Ethics and registration
This study was registered in the Chinese Clinical Trial Registry (www.chictr.org.cn, registration number: ChiCTR2300075300, 31/08/2023). The study was approved by the medical ethics committee of The Sixth Affiliated Hospital of Wenzhou Medical University (approval no. 2023-137), and all enrolled patients provided written informed consent.
Patient inclusion and exclusion criteria
This study involved 86 adult patients who were admitted to Lishui People’s Hospital (Wenzhou Medical University Lishui Hospital) for nasal surgery from September 2023 to October 2023.
The inclusion criteria were (1) elective nasal surgery, (2) age of 18 to 65 years, (3) an American Society of Anesthesiologists physical status of Ⅰ or II, and (4) a body mass index of 18.5 to 27.9 kg/m2. The exclusion criteria were (1) preoperative mental disorders or communication difficulties, (2) Patients with severe arrhythmia, such as sick sinus syndrome, second and third degree atrioventricular block, or heart rate (HR) <50 beats/minute); (3) Preoperative diagnosis of respiratory failure (PaO2<60mmHg), New York Heart Association (NYHA) cardiac function grading III or IV, (4) patients scheduled to be sent to the intensive care unit after surgery and (5) allergy to benzodiazepines, or have a long-term history of benzodiazepines.
Randomization and masking
Patients were randomly assigned into two groups (Group L and Group C) by computer-generated random numbers, 43 patients in each group. We discreetly placed the randomization results in envelopes until the end of the study. Study drugs were prepared by a nurse who was not involved in other parts of the study. Both remimazolam and saline are colorless liquids, and they were digitally encoded so that the researchers who were responsible for postoperative follow-up and data processing were blinded to the group allocation during the whole study period. All anaesthetists and patients were also blinded to the group allocation.
Perioperative management and interventions
No premedication was administered in all surgical patients. Upon arrival in the operating room, all patients underwent pulse oxygen saturation, mean arterial pressure (MAP), and electrocardiogram monitoring using a Carestation 620 A2 monitor (GE Healthcare, Chicago, IL, USA). The depth of general anesthesia of patients was continuously monitored by the bispectral index (BIS) sensor (Canwell Medical Co., Ltd., Jinhua, Zhejiang, China). All patients were anesthetized using standard protocols as follows. Anesthesia was induced with 2.0 to 2.5 mg/kg propofol (Beijing Fresenius Kabi Pharmaceutical Co., Ltd., Beijing, China), 0.4 to 0.5 mg/kg sufentanil (Yichang Humanwell Pharmaceutical Co., Ltd., Yichang, China) and 0.2 mg/kg cis-atracurium (Jiangsu Hengrui Pharmaceutical Co., Ltd., Jiangsu, China). After successful induction of general anesthesia, endotracheal intubation was performed. Volume-controlled mechanical ventilation was administered to maintain an end-tidal carbon dioxide partial pressure of 35 to 45 mmHg. Anesthesia was maintained with inhalation of 1.5 to 3.5% sevoflurane concentration (Jiangsu Hengrui Pharmaceutical Co., Ltd., Jiangsu, China) and 4 to 12mg/kg/h propofol (Beijing Fresenius Kabi Pharmaceutical Co., Ltd., Beijing, China) were used for maintenance of anaesthesia. The sevoflurane concentration was controlled according to the haemodynamics and BIS value of each patient (maintaining both MAP and HR changes within 20% of baseline, and a BIS value of 40 to 60). During the surgery, sufentanil and cis-atracurium were injected as needed. When the surgery was over, the anesthetic drugs was stopped immediately. Then the intervention measures was started: (1) Group R (n=43): 0.1mg/kg remimazolam was injected intravenously after surgery, and the infusion time was 1 min. (2) Group C (n = 43), normal saline was injected intravenously after surgery, and the volume and rate changes were the same as those in Group R. When we confirmed the return of neuromuscular function by using a train-of-four monitor, neuromuscular blocking was reversed with glycopyrrolate 0.004 mg/kg and 0.02 mg/kg neostigmine. Then, we administered verbal stimulation to the patients every 30 seconds, patients were extubated once they regained consciousness and were able to obey verbal commands. The RSAS scores were assessed by independent anesthesiologists every 10 seconds who were blinded to the anesthetic methods administered in this study. Finally, all patients were transferred to the post-anesthesia care unit (PACU) for close observation. A well-trained nurse blinded to randomized study group evaluated pain intensity by using the NRS (numeric rating scale) (range, 0-10, with higher scores indicating worse pain) every 5 minutes. Nonsteroidal anti-inflammatory drugs were administered when the NRS score ≥ 5. Patients were discharged from the PACU when their Aldrete score was ≥ 9. 8 The following evaluation time points were defined: T0: admission (basal); T1: at the end of the surgery; T2: after investigational drug infusion; T3: tracheal extubation; T4: 2 min after tracheal extubation; T5: 5 min after tracheal extubation.
