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Table of Contents
Year : 2015  |  Volume : 31  |  Issue : 4  |  Page : 522-525

Can low dose of propofol effectively suppress fentanyl-induced cough during induction of anaesthesia? A double blind randomized controlled trial

1 Department of Anaesthesiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
2 General Practitioner, Mazandaran University of Medical Sciences, Sari, Iran

Date of Web Publication5-Nov-2015

Correspondence Address:
Alieh Zamani Kiasari
Department of Anaesthesiology, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0970-9185.169082

Clinical trial registration IRCT201305216803N4

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Background and Aims: Fentanyl-induced cough (FIC) is often seen after intravenous (IV) administration of fentanyl during the induction of general anesthesia.The aim of this study was to evaluate the effectiveness of low dose of propofol in suppressing of FIC during induction of anesthesia.
Material and Methods: In a prospective double-blind randomized controlled trial, a total of 240 patients, American Society of Anesthesiologists physical status Class I and II, scheduled for elective surgery were randomly assigned into two equally sized groups (n = 120). Patients in Group A received low dose of propofol (10 mg) and patients in Group B received the same volume of normal saline (control group). Two minutes later, all patients were given fentanyl (2 μg/kg) over 2 s through the peripheral IV line in the forearm. The vital sign profiles and frequency and intensity of cough were recorded within 2 min after fentanyl bolus by a nurse blinded to study design. Data were analyzed using independent t-test, paired t-test and Chi-square test.
Results: The incidences of FIC were 9.2% and 40.8% in Group A (propofol) and Group B (placebo) respectively (P = 0.04). Furthermore, there was a significant difference in the intensity of cough between Groups A and B (P < 0.0001). The hemodynamic value (systolic blood pressure, diastolic blood pressure, heart rate, mean arterial pressure and saturation of oxygen) were similar, and there was no significant difference between two groups in the baseline value or after propofol or placebo injection.
Conclusions: Administration low dose of propofol (10 mg) may effectively reduce the FIC frequency and intensity during induction of anesthesia without hemodynamic disturbances.

Keywords: Cough, fentanyl, general anesthesia, propofol

How to cite this article:
Firouzian A, Emadi SA, Baradari AG, Mousavi R, Kiasari AZ. Can low dose of propofol effectively suppress fentanyl-induced cough during induction of anaesthesia? A double blind randomized controlled trial . J Anaesthesiol Clin Pharmacol 2015;31:522-5

How to cite this URL:
Firouzian A, Emadi SA, Baradari AG, Mousavi R, Kiasari AZ. Can low dose of propofol effectively suppress fentanyl-induced cough during induction of anaesthesia? A double blind randomized controlled trial . J Anaesthesiol Clin Pharmacol [serial online] 2015 [cited 2020 Jul 14];31:522-5. Available from:

  Introduction Top

Fentanyl, a synthetic opioid, is used during the induction of general anesthesia because of its rapid onset, short duration of action, intense analgesia, ease of titrability, cardiovascular stability and low histamine release. [1],[2] Reflex coughing after intravenous (IV) fentanyl administration occurs in 28-80% of cases. [3],[4],[5],[6],[7],[8] FIC is usually benign, transient and self-limited, but at times may be spasmodic or explosive requiring immediate therapeutic intervention. [9],[10] Although the mechanism of FIC is still unclear, but various interventions have been implemented to reduce its incidence during the induction of anesthesia by using adjuncts and other maneuver, with varying success. These interventions include the use of β2 receptor agonist, ephedrine, lidocaine, ketamine, clonidine, dexamethasone, dexmedetomidine, a huffing maneuver prior to induction etc. However these approaches are not uniformly effective. [3],[4],[5],[7],[11],[12],[13],[14],[15] Propofol, a short acting nonopioid, nonbarbiturate, sedative-hypnotic agent with quick onset and short duration of action is one of the pharmacologic agents that have been used for suppressing of FIC, in varying doses by few researchers with conflicting results. [4],[8],[16],[17]

Hence we conducted this study to investigate efficacy of 10 mg of propofol to suppress FIC during induction of anesthesia.

