Effects of remifentanil pretreatment on sufentanil-induced cough suppression during the induction of general anesthesia: a randomized controlled trial

doi:10.21203/rs.3.rs-1962692/v1

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Effects of remifentanil pretreatment on sufentanil-induced cough suppression during the induction of general anesthesia: a randomized controlled trial

https://doi.org/10.21203/rs.3.rs-1962692/v1

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Background: Sufentanil is widely used for induction of general anesthesia, however, sufentanil can lead to cough during general anesthesia induction. This study aimed to observe the effect of remifentanil pretreatment on sufentanil-induced cough (SIC) during general anesthesia induction.

Methods: A total of 120 patients who were scheduled for elective surgery were equally randomized into two groups (n=60 each). Patients in R group received 0.5 μg/kg remifentanil and N group received same volume of normal saline 1 minute before sufentanil (0.5 μg/kg) intravenous injection. Remifentanil and sufentanil were diluted to 5ml and then administered to patients in both R and N groups within 5 seconds. Then midazolam (0.04mg/kg), etomidate (0.3mg/kg) and rocuronium bromide (0.6mg/kg) were given to facilitate tracheal intubation. The incidence and severity of cough in both groups were recorded within 2 minutes after sufentanil administration during general anesthesia induction. The mean arterial pressure (MAP), heart rate (HR), and pulse oxygen saturation (SpO2) were recorded at T1(before the injection of remifentanil or normal saline), T2 (1 minute after remifentanil administration), T3 (before intubation) and T4 (1 minute after intubation). Additionally, the incidences of adverse events, including dizziness, nausea, apnea, truncal rigidity, bradycardia or other adverse effects were also recorded.

Results: The incidence of SIC in R group was significantly decreased when compared with N group (3.33% vs 35.00%, respectively; P < 0.001). No statistical differences were found in MAP, HR, SpO2, and the incidences of other side effects between two groups at T1, T2, T3, and T4 (P > 0.05).Two patients experienced dizziness in R group, and one patient in N group suffered from muscle rigidity.

Conclusion: Pretreatment with remifentanil 0.5 μg/kg can effectively and safely suppress the incidence and severity of sufentanil-induced cough, and provide a reference for the medication of patients during general anesthesia induction.

Trial registration: Chinese Clinical Trial Registry (30/09/2020, ChiCTR2000038756)

Remifentanil

Sufentanil

Cough

General anesthesia

Sufentanil is widely used for induction of general anesthesia due to its potent analgesic properties, rapid onset and stable hemodynamics. Nevertheless, intravenous administration of sufentanil can lead to cough during general anesthesia induction. The incidence of sufentanil-induced cough (SIC) varies between 15.8% and 47.1% [1–4]. Sufentanil-induced cough might increase the blood, intraocular, intracranial, intrapulmonary and intra-abdominal pressure suddenly. Therefore, SIC might bring a serious damage to patients with hypertension, cerebral aneurysm, open eye injury, a full stomach, pulmonary bullae or abdominal aortic aneurysm[5, 6]. However, the mechanism of SIC still remain to be unclear. Previous studies have suggested that it may be related to the activation of µ-opioid receptors, vagus nerve excitation, citrate-induced cough, increased histamine release, and stiffness of small muscles near the vocal cords[7, 8]. Various pharmacological strategies, including magnesium, lidocaine, tramadol, dezocine, dexmedetomidine, butorphanol, nalbuphine, and ketorolac tromethamine, were used to suppress the occurrence of SIC during general anesthesia induction[1–3, 5, 6, 9–12].

Remifentanil is an ultra-short-acting and rapid-onset opioid with strong analgesic effects. Previous study has shown that remifentanil is effective in lowering the heart rate and blood pressure when used as an adjuvant in anesthesia[13]. Previous studies have shown that maintaining low-dose remifentanil during the emergence reduces the incidence and severity of cough from the endotracheal tube[14]. However, few other reports have reported the effect of remifentanil in suppressing SIC. The mechanism of remifentanil inhibits SIC remains unclear. We hypothesized that opioid receptor dualism may be a potential mechanism. Therefore, in this study, the effectiveness of remifentanil on the incidence and severity of SIC in patients during general anesthesia induction was evaluated.

