A sore throat after tracheal intubation is one of the most common postoperative problems causing dissatisfaction to patients.1 In fact, it ranked sixth among the 10 most undesirable adverse effects related to general anesthesia.2 Its incidence varies from 30% to 70%.1 Irritation and inflammation of the airway caused by pressure exerted on the tracheal wall by the endotracheal tube (ETT),3 trauma during intubation, and mucosal dehydration4 are thought to be the mechanistic basis for a postoperative sore throat (POST).
Both nonpharmacological and pharmacological measures have been attempted to alleviate the incidence and severity of POST with variable success.5,6 Prophylactic use of lidocaine and steroids has been used independently for this purpose.1,7,8 Dexamethasone as an adjuvant to lidocaine has been shown to improve the quality of analgesia.9,10 We, therefore, hypothesized that the combination of dexamethasone and lidocaine might reduce POST more effectively than either drug alone. The primary objective of this study was to compare the effect of a dexamethasone or lidocaine with placebo on the incidence of POST in patients requiring endotracheal intubation (>90 minutes) for general anesthesia. The secondary objective was to compare the incidence and severity of POST hoarseness and cough among the 4 groups (dexamethasone, lidocaine, dexamethasone/lidocaine combination, and placebo).
After approval from the institutional ethical review board (Ref No. Acd.631/069/070), this prospective 2-by-2 factorial design (Table 1), randomized, double-blind study was registered at www.clinicaltrial.gov (NCT01990781). The trial was registered by principal investigator (A.S.) on November 2013. The study was conducted from December 2013 to January 2016 at BP Koirala Institute of Health Sciences. We have enclosed the protocol as Supplemental Digital Content 1, Study Protocol, http://links.lww.com/AA/C598. This manuscript adheres to the applicable Consolidated Standards Of Reporting Trials (CONSORT) guidelines. After obtaining written informed consent, 180 patients of American Society of Anesthesiologists physical status 1 and 2, 18–60 years of age, requiring general anesthesia with endotracheal intubation were enrolled. Those with a preexisting cough, hoarseness or a sore throat, smoker, vocal performer by occupation, recent or recurrent respiratory tract infection, risk factors for postoperative aspiration, obesity, pregnancy, on pain medications, corticosteroids and calcium channel blockers, and contraindication to corticosteroid medications were excluded. Anticipated difficult intubation, Mallampati grade >2, difficult mask ventilation requiring oral or nasal airway, Cormack and Lehane grade III and IV on laryngoscopy, intubation attempt >1, and those requiring orogastric or nasogastric tubes were other exclusion criteria.
During a preanesthetic visit at the inpatient unit the night before surgery, patients were made familiar with the questionnaire to be used for POST. The randomization list was generated using computer sequence number, and patient allocation ratio was 1:1. Written allocation group was sealed in individual opaque envelopes marked externally only with study identification numbers. An anesthetic assistant not participating in the study prepared the drug solution after breaking the codes. Patients received 1 of the 4 assigned study medications intravenously (IV) before induction of anesthesia: group L, lidocaine (1.5 mg/kg) (Xylocard 2%; Astra Zeneca, Bangalore, India); group D, dexamethasone (8 mg) (Dexona; Zydus Cadila, Ahmedabad, India); group DL, lidocaine (1.5 mg/kg) with dexamethasone (8 mg); and group NS, equivalent volume of normal saline. The groups were later reclassified as 2 experimental groups (all dexamethasone, all lidocaine) and placebo for assessment of primary outcome with factorial design (Table 1).
All the patients were premedicated with oral diazepam 0.2 mg/kg at night and 2 hours before surgery. In the operating room, in addition to standard monitoring, neuromuscular blockade was assessed using the train of four. Patients received study drug according to the group allocation. Anesthesia was induced with IV fentanyl 2 µg/kg and propofol 2 mg/kg, followed by vecuronium 0.1 mg/kg. After achieving adequate neuromuscular blockade, an anesthesiologist (experience >5 years), unaware of the group allocation, performed laryngoscopy in all the groups using standard 3 or 4 Macintosh blades. Polyvinylchloride ETTs (Rüschelit; Rusch, Kernen, Germany) with a 7-mm ID for male and 6.5-mm ID for female were used for orotracheal intubation. No lubrication was applied on the ETT. The cuff was inflated with air to the point just capable of sealing leakage. The cuff pressure was checked and adjusted to 25–30 cmH2O with the help of pressure gauge.
