Interventions affecting mortality in critically ill and perioperative patients: A systematic review of contemporary trials

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Confounders in randomized controlled trials (RCTs) reporting significant effects on mortality in critically ill patients using non-surgical techniques have not been systematically explored. We aimed to identify factors unrelated to the reported intervention that might have affected the findings and robustness of such trials.


We searched Pubmed/MEDLINE for all RCTs on any non-surgical interventions reporting an effect on unadjusted mortality in critically ill patients between 1/1/2000 and 1/12/2015. We assessed: the number needed to treat/harm (NNT or NNH), sample size, trial design (blinded/unblinded, single or multinational, single or multicenter (sRCT or mRCT)), intention to treat (ITT) analysis, and countries of origin.


Almost half of RCTs were sRCTs. Median sample size was small, and 1/3 were not analyzed according to ITT principle. Lack of ITT analysis was associated with greater effect size (p = 0.0028). Harm was more likely in mRCTs (p = 0.002) and/or in blinded RCTs (p = 0.003). Blinded RCTs had double sample size (p = 0.007) and an increased NNT/NNH (p = 0.002). Finally, mRCTs had higher NNT (p = 0.005) and NNH (p = 0.02), and harm was only detected in studies from Western countries (p = 0.007).


These observations imply that major systematic biases exist and affect trial findings irrespective of the intervention being studied.

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