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From the Department of Anesthesia, Gifu University School of Medicine, Gifu-City, Gifu, Japan.
Address correspondence to: Dr. Tsutomu Oshima, Department of Anesthesia, Teikyo University School of Medicine Ichihara Hospital, 3426-3 Anesaki, Ichihara, Chiba 299-0111, Japan. Phone: 81-436-62-1211; Fax: 81-436-62-2621; E-mail: oshimat{at}med.teikyo-u.ac.jp
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Abstract |
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Methods: We analyzed data from a cohort of 1,311 adult patients undergoing elective surgery under general anesthesia, accompanied by iv fentanyl. The following data were collected: patient demographics, history of cigarette smoking, presence of bronchial asthma or chronic obstructive pulmonary disease, administration of angiotensin converting enzyme inhibitors; and anesthetic technique, including: preanesthetic anxiolytic medication, prior use of atropine, epidural lidocaine, a priming dose of vecuronium, and the dose of iv fentanyl. Associations between individual variables in the clinical evaluation model and the likelihood of fentanyl-induced cough were characterized by calculating odds ratios. Multiple logistic regression analysis was used to examine the independent contribution of each variable while controlling for all variables.
Results: Fentanyl-induced cough was independently associated with the following: aging, cigarette smoking, a prior epidural injection of lidocaine, and a priming dose of vecuronium. Fentanyl-induced cough was unaffected by gender, the presence of either bronchial asthma or chronic obstructive pulmonary disease, or prior use of atropine.
Conclusions: Fentanyl-induced cough may be suppressed by aging, cigarette smoking, prior epidural injection of lidocaine, or a priming dose of vecuronium. These findings may allow insights into the mechanism of this phenomenon, thereby leading to its prevention.
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Introduction |
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Cough is the result of mechanical or chemical stimulation of sensory receptors within the respiratory tract, the afferent impulses from these receptors activating a putative brainstem cough centre.6 In addition to angiotensin converting enzyme (ACE) inhibitors,7 fentanyl is regarded as a valuable tussive medication among the systemically administered drugs available for humans. Therefore, exploration into the mechanism of fentanyl-induced cough may provide insights into the physiology of the cough reflexes in humans, while leading to development of the preventive methods for this phenomenon in the clinical setting.
In the present study, we carried out an epidemiologic investigation of the likelihood of fentanyl-induced cough occurring during induction of general anesthesia. Our aim was, by comparing the present findings with the previous data accumulated from the conventional cough models elicited by inhalation of capsaicin,8 citric acid,9 or distilled water aerosol,10 or by oral administration of ACE inhibitors,7 to allow insights into the mechanism of fentanyl-induced cough.
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Methods |
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The database included each patient’s age, sex, height, and weight. Other data included history of cigarette smoking, the existence of bronchial asthma or chronic obstructive pulmonary disease (COPD), and administration of ACE inhibitors. With respect to anesthetic technique, the type of anxiolytic drug given as preanesthetic medication (benzodiazepines, clonidine, or hydroxyzine), prior use of atropine, epidural catheterization and injection of lidocaine, a priming dose of vecuronium, and the dose of intravenously injected fentanyl were recorded. As the only clinical endpoint, one observer continuously assessed the occurrence of cough responses after iv injection of fentanyl as a bolus in a peripheral iv infusion. The one-minute data collection period was followed by termination of this observation.
Statistical analysis
To compare the group data as demographic or anesthesia-related findings between patient groups with and without fentanyl-induced cough, categorical data were analyzed using the Pearson Chi-square tests with Yates’ correction or Fisher’s exact probability test, as appropriate. Continuous data were analyzed by means of a one-way analysis of variance. With all tests, a P value < 0.05 was considered statistically different. Group data are presented as the mean ± SD, number, or percentage. The relative magnitudes of the associations between individual variables as demographic or anesthesia-related findings, and the likelihood of fentanyl-induced cough, were compared by calculating crude odds ratios (OR). The precision of the estimated OR was assessed by the use of 95% confidence intervals (CI), the association between a specific variable and fentanyl-induced cough being considered significant unless the CI included one. The second step in the analysis involved use of a multivariable logistic regression model containing all candidate variables. The final model was used to examine the independent contribution made by each variable while controlling for all variables, and it resulted in an adjusted OR and a calculated 95% CI. To evaluate the discrimination and calibration for the final model, the c-statistic and the Hosmer-Lemeshow goodness of fit Chi-square were calculated, respectively. Furthermore, to indicate the relative contribution of each variable to the final model, the likelihood Chi-square value for the predictors was presented. The statistics program used for the analysis was SPSS 11.5 J for Windows (SPSS Japan Inc., Tokyo, Japan).
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Results |
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). With respect to anesthetic factors, the group experiencing cough contained a higher percentage of patients who received benzodiazepine premedication, a lower percentage who had received atropine, and a lower percentage receiving epidural lidocaine; moreover, the former group had received a higher dose of fentanyl (Table I).
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displays (a) the number of patients found to have each demographic and anesthesia-related risk factor, as well as the percentage exhibiting fentanyl-induced cough, (b) the crude OR and 95% CI for each factor, and (c) the adjusted OR and the likelihood Chi-square value for each demographic and anesthesia-related possible risk factor (when adjusted for all variables in the model). The results exhibited by (b) crude OR were similar to those shown in Table I
. However, the results obtained from (c) the adjusted OR were found to differ from these results as follows: a younger age, being a non-smoker, premedication with benzodiazepine, absence of epidural lidocaine, and absence of a priming dose of vecuronium were shown to be significant independent risk factors for the development of fentanyl-induced cough. Conversely, increased age, cigarette smoking, epidural lidocaine, and a priming dose of vecuronium were all associated with a decreased risk for fentanyl-induced cough. When given as anxiolytic premedication, hydroxyzine and clonidine each reduced the risk for fentanyl-induced cough, as compared with benzodiazepine.
