the optimization of ventilator settings, neuro-
muscular blockade, prone positioning, and inhaled pulmonary
vasodilators are deemed to have “refractory” ARDS. In such
cases, consideration should be given to initiation of venove-
nous extracorporeal membrane oxygenation (VV-ECMO) or
transfer to a center where this therapy is available.180,181 Trial
data are mixed and complex on the question of timing of
ECMO initiation, but point to improved outcomes in refractory
ARDS.180-182 Society guidelines generally recommend initia-
tion of ECMO in COVID-19 patients only after the failure of
less invasive therapies including mechanical ventilation and
prone positioning.183 As ECMO therapy is associated with very
high resource utilization184 and resources may be limited in the
setting of a SARS-CoV-2 surge, the criteria for initiation of
ECMO in the setting of COVID-19 may differ from criteria for
non-COVID-19 ARDS. The Extracorporeal Life Support Orga-
nization (ELSO) has published guidelines185 which stress the
dynamic nature of ECMO triage and emphasize the guiding
principle that resource intensive therapies should be directed
towards patients who are most likely to benefit. For that reason,
guidelines suggest usual criteria for the initiation of ECMO
while hospitals are functioning within normal capacity and
more stringent criteria (prioritizing younger patients, those in
single organ failure and those with non-COVID-19 indications
which have been proven to benefit from ECMO) when capacity
is stretched. Absolute contraindications to ECMO in
COVID-19, according to ELSO guidelines, include limited life
expectancy, clinical frailty, mechanical ventilation >10 days,
inability to tolerate anticoagulation, severe neurologic injury,
or severe multi-organ failure.186 Relative contraindications
include body mass index (BMI) >40, immunocompromise, and
multipressor shock not being considered for veno-arterial sup-
port.185 The decision to offer ECMO support should be multi-
disciplinary and take into consideration patient prognosis,
resource availability, and comorbidities.186 Patients with
co-existing cardiogenic shock may be candidates for venoar-
terial ECMO (VA-ECMO), though the precise etiology and
potential reversibility of myocardial dysfunction in
COVID-19 remains poorly defined (discussed further below).
Little outcome data is available for ECMO specifically in
27
COVID-19 but some early reports183 indicate survival in line
with pre-COVID-19 ECMO data.
General Care of the Critically Ill
COVID-19 Patient
In addition to lung protective ventilation, ICU management of
severe COVID-19 should focus on support of organ function
while minimizing risk of transmission with effective isolation
practices and avoidance of low-value diagnostics. 3
Evidence-based management of common problems in the ICU
should be employed as per usual care of ARDS and sepsis187
and a comprehensive review of topics such as transfusion
thresholds, indications for renal replacement therapy, glucose
control, stress ulcer prophylaxis, nutrition, etc. are well beyond
the scope of this work. Instead, below we discuss some of the
ways in which care for critically ill COVID-19 patients may
differ from standard practice, but stress again that these meth-
ods are more similar than not to those provided to patients with
ARDS and/or sepsis generally (Figure 2).
Antimicrobial Therapy
Bacterial superinfection has been reported in ICU patients with
COVID-19 but is not a frequent finding on initial presenta-
tion.16 If initial clinical or laboratory features raise concern for
coincident bacterial infection (neutrophilia, elevated serum
procalcitonin, lobar consolidation, purulent sputum, etc.), con-
sideration should be given to the early initiation of empiric
antibiotics with rapid de-escalation, as outlined in the ATS/
IDSA guidelines.188 Intubated and critically ill patients should
receive ventilator-associated pneumonia (VAP) therapy guided
by cultures or, if an organism is not identified, empirically per
usual hospital protocol. Invasive diagnostic techniques such as
bronchoscopy and mini-BAL offer little benefit over endotra-
cheal aspiration (using an in-line catheter and semiquantitative
culture),188,189 increase transmission risk to staff, and should
therefore generally be avoided. COVID-19 may alter the ease
of providing evidence-based bundled care to reduce VAP
risk.190 Some interventions, such as head of bed elevation and
avoidance of protocolized ventilator circuit changes, should be
largely unaffected. Others, including subglottic suctioning and
targeted sedation may be impractical or unsafe given aerosol
risks and inability for staff to rapidly enter rooms.
