Indirect (herd) effects of topical antibiotic prophylaxis and oral care versus non-antimicrobial methods increase mortality among ICU patients: realigning Cochrane review data to emulate a three-tier cluster randomised trial

Abstract

Objective This study aimed to estimate the direct effects to recipients and indirect (herd) effects to non-recipients of each of topical antibiotic prophylaxis (TAP) and oral care methods on patient mortality within randomised concurrent controlled trials (RCCT) using Cochrane review data.Design Control and intervention groups from 209 RCCTs of TAP (tier 3), oral care (tier 2) each versus non-antimicrobial (tier 1) ventilator-associated pneumonia (VAP) prevention interventions arranged to emulate a three-tiered cluster randomised trial (CRT). Eligible RCCTs were those including ICU patients with >50% of patients receiving >24 hours of mechanical ventilation (MV) with mortality data available as abstracted in 13 Cochrane reviews.Exposures Direct and indirect exposures to either TAP or oral care within RCCTs versus non-antimicrobial VAP prevention interventions.Main outcomes and measures The ICU mortality within control and intervention groups, respectively, within RCCTs of either TAP or oral care versus that within non-antimicrobial VAP prevention RCCTs serving as benchmark.Results The ICU mortality was 23.9%, 23.0% and 20.3% for intervention groups and 28.7%, 25.5% and 19.5% for control groups of RCCTs of TAP (tier 1), oral care (tier 2) and non-antimicrobial (tier 3) methods of VAP prevention, respectively. In a random effects meta-regression including late mortality data and adjusting for group mean age, year of study publication and MV proportion, the direct effect of TAP and oral care versus non-antimicrobial methods were 1.04 (95% CI 0.78 to 1.30) and 1.1 (95% CI 0.77 to 1.43) whereas the indirect effects were 1.39 (95% CI 1.03 to 1.74) and 1.26 (95% CI 0.89 to 1.62), respectively.Conclusions Indirect (herd) effects from TAP and oral care methods on mortality are stronger than the direct effects as made apparent by the three-tiered CRT. These indirect effects, being harmful to concurrent control groups by increasing mortality, perversely inflate the appearance of benefit within RCCTs.