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Discussion |
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These results differ from those shown in Tables I and II (b), which suggest that the predisposing factors for fentanyl-induced cough also include female gender, no prior administration of atropine, and a higher dose of fentanyl while excluding the absence of a priming dose of vecuronium. This study is a secondary historical cohort analysis of data obtained from our database. Use of a multiple logistic regression model allowed calculation of adjusted OR and 95% CI so as to assess the independent contribution made by each candidate variable, while controlling for all candidates. As predisposing factors for fentanyl-induced cough, multivariable logistic analysis excluded female gender, no prior administration of atropine, and a higher dose of fentanyl, while also including the absence of a priming dose of vecuronium.
Several experimental cough models have been proposed: cough elicited by inhalation of capsaicin,8 citric acid,9 or distilled water aerosol,10 or by oral administration of ACE inhibitors.7 The present findings need to be compared with the previous data accumulated from these conventional cough models. Firstly, we found that aging was associated with suppression of fentanyl-induced cough. This finding is supported by a decrease in the number of rapidly adapting stretch receptors with aging in dogs,11 although in humans the capsaicin cough threshold has been shown to be similar among different age groups of the same sex.12 Secondly, a cigarette smoking-induced inhibition of fentanyl-induced cough is consistent with the increase in the capsaicin cough threshold in smokers.13 Thirdly, the antitussive effect of epidurally administered lidocaine may be attributed to the systemic effects of this local anesthetic.5,14 Since use of a capsaicin cough challenge has demonstrated that cough-reflex sensitivity is preserved after cervical spinal cord injury,15 an epidural anesthesia-induced sensory and motor blockade is unlikely to contribute to a suppression of fentanyl-induced cough. Fourthly, the effects of non-depolarizing neuromuscular blocking drugs, including vecuronium, on cough threshold, remain to be established. Lastly, a hydroxyzine-induced reduction in the probability of fentanyl-induced cough is supported by the efficacy of the first generation antihistamines against postnasal drip syndrome, one of the major causes of persistently troublesome cough.16 Moreover, histamine release may be involved in the onset of fentanyl-induced cough.4 A clonidine-induced suppression of fentanyl-induced cough is inconsistent with a previous report that the inhaled-capsaicin cough threshold is not affected by oral administration of clonidine.17 Further controlled studies with placebo in humans are needed to elucidate these problems.
Several promising demographic and anesthesia-related factors were found to be unrelated to the probability of fentanyl-induced cough. Firstly, no gender difference in the probability of fentanyl-induced cough was observed in this study, although female gender has previously been reported to increase capsaicin cough sensitivity.9,18 Secondly, there was no influence of bronchial asthma or COPD on the probability of fentanyl-induced cough. This finding is inconsistent with clinical data suggesting a hyperreactive response to tussive stimuli such as capsaicin in these pathologic conditions.19 These differences could reflect the use of different tussive drugs, differing patterns of symptoms, differences in disease severity, or alleviating effects of therapeutic drugs such as ß2 adrenergic agonists and corticosteroids on the cough response,4 whether elicited by fentanyl or capsaicin. Lastly, an antitussive effect of atropine was excluded by the multiple logistic regression analysis carried out in this study, a result supported by data previously obtained in humans and animals.20
Apart from fentanyl, ACE inhibitors are the only medications widely known to provoke cough attacks amongst the systemically administered drugs available for humans.7 ACE inhibitors presumably cause cough by preventing the breakdown of endogenous tachykinins or bradykinin, which in turn stimulate rapidly adapting stretch receptors within the airway.6 Given this proposed mechanism of ACE inhibitor-induced cough, we hypothesize that intravenously administered fentanyl may provoke cough by transiently stimulating pulmonary C-fibre receptors, which in turn release tachykinin, thereby indirectly activating rapidly adapting stretch receptors. Alternative hypotheses include sudden adduction of vocal cords or supraglottic obstruction by soft tissues secondary to fentanyl-induced muscle rigidity, and histamine release. Verification of these hypotheses regarding the mechanism of fentanyl-induced cough awaits the results of further studies. On the other hand, the present findings also suggest that a young, non-smoker may represent a high-risk patient for fentanyl-induced cough, and that both a priming dose of vecuronium and systemic administration of lidocaine may be recommended to prevent fentanyl-induced cough during induction of general anesthesia. This study is the first to demonstrate the preventive efficacy of a priming dose of vecuronium for fentanyl-induced cough, although iv lidocaine has been shown recently to suppress fentanyl-induced cough in a prospective, randomized controlled study.5 Further clinical trials examining fentanyl-induced cough, focusing on selective influencing factors, may provide new insights into the mechanism of fentanyl-induced cough in humans, thereby developing the means by which this phenomenon can be prevented in the clinical setting.
In conclusion, the probability of fentanyl-induced cough is decreased by aging, cigarette smoking, epidural administration of lidocaine, and a priming dose of vecuronium. There is no effect by gender, the presence of either bronchial asthma or COPD, or prior use of atropine in this survey population.
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Footnotes |
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Accepted for publication January 18, 2006. Revision accepted February 25, 2006.
Competing interests: None declared.
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References |
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2 Phua WT, Teh BT, Jong W, Lee TL, Tweed WA. Tussive effect of a fentanyl bolus. Can J Anaesth 1991; 38: 330–4.
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