Postoperative sore throat is a common and annoying complication of endotracheal intubation.1 2 , 3 4
Nonpharmacological methods for preventing an intubation-related sore throat include using smaller-sized endotracheal tubes, lubricating the endotracheal tube with water-soluble jelly, careful airway instrumentation, intubation after full relaxation, gentle oropharyngeal suctioning, minimizing cuff pressure, and extubation in deeper planes of anesthesia and with a fully deflated tracheal tube cuff.5 6 7 8 4 9 4 10 2 11 12 13
Recently, Agarwal et al.14 15 16 17 18
METHODS
The study was approved by the local Ethics Committee of the Medical University of Vienna (Ref. 2010/332). According to the Declaration of Helsinki, the approval was published in the publicly accessible register of the Ethics Committee of the Medical University of Vienna (http://ethikkommission.meduniwien.ac.at/register ClinicalTrials.gov
After receiving informed written consent, at least a day before surgery, we enrolled 236 adult patients undergoing elective thoracic surgery requiring a double-lumen endotracheal tube. Patients were enrolled at the General Hospital of Vienna between October 2010 and May 2011. All patients were designated ASA physical status I to III and were aged 18 to 90 years; immediate postoperative extubation was planned