Establishing the safety of selective digestive decontamination within the ICU population: a bridge too far?

Abstract

Background Infection 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. Findings Surprisingly, 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? Conclusion The 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.

Rebound Inverts the Staphylococcus aureus Bacteremia Prevention Effect of Antibiotic Based Decontamination Interventions in ICU Cohorts with Prolonged Length of Stay

“…The high S. aureus VAP and S. aureus BSI incidences within the concurrent control groups of antibiotic-BDI studies noted here as a spill-over effect, which is as previously noted for several end points [8,[17][18][19]23,43,45,46], would conflate the apparent prevention effect.…”

Trends in ICU mortality and underlying risk over three decades among mechanically ventilated patients. A group level analysis of cohorts from infection prevention studies

“…Resolving the paradox between the infection prevention and mortality prevention that is seen in RCCT’s of TAP but not in CRT’s of TAP would require a purpose designed study to estimate the contextual effect arising from the use of decontamination interventions within the ICU. Such a trial would be both ethically and logistically problematic [ 53 ].…”

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

“…47 The rationale and design for a postulated CRT (The SHEET trial) to demonstrate the population safety of TAP has been published. 48 The postulated SHEET trial will never be undertaken for two reasons. First, SHEET would be logistically complex and second, it would be unethical to randomise patients to possible harm.…”

“…First, SHEET would be logistically complex and second, it would be unethical to randomise patients to possible harm. 48 Length of stay behaves differently as a confounder of study effect size for the non-antimicrobial versus antimicrobial Cochrane review RCCT's. 49…”