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Canadian Journal of Anesthesia 51:654-659 (2004)
© Canadian Anesthesiologists' Society, 2004
General Anesthesia

Intravenous lidocaine and ephedrine, but not propofol, suppress fentanyl-induced cough

[L’administration iv de lidocaïne et d’éphédrine, mais non de propofol, supprime la toux causée par le fentanyl]

Chin-Shuang Lin, MD*, Wei-Zen Sun, MD*, Wei-Hung Chan, MD*, Chen-Jung Lin, MD*, Huei-Ming Yeh, MD* and Martin S. Mok, MD{dagger}

* From the Departments of Anesthesiology, National Taiwan University Hospital and National Taiwan University College of Medicine, and
{dagger} the Taipei Medical University Hospital, Taipei, Taiwan.

Address correspondence to: Dr. Wei-Hung Chan, Department of Anesthesiology, National Taiwan University Hospital, No. 7, Chung-Shan South Rd., Taipei, Taiwan, 100. Phone: +886-2-23123456, ext. 5519; Fax: +886-2-23415736; E-mail: andrchan{at}ms34.hinet.net


   Abstract
TOP
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Purpose: The aim of this study was to evaluate the effectiveness of lidocaine, propofol and ephedrine in suppressing fentanyl-induced cough.

Methods: One hundred and eighteen patients were randomly assigned into four groups and the following medications were given intravenously: patients in Group I (n = 31) received normal saline 2 mL, Group II (n = 29) received lidocaine 2 mg·kg–1, Group III (n = 30) received propofol 0.6 mg·kg–1 and Group IV (n = 28) received ephedrine 5 mg. At one minute after the study medication, fentanyl 2.5 µg·kg–1 was given intravenously within two seconds. The occurrence of cough and vital sign profiles were recorded within two minutes after fentanyl bolus by an anesthesiologist blinded to study design.

Results: Sixty-five percent of patients in the placebo group had cough, whereas the frequency was significantly decreased in Groups II (14%) and IV (21%). Although a numerically lower frequency of cough was noted in Group III (37%), it was not statistically different from that of the placebo group. SpO2 decreased significantly in patients of Group III compared to placebo; one patient experienced hypoxemia necessitating mask ventilation. Patients in Group III showed a decrease in heart rate and systolic blood pressure (2 beats·min–1 and 8 mmHg vs baseline). Patients in Group IV showed an increase in both measurements (5 beats·min–1 and 8 mmHg vs baseline). No truncal rigidity was observed throughout the study.

Conclusions: Intravenous lidocaine 2 mg·kg–1 or ephedrine 5 mg, but not propofol 0.6 mg·kg–1, was effective in preventing fentanyl-induced cough. The results provide a convenient method to decrease fentanyl-induced cough.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
REFLEX cough is often observed after an iv bolus of fentanyl during induction. The incidence of fentanyl-induced cough varies from 28 to 46% according to previous reports.1–4 The tussive effect of fentanyl is usually transient and self-limited for most patients. Yet this phenomenon may be undesirable in patients with some co-existing diseases including increased intracranial pressure, open eye injury, dissecting aortic aneurysm, pneumothorax or reactive airway disease. Recently Tweed and Dakin even reported that an episode of explosive coughing after iv fentanyl in a seven-year-old boy led to multiple conjunctival and periorbital petechiae.5

