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Intravenous Lidocaine Suppresses Fentanyl-Induced Coughing: A Double-Blind, Prospective, Randomized Placebo-Controlled Study

Pandey, Chandra K. MD; Raza, Mehdi MD; Ranjan, Rajeev MD; Lakra, Archana MD; Agarwal, Anil MD; Singh, Uttam PhD; Singh, R B. MD, PDCC; Singh, Prabhat K. MD

doi: 10.1213/01.ANE.0000136967.82197.82
Anesthetic Pharmocology: Research Report
Chinese Language Editions

IV lidocaine is effective in suppressing the cough reflex of tracheal intubation, extubation, bronchography, bronchoscopy, and laryngoscopy. We investigated this effect of lidocaine on fentanyl-induced cough in 502 patients of ASA physical status I and II scheduled for elective surgery. The patients were assigned to 2 equal groups to receive either lidocaine 1.5 mg/kg or placebo (0.9% saline) over 5 s 1 min before the administration of fentanyl 3 μg/kg in a randomized and double-blind fashion. Coughs were classified as coughing and graded as mild (1–2), moderate (3–4), or severe (5 or more). The results of the study suggest that IV lidocaine 1.5 mg/kg, when administered 1 min before fentanyl, is significantly effective in suppressing fentanyl-induced cough compared to placebo (0.9% saline) (218 versus 165 patients) (P < 0.002) but without affecting the severity of cough (P > 0.05).

IMPLICATIONS: Fentanyl administration elicits cough. IV lidocaine 1.5 mg/kg suppresses fentanyl-induced coughing.

Department of Anaesthesiology and Biostatistics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

Accepted for publication June 11, 2004.

Address correspondence to Chandra Kant Pandey, MD, Department of Anaesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India. Address e-mail to

Fentanyl is often given before the actual induction of anesthesia, but it sometimes elicits cough (1). In a controlled clinical trial, 46% of patients coughed after receiving 7 μg/kg of fentanyl through a central venous catheter, and nearly 28% of patients coughed after a 1.5-μg/kg IV dose of fentanyl injected through a peripheral cannula (2,3). Fentanyl-induced cough is not always brief and benign. It may be explosive at times, may require immediate intervention, and is associated with undesirable increases in intracranial, intraocular, and intraabdominal pressures (1,4).

IV administration of lidocaine suppresses the cough reflex during endotracheal intubation, extubation, bronchography, bronchoscopy, and laryngoscopy (5–7). It is effective when given IV to suppress cough reflex of endotracheal intubation and cough induced by manual displacement of the endotracheal tube and instillation of distilled water into the trachea in anesthetized patients (8–10). Therefore, the effect of IV lidocaine on fentanyl-induced cough was evaluated.

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The Institute’s Ethics Committee approved this study, and written informed consent was obtained from each participant. Five-hundred-two patients of both sexes, ASA physical status I and II, and scheduled for elective surgery were recruited for the study. The exclusion criteria were body weight exceeding 20% of the ideal body weight, those older than 60 yr or younger than 18 yr, impaired kidney or liver functions, a history of bronchial asthma and chronic obstructive pulmonary disease, a history of smoking, respiratory tract infection, hypertensive patients on angiotensin converting enzyme inhibitors, and a hypersensitivity to local anesthetics.

Oral lorazepam 0.04 mg/kg was given the evening before surgery and in the morning 1 h before surgery. In the operating room, venous access was established on the dorsum of the nondominant hand, and electrocardiogram, noninvasive arterial blood pressure, and pulse oximeter were applied. Patients were randomly assigned to 2 groups of 251 each, using a computer-generated table of random numbers, to receive IV lidocaine 1.5 mg/kg or placebo (equal volume of 0.9% saline) over 5 s 1 min before the IV administration of fentanyl 3 μg/kg. Coughs were classified as coughing. A blinded observer, who was unaware of the type of medication given to the patients, recorded the number of episodes of coughing, if any. Severity of coughing was graded based on the number of episodes of cough (mild, 1–2; moderate, 3–4; and severe, 5 or >5). Considering that the prevalence of coughing after peripherally administered IV fentanyl is 25%, and assuming a reduction of 10% after lidocaine treatment for an 80% power of the test, a minimum of 250 patients were required in each group. The demographic data were compared by unpaired Student’s t-test. Comparison between groups was performed for overall incidence of coughing by test of proportion (Z test). A P value < 0.05 was considered statistically significant.

