This systematic review and meta-analysis demonstrates that intravenous corticosteroids administered in the setting of cardiac arrest have an uncertain effect on the risk of mortality, while increasing the frequency of ROSC and survival with good functional outcome. Certainty related to data on mortality was very low, limited by inconsistency and imprecision. Corticosteroids may increase complications such as ventilator associated pneumonia and renal failure, however the pooled evidence examining these outcomes was sparse and imprecision contributed to low or very low certainty of evidence.
Previously published systematic reviews and meta-analyses assessing corticosteroids post cardiac arrest have shown variable and inconclusive results (21–23). One review found that corticosteroids were associated with increased ROSC and survival to discharge, but retrospective observational studies and randomized controlled trials were pooled in their analysis, an approach that is discouraged by the Cochrane working group (22). Another meta-analysis, including only RCTs, did not perform quantitative analysis due to insufficient data and instead only provided a narrative summary (23). A more recent review focused only on IHCA found improvements in neurologic outcomes and survival to hospital discharge with corticosteroids, consistent with our findings (21). Compared to previous reviews, this report includes the most RCTs, and the largest number of patients, thereby providing important precision around key outcomes of interest.
The finding that corticosteroids probably increase ROSC with an uncertain effect on mortality is interesting. Examining the pooled point estimate for mortality and the 95% confidence intervals, the uncertainty does not suggest no effect, rather the pooled estimate (RR 0.96) is actually consistent with the other outcomes of ROSC and good neurologic recovery, however limitations in GRADE domains of inconsistency and imprecision led to very low certainty evidence in this outcome. We would be cautious about an intervention that increases ROSC without a clear mortality benefit, however the possible improvement in survival with good functional outcome with corticosteroids is hopeful. The low certainty evidence for survival with good functional outcome, rated down for inconsistency and imprecision, should provide some caution, and further research is warranted for clarification. Survival with good functional outcome is an outcome that can be challenging to adjudicate given different evaluation time points and issues with loss to follow-up.
Despite a number of RCTs examining the role of corticosteroids in cardiac arrest, there was no standard regimen and variable administration schedules were used amongst the included trials. It is possible that differences in steroid type, dosage, administration timeline, and combination with other drugs (e.g. vasopressin) contributed to the statistical heterogeneity observed in this meta-analysis. This was appropriately accounted for in the GRADE certainty ratings but does contribute to ongoing uncertainty. However, meta-analyses of corticosteroids in other inflammatory conditions (eg. sepsis and ARDS) have not demonstrated effect modification based on corticosteroid molecule or dose (24, 25). Further high-quality RCTs assessing the effects of corticosteroids in patients post cardiac arrest need to be completed to further examine these important considerations.
This review has several strengths. We performed a comprehensive literature search that included recently published trials, undertook dual and independent screening and data abstraction, adhered to our pre-registered protocol, and assessed certainty of outcomes using the GRADE approach. This study also has improved generalizability compared to previous published meta-analyses with the inclusion of IHCA and OHCA patients. This review is the most comprehensive and inclusive to date including data from 2,213 patients as compared to the most recently published MA addressing this topic which evaluated data from four RCTs totaling 499 patients (21). We have included the Andersen study, published in 2021, which enrolled 501 patients (16) and contributes over a quarter of the total patients, increasing the precision in findings and the certainty for overall findings. Additionally, we are the only MA to date to include the Rafiei study, published in 2022 which enrolled 347 patients (19).
This review has several limitations. There was insufficient trial level data to perform most of the planned subgroup analyses. Also, the majority of included RCTs had a high risk of bias and this contributed to low or very low certainty of data of most outcomes of interest. There was also important clinical heterogeneity amongst included studies including cardiac vs non-cardiac cause for cardiac arrest, timing and prevalence of bystander CPR, witnessed versus unwitnessed arrest, use of co-interventions such as vasopressin, and steroid type, dose, and timing. Despite this, reassuringly, there was minimal statistical heterogeneity suggesting this clinical variability may not impact the effect of corticosteroids.