Journal of Cardiothoracic and Vascular Anesthesia 36 (2022) 11881195

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Journal of Cardiothoracic and Vascular Anesthesia

journal homepage: www.jcvaonline.com

Expert Review
2021 Acute Respiratory Distress Syndrome Update,
With Coronavirus Disease 2019 Focus
Carson Welker, MD*, Jeffrey Huang, MD*,
nez Gil, MD, PhD, FESCy,
u~
Iv
an J. N

Harish Ramakrishna, MD, FACC, FESC, FASEz
,1

*
Division of Critical Care Medicine, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic,
Rochester, MN
y
Department of Cardiology, Cardiovascular Institute, Hospital Cl
ınico San Carlos, Madrid, Spain
z
Division of Cardiovascular and Thoracic Anesthesiology, Department of Anesthesiology and Perioperative
Medicine, Mayo Clinic, Rochester, MN

Acute respiratory distress syndrome (ARDS) is a heterogeneous lung disease responsible for significant morbidity and mortality among
critically ill patients, including those infected with severe acute respiratory syndrome coronavirus 2, the virus responsible for coronavirus
disease 2019. Despite recent advances in pathophysiology, diagnostics, and therapeutics, ARDS is dangerously underdiagnosed, and sup-
portive lung protective ventilation and prone positioning remain the mainstay interventions. Rescue therapies, including neuromuscular
blockade and venovenous extracorporeal membrane oxygenation, remain a key component of clinical practice, although benefits are
unclear. Even though coronavirus disease 2019 ARDS has some distinguishing features from traditional ARDS, including delayed onset,
hyperinflammatory response, and pulmonary microthrombi, it clinically is similar to traditional ARDS and should be treated with estab-
lished supportive therapies.
Ó 2021 Elsevier Inc. All rights reserved.

Key Words: acute respiratory distress syndrome; ventilator-induced lung injury; mechanical ventilation; coronavirus disease 2019; COVID-19; prone position;
neuromuscular blocking agents; extracorporeal membrane oxygenation; nitric oxide; positive end-expiratory pressure

ADVANCES in acute respiratory distress syndrome widely underrecognized, with resulting underutilization of
(ARDS) diagnosis and therapy have developed steadily over LPV. Morbidity burden remains extremely high in survivors
the last 50 years. However, mortality has remained static at of ARDS who may experience post-traumatic stress disorder,
30%-to-40% the last ten years, and the disease is underdiag- post-intensive care syndrome, long-term physical disability,
nosed, with disparate effects on race, poverty, and sex.1 and neuromuscular weakness.
Although lung-protective ventilation (LPV) and prone posi- Although severe coronavirus disease 2019 (COVID-19)
tioning clearly have been shown to reduce mortality, questions often meets diagnostic criteria of traditional ARDS, additional
remain about the benefit of rescue therapies such as paralysis, features have been reported, such as delayed onset, binary pul-
inhaled pulmonary-vascular vasodilators, extracorporeal mem- monary compliant states, and hypercoagulable profile, which
brane oxygenation (ECMO), and other pharmacologic thera- have obscured the utility of traditional ARDS therapies. The
pies. Despite the expansion of ARDS management, it remains efficacy of steroids in COVID-19 and need for systemic anti-
coagulation have been established, but other targeted COVID-
1
Address correspondence to Harish Ramakrishna, MD, FACC, FESC,
19 therapies have not been found to be effective in reducing
FASE, Division of Cardiovascular and Thoracic Anesthesiology, Department mortality. Despite its novelty, COVID-19 ARDS has clear
of Anesthesia and Perioperative Medicine, Mayo Clinic, 200 First St SW, crossover with traditional ARDS therapy, and lung-protective
Rochester, MN 55901. ventilation and prone positioning should be widely used.
E-mail address: Ramakrishna.harish@mayo.edu (H. Ramakrishna).

https://doi.org/10.1053/j.jvca.2021.02.053
1053-0770/Ó 2021 Elsevier Inc. All rights reserved.
 C. Welker et al. / Journal of Cardiothoracic and Vascular Anesthesia 36 (2022) 11881195 1189

ARDS Epidemiology and Diagnosis respiratory distress syndrome coronavirus 2 (SARS-CoV-2).15