  Material and Methods Top

After obtaining an Institutional Ethics Committee approval and an informed patient consent, a continuous sample of 240 adults' patients of both sexes, American Society of Anesthesiologists Class I or II, aged 18-50 years, scheduled for various elective surgical procedures under general anesthesia were enrolled in this prospective double-blind randomized, placebo control study. Patients with a history of asthma, chronic cough, smoking or substance abuse, cardiac disease, upper respiratory tract infection in the previous 4 weeks, any disease or surgery of trachea or larynx, impaired kidney or liver functions, pregnancy, medication with angiotensin-converting enzyme inhibitors, steroids, antihistamine or antitussive drugs in the previous 4 weeks, were excluded from the study. No premedication was allowed. The study was performed between December 2012 and July 2013. Patients who fulfilled the inclusion criteria were randomly allocated into Group A (n = 120) and Group B (n = 120) by sealed envelope technique. Patient allocation was performed by a nurse who was unaware of the study groups, according to numbers generated by the computer generated list. A venous access was obtained and monitoring instituted in the form of electrocardiogram, noninvasive blood pressure, and pulse oximeter. Baseline systolic and diastolic blood pressure (SBP, DBP), mean arterial pressure (MAP), oxygen saturation (SpO 2 ) and heart rate (HR) were recorded. Then, patients in Group A, received propofol 10 mg and Group B received same volume (1 ml) normal saline 0.9% as placebo. All syringes containing propofol or placebo were covered with masking tape to conceal any details of product. At 2 min after the aforementioned treatment in each group, fentanyl 2 μg/kg was administered through the peripheral IV line within 2 s. The occurrence and intensity of cough within 2 min after the fentanyl injection (since the cough generally happens within this period of time), were observed and recorded by a nurse who was blinded to the study groups. The intensity of cough was arbitrarily graded as the following: No cough (None), 1-2 cough (Mild), 3-4 cough (Moderate) and 5 cough or more (Severe) (5). Moreover, systolic and DBP, MAP, SpO 2 and pulse rate were measured and recorded. This study registered in the Iranian Registry of Clinical Trials Database (IRCT201305216803N4). Estimation of sample size was based on a pilot study using this protocol in 30 patients and observed that 43% (n = 13) of patients had cough. We defined a significant suppressive effect as decreasing the incidence of cough to half of control. At a level of α = 0.05 with a power of 0.8, the sample size calculation was 105 in each groups; we therefore, recruited 120 patients to account for any dropouts.

Statistical analysis

Statistical analysis was performed with Statistical Package for the Social Sciences (SPSS), version 16 (SPSS Inc., Chicago, IL, USA), using the Chi-square tests, Student's t-test, and paired t-test. Significance level was set at P < 0.05.

  Results Top

All patients completed the present study and data from all patients were analyzed.

Demographic profile of all patients in both groups was comparable [Table 1].
Table 1: Demographic characteristics of patients in the two groups

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Fentanyl-induced coughing on induction of anesthesia presented in 60 (25%) patients. There was a statistically significant difference for FIC frequency and intensity between two groups [Table 2].
Table 2: Frequency and intensity of FIC in two groups

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The hemodynamic value (SBP, DBP, HR, MAP and SpO 2 ) were also similar and there was no significant difference between two groups in the baseline value or after propofol or placebo injection [Table 3].
Table 3: Changes in vital signs after intervention in two groups

