Median effective dose of sufentanil combined with remimazolam for suppressing the response to tracheal intubation

Abstract

To ascertain the median effective dose (ED50) and 95% effective dose (ED95) of a combination of sufentanil and remimazolam for suppressing the tracheal intubation response in patients receiving general anesthesia and to assess the hemodynamic stability and incidence of adverse events related to this drug regimen, this prospective dose-finding study used Dixon’s up-and-down sequential method. Thirty-one patients scheduled for surgery under general anesthesia between October 2023 and December 2023 were assessed for eligibility; 7 were excluded, and 24 completed the dose-finding sequence and were analyzed (12 with a negative and 12 with a positive intubation response). Anesthesia was induced with remimazolam 0.35 mg/kg, followed by sufentanil at an initial dose of 0.4 µg/kg, with subsequent dose adjustments based on the intubation response. The primary endpoint was the ED50 of sufentanil, and secondary endpoints included hemodynamic indices and adverse events. The ED50 and ED95 of sufentanil required to suppress the tracheal intubation response were 0.358 µg/kg (95% confidence interval, 0.340–0.376 µg/kg) and 0.436 µg/kg (95% CI, 0.409–0.504 µg/kg), respectively. Heart rate did not differ significantly between response groups. Mean arterial pressure at T2 and the incidence of hypertension were higher in the positive-response group. When remimazolam 0.35 mg/kg was used for induction, the ED50 and ED95 of sufentanil for suppressing the tracheal intubation response were 0.358 and 0.436 µg/kg, respectively. These estimates should be interpreted within the study population and dose-finding design.

1. Introduction

Tracheal intubation under general anesthesia is a routine form of airway management during surgery. The so-called tracheal intubation reaction refers to the massive release of catecholamines triggered by the stimulation of sympathetic nerves in the pharynx and tracheal mucosa during tracheal intubation using a laryngoscope after the induction of anesthesia. This reaction can cause intense stress, such as tachycardia and hypertension, in patients in a short period of time, and in severe cases, it may even induce serious complications such as malignant arrhythmia and cardiovascular accidents.^[1-3]

Sufentanil, a potent opioid analgesic, exerts pharmacological effects by inhibiting adrenal secretion, enhancing vagal tone, and attenuating the stress response by stimulating μ-opioid receptors. It is effective in blocking the transmission of laryngeal stimuli to the center during tracheal intubation, which in turn attenuates intubation-induced cardiovascular responses.^[4-6] However, the dosage of sufentanil should be used with extreme caution, as inappropriate dosages may trigger adverse reactions. At a dose that is too low, the response to tracheal intubation may not be effectively suppressed, and severe tracheal intubation stress may occur. A dose that is too high may result in severe hypotension after anesthesia induction, postoperative nausea and vomiting, and postoperative cognitive dysfunction.^[7,8] Therefore, determining the appropriate dose of sufentanil for the induction of general anesthesia is of paramount importance.

Remimazolam is a novel benzodiazepine sedative, whose main target of action is the γ-aminobutyric acid A receptor.^[9-11] Compared with midazolam, remimazolam exhibits multiple advantages, such as rapid onset of action, rapid metabolism, low accumulation in the body, mild inhibition of the respiratory and circulatory systems, and rapid recovery from anesthesia. In addition, remimazolam is rapidly hydrolyzed to inactive metabolites by nonspecific esterases in the plasma and therefore has no adverse effects on hepatic or renal function. Moreover, its efficacy can be rapidly reversed by flumazenil, which contributes to more precise anesthetic management.^[12,13] Xie et al found that remimazolam in combination with sufentanil was more effective in providing analgesia and had a lower incidence of adverse events than propofol in a study involving 60 elderly hysteroscopic surgery patients.^[14] However, there are insufficient studies on the dosage of sufentanil in combination with remimazolam for the induction of anesthesia. Therefore, this study aimed to investigate and determine the median effective dose (ED50) of sufentanil in combination with remimazolam using Dixon’s up-down sequential allocation method to provide a reference for clinical practice.^[15]

2. Materials and methods

2.1. Study design and ethical approval

This report presents the prespecified remimazolam 0.35 mg/kg arm of a 2-dose prospective protocol registered in the Chinese Clinical Trial Registry (ChiCTR2300075949; https://www.chictr.org.cn/showproj.html?proj=207603). The study was approved by the Ethics Committee of Nanchong Central Hospital (2023, trial [061]). The study was conducted in accordance with the Declaration of Helsinki, and all patients provided written informed consent.

