key: cord-0966805-dn9leknd
authors: Welker, Carson; Huang, Jeffrey; Gil, Iván J Núñez; Ramakrishna, Harish
title: 2021 Acute Respiratory Distress Syndrome (ARDS) Update with COVID 19 Focus
date: 2021-02-27
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2021.02.053
sha: 78fc901aa6b89955d5586a8365ef38e9a1385ff3
doc_id: 966805
cord_uid: dn9leknd

Acute Respiratory Distress Syndrome (ARDS) is a heterogeneous lung disease responsible for significant morbidity and mortality among critically ill patients, including those infected with SARS-CoV-2, the virus responsible for COVID-19. Despite recent advances in pathophysiology, diagnostics, and therapeutics, ARDS is dangerously underdiagnosed and supportive lung protective ventilation and prone position remain the mainstay intervention. Rescue therapies including neuromuscular blockade and veno-venous extracorporeal membrane oxygenation (VV-ECMO) remain a key component of clinical practice though benefits are uncertain. While COVID-19 ARDS has some distinguishing features from traditional ARDS, including delayed onset, hyperinflammatory response, and pulmonary microthrombi, it is clinically similar to traditional ARDS and should be treated with established supportive therapies.

Advances in ARDS diagnosis and therapy have developed steadily over the last fifty years.

However, mortality has remained static at 30-40% the last ten years and the disease is underdiagnosed with disparate effects on race, poverty and sex. 1 Despite its novelty, COVID-19 ARDS has clear cross-over with traditional ARDS therapy and lung protective ventilation and prone position should be widely employed.

Since the seminal work of the ARDS Network trial there has been minimal improvement in mortality rates and incidence of ARDS. 2 Mortality rates remain between 34.9% and 40%, depending on severity. 3 Additionally, recognition of ARDS ranges from 51.3% to 78.5% resulting in failure to implement LPV strategies. 4 ARDS mortality rates disproportionately affect black and hispanic patients compared to white patients, and men compared to women, with an outsized burden on low income patients and developing countries. 1, 5 Living in higher population density and Black ethnicity have shown to have higher risk for hospitalization in COVID-19, although no statistical racial trend has been found for mortality. 6, 7 Morbidity in ARDS survivors remains a concern with high incidence of critical illness polyneuropathies, cognitive impairment, PICS, PTSD and employment loss. 8, 9 The heterogeneity of causes and presentations of ARDS results in dangerous underdiagnosis.

Traditional risk factors such as pneumonia, aspiration, pulmonary contusion, inhalational injury, sepsis, pancreatitis, blood product transfusion, and smoking history remain important risk factors. 10, 11 Diagnosis of ARDS remains largely clinical based on the Berlin criteria, which requires a patient to have bilateral opacification on chest X-ray or CT within 7 days of a clinical insult that cannot otherwise be explained by pulmonary edema from heart failure. 12 The Berlin criteria stratifies disease severity based on the PaO2/FiO2 (P/F) ratio: mild (200 mmHg < PaO2/FiO2 ≤ 300 mmHg), moderate (100 mmHg < PaO2/FiO2 ≤ 200 mmHg), and severe (PaO2/FiO2 ≤ 100 mmHg), assuming PEEP at 5 cm H2O. This P/F criteria has been modified in COVID-19 ARDS to improve detection of mild-moderate disease between 150 mmHg and 200 mmHg, and moderate-severe less than 150 mmHg. Another notable difference with COVID-19 ARDS is the delayed onset of 8 to 12 days from symptom onset, which falls outside the 1 week onset Berlin ARDS criteria. 12, 13 In resource restrained settings, the Kigali modification of the Berlin criteria offers a streamlined algorithm which uses SpO2/FiO2 instead of PaO2/FiO2 and eliminating the PEEP requirement. 14

