Effect of remimazolam besylate vs propofol on incidence of postoperative delirium in older patients undergoing hip surgery: a randomized noninferiority trial

Highlights We investigated the effect of remimazolam besylate, compared with propofol, on postoperative delirium (POD) among older patients undergoing hip surgery. POD occurred in 42 of 364 patients (11.5%) in group R and 38 of 364 patients (10.4%) in group P (unadjusted relative risk [RR], 1.1 [95% CI: 0.7–1.7]; P=0.64). Among older adults undergoing hip surgery, general anesthesia with remimazolam besylate was not inferior to propofol with regard to the incidence of POD or adverse events. Dear Editor, Postoperative delirium (POD) is an acute perioperative neuropsychiatric syndrome characterized by an acute onset and fluctuating course of inattention, disorganized thinking, and altered level of consciousness1. The development of POD is attributable to complex inter-relationships between predisposing factors and precipitating factors; avoiding precipitating factors is a strategy for preventing POD. However, there remains equipoise regarding the relative risk for POD when benzodiazepines are used compared to the more commonly used hypnotic, propofol. Remimazolam besylate is a novel, ultra-short acting, benzodiazepine2 and provides effective procedural sedation with a superior recovery profile when compared with midazolam3. There are few studies investigating whether remimazolam, with its superior pharmacokinetic profile (shorter half-life, higher clearance4, lack of accumulation5, and smaller volume of distribution), affects the risk of POD; specifically, data from large, multicenter, randomized controlled trials to address POD risk from remimazolam is lacking. To compare the relative risk of developing POD when anesthetized with remimazolam vs propofol, we conducted a noninferiority, randomized, clinical trial identified as REMPPOD (REMimazolam vs Propofol on incidence of PostOperative Delirium). Methods REMPPOD was a randomized, allocation-concealed, multicenter trial conducted at 13 hospitals in Anhui province, China. This study was approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (approval number: PJ2020-13-08) and was registered in the Chinese Clinical Trial Registry (ChiCTR2000038223). Eligible patients were American Society of Anesthesiologists (ASA) Physical Status Classification System class 1 to 3, aged 60–90 years and undergoing hip surgery with general anesthesia. Patients were excluded if they had severe cardiac, pulmonary, hepatic or kidney dysfunction; history of psychiatric disorders; delirium before surgery; severe cognitive impairment; cerebrovascular accident within 3 months; severe diabetic complications; severe infections; arterial oxygen pressure <60 mmHg and pulse oxygen saturation <92%; participated in another clinical study of drugs within 30 days; unable to complete cognitive function test; prosthetic fracture revision or other combined severe trauma; allergic to study drugs or had contraindications to the performance of a suprainguinal fascia iliaca block. Eligible patients were randomized with a 1:1 ratio, using a random number generator in R software, to receive either remimazolam besylate (group R) or propofol (group P) for general anesthesia. Standard monitoring and anesthesia depth monitoring were initiated upon the patient’s arrival in the operating room. Prior to anesthesia induction, an ultrasound-guided suprainguinal fascia iliaca plane block was performed with 0.25% ropivacaine 40 ml on the surgical side. Participants received 0.2–0.25 mg/kg of remimazolam besylate or 1.5–2.0 mg/kg of propofol, 0.2–0.3 μg/kg of sufentanil, and 0.2–0.3 mg/kg cisatracurium for anesthesia induction. Continuous intravenous infusions of remimazolam besylate or propofol, supplemented with remifentanil, were used for the maintenance of anesthesia. Infusion rates were titrated to maintain a bispectral index (BIS) of 45–60 during surgery. Heart rate and blood pressure were maintained within 20% of the baseline values. The primary outcome was the incidence of delirium from postoperative day 1 to postoperative day 3, or before discharge, whichever occurred first. Diagnosis of POD was based on the results of 3-Minute Diagnostic Interview for Confusion Assessment Method (3D-CAM) or CAM for the intensive care unit (CAM-ICU). As prespecified exploratory outcomes, we compared the cumulative incidence of POD; rate of post-anesthesia care unit (PACU) agitation; days alive out of hospital 30 (DAOH30) after surgery; time to loss of consciousness (RASS score≤−4), time to a BIS value of 60, and time to readiness for discharge from the PACU (Steward score ≥4)6. As prespecified adverse events, we compared the frequency of hypotensive, hypertensive, bradycardic, and tachycardic episodes, intraoperative awareness, postoperative complications, and 30-day all-cause mortality. Primary and exploratory outcomes were analyzed on the intention-to-treat population. The incidence of POD between the two groups was compared with χ2 tests. The relative risks (RR), and relative difference (RD) were calculated with 95% CI. A post-hoc analysis using logistic mixed-effects models was conducted to adjust for other factors and to further estimate the effect of the hypnotics on the incidence of POD. We also conducted a time-to-event analysis to compare the cumulative incidence of POD between the groups. Kaplan–Meier analysis was used