2.2. Participants

A total of 31 patients scheduled for surgical procedures requiring general anesthesia were assessed for eligibility between October 2023 and December 2023. Eligibility criteria were age 18 to 65 years, body mass index 19 to 28 kg/m², and American Society of Anesthesiologists physical status I-III. Exclusion criteria were severe cardiopulmonary disease, baseline systolic blood pressure > 160 mm Hg, resting heart rate (HR) > 100 beats/min, liver or kidney dysfunction, allergy to a study medication, or an anticipated difficult airway. All patients included in the analyzed cohort were Han Chinese; ethnicity was not a prespecified eligibility criterion.

2.3. Anesthesia

Patients were instructed to fast for 8 hours and avoid liquids for 6 hours before surgery. Upon arrival in the operating room, intravenous access was established for the administration of a compound sodium chloride solution, and oxygen was provided at 3 L/min via a facemask. Vital signs such as electrocardiogram (ECG), pulse oximetry (SpO₂), HR, blood pressure, and bispectral index (BIS) were continuously monitored. Anesthesia was induced through a gradual intravenous infusion of remimazolam at a dose of 0.35 mg/kg. Once BIS dropped to ≤60 and the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score was ≤1, sufentanil (0.4 µg/kg) and cisatracurium (0.2 mg/kg) were administered intravenously. After muscle relaxation, tracheal intubation was performed using a video laryngoscope by an experienced anesthesiologist with over a decade of practice. Mechanical ventilation was initiated after successful intubation. The initial sufentanil dose for the first patient was 0.4 µg/kg, with subsequent doses adjusted according to the presence or absence of an intubation response. In this study, a positive tracheal intubation reaction was defined as an increase in mean arterial pressure (MAP) or HR exceeding 20% from baseline or an MOAA/S score > 1 during and within 2 minutes after intubation.^[16] If no intubation response was observed, the sufentanil dose for the next patient was reduced by 0.05 µg/kg. If an intubation response occurred, the sufentanil dose for the subsequent patient was increased by 0.05 µg/kg. Additional sufentanil or remimazolam was administered if the MOAA/S score was >1 during intubation. Throughout the surgical procedure, sevoflurane was utilized to maintain anesthesia depth, with intermittent boluses of sufentanil and cisatracurium administered to ensure analgesia and muscle relaxation. Postoperatively, the endotracheal tube was removed, and the patient was transferred to the post-anesthesia care unit.

2.4. Determination of ED50

The ED50 of sufentanil for suppressing the tracheal intubation response was evaluated using the up-and-down sequential allocation method. The initial sufentanil dose was 0.4 µg/kg, and the dose step was 0.05 µg/kg. Enrollment in the dose-finding sequence continued until 7 positive-negative crossover pairs had been observed.^[17,18]

2.5. Study outcomes

The primary outcome was the ED50 of sufentanil when combined with remimazolam 0.35 mg/kg for suppressing the tracheal intubation response. Secondary outcomes included baseline characteristics (age, sex, height, weight, body mass index, and American Society of Anesthesiologists classification), hemodynamic parameters recorded before induction (T1), 1 minute after induction (T2), and 2 minutes after tracheal intubation (T3), and adverse events. Hypertension and hypotension were defined as increases or decreases in blood pressure exceeding 30% of baseline, respectively. Bradycardia was defined as HR < 50 beats/min, tachycardia as HR > 100 beats/min, and hypoxemia as peripheral oxygen saturation < 90%. Body movement and injection pain were also recorded.

