Low-Dose Alfentanil Inhibits Sufentanil-Induced Cough During Anesthesia Induction: A Prospective, Randomized, Double-Blind Study

Introduction

Sufentanil, a synthesized opioid agonist, has been widely used for the induction of general anesthesia in clinical practice due to its reliable analgesic efficacy, lack of histamine release and little effect on hemodynamics. Whereas, the use of intravenous sufentanil can be associated with a number of undesirable effects, such as nausea, vomiting, cough, chest tightness, dizziness and even respiratory depression, depending on the dose, injection speed and individual variation. Sufentanil-induced cough, with an incidence of up to 31.9%,¹ is usually transient and explosive, and in severe cases it can increase intracranial, intraocular and intraabdominal pressures, which may even cause a range of adverse effects in patients with high-risk comorbidities.² Several medicines, such as lidocaine, propofol, fentanyl, remifentanil, dezocine, dexmedetomidine, tramadol or magnesium sulfate, have been shown to be effective in reducing the incidence and / or severity of opioid-induced cough.^1,3–9 However, there are potential risks associated with these pharmacological interventions and it is therefore necessary to identify an alternative pretreatment agent with minimal complications to reduce sufentanil-induced cough.

Alfentanil is a synthetic, short-acting opioid analgesic classified as a small molecule derivative of fentanyl. Alfentanil exhibits the less potency, the faster onset and shorter duration of action compared to analogous anesthetics such as fentanyl and sufentanil, making it an ideal analgesic supplement during various surgical procedures. In addition, alfentanil injection could prevent bronchial spasms and reduce airway secretions,¹⁰ and its single bolus administration has been reported to be useful in reducing cough during emergence from desflurane or isoflurane anesthesia.^11,12 The intravenous bolus of alfentanil is associated with a significantly lower incidence of cough than the equipotent dose of remifentanil,¹³ so alfentanil would theoretically be superior to remifentanil as a pretreatment for reducing sufentanil-induced cough, but there are no studies investigating the protective effect of alfentanil in preventing opioid-induced cough.

Herein, the present study was designed to evaluate the efficacy and safety of low-dose alfentanil pretreatment against sufentanil-induced cough. Outcomes measures included the incidence and severity of cough and common side effects of opioids after the administration of sufentanil during the induction of general anesthesia, intraoperative hemodynamics parameters and major adverse events during anesthesia recovery.

Methods

This study was approved by the Medical Ethics Committee of The Lishui People’s Hospital in Lishui, China (LLW-FO-403), and was registered with the Chinese Clinical Trial Registry (ChiCTR2300069286, 12 March 2023). Written informed consent was obtained from all the enrolled patients. The study was conducted at Lishui People’s Hospital from March 2023 to June 2023 in accordance with the criteria of the Declaration of Helsinki.

Patient Enrollment

Patients who were scheduled for elective thyroid surgery under general anesthesia were screened. Inclusion criteria included American Society of Anesthesiologists (ASA) physical status I or II, New York Heart Association (NYHA) functional class I or II, age between 18–65 years old, body mass index (BMI) between 18–30 kg/m² and procedure time between 1–6 hours. Exclusion criteria were current or recent (within 2 weeks) upper respiratory tract infection; history of smoking or chronic respiratory disease (eg, asthma, chronic bronchitis, chronic obstructive pulmonary disease); prevalent gastroesophageal reflux disease; the presence of signs indicating elevated intracranial pressure, intraabdominal pressure or intraocular pressure; prevalent severe cardiac, cerebral and renal diseases (eg, uncontrolled hypertension, diabetes mellitus, heart disease); preoperative use of cough-inducing or suppressing medications; long-term opioid use; psychiatric disorders; Modified Mallampati Score of IV or predicted difficult airway; known allergies or contraindications to the agents. Patients with intraoperative blood loss greater than 600 mL or unplanned transfer to Intensive Care Unit after the surgery were also excluded.

Randomization and Group Allocation

All the patients were visited and assessed the day before surgery. After screening, eighty patients were recruited and randomized by computer-generated codes into 2 groups, designated as the alfentanil group (group A) and the normal saline group (group C), with 40 patients in each group. Patients in the group A received intravenous administration of 2 μg/kg afentanil (diluted with normal saline to a final volume of 5 mL) 1 minute prior to the sufentanil injection, and the same volume of normal saline was administered in the group C in the same manner. The group allocation was sealed in the closed envelopes by investigator Haiyan Lan, and only opened before induction of general anesthesia by the investigator Qiaomin Xu who was not involved in data collection. Both the patients and the investigators who performed anesthesia and assessment were blinded to the group allocation.

