Butorphanol suppresses fentanyl-induced cough during general anesthesia induction: A randomized, double-blinded, placebo-controlled clinical trial.

Fentanyl-induced cough (FIC) is unwanted in the patients requiring stable induction of general anesthesia. This study was designed to evaluate the suppressive effects of butorphanol pretreatment on the incidence and severity of FIC during the induction of general anesthesia. A total of 315 patients of American Society of Anesthesiologists physical status I and II, scheduled for elective surgery under general anesthesia were randomized into 3 equally sized groups (n = 0105). Two minutes before fentanyl bolus, group I received intravenously 5 mL normal saline, groups II and III received butorphanol 0.015 and 0.03 mg/kg (diluted with saline to 5 mL), respectively. Patients were then administrated with fentanyl 2.5 μg/kg within 5 s. The incidence and severity of FIC was recorded for 2 minutes after fentanyl bolus. During experimental period, the mean arterial pressure, heart rate, and peripheral capillary oxygen saturation (SpO2) were recorded before the administration of butorphanol or normal saline (T0), 2 minutes (T1) after butorphanol injection, and 2 minutes (T2) after fentanyl injection. The incidence of FIC was 31.4% in group I, 11.4% in group II, and 3.8% in group III. Group III had a lowest incidence of FIC among 3 groups (P < 0.001, vs group I; P < 0.05, vs group II). The severe FIC was not observed in groups II and III, but was recoded from 6 patients in group I. At 2 minutes after fentanyl injection (T2), the mean arterial pressure was significantly higher in group I than that in groups II and III (P < 0.01, vs group II; P < 0.05, vs group III), but the values remained within safe limits. In conclusion, pretreatment with butorphanol could effectively and safely suppress FIC during anesthesia induction.

RCT Entities:   Population Interventions Outcomes

Introduction

Advantages, such as quick onset, short duration of action, intense analgesia, cardiovascular stability as well as low histamine release, make fentanyl widely used by anesthesiologists for induction and maintenance of general anesthesia.[ However, intravenous bolus administration of fentanyl could elicit cough during induction, which is accompanied with increased intracranial, intraocular, and intra-abdominal pressure.[ From our own experiences, the fentanyl-induced cough (FIC) is transient and self-limiting in most patients. But, FIC should be effectively prevented in certain patients who are suffering from open eye injury, pneumothorax, cerebral aneurysm, brain trauma, brain hernia, dissecting aneurysm, hypersensitive airway disease, nonfasting, and so on.[ In some situations, severe FIC could even lead to life-threatening upper airway obstruction[ and aspiration pneumonia[ that require immediate intervention.

To date, various drugs have been used to reduce the incidence and severity of FIC. Among them, prototypical agonist-antagonist opioid analgesic agents, such as pentazocine and dezocine, have shown their efficacy in suppressing fentanyl- and sufentanyl-induced cough during general anesthesia induction with rarely adverse side effects.[ Butorphanol is another agonist-antagonist opioid that is extensively used in clinical practice with more potent analgesic effect and a better pharmaceutical formulation. Besides, it has been used as the antitussive drug in animals.[ However, there is no investigation regarding the effectiveness of butorphanol on preventing unwanted FIC. Hence, we designed this study to assess the effects of pretreatment with butorphanol on the incidence and severity of FIC during induction of general anesthesia.

Material and methods

This prospective, randomized, double-blinded, and placebo-controlled clinical trial was approved by the Institutional Medical Ethics Committee of Nanjing Medical University. After obtained written informed consents, 315 American Society of Anesthesiologists (ASA) physical status I–II patients of both genders, aged 18–65 years and scheduled for elective surgery under general anesthesia were included in this trial. Exclusion criteria included pregnancy; impaired kidney or liver function; a history of chronic cough, asthma, smoking; upper respiratory tract infection, treatment with angiotensin converting enzyme inhibitors, bronchodilators, or steroids within the previous 2 weeks. Patients with increased intracranial, intraocular, or intra-abdominal pressures were also excluded.

Patients were randomly assigned to 3 groups of 105 patients each. Randomization was achieved by use of computer-generated random codes that were placed in consecutively numbered, opaque envelopes. Drugs were prepared in unlabeled 10 mL syringes outside the operating room by an anesthesiologist who was not involved in the induction of anesthesia.

None of the patients received any premedication. After the patients arrived, the operating room, a 20-gauge cannula was inserted into the dorsum of their hands and connected to a T-connector for drug administration. Standard monitors, including noninvasive arterial pressure, heart rate (HR), electrocardiography, and peripheral capillary oxygen saturation (SpO2) were applied. Oxygen gas flow at 2 L/min was given via a facial mask and ringer lactate was infused at a rate of 4–6 mL/min.

