Fig. 2

SHEET trial design. ICUs (n = 52) are cluster randomized to be either a TAP (half red ICUs) or a non-decontamination (i.e. non-antimicrobial) intervention (half blue ICUs) ICU in period 1 and to then cross over after a washout period. Within each ICU, all eligible MV patients are individually randomized to receive either the investigation agent (closed symbol ●) assigned to that ICU or not (open symbol ○). The SHEET trial is designed to enable the estimation of the indirect (population level) effect of TAP on mortality (spillover effect of the red colour onto the yellow) within ICUs. The washout period is necessary to enable any patients that have received the agent to be discharged from the ICU and any contextual effects associated with each investigational agent to dissipate. In previous CRTs, this period has been 3 months. Period 1 and period 2 are anticipated to be 12 months each. SHEET trial analysis. The RCCT component estimates the direct effect of each intervention at the level of individual patients by comparing the mortality among the patients randomly assigned to receive it or not within each ICU. The CRT component estimates the indirect effect of TAP at the population level by comparing the mortality among the patients randomly assigned to not receive the investigation agent (yellow half) within each ICU. The analysis presumes that the non-decontamination intervention will have no effect (direct or indirect) on mortality, as generally observed previously. The expected effects of TAP on mortality would be a lower mortality in those patient populations receiving TAP as the investigational agent versus those populations receiving the non-decontamination intervention. There is no capacity within the SHEET trial to estimate the possibility of any reverse spillover effect, that is the indirect effect from patients not receiving TAP on mortality (spillover effect of the yellow colour onto the red) within ICUs. This would require benchmarking the mortality among patients receiving TAP within the SHEET trial against the mortality among the four TAP CRTs in the literature