In our meta-analysis, use of glucocorticoids in patients with ARDS was associated with a significant reduction in hospital and ICU mortality and duration of mechanical ventilation. While there was no increased risk of hospital-acquired infections with glucocorticoid use, there was an increased risk of hyperglycemia. In trial sequential analysis, these findings could be secondary to a false-positive (type I) error, and further studies are needed for sufficient evidence as the required sample size was not reached by the available RCTs.
Current guidelines of American Thoracic Society/European Society of intensive care medicine/Society of Critical Care Medicine have strong recommendations for the use of low tidal volume (4–8 ml/kg of ideal body weight), limiting inspiratory pressure (plateau pressure < 30 cm H2O), and prone positioning in moderate-to-severe ARDS. Furthermore, the use of recruitment maneuvers and higher PEEP strategies have conditional recommendations in patients with moderate-to-severe ARDS. In addition, glucocorticoids have a conditional recommendation in early moderate-to-severe ARDS, and their use is still controversial [6, 19].
There are three distinct phases in the development of ARDS including exudative, proliferative, and fibrotic phases . As lung fibrosis is associated with increased duration of mechanical ventilation and increased rates of mortality, steroids are considered a potent anti-inflammatory agent that can attenuate the inflammatory process and subsequently decrease further lung injury and fibrosis .
A recently published randomized controlled trial revealed that early use of dexamethasone in patients with moderate-to-severe ARDS was associated with a significant reduction in mortality and duration of mechanical ventilation . Similar results were noticed in patients with sepsis or septic shock with moderate-to-severe ARDS treated with methylprednisolone in comparison to placebo . In these two recent trials, glucocorticoid use was evaluated with lung protective mechanical ventilation and low tidal volume, as opposed to the other trials conducted before 2005 where low tidal volumes were not implemented in the trial protocols. This strategy which limits tidal volume to 4–8 ml/kg of ideal body weight and alveolar pressure to less than 30 cm H2O showed a significant reduction in mortality and increased number of ventilator-free days at day 28 .
In our subgroup analysis, we found that there was no mortality benefit in studies that evaluated glucocorticoids without a lung-protective ventilation strategy likely secondary to worsening lung injury. High tidal volumes delivered to an already injured lung may worsen lung injury leading to alveolar rupture, air leaks, and barotrauma with worse clinical outcomes [20,21,22]. Furthermore, we found that late administration of glucocorticoids (after 7 days of ARDS onset) was not associated with improved outcomes despite lower risk ratio (0.52) but with a high p value, a finding that is limited by the low number of patients and studies in this subgroup (2 studies, 204 patients). However, this supports the concept that steroids exert their action through downregulation of the inflammatory response and decrease alveolar capillary permeability which occurs early in the exudative phase and is linked to lung injury . In exploratory meta-regression, we found that patients who were treated with prolonged duration of glucocorticoid administration and received higher PEEP had lower ICU but not hospital mortality; a finding that is limited by the low number of studies that reported ICU mortality and needs to be examined in further trials.
Our analysis revealed a 21% risk reduction in hospital mortality among ARDS patients treated with glucocorticoids with a number needed to treat of nine patients to prevent one death. In addition, there was a 4-day increase in the number of ventilator-free days at day 28. Despite these favorable outcomes, there was no increased risk of hospital acquired infections; in contrast, our analysis showed a tendency toward reduction of acquired infections, a finding that could be explained by the decreased duration of mechanical ventilation and subsequently ICU length of stay. However, these findings should be interpreted cautiously until confirmed in further larger studies.
In order to examine the strength of the evidence and whether more randomized controlled trials are needed for sufficient conclusion regarding mortality benefit, we performed a trial sequential analysis to guard against false positive (type I) or false negative (type II) errors. While the mortality benefit reached statistical significance, based on our analysis, the mortality benefit could be secondary to a false positive (type I) error, and the evidence is insufficient as the sample size required for detection of 20% RRR in mortality between the two groups while avoiding statistical errors is 2692 patients that was not reached by the available data (1091) patients were included in our analysis). Further, well-controlled randomized clinical trials are required for a strong conclusion about the efficacy of steroids in managing ARDS patients. Additionally, the focus should be on the type, dose, and duration of glucocorticoids therapy as we included studies that evaluated different glucocorticoids with variable dosages and durations. However, until further studies are performed, the significant risk reduction and the low number needed to treat may justify the use of glucocorticoids in patients with ARDS, especially those with an underlying etiology similar to patients enrolled in the included RCTs (sepsis, septic shock, and pneumonia).
Our results are consistent with previously published meta-analyses. However, we included the recently published trial and only included patients with established ARDS, and we excluded studies with high risk of bias as well as retrospective studies which were included in previous reviews [23, 24]. Furthermore, we were able to perform subgroup and meta-regression analyses based on study-level covariates. In addition, we conducted trial sequential analysis to examine the strength of the evidence and concluded that further studies are needed for a strong and firm evidence of glucocorticoids efficacy in ARDS patients with paying special attention of the duration, dose, and timing of glucocorticoids administration.
Our results are non-generalizable to patients with ARDS secondary to coronavirus disease-2019 (COVID-19) and other viral pneumonias such as H1N1 influenza. To date, there is only one retrospective study that examined outcomes of COVID-19 patients treated with steroids. The study by Wu et al. found lower risk of death (hazard ratio 0.38; 95% CI 0.20–0.72; p = 0.003) in patients with ARDS treated with methylprednisolone . In addition, a non-peer reviewed article was published recently and reported reduction in the duration of supplemental oxygen and improved radiographic findings in 26 patients with severe COVID-19 but it is unknown how many patients had ARDS in this cohort . Since we lack patient-level data and the information are missing in the published literature, we were unable to perform a subgroup analysis for patients with viral etiology of ARDS. However, it is known that glucocorticoids are associated with worse outcomes in patients with ARDS secondary to H1N1 influenza virus as demonstrated by previous cohort studies and meta-analyses [27,28,29]. Based on the current available evidence for the management of COVID-19 patients, Society of Critical Care Medicine and European Society of intensive care medicine guidelines have recommended against the use of corticosteroids in mechanically ventilated patients without ARDS and issued a weak recommendation for the use of low dose steroids (hydrocortisone 200 mg per day) in those with ARDS and/or refractory septic shock .