The Institutional Research Ethics Board of Zhongshan Hospital, Fudan University (B2020-082) approved this prospective, randomized, controlled, patient- and assessor-blinded, noninferiority, single-center clinical study on April 26th, 2020. All patients signed informed consent forms before recruitment. This study was conducted in accordance with the Declaration of Helsinki. The authors adhered to the CONSORT statement for reporting randomized controlled trials.
A total of 158 patients aged between 18 and 65 years old with American Society of Anesthesiologists (ASA) grade I–II receiving elective surgery under general anesthesia with tracheal intubation in Zhongshan Hospital, Fudan University between April 2020 and August 2020 were enrolled. Exclusion criteria included predicted difficult airway; history of bronchial asthma; decompensated cardiac disease; abnormal hepatic or renal function; known neuromuscular disease; use of NMBAs within one week; known allergy to any of the induction medications; known butyrylcholinesterase deficiency; and pregnancy or lactating women. The withdrawal criterion was unexpected difficult airway requiring tools other than a visual laryngoscope. The subjects were randomized to Group Miva (n = 79) or Group Rocu (n = 79) according to computer-generated random numbers by statistician and were concealed in opaque envelopes.
Patients were placed in the supine position in the operating room, an 18-gauge indwelling needle was used to establish anterior cubital venous access, and lactated Ringer's solution was given. ECG, heart rate (HR), noninvasive blood pressure (NIBP) and oxygen saturation (SpO2) were monitored. After sufficient preoxygenation with tidal volume breathing through a mask until the end-expiratory oxygen concentration reached ≥ 90% or above, lidocaine 1.5 mg/kg, propofol 2.0 mg/kg and ephedrine 6 mg were given sequentially. Then, for the patients in Group Miva, 0.25 mg/kg mivacurium (The Wellcome Foundation Limited; MIDDLESEX, UK) was given in divided doses (0.15 mg/kg injected in 10 s and 0.1 mg/kg in 5 s), separated by remifentanil 1 µg/kg injected in 30 s. Patients in Group Rocu were given rocuronium 0.9 mg/kg (N.V. Organon; Amsterdam, the Netherlands), followed by remifentanil 1 µg/kg injected in 30 s. Ideal body weight was used to calculate the dose of NMBAs for the patients whose actual weight was 30% or more above their ideal weight. Tracheal intubation was performed under a visual laryngoscope (TD-C-IV adult visual laryngoscope, Zhejiang Youyi Medical Apparatus Co., Ltd., Taizhou, China) 90 s after the completion of the initial dose in Group Miva and the completion of rocuronium in Group Rocu. Mechanical ventilation was started with a fraction of inspired oxygen (FiO2) of 50%, tidal volume of 6–8 mL/kg, respiratory frequency of 10 times/min, and fresh gas flow of 1.0 L/min. Patient end-tidal carbon dioxide (PETCO2) was kept in the range of 35–45 mmHg and 0.8–1.0 MAC sevoflurane inhalation was initiated. If MAP decreased by 30% or more from baseline while HR was < 60 beats per min (bpm), ephedrine 6 mg was given iv, while phenylephrine 100 µg was given if HR was > 60 bpm. If the HR dropped < 40 bpm without hypotension, 0.5 mg atropine was given. Patients whose MAP increased by 30% of baseline or HR > 100 bpm during or immediately after the intubation attempt were treated with propofol 0.5 mg/kg. For patients with choking or active vocal cord activity, an extra dose of propofol 0.5 mg/kg was given.
Blinded to the grouping information, the same attending anesthesiologist waited outside the operating room during anesthesia induction. After all medications were given, he was called into the operating room to perform tracheal intubation, and the intubation conditions of three variables were evaluated as per the intubation rating system of Cooper  immediately after intubation. Jaw relaxation or ease blade insertion was graded as easy (3), moderate (2), difficult (1) and impossible (0). Vocal cord positions were ranked as abducted (3), moving (2), closing (1) and closed (0). Response to intubation was graded as no movement (3), slight diaphragmatic movement (2), mild coughing (1) and severe coughing or bucking (0). The total scores of the three variables were rated as excellent (8–9), good (6–7), fair (3–5) and poor (0–2). Good and excellent intubating conditions were considered 'clinically acceptable'. The MAP and HR were recorded minutely from the minute prior to induction (T0) to the 10th minute (T10) postinduction. RSII time was defined as the time from the start of lidocaine injection to the completion of cuff inflation. The tracheal intubation time was defined as the time from the placement of the blade between the upper and lower incisors to the completion of cuff inflation . The need for additional vasopressors administered within T10 was recorded. Adverse reactions, including newly developed arrhythmia, skin manifestations of histamine release (macula, erythema, hives, flushing skin, etc. ), and wheezes detected by auscultation after intubation were also recorded.
The primary outcome was the rate of excellent intubation conditions evaluated by Cooper’s scale. According to the principle of choosing the margin of noninferiority, it was set to 1/10 − 1/5 of the rate of the comparator rocuronium and referring to equivalent studies, as well as the evaluation from our researchers and statisticians [17–19]. We chose a 10% difference as a clinically acceptable borderline with clinical relevance. The test level (α) was set as 0.025, the test power (1-β) was 0.80 and the ratio of patients enrolled in the two groups was 1:1. The number of patients was calculated to be 75 in each group, with an expected drop-out rate of 5%, and 158 patients were recruited.
All statistical analyses were performed with IBM Statistics SPSS 22 (IBM Corp, Armonk, NY, USA), while SAS 9.4 statistical software (SAS Institute, Cary, NC, USA) was used for noninferiority testing. Quantitative data are expressed as the mean ± standard deviation and were compared by two independent sample t-tests, while χ2 tests were used for comparison of categorical variables. To explore whether the two groups had similar baseline hemodynamic variables, Student’s t-tests were used to compare MAP and HR. Repeated measures analysis of variance (ANOVA) was used to compare the magnitude of MAP and HR responses to tracheal intubation. Analyses included fixed effects for time (T1 to T10), treatments (mivacurium and rocuronium), and treatments × time interactions. If the interaction was statistically significant, post hoc analysis using the Sidak correction method for mean differences was performed to determine whether there was any statistically significant difference between Group Miva and Group Rocu regarding the changes in MAP and HR between the longitudinal assessments. A P < 0.05 was considered statistically significant, while a P < 0.025 was considered significantly different for noninferiority testing.