Mechanisms of pulmonary perfusion dysregulation in COVID-
Since the seminal work of the ARDS Network trial, there 19 include abolition of hypoxic pulmonary vasoconstriction,
have been minimal improvements in mortality rates and inci- excessive pulmonary vasoconstriction, and thrombosis.16 The
dence of ARDS.2 Mortality rates remain between 34.9% and clinical course on presentation with COVID-19 typically fol-
40%, depending on severity.3 In addition, recognition of lows one of the following three patterns: hyperacute respira-
ARDS ranges from 51.3%-to-78.5%, resulting in failure to tory failure requiring immediate intubation, indolent course
implement LPV strategies.4 ARDS mortality rates dispropor- with only moderate work of breathing, or a biphasic course
tionately affect black and Hispanic patients compared with with initially indolent course followed by acute deterioration
white patients and males compared with females, with an out- typically after five-to-seven days.16
sized burden on low-income patients and patients in develop- A host of biomarkers are released in the initial pathophysi-
ing countries.1,5 Living in a higher population density and ologic cascade, providing new opportunities for early diagno-
black ethnicity have been shown to have higher risk for hospi- sis, which is especially important because ARDS can develop
talization in COVID-19, although no statistical racial trend has in the absence of traditional risk factors.17 A recent study
been found for mortality.6,7 Morbidity in ARDS survivors suggested that some patients may have increased biomarkers
remains a concern, with a high incidence of critical illness pol- associated with direct lung injury, whereas other patients
yneuropathies, cognitive impairment, post-intensive care syn- may have biomarkers associated with hyperinflammatory
drome, post-traumatic stress disorder, and employment loss.8,9 lung injury.18 Additional investigations have revealed the
The heterogeneity of causes and presentations of ARDS have possibility of the following two subphenotypes: a hyperin-
resulted in a dangerous underdiagnosis. Traditional risk factors flammatory response characterized by interleukin 6 and 8 and
such as pneumonia, aspiration, pulmonary contusion, inhalation tumor necrosis factor-1, and a hypoinflammatory response
injury, sepsis, pancreatitis, blood product transfusion, and smok- associated with fewer biomarkers and an attenuated shock
ing history remain important risk factors.10,11 Diagnosis of state.19,20 Stratified fluid management strategies and differing
ARDS remains largely clinically-based on the Berlin criteria, ventilatory managements based on subphenotypes have been
which require a patient to have bilateral opacification on chest suggested.21,22 Despite there being more than 40 genes asso-
x-ray or computed tomography within seven days of a clinical ciated with the development of ARDS, subphenotypic diag-
insult that otherwise cannot be explained by pulmonary edema nostics have had little bearing on current clinical practice of
from heart failure.12 The Berlin criteria stratify disease severity ARDS, and no gene-specific loci for ARDS have been identi-
based on the partial pressure of arterial oxygen/fraction of fied.23,24 Early anecdotal reports described high- and low-
inspired oxygen (PaO2/FIO2) as follows: mild (200 mmHg < compliance phenotypes with COVID-19 ARDS.25 However,
PaO2/FIO2 300 mmHg), moderate (100 mmHg < PaO2/FIO2 this phenotype distinction likely also has minimal clinical
200 mmHg), and severe (PaO2/FIO2 100 mmHg), assuming significance in the management of COVID-19 ARDS.26
a positive end-expiratory pressure (PEEP) of 5 cmH2O. The cri- Patients with COVID-19 ARDS demonstrate significant het-
teria for the PaO2/FIO2 ratio were modified in COVID-19 erogeneity in respiratory mechanics, similar to patients with
ARDS to improve detection of mild-moderate disease between ARDS from other causes, and average lung recruitability is
150 mmHg and 200 mmHg, and moderate-severe disease <150 similar in patients with and without COVID-19.27 When hyp-
mmHg. Another notable difference with COVID-19 ARDS is oxemia and lung mechanics are managed properly, mortality
the delayed onset of eight-to-12 days from symptom onset, from COVID-19 ARDS is similar to mortality from other
which falls outside the one-week onset of the Berlin ARDS causes of ARDS.28 Spontaneous pneumothorax, pneumome-
criteria.12,13 In resource-strained settings, the Kigali modifica- diastinum, and subcutaneous emphysema have been reported
tion of the Berlin criteria offers a streamlined algorithm, which as complications of COVID-19 pneumonia and should be
uses oxygen saturation/FIO2 instead of PaO2/FIO2 and elimi- ruled out in patients with rapid clinical deterioration in the
nates the PEEP requirement.14 setting of COVID-19 ARDS.29
The RECOVERY trial demonstrated impressive mortality
ARDS Pathophysiology reduction with the use of steroids in COVID-19 ARDS,
whereas older studies failed to demonstrate benefit from ste-
Diffuse alveolar damage occurs in ARDS as a result of neu- roids in traditional ARDS. It is likely that attenuating a dysre-
trophil-related epithelial necrosis, with subsequent interstitial gulated inflammatory response in all-comers of ARDS may be
flooding followed by endothelial injury. This results in ventila- a target in need of revisitation.30,31
tion-to-perfusion mismatch and right-to-left intrapulmonary
shunting, leading to worsened deadspace ventilation and
Validated ARDS Therapies: LPV, Prone Positioning, and
reduced lung compliance. After the initial exudative insult, a
Restrictive Fluid Management
fibroproliferative phase of ARDS causes scarring responsible
for worsening lung compliance and long-term pulmonary LPV
recovery.2
The angiotensin-converting enzyme 2 (ACE2) receptor has Despite emerging techniques in diagnostics and therapies,
been implicated as the entry receptor of severe acute supportive care and LPV strategies aimed at mitigating
1190 C. Welker et al. / Journal of Cardiothoracic and Vascular Anesthesia 36 (2022) 11881195