Several pharmacological measures have been studied to mitigate this adverse effect with varying success. One study showed that premedication with morphine given one hour before induction is effective.2 Another study demonstrated that the inhalation of terbutaline, a selective ß2-adrenergic bronchodilator, could effectively suppress this reflex.3 More recently Agarwal et al.4 reported that aerosol inhalation of salbutamol, beclomethasone or sodium chromoglycate 15 min prior to entering the operating room could also reduce the incidence of cough. However, these methods can be inconvenient, so their clinical acceptance is somewhat limited. We conducted the present study in an attempt to find other drugs that could effectively attenuate fentanyl-induced cough while being convenient in clinical practice. We selected lidocaine, propofol and ephedrine, which are all readily available in the operation room. Both lidocaine and propofol have been shown to reduce airway reactiveness.6,7 With its ß-adrenergic agonism, ephedrine has a bronchodilating effect and may be effective in suppressing the cough reflex. We investigated the effectiveness and adverse events of the three drugs in a randomized, prospective study.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After obtaining approval from the Institutional Review Board of our hospital and informed consents from the patients, 118 adult patients of ASA physical status class I or II were enrolled in the study. All patients were scheduled for elective surgical procedures, and their ages were between 18 and 65 yr. Exclusion criteria included history of asthma, chronic cough, smoking, upper respiratory tract infection in the previous two weeks, or medication with angiotensin-converting enzyme inhibitors. No pre-medication was allowed. Patients were randomly assigned into four groups. The table of random digits was used for randomization according to the four possible combinations which were obtained from the last two digits of the random number by odd or even number (i.e., odd + odd, odd + even, even + odd, or even + even). Each combination was assigned to one group in a random manner. All patients were monitored with a continuous electrocardiogram, pulse oximeter and noninvasive blood pressure measurement throughout the study. After establishing a freely running iv line, subjects were left undisturbed for one minute. Then, patients were given the following medications intravenously: Group I received 2 mL saline as placebo; Group II received lidocaine 2 mg·kg–1; Group III received propofol 0.6 mg·kg–1 and Group IV received ephedrine 5 mg.

At one minute after the aforementioned treatment in each group, fentanyl 2.5 µg·kg–1 was rapidly administered through the peripheral iv line within two seconds. The occurrence and intensity of cough within two minutes after the fentanyl injection were recorded since the cough generally happens within this period of time. The intensity of cough was arbitrarily graded as the following: no cough (grade zero), cough less than three seconds (grade one) and cough more than three seconds (grade two). A resident who was blind to group assignment recorded the cough intensity.

Blood pressure and heart rate were recorded before the administration of each drug and after the injection of fentanyl. The oxygen saturation was closely observed and when SpO2 dropped below 90%, manually assisted mask ventilation with oxygen was to be applied immediately. The SpO2 before the administration of the test drugs and the lowest reading after the administration of fentanyl were recorded for comparison. The occurrence of other side effects possibly related to drug treatment such as truncal rigidity, dizziness, injection pain, arrhythmia, nausea or vomiting, was also recorded.

We conducted a pilot study using this protocol in 30 patients and observed that 22 patients had cough. We defined a significant suppressive effect as decreasing the incidence of cough to half of control. The smallest sample size required to detect such a difference was a total of 106 patients with an {alpha} value equaling 0.05 and a power of 0.8. One hundred and eighteen patients were enrolled in the present study. Results are expressed as mean ± standard deviation or mean (range). The frequency of cough in Groups II, III and IV was compared to that of the placebo group by Chi-square test or Fisher’s exact test when appropriate with Bonferroni correction, as were other nominal data. One-way analysis of variance was used to compare the age, weight and height among the four groups. The differences between the vital sign profiles recorded before and after the treatment were compared by paired t test. The drop in SpO2 was analyzed by Kruskal-Wallis test and subsequent Dunn test for post hoc comparisons against the placebo group. A P value less than 0.05 was considered to be statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The demographic data including age, weight, height, sex, ASA physical status and indications of surgery did not differ significantly among the four groups (Table IGo). In the placebo group 65% (20/31) of patients had cough, whereas the frequency was significantly decreased in Group II (4/29, 14%) and Group IV (6/28, 21%; P < 0.001 and P = 0.002, respectively; Table IIGo). Although a numerically lower frequency of cough was noted in Group III (37%), it failed to show a statistically significant difference from that of the placebo group (P = 0.055). Incidentally, we found that there was an age-related incidence of fentanyl-induced cough. In the control group, 92% of patients (12/13) younger than 35 yr old, 54% of patients (7/13) between 36 and 50 yr old and only 20% of patients (1/5) older than 51 yr experienced cough, respectively (P < 0.05 by Chi-square test).