A heat and moist exchanger unit was attached to the breathing circuit, and mechanical ventilation was initiated with O2 in the air (Fio2, 0.4) with isoflurane (1.5–2 vol %), keeping the end-tidal CO2 between 32 and 35 mm Hg. Supplemental doses of fentanyl and vecuronium were administered as required during anesthesia. Cuff pressure was checked every 10 minutes and maintained between 25 and 30 cmH2O. At the end of surgery, IV ondansetron 0.1 mg/kg was administered and the residual neuromuscular block was antagonized with IV neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg. Gentle suctioning of oral secretions was done with 12F soft suction catheter while limiting the suction pressure to 50 cmH2O before tracheal extubation. After tracheal extubation, patients were transferred to the postanesthetic care unit. A standardized protocol was implemented for postoperative pain management. At the end of surgery, IV ketorolac 30 mg was administered and repeated 8 hourly. If the numerical rating scale for pain was >3 at rest, IV bolus of morphine (2 mg) was administered and repeated at 5-minute intervals until the numerical rating scale score was ≤3.
The following variables at the time of tracheal intubation and extubation were recorded: Cormack and Lehane laryngoscopy score; resistance to ETT insertion (none/mild/moderate); the time to achieve intubation was defined as the time from opening of mouth for insertion of laryngoscope blade to confirmed placement of ETT (assessed with chest auscultation and capnograph); application of external laryngeal pressure to aid endotracheal intubation; duration of tracheal intubation defined as the time from placement of ETT to its removal; repositioning of ETT; blood tinge on the suction catheter during oral suctioning; blood stain on ET after its removal; and total opioid consumption in the postoperative period.
Our primary outcome was the incidence of POST, and the main effects of dexamethasone and lidocaine were the primary interest. The incidence of POST was also compared among the 4 groups (Table 1). Secondary outcomes included the severity of POST, incidences and severity of cough, and hoarseness. The investigator (A.S.) blinded to the group allocation assessed the incidence and severity of POST, cough, and hoarseness of voice at 1–2, 6, 12, and 24 hours after surgery. The patients rated their intensity of a sore throat, cough, and hoarseness of voice using the scoring system as described previously11: sore throat: 0 = no sore throat at any time since the operation, 1 = minimal sore throat, 2 = moderate sore throat, and 3, severe sore throat; cough: 0 = no cough at any time since the operation, 1 = minimal cough or scratchy throat, 2 = moderate cough, and 3 = severe cough; and hoarseness: 0 = no evidence of hoarseness at any time since the operation, 1 = no evidence of hoarseness at the time of the interview, 2 = hoarseness at the time of interview noted by the patient only, and 3 = hoarseness that is easily noted at the time of interview.
Our analysis was based on modified intention to treat principle (postrandomization exclusions of participants due to any deviation from the protocol). The distribution of the data was tested for normality using histograms and Shapiro–Wilk test. Comparison of continuous data among groups was performed with 1-way analysis of variance. For nonparametric data, Kruskal–Wallis test was applied. Categorical data were compared using the Pearson χ2 test or Fisher exact test, as appropriate. First the interaction effect between dexamethasone and lidocaine was tested. Then analysis of the primary outcome, that is, incidence of POST in the 2 interventional group (dexamethasone or lidocaine) compared to placebo, was performed using factorial design. It was performed “at the margins” of the table, that is, the efficacy of dexamethasone was determined by comparing the outcomes among all patients treated with dexamethasone (cells DL and D) with those not receiving dexamethasone (cells L and NS) (Table 1). Similarly, efficacy of lidocaine was evaluated by comparing cells DL and L with cells D and NS. Further, a logistic regression was conducted to determine the effect of various interventions on the incidence of POST when adjusted for risk factors (age, sex, blood-stained suction catheter, and duration of intubation) and reported as odds ratios (ORs) with 95% confidence intervals. Statistical analysis was performed using STATA version 13.0 (Stata Corporation, College Station, TX), and a P value of <.05 was considered statistically significant.
