The Pre-brief
Understanding of the COVID-19 disease process caused by the SARS-2-CoV virus is evolving. While the majority of cases are asymptomatic or result in mild disease, some patients develop acute respiratory distress syndrome (ARDS), a highly inflammatory lung pathology which may persist beyond the infectious period of the virus, and require prolonged ventilator support.1
Pathophysiology
ARDS, a subset of acute lung injury (ALI), is an intense inflammatory response to acute pulmonary (direct) and systemic (indirect) insults. Clinically, this syndrome is characterized by acute hypoxemic respiratory failure and diffuse pulmonary infiltrates on chest x-ray not attributable to poor cardiac function.2 The acute phase of ALI is characterized by diffuse alveolar damage resulting in reduced surfactant production and subsequent exudative fluid accumulation in the lungs with deposition of proteins and inflammatory cells. This is followed by a fibroproliferative phase caused by an amplified inflammatory response and activation of procoagulant pathways. Collagen deposition in the lung parenchyma results in the final fibrotic phase.2
Diagnosis
ARDS is defined and diagnosed according to the Berlin criteria: presence of new or worsening respiratory symptoms within 7 days of a known clinical insult and a combination of acute hypoxemia (PaO2/FiO2 ≤300 mmHg), positive end-expiratory pressure (PEEP) of at least 5 cmH2O in a ventilated patient, and bilateral opacities not fully explained by heart failure or volume overload. Patients with moderate and severe ARDS have a PaO2/FiO2 ≤200 and ≤100, respectively.3
Treatment
The cornerstone of ARDS management is lung protective ventilatory strategies with low tidal volume ventilation (4-8 mL/kg ideal body weight) targeting low plateau pressures <30 cmH2O and use of PEEP >5 cmH2O. For patients with severe ARDS (P/F ratio <100), prone positioning for 12-16 hours a day and use of neuromuscular blocking agents (NMBA) are recommended, although recent literature may change future recommendations for the routine use of NMBA.3,4,5 Detailed discussion on these strategies is beyond the scope of this brief review, but should be acknowledged as the standard of care in modern trials of corticosteroids in ARDS and COVID-19 associated ARDS.
Based on the mechanism and progression of ARDS, corticosteroids would appear to provide benefit by blocking numerous points in the inflammatory pathway. However, use in ARDS has been studied over the past 20 years with mixed results. More recent evaluations appear to show benefit.
Review of Literature: Corticosteroids in ARDS
In 2017, SCCM and ESICM recommended use of corticosteroids for patients with ARDS and a P/F ratio <200 in the critical illness-related corticosteroid insufficiency (CIRCI) guideline.6 This was largely based on the findings from an updated individual patient data analysis of the four largest trials from evaluating initiation of prolonged courses of methylprednisolone in early (<72 hours) and late (≥7 days) onset ARDS which demonstrated a reduced mortality and duration of mechanical ventilation with use of corticosteroids. Hyperglycemia was the only notable complication associated with therapy. The Task Force recommends methylprednisolone 1 mg/kg/day for patients with ARDS up to 7 days from onset and 2 mg/kg/day for persistent ARDS (after day 6 from onset) followed by slow tapers over 13 days.6
Corticosteroids in COVID-19 had been controversial during the initial surges. Cohorts from the Wuhan outbreak received early and uniform administration of corticosteroids, and one small study of 26 patients demonstrated faster improvement of SpO2 and resolution of signs and symptoms of infection with methylprednisolone 1-2 mg/kg/day x 5-7 days.7 However, this study is not yet peer reviewed, and due to concerns of prolonged viral shedding and potential increased all-cause mortality extrapolated from data in influenza, most early U.S. cohorts did not receive corticosteroids.8 Following the initial publication of the Surviving Sepsis Campaign guidelines for management of adult COVID-19, Fang et al. showed low-dose corticosteroids did not prolong viral shedding when administered in late (>7 days after onset) COVID-19 disease.9 This sparked renewed interest in use of corticosteroids for COVID-19 associated ARDS.
It is unclear if ARDS corticosteroid studies can be generalized to COVID-19, but with a paucity of high-quality literature during the beginning of the pandemic, clinicians had no choice but to draw upon this literature including the DEXA-ARDS trial and Meduri methylprednisolone corticosteroid protocols.10,11 Patients assigned dexamethasone 20 mg IV daily x 5 days followed by 10 mg IV daily x 5 days in DEXA-ARDS had a significantly reduced number of ventilator-free days and mortality compared to placebo.10 Re-evaluation of earlier data from the same investigator group of methylprednisolone 2 mg/kg/day demonstrated a reduced mortality prior to extubation, shorter time to extubation, and a greater number of patients successfully extubated. However, more patients in the methylprednisolone group required re-intubation upon treatment discontinuation which was largely attributed to reconstituted SIRS response in the setting of adrenal insufficiency. The authors suggest a more gradual taper may be required in this population, up to 28-30 days.11
The preliminary findings of the RECOVERY trial, a randomized, controlled, open-label study evaluating dexamethasone 6 mg once daily for up to ten days vs. usual care alone in patients hospitalized with COVID-19, showed a significant reduction in 28 day mortality, 21.6% vs. 24.6%, RR 0.83 (95% CI 0.74 to 0.92, p<0.001) with the effect more profound in patients requiring invasive mechanical ventilation, 29.0% vs. 40.7%, RR 0.65 (95% CI 0.51 to 0.82, p<0.001).1 Notably, this study did not report important baseline characteristics to characterize the degree of respiratory impairment (e.g. P/F ratio, oxygen requirements) and concomitant therapies received (e.g. NMBA, prone positioning, etc.) potentially limiting the generalizability to COVID-19 ARDS patients until this data is made available.
In June 2020, The Surviving Sepsis Campaign guidelines for management of COVID-19 updated the recommendations for use of corticosteroids in patients who develop ARDS after re-evaluating data from a Cochrane review plus an additional study and found corticosteroids were associated with reduced mortality and duration of mechanical ventilation.8
The Debrief
- Patients with COVID-19 requiring oxygen support, especially those requiring mechanical ventilation, should be considered for corticosteroid therapy due to improved mortality
- Numerous corticosteroid dosing regimens have been evaluated in ARDS and in COVID-19 associated ARDS.
- Dexamethasone 6 mg daily x 10 days may be preferred for COVID-19 patients based on the preliminary findings of the RECOVERY trial. Further review of patient baseline severity of illness in this study is needed to clarify if these findings can be extrapolated to patients with severe ARDS.
- Dexamethasone 20 mg IV daily x 5 days followed by 10 mg IV daily x 5 days based on the DEXA-ARDS trial may be considered for patients with COVID-19 and severe ARDS.
- Long, tapered methylprednisolone regimens may be considered for COVID-19 patients who present in late stage ARDS.
References
- Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020; 8(3):257-76.
- Ware LB, Matthaw MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334-49.
- Papazian L, Aubron C, Brochard, L, et al. Formal guidelines: management of acute respiratory distress syndrome. Ann Intensive Care. 2019; 9:69:1-18.
- Fan E, Del Sorbo L, Goligher EC, et al. An official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guideline: mechanical ventilation in adults with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017; 195(9):1253-63.
- National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss M, Huang DT, et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(21):1997-2008.
- Annane D, Pastores S, Rochwerg B, et al. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society
Impressive