Efficacy and safety of remimazolam tosilate versus propofol in patients undergoing day surgery: a prospective randomized controlled trial

Ethical approval

This study was a single-center randomized, single-blinded, positive-controlled, parallel trial performed in Zhongshan Hospital Fudan University in Shanghai. It was approved by the Ethics Committee of Zhongshan Hospital (Number B2021–360) and was registered with the Chinese Clinical Trial Registry prior to patient enrollment (ChiCTR2100048904; Principal investigator: CM; Date of registration: July 19, 2021). The trial was modified on September 23, 2021 to add an additional arm to test RT + flumazenil. Patients were recruited from October 2021 to December 2021. Written informed consent was obtained from all participants included in the study. This manuscript adheres to the applicable Consolidated Standards of Reporting Trials guidelines.

Participants

This trial included male and female patients aged 18 to 75 years old who had an American Society of Anesthesiologists physical status (ASA) of I or II, a body mass index of 18 to < 30 kg/m2 and underwent day surgery utilizing general anesthesia with a laryngeal mask airway (LMA). Participants were excluded if they had a history of a benzodiazepine allergy, a history of benzodiazepine or opioid use within 1 month of surgery, a history of alcohol abuse, clinically significant renal or hepatic dysfunction, significant cardiorespiratory instability (heart failure, acute lung injury, hypovolemia or sepsis), participated in different drug trials within 3 months of enrollment or were pregnant or breast-feeding.

Randomization and blinding

Participants were divided into three groups in a 1:1:1 ratio via block randomization: RT, RT + flumazenil and propofol. The randomization chart was generated using a web-based randomization system (http://www.randomization.com, USA) that employed a Wichmann and Hill number generator as modified by McLeod. Sealed and numbered envelopes were handed to an anesthesiologist who was involved in drug administration. Intraoperative data was recorded by an anesthesiology assistant. A blinded investigator who was not directly involved in intraoperative anesthesia collected all postoperative data. Both patients and surgeons were blinded to group allocation. Because propofol and RT had different colors and infusion methods, the anesthesiologists and anesthesiology assistants were unblinded to group allocation.

Interventions

General anesthesia was induced with RT (0.3 mg/kg, iv) (Jiangsu Hengrui Medicine Co, Ltd, Jiangsu, China) or propofol (2.0–2.5 mg/kg, iv) (AstraZeneca, United Kingdom) in combination with sufentanil (0.2–0.4 µg/kg, iv). If loss of consciousness (LoC) did not occur within 3 min, an IV dose of RT (0.1 mg/kg) or propofol (1.0 mg/kg) was administered. After LoC was confirmed, muscular paralysis was achieved using rocuronium (0.2–0.4 mg/kg, iv) and an LMA was inserted.

RT was maintained at 1–3 mg/kg/h and propofol was maintained within a range of 6–12 mg/kg/h. Remifentanil was administered at an infusion rate of 0.05–0.15 µg/kg/min. Bispectral index (BIS) was used to evaluate anesthesia depth. IV anesthetic infusion was discontinued when the final surgical dressing was applied. The participant who developed hypotension, defined as systolic blood pressure (SBP) < 80% of baseline, was administered a bolus dose of 6 mg ephedrine or 0.1 mg phenylephrine that was repeated as necessary. Sinus bradycardia, defined as a heart rate (HR) below 40 beats/min, was treated with 0.5 mg of atropine.

Towards the end of the surgery, nalmefene (20 µg, iv), neostigmine (0.04 mg/kg, iv) and atropine (0.02 mg/kg, iv) were allowed to be administered as necessary. In the RT + flumazenil group, 0.2 mg flumazenil (Zhejiang Aotuokang Medicine Co, Ltd, Zhejiang, China) was administered 10 min after the discontinuation of RT. If necessary, a repeated dose of 0.1 mg flumazenil was permitted every minute until the total dose reached 1 mg. Blood pressure, HR, blood oxygen saturation (SpO2) and the BIS were monitored and recorded throughout the course of anesthesia.

Outcome variables

The primary outcomes were anesthesia induction time and time until the patient was fully alert post-operatively. Induction time was defined as the time from when the participant became unresponsive to painful stimulation (namely the squeezing of his/her trapezius) after the start of anesthesia administration. Time to fully alert was defined as the time from the stopping of anesthetic dosing to the patient accurately stating his/her date of birth [13].