We followed the recommendation suggested by Montgomery et al12 for sample size calculation related to factorial trial powered to detect the main effects of each intervention with an assumption that there was no interaction. To achieve a power of 90% (with 2-sided type I error rate of 5% and applying Pearson χ2 test) to detect 25% reduction in incidence of POST in intervention dexamethasone (factor 1) or lidocaine (factor 2) from reported incidence of 56% in control group, the estimated sample size was 178 (89 allocated to Intervention D or L, 89 allocated to the relevant control). We enrolled 180 patients to account for drop outs (Table 1).
Among the 180 patients enrolled in the study, 4 patients were excluded from the analysis: 2 violated the protocol, 1 withdrew from the study, and 1 required reintubation (Figure). There were no missing data. Patient demographic data and surgery characteristics were comparable between the 4 groups (Table 2). The groups were comparable in terms of airway characteristics, duration of intubation, and postoperative total morphine consumption (Table 3).
Margin analysis (the primary comparison of main effect) showed that the magnitude of POST reduced significantly with dexamethasone (either dexamethasone alone or dexamethasone and lidocaine combination) regardless of lidocaine use (Table 4). However, lidocaine with or without dexamethasone did not reduce the incidence of POST (P = .11). We found no statistically significant interaction effect between dexamethasone and lidocaine (P = .38, Table 4). The overall incidence of POST among the groups showed that the proportion of patients with POST in group DL (11/44; 25%) was significantly less compared to group L (19/44; 44%), group D (16/45; 36%), and group NS (24/43; 56%) (P = .02). Univariable and multivariable logistic regression for the risk of POST observed among the groups and other independent variables (age, sex, duration of intubation, and blood stain in the suction catheter) are depicted in Table 5. Significant reduction in the incidence of POST was observed in both group DL and group D after adjustment for the risk factors.
There were no significant differences between the groups in POST severity at any time points during the study (Supplemental Digital Content 2, Table 1, http://links.lww.com/AA/C599). The incidence of postoperative cough observed in group DL, group D, group L, and group NS was 13%, 28%, 20%, and 32%, respectively (P = .15). The incidences of postoperative hoarseness were 15% in DL, 20% in D, 20% in L, and 22% in NS (P = .89). The number of patients with severity of postoperative cough and hoarseness at various time points between the groups was comparable (Supplemental Digital Content 2, Table 1, http://links.lww.com/AA/C599).
This trial demonstrated that the IV dexamethasone (8 mg) by itself or in combination with lidocaine 1.5 mg/kg markedly reduced the incidence of POST compared to placebo in patients intubated for >90 minutes. However, no significant reduction in frequency of POST was observed in patients receiving lidocaine. When adjusted for independent risk factors, dexamethasone and lidocaine combination and dexamethasone alone significantly protected against POST with the combination group having a greater protective effect. No difference was observed for the severity of POST at any time points. Likewise, the incidence of hoarseness and cough and their severity were comparable.
Several interventions have been attempted to reduce the incidence of POST, but none of them were able to eliminate it completely. Systemic dexamethasone is the most widely studied drug for POST. Two previous meta-analyses have proven that IV dexamethasone reduces the incidence of POST at 24 hours with reported risk ratios of 0.45 and 0.68.13,14 Lidocaine is another agent used extensively via various routes and concentrations to counter POST. A meta-analysis by Cochrane database of systematic reviews showed a significant reduction in overall risk of POST (risk ratio = 0.64) with lidocaine.1 However, a subgroup analysis including only high-quality studies related to systemic lidocaine therapy failed to attain statistically significant difference in preventing POST.
