Abstract

Objectives

An intravenous bolus of fentanyl often induces a cough reflex. This study investigates whether priming with rocuronium can effectively attenuate fentanyl-induced coughing.

Methods

The study involved 260 participants, aged between 18 and 80 years of age, who were undergoing various elective surgeries. They were randomly assigned to two groups. Patients in the study group (the rocuronium group) were treated with intravenous (IV) 0.06 mg/kg rocuronium, whereas those in the control group were treated with the same volume of normal saline. Fentanyl (1.5 μg/kg IV, given over 2 seconds) was administered 30 seconds after the injection of rocuronium or normal saline. We recorded the number of coughs for 1 minute after the fentanyl injection.

Results

Patients in the rocuronium group showed a significantly lower incidence of coughing (8.5% vs. 23.1%, in the control group; p < 0.05) and a milder severity of cough in comparison with the patients in the control group.

Conclusion

Pretreatment with IV rocuronium (0.06 mg/kg) suppressed the cough reflex induced by fentanyl. Therefore, priming with rocuronium may be a clinically useful method for preventing fentanyl-induced cough.

Keywords

cough; fentanyl; neuromuscular nondepolarizing agents: rocuronium bromide;

1. Introduction

Fentanyl is widely used for analgesia and anesthesia because of its rapid onset of action, intense analgesic effect, lower cardiovascular depressive effect, and low histamine release.1, 2 However, fentanyl-induced coughing (FIC) often occurs. According to previous reports, the incidence of FIC can be as high as 65% depending on the given dose, infusion route, and speed of infusion.3, 4, 5 Although the cough reflex is usually transient and self-limiting, it should be avoided in situations of elevated intracranial, intraocular, or intra-abdominal pressure, and with unstable hemodynamics.6, 7

The cause of FIC is unclear. One hypothesis is that vocal cord spasms might induce coughing because of fentanyl-induced muscle rigidity and histamine release.⁸ Muscle relaxants are commonly used to treat this disorder.⁹ We hypothesized that priming with muscle relaxants could prevent or suppress FIC and ventured to investigate whether the muscle relaxant rocuronium could effectively attenuate FIC.

2. Materials and methods

After the study (no. TC100-05) had been approved by the ethical committee of Tri-Service General Hospital, written informed consent was obtained from each patient. This randomized, prospective, placebo-controlled study involved 260 American Society of Anesthesiologists (ASA) physical status Grade I–III patients, aged between 18 and 80 years, who were undergoing general anesthesia for various elective surgeries at Taichung Armed Forces General Hospital. Exclusion criteria included a history of asthma, chronic cough, smoking, an upper respiratory tract infection in the previous 2 weeks, medication containing angiotensin-converting enzyme inhibitors, and anesthetic premedication.

Using a computer-generated table of random numbers, patients were randomly assigned to two groups to receive either rocuronium or normal saline. Intraoperative monitory included pulse oximetry, noninvasive blood pressure, and electrocardiography. A freely running intravenous line was established on the dorsum of either hand. All patients were given oxygen via a face mask, and premedication was omitted. The patients were then given the designated medications intravenously in accordance with the protocol; that is, patients in the rocuronium group were given rocuronium at 0.06 mg/kg, and those in the control group were given the same volume of normal saline 30 seconds before intravenous injection of the fentanyl bolus (1.5 μg/kg, given over 2 seconds).

Following the fentanyl injection, an anesthetist who was blind to the treatment recorded the number of coughs for 1 minute. The severity of coughing was graded as mild (1–2 times), moderate (3–5 times), or severe (>5 times) based on the number of coughs within the 1 minute following the fentanyl injection. Assisted mask ventilation with oxygen was applied if oxygen desaturation occurred (SpO₂ < 90%).

For estimation of the sample size, the pilot study we performed showed that the treatment of rocuronium could cause a 15% reduction in the incidence of FIC (in each group of 20 patients). With α = 0.05 and β = 0.1, we required an enrollment of 100 patients for each group; we therefore aimed to recruit 130 patients for each group to compensate for any dropouts.

