Discordant Evidence on Corticosteroids in Sepsis: A Meta-Research Study

Background

Despite numerous randomized controlled trials (RCTs) and systematic reviews (SRs), current sepsis guidelines continue to issue only weak recommendations for corticosteroids. We examined the clinical scope, underlying study pools, and mortality conclusions of SRs evaluating corticosteroids for sepsis.

Methods

We conducted a meta-research study of SRs on corticosteroids in sepsis (2015– 2025), extracting SR characteristics, mortality results, and included RCTs. Study-pool overlap was assessed using an SR×RCT inclusion matrix, Jaccard similarity (J), and hierarchical clustering. SRs and RCTs were classified according to standardized Population, Intervention, Comparison, Outcome (PICO) profiles. We explored discordance in short-term mortality conclusions among clinically comparable SRs and potential associations with study-pool composition, target populations, and methodological characteristics.

Results

Forty-two SRs including 121 unique RCTs were identified. More than half of pairwise SR comparisons shared no RCTs, and only three pairs showed high overlap (J>0.8). SRs addressing similar intervention and target population profiles frequently relied on different study pools. Among 38 SRs with short-term mortality meta-analyses, 15 (39%) reported benefit and 23 (61%) no evidence of effect. Discordance occurred exclusively among SRs evaluating broad, non-specific corticosteroid strategies; conclusions were consistent for hydrocortisone plus fludrocortisone (benefit) and hydrocortisone, ascorbic acid, and thiamine (no evidence of effect). SRs including sepsis ± shock populations more frequently reported benefit than those restricted to septic shock (62% vs 22%), although estimates were imprecise. No single methodological or clinical factor consistently explained discordance.

Conclusions

SRs addressing apparently similar clinical questions frequently synthesized different underlying evidence bases and reported discordant conclusions. Guideline developers should therefore consider not only methodological quality and reported PICO, but also whether the RCTs included in an SR adequately represent the intended clinical question. Clinically coherent evidence syntheses may improve the interpretability of pooled treatment effects and support more targeted corticosteroid therapy in sepsis.

Key messages

• SRs addressing clinically similar questions frequently relied on different and only partially overlapping sets of RCTs.

• Discordant mortality conclusions occurred exclusively among SRs evaluating non-specific broad corticosteroid strategies, whereas SRs of hydrocortisone plus fludrocortisone and hydrocortisone, ascorbic acid, and thiamine reported consistent findings.

• Differences in target populations (sepsis ± shock vs septic shock) may contribute to discordant findings, although no single methodological or clinical factor consistently explained the observed discordance.

• Clinical guideline developers should evaluate the clinical scope and underlying evidence base of SRs, not only their methodological quality, when formulating recommendations.