Imaging
Radiographic findings consistent with a diagnosis of
COVID-19 are discussed above (See Clinical Features). Rou-
tine daily chest radiographs do not alter ICU outcomes191 and
should certainly be avoided in the care of COVID-19 patients
in light of staff exposure risks. Possible indications for chest
radiography subsequent to ICU admission include hemoptysis,
suspected lung volume loss consistent with mucus plugging,
rapidly progressive hypoxemia and/or hypotension suggestive
of pneumothorax, or concern for VAP. Various patterns
28
(primarily bilateral ground glass opacity and/or consolidation)
on chest CT have been associated with COVID-19 but these are
non-specific and are not likely to inform daily management nor
to improve during a typical ICU admission.192 Transport of
patients to the CT scanner presents risks to staff and other
patients (viral transmission), as well as to the critically ill
patient undergoing transport (potential for derecruitment and
instability). For these reasons, chest CT should be reserved for
situations in which an alternative and actionable diagnosis
(i.e. pulmonary embolus) is suspected and the risks of empiric
therapy (ex. anticoagulation) are deemed significant.
Laboratory Investigation
Recommended laboratory testing includes CBC with differen-
tial (in order to trend total lymphocyte count and surveil for
superimposed infection) and complete metabolic panel
(in order to surveil for renal and hepatic injury). Elevations
in CRP, CPK, LDH, and D-dimer193 have been associated with
poor outcome and are indicated for prognosis and triage; their
role beyond initial risk-stratification remains ill-defined. Bac-
terial and fungal superinfection have been reported in a minor-
ity of cases, so routine sputum and blood cultures on ICU
admission are reasonable. As discussed previously, the role
of measuring inflammatory markers such as ferritin, IL-6, solu-
ble IL-2 receptor, and CRP remains unclear outside of clinical
trial settings in which immunomodulatory therapy may be con-
sidered, but may be reasonable to consider in patients with
refractory shock, sustained fever, MODS, or other signs sug-
gestive of “cytokine storm.” The role for biomarkers such as
procalcitonin remains unvalidated, though low procalcitonin
levels have previously predicted absence of bacterial infection
in critically ill patients with influenza.194
Aerosol Generating Procedures
It was has been postulated195 that procedures such as broncho-
scopy, endotracheal intubation, extubation, nebulizer adminis-
tration, and tracheostomy placement/manipulation may
generate smaller, more persistent particles and thereby facili-
tate airborne transmission of agents more typically spread by
respiratory droplets. That said, there is no experimentally vali-
dated reference list of such procedures101 and it is likely such
activities represent a spectrum of risk rather than a binary dis-
tinction. While the risk of most such aerosol generating proce-
dures (AGPs) remains somewhat controversial, both the
CDC101 and WHO196 recommend conducting potentially aero-
sol generating procedures with all staff wearing N95 respirators
and other appropriate PPE. The CDC further recommends such
procedures ideally be performed in airborne infection isolation
rooms (AIIRs). Intubation, in particular, seems to be high risk
for aerosol generation197 and the decision to intubate should
therefore be made early in the course of anticipated clinical
deterioration to reduce the need for urgent or uncontrolled
procedures which may carry higher risks of transmission. As
outlined above, bronchoscopy is not indicated unless less
Journal of Intensive Care Medicine 36(1)
invasive tests have not yielded sufficient diagnostic informa-
tion both due to aerosol risk and limited evidence for additional
diagnostic yield. Respiratory samples for diagnosis of bacterial
superinfection may be obtained by close-loop endotracheal
aspirate in intubated patients. Inhaled medications should be
given by metered dose inhaler instead of nebulizer whenever
possible to decrease the risk of viral transmission and ventila-
tors should be set up with adaptors in the dry arm of the circuit
to facilitate subsequent use of inhalers without opening the
circuit.