All data were presented as means ± standard deviations or as percentages. The demographic characteristics of the patients in both groups were evaluated with the Student t test for continuous variables and Chi-square test for categorical variables. The incidence of FIC was analyzed using the Chi-square test, and severity was analyzed with the Mann–Whitney U test. A value of p < 0.05 was considered statistically significant.zxz.

3. Results

From March 2011 to October 2011, we evaluated 298 consecutive patients. Thirty-eight patients were excluded from the study due to violation of the exclusion criteria or refusal to participate. Therefore, 130 patients in each group were subjected to further statistical analysis (Fig. 1).

Download full-size image

Fig. 1. Flow diagram for the trial.

No significant differences were found between the two groups for the demographic data, including age, ASA status, body height, and gender, although body weight was found to differ (Table 1). Following the fentanyl bolus, patients in the rocuronium group showed a significantly lower incidence of coughing than those in the control group (8.5% vs. 23.1%; p < 0.05) (Table 2). The rocuronium group also had a lower severity of cough (Table 2). No patient in either group suffered from hypoxemia, apnea, truncal rigidity, nausea, vomiting, or other adverse effects.

Table 1. Patient characteristics.

Download full-size image

Table 2. Incidence and severity of cough.

Download full-size image

4. Discussion

The major finding of this study is that pretreatment with intravenous rocuronium (0.06 mg/kg) was able to reduce the incidence of FIC from 23.1% to 8.5% and lower the severity of coughing. These results are consistent with those of a previous study by Oshima et al,¹⁰ who demonstrated that the absence of a priming dose of vecuronium was a significant independent risk factor for the development of FIC. This suggests preventive efficacy of a priming dose of vecuronium for FIC.

Although intravenous rocuronium was able to reduce the incidence of FIC, as demonstrated in the present study, the actual mechanism by which rocuronium achieves this result remains unknown. Many theories have proposed for the mechanisms by which FIC is generated. These include the stimulation of vagal C-fiber receptors, citric acid stimulating C-fibers in the airway,⁴ the release of histamine, sudden adduction of the vocal cords or supraglottic obstruction by soft tissue,¹¹ or deformation of the tracheobronchial wall stimulating irritant receptors that leads to reflex bronchoconstriction and cough.12, 13, 14

A muscle relaxant is usually applied to treat vocal cord spasms or muscle rigidity secondary to the use of members of the fentanyl family.⁹ The preventive effect of a priming muscle relaxant for this condition had not been proven until a recent study¹⁵ revealed that priming with rocuronium or vecuronium reduced the incidence of difficult ventilation secondary to muscle rigidity after the use of remifentanil during anesthesia induction. In addition, pretreatment with, or the concomitant use of, pancuronium significantly decreases the incidence and severity of fentanyl-mediated rigidity.¹⁶ This suggests that a priming dose of muscle relaxant has a forestalling effect on fentanyl-induced muscle rigidity. Furthermore, our study showed that muscle relaxant priming has a preventive effect on FIC induced by vocal cord spasms.

Previous research suggests that priming with rocuronium or vecuronium leads to the development of partial neuromuscular blockage with serious complications (regurgitation and severe muscle weakness) following administration.17, 18 When priming with muscle relaxant for patients is decided upon, anesthesiologists should cautiously guard against these complications. None of the patients in our study developed serious complications from the priming. Further investigation is required to determine the ideal priming dose and waiting time.

Many patients have reported pain on injection of rocuronium.¹⁹ Although none of the patients in this study complained of severe pain, mild or moderate pain could have developed. Certain studies suggest that pretreatment with lidocaine, fentanyl, sufentanil, or esmolol can alleviate the pain on injection of rocuronium.19, 20, 21 When applying priming with rocuronium, the use of these palliative measures should be considered.

We therefore conclude that intravenous rocuronium (0.06 mg/kg) administered 30 seconds before the use of fentanyl can suppress the cough reflex induced by fentanyl, thus avoiding FIC.

Acknowledgments

This work was supported by grants from the Taichung Armed Forces General Hospital of Taiwan.