Spillover effects on mortality within randomized concurrent controlled trials of antimicrobial-based infection prevention interventions among the mechanically ventilated patient population. A reappraisal of Cochrane review data.

Abstract

Background: The ventilator-associated pneumonia (VAP) and mortality prevention effects of topical chlorhexidine and topical antibiotic prophylaxis (TAP) have been widely studied in randomized concurrent controlled trials (RCCTs) among intensive care unit (ICU) patients receiving mechanical ventilation. Aim: To determine whether interventions have spillover (population) effects on VAP and mortality incidences among these RCCTs additional to any direct (individual level) effects. Methods: The per-protocol (PP) and intention-to-treat (ITT) VAP and mortality data within five recent Cochrane reviews of antimicrobial-based VAP prevention interventions were reconciled. VAP and mortality prevention effect size risk ratio estimates were derived using random effects for RCCTs with control group VAP incidences above versus below the upper limit of the widely accepted VAP incidence range. Findings: The mortality prevention effect size for RCCTs with control group VAP incidence >40% versus ≤40% was: risk ratio: 0.85 (95% confidence interval (CI): 0.76–0.96; N = 24) versus 1.0 (0.91–1.1; N = 29), respectively. The corresponding summary control group mortality incidences were 29% (95% CI: 24–35) versus 25% (20–30), respectively, whereas the corresponding intervention group mortality incidences were 24% (20–29) versus 23% (19–28). Paradoxically, there was more dispersion among the control group mortality and VAP incidences than among the intervention group incidences. Conclusion: The findings here implicate spillover increasing VAP and mortality incidences and dispersion within control groups of topical antimicrobial intervention RCCTs. Hence, any inference of prevention is spurious. Moreover, these topical antimicrobial interventions increase mortality and are unsafe for ICU populations.