This study was approved by the Medical Research Ethics Committee of the Second Affiliated Hospital of Nanchang University (2020–027) and this trial was registered in the Chinese Clinical Trial Registry (30/09/2020, ChiCTR2000038756). This study was conducted from September 2020 to February 2021, altogether 120 patients aged 18 to 60 years of both genders undergoing elective surgery with American Society of Anesthesiologists (ASA) physical status classification I or II were recruited. The exclusion criteria were as follows: Patients 1) with abnormal liver and kidney function; 2) with history of cardiovascular and cerebrovascular diseases; 3) with history of asthma; 4) with history of chronic cough; 5) with history of smoking; 6) with history of upper respiratory tract infection 2 weeks before surgery; 7) who underwent operation by receiving opioid therapy 2 weeks before surgery; and 8) who received angiotensin converting enzyme inhibitors, bronchodilators or steroids 2 weeks before surgery.

All 120 participants were randomly divided into R group and N group by computer-generated random numbers. The patients in R group were pretreated with 0.5 µg/kg remifentanil (diluted to 5 ml) intravenous infusion within 5 seconds, and the patients in N group who received 5ml isotonic saline were considered as the control group. After pretreatment with drug administration for 60 seconds, 0.5 µg/kg sufentanil was given to each patient within 5 seconds. Then midazolam (0.04 mg/kg), etomidate (0.3 mg/kg) and rocuronium bromide (0.6 mg/kg) were given to facilitate tracheal intubation which was commenced only after any coughing had subsided.

The episodes of coughs that occurred within 2 minutes were recorded after sufentanil administration and the severity of cough was graded based on the number of coughs per day: mild (1 ~ 2 times), moderate (3 ~ 5 times), and severe (> 5 times)[2]. The mean arterial pressure (MAP), heart rate (HR), and pulse oxygen saturation (SpO₂) were recorded at T₁ (before injection of remifentanil or normal saline), T₂ (1 minute after remifentanil injection), T₃ (before intubation) and T₄ (1 minute after intubation). Additionally, the incidence of adverse events, such as dizziness, nausea, apnea, truncal rigidity, bradycardia and other adverse effects were also recorded.

Sample Size Calculation

In our previous study, the estimated incidence of cough following injection of 0.5µg/kg sufentanil within 5 seconds was 35% (7/20). Assuming that remifentanil pretreatment reduces the incidence of SIC to 10%, each group would require a minimum of 54 patients to attain 90% statistical power with a two-tailed α = 0.05. Therefore, we included 60 patients per group anticipating a study dropout rate of 10%.

Statistical Analysis

All values were presented as mean ± SD, number or percentage. PASS 15 software (PASS, Kaysville, USA) was used to estimate the sample size. Statistical analysis was performed by using SPSS software version 26.0 (IBM Corp, Armonk, USA). We used the Shapiro-Wilk test to analyze the normality of measurement data distribution. Comparison of age, height, weight, and BMI was analyzed by the Student’s t test. The incidences of cough, dizziness, muscle rigidity, gender, ASA class, and cough severity were compared using the Chi-square test or Fisher’s exact test. Two-way ANOVA was used to compare differences of the MAP, HR and SpO₂ at different time points. P < 0.05 was considered as statistically significant.