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  Discussion Top

The results of our study indicate significantly reduced incidence (frequency and intensity) of FIC with administration of 10 mg propofol prior to administration of fentanyl during induction of anesthesia. In a study conducted by Böhrer et al. FIC was observed in 45% of patients when fentanyl was given through a central venous line. [6] Yu et al. observed FIC in 32% of patients when fentanyl was administered through a peripheral IV line. [22] In a study by Sedighinejad et al. the incidence of FIC was reported 74.4%. [17] The differences in the incidence of cough may be related to the different doses of fentanyl and speed of injection. The mechanisms of FIC are not well understood, but various theories have been proposed. Fentanyl may cause vagal predominance and provoke reflex bronchoconstriction and cough. [8] In addition, substances like histamine and neuropeptides, released by an action on prejunctional μ-opioid receptors after IV fentanyl administration, play an important role in contributing to this cough. [13],[20] The study by Yu et al. showed that dilution of fentanyl combined with a prolonged injection time could eliminate FIC. [22] However, according to Schδpermeier and Hopf's study, FIC does not depend on injection speed. [18] Another strategy that was reported as a useful way to prevent FIC is huffing maneuver. [15] Although it has been shown that this maneuver can prevent FIC, but some patients who receive propofol or midazolam during induction of general anesthesia cannot use this maneuver. Tang et al., Zeidan and El Sayed observed effective suppression of FIC by a priming dose of >1 mg/Kg of propofol. [8],[ 23] One possible explanation for the effect of propofol in suppressing FIC may be its bronchodilatory effect. [23] 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. [24] Cigarini et al. demonstrated that propofol was able to prevent fentanyl-induced bronchoconstriction in surgical patients. [25] There are several potential targets for propofol-induced bronchodilatation. Propofol has been found to attenuate vagal and methacholine-induced bronchoconstriction, with possible direct actions on muscarinic receptors. [27],[28] The result of a study that conducted by Kamei et al. have been shown that IV injection of fentanyl markedly increased the histamine levels and suggested that fentanyl enhances the excitability of rapidly adapting receptors to cause cough, and enhancement of histamine release in the airways may somehow be related to this change. [1] Also in a study related to the propofol-induced bronchodilatation, it has been shown that propofol decreased peak intracellular calcium responses to histamine. [29] In a study by Lin et al. although the lower frequency of cough was noted in patients' receiving propofol (0.6 mg/kg), but it was not statistically different from that of the placebo group. Ineffectiveness of propofol for reducing FIC in this study may be due to the small sample size (n = 30) and also the higher dose of fentanyl (2.5 μg/kg) that was administered for the patients. [4] However, our study demonstrates that propofol in doses of 10 mg (sub-hypnotic dose) can be safely used, with stable hemodynamic profile. A limitation of this study was that we did not estimate the peak plasma concentration of propofol required suppressing the FIC. Therefore, a further study needs to be conducted to determine the timing of administration and the peak plasma concentration of propofol required to suppress FIC.

  Conclusion Top

Our study suggests that low dose of propofol (10 mg, IV) bolus injection 2 min before fentanyl injection seemed to be feasible, simple, and cost-effective method to prevent FIC.