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  		TABLE I Demographic characteristics of the study population
 

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  		TABLE II Frequency and intensity of cough induced by fentanyl
 
The baseline vital sign profiles were comparable among the four groups. The systolic blood pressure and heart rate readings did not differ significantly after treatment in Groups I and II, whereas a decrease in systolic blood pressure (about 8 mmHg) was observed in Group III and an increase (about 8 mmHg) was found in Group IV (both P < 0.001) after treatment (Table IIIGo). Similarly, a slight decrease in heart rate (P < 0.05) was found in Group III and an increase in heart rate was noted in the ephedrine group (P < 0.001). The patients in all four groups showed a decrease in SpO2. On examining the extent of SpO2 drop, we found that only the readings of Group III dropped significantly compared to placebo.


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  		TABLE III Changes in vital signs after treatment in each group
 
One patient in Group III suffered from hypoxemia (SpO2 < 90%) after the administration of fentanyl, necessitating manually assisted mask ventilation. Injection pain was most noticeable in the propofol group. Other adverse effects occurred rarely with no significant difference among the groups, as listed in Table IVGo. There was no cardiac arrhythmia or truncal rigidity in any of the patients throughout the study.


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  		TABLE IV Adverse effects
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We have shown that fentanyl, when administered through a peripheral venous line, provokes reflex cough in up to 65% of patients. The tussive effect induced by fentanyl can be suppressed by pretreatment with lidocaine 2 mg·kg–1 or ephedrine 5 mg given intravenously at one minute before fentanyl, but not by the administration of 0.6 mg·kg–1 propofol.

Fentanyl-induced cough is commonly observed during the induction of anesthesia. In the study by Bohrer et al.,1 46% of the patients coughed after receiving 7 µg·kg–1 fentanyl through a central venous catheter. Another study by Lui et al.3 showed that 43% of patients coughed after receiving 5 µg·kg–1 fentanyl injected through a peripheral venous line. Phua et al.2 found that fentanyl 1.5 µg·kg–1 given through a peripheral venous line elicited cough in 28% of the patients and a similar incidence of cough was observed by Agarwal et al.4 following 2 µg·kg–1 iv fentanyl through the same route over a period of five seconds. The discrepancy in the incidence of cough among these studies could be explained by different doses and routes of administration. In the present study, we chose a dose of fentanyl which is lower than those used in previous reports because this dose (2.5 µg·kg–1) is closer to that commonly administered in daily practice. It is noteworthy that the incidence of cough is still high, even at this dose. The reason why we observed such a high incidence of cough with a relatively low dose of fentanyl is uncertain. We propose two explanations for this phenomenon. First, we injected the bolus of fentanyl rapidly (in less than two seconds) as compared with five seconds in the study of Lui et al.3 and Agarwal et al.4 Nonetheless, we do not recommend that fentanyl should be administered with such rapidity as a clinical routine. Second, we noticed that the incidence of cough appears to be higher in younger patients. Hence the difference in the incidence of fentanyl-induced cough could be, in part, age-related. In the report by Bohrer et al.,1 the average age of the control group was over 60 yr old. The possible age-related incidence of fentanyl-induced cough may be attributed to the different activity of underlying mechanisms, for example, heightened irritant receptor activity in the younger population.

Various hypotheses to explain the mechanism of fentanyl-induced cough have been proposed in the literature. Fentanyl is known to enhance vagal activity,8,9 which could trigger cough and reflex bronchoconstriction. However, the involvement of a vagal-dependent pathway was not favoured in the previous studies because atropine, an antimuscarinic agent, failed to suppress cough.2,3 Additionally, possible mechanisms of fentanyl-induced cough include a pulmonary chemoreflex mediated by vagal C-fibre receptors (also known as J-receptors) with its nonmyelinated afferent fibres,1,10 direct stimulation of the vagal nucleus which augments the bronchomotor tone,8,9 opioid-induced histamine release,11,12 the release of neuropeptides after activation of prejunctional µ-opioid receptors by fentanyl and subsequent activation of presynaptic sensory C fibres,13 and stimulation of the irritant receptors in upper pulmonary mucosa secondary to fentanyl-induced tracheal smooth muscle constriction or bronchoconstriction.14 Sudden adduction of the vocal cords or supraglottic obstruction by soft tissue caused by opioid-induced muscle rigidity has also been proposed.15 Despite a wide range of mechanistic studies, only im morphine, or inhalational treatments, including terbutaline, salbutamol, beclomethasone and sodium chromoglycate, were shown to attenuate the cough reflex.2–4