Anaesthetic Management

Patients received no premedication before the surgery. Continuous monitoring including electrocardiography, non-invasive blood pressure and pulse oximetry saturation (SpO₂), was initiated after the patients were admitted to the operating room. Venous access was established on the dorsal vein using an 18-G intravenous cannula, which was then connected to a T-connector for the administration of the agents (Figure 1). Patients were preoxygenated with 100% oxygen 6L/min via a tight-fitting mask for 3 minutes before induction of anesthesia. Intravenous pretreatment of 2 μg/kg alfentanil that diluted to 5 mL with normal saline or an equal volume of normal saline was completed within 5 seconds.⁸ One minute after the pretreatment, sufentanil was administered at a dose of 0.5 μg/kg, which was completed within 5 seconds. One minute after sufentanil bolus, an intravenous injection of 1.5 mg/kg propofol and 0.1 mg/kg vecuronium bromide was consequently initiated for anesthesia induction, followed by endotracheal intubation and mechanical ventilation. A tidal volume of 6–8 mL/kg, a respiratory rate of 12–14 breaths/minute, a positive end-expiratory pressure of 5 cmH₂O and an I:E ratio of 1:2 were set and adjusted to keep end-tidal carbon dioxide between 35 and 45 mm Hg. Maintenance of anaesthesia was achieved with 1% to 3% sevoflurane, and the inhalational concentration was adjusted according to the bispectral index (BIS) value, which was expected to remain between 40 and 60. Intermittent boluses of 0.1μg/kg sufentanil and 0.02 mg/kg vecuronium bromide were injected as required. At the end of the procedure, the administration of sevoflurane was terminated, the patient was then transferred to the Post-Anesthesia Care Unit (PACU), and the tracheal tube was removed when regular breathing with adequate tidal volume (> 6 mL/kg) and recovery of consciousness were confirmed.

Figure 1 T-connector.

Outcome Measurements

The primary outcome was the incidence of cough within one minute after the injection of sufentanil during anesthesia induction.

The secondary outcomes were measured as followings:

1. The severity of cough within one minute after the injection of sufentanil during anesthesia induction: the severity of cough was scaled based on its frequency, with “mild” indicating 1–2 coughs, “moderate” indicating 2–4 coughs and “severe” indicating 5 or more coughs.^13,14
2. Common side effects of opioids: the occurrence of dizziness, nausea and vomiting, chest tightness and respiratory depression within one minute after the injection of sufentanil during anesthesia induction were recorded, where respiratory depression was defined as a persistent decrease in respiratory rate (< 10 breaths/minute) and / or SpO₂ value (<90%). When respiratory depression occurred, manual ventilation was provided to improve the patient’s oxygenation until SpO₂ ≥ 98%.
3. Hemodynamic parameters and pulse oximetry: mean arterial pressure (MAP), heart rate (HR) and SpO₂ were recorded immediately before (T0) and 2 minutes after (T1) the initiation of pretreatment, immediately before (T2) and after (T3) intubation, and 2 minutes after intubation (T4). Hypotension, defined by a systolic blood pressure < 80 mmHg or a fall in blood pressure of more than 20% from baseline, was treated with intravenous administration of 5 mg ephedrine, and hypertension was defined as a blood pressure > 160 / 95 mmHg or an increase of more than 20% from baseline, and appropriate antihypertensive medication was given. Tachycardia (HR greater than 100 beats per minute) and bradycardia (HR less than 50 beats per minute) were treated with intravenous administration of esmolol and 0.5 mg atropine, respectively.
4. Extubation time: extubation time was defined as the time (min) from discontinuation of sevoflurane to extubation.
5. Adverse events during PACU stay: emergence agitation, respiratory depression, delayed recovery from anesthesia and postoperative nausea and vomiting (PONV) were documented during PACU stay. Emergence agitation was defined as a Riker sedation-agitation score ≥ 5¹⁵ and treated appropriately according to the cause. Delayed recovery from anesthesia was defined as the failure to regain consciousness 90 minutes after the termination of general anesthetic. One or more episodes of nausea or vomiting were considered PONV, where nausea was defined as the subjectively unpleasant feeling associated with the perception of the urge to vomit, and vomiting was defined as the forceful expulsion of gastric contents from the mouth. When PONV occurred, the serotonin type 3 (5-HT3) receptor antagonists were used.

Sample Size Calculation

The sample size was calculated using G*power 3.1 software based on the incidence of cough within one minute after the injection of sufentanil during anesthesia induction as the primary outcome. In our pilot study with 20 patients in each group, we found that the incidence of cough after the injection of sufentanil was 45%, and the incidence of sufentanil-induced cough decreased to 10% when the patients were pretreated with 2 μg/kg alfentanil. For a two-tailed significance level of 5% alpha error level and 80% power, 32 cases in each group was needed. To allow for a 20% dropout rate, a sample size of 40 patients per group (80 in total) was required.