Key secondary endpoints included: anesthesia success rate, defined as the absence of (1) intraoperative awakening or recall, (2) the need for rescue sedative medication and (3) body movement; LMA insertion time; the BIS values; the number of patients with BIS values > 60 or < 40 during anesthesia maintenance; % time BIS > 60 during anesthesia maintenance, defined as the percentage of time with BIS values > 60 in the whole anesthesia maintenance period; the recovery time including the time to eye opening, time to LMA extraction and time to the third consecutive Aldrete score ≥ 9 in the post-anesthesia care unit (PACU); postoperative delirium. Time to the third consecutive Aldrete score ≥ 9 was defined as the period from LMA extraction to the measurement of the third consecutive Aldrete score ≥ 9. Postoperative delirium was assessed prior to PACU discharge using the Diagnostic and Statistical Manual of Mental Disorders. After stopping the anesthetic, the dosages of opioids and vasoactive drugs were also recorded. Patients were under monitoring in PACU 60 min after flumazenil administration or 60 min after entering PACU to assess the recovery profiles, especially the sedation status after flumazenil administration. Recovery profiles were assessed based on the scores of the following assessments: modified observer’s alertness/sedation scale (MOAA/S) before the surgery and 60 min after flumazenil administration or 60 min after entering PACU; Aldrete score 60 min after entering PACU; mini-mental state examination (MMSE) before the surgery, in PACU and on 1 day after surgery (POD1); visual analogue scale (VAS) before the surgery, in PACU and on POD1; the post-operative quality of recovery scale (PostopQRS) before the surgery, on POD1 and 14 days after surgery (POD14); a telephone interview to evaluate cognitive status on POD14. Residual cognitive effects (more than 7 days) following ambulatory anesthesia in middle-aged patients have been previously reported [14]. The postoperative follow-up time point was therefore extended to POD14 to permit a comprehensive evaluation of cognitive recovery and complications [15, 16]. Vital signs including SpO2, HR, SBP and diastolic blood pressure (DBP) were recorded at twelve time points: before induction (T1), after induction (T2), after LMA insertion (T3), 5 min after the beginning of surgery (T4), 10 min after the beginning of surgery (T5), 10 min before stopping the study drug (T6), 5 min before stopping the study drug (T7), immediately after stopping the study drug (T8), 10 min after stopping the study drug (T9), 15 min after stopping the study drug (T10), LMA extraction (T11) and before leaving the operating room (T12).

Blood samples were drawn before anesthesia induction and at PACU discharge to measure inflammatory factors and biomarkers relevant to cognitive and lipid profiles, such as neuropeptide Y (NPY), interleukin (IL)-8, IL-1β, IL-10, triglyceride (TG) and very low density lipoprotein (VLDL) levels. The above factors were measured using enzyme-linked immunosorbent assay kits obtained from XLPCC (Shanghai, China) according to the manufacturer’s instructions. In order to explore whether RT had the similar effect to propofol in terms of inflammatory factors activation and Th17/Treg cell balance [2], neutrophil (CD11b/CD18) and Treg cell (CD39/CD73) surface markers were also measured in peripheral blood samples according to the manufacturer’s instructions (BD, San Diego, CA, USA) and then detected using flow cytometry.

Drug-related adverse events (AEs) including hypotension, sinus bradycardia and hypoxia (defined as SpO2 < 90%) were monitored throughout this study. Any AEs related to flumazenil were also recorded. In addition, the incidence of injection pain, intraoperative awareness, body movement, airway intervention after LMA extraction, postoperative nausea and vomiting and complications up to POD14 were calculated.

Statistical analysis

The sample size required for this study was based on pre-trial estimates of induction time and the time until fully alert. The mean induction times of the RT, RT + flumazenil and propofol groups were 55s, 58s and 51s, respectively, and the standard deviations (SD) for each group were 5s, 3s and 2s, respectively. Assuming an α = 0.05 and a power of 80% (two-sided tests), we calculated that a sample of 33 participants for each arm were required using the PASS 15 software (NCSS Corp., USA). The same method was used to estimate that at least 15 participants per arm were required to evaluate time until fully alert. Allowing for dropouts and non-evaluable data, a minimum of 38 participants were recruited for each group.

Analysis was performed according to the modified intention-to-treat principle. Data were presented using mean ± SD or median (25th, 75th percentiles) for continuous variables, and frequency counts and percentages for nominal variables. The Shapiro–Wilk test was used to determine whether continuous outcomes were normally distributed. Normally distributed data were tested using a one-way analysis of variance (ANOVA), with pairwise comparisons made with the least square mean values t test. Nonparametric data were tested with the Kruskal–Wallis test, with pairwise comparisons made with the Wilcoxon-rank sum test. Categorical outcomes were compared with the χ2 analysis or Fisher’s exact test in the setting of low expected cell counts. Endpoints assessed at different times were analyzed using the mixed-model repeated measures analysis. All outcomes were considered exploratory in nature and thus no correction for multiple comparisons was made. All statistical tests were two-tailed, and significance was defined using a P value < 0.05. All statistical analyses were performed using SPSS19.0 software (IBM, Armonk, NY, USA) and R software version 4.1.0 (The R Foundation, Vienna, Austria).

留言 (0)

沒有登入
gif