Hemodynamics and Fluid Management
Case series from China and Italy18,67 indicated a predominance
of isolated respiratory failure associated with COVID-19 with
lower than expected rates of secondary organ failure, shock,
and renal failure than unselected ARDS patients. Nevertheless,
shock occurs in approximately a third of critically ill
COVID-19 patients.16,18,67 Importantly, while distributive
shock due to viral sepsis likely underlies the majority of such
cases, it remains important for clinicians to entertain a broader
differential diagnosis. Multiple case reports have described the
occurrence of acute heart failure198 and cardiogenic shock199
associated with severe COVID-19. ACE2 is expressed in the
heart and some reports have described the isolation of viral
RNA in post-mortem samples of cardiac tissue.200 One small
Chinese series reported an isolated cardiac cause of death in 7%
of patients and an additional third of whom died of combined
cardiac and respiratory failure.65 The extent to which these
reports constitute evidence of a true viral myocarditis201
remains controversial, however, as endomyocardial biopsies
in the setting of COVID-19 related heart failure showed no
evidence of direct viral infection of cardiac myocytes.202 The
diagnosis of a genuine myocarditis is also made challenging by
the high prevalence of cardiac biomarker elevation in the cri-
tically ill, with COVID-19 patients being no exception.69 Thus,
while the true incidence of viral myocarditis accompanying
SARS-CoV-2 infection remains unclear, acute heart failure is
well-appreciated in COVID-19 critical illness and requires
exoneration in the decompensating patient. Beyond cardio-
genic shock, multiple case reports have also suggested the
presence of an elevated rate of acute mesenteric ischemia and
accompanying shock in COVID-19. Kaafarani et al. reported
acute mesenteric ischemia in 4/141 critically ill patients with
COVID-19203 with similar findings independently reported
elsewhere.204 Although ACE2 expression in the gut has been
reported205 and SARS-CoV-2 can infect enterocytes in vitro,205
whether these observations are attributable to GI infection,
microvascular thrombosis (see below), or some other patho-
physiological process remains unclear. Computed tomography
angiography (CTA) is the preferred imaging technique for the
diagnosis of acute mesenteric ischemia.206 As abdominal CTA
is not routinely performed in respiratory failure patients, the
diagnosis of acute mesenteric ischemia requires a high index of
suspicion in the face of evolving hemodynamic instability with
urgent involvement of surgical consultants if identified.
Chivukula et al
In the majority of COVID-19 patients experiencing shock
related to progressive viral sepsis, it is appropriate to treat per
usual protocols for distributive shock with particular care taken
to avoid fluid overload. Patients with hypoxemic respiratory
failure should generally be managed with a conservative fluid
strategy207 which includes (1) limiting fluid boluses to patients
in shock who have indications of volume responsiveness,208,209
and (2) early initiation of diuresis in those with resolved shock.
Positive fluid balance should be avoided in patients who are not
volume responsive, a practice supported by high-quality ran-
domized trial data.210 In addition, positive fluid balance over
the course of ICU stay is associated with increased mortal-
ity.211,212 As for most critically ill patients, the use of balanced
crystalloids (ex. lactated Ringer’s solution) is preferred over
normal saline, albumin, or alternative colloid prepara-
tions.213,214 Current guidelines for treatment of distributive
shock3 suggest titrating therapy to end-organ perfusion as indi-
cated by renal function, mental status, serum lactate, and (if
available) central venous oxygen saturation.187 Adjunctive
therapies for septic shock such as glucocorticoids are the sub-
ject of conflicting trial data215-217 with evidence of minimal
benefit or harm in prior respiratory viral illnesses.218-221 Nev-
ertheless, steroids should be considered in refractory distribu-
tive shock associated with COVID-19, particularly in light of
strong evidence for glucocorticoid benefit in COVID-19 ARDS
(discussed below).