Of 130 screened patients, 10 patients were excluded from the study due to refuse to participate, unacceptable hypertension or anesthesia plan changed. Finally, 120 patients completed the present study and participated in the final analysis (Fig. 1). There were no statistically significant differences observed in the demographic characteristics, including age, height, weight, BMI, gender, and the ASA class of patients (Table 1). The incidence of cough in N group was 35.00%, while in R group was 3.33%. Compared with group N, the incidence and severity of cough were significantly decreased in group R (Table 2). No significant differences were found in MAP, HR, and SpO₂ between group R and group N at T₁, T₂, T₃, and T₄ (Fig. 2). Two patients with motion sickness history experienced dizziness in group R, and one patient in group N suffered from muscle rigidity without any harmful consequences (Table 3).

Table 1

Demographic date
	Group N (n = 60)	Group R (n = 60)	P value
Age	42.42 ± 8.89	43.35 ± 8.23	0.329
Height	162.78 ± 6.86	162.93 ± 7.96	0.619
Weight	60.52 ± 8.31	60.92 ± 6.34	0.468
BMI	22.80 ± 2.40	22.98 ± 2.22	0.700
Gender (F/M)	37/23	35/25	0.709
ASA class (Ⅰ/Ⅱ)	19/41	21/39	0.699

Table 2

Incidence and severity of sufentanil-induced cough
Variables	Group N (n = 60)	Group R (n = 60)	P-value
Incidence of cough, n (%)	21(35.0)	3(5.0)	< 0.001***
Severity of cough, n (%)	-	-
Mild	6(10.0)	2(3.3)	0.272
Moderate	5(8.3)	0(0.0)	0.057
Severe	10(16.7)	1(1.7)	0.004**
Notes: *P value < 0.001; P value < 0.01; The severity of cough: mild (1–2 times), moderate (3–5 times), severe (> 5 times).

Table 3

Incidences of adverse events
Variables	Group N (n = 60)	Group R (n = 60)	P-value
Incidence of adverse events, n (%)	1 (1.7)	2 (3.3)	1.000
Adverse events, n (%)	-	-
Dizziness	0 (0.0)	2 (3.3)	0.496
Muscle rigidity	1 (1.7)	0 (0.0)	1.000

The results of this study demonstrated that pretreatment with 0.5 µg/kg remifentanil significantly reduced the incidence and severity of SIC without affecting the hemodynamics when compared to the N group. Sufentanil, with potent analgesic effects, had little influence on hemodynamic indexes, and is widely used for general anesthesia induction as well as maintenance. However, it is often reported that sufentanil causes cough during general anesthesia induction. The results of this study showed that the incidence of SIC in the N group was 35%, which was consistent with the results of previous reports[3, 15]. SIC might cause a dramatical increase in the blood, intraocular, intracranial, intrapulmonary and intra-abdominal pressure, causing damage to patients with hypertension, cerebral aneurysm, open eye injury, a full stomach, pulmonary bullae or abdominal aortic aneurysm[5, 6]. Therefore, it is necessary to prevent sufentanil-induced cough in those patients.

However, the current mechanism of SIC still remain to be controversial. This might be related to sufentanil enhancement of the excitability in rapidly adapting the receptors, stimulating the histamine release in the airways, inducing airway hyperresponsiveness, adapting the pulmonary stretch receptors, activating the vagal C-fiber receptor close to pulmonary vessels, inhibiting sympathetic nerve impulse, and eventually resulting in the incidence of cough[2, 7, 16–21].

Various measures including pharmacological or non-pharmacological measures have been taken to suppress the occurrence of SIC. Among these, pharmacological measures included magnesium[3], lidocaine[9], tramadol[12], dezocine[2, 10], dexmedetomidine[1], butorphanol[11], nalbuphine[6], and ketorolac tromethamine[5]. Nonpharmacological measures included prolonging the time of injection[22], diluting the concentration of drug[23], adjusting the sequence of administration drug[24], use of a mechanical dropper[25], choosing central venous administration[26], and performance of swallowing action immediately before intravenous sufentanil[27].