Outcomes
Primary outcome
The primary outcome was the incidence of EA. Emergence was defined as the time interval from the end of surgery to 2 minutes after tracheal extubation. During emergence, EA was defined as the Riker sedation–agitation scale (RSAS) >4 score, 1 = unarousable, no response to noxious stimuli; 2 = very sedated, arouse to physical stimuli but dose not communicate; 3 = sedated, awakens to verbal commands or gentle shaking but drifts off again; 4 = calm, awakens easily, follows verbal commands; 5 = agitated, anxious or mildly agitated, calms down to verbal instructions; 6 = very agitated, requiring physical restraint and frequent verbal reminding of limits; and 7 = dangerous agitation, pulling at tracheal tube, trying to remove catheters or striking at staff.9
Secondary outcomes
The secondary outcomes were as follows.
- The incidence of severe EA (RSAS = 7) and the maximal RSAS score during emergence were also recorded.
- Recovery characteristics included extubation time, the length of PACU stay and Maximum NRS score in PACU.
- Intraoperative characteristics included intraoperative sufentanil dosage, duration of surgery, sevoflurane used time , amount of intraoperative fluid and blood loss.
- Haemodynamic parameters (including MAP and HR) were recorded at six different time points: T0, T1, T2, T3,T4, and T5.
- The observation period of postoperative adverse events was from the end of surgery to discharged from the PACU. Postoperative adverse events included hypotension (MAP ≤ 70% of baseline and/or < 65 mmHg), hypertension (MAP ≥ 120% of baseline), bradycardia (HR ≤ 45 beats/min), and tachycardia (HR of ≥ 120% of baseline), 10 postoperative nausea and vomiting (PONV), laryngospasm, cough (Cough level: 0= no coughing; 1= single cough; 2= persistent cough lasting< 5s; 3= persistent cough lasting ≥ 5s) .If these events occurred, intravenous injection of drugs such as ephedrine, urapidil, atropine, esmolol, and tropisetron can be used to treate.
- The incidence of postoperative delirium (POD) within 3 days after surgery, which was assessed by Confusion Assessment Method. 11
Sample size and statistical analysis
A total of 40 patients completed this pre-experiment. According to the results of the pre-experiment, the incidence of EA was 55% in Group C and 25% in Group R. Therefore, a sample size of 76 patients was needed to provide a power of 80% and a significance of 0.05. Considering a 10% attrition rate, we concluded to enroll 86 patients for this study (43 patients in each group).
The data processing and analyses were performed using SPSS 20.0 statistical software (IBM Corp., Armonk, NY, USA). All data are presented as mean ± standard deviation, number (percentage), or median (interquartile range) as appropriate. The normality of distribution was assessed with the Shapiro-Wilk test. Normally distributed data were compared between the groups using an independent-samples t-test, and non-normally distributed data were compared between the groups using the Mann–Whitney U test. Repeated-measures ANOVA was used for intra group comparisons, and Bonferroni Corrections to determine the P value significance threshold. The chi-square test or Fisher’s exact test was used for comparison of enumeration data between the groups. The significance level for this analysis was set at α = 0.05.