Statistical Analysis

All statistical analyses were performed using SPSS statistical software (version 26.0, IBM Corp). Continuous variables were tested for normal distribution using the Shapiro–Wilk test. Continuous data are presented as mean ± standard deviation (SD) and were compared between the two groups using the independent t-test. Categorical data are presented as frequencies or percentages and were compared between the two groups using the chi-square test or Fisher’s exact test according to their expected counts. The data of hemodynamic parameters and pulse oximetry were analyzed by two-way repeated measures analysis of variance (ANOVA) followed by Bonferroni multiple comparison correction. A P < 0.05 was considered statistically significant, except for the repeated measured variables.

Results

One hundred patients scheduled for elective thyroid surgery under general anesthesia were screened, and eighty of them who met the inclusion and exclusion criteria were randomly assigned in a 1:1 ratio to either the group A or group C, with 40 cases in each group. All the patients completed the study and were included in the final analysis. The Consolidated Standards of Reporting Trials (CONSORT) flowchart diagram of the study was demonstrated in Figure 2. The demographics and clinical data were comparable between the two groups, as shown in Table 1 (p > 0.05).

Table 1 Demographic and Clinical Data of the Patients

Figure 2 The Consolidated Standards of Reporting Trials (CONSORT) flowchart diagram of the study.

The Incidence and Severity of Sufentanil-Induced Cough

During anesthesia induction, 40% of the patients in the group C and 5% in the group A developed cough within one minute after sufentanil injection, respectively (p < 0.05). The group A had a lower proportion of mild cough compared to the group C among those who developed cough (p < 0.05). However, there were no significant differences in the proportion of moderate and severe cough between the two groups (p > 0.05, see Table 2).

Table 2 The Incidence and Severity of Sufentanil-Induced Cough

Common Side Effects of Opioids During Anesthesia Induction

There were no significant differences between the two groups in the incidence of dizziness, nausea and vomiting, chest tightness and respiratory depression within one minute after sufentanil injection during the induction of anesthesia (p > 0.05, see Table 3).

Table 3 The Common Side Effects of Opioids During Anesthesia Induction

Hemodynamic Data and SpO₂ Values

There were no statistical differences in the data of MAP, HR and SpO₂ between two groups at five corresponding time points (p > 0.05, see Table 4).

Table 4 Hemodynamic Data and SpO2 Values

Extubation Time and Adverse Events During PACU Stay

As demonstrated in Table 5, extubation time was comparable between the two groups, and there were no significant differences in incidence of emergence agitation, respiratory depression, delayed recovery from anesthesia and PONV during PACU stay (p > 0.05).

Table 5 Extubation Time and Adverse Events During PACU Stay

Discussion

The main findings of our present study were that 1) the pretreatment with low-dose alfentanil (2 μg/kg) significantly reduced both the incidence and severity of sufentanil-induced cough during the induction of anesthesia; and 2) pretreatment with low-dose alfentanil did not increase the common side effects of opioids or had little effect on intraoperative hemodynamic stability and postoperative emergence from anesthesia. To sum up, our study provided a safe and effective alternative method to prevent sufentanil-induced cough during the induction of anesthesia.

Cough following opioid administration during the induction of anesthesia is not uncommon, and independent risk factors, such as age, cigarette smoking, previous epidural injection of lidocaine or a priming dose of muscle relaxant, may contribute to the variable incidence and severity of cough following opioid administration, but gender, the presence of either bronchial asthma and chronic obstructive pulmonary disease and the use of atropine have limited effects on the occurrence of opioid-induced cough.¹⁶ Additionally, variations in dose, concentration, route of administration and injection speed of opioids also affect the incidence of cough.¹⁷ To date, the mechanisms involved in sufentanil-induced cough are still undetermined and several possibilities have been proposed to explain it. The relative vagal predominance secondary to central sympathetic outflow inhibition by sufentanil administration would facilitate cough and reflex bronchoconstriction.^14,18 As the pulmonary chemoreflex, mediated by either fast adapting receptors (irritant receptors) or vagal C-fibre receptors, is located close to the pulmonary vessels, stimulation or enhancement of irritant receptor excitability by opioid drugs could induce tracheal smooth muscle constriction.^19,20 By acting on prejunctional μ-receptors, opioids cause an increased release of histamine and neuropeptides^21,22 and decreased compliance of the chest wall, which would lead to sudden vocal cord closure or supraglottic obstruction by soft tissue, causing tussive effects. In addition, several studies have shown that opioid receptor dualism may be an important factor contributing to opioid-induced cough.^1,20