iatrogenic damage from mechanical ventilation remain the pil- diastolic area to left ventricular end-diastolic area (RVEDA/
lar of ARDS therapy. During mechanical ventilation, lung LVEDA) ratio and septal dyskinesia.40 Prone positioning, in
injury can occur on either end of the pulmonary hysteresis conjunction with LPV, is a well-validated therapy in ARDS,
curve where overdistention can cause volutrauma and baro- and a clear mortality benefit has been demonstrated when used
trauma, whereas negative transpulmonary pressures during in a protocolized fashion in ten-to-12-hour sessions.41 Prone
exhalation can cause atelectrauma from repetitive small airway positioning in awake, non-intubated patients with COVID-19
collapse and reexpansion. A recent systematic review and pneumonia has been shown to improve oxygenation, but the
meta-analysis confirmed the tenets of LPV (ie, tidal volume effect on survival remains unclear.42 Successful proning has
limited to 4-8 mL/kg [predicted body weight based on height], been described in both awake and intubated pregnant patients
plateau pressures <30 cmH2O, and higher PEEP).32 A signifi- with COVID-19.43 Current guidelines from the National Insti-
cant recent addition revealed that lower driving pressures tutes of Health recommend that mechanically ventilated
(defined as plateau pressure minus PEEP) are associated with patients with moderate-to-severe COVID-19 ARDS undergo
decreased mortality.33 Higher PEEP titration generally is con- prone ventilation for 12- to-16 hours per day.44
sidered to be a reasonable strategy to aid in oxygenation.34
The ART trial, a recent multicenter, randomized controlled Fluid Management
trial, showed worsened 28-day mortality with such a strategy,
although the results should be interpreted with caution because Fluid overload has deleterious effects in ARDS, as shown
the trial used recruitment maneuvers as high as 45 cmH2O.35 by the landmark FACTT trial, in which conservative fluid
High-frequency oscillation is not recommended in ARDS.34 management resulted in fewer days of mechanical ventila-
Given the similar respiratory mechanics between patients with tion and intensive care unit (ICU) stay.45 Positive-pressure
ARDS from COVID-19 versus other causes, and absence of ventilation and increased pulmonary vascular constriction
evidence to the contrary, patients with COVID-19 should be can independently increase fluid retention and interstitial
ventilated with traditional lung-protective strategies and indi- edema regardless of fluid administration.46 Based on recent
vidualized levels of PEEP.32 randomized controlled trials and meta-analyses, a fluid-
Esophageal manometry has gained popularity as a tool for restrictive strategy remains the preferred management, with
individually tailoring plateau and driving pressures. This benefits including enhanced oxygenation, fewer days on
technology estimates the transpulmonary pressure (the pres- mechanical ventilation, and fewer days in the ICU.46,47 A
sure gradient across alveoli) by accounting for intrapleural recent large, retrospective study also suggested mortality
pressures, in contrast to traditional direct airway pressure benefit with a fluid restrictive strategy.48 Although there is
measurements.36 Measuring the end-inspiratory and end- no consensus on specific fluid restriction goals, limiting
expiratory pressures in both the airway and the esophagus maintenance intravenous fluids and active diuresis are com-
generates a transpulmonary pressure profile that is useful in mon clinical practices.
obesity, when chest wall compliance can become so poor that
the effective PEEP can remain negative even with high PEEP ARDS Rescue Therapies: Paralysis, Inhaled Pulmonary
settings. In the 2019 EPVent-2 randomized controlled trial, Vasodilators, and Venovenous ECMO
there was no difference in mortality between ventilation man-
agement using esophageal manometry and traditional PEEP/ Even with the previously discussed standard ARDS thera-
FIO2 titration. However, the control PEEP was never lower pies, refractory hypoxemia in ARDS is a common clinical
than 20 cmH2O, and a prone position strategy was not used in feature requiring rescue therapies to maintain adequate oxy-
the trial, two factors that limit generalizability.37 Esophageal genation. Neuromuscular blockade commonly has been
manometry remains heavily institutionally-dependent with used to promote ventilator synchrony, particularly after the
unclear benefit. landmark ACURASYS trial demonstrated a 90-day mortal-
ity benefit from 48 hours of continuous cisatracurium infu-
Prone Positioning in ARDS and COVID-19 sion in a multicenter, randomized controlled trial.49
However, the mortality benefit has come into question with
Prone positioning is a well-established therapy in ARDS, the subsequent ROSE trial in 2019, which demonstrated no
with a 90-day mortality benefit first elucidated in the landmark mortality benefit.50 Even though the ROSE trial had a large,
PROSEVA trial.38 Prone positioning optimizes lung recruit- randomized cohort, it was unblinded and a significant num-
ment and lung perfusion while augmenting the functional size ber of patients who received paralysis were excluded from
of the lung, which can prevent regional barotrauma. Prone the trial, which may have favored the control group. In addi-
positioning also enhances secretion clearance and may tion, the ROSE trial was stopped for futility, which rendered
decrease rates of ventilator-associated pneumonia.39 Prone the trial underpowered. Despite conflicting data, paralysis
positioning also may alleviate the right ventricular strain that remains common practice in severe ARDS as both rescue
occurs secondary to increased pulmonary vascular resistance and routine therapy.
during hypoxemia and hypercarbia. Right ventricular strain Pulmonary vasodilators, such as inhaled nitrous oxide, never
has been shown to demonstrably improve on echocardiography have demonstrated mortality benefit and have been believed to
during prone positioning, with a reduced right ventricular end- contribute to renal injury. However, they remain in clinical use
 C. Welker et al. / Journal of Cardiothoracic and Vascular Anesthesia 36 (2022) 11881195 1191