  References Top

Kamei J, Nakanishi Y, Asato M, Ikeda H. Fentanyl enhances the excitability of rapidly adapting receptors to cause cough via the enhancement of histamine release in the airways. Cough 2013;9:3.  Back to cited text no. 1
Shrestha SK, Bhattarai B, Shah RS. Preemptive use of small dose fentanyl suppresses fentanyl induced cough. Kathmandu Univ Med J (KUMJ) 2012;10:16-9.  Back to cited text no. 2
Agarwal A, Azim A, Ambesh S, Bose N, Dhiraj S, Sahu D, et al. Salbutamol, beclomethasone or sodium chromoglycate suppress coughing induced by iv fentanyl. Can J Anaesth 2003;50:297-300.  Back to cited text no. 3
Lin CS, Sun WZ, Chan WH, Lin CJ, Yeh HM, Mok MS. Intravenous lidocaine and ephedrine, but not propofol, suppress fentanyl-induced cough. Can J Anaesth 2004;51:654-9.  Back to cited text no. 4
Pandey CK, Raza M, Ranjan R, Lakra A, Agarwal A, Singh U, et al. Intravenous lidocaine suppresses fentanyl-induced coughing: A double-blind, prospective, randomized placebo-controlled study. Anesth Analg 2004;99:1696-8.  Back to cited text no. 5
Böhrer H, Fleischer F, Werning P. Tussive effect of a fentanyl bolus administered through a central venous catheter. Anaesthesia 1990;45:18-21.  Back to cited text no. 6
Yu J, Lu Y, Dong C, Zhu H, Xu R. Premedication with intravenous dexmedetomidine-midazolam suppresses fentanyl-induced cough. Ir J Med Sci 2012;181:517-20.  Back to cited text no. 7
Tang Q, Qian Y, Zhang Q, Yang J, Wang Z. Effects of different priming doses of propofol on fentanyl-induced cough during anesthesia induction: A preliminary randomized controlled study. Ups J Med Sci 2010;115:121-4.  Back to cited text no. 8
Tweed WA, Dakin D. Explosive coughing after bolus fentanyl injection. Anesth Analg 2001;92:1442-3.  Back to cited text no. 9
Ambesh SP, Singh N, Srivastava K. Fentanyl induced coughing caused life-threatening airway obstruction in a patient with arteriovenous malformation of tongue and hypopharynx. Int J Anesthesiol 2008;20. Available at:  Back to cited text no. 10
Horng HC, Wong CS, Hsiao KN, Huh BK, Kuo CP, Cherng CH, et al. Pre-medication with intravenous clonidine suppresses fentanyl-induced cough. Acta Anaesthesiol Scand 2007;51:862-5.  Back to cited text no. 11
Yeh CC, Wu CT, Huh BK, Lee MS, Lin SL, J Sheen M, et al. Premedication with intravenous low-dose ketamine suppresses fentanyl-induced cough. J Clin Anesth 2007;19:53-6.  Back to cited text no. 12
Lin JA, Chen FC, Lee MS. Intravenous dexamethasone pretreatment reduces fentanyl induced cough. J Formos Med Assoc 2007;106:649-55.  Back to cited text no. 13
He L, Xu JM, Dai RP. Dexmedetomidine reduces the incidence of fentanyl-induced cough: A double-blind, randomized, and placebo-controlled study. Ups J Med Sci 2012;117:18-21.  Back to cited text no. 14
Ambesh SP, Singh N, Gupta D, Singh PK, Singh U. A huffing manoeuvre, immediately before induction of anaesthesia, prevents fentanyl-induced coughing: A prospective, randomized, and controlled study. Br J Anaesth 2010;104:40-3.  Back to cited text no. 15
Miller RD, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Young WL. Intravenous anesthetics. Miller Anesthesia. 7 th ed. Philadelphia, PA: Churchill Livingstone/Elsevier; 2010.  Back to cited text no. 16
Sedighinejad A, Naderi Nabi B, Haghighi M, Imantalab V, Hadadi S, Erfani Sayar R, et al. Propofol is effective to depress fentanyl-induced cough during induction of anesthesia. Anesth Pain Med 2013;2:170-3.  Back to cited text no. 17
Schäpermeier U, Hopf HB. Fentanyl-induced cough does not depend on injection speed: A randomized study. Acta Anaesthesiol Scand 2008;52:1071-5.  Back to cited text no. 18
Phua WT, Teh BT, Jong W, Lee TL, Tweed WA. Tussive effect of a fentanyl bolus. Can J Anaesth 1991;38:330-4.  Back to cited text no. 19
Gu C, Zhou M, Wu H, Li F, Tang Q. Effects of different priming doses of fentanyl on fentanyl-induced cough: A double-blind, randomized, controlled study. Pharmacol Rep 2012;64:321-5.  Back to cited text no. 20
Mukherjee A, Kundu AK, Ghosh S, Choudhuri R, Bandopadhyay BK, Dasgupta S. Pre-emptive oral dexmethorphan reduces fentanyl-induced cough as well as immediate postoperative adrenocortico-tropic hormone and growth hormone level. J Anaesthesiol Clin Pharmacol 2011;27:489-94.  Back to cited text no. 21
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Yu H, Yang XY, Zhang X, Li Q, Zhu T, Wang Y, et al. The effect of dilution and prolonged injection time on fentanyl-induced coughing. Anaesthesia 2007;62:919-22.  Back to cited text no. 22
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Pizov R, Brown RH, Weiss YS, Baranov D, Hennes H, Baker S, et al. Wheezing during induction of general anesthesia in patients with and without asthma. A randomized, blinded trial. Anesthesiology 1995;82:1111-6.  Back to cited text no. 24
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.  Back to cited text no. 25
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  [Table 1], [Table 2], [Table 3]

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