BackgroundInfection prevention interventions within the intensive care unit (ICU) setting, whether studied within quality improvement projects or cluster randomized trials (CRT), are seen as low risk and grounded in an ethical imperative. Selective digestive decontamination (SDD) appears highly effective at preventing ICU infections within randomized concurrent control trials (RCCTs) prompting mega-CRTs with mortality as the primary endpoint.FindingsSurprisingly, the summary results of RCCTs versus CRTs differ strikingly, being respectively, a 15-percentage-point versus a zero-percentage-point ICU mortality difference between control versus SDD intervention groups. Multiple other discrepancies are equally puzzling and contrary to both prior expectations and the experience within population-based studies of infection prevention interventions using vaccines. Could spillover effects from SDD conflate the RCCT control group event rate differences and represent population harm? Evidence that SDD is fundamentally safe to concurrent non-recipients in ICU populations is absent. A postulated CRT to realize this, the SDD Herd Effects Estimation Trial (SHEET), would require > 100 ICUs to achieve sufficient statistical power to find a two-percentage-point mortality spillover effect. Moreover, as a potentially harmful population-based intervention, SHEET would pose novel and insurmountable ethical issues including who is the research subject; whether informed consent is required and from whom; whether there is equipoise; the benefit versus the risk; considerations of vulnerable groups; and who should be the gatekeeper?ConclusionThe basis for the mortality difference between control and intervention groups of SDD studies remains unclear. Several paradoxical results are consistent with a spillover effect that would conflate the inference of benefit originating from RCCTs. Moreover, this spillover effect would constitute to herd peril.