for refractory hypoxemia.51 Evidence remains limited. Recent Traditional ARDS Pharmacologic Therapies
Cochrane reviews suggest that even though inhaled nitrous
oxide and inhaled prostaglandins may confer transiently Aside from glucocorticoids in COVID-19 ARDS, no other
improved oxygenation, they likely are harmful and worsen pharmacologic therapy has been shown to decrease mortality
renal function.52,53 in ARDS. Glucocorticoids have been studied extensively in
Venovenous (VV)-ECMO clearly can improve oxygenation nonCOVID-19 ARDS and traditionally have been believed
in severe ARDS, but there remains a paucity of clinical trials, to worsen mortality.59 Recent randomized trials and meta-
including the recent randomized controlled EOLIA trial, which analyses have suggested mixed results with some signal of
showed no mortality benefit but was limited by significant faster clinical improvement with glucocorticoids.60,61
treatment crossover.54,55 Proposed benefits of VV-ECMO Other potential pharmacologic therapies in traditional
include the ability to “rest” the lungs to mitigate iatrogenesis ARDS, including dual budesonide and formoterol therapy,
or even facilitate extubation followed by physical therapy. which has been shown to reduce hospital length of stay,
Exclusion criteria vary by institution but typically include pro- improve oxygenation and perhaps even attenuate severity.62
longed mechanical ventilation, older age, obesity, active can- Sivelestat sodium, a neutrophil elastase inhibitor, may improve
cer, neurologic injury, and unwitnessed cardiac arrest. Even oxygenation but with no mortality or duration benefit.63 A
though VV-ECMO cannulation is highly dependent on institu- recent randomized controlled trial showed no improvement
tion and resource availability, it commonly is used as rescue with adult surfactant, and this therapy currently is not recom-
therapy, and referral should be considered early in the disease mended.64 Statins also have been investigated as ARDS treat-
course. Because of the resource-intensive nature of ECMO ment based on animal studies but have not been found to be
and the large pool of potential candidates, patients with beneficial in humans.65 A summary of recent and pertinent
COVID-19 should exhaust traditional therapies before initia- clinical trial outcomes for traditional ARDS can be found in
tion of ECMO. Stringency of selection criteria should be Table 1.33,35,37,38,45,49,50,54,55,59,60,62,64
adjusted as healthcare systems escalate in surge capacity.56
The mortality rate of patients with COVID-19 ARDS requiring COVID-19 ARDS Pharmacologic Therapies
any form of ECMO has been estimated at 39%.57 Optimal
mechanical ventilation strategies on VV-ECMO in the setting Patients hospitalized with COVID-19 ARDS requiring sup-
of COVID-19 ARDS remain unclear.58 plemental oxygen or invasive mechanical ventilation had

