Meta-analysis of Two Decades of Sepsis Randomized Controlled Trials: Lessons for Future Trial Design

Despite advances in sepsis pathophysiology and targeted therapies, more than two decades of adult sepsis randomized controlled trials (RCTs) continue to show largely neutral mortality outcomes. To determine whether this reflects therapeutic limitations or modifiable trial design factors, we conducted a comprehensive meta-analysis of major adult sepsis randomized controlled trials across multiple therapeutic domains. We additionally performed a thematic analysis of frequently occurring methodological limitations to inform future trial design.

We performed a meta-analysis of adult patient sepsis RCTs published from 2000-2025 across six therapeutic domains. Using fixed-effect models, mortality endpoints were estimated as risk ratios (RRs) pooled within each domain. We identified trial design limitations through a thematic framework analysis of patient selection, intervention strategies, outcome measures, and trial logistics.

Twenty-five adult patient sepsis RCTs (26,558 patients) yielded no consistent mortality benefit across any of these six therapeutic domains: resuscitation strategy (RR=0.93, 95% CI 0.82-1.06), fluid quantity (RR=0.99, 95% CI 0.89-1.10), fluid type (RR=1.01, 95% CI 0.92-1.12), vasopressors (RR=0.97, 95% CI 0.89-1.07), corticosteroids (RR=0.93, 95% CI 0.87-0.98), and vitamin c-based therapies (RR=0.95, 95% CI 0.79-1.15). Design limitations identified included heterogeneous populations, late ICU enrollment, “one-size-fits-all” interventions misaligned with biologic heterogeneity, reliance on all-cause mortality endpoints, limited adaptive capacity, transient trial infrastructure, and minimal evaluation of mechanistically informed therapies.

Methodological constraints across trials may help explain the lack of mortality benefit observed in sepsis RCTs. A deliberate shift toward earlier enrollment, biologically informed patient selection, adaptive trial designs, and clinically meaningful endpoints may improve the likelihood of detecting therapeutic benefit in future sepsis trials.