Although the bronchodilating effect of lidocaine has been questioned,16 iv lidocaine was proved to be a suppressant of coughing during tracheal intubation.17,18 Our results also clearly demonstrate that iv lidocaine can prevent fentanyl-induced cough. Nonetheless, relatively high plasma concentrations of lidocaine are required for suppression of coughing. Yukioka et al.18 reported that a dose of 2 mg·kg–1, with resultant plasma concentrations in excess of 4 µg·mL–1, was more effective than the dose of 1 or 1.5 mg·kg–1 in suppressing cough during tracheal intubation in elderly patients. Accordingly we decided to use lidocaine at the dose of 2 mg·kg–1. No serious complications possibly related to iv lidocaine were observed.

There were two reasons that prompted us to evaluate the effect of propofol on fentanyl-induced cough. Pizov et al. showed that the incidence of wheezing was significantly reduced in asthmatic patients receiving a propofol-based induction of anesthesia compared to a barbiturate-based induction.19 Cigarini et al. demonstrated that propofol was able to prevent fentanyl-induced bronchoconstriction in surgical patients.7 Thus propofol could be a promising drug to suppress fentanyl-induced cough. However, we did not see significant cough suppression with 0.6 mg·kg–1 propofol in the present study. While this dose may be subtherapeutic, higher doses may not be well tolerated for this indication. A decrease in was identified in the SpO2 propofol group. This was probably due to the synergistic, depressant effect of fentanyl and propofol on respiration. Therefore, we do not recommend the use of propofol to decrease fentanyl-induced cough.

Ephedrine has long been recognized as a bronchodilator due to its ß-adrenergic activity and is readily available in the operating room. Our study showed that iv ephedrine at the dose of 5 mg was indeed effective in suppressing fentanyl-induced cough. The adrenergic agonism of the drug might simply suppress cough by reversing the fentanyl-triggered bronchoconstriction. Even though the relationship between reflex bronchoconstriction and fentanyl-induced cough has been questioned recently,20 ß-agonists were shown to suppress the cough reflex in different studies.3,4 We chose to test the effect of ephedrine at a relatively low dose to avoid major hemodynamic changes. The mild cardiovascular stimulating effect of low dose ephedrine should be well tolerated in an otherwise healthy patient. Hence ephedrine remains a reasonable alternative to suppress fentanyl-induced cough, considering its convenience compared with inhalational agents. Although ephedrine may not have reached its peak effect before fentanyl was administered in our study, it still suppressed fentanyl-induced cough, indicating its rapid onset by iv administration. Nonetheless, additional studies are needed to define the optimal injection time of ephedrine for this indication.

In conclusion, our study demonstrates that pre-treatment with lidocaine 2 mg·kg–1 or ephedrine 5 mg given intravenously at one minute before fentanyl are effective in preventing fentanyl-induced cough. On the other hand, propofol at the dose of 0.6 mg·kg–1 is ineffective for the suppression of this reflex. Our results suggest convenient alternatives to suppress fentanyl-induced cough in clinical practice.


   Footnotes
 
Accepted for publication December 22, 2003. Revision accepted March 26, 2004.