Table 1
Key ARDS Trials

Topic and Trial Author Year Outcome

45
Restrictive v liberal fluid management (FACTT trial) Wiedemann et al. 2006 Conservative fluid strategy and shortened days of mechanical ventilation
and intensive care (2.5 d [p < 0.001] and 2.2 d [p < 0.001]),
respectively).
Steroids Steinberg et al.59 2006 No statistical 60-d mortality difference with steroid use (p = 1.0).
Steroids Meduri et al.60 2016 Improved 28-d mortality with steroid use (20% v 33%; p = 0.006), decrease
in days of mechanical ventilation (5.7 d p < 0.001), and ICU-free days
(4.4 d; p < 0.001).
ECMO (CESAR trial) Peek et al.54 2009 Relative risk reduction of death associated with ECMO-capable facility
(RR 0.69, p = 0.03, NNT 7).
ECMO (EOLIA trial) Combes et al.55 2018 No statistical difference in 60-d mortality with VV-ECMO v standard care
(p = 0.09). Significant crossover likely diluted positive benefit of ECMO.
Prone position (PROSEVA trial) Gu
erin et al.38 2013 Proning improved mortality in severe ARDS by 16.8% (p < 0.001).
Neuromuscular blockade (ACURASYS trial) Papazian et al.49 2010 Neuromuscular blockade reduces mortality with AHR 0.68 (p = 0.04).
Neuromuscular blockade (ROSE trial) Moss et al.50 2019 No difference in 90-d mortality with neuromuscular blockade; trial
stopped for futility.
Driving pressure Amato et al.33 2015 High driving pressures associated with higher mortality (RR 1.4; p <
0.001).
Recruitment maneuvers (ART trial) Cavalcanti et al.35 2017 Large recruitment maneuvers (45 cmH2O) associated with worse 28-d
mortality (HR 1.2; p = 0.041).
Esophageal manometry (EPVENT-2 trial) Beitler et al.37 2019 Routine esophageal manometry offers little benefit over empirical PEEP
titration.
Budesonide/formoterol Festic et al.62 2017 Combination budesonide and formoterol resulted in better oxygenation
(p = 0.01).
Surfactant Willson et al.64 2015 Calfactant administration was not associated with improved survival,
lengths of stay, or oxygenation.