to estimate the cumulative incidence of POD, and difference of incidence between groups was compared with the log-rank test. Results Of 1283 patients screened for eligibility, 728 were randomized. There were 364 patients randomized to receive remimazolam besylate and 364 randomized to receive propofol (Fig. 1). There was a statistical difference in the preoperative sleep quality one day before surgery (median, IQR, 60 [50–71] in group R vs. 65 [53–76] in group P, P=0.03). The remaining baseline patient characteristics were well balanced between the two groups (Table S1 in Supplementary Materials, Supplemental Digital Content 1, https://links.lww.com/JS9/D52).Figure 1: Flow Diagram for the REMPPOD trial. The flow chart shows this multicenter, randomized trial conducted on elderly patients undergoing hip surgery. Group R, patients received remimazolam besylate for induction and maintenance of general anesthesia. Group P, patients received propofol for induction and maintenance of general anesthesia.The incidence of POD was 42 of 364 patients (11.5%) in group R and 38 of 364 (10.4%) in group P (unadjusted RD, 1.1% [95% CI: –3.4% to 5.6%; P=0.64]; unadjusted RR, 1.1 [95% CI: 0.7–1.7]; P=0.64) (Table 1). The cumulative incidence of POD was also similar between group R and group P (hazard ratio [HR], 1.1 [95% CI: 0.7–1.7]; log-rank P=0.64) (Fig. 2). Per-protocol analysis obtained a similar result for the primary endpoint (Table S2, Supplemental Digital Content 1, https://links.lww.com/JS9/D52). Similar incidence of POD was observed across subgroups, including age, sex, preoperative cognitive level, and the presence or absence of CNS disease before surgery (Figure S1, Supplemental Digital Content 1, https://links.lww.com/JS9/D52). Table 1 - Primary outcome between the two groups. Group R (364) Group P (364) Relative risk (95% CI) P Overall incidence of POD, n (%) 42 (11.5%) 38 (10.4%) Unadjusted 1.1 (0.7–1.7) 0.64 Adjusted for center 1.1 (0.7–1.8) 0.70 Adjusted for preoperative sleep quality and center 1.1 (0.6–1.7) 0.82 Adjusted for preoperative sleep quality, age, sex, education level and baseline cognitive function, history of CNS disease, and center 1.1 (0.7–1.9) 0.67 Group R, patients were received remimazolam besylate for induction and maintenance of general anesthesia. Group P, patients were received propofol for induction and maintenance of general anesthesia.CNS, Central Nervous System (included cerebral infarction, cerebral hemorrhage, brain trauma, and brain tumor); POD, postoperative delirium. Figure 2: Kaplan–Meier curve showing intention-to-treat analysis of cumulative incidence of delirium during postoperative days 1 to 3 between two groups. Group R, patients received remimazolam besylate for induction and maintenance of general anesthesia. Group P, patients received propofol for induction and maintenance of general anesthesia.The time to a BIS value of 60, time to intubation, and time to readiness for discharge from the PACU were shorter in group P when compared with group R. The incidence of PACU agitation in group R was significantly lower than in group P (2.3 vs. 8.1%, P<0.001) (Table S3, Supplemental Digital Content 1, https://links.lww.com/JS9/D52). The frequency of hypotensive episodes (Table S4, Supplemental Digital Content 1, https://links.lww.com/JS9/D52) in group R was significantly lower than that in group P (P=0.02). Summary This multicenter randomized clinical trial demonstrated the noninferiority of remimazolam besylate compared with propofol regarding the incidence of POD in older patients who underwent hip surgery. After adjusting for center, age, sex, preoperative sleep quality, education level, baseline cognitive function, and history of CNS disease, there was still no statistical difference in the incidence of POD during the first 3 days after surgery. Ethical approval This study was approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (approval number: PJ2020-13-08). Consent Yes, all the patients provided informed consent prior to enrollment. Source of funding This work was supported by a Key project of the 2021 clinical research start-up plan of the First Affiliated Hospital of Anhui Medical University (LCYJ2021D004). Author contribution P.F., Y.L., Q.S., and X.L.: concept and design; P.F., Y.F., Y.L., X.L., and M.M.: acquisition, analysis, or interpretation of data; P.F., J.H., Q.W., and M.M.: drafting of the manuscript; P.F., J.H., X.L., and M.M.: critical revision of the manuscript for important intellectual content; Y.F. and Y.L.: statistical analysis; X.L.: obtained funding; J.H., Q.W., Y.L., and X.L.: administrative, technical, or material support; Y.L., Q.S., and X.L.: supervision. Conflicts of interest disclosure None of the authors report having a conflict of interest of this study. Research registration unique identifying number (UIN) The trial was registered in the Chinese Clinical Trial Registry (ChiCTR2000038223; Principal Investigator: X-SL; Date of Registration: 14 September 2020). Guarantor Xue-sheng Liu, the corresponding author. Data availability statement This study collected primary endpoints and demographic information, including deidentified individual participant data and a data dictionary defining each field in the set, will be made available immediately after publication with no end date to researchers with a signed data access agreement. Provenance and peer review Yes, we agree to peer review. Presentation None.