Diffuse alveolar damage occurs in ARDS due to neutrophil-related epithelial necrosis with subsequent interstitial flooding followed by endothelial injury. This results in ventilation-toperfusion (V/Q) mismatch and right-to-left intrapulmonary shunting, leading to worsened deadspace ventilation and reduced lung compliance. After the initial exudative insult, a fibroproliferative phase of ARDS causes scarring responsible for worsening lung compliance and long term pulmonary recovery. 2 The angiotensin-converting enzyme 2 (ACE2) receptor has been implicated as the entry receptor of SARS-CoV-2. 15 Mechanisms of pulmonary perfusion dysregulation in COVID-19 include abolition of hypoxic pulmonary vasoconstriction, excessive pulmonary vasoconstriction, and thrombosis. 16 Clinical course on presentation with COVID-19 typically follows one of three patterns: hyperacute respiratory failure requiring immediate intubation, indolent course with only moderate work of breathing, or a biphasic course with initially indolent course followed by acute deterioration typically after 5-7 days. 16 A host of biomarkers are released in the initial pathophysiological cascade providing new opportunities for early diagnosis which is especially important because ARDS can develop in the absence of traditional risk factors. 17 A recent study suggested that some patients may have increased biomarkers associated with direct lung injury, whereas other patients may have biomarkers associated with hyper-inflammatory lung injury. 18 Further investigations have revealed the possibility of two subphenotypes: a hyperinflammatory response characterized by IL-6, IL-8 and TNF-1 as well as a hypoinflammatory response associated with less biomarkers and an attenuated shock state 19, 20 Stratified fluid management strategies and differing ventilatory managements based on subphenotypes have been suggested. 21, 22 Despite over 40 genes associated with development of ARDS, subphenotypic diagnostics have had little bearing on current clinical practice of ARDS and no gene-specific loci for ARDS has been identified. 23, 24 Early anecdotal reports have also described high and low compliance phenotypes with COVID-19 ARDS. 25 The RECOVERY trial demonstrated impressive mortality reduction with the use of steroids in COVID-19 ARDS while older studies have failed to demonstrate benefit from steroids in traditional ARDS. It is likely that attenuating a dysregulated inflammatory response in allcomers of ARDS may be a target in need of revisitation. 30, 31 Validated ARDS Therapies: Lung Protective Ventilation (LPV),

Despite emerging techniques in diagnostics and therapies, supportive care and lung protective ventilation (LPV) strategies aimed at mitigating iatrogenic damage from mechanical ventilation remain the pillar of ARDS therapy. During mechanical ventilation, lung injury can occur on either end of the pulmonary hysteresis curve where overdistention can cause volutrauma and barotrauma while negative transpulmonary pressures during exhalation can cause atelectrauma from repetitive small airway collapse and re-expansion. A recent systematic review and metaanalysis confirms the tenets of LPV: tidal volume limited to 4-8cc/kg (predicted body weight based on height), plateau pressures less than 30 cm H2O and higher positive end-expiratory pressure (PEEP). 32 A significant recent addition reveals lower driving pressures (defined as plateau pressure minus PEEP) are associated with decreased mortality. 33 Higher PEEP titration is generally considered to be a reasonable strategy to aid in oxygenation. 34 The ART trial, a recent multicenter, randomized controlled trial, showed worsened 28-day mortality with such a strategy, although the results should be interpreted with caution as this trial employed recruitment maneuvers as high as 45 cm H2O. 35 High frequency oscillation is not recommended in ARDS. 34 Given the similar respiratory mechanics between patients with ARDS from COVID-19 versus other causes, and absence of evidence to the contrary, patients with COVID-19 should be ventilated with traditional lung protective strategies and individualized levels of PEEP. 32 Esophageal manometry has gained popularity as a tool for individually tailoring plateau and driving pressures. This technology estimates transpulmonary pressure (the pressure gradient across alveoli) by accounting for intrapleural pressures, in contrast to traditional direct airway pressure measurements. 36 Measuring the end-inspiratory and end-expiratory pressures in both the airway and the esophagus generates a transpulmonary pressure profile that is useful in obesity, where chest wall compliance can become so poor that the effective PEEP can remain negative even with high PEEP settings. In the 2019 EPVent-2 randomized control trial, there was no difference in mortality between ventilation management using esophageal manometry and traditional PEEP/FiO2 titration. However, the control PEEP was never lower than 20 cm H2O and prone position strategy was not used in the trial, two factors that limit generalizability. 37 Esophageal manometry remains heavily institutionally dependent with unclear benefit.

