Inclusion and exclusion criteria
This prospective, double-blind, dose-finding clinical trial was approved by the Ethics Committee of the Peking University Shenzhen Hospital (approval number: 2021 No.096, date of approval: 06/12/2021) and registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2100054565, date of registration: 20/12/2021). We obtained written informed consent from all enrolled patients.
ASA I-II patients who were 18 to 64 years old, with a body mass index between 18.5 and 30 kg/m2, and scheduled for general anesthesia for elective surgery (Otorhinolaryngology or gynecology) were approached to participate in this trial from January 2022 to March 2022. Patients were excluded if they (1) suffered from severe cardiovascular or respiratory diseases; (2) had renal, liver, or hematological dysfunctions; (3) diagnosed with obstructive sleep apnea-hypopnea syndrome or once had difficulty intubating; (4) had high risk factors of aspiration or regurgitation; (5) were taking beta-blockers, analgesics or psychotropic medications; (6) had contraindications to use remifentanil.
Study protocol
All patients were fasted overnight and received no premedication prior to surgery. One of the arms was inserted with a venous catheter of 20- or 22-gauge after entering the operating room. During the perioperative period, electrocardiograms (ECG), pulse oximetry (SpO2), noninvasive blood pressure (NIBP) and end-tidal carbon dioxide (PetCO2) were monitored (N15 Anesthesia Monitor, Mindray, China). The MGRSSI and MGRNOX were also continuously monitored using electroencephalogram (EEG) derivative collected from forehead sensor (Belive Drive A2 Monitor, Maygreen, China).
The MGRSSI was recorded to assess the hypnotic effect of the anesthesia, while the MGRNOX was recorded to assess the nociception/antinociception balance. The MGRSSI and MGRNOX indices are based on calculation of the Fast Fourier Transform (FFT) and the Burst Suppression (BSR) that are fed into a regressive model which generates the output on a 0–100 scale. According to the manufacture’s recommendation, adequate sedation is typically represented by a MGRSSI range between 40 and 60, and adequate analgesia is represented by a MGRNOX range between 30 and 50.
Preoxygenation of patients with 100% oxygen via facial masks for 3 min was applied before intravenous induction. Anesthesia was performed using a TCI for administering remifentanil, which was started with a predetermined target effect-site concentration and infused according to Minto model [
19], by an infusion pump (Fresenius Kabi, France). Two min after the remifentanil infusion began, etomidate (0.3 mg/kg) was injected intravenously within 30 s. When the patients lost consciousness (failed to respond to verbal commands), rocuronium (0.6 mg/kg) was given within 30 s, and artificial ventilation was initiated. A laryngoscopy was performed and endotracheal intubation was attempted 2 min after rocuronium injections, using a unified visual laryngoscope (E.An IIL, Tianjin Medan Medical corporation, China) and an ordinary endotracheal tube, the diameter of the tube was individualized by the patient’s height. All intubations were performed by one experienced attending anesthesiologist, those patients whose endotracheal intubation was not successful at one time or whose intubation time was longer than 1 min were excluded from the study. General anesthesia was maintained using 2% sevoflurane with 50% oxygen, end-tidal carbon dioxide concentrations were maintained at 35–45 mmHg using mechanical ventilation. Three min after endotracheal intubation, remifentanil’s effect-site concentration remained unchanged.
Systolic blood pressure (SBP), diastolic blood pressure (DBP), MAP, HR, SpO2, MGRSSI and MGRNOX were recorded 1 min before induction, 2 min and 1 min before intubation, at intubation and at each min for 3 min after intubation. Time 1 (T1) was defined as 1 min before induction and Time 2 (T2) was defined as 1 min before intubation. The pre-intubation values of MAP and HR were calculated as the mean of measurements taken 2 min and 1 min before intubation. The changes of MAP, HR, MGRSSI and MGRNOX during intubation (ΔMAP, ΔHR, ΔMGRSSI and ΔMGRNOX) were defined as the difference between the value 1 min before intubation and the maximal value within the first 3 min following intubation.
A modified Dixon’s up-and-down method was used to calculate the concentration of remifentanil [
20‐
22]. Based on a previous study [
15], remifentanil was administered at an effect-site concentration of 6 ng/ml to the first patient. If the cardiovascular response during endotracheal intubation (intubation response) was positive (MAP or HR is 20% higher than the pre-intubation value), the concentration of remifentanil in the next patient would decrease by 1 ng/ml. Conversely, if the intubation response was negative, the concentration of remifentanil would increase by 1 ng/ml. The modified up-and-down method we used was based on modifying the test space, so as to improve the accuracy of final results [
21]. Specifically, following the first three “negative-positive” crossovers, the step change of dose was reduced to 0.5 ng/ml, this process was repeated until seven crossover points had been obtained.
During the data collection period, excessive hemodynamic fluctuations including: SBP < 80 or > 180 mmHg; HR < 50 bpm or > 120 bpm. Hypoxemia was defined as SpO2 ≤ 92% for more than 10 s. If the patients experienced excessive hemodynamic fluctuations, hypoxemia, severe muscle tremor, or persistent chest wall rigidity, we would handle it according to the emergency disposal plan and the patients were withdrawn from this study, the following case was treated with the same concentration of remifentanil.
Outcome measures
The primary outcomes were effective concentration of remifentanil blunting cardiovascular responses of intubation during etomidate anesthesia in 50% (EC50) and 95% (EC95) of the study population. Following EC50 calculation, the data were further analyzed for secondary outcomes to compare those who were positive and negative for tracheal intubation responses. The secondary outcomes including: (1) The changes of the hemodynamic indices (ΔMAP and ΔHR) and indices derived from electroencephalogram (ΔMGRSSI and ΔMGRNOX) during endotracheal intubation; (2) adverse events (great hemodynamic change, hypoxemia, muscle tremor, symptoms of chest wall rigidity, choking cough, and postoperative nausea and vomiting) related to remifentanil combined with etomidate anesthesia.
Statistical analysis
Statistical analysis was performed using SPSS version 25.0 software (IBM, Armonk, NY, USA). For normal distribution, the data are presented as the mean ± standard deviation, while for nonnormal distributions, the date are presented as median (interquartile range). A Shapiro-Wilk test was used to check for normal distribution of continuous variables. The t-test was used to compare parametric data. Categorical variables were analyzed by the Chi‑square test or Fisher’s exact test. Significant differences were defined as P value < 0.05 (two-tailed). In order to calculate sample size, we conducted a pretest, assuming a standard deviation (SD) of 0.74 ng/ml and a standard error of the mean (SEM) of 0.23 ng/ml. Following Dixon and Massey’s suggestion, sample size needed to estimate EC
50 was derived by n = 2*(SD/SEM)
2 [
23]. Considering an attrition rate of 10%, sample size needed to be at least 23 patients. When fewer than seven “negative-positive” crossovers appeared during the up-and-down sequence, the number should be increased. Based on the modified Dixon’s up-and-down method data, we calculated the EC
50 and EC
95 using a probit analysis. Statistical results are presented as point estimates (95% CI). To assess goodness-of-fit, Pearson’s Chi-squared test was used (P value > 0.05 indicates good fit).