Study-Level Versus Patient-Level Effect Modification by Chronic Hypertension in Mean Arterial Pressure Targets for Septic Shock: A Meta-Analysis Demonstrating Ecological Fallacy

Introduction: Optimal mean arterial pressure (MAP) targets in septic shock remain controversial, with prior study-level meta-regression suggesting that chronic hypertension modifies treatment effects. However, ecological associations may not reflect individual-level causation. We investigated whether study-level hypertension prevalence predicts treatment effects and compared this to within-study hypertension subgroup analyses. Methods: We conducted a systematic review and meta-analysis following the PRISMA 2020 guideline through multiple literature databases up to October 8, 2025. We included randomized controlled trials (RCTs) comparing higher (≥75 mmHg) versus standard (60-70 mmHg) MAP targets in septic shock that reported mortality outcomes. We performed random-effects meta-analysis and univariable meta-regression testing six study-level covariates, and pooled within-study hypertension subgroup data using inverse-variance methods. Results: Six RCTs enrolling 4,060 patients were included. Overall mortality showed no significant difference between higher versus standard MAP targets (random-effects risk ratio [RR] 1.03, 95% confidence interval [CI] 0.90-1.17, P-value = 0.72, I² = 22.5%). Study-level meta-regression found no significant effect modification by hypertension prevalence (β = -0.0015 per 1% increase, P-value = 0.80, R² = 1.0%) or other covariates (all P-values > 0.05) in this six-study subset. However, within-study hypertension subgroup analysis (two trials, 1,405 patients) revealed higher MAP targets increased mortality in hypertensive patients (pooled RR 1.22, 95% CI 1.05-1.41, P-value = 0.009), demonstrating ecological fallacy where aggregate associations contradicted individual-level effects. Conclusions: Our performed study-level meta-regression demonstrated unreliable evidence for effect modification. Within-study hypertension subgroup data suggest higher MAP targets may harm rather than benefit hypertensive patients, contradicting ecological inferences and highlighting the necessity of individual patient data meta-analyses in further, better-sampled studies.