Prone positioning is a well-established therapy in ARDS with a 90-day mortality benefit first elucidated in the landmark PROSEVA trial. 38 Prone positioning optimizes lung recruitment and lung perfusion while augmenting the functional size of the lung which can prevent regional barotrauma. Prone positioning also enhances secretion clearance and may decrease rates of ventilator-associated pneumonia (VAP). 39 Prone positioning may also alleviate the right ventricular strain that occurs secondary to increased pulmonary vascular resistance during hypoxemia and hypercarbia. RV strain has been shown to demonstrably improve on echocardiography during prone positioning with reduced RVEDA/LVEDA ratio and septal dyskinesia. 40 Prone positioning, in conjunction with LPV, is a well validated therapy in ARDS and a clear mortality benefit has been demonstrated when employed in a protocolized fashion in 10-12 hour sessions. 41 Prone positioning in awake non-intubated patients with COVID-19 pneumonia has been shown to improve oxygenation, but the effect on survival remains unclear. 42 Successful proning has been described in both awake and intubated pregnant patients with COVID-19 disease. 43 Current guidelines from the NIH recommend that mechanically ventilated patients with moderate-to-severe COVID-19 ARDS undergo prone ventilation for 12 to 16 hours per day. 44

Fluid overload has deleterious effects in ARDS as shown by the landmark FACTT trial where conservative fluid management resulted in fewer days of mechanical ventilation and ICU stay. 45 Positive-pressure ventilation and increased pulmonary vascular constriction can independently increase fluid retention and interstitial edema regardless of fluid administration. 46 Based on recent randomized controlled trials and meta-analysis, a fluid restrictive strategy remains the preferred management, with benefits including enhanced oxygenation, fewer days on mechanical ventilation, and fewer days in the ICU. 46, 47 A recent, large retrospective study has also suggested mortality benefit with a fluid restrictive strategy. 48 While there is no consensus on specific fluid restriction goals, limiting maintenance intravenous fluids and active diuresis are common clinical practices.

Even with the previously discussed standard ARDS therapies, refractory hypoxemia in ARDS is a common clinical feature requiring rescue therapies to maintain adequate oxygenation. Neuromuscular blockade has commonly been used to promote ventilator synchrony, particularly after the landmark ACURASYS trial demonstrated a 90-day mortality benefit from 48 hours of continuous cisatracurium infusion in a multicenter, randomized control trial. 49 However, the mortality benefit has come into question with the subsequent ROSE trial in 2019 which demonstrated no mortality benefit. 50 While the ROSE trial had a large, randomized cohort, it was unblinded and a significant number of patients who received paralysis were excluded from the trial, which may have favored the control group. Additionally, the ROSE trial was stopped for futility which rendered the trial underpowered. Despite conflicting data, paralysis remains common practice in severe ARDS as both rescue and routine therapy.

Pulmonary vasodilators, such as inhaled nitrous oxide (iNO), have never demonstrated mortality benefit and have been thought to contribute to renal injury. However, they remain in clinical use for refractory hypoxemia. 51 Evidence remains limited. Recent Cochrane reviews suggest that while iNO and inhaled prostaglandins may confer transiently improved oxygenation, they are likely harmful and worsen renal function. 52, 53 VV-ECMO can clearly improve oxygenation in severe ARDS, but there remains a paucity of clinical trials, including the recent randomized controlled EOLIA trial, which showed no mortality benefit but was limited by significant treatment crossover. 54, 55 Proposed benefits of VV-ECMO include the ability to "rest" the lungs to mitigate iatrogenesis or even facilitate extubation followed by physical therapy. Exclusion criteria vary by institution but typically include prolonged mechanical ventilation, older age, obesity, active cancer, neurological injury, and unwitnessed cardiac arrest. While VV-ECMO cannulation is highly dependent on institution and resource availability, it is commonly used as rescue therapy and referral should be considered early in the disease course. Due to the resource-intensive nature of ECMO and the large pool of potential candidates, patients with COVID-19 should exhaust traditional therapies prior to initiation of ECMO. Stringency of selection criteria should be adjusted as health care systems escalate in surge capacity. 56 The mortality rate of patients with COVID-19 ARDS requiring any form of ECMO has been estimated at 39%. 57 Optimal mechanical ventilation strategies on VV-ECMO in the setting of COVID-19 ARDS remain unclear. 58