The beneficial role of combining dexamethasone and lidocaine has been reported for various perioperative outcomes such as longer duration of analgesia following nerve block, postoperative pain relief, and reduced pain on propofol injection.9,10,15,16 In a study by Cho et al,17 fewer patients in the IV dexamethasone and lidocaine combination group complained of POST as compared to dexamethasone group. However, the study differs in methodology from ours as IV lidocaine was repeated in the combination group at the end of surgery. In our study, patients were given a combination of dexamethasone and lidocaine only before induction of anesthesia and were less likely to develop POST in the first 24 hours after surgery. As postulated elsewhere, the adjunctive anti-inflammatory and analgesic effects of both dexamethasone and lidocaine probably helped to reduce POST incidence.18–21
We did not observe any difference in the severity of POST among the groups. Two separate meta-analyses have shown that dexamethasone13,14 alone and lidocaine1 alone alleviated the severity of POST. However, high heterogeneity was observed in both meta-analyses (Dexamethasone study, I2 = 91.7%; Lidocaine study, I2 = 83%), even though the effect was statistically significant. This was probably because of the different doses and routes of administration of the active agents, technical variation in the monitoring of cuff pressure, variation in the measurement of a sore throat, and duration of intubation. Authors have, therefore, suggested that results from these meta-analyses need to be interpreted cautiously. Moreover, in these meta-analyses, we did not find any comparative study of dexamethasone and lidocaine. The studies comparing the beneficial effect of steroid and lidocaine on POST have conflicting results, with some reported insignificant findings while others favored steroid over lidocaine.22–25 Therefore, further investigation, including large randomized control trials, is needed to assess the effect of systemic lidocaine and dexamethasone combination on the intensity of POST.
Several identified independent risk factors for POST include larger ETT size, age, female sex, prolonged intubation, and trauma during airway manipulation.26 As intubation lasting longer than 90 minutes had higher odds (OR = 1.27) of POST,27 we included only patients meeting this criterion. There is a strong evidence that female patients are at 1.5-fold risk for POST than men.27 One of the reasons for this difference is because of the reporting bias because woman are more likely to report such postoperative adverse effects.28 To avoid the confounding effect of sex, we also analyzed our data using a logistic regression model. Univariable analysis revealed that LD group had a marked reduction in the incidence of POST by 74% (OR = 0.26; P = .004). After adjusting for sex, age, presence of blood stain in the suction catheter, and duration of intubation, the occurrence of POST reduced significantly only in the dexamethasone and dexamethasone/lidocaine groups when compared to placebo. Moreover, the combination of dexamethasone and lidocaine had greater protective effect against POST when adjusted for risk factors (LD group: OR = 0.22, P = .002; D group: OR = 0.36, P = .03).
There are some limitations in our study. First, we used 8 mg of IV dexamethasone as the fixed dose. There is a wide variation in the doses of IV dexamethasone tested for POST, with some using fixed dose (4 mg, 8 mg), while others have used doses based on body weight (ranging from 0.1 to 0.2 mg/kg).13,14 Hence, high-quality dose-finding studies related to the effect of dexamethasone on POST are needed. Second, we did not encounter any potential adverse effects associated with the administration of dexamethasone because our study was not powered enough to detect the difference in major adverse events. Nevertheless, a meta-analysis on postoperative adverse outcomes found mild hyperglycemia with perioperative use of single dose of dexamethasone.29 However, its use was not associated with any risk of infection or delayed wound healing.
In conclusion, both dexamethasone alone and in combination with lidocaine reduced the incidence of POST in patients requiring tracheal intubation for general anesthesia. However, no difference was observed in patients receiving only lidocaine. When adjusted for independent risk factors, both dexamethasone and lidocaine combination and dexamethasone alone reduced the incidence of POST with the combination drugs showing more protective effect. No difference was detected in terms of severity of a sore throat, incidence and severity of hoarseness, and cough.
Name: Asish Subedi, MD.
Contribution: This author helped recruit the patient, collect the data, write the first draft of the paper, analyze and interpret the data, and revise the manuscript revision and final draft.
Name: Mukesh Tripathi, MD.
Contribution: This author helped design the study, analyze and interpret the data, revise the manuscript, and approve final manuscript.
Name: Krishna Pokharel, MD.
Contribution: This author helped analyze and interpret the data and revise the manuscript and final draft.
Name: Sindhu Khatiwada, MD.
Contribution: This author helped design the study, recruit the patient, and collect the data.
This manuscript was handled by: Angela Enright, MB, FRCPC.
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