After preoxygenation for 2 minutes, the pretreatment drug, butorphanol (#15081532, Hengrui, China) or saline was given. Group I received 5 mL saline; group II received butorphanol 0.015 mg/kg; group III received butorphanol 0.03 mg/kg. The butorphanol patients in groups II and III received were diluted with saline to 5 mL. Two minutes after infusion, fentanyl 2.5 μg/kg was administered through the peripheral venous line within 5 s. The incidence and severity of cough were observed continuously by another anesthesiologist who was blinded to group allocation for 2 minutes, as the cough generally happens within this period. Patients also were not aware of the pretreatment drug. The severity of cough was graded, based on the numbers of cough, as none (0), mild (1–2), moderate (3–4), and severe (5 or more). Mean arterial pressure (MAP), HR, and SpO2 were recorded before the administration of butorphanol or normal saline (T0), 2 minutes (T1) later after butorphanol injection, and 2 minutes (T2) later after fentanyl injection. If SpO2 dropped below 94%, manually assisted mask ventilation with oxygen was applied immediately. Then midazolam (0.05 mg/kg), etomidate (0.3 mg/kg), and rocuronium (0.6 mg/kg) were given to facilitate tracheal intubation.

In a pilot study, the incidence of FIC was 30% in 50 patients. We estimated that 96 patients in each group would be required to detect a 50% reduction in the incidence of cough with 80% power at a significance of P < 0.05. We factored in a 10% dropout rate and enrolled 105 patients in each group.

All statistical analyses were performed with GraphPad Prism 5.0 software (GraphPad Software Inc, San Diego, CA). Continuous variables are presented as mean ± standard deviation (SD). Parameters, such as age and weight, were compared among the groups using 1-way analysis of variance (ANOVA) followed by Turkey post-hoc test. MAP, HR, and SpO2 at different time points were compared by using 2-way ANOVA followed by Bonferroni post-hoc test. Categorized variables were described as frequency and analyzed by chi-square test or Fisher's exact test. Severity of FIC were presented as ranked data (none, mild, moderate, and severe) and compared by Mann–Whitney U test. P value < 0.05 was considered to be statistically significant.

Results

Demographic characteristics

In the present study, 330 patients were recruited and 15 patients were excluded, as they met the exclusion criteria. Therefore, a total of 315 patients were randomized into 3 groups of 105 each and included in the final analyses (Fig. 1). The demographic characteristics, such as age, gender, body weight, and ASA physical status, were similar among the 3 groups (Table 1).

Figure 1

Patient flow (according to the consort chart).

Table 1

Demographic data.

Incidence and severity of FIC

As shown in Table 2, the incidence of FIC in group I was significantly higher than that in groups II and III (31.4% vs 11.4% and 3.8%; P < 0.001, vs group II; P < 0.001, vs group III). Group II had a significantly higher incidence of FIC than group III (P < 0.05, vs group III). The severe FIC was not observed in group II and III, but was recoded from 6 patients in group I. The overall severity level of FIC in group I was also much higher than that in group II and III (P < 0.001, vs group II; P < 0.001, vs group III). Group III had the lowest severity of FIC among all the groups.

Table 2

Incidence and severity of fentanyl-induced cough.

Vital signs

At 2 minutes after fentanyl injection (T2), the MAP was significantly higher in group I than that in group II and group III (P < 0.01, vs group II; P < 0.05, vs group III) (Fig. 2A). There was no difference in the HR data at 3 time points among the 3 groups (Fig. 2B). SpO2 of all 3 groups at T2 time point were significantly lower than their levels at T1 time point (P < 0.001 in all 3 groups T2 vs T1), but there's no significant difference among 3 groups at T2 time point (Fig. 2C). None of patients suffered from hypoxemia (SpO2 < 90%) during this study.

Figure 2

Changes of MAP, HR, and SpO2 during study period. (A) MAP at different time points. P < 0.05, P < 0.01, compared to group I (B) HR at different time points. (C) SpO2 at different time points. P < 0.001, compared to their own levels at T1 time point. T0, time before administration of butorphanol or saline; T1, 2 minutes after butorphanol or saline injection; T2, 2 minutes after fentanyl injection; MAP, mean arterial pressure; HR, heart rate; SpO2, peripheral capillary oxygen saturation.