2.6. Statistical analysis

The study was stopped after 7 positive-negative crossover pairs, in accordance with the up-and-down design. ED50 and 95% effective dose (ED95) values and their 95% CIs were estimated by probit regression in SPSS. Normally distributed continuous variables are reported as mean ± standard deviation and were compared between independent groups using the independent-samples t-test. Non-normally distributed continuous variables are reported as median (interquartile range) and were compared using the Mann–Whitney U test. Hemodynamic variables were analyzed using a 2-way repeated-measures analysis of variance with time as the within-participant factor and intubation-response group as the between-participant factor; Bonferroni-adjusted pairwise comparisons were used when appropriate. Categorical variables were compared using the Pearson chi-square test or Fisher exact test, as appropriate. Statistical significance was set at P < .05.

3. Results

A flowchart of this study is shown in Figure 1. We assessed 31 patients between October 2023 and December 2023 for eligibility. Seven patients were excluded, of whom 2 had severe cardiac disease, 4 had severe hypertension, and 1 had a difficult airway. Ultimately, 24 patients were included in the final analysis, with 12 patients exhibiting a negative response to tracheal intubation and the remaining 12 demonstrating a positive response. The baseline demographic characteristics of the study participants are detailed in Table 1.

Figure 1.

Study flow chart.

Table 1.

Baseline characteristics of the study participants.

Item	Negative (n = 12)	Positive (n = 12)	P
Sex (M/F)	4/8	7/5	.219
Age (yr)	41.0 ± 14.6	47.1 ± 9.7	.243
Weight (kg)	64.9 ± 9.4	70.3 ± 7.4	.133
BMI (kg/m2)	23.5 ± 2.0	25.0 ± 2.2	.091
ASA (I/II)	4/8	0/12	.093
Hypertension	1 (8.3%)	0	1.000
Diabetes	0	0	–

Data are presented as mean ± SD or number (percentage of patients). Continuous variables were compared using independent-samples t-tests. Sex was compared using the Pearson chi-square test; ASA physical status and medical history were compared using Fisher’s exact test.

ASA = American Society of Anesthesiologists, BMI = body mass index, –, not applicable.

Figure 2 shows the up-and-down sequential responses of the 24 patients who completed the dose-finding sequence. Table 2 summarizes the numbers of positive and negative responses at each sufentanil dose. All patients receiving 0.45 µg/kg had a negative response, whereas all patients receiving 0.30 µg/kg had a positive response. The study ended after 7 positive-negative crossover pairs.

Figure 2.

Up-and-down sequence of sufentanil doses and tracheal intubation responses for the 24 analyzed patients. Red filled circles indicate a positive intubation response; open circles indicate a negative response (successful suppression).

Table 2.

Number of positive and negative intubations induced by different doses of sufentanil.

Sufentanil dose (μ/kg)	Negative (number)	Positive (number)	Sample size (number)
0.30	0	6	6
0.35	6	4	10
0.40	4	2	6
0.45	2	0	2

Table 3 shows that the ED50 and ED95 of sufentanil combined with remimazolam for suppressing the tracheal intubation response were 0.358 µg/kg (95% confidence interval [CI], 0.340–0.376 µg/kg) and 0.436 µg/kg (95% CI, 0.409–0.504 µg/kg), respectively.

Table 3.

ED50 and ED95 and their 95% CI.

	Sufentanil for induction	95% CI for sufentanil
ED50 (μg/kg)	0.358	0.340–0.376
ED95 (μg/kg)	0.436	0.409–0.504

CI = confidence interval, ED50 = median effective dose, ED95 = 95% effective dose.

Hemodynamic data are shown in Table 4 and Figure 3. HR did not differ significantly between the response groups at any time point, and within-group HR changes were not significant (all P > .05).

Table 4.

Hemodynamic data.