Abbreviations: AHR, adjusted hazard ratio; ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; HR, hazard ratio; ICU,
intensive care unit; NNT, number needed to treat; PEEP, positive end-expiratory pressure; RR, relative risk; VV, venovenous.
1192 C. Welker et al. / Journal of Cardiothoracic and Vascular Anesthesia 36 (2022) 11881195

lower 28-day mortality with the use of dexamethasone 6 mg patients with COVID-19 who required ICU admission.80 This
daily for ten days. There was no mortality benefit for those was much higher than the incidence of 2.8%-to-5.6% reported
receiving no respiratory support.30 In patients with moderate in nonCOVID-19 hospitalized patients.81-83 Subgroup analy-
or severe COVID-19 ARDS receiving standard of care, addi- sis of a retrospective study showed that among mechanically
tion of a ten-day course of intravenous dexamethasone (20 mg ventilated patients, mortality was 29.1% with therapeutic anti-
daily for five days followed by 10 mg daily for five days) coagulation compared with 62.7%. However, the study did not
increased the number of ventilator-free days during the first report patient characteristics, indications for anticoagulation,
28 days.31 Studies have failed to demonstrate a benefit with or descriptions of other therapies and did not discuss survival
hydrocortisone or methylprednisolone.66,67 A recent system- bias.84 A meta-analysis by the American Society of Hematol-
atic review and meta-analysis demonstrated that corticosteroid ogy compared therapeutic with prophylactic anticoagulation
treatment for COVID-19 infection was associated with signifi- and found that therapeutic anticoagulation decreased pulmo-
cant reductions in mortality and need for invasive mechanical nary embolism (odds ratio 0.09) but significantly increased
ventilation, but may be associated with delayed viral clearance major bleeding (odds ratio 3.84), with a statistically insignifi-
and increased secondary infections.68 cant decrease in mortality.85 Large multicenter trials compar-
Remdesivir has been shown to shorten time to recovery in ing therapeutic with prophylactic anticoagulation are in
adult patients hospitalized with COVID-19 with evidence of progress. At present, the National Institutes of Health recom-
lower respiratory tract infection.69 At the time of this writing, mends that all hospitalized COVID-19 patients without evi-
the National Institutes of Health guidelines did not recommend dence of venous thromboembolism should be placed on
remdesivir for patients who require mechanical ventilation prophylactic anticoagulation, while acknowledging that there
because of insufficient evidence of benefit in this population.44 is controversy regarding initiating intermediate-dose anticoa-
Many other therapies currently are being studied, including gulation among critically ill patients.44
convalescent plasma, monoclonal antibodies against the sur- Although SARS-CoV-2 viral entry into cells is mediated by
face spike glycoprotein of the SARS-CoV-2 virus, mesenchy- the ACE2 receptor, and chronic use of angiotensin-converting
mal stem cell infusion, ruxolitinib, interferon-a2b, and enzyme inhibitors or angiotensin-receptor blockers theoreti-
tocilizumab.70-76 Hydroxychloroquine has not been associated cally upregulates ACE2 receptor expression, patients who are
with a significant clinical benefit.77,78 on chronic angiotensin-converting enzyme inhibitors or angio-
COVID-19 infection results in an inflammatory and pro- tensin- receptor blockers do not have a clinically significantly
thrombotic state.79 A systematic review and meta-analysis increased risk of COVID-19 diagnosis or hospitalization.86 A
demonstrated a venous thromboembolism incidence of 14.1% summary of important COVID-19 ARDS trials can be found
among all patients hospitalized with COVID-19 and 22.7% in in Table 2.30,31,66,67,69,71,74,76-78

