Evidance Health Sciences | ISSN: 3122-3354
Study-Level Versus Patient-Level Effect Modification by Chronic Hypertension in Mean Arterial Pressure Targets for Septic Shock: A Meta-Analysis Demonstrating Ecological Fallacy
Department of Emergency and Critical Care Medicine, King Fahad University Hospital, Imam Abdulrahman Bin Faisal University, Khobar, Saudi Arabia
Yazan Alalwani
College of Medicine, Imam Abdulrahman Bin Faisal University, Khobar, Saudi Arabia
Rayhanah Saad A. Binobaid
College of Medicine, Vision College, Riyadh, Saudi Arabia
Osama Hamdi Asiri
College of Medicine, King Khalid University, Abha, Saudi Arabia
Abdulrahman Emad Mashat
College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
Sultan Hassan Qurban
College of Medicine, Ibn Sina National College For Medical Studies, Jeddah, Saudi Arabia
Saja Abdullah Alharbi
College of Medicine, Majmaah University, Al Majma'ah, Saudi Arabia
Layan Khalid Alsaif
College of Medicine, Majmaah University, Al Majma'ah, Saudi Arabia
Osama Saeed Alghamdi
College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Khobar, Saudi Arabia
Maryah Mohammed Al Shehab
College of Medicine, Imam Abdulrahman Bin Faisal University, Khobar, Saudi Arabia
Norah Hamad Alabdullatif
College of Medicine, Qassim University, Buraydah, Saudi Arabia
Tasniem Elsadig Zubair Mohammed
Faculty of Medicine & Surgery, National University - Sudan, Khartoum, Sudan
Abdulrahman Mohammed Alrasheed
College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
Ahmed Y. Azzam
Division of Global Health and Public Health, School of Nursing, Midwifery and Public Health, University of Suffolk, Ipswich, United Kingdom
Published: 2026/03/29
Abstract
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 RR 1.03, 95% 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.
Keywords: Mean Arterial Pressure, Septic Shock, Shock, Hypertension, Mortality