Discussion

In this study, we found that preemptive infusion of butorphanol 0.015 and 0.03 mg/kg 2 minutes before fentanyl bolus administration effectively and safely reduced the incidence and severity of FIC during general anesthesia induction. Besides, butorphanol showed capacity to prevent the elevated blood pressure that may be induced by cough reflex after fentanyl injection, although the highest MAP was still within safe limits. The drop of SpO2 in all 3 groups was supposed to be due to fentanyl-induced respiratory depression.

As reported, the incidence of FIC varies over a wide range from 2.7% to 80%.[ Here, we found the incidence of FIC in group I and our former pilot study in which patients did not receive the preemptive butorphanol were both around 30%. The discrepancy among various studies may primarily depend on the doses and concentration of fentanyl injected, the rates, and the routes of injection. However, 2 recently published meta-analysis results support our finding. Kim et al.[ assessed 28 articles which focused on pharmacological and nonpharmacological prevention of FIC including 5660 patients in intervention groups and 3188 patients in control group. They concluded that the overall incidence of FIC in control group was approximately 31.4%. Another meta-analysis (2370 patients) according to the effects of preemptive small dose fentanyl on the incidence of FIC found that 31.0% of patients without priming fentanyl experienced FIC.[

Up to now, the exact mechanism for FIC remains unclear, but some theories have been proposed to explain this phenomenon. After bolus injection, fentanyl could inhibit central sympathetic outflow, and the relatively vagal predominance may induce cough and reflex bronchoconstriction.[ Besides, fentanyl-induced tracheal smooth muscle constriction could elicit pulmonary chemoreflexes mediated by rapidly adapting receptors (irritant receptors) or vagal C-fiber receptors (also known as J or juxtacapillary receptors) located in close proximity to pulmonary vessels and which then contributes to FIC.[ In addition, substances like histamine and neuropeptides, released by an action on prejunctional μ-opioid receptors after fentanyl administration,[ the sudden adduction of the vocal cords or supraglottic obstruction caused by opioid-induced muscle rigidity,[ and the relative fluctuation in plasma fentanyl concentration during injection[ also play important roles in the occurrence of FIC.

According to the possible mechanisms, many pharmacological interventions have been used to prevent FIC, including lidocaine,[ ephedrine,[ α2-receptor agonist (clonidine and dexmedetomidine),[ dexamethasone,[ ketamine,[ and propofol.[ Though the medicines mentioned earlier could partly reduce the incidence of cough, some unexpected side effects, such as arrhythmia, cardiovascular depression, respiratory depression, bradycardia, and hyper- or hypotension, have occurred during drug administration. However, it is noteworthy that the prototypical agonist-antagonist opioid analgesic agents, such as pentazocine and dezocine showed their high efficacy in reducing the incidence of fentanyl and/or sufentanyl-induced cough without obviously adverse side effects.[

Butorphanol is another agonist-antagonist opioid with a published affinity for opioid receptors in vitro of 1:4:25 (μ:δ:κ).[ It is proven to be with more potent analgesic effect and a better pharmaceutical formulation and has also been extensively used for perioperative analgesia over the world. What's more, it is also used as the antitussive drug in animals.[ Here, we demonstrated that butorphanol could effectively and safely suppress the FIC with the most prominent effect at a dose of 0.03 mg/kg. We speculate that the possible mechanism of butorphanol suppressing FIC could be as follows: first, butorphanol has an excellent central nervous system penetration due to its high lipid solubility. The preemptive use of butorphanol could inhibit the cough reflex by directly inhibiting the cough center neurons in the medulla. Second, since Butorphanol is a partial μ-receptor agonist, priming use of butorphanol may result in depletion of neurotransmitters in peripheral nerve fibers. Besides, it can also occupy the μ-receptor, which is responsible for cough, preventing the later combination of fentanyl with related μ-receptor. Third, butorphanol may exert its antitussive effects by activating δ- and κ-receptor through central or peripheral mechanisms, which have been demonstrated in rats and guinea pigs.[

There are 2 limitations in our study. First, the main outcome measures (incidence and severity) were subjective, but we did not find other more accurate and convenient monitoring indicators in the previous clinical studies. Secondly, our study provides evidence for the efficacy of butorphanol in suppressing FIC in clinical practice; but we did not verify the exact mechanisms by which fentanyl induces cough and butorphanol prevents FIC. Hence, more animal and basic experiments are warranted.

In conclusion, we suggest that using a priming dose of butorphanol 0.03 mg/kg is a feasible, effective, and safe method to suppress FIC during the induction of general anesthesia in clinical practice.

Acknowledgments

The authors thank all nursing staff in operating rooms and wards for their efforts and performance during this study.