• Olav L Schjørring, Theis Lange, Mette Krag, Nina Christine Andersen-Ranberg, Tine S Meyhoff, Søren Marker, Thomas L Klitgaard, Stine Estrup, MøllerMorten HylanderMHhttps://orcid.org/0000-0002-6378-9673Centre for Research in Intensive Care (CRIC), Copenhagen, Denmark.Department of Intensive Care, Rigshospitalet, Copenhagen, Denmark.Department of Clinical Medicine, University of Copenhagen, Cope, Bodil S Rasmussen, Lone M Poulsen, and Anders Perner.
• Department of Anaesthesia and Intensive Care, Aalborg University Hospital, Aalborg, Denmark.
• Acta Anaesthesiol Scand. 2022 Jan 1; 66 (1): 156-162.

BackgroundIntensive care unit (ICU) patients receive numerous interventions, but knowledge about potential interactions between these interventions is limited. Co-enrolment in randomized clinical trials represents a unique opportunity to investigate any such interactions. We aim to assess interactions in four randomized clinical trials with overlap in inclusion periods and patient populations.MethodsThis protocol and statistical analysis plan describes a secondary explorative analysis of interactions in four international ICU trials on pantoprazole, oxygenations targets, haloperidol and intravenous fluids, respectively. The primary outcome will be 90-day all-cause mortality. The secondary outcome will be days alive and out of hospital in 90 days after randomization. All patients included in the intention-to-treat populations of the four trials will be included. Four co-primary analyses will be conducted, one with each of the included trials as reference using a logistic regression model adjusted for the reference trial's stratification variables and for the co-interventions with interactions terms. The primary analytical measure of interest will be the analyses' tests of interaction. A p-value below .05 will be considered statically significant. The stratification variable- and co-intervention-adjusted effect estimates will be reported with 95% confidence intervals without adjustments for multiplicity.ConclusionThis exploratory analysis will investigate the presence of any interactions between pantoprazole, oxygenation targets, haloperidol and amount of intravenous fluids in four international ICU trials using co-enrolment. Assessment of possible interactions represents valuable information to guide the design, statistical powering and conduct of future trials.© 2021 Acta Anaesthesiologica Scandinavica Foundation.

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