Coagulation Abnormalities and Thrombotic Risk
While microvascular and macrovascular pulmonary thrombo-
sis are long-recognized features of ARDS,222,223 efforts at
blunting coagulation in the setting of ARDS have largely failed
to show benefit in clinical trials.224-226 Early observational
reports from China67 indicated that COVID-19 was associated
with abnormal indices of coagulation, a finding subsequently
confirmed in larger independent cohorts which highlighted ele-
vations in d-dimer and fibrinogen as consistent features of
COVID-19.227 These findings have led multiple investigators
to hypothesize that the tropism of SARS-CoV-2 for ACE2 and
the expression of that receptor on endothelial cells228 might
result in a systematic endothelialitis and resultant widespread
coagulation abnormalities. However these reports remain con-
troversial, both because the extent of genuine endothelial cell
involvement has come under scrutiny229 and because abnorm-
alities in such parameters are common in the critically ill.193
Klok et al reported230 venous or arterial thrombosis in 31/184
(16.8%) critically ill patients with COVID-19, consistent with
other case series from Italy, 231 the United States, 12 and
France.232 By comparison, a large cohort of ICU patients with
severe H1N1 influenza233 pneumonia was reported to have an
incidence of venous thromboembolism of 10%. Complicating
matters, however, the rates of bleeding complications in
COVID-19 have not been fully characterized and there is some
evidence that bleeding risk is elevated as well.234 Due to the
uncertainties as to the magnitude thrombotic risk and possibly
offsetting risks of bleeding, guidelines 235 and published
29
recommendations193 largely advise prophylactic anticoagula-
tion for all COVID-19 patients and reserve therapeutic antic-
oagulation for those with confirmed thrombosis or pre-existing
indications. Whether there is a role for augmented intensity
VTE prophylaxis remains to be studied in controlled trials.
Role for Targeted Therapies and
Immunomodulation
The pathophysiology of SARS-CoV-2 remains poorly defined
and the precise mechanistic basis underlying severe,
life-threatening COVID-19 is unknown. To date, 2 therapies
have been shown in randomized controlled trials to improve
outcomes in COVID-19: the antiviral nucleoside analog remde-
sivir20 and the steroid dexamethasone.19 However, dozens of
additional trials are ongoing and can be broadly divided into
2 classes: (1) those that aim to directly target viral infectivity or
replication and (2) those that aim to alter or modulate the host
response to infection.
Experimental Therapies Targeting SARS-CoV-2 Life Cycle
As outlined in the “Virology and pathophysiology” section
above, SARS-CoV-2 employs a well-characterized series of
steps to enter host cells and replicate (Figure 1). A number of
efforts aim to block viral engagement of the cell surface ACE2
receptor. One strategy centers on anti-spike protein neutraliz-
ing antibodies. Analogous blocking antibodies have been iden-
tified against SARS-CoV and there is intense interest in
characterizing the structural basis for antibody recognition.236
One such antibody has been reported to efficiently block
SARS-CoV-2 infection in vitro237 and it (among others) are
moving toward clinical trials. However, it remains unclear
whether such strategies will be effective in vivo or even
whether they are necessarily safe, particularly in light of a
recent report of anti-S protein immunoglobulin induced
exacerbation of acute lung injury in SARS-CoV-infected
non-human primates.238 The use of “decoy” ACE2 receptor
to inhibit viral infection in human tissue organoids was also
recently reported,239 but whether such a strategy is viable in
patients remains unclear.
On August 23, 2020 the U.S. Food and Drug Administration
(FDA) issued an emergency use authorization (EUA) for con-
valescent plasma therapy in COVID-19. Convalescent plasma
involves the transfusion of plasma from recovered patients in
order to achieve a passive immunization. To date, there are no
randomized clinical trials on the use of convalescent plasma.
The administration of convalescent plasma resulted in
decreased viral load and clinical improvement in 5 mechani-
cally ventilated patients in an early report from China,240 The
FDA based its decision, in part, on analysis of data from an
expanded use program run by the Mayo Clinic. These data
have, at the time of this writing, been released only as a
non-peer reviewed pre-print(241) and describe the transfusion
of plasma in a total of 35,322 patients (52% requiring critical
care). Mortality was 8.7% in patients who were transfused
30
within 3 days of diagnosis and 11.9% in patients transfused
after 4 days. A potential issue with convalescent plasma ther-
apy is that the repertoire and titer of antibodies may vary by
donor. Indeed, reported mortality was lower in patients trans-
fused with high-titer plasma than those transfused with
low-titer plasma. While the Mayo Clinic experience suggests
that convalescent plasma therapy is likely to be safe, guidelines
continue to recommend against consideration of convalescent
plasma as standard of care242 until controlled trials are per-
formed. It is thus too soon to know if convalescent plasma
therapy is truly effective.
