Rationale The blood pressure value below which the benefits of vasopressors clearly outweigh their disadvantages is uncertain.

Objectives The main objective of this analysis was to investigate the statistical properties and potential utility of indices estimating the vasopressor dose-rates as a function of blood pressure values over time.

Methods In this single-center observational study, we collected blood pressure values from intensive care unit (ICU) monitors and norepinephrine dose-rates from infusion pumps corresponding to a derivation and a validation cohort. Patients included in each cohort were 18 years or older and received norepinephrine in the ICU. We defined and derived indices corresponding to vasopressor therapy above (>65 mmHg) and below (<60 mmHg) targets. We report the distribution of both indices over time from both cohorts as well as their associations with hospital mortality using logistic regression models adjusted for baseline variables.

Results Between July 30 2020 and March 28 2022, 283 patients were included in the derivation cohort. The median ICU stay was 5 days (interquartile range [IQR] 2-10.5) and the median duration of norepinephrine therapy was 27.3 hours (IQR 13.9-54.2). The median cumulative time with a MAP below 60 mmHg was 0.9 hours (IQR 0.2-3.1), whereas the cumulative time with a MAP above 65 mmHg was 22.5 hours (IQR 10.9-40.4). Adjusting for prespecified baseline variables, the above target index was associated with hospital mortality (OR 1.6, 95% CI 1.2 –2.3) but not the below target index (OR 1.1 95% CI 0.8 – 1.5). Between May 5 2022 and December 16 2022, 83 patients were included in the validation cohort. The duration of ICU stay and the proportion of norepinephrine exposure above MAP target were consistent with the derivation cohort. The point estimates of the associations between each index and mortality were also consistent with the derivation cohort, but not statistically significant.

Conclusion Indices of vasopressor administration as a function of blood pressure suggest that during most of vasopressor therapy episodes, patients are treated above target. The association of these indices with patient outcomes remains uncertain but could be explored in larger datasets, and future clinical trials of target MAPs may consider measurement of these indices to adjust results for treatment adherence.

FLamontagne, JBMichaud, AGervais, and FCamirand-Lemyre have developed a closed-loop system for the delivery of vasopressors subject to intellectual property protection. INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) Patent Application no: PCT/CA2022/050684 - Pending Title: System for controlling an administration of infused substances. Inventors: Lamontagne F, Michaud JB, Gervais A, Camirand Lemyre F.

This study was funded by the chair on patient-centered research in acute care awarded to FLamontagne by the Universite de Sherbrooke.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Comite d'ethique de la recherche du Centre integre universitaire de sante et de services sociaux de l'Estrie - Centre hospitalier universitaire de Sherbrooke has approved this project on November 24, 2017.

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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All data produced in the present study are available upon reasonable request and submission of detailed analysis plan to the authors