Higher- versus Lower-Dose Corticosteroids for Severe to Critical COVID-19: A Systematic Review and Dose–Response Meta-analysis

Abstract

RationaleCorticosteroids are standard of care for patients with severe COVID-19. However, the optimal dose is uncertain. ObjectiveTo compare higher doses of corticosteroids with lower doses in patients with COVID-19. MethodsWe searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, MedRxiv, and Web of Science from inception to August 1 st , 2022, for trials that randomized patients with severe-to-critical COVID-19 to corticosteroids, standard care, or placebo. Reviewers, working in duplicate, screened references, extracted data, and assessed risk of bias using a modi ed version of the Cochrane risk of bias 2.0 tool. We performed a dose-response meta-analysis and used the GRADE framework to assess the certainty of evidence. We present our results both in relative risk and absolute risk difference (RD) per 1000 with 95% con dence intervals (CI). ResultsWe included 20 trials, with 10,155 patients. We show that, compared to lower-dose corticosteroids, higher-dose corticosteroids probably reduce mortality (RD 14 fewer deaths per 1000 [95% CI 26 to 2 fewer]; moderate certainty), may reduce the need for mechanical ventilation (RD 11.6 fewer per 1000 [95% CI 23.2 fewer to 6.9 more]; low certainty) and may or may not reduce risk of nosocomial infections (16.7 fewer infections per 1000 [95% CI 5.4 to 25.0 fewer]; very low certainty). ConclusionsRelatively higher doses of corticosteroids may be bene cial in patients with severe-to-critical COVID-19 and may not increase the risk of nosocomial infections.We present a systematic review and dose-response meta-analysis comparing relatively higher versus lower dose corticosteroids for severe-to-critical COVID-19. MethodsWe registered a protocol on Open Science Framework (osf.io/2n6qw). eProtocol presents the registered protocol (6). Search strategyWe developed a search strategy with the help of an experienced medical librarian. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, MedRxiv, and Web of Science from inception to January 7, 2022, with an update on August 1, 2022. eTable 1 presents the search strategy. We supplemented our search by reviewing two large living systematic review and network meta-analyses addressing therapies for COVID-19 and a prospective meta-analysis addressing corticosteroids for critically ill patients with 7,8). We did not restrict our search based on language of publication. When non-English abstracts were encountered, we reached out to colleagues with the appropriate language skills. In cases where this was not possible, we planned to use institutional language translation services. We only included primary source clinical trial data but reviewed secondary analysis and post-hoc analysis for subgroup data.

Low-Dose Corticosteroids for Critically Ill Adults With Severe Pulmonary Infections

“…However, a meta-analysis that included 20 studies of 10 155 patients with severe or critical COVID pneumonia (defined as tachypnea >30/min, oxygen saturation <90% on room air, or ARDS) concluded that dexamethasone 12 mg daily for 10 days was associated with reduced mortality compared with 6 mg daily for 10 days (absolute risk difference, −14 per 1000; 95% CI, −26 to −2) . Therefore, according to this study, patients requiring supplemental oxygen at greater than or equal to 10 L/min, noninvasive ventilation, or invasive mechanical ventilation may benefit from treatment with higher-dose dexamethasone…”

Dexamethasone doses in patients with COVID‐19 and hypoxia: A systematic review and meta‐analysis

“…Higher versus lower doses of corticosteroids in hospitalised adults with COVID‐19 have also been compared in other systematic reviews and meta‐analyses of observational studies and RCTs 14–17 . All used a higher cut‐off for high‐dose treatment (range 10–20 mg of dexamethasone) than in our review 14–17 . None assessed days alive without life support, which may be of importance during periods with high caseloads and strained ICU capacity.…”

“…In one systematic review of both observational studies and RCTs comparing different doses of corticosteroids, several RCTs 18,20,28 included in our systematic review were not eligible as high‐dose treatment was defined as >100 mg methylprednisolone or >20 mg dexamethasone daily 14 . Pitre et al 15 included 20 RCTs assessing corticosteroids versus placebo or no treatment or different doses of corticosteroids in patients with severe or critical COVID‐19 and found that higher doses probably reduced mortality (moderate certainty of evidence). This review only included seven out of the 17 RCTs in our review, which may explain the observed difference 15 .…”

“…Pitre et al 15 included 20 RCTs assessing corticosteroids versus placebo or no treatment or different doses of corticosteroids in patients with severe or critical COVID‐19 and found that higher doses probably reduced mortality (moderate certainty of evidence). This review only included seven out of the 17 RCTs in our review, which may explain the observed difference 15 . Of note, the results from our sensitivity analyses assessing all corticosteroids were similar to their findings, although we could not rule out an increase in mortality.…”

“…We searched PubMed, http://clinicaltrials.gov, EU Clinical Trials register, WHO International Clinical Trials Registry Platform Search Portal, and the COVID‐NMA database until 23 June 2023. We also hand searched the reference lists of relevant records 14–17 . All search strings are presented in the Supporting information S1.…”