Several agents, including lidocaine, tramadol, dezocine, dexmedetomidine and magnesium sulfate, have been reported to be effective in reducing opioid-induced cough.^1,3,5,9,23 The additional pretreatments are likely to increase the drug-related side effects and potentially compromise patient safety. For instance, an injection with dexmedetomidine is liable to cause bradycardia and hypotension, and the 10-minute onset of action may be inappropriate for emergency use. In addition, magnesium sulfate may cause obvious burning and significantly increased plasma magnesium levels. Intravenous lidocaine increases the risk of systemic toxicity of the local anesthetic, while a mixed agonist-antagonist opioid, dezocine, is not suitable for the anesthesia for long surgical procedures. Tramadol-induced dizziness, nausea and vomiting may also be a problem, affecting the patient experience. What’s more, although long-acting opioids such as priming fentanyl or intramuscular morphine are effective in reducing opioid-induced cough, they also have major drawbacks, including a long onset time or prolonged duration of action.^4,20 To avoid the side effects of the additional agents, opioids with short onset time and short duration of action will be favoured to provide protection against sufentanil-induced cough during anesthesia induction, and remifentanil and alfentanil are two promising candidates. Recently, low-dose (0.3 μg/kg) pretreatment with remifentanil has been shown to effectively and safely reduce the incidence and severity of sufentanil-induced cough during induction of anesthesia.⁸ But, rapid administration of remifentanil may cause muscle rigidity, hypotension and significant bradycardia.²⁴ Apart from the almost 20-fold greater potency of remifentanil, the two opioid drugs are pharmacodynamically similar.²⁵ In a study comparing the effects of a bolus injection of remifentanil and alfentanil on reducing the incidence of cough on emergence from isoflurane anaesthesia, alfentanil at 15 µg/kg significantly reduced the incidence of cough from 82% to 6%,¹² whereas 1 µg/kg of remifentanil at the end of surgery was found to be ineffective, while 1 µg/kg remifentanil at the end of surgery was proved invalid.²⁶ Collectively, alfentanil therefore appears to be favourable alternative to remifentanil in suppressing sufentanil-induced cough.

Indeed, as shown in our study, the pretreatment of low-dose alfentanil significantly decreased both the incidence and severity of sufentanil-induced cough during the induction of anesthesia. We hypothesized that opioid receptor dualism may be a possible mechanism to partially explain this phenomenon. Alfentanil at a low and subanalgesic dose may inhibit the cough reflex by acting directly on the cough centre in the medulla, thus exerting a central anti-tussive effect against cough induced by a subsequent large dose of sufentanil.¹ Furthermore, pretreatment with alfentanil at a dose of 2 μg/kg was not associated with increased opioid-related side effects during induction or impaired recovery quality after surgery. Alfentanil has a different pharmacokinetic profile from fentanyl. Theoretically, alfentanil, with a lower blood / brain solubility, is able to easily penetrate through the blood-brain barrier and the equilibrium between plasma and central nervous system can be rapidly achieved (1.5 minutes), ensuring a very rapid onset of action when compared to fentanyl or sufentanil.^27,28 In addition, compared with an equipotent dose of fentanyl, alfentanil has a more rapid redistribution and a sharp decrease in concentration below the therapeutic threshold, also the small volume of distribution indicates a short terminal elimination half-time.²⁹ These factors result in a short duration of action of alfentanil. We assumed that the low dose of alfentanil and its less potency and relatively short duration of action would help to explain these findings.

It was noticed that although there was no significant difference in the incidence of dizziness between the two groups, approximately 25% of cases in each group complained of this side effect with 1 minute after intravenous sufentanil injection, which was similar to the previous report by Chen et al.³⁰ In this study, the authors found that the incidence of dizziness after the intravenous administration of sufentanil did not differ within the dose range of 0.1–1.0 μg/kg. In addition, bolus alfentanil administration also shows specific advantage in clinical anesthesia because of its relatively fewer adverse effects. Previous studies have shown hemodynamic fluctuation in patients during remifentanil anesthesia, whereas alfentanil is associated with a significantly lower incidence of respiratory depression and improved hemodynamic stability when compared with remifentanil,^31,32 and our present study showed that pretreatment with low-dose alfentanil did not cause intraoperative hemodynamic instability, suggesting the safety of this regimen.

Our study has several limitations. Firstly, the current study did not evaluate the effects of different doses of alfentanil pretreatment in reducing the incidence and severity of sufentanil-induced cough during the induction of anaesthesia, therefore, the dose-response effect of alfentanil pretreatment was not studied and the optimal dose of alfentanil pretreatment was not investigated. Secondly, the clinical efficacy of low-dose alfentanil pretreatment in reducing sufentanil-induced cough during the induction of anaesthesia has been demonstrated, but the underlying physiological or molecular mechanisms have not yet been determined. Finally, the efficacy and safety of alfentanil pretreatment in preventing sufentanil-induced cough was not evaluated in specific patient populations, such as obese and pediatric patients, which may limit the generality of the conclusion.

Conclusion

In conclusion, pretreatment with low-dose alfentanil effectively reduced both the incidence and severity of sufentanil-induced cough during the induction of anesthesia without increasing adverse events and complications.