Dose-dependent effects of intravenous methoxamine infusion during hip-joint replacement surgery on postoperative cognitive dysfunction and blood TNF-α level in elderly patients: a randomized controlled trial

BACKGROUND Postoperative cognitive dysfunction (POCD), common in elderly patients, is thought to be closely associated with intraoperative instability of hemodynamics and excessive excretion of tumor necrosis factor-α (TNF-α). Methoxamine is a blood-pressure increasing drug commonly used for maintaining intraoperative hemodynamics. Methoxamine potentially promotes TNF-α expression, leading to an increased risk of POCD. This study aimed to investigate the dose-dependent effect of methoxamine on the incidence of early POCD and blood TNF-α level. METHODS This single-center prospective double-blind controlled clinical trial included a total of 300 adult patients (75-90 years old, American Society of Anesthesiologists class II-III) who underwent unilateral hip-joint replacement surgery under epidural anesthesia. Patients were randomly divided into three methoxamine groups (M1, M2, and M3), and one control group (n = 75 per group). During surgery, M1, M2, and M3 patients received intravenous infusion of methoxamine at 2, 3, or 4 μg·kg-1·min-1, respectively; the control group received saline of same volume at the same infusion rate. All patients received standard transfusion to maintain stable circulation. Hemodynamics, cardiovascular events, and serum TNF-α levels were monitored. Mini Mental State Examination was performed both before and after surgery to diagnose POCD. RESULTS The primary outcome of this study was the incidence of POCD, which was higher in the M3 group (18.7%) than in the control group (5.3%), the M1 group (6.7%), or the M2 group (6.7%) (all P < 0.05). The secondary outcomes were the postoperative blood TNF-α level and intraoperative hemodynamic parameters. The postoperative TNF-α level was found to be higher than baseline in all groups and was highest in M3 patients (P < 0.05). The intraoperative hemodynamic parameters showed improved stability in the M1 and M2 groups compared with the control group. However, in the M3 group, abnormally increased intraoperative blood pressure, cardiac output, and systolic stroke volume were observed. CONCLUSIONS Intravenous infusion of methoxamine at 2-3 μg·kg-1·min-1 can maintain stable hemodynamics in elderly patients during epidural anesthesia for hip-joint replacement surgery, without increasing the incidence of POCD. Increasing the dose to 4 μg·kg-1·min-1 provided no further advantages but induced adverse effects on the intraoperative hemodynamics. TRIAL REGISTRATION Chinese Clinical Trial Register (Unique identifier: ChiCTR-INR-15007607 , retrospectively registered 18 Dec 2015).