As outlined previously, following receptor engagement
SARS-CoV-2 can enter cells by fusion or by endocytosis. The
fusion-dependent pathway depends on host cell surface pro-
tease activity, a process recently found to be inhibited by the
pancreatitis drug camostat mesylate.11 A placebo-controlled
phase IIa trial of camostat is now underway (trial
NCT04321096) following promising results in mouse models.
As the endocytic pathway depends on endosome/lysosome
escape, inhibitors of this process (particularly chloroquine deri-
vatives) have also received intense interest in the scientific and
lay communities. Chloroquine (CQ) belongs to a class of
agents known as cationic amphiphilic drugs (CADs), which
become trapped and highly concentrated in acidified subcellu-
lar compartments such as endosomes and lysosomes. By virtue
of this trapping, CADs can increase pH and inhibit enzyme
function within these organelles. CQ’s interference with
endo-lysosomal processing of antigens likely accounts for its
immunosuppressant activities, and a similar mechanism in
virally infected cells provides an opportunity to block viral
endosome escape and replication.243 Indeed, it has been appre-
ciated for decades that various CADs can interfere with the
replication of a diverse array of enveloped viruses including
influenza, Ebola virus, HIV, dengue, Zika and hepatitis C in
vitro . Building on these data, Wang and colleagues published
2 papers47,244 examining the effects of CQ and hydroxychlor-
oquine (HCQ, more widely available and less toxic) on the
novel SARS-CoV-2 in vitro, uncovering that CQ dramatically
inhibits SARS-CoV-2 replication at low micromolar concen-
trations, while HCQ inhibits replication at *10 mM. However,
previous experience with CQ/HCQ suggested skepticism was
warranted; chloroquine failed to prevent influenza infection in
a clinical trial, 245 increased viral load in HIV-infected
patients, 246 and paradoxically increased viremia in
non-human primates infected with Chikungunya virus.247
Indeed, more systematic investigations of the efficacy of CQ/
HCQ in COVID-19 have largely disproved its suggested utility.
Large observational series248 showed no evidence of benefit
and large NIH- and WHO-sponsored trials of HCQ were
stopped for futility249,250 (final data pending). Published clin-
ical trials have also failed to demonstrate benefit251 and
recently published data failed to identify any treatment effect
to HCQ in non-human primates infected with SARS-CoV-2.252
Taken together, in line with the IDSA, 253 FDA, 254 and
CDC101), we believe evidence for a therapeutic benefit for
Journal of Intensive Care Medicine 36(1)
CQ/HCQ is lacking and that these drugs should therefore not
be used for the treatment of SARS-CoV-2 infection.
As for HIV, HCV, and other clinically relevant viral patho-
gens, specific small molecule inhibitors of viral enzymes have
proven more promising. Remdesivir (GS-5734), a nucleoside
analog of adenosine, is an inhibitor of viral RNA-dependent
RNA polymerases with broad antiviral activity.255 Notably,
remdesivir exhibits potent inhibitory activity against
SARS-CoV and MERS-CoV in vitro and in animal models256
and is not associated with development of fitness-maintaining
resistance mutations. In non-human primates, remdesivir
reduced lung injury after infection with SARS-CoV-2,257
though this model is notable for not inducing ARDS as
observed in human patients. Remdesivir received an emer-
gency use authorization from the FDA on the basis of the
preliminary results from the Adaptive COVID-19 Treatment
Trial-1 (ACTT-1). In ACTT-1, 1063 participants were rando-
mized to receive up to 10 days of remdesivir versus placebo;
patients in the remdesivir arm had a shorter time to recovery
than those in the placebo group (11 versus 15 days).20 A sub-
group analysis revealed this benefit was driven by the group
requiring oxygen, rather than those requiring HFNC, NIPPV,
mechanical ventilation, or ECMO. A subsequent trial 258
showed comparable outcomes in oxygen-requiring
non-critically ill patients treated with 5 and 10 days of remde-
sivir. Based on these data, current guidelines suggest remdesi-
vir for hospitalized COVID-19 patients requiring oxygen,
suggesting 5 (non-intubated patients) or 10 days (intubated
patients) of therapy.253 Guidelines for the use of remdesivir are
rapidly evolving, however, in part driven by drug shortages.259
Like RdRp, the viral Mpro protease represents an attractive
target for therapy as several existing antiviral agents may effec-
tively inhibit its function. To date, attempts to repurpose HIV
protease inhibitors have not borne fruit260 and more recent
large clinical trials have been halted at interim analyses due
to lack of evidence of benefit. Other trials remain ongoing261
but as of this writing off-label use of such agents outside of
clinical trials is not supported by the evidence.