Item	Time	Negative (n = 12)	Positive (n = 12)
HR (beats/min)	T1	81.7 ± 13.3	73.4 ± 10.8
	T2	80.5 ± 15.3	72.5 ± 10.4
	T3	77.5 ± 11.3	72.8 ± 12.8
MAP (mm Hg)	T1	90.4 ± 13.4	94.5 ± 10.7
	T2	67.9 ± 9.5	80.3 ± 8.9*
	T3	76.8 ± 11.5	85.8 ± 19.3

Values are mean ± standard deviation. Hemodynamic variables were analyzed using 2-way repeated-measures analysis of variance with Bonferroni-adjusted pairwise comparisons.

HR = heart rate, MAP = mean arterial pressure, T1 = before induction, T2 = 1 minute after induction, T3 = 2 minutes after tracheal intubation.

^*P = .006 vs the negative-response group at T2.

Figure 3.

Hemodynamic changes by tracheal intubation response. Values are mean ± standard deviation. *P = .006 for the between-group comparison of MAP at T2. HR = heart rate, MAP = mean arterial pressure, T1 = before induction, T2 = 1 minute after induction, T3 = 2 minutes after tracheal intubation.

For MAP, the time effect was significant. In the negative-response group, MAP was lower at T2 and T3 than at T1 (P < .001 and P = .002, respectively). In the positive-response group, MAP was lower at T2 than at T1 (P = .001). Between groups, MAP was higher in the positive-response group at T2 (P = .006), with no significant between-group difference at T1 or T3.

Adverse events are presented in Table 5. Hypertension occurred more frequently in the positive-response group (0/12 vs. 5/12; Fisher exact P = .037). No significant between-group differences were observed for the other adverse events, and no patient experienced bradycardia or hypoxemia. The sufentanil induction dose was higher in the negative-response group than in the positive-response group (0.383 ± 0.039 vs. 0.333 ± 0.039 µg/kg; P = .005).

Table 5.

Adverse events and sufentanil induction dose.

Outcome	Negative (n = 12)	Positive (n = 12)	P
Hypertension, n (%)	0	5 (41.7%)	.037
Hypotension, n (%)	3 (25.0%)	0	.217
Bradycardia, n (%)	0	0	–
Tachycardia, n (%)	0	1 (8.3%)	1.000
Hypoxemia, n (%)	0	0	–
Injection pain, n (%)	1 (8.3%)	0	1.000
Body movement, n (%)	0	1 (8.3%)	1.000
Sufentanil dose (µg/kg)	0.383 ± 0.039	0.333 ± 0.039	.005

Categorical data are presented as number (percentage) and were compared using Fisher’s exact test when appropriate. Sufentanil dose is mean ± standard deviation and was compared using the independent-samples t-test.

4. Discussion

In this prospective dose-finding study, the ED50 and ED95 of sufentanil combined with remimazolam 0.35 mg/kg for suppressing the tracheal intubation response were 0.358 µg/kg (95% CI, 0.340–0.376 µg/kg) and 0.436 µg/kg (95% CI, 0.409–0.504 µg/kg), respectively. These estimates characterize the dose-response relationship in the present single-center population and may inform the design of larger confirmatory studies. They should not be interpreted as universal dosing recommendations because the up-and-down design was optimized for ED50 estimation and included a limited number of patients.

As a new type of benzodiazepine sedative, remimazolam has the advantages of fast onset of action, rapid metabolism, low accumulation, little respiratory and circulatory depression, and precise anesthetic effects. Many recent studies have found that remimazolam, in combination with sufentanil for the induction of anesthesia, has stable hemodynamics and fewer adverse effects.^[19,20] Xu et al studied 60 elderly hypertensive patients and found that remimazolam, in combination with sufentanil, had the advantages of less hemodynamic fluctuation, circulatory stability, and fewer adverse effects compared to propofol in elderly patients with mild hypertension.^[21] Zhao et al’s meta-analysis of 1147 patients who underwent painless endoscopy found a significant reduction in the incidence of injection pain, hypotension, and respiratory depression compared to propofol.^[22] Chen et al’s study of 240 elderly patients undergoing gastroscopy found that sedation success was the same in the remimazolam combined with sufentanil group compared to that in the propofol group, but adverse effects such as injection pain and hypotension were lower in the remimazolam group.^[23] For pediatric populations, Li et al established age-stratified remimazolam ED50 doses: 0.476 mg/kg for preschoolers (3–6 years) versus 0.427 mg/kg for school-aged children (6–12 years) when combined with sufentanil 0.3 μg/kg during LMA induction.^[24] Considering that remimazolam combined with sufentanil showed stable effects in the induction of anesthesia, we further explored their dosage in this study.