   References
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Bohrer H, Fleischer F, Werning P. Tussive effect of a fentanyl bolus administered through a central venous catheter. Anaesthesia 1990; 45: 18–21.[Medline]

2 Phua WT, Teh BT, Jong W, Lee TL, Tweed WA. Tussive effect of a fentanyl bolus. Can J Anaesth 1991; 38: 330–4.[Abstract/Free Full Text]

3 Lui PW, Hsing CH, Chu YC. Terbutaline inhalation suppresses fentanyl-induced coughing. Can J Anaesth 1996; 43: 1216–9.[Abstract/Free Full Text]

4 Agarwal A, Azim A, Ambesh S, et al. Salbutamol, beclomethasone or sodium chromoglycate suppress coughing induced by iv fentanyl. Can J Anesth 2003; 50: 297–300.[Abstract/Free Full Text]

5 Tweed WA, Dakin D. Explosive coughing after bolus fentanyl injection. Anesth Analg 2001; 92: 1442–3.[Free Full Text]

6 Poulton TJ, James FM 3rd. Cough suppression by lidocaine. Anesthesiology 1979; 50: 470–2.[Medline]

7 Cigarini I, Bonnet F, Lorino AM, Harf A, Desmonts JM. Comparison of the effects of fentanyl on respiratory mechanics under propofol or thiopental anaesthesia. Acta Anaesthesiol Scand 1990; 34: 253–6.[Medline]

8 Reitan JA, Stengert KB, Wymore ML, Martucci RW. Central vagal control of fentanyl-induced bradycardia during halothane anesthesia. Anesth Analg 1978; 57: 31–6.[Abstract/Free Full Text]

9 Inoue K, Samodelov LF, Arndt JO. Fentanyl activates a particular population of vagal efferents which are cardioinhibitory. Naunyn-Schmiedeberg Arch Pharmacol 1980; 312: 57–61.[Medline]

10 Paintal AS. Mechanism of stimulation of type J pulmonary receptors. J Physiol 1969; 203: 511–32.[Abstract/Free Full Text]

11 Karlsson JA, Sant’Ambrogio G, Widdicombe J. Afferent neural pathways in cough and reflex bronchoconstriction. J Appl Physiol 1988; 65: 1007–23.[Abstract/Free Full Text]

12 Vidruk EH, Hahn HL, Nadel JA, Sampson SR. Mechanisms by which histamine stimulates rapidly adapting receptors in dog lungs. J Appl Physiol 1977; 43: 397–402.[Abstract/Free Full Text]

13 Lou YP. Regulation of neuropeptide release from pulmonary capsaicin-sensitive afferents in relation to bronchoconstriction. Acta Physiol Scand 1993; 62(Suppl 612): 1–88.

14 Yasuda I, Hirano T, Yusa T, Satoh M. Tracheal constriction by morphine and by fentanyl in man. Anesthesiology 1978; 49: 117–9.[Medline]

15 Benthuysen JL, Smith NT, Sanford TJ, Head N, Dec-Silver H. Physiology of alfentanil-induced rigidity. Anesthesiology 1986; 64: 440–6.[Medline]

16 Hirota K, Hashimoto Y, Sato T, et al. I.v. lidocaine worsens histamine-induced bronchoconstriction in dogs. Br J Anaesth 1999; 82: 87–9.[Abstract/Free Full Text]

17 Yukioka H, Yoshimoto N, Nishimura K, Fujimori M. Intravenous lidocaine as a suppressant of coughing during tracheal intubation. Anesth Analg 1985; 64: 189–92.

18 Yukioka H, Hayashi M, Terai T, Fujimori M. Intravenous lidocaine as a suppressant of coughing during tracheal intubation in elderly patients. Anesth Analg 1993; 77: 309–12.[Medline]

19 Pizov R, Brown RH, Weiss YS, et al. Wheezing during induction of general anesthesia in patients with and without asthma. A randomized, blinded trial. Anesthesiology 1995; 82: 1111–6.[Medline]

20 Tsou CH, Luk HN, Chiang SC, Hsin ST, Wang JH. Fentanyl-induced coughing and airway hyperresponsiveness. Acta Anaesthesiol Sin 2002; 40: 165–72.[Medline]




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