Purpose
Corticosteroids are now recommended for patients with severe COVID-19 including those with COVID-related ARDS. This has generated renewed interest regarding whether corticosteroids should be ...used in non-COVID ARDS as well. The objective of this study was to summarize all RCTs examining the use of corticosteroids in ARDS.
Methods
The protocol of this study was pre-registered on PROSPERO (CRD42020200659). We searched online databases including MEDLINE, EMBASE, CDC library of COVID research, CINAHL, and COCHRANE. We included RCTs that compared the effect of corticosteroids to placebo or usual care in adult patients with ARDS, including patients with COVID-19. Three reviewers abstracted data independently and in duplicate using a pre-specified standardized form. We assessed individual study risk of bias using the revised Cochrane ROB-2 tool and rated certainty in outcomes using GRADE methodology. We pooled data using a random effects model. The main outcome for this review was 28-day-mortality.
Results
We included 18 RCTs enrolling 2826 patients. The use of corticosteroids probably reduced mortality in patients with ARDS of any etiology (2740 patients in 16 trials, RR 0.82, 95% CI 0.72–0.95, ARR 8.0%, 95% CI 2.2–12.5%, moderate certainty). Patients who received a longer course of corticosteroids (over 7 days) had higher rates of survival compared to a shorter course.
Conclusion
The use of corticosteroids probably reduces mortality in patients with ARDS. This effect was consistent between patients with COVID-19 and non-COVID-19 ARDS, corticosteroid types, and dosage.
•Vitamin C deficiency is highly prevalent in the critically ill population, reaching 30% in the heterogeneous population and 40% in septic patients.•Vitamin C deficiency has been associated with ...worse severity scores in critically ill patients, but causality has not been discerned from a simple epiphenomenon. High severity score should increase suspicion of ascorbate deficiency.•Preclinical and clinical trials have reported benefits of vitamin C supplementation on neurologic, cardiovascular, respiratory, renal, gastrointestinal, and hematologic systems.•The positive results in one retrospective trial, later supported by two small trials in which high-dose intravenous vitamin C monotherapy improved clinical outcomes, have set the table for future investigation of vitamin C in critically ill patients.•Recent systematic review found no clinical benefits after supplementation of low-dose vitamin C. These results could be attributed to insufficient or suboptimal repletion strategies and supports investigating high-dose supplementation.
Vitamin C exhibits interesting properties in the context of critical illness, with benefits described in neurologic, cardiovascular, renal, and hematologic systems, both in in vitro and in animal models. Through direct effects on bacterial replication, immunomodulation, and antioxidant reserve of the organism, vitamin C directly affects the pathophysiological process of sepsis, trauma, burn, and systemic inflammation. Even if several observational trials have linked vitamin C deficiency to worse outcomes, the evidence is not such as to provide us with a distinction between causality effects or simple epiphenomenon, and the current focus is on interventional trials.
Pharmacokinetic data suggest that a minimal supplementation of 3 g/d intravenously is required to restore normal serum values in critically ill patients with known deficiency. According to these data, only five trials, including a retrospective analysis, studied pharmacologic dose: three as an antioxidant cocktail and two as monotherapy. The largest trial, conducted in 2002, reported reduced incidence of multiorgan failure and duration of mechanical ventilation. Recently a retrospective analysis reported impressive results after administration of vitamin C, thiamine, and hydrocortisone. The two most recent trials reported improved clinical outcomes, including improved mortality, but contained significant methodological limitations. A recent systematic review did not find clinical benefits with the most-studied low-dose oral supplementation, potentially because of suboptimal or insufficient repletion.
Current guidelines do not support the administration of high-dose vitamin C in critically ill patients. Future larger trials are required to support any therapy, but the low cost and safety profile can justify supplementation in the meantime. Metabolomics study will further help understand biological effect.
Despite Canada's investment of hundreds of millions of dollars into researching coronavirus disease 2019 (COVID-19), contributions from other countries have greatly exceeded Canada's research ...productivity. Additional research funds in Canada have been leveraged during the pandemic, and more may be needed. However, it will take more than just funding to fulfill Canada's health research potential; a culture change is required, along with the will to forge a partnership among the provincial and territorial health systems and the various research institutes and organizations. Here, Lamontagne et al discuss the limitations of the existing clinical research infrastructure in Canada, describe the mechanisms implemented to successfully embed clinical research in the UK health system and provide a roadmap to a Canadian version of the UK system.
...applying an EC90 fold-change in neutralisation activity between BA.2 omicron and delta (B.1.617.2) variants, the serum neutralisation titres were likely to be less than the serum neutralisation ...titres among participants allocated to the 250 mg intramuscular group of the COMET-TAIL randomised controlled trial (RCT). ...ineffectiveness would be anticipated at this level. ...the COMET-TAIL trial was conducted while the delta variant was most prevalent in the US population, and the difference in EC50 between the BA.2 omicron variant and the delta variant was 51·4-fold according to Wu and colleagues.1 Considered together, the in-vitro neutralisation data presented by Wu and colleagues1 do not materially change the interpretation of the analysis considered by the GDG, but they do provide additional evidence that the evaluation of BA.2 omicron neutralisation by sotrovimab is also applicable to BA.4 and BA.5 omicron. ...trustworthy living guidelines, created by panels free of competing interests, need to continuously interpret clinical effectiveness beyond initial authorisation from regulatory agencies.
The dilemma of whether and when to start renal replacement therapy among critically ill patients with acute kidney injury in the absence of conventional indications has long been a vexing challenge ...for clinicians. The lack of high-quality evidence has undoubtedly contributed decisional uncertainty and unnecessary practice variation. Recently, two randomized trials (ELAIN and AKIKI) reported specifically on the issue of the timing of initiation of renal replacement therapy in critically ill patients with acute kidney injury. In this commentary, their fundamental differences in trial design, sample size, and widely discrepant findings are considered in context. While both trials are important contributions towards informing practice on this issue, additional evidence from large multicenter randomized trials is needed.
PDF