The Dixon Sequential Assignment Method is often used in clinical practice to study the dose-effect relationship of anesthetic drugs. It is a simple and rapid method that accurately determines the ED50. Specifically, the Dixon up-and-down sequential allocation method starts with a predicted optimal dose of ED50 and increases or decreases the dose for the next subject accordingly, depending on the response of the previous subject. Typically, this method achieves the desired sample size after 7 crossovers.^[25] In this study, the initial dose of sufentanil was set at 0.4 μg/kg, which is commonly used in clinical studies, and the sample size fulfilled the requirements of the sequential allocation method.

In the hemodynamic analysis, MAP decreased after induction in both response groups. Three hypotensive events occurred in the negative-response group, but the incidence of hypotension did not differ significantly between groups. The negative-response group received a higher mean sufentanil dose, whereas the lower doses in the positive-response group were associated with more frequent hypertension during intubation. HR did not differ significantly between groups. These findings support balancing suppression of the intubation response against dose-related hemodynamic depression.

The present report and the study by Feng et al^[26] derive from the same registered 2-dose parent protocol and share the same ethics approval and registration number. Feng et al reported the prespecified 0.25 mg/kg remimazolam arm, whereas the present report analyzes the prespecified 0.35 mg/kg arm. Thus, the present report is not a secondary analysis of the cohort published by Feng et al; it is the complementary arm-level analysis of the parent protocol. The higher remimazolam dose was associated with a lower estimated sufentanil ED50, although cross-arm comparisons should be interpreted cautiously because the 2 dose-finding sequences were analyzed separately.

In addition, 24 patients were included in our study, of which 1 patient developed injection pain with an incidence of 4.17%, a finding similar to that of Zhang et al (2.4%).^[27] In a meta-analysis study of 7315 patients by Bakhtiari et al, the incidence of injection pain with propofol ranged from 40.91% to 66.27%. Remimazolam has an advantage over propofol in terms of pain.^[28]

Several limitations should be acknowledged. First, the sample size was determined for the up-and-down estimation of ED50 and was insufficient for definitive inference about secondary outcomes or uncommon adverse events. Second, ED95 was model-based and therefore less precise than ED50 in this small dose-finding sample. Third, postoperative outcomes such as nausea, vomiting, and delirium were not assessed. Finally, all analyzed participants were Han Chinese at a single center, which limits the generalizability of the findings. Larger multicenter studies should validate these estimates in more diverse populations.

5. Conclusion

When remimazolam 0.35 mg/kg was used for anesthesia induction, the estimated ED50 and ED95 of sufentanil for suppressing the tracheal intubation response were 0.358 µg/kg and 0.436 µg/kg, respectively.

Author contributions

Conceptualization: Qin Chen, Yalan Yong.

Data curation: Yalan Yong, Gui Yang.

Formal analysis: Yalan Yong, Gui Yang.

Investigation: Yalan Yong.

Methodology: Yalan Yong, Huanhuan Dai.

Project administration: Li Zhao.

Resources: Li Zhao.

Software: Yalan Yong, Huanhuan Dai, Li Zhao.

Supervision: Li Zhao.

Validation: Li Zhao.

Visualization: Li Zhao.

Writing – original draft: Qin Chen.

Writing – review & editing: Qin Chen.