Table 2
Key COVID-19 ARDS Trials

Topic and Trial Author Year Outcome

30
Dexamethasone (RECOVERY trial) Horby et al. 2020 Dexamethasone (6 mg daily for up to 10 d) was associated with lower 28-d mortality
among those receiving supplemental oxygen or invasive mechanical ventilation but not
those receiving no respiratory support.
High-dose dexamethasone (CoDEX trial) Tomazini et al.31 2020 Dexamethasone (20 mg daily for 5 d then 10 mg daily for 5 d) resulted in a statistically
significant increase in number of ventilator-free days over the first 28 d for patients with
moderate-to-severe COVID-19 ARDS.
Hydrocortisone (CAPE COVID trial) Dequin et al.66 2020 Low dose hydrocortisone resulted in no significant difference in the rate of treatment
failure at d 21 (defined as death or persistent mechanical ventilation or high-flow
oxygen)
Methylprednisolone (METCOVID trial) Jeronimo et al.67 2020 Methylprednisolone 0.5 mg/kg twice daily for 5 d did not reduce 28-d mortality.
Remdesivir (ACTT-1 trial) Beigel et al.69 2020 Remdesivir (200 mg loading dose then 100 mg daily for 9 d) was superior to placebo at
shortening time to recovery in patients with COVID-19 lower respiratory tract
infection.
Tocilizumab (EMPACTA trial) Salama et al.76 2021 Among patients not on mechanical ventilation, tocilizumab reduced the likelihood of
progression to mechanical ventilation or death but did not improve survival.
Ruxolitinib Cao et al.74 2020 No statistically significant difference was observed, but ruxolitinib recipients trended
toward faster clinical improvement, greater chest CT improvement, and faster recovery
from lymphopenia.
Convalescent plasma (PLACID trial) Agarwal et al.71 2020 Convalescent plasma did not reduce progression to severe COVID-19 or all-cause 28-d
mortality in patients with moderate COVID-19.
Hydroxychloroquine (ORCHID trial) Self et al.77 2020 Hydroxychloroquine did not significantly improve clinical status at 14 d among adults
hospitalized with COVID-19 respiratory illness.
Hydroxychloroquine (RECOVERY trial) Horby et al.78 2020 Hydroxychloroquine did not reduce 28-d mortality in patients hospitalized with COVID-
19.

Abbreviations: ARDS, acute respiratory distress syndrome; COVID-19, coronavirus disease 2019; CT, computed tomography.
 C. Welker et al. / Journal of Cardiothoracic and Vascular Anesthesia 36 (2022) 11881195 1193

Conclusion modification of the Berlin definition. Am J Respir Crit Care Med

2016;193:52–9.
ARDS is a heterogeneous disease characterized by diffuse 15 Zamorano Cuervo N, Grandvaux N. ACE2: Evidence of role as entry
receptor for SARS-CoV-2 and implications in comorbidities. Elife 2020;9.
alveolar damage with likely variable phenotypic penetration. 16 Camporota L, Vasques F, Sanderson B, et al. Identification of pathophysio-
ARDS remains underdiagnosed and associated with high mor- logical patterns for triage and respiratory support in COVID-19. Lancet
tality despite recent advances in diagnostics and therapeutics. Respir Med 2020;8:752–4.
LPV and prone positioning remain the mainstay of supportive 17 Gibelin A, Parrot A, Maitre B, et al. Acute respiratory distress syndrome
care. The benefit of rescue therapies remains unclear. Even mimickers lacking common risk factors of the Berlin definition. Intensive
Care Med 2016;42:164–72.
though a dysregulated inflammatory response and endothelial 18 Calfee CS, Janz DR, Bernard GR, et al. Distinct molecular phenotypes of
thrombosis may be key features differentiating COVID-19 direct vs indirect ARDS in single-center and multicenter studies. Chest
from traditional ARDS, ultimately they are the same clinical 2015;147:1539–48.
disease process. COVID-19 ARDS should be treated with the 19 Papazian L, Calfee CS, Chiumello D, et al. Diagnostic workup for ARDS
existing validated therapies of LPV and prone positioning. patients. Intensive Care Med 2016;42:674–85.
20 Calfee CS, Delucchi K, Parsons PE, et al. Subphenotypes in acute respira-
tory distress syndrome: Latent class analysis of data from 2 randomised
Acknowledgments controlled trials. Lancet Respir Med 2014;2:611–20.
21 Mrozek S, Jabaudon M, Jaber S, et al. Elevated plasma levels of sRAGE
The authors acknowledge Barbara Weisser, Mayo Clinic are associated with nonfocal CT-based lung imaging in patients with
ARDS: A prospective multicenter study. Chest 2016;150:998–1007.
Academic Support Office, Scottsdale, AZ.
22 Famous KR, Delucchi K, Ware LB, et al. Acute respiratory distress syn-
drome subphenotypes respond differently to randomized fluid management
Conflict of Interest strategy. Am J Respir Crit Care Med 2017;195:331–8.
23 Reilly JP, Christie JD, Meyer NJ. Fifty years of research in ARDS. Geno-
The authors have no conflict of interest or financial involve- mic contributions and opportunities. Am J Respir Crit Care Med
ment with this manuscript. 2017;196:1113–21.
24 Christie JD, Wurfel MM, Feng R, et al. Genome wide association identifies
PPFIA1 as a candidate gene for acute lung injury risk following major
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