Aside from glucocorticoids in COVID-19 ARDS, no other pharmacological therapy has been shown to decrease mortality in ARDS. Glucocorticoids have been trialed extensively in non-COVID-19 ARDS and have traditionally been thought to worsen mortality. 59 Recent randomized trials and meta-analysis have suggested mixed results with some signal of faster clinical improvement with glucocorticoids. 60, 61 Other potential pharmacological therapies in traditional ARDS including dual budesonide and formoterol therapy which has been shown to reduce hospital length of stay, improve oxygenation and perhaps even attenuate severity. 62 Sivelestat sodium, a neutrophil elastase inhibitor, may improve oxygenation but with no mortality or duration benefit. 63 A recent randomized controlled trial showed no improvement with adult surfactant and this therapy is not currently recommended. 64 Statins have also been investigated as ARDS treatment based on animal studies, but have not been found to be beneficial in humans. 65 A summary of recent and pertinent clinical trial outcomes for traditional ARDS can be found in Table 1 .

Patients hospitalized with COVID-19 ARDS requiring supplemental oxygen or invasive mechanical ventilation had lower 28-day mortality with the use of dexamethasone 6 mg daily for 10 days. There was no mortality benefit for those receiving no respiratory support. 30 In patients with moderate or severe COVID-19 ARDS receiving standard of care, addition of a 10 day course of intravenous dexamethasone (20 mg daily for 5 days followed by 10 mg daily for 5 days) increased the number of ventilator free days during the first 28 days. 31 Studies have failed to demonstrate a benefit with hydrocortisone or methylprednisolone. 66,67 A recent systematic review and meta-analysis demonstrated that corticosteroid treatment for COVID-19 infection was associated with a significant reduction in mortality and need for invasive mechanical ventilation but may be associated with delayed viral clearance and increased secondary infections. 68

Remdesivir has been shown to shorten time to recovery in adult patients hospitalized with COVID-19 with evidence of lower respiratory tract infection. 69 At the time of this writing, the National Institutes of Health guidelines do not recommend remdesivir for patients who require mechanical ventilation due to insufficient evidence of benefit in this population. 44 Many other therapies are currently being studied including convalescent plasma, monoclonal antibodies against the surface spike glycoprotein of the SARS-CoV-2 virus, mesenchymal stem cell infusion, ruxolitinib, interferon-α2b, and tocilizumab. [70] [71] [72] [73] [74] [75] [76] Hydroxychloroquine has not been associated with a significant clinical benefit. 77, 78 COVID-19 infection results in an inflammatory and prothrombotic state. 79 A systematic review and meta-analysis demonstrated a venous thromboembolism (VTE) incidence of 14.1% among all patients hospitalized with COVID-19 and 22.7% in patients with COVID-19 who require ICU admission. 80 This is much higher than the incidence of 2.8% to 5.6% reported in non-COVID-19 hospitalized patients. [81] [82] [83] Subgroup analysis of a retrospective study showed that among mechanically ventilated patients, mortality was 29.1% with therapeutic anticoagulation compared to 62.7%. However the study did not report patient characteristics, indications for anticoagulation, or descriptions of other therapies and did not discuss survival bias. 84 A metaanalysis by the American Society of Hematology compared therapeutic to prophylactic anticoagulation and found that therapeutic anticoagulation decreased pulmonary embolism (OR 0.09), but significantly increased major bleeding (OR 3.84) with a statistically insignificant decrease in mortality. 85 Large multicenter trials comparing therapeutic to prophylactic anticoagulation are in progress. At present, the NIH recommends that all hospitalized COVID-19 patients without evidence of venous thromboembolism should be placed on prophylactic anticoagulation, while acknowledging that there is controversy regarding initiating intermediate dose anticoagulation among critically ill patients. 44 While SARS-CoV-2 viral entry into cells is mediated by the ACE2 receptor, and chronic use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) theoretically upregulates ACE2 receptor expression, patients who are on chronic ACE inhibitors or ARBs do not have a clinically significantly increased risk of COVID-19 diagnosis or hospitalization. 86 A summary of important COVID-19 ARDS trials can be found in Table 2 . 

Mortality Trends of Acute Respiratory Distress Syndrome in the United States from 1999 to 2013

Acute respiratory distress syndrome

Current incidence and outcome of the acute respiratory distress syndrome

Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units

Geo-economic variations in epidemiology, patterns of care, and outcomes in patients with acute respiratory distress syndrome: insights from the LUNG SAFE prospective cohort study

Factors Associated With Death in Critically Ill Patients With Coronavirus Disease 2019 in the US

Characteristics Associated With Racial/Ethnic Disparities in COVID-19 Outcomes in an Academic Health Care System

Recovery and outcomes after the acute respiratory distress syndrome (ARDS) in patients and their family caregivers

Long-term outcome after the acute respiratory distress syndrome: different from general critical illness?