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The demographic data were comparable in both the groups (Table 1). Thirty-three and 86 patients (13.1% versus 34.22%) had cough in the lidocaine and placebo groups, respectively (P < 0.05) (Table 2). However, there was no significant difference in the severity of cough between groups (P > 0.05) (Table 2). The results of this study demonstrated an absolute-risk reduction of 21.12% and relative-risk reduction of 62% for fentanyl-induced coughing when pretreated with IV lidocaine.

Table 1

Table 1

Table 2

Table 2

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In our series, coughing occurred in 34.22% of patients at the fentanyl dose of 3 μg/kg in the placebo group, which is slightly more frequent than the previous reports of 28% (1,2), and pretreatment with IV lidocaine 1.5 mg/kg decreased the incidence of fentanyl-induced cough from 34.22% to 13.1% (absolute risk reduction, 21.12%; relative-risk reduction, 62%). The more frequent incidence of fentanyl-induced cough in our study is probably because of a larger fentanyl dose (3 μg/kg) compared with Agarwal et al. (1) (2 μg/kg) and Phua et al. (3) (1.5 μg/kg), who reported a 28% incidence of cough in their series. A 46% incidence of cough occurred when 7 μg/kg of fentanyl was administered through a central venous catheter by Bohrer et al. (2), whereas the same incidence is reported by Lui et al. (11) with 5 μg/kg when it was administered through a peripheral vein.

The mechanisms of fentanyl-induced cough are not well understood, but various theories have been proposed. Fentanyl inhibits central sympathetic outflow causing vagal predominance and inducing cough and reflex bronchoconstriction (1,11,12). Terbutaline and salbutamol (selective β-2-adrenergic bronchodilator) inhalation and effective suppression of cough response from 43% to 3% support the concept of bronchoconstriction (11). The rapid response of the reflex and morphine’s efficacy in preventing cough suggests that a pulmonary chemoreflex is also the likely mechanism that is mediated by either irritant-receptors (rapidly adapting receptors) or by vagal C fibers receptors that are in proximity to pulmonary vessels (juxta-capillary receptors), whereas suppression of cough with inhaled betamethasone supports the trigger stimulus and bronchial hyperirritability theory (1,4,11). Histamine release from mast cells in the lungs (though this seems unlikely because fentanyl rarely causes histamine release), constriction of the tracheal smooth muscles, and the possible stimulation of irritant receptors after deformation of the tracheobronchial wall triggering the cough are other plausible explanations (1,2,13).

IV administration of lidocaine suppressed both the mechanical- and chemical-induced airway reflexes, including the cough reflex (5,6,8–10). The dose of lidocaine required for effective suppression of cough ranged between 1.5 and 2.0 mg/kg, and the duration of cough suppression was five to eight minutes in previous reports (5,9,10). The effect of IV lidocaine on cough suppression was increased in a dose-dependent manner and correlated well with plasma levels of lidocaine. Administration of 2 mg/kg IV of lidocaine one to five minutes before intubation suppressed the cough reflex significantly in a group of patients receiving nitrous oxide-halothane and oxygen anesthesia whose ages ranged between 15 and 55 years and who were not receiving a muscle relaxant (10). A plasma concentration of IV lidocaine after 2 mg/kg may be large enough to be associated with possible systemic toxicity (10). Thus, we opted for 1.5 mg/kg IV of lidocaine, which seems to be optimal to keep the plasma concentration of lidocaine in excess of 2.3 μg/mL—the concentration required to suppress the cough reflex for approximately eight minutes (9), during which time the anesthetic induction and endotracheal intubation is usually accomplished.

Our study has demonstrated that IV-administered lidocaine had a significant effect in decreasing the incidence of fentanyl-induced coughing, but it had no effect on cough severity. Of 33 patients who had cough in the lidocaine group, 69.69%, 21.21%, and 9.09% of patients had mild, moderate, and severe cough, respectively, which is similar to the placebo group in which of 86 patients, 69.76% had mild, 24.41% had moderate, and 5.81% had severe cough (Table 2).

In conclusion, our result has demonstrated that IV lidocaine 1.5 mg/kg, when administered one minute before fentanyl, is an effective and clinically feasible method for suppressing fentanyl-induced cough without possible systemic lidocaine toxicity and without affecting the severity of the cough.

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