Intraoperative Use of Phenylephrine versus Ephedrine and Postoperative Delirium: A Multicenter Retrospective Cohort Study

Abstract

Background The treatment of intraoperative hypotension with phenylephrine may impair cerebral perfusion through vasoconstriction, which has been linked to postoperative delirium. We hypothesized that intraoperative administration of phenylephrine, compared to ephedrine, is associated with higher odds of postoperative delirium. Methods 103,094 hospitalized adults undergoing general anesthesia for non-cardiac, non-neurosurgical procedures between 2008 and 2020 at two tertiary academic healthcare networks in Massachusetts, USA were included in this multicenter hospital registry study. The primary exposure was the administration of phenylephrine versus ephedrine during surgery, and the primary outcome was postoperative delirium within seven days. Multivariable logistic regression analyses adjusted for a priori defined confounding variables including patient demographics, comorbidities, and procedural factors including magnitude of intraoperative hypotension were applied. Results 78,982 (76.6%) patients received phenylephrine, and 24,112 (23.4%) patients received ephedrine during surgery. 770 patients (0.8%) developed delirium within seven days. The median (interquartile range [IQR]) total intraoperative dose of phenylephrine was 1.0 (0.2–3.3) mg and 10.0 (10.0–20.0) mg for ephedrine. In adjusted analyses, the administration of phenylephrine, compared to ephedrine, was associated with higher odds of developing postoperative delirium within seven days (adjusted odds ratio [ORadj] 1.35; 95%CI 1.06–1.71; adjusted absolute risk difference [ARDadj] 0.2%; 95%CI 0.1%–0.3%; p=0.015). A keyword and manual chart review-based approach in a subset of 45,465 patients further validated these findings (delirium incidence 3.2%, ORadj 1.88; 95%CI 1.49–2.37; p<0.001). Fractional polynomial regression analysis further indicated a dose-dependent effect of phenylephrine (adjusted coefficient 0.08; 95%CI 0.02–0.14; p=0.013, per each mcg/kg increase in the cumulative phenylephrine dose). Conclusions The administration of phenylephrine compared to ephedrine during general anesthesia was associated with higher odds of developing postoperative delirium. Based on our data, clinical trials are warranted to determine whether favoring ephedrine over phenylephrine for treatment of intraoperative hypotension can reduce delirium after surgery.