Acute Respiratory Distress Syndrome

Cigarette Smoke Exposure and the Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome: the Berlin Definition

Acute respiratory failure in COVID-19: is it "typical

Hospital Incidence and Outcomes of the Acute Respiratory Distress Syndrome Using the Kigali Modification of the Berlin Definition

ACE2: Evidence of role as entry receptor for SARS-CoV-2 and implications in comorbidities

Identification of pathophysiological patterns for triage and respiratory support in COVID-19

Acute respiratory distress syndrome mimickers lacking common risk factors of the Berlin definition

Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies

Diagnostic workup for ARDS patients

Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials

Elevated Plasma Levels of sRAGE Are Associated With Nonfocal CT-Based Lung Imaging in Patients With ARDS: A Prospective Multicenter Study

Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy

Fifty Years of Research in ARDS. Genomic Contributions and Opportunities

Genome wide association identifies PPFIA1 as a candidate gene for acute lung injury risk following major trauma

Management of COVID-19 Respiratory Distress

Guidelines on the management of acute respiratory distress syndrome

Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial

Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial

Prone positioning in severe acute respiratory distress syndrome

Treatment of ARDS With Prone Positioning

Protecting the Right Ventricle in ARDS: The Role of Prone Ventilation

A Comprehensive Review of Prone Position in ARDS

Prone Positioning in Awake, Nonintubated Patients With COVID-19 Hypoxemic Respiratory Failure

Prone Positioning for Pregnant Women With Hypoxemia Due to Coronavirus Disease 2019 (COVID-19)

COVID-19) Treatment Guidelines. National Institutes of Health

Comparison of two fluid-management strategies in acute lung injury

Fluid administration and monitoring in ARDS: which management?

Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis

Impact of Initial Central Venous Pressure on Outcomes of Conservative Versus Liberal Fluid Management in Acute Respiratory Distress Syndrome

Neuromuscular blockers in early acute respiratory distress syndrome

Early Neuromuscular Blockade in the Acute 51

Inhaled nitric oxide therapy in adults

Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults

The use of inhaled prostaglandins in patients with ARDS: a systematic review and meta-analysis

Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome

Extracorporeal Life Support Organization Coronavirus Disease 2019 Interim Guidelines: A Consensus Document from an International Group of Interdisciplinary Extracorporeal Membrane Oxygenation Providers

Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry

Mechanical Ventilation Management during Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome. An International Multicenter Prospective Cohort

Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome

Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature

Pharmacological agents for adults with acute respiratory distress syndrome

Randomized Clinical Trial of a Combination of an Inhaled Corticosteroid and Beta Agonist in Patients at Risk of Developing the Acute Respiratory Distress Syndrome

Effect of sivelestat sodium in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of randomized controlled trials

The Adult Calfactant in Acute Respiratory Distress Syndrome Trial

Statin in the treatment of ALI/ARDS: a systematic review and Meta-analysis based on international databases

Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With COVID-19 (Metcovid): A Randomised, Double-Blind, Phase IIb, Placebo-Controlled Trial

Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes

Remdesivir for the Treatment of Covid-19 -Final Report

Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review

Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial)

Monoclonal Antibodies for Prevention and Treatment of COVID-19

Mesenchymal Stem Cell Infusion Shows Promise for Combating Coronavirus (COVID-19)-Induced Pneumonia

Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial

Interferon-α2b Treatment for COVID-19

Tocilizumab in Patients Hospitalized with Covid-19

Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial

Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19

Prominent changes in blood coagulation of patients with SARS-CoV-2 infection

Risk of venous thromboembolism in patients with COVID-19: A systematic review and meta-analysis

A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients

Prophylaxis in Medical Patients with Enoxaparin Study Group

placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients

Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial

Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19

ASH 2020 guidelines on the use of anticoagulation in patients with COVID-19: Draft recommendations

Renin-angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis

Horby P, et al. 78 2020 Hydroxychloroquine did not reduce 28-day mortality in patients hospitalized with COVID-19.