Remifentanil is a µ-opioid receptor agonist that is commonly used for intraoperative analgesia and sedation[28]. Remifentanil has unique pharmacokinetic properties of fast-onset and offset, and is metabolized through ester linkage that is susceptible to hydrolysis by non-specific plasma and tissue esterases[29]. The mechanism of onset time of remifentanil was 1 minute[30], and therefore sufentanil was injected at 60s after remifentanil pretreatment in our study. The results of this study demonstrated that remifentanil pretreatment significantly reduced the incidence and severity of SIC. The mechanism of this might be explained by remifentanil suppression of SIC by occupying µ-opioid receptor and antagonize the part of sufentanil-activated µ-opioid receptor. This hypothesis was partially approved by a previous study, in which pretreatment with nalbuphine effectively attenuated the incidence of SIC[6]. Moreover, remifentanil might inhibit the central cough effect and then suppress the cough induced by large dose of sufentanil. In a previous report, a pre-emptive 0.3µg/kg remifentanil was used to suppress sufentanil-induced cough, which could avoid the additional side effects or potential risks of other types of drugs[31]. However, the study only investigated the effect of the single dose concentration and did not observe the preventive effect of other doses of remifentanil. Therefore, the dose of 0.5µg/kg remifentanil was used to observe the effect of suppressing SIC.

There are several limitations in this study. Firstly, the sample size of this study was small. A large sample with multicenter study is needed to confirm whether pretreatment with remifentanil can prevent SIC. Secondly, the dose of remifentanil for pretreatment might not be an optimal dose for remifentanil to suppress SIC. The efficacy of different doses of remifentanil pretreatment on SIC has not been studied. Thirdly, this study lacked of a comparison of remifentanil pretreatment with other treatments, therefore, it’s hard to answer whether remifentanil pretreatment is superior to other treatments. In the future, we will evaluate remifentanil and other drugs on the frequency and reflex degree of sufentanil-induced cough during the induction of anesthesia. Finally, both sufentanil and remifentanil are opioids, the total amount of opioids is not equal in both groups, the different analgesia effect for both groups should be evaluated. However, it still needs to be confirmed by further experiments.

In conclusion, pretreatment with 0.5 µg/kg remifentanil has effectively suppressed the incidence and severity of SIC and provide a reference for the medication of patients during general anesthesia induction. To a certain extent, it might be used as an effective way to prevent SIC, and is worth promoting.

Acknowledgements

We would like to thank Yuhan Liu from School of Basic Medical Sciences·Nanchang University for assistance of data analysis.

Authors’ contributions

JJZ drafted and wrote the manuscript. DYZ assisted with manuscript revision. WJY and YL collected the data and did statistical analysis. GW and JZ prepared figures 1-2. FZH and JY designed the study and revised the manuscript. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

This study was approved by the Medical Research Ethics Committee of the Second Affiliated Hospital of Nanchang University (2020-027) and this trial was registered in the Chinese Clinical Trial Registry (30/09/2020, ChiCTR2000038756). The study protocol followed the CONSORT guidelines. The study protocol was performed according to the relevant guidelines. Written informed consent was obtained from all patients.

Availability of data and materials

The data of this study including figures and tables will be available by contacting corresponding author on reasonable request. The data can be used permanently after the article is published.

Funding

This study is supported by Natural Science Foundation of Jiangxi Province (20192BCB23024).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author details

¹Department of Pain Medicine, the First Affiliated Hospital of Nanchang University, Nanchang, China.²Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, Nanchang, China.³Department of Anesthesiology, First People’s Hospital of Fuzhou, Fuzhou, China⁴Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang, China.

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No competing interests reported.

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Effects of remifentanil pretreatment on sufentanil-induced cough suppression during the induction of general anesthesia: a randomized controlled trial

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Version 1

Abstract

Figures

Introduction

Material And Methods

Sample Size Calculation

Statistical Analysis

Results

Discussion

Conclusion

Declarations

Acknowledgements

Authors’ contributions

Ethics approval and consent to participate

Availability of data and materials

Funding

Consent for publication

Competing interests

Author details

References

Additional Declarations

Status:

Version 1