Experimental Immunomodulators
As introduced above, it has been suggested that some patients
with SARS-CoV-2 infection may exhibit a hyperinflammatory
phenotype or “cytokine storm”9,77,88 meriting therapy with
immunomodulatory agents. Interest in such syndromes has bur-
geoned in recent years as targeted therapies have become avail-
able for the treatment of cytokine release syndrome (CRS)
triggered by immune-activating oncologic therapies. However,
it remains unclear whether such putative “hyperactivation” is
necessarily a rational therapeutic target in COVID-19 given the
challenges in distinguishing immune activation as a cause
rather than a consequence of critical illness. Indeed, prior
attempts at targeted immunomodulation262,263 in critical illness
have largely proven ineffective. IL-6 antagonists such as toci-
lizumab have seen widespread recent use in the management of
immunotherapy side effects, a context in which they mitigate
Chivukula et al
CRS and reduce need for steroids. It is less clear whether IL-6 is
causally related to the pathogenesis of ARDS, though elevated
cytokine levels have been associated retrospectively with
improved response to steroids in septic shock.264 Numerous clin-
ical trials are evaluating the use of IL-6 blockade (NCT04315480,
NCT04320615, NCT04322773, NCT04330638, NCT04332913,
NCT04335071), though at least one has already been stopped for
futility and potential harm.265 In line with IDSA guidelines,253
therefore, we suggest limiting cytokine-targeting therapy to the
clinical trial setting.
Beyond such targeted therapies, a role for corticosteroids
(which have a long and complex history of use in ARDS) is
emerging in the management of severe COVID-19. The theo-
retical rationale for steroid therapy in ARDS generally
(reviewed extensively elsewhere266,267) stems from the obser-
vation that this disease is characterized by exuberant lung
inflammation and that glucocorticoids provide benefit in a vari-
ety of inflammatory human disease states via pleiotropic
effects.268 That said, glucocorticoids exert myriad complex
effects in the critically ill and the precise mechanistic basis for
any steroid treatment effects in ARDS remains to be clarified.
The history of steroid trials in ARDS spans some 3 decades269
and cannot be reviewed here comprehensively but, in brief,
early data did not support the use of high-dose “pulse” ther-
apy.270-273 Subsequent studies of lower-dose regimens indi-
cated a benefit as evidenced by more rapid liberation from
mechanical ventilation263,274 but without mortality benefit.
A recent multicenter RCT275 reported a 60 day mortality ben-
efit in moderate to severe ARDS patients treated with dexa-
methasone, but was hampered by low enrollment rates and
open label design. These potential benefits of steroids in ARDS
are tempered by signals for harm. Steinberg and colleagues
identified an increase in mortality and rates of re-intubation
associated with steroid therapy in late (>14d) ARDS.263
Furthermore, observational data from epidemics of influ-
enza,276-278 SARS,279 and MERS220 suggested the immunosup-
pressive properties of glucocorticoids might actually
exacerbate virally-induced acute lung injury. Accordingly,
early expert opinion argued against the routine use of corticos-
teroids in COVID-19.280 This was the setting in which initial
results from the RECOVERY trial were recently published.19
RECOVERY is a multi-arm, open-label platform trial testing a
number of specific therapies for COVID-19 in hospitalized
patients. Patients received dexamethasone (6 mg daily for up
to 10 days, n ¼ 2104) or usual care (n ¼ 4321) with primary
outcome of all-cause 28 day mortality. The trial revealed a 3%
absolute risk reduction in favor of the steroid group, a benefit
which varied by degree of respiratory support with greater
benefit in the mechanically ventilated (absolute risk reduction
12%) and a trend towards harm in non-oxygen-requiring
patients. With the caveats that long-term mortality data remain
to be seen and that control arm mortality was at the upper end
of reported ranges, these findings support a therapeutic effect
for glucocorticoids in severe COVID-19. At the time of publi-
cation of RECOVERY a number of other trials of steroid ther-
apy in COVID-19 were underway—using various steroid
31
formulations and dosing strategies. A recent meta-analysis281
of data from 7 of these trials demonstrated lower mortality in
steroid treated patients—increasing confidence in the RECOV-
ERY results. Accordingly, steroid therapy should be consid-
ered standard of care in hospitalized COVID-19 patients
requiring supplemental oxygen, mechanical ventilation, or
ECMO support.
Statins, inhibitors of HMG CoA-reductase, mediate wide-
spread effects on cellular metabolism beyond their roles in reg-
ulating serum LDL cholesterol levels. Arguments for the use of
statins in severe COVID-19 infection arise from 2 independent
rationales. The first is that patients with pre-existing cardiovas-
cular disease appear to be at high risk for severe disease and
death after SARS-CoV-2 infection; many of these patients are
likely to meet existing guideline-based indications for statin
therapy as primary or secondary prevention. A second, much
more speculative, proposed indication for statin use is as mod-
ulators of the innate immune system. Because they inhibit sig-
naling through the innate immune adaptor MYD88, statins have
been posited to act as beneficial “anti-inflammatory” agents in
viral respiratory infections,282 though it should be noted that
such signaling is complex and exquisitely tightly controlled in
vivo. Highlighting this point, genetic knockout of Myd88 has
proven fatal in mouse models of SARS.256 As for ARDS more
generally,283 there may exist a subgroup of hyperinflammatory
COVID-19 patients in whom statins mediate protective effects,
but there is no validated way to identify them prospectively at
this time. In light of the risks of transaminitis and rhabdomyo-
lysis with these agents, we therefore do not recommend their
universal use in SARS-CoV-2 infection absent an
evidence-based primary indication.
A final approach for immunomodulation in severe
COVID-19 aims to augment, rather than inhibit, host response
to SARS-CoV-2 in order to potentiate viral clearance.
Granulocyte-monocyte colony stimulating factor (GM-CSF)
is a growth factor with important functions in the lung—sup-
porting the maturation of alveolar macrophages284 and promot-
ing surfactant turnover and recycling. GM-CSF levels are
elevated in the blood of COVID-19 patients,285 an observation
that has triggered attempts both to augment and to inhibit sig-
naling through this pathway—highlighting the urgent need for
deeper pathophysiological understanding. Although it failed to
show benefit in an RCT in ARDS,286 recombinant GM-CSF
has shown preclinical promise in ameliorating influenza acute
lung injury287 and is being studied in an active COVID-19 trial
(trial NCT04326920). As for many of the experimental thera-
pies discussed here, our conclusion is that there is an inade-
quate understanding of viral pathogenesis and host response to
justify use of such agents outside of monitored clinical trial
settings.
Conclusion
SARS-CoV-2 is a novel coronavirus of zoonotic origin that has
infected millions of people worldwide and is placing severe
demands on intensive care resource utilization across the globe.
32
The biology and natural history of COVID-19 is becoming
increasingly well-understood and should inform the approach
to diagnostic testing, healthcare worker precautions, and ICU
triage. COVID-19 associated acute hypoxemic respiratory fail-
ure develops in a substantial fraction of affected patients and
represents a form of ARDS, a finding consistent with what is
now understood regarding the virology and pathophysiology of
SARS-CoV-2. The keys to evidence-based management of
COVID-19 therefore include lung-protective low-tidal volume
ventilation, avoidance of barotrauma, a conservative fluid strat-
egy, and prone ventilation, with utilization of inhaled pulmon-
ary vasodilators, neuromuscular blockade, and ECMO when
necessary. The lifecycle of SARS-CoV-2 and its effects on the
host immune system suggest possible targets for therapy and, to
date, 2 such drugs are indicated in hospitalized COVID-19
patients. In time, we anticipate the continued development and
adoption of additional targeted therapies which will help bring
the pandemic under control.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship, and/or publication of this article: RRC
received support from NIH T32HL116275 and is a fellow of the
Parker B. Francis Family Foundation.
ORCID iDs
David M. Dudzinski, MD https://orcid.org/0000-0001-9363-9345
C. Corey Hardin, MD, PhD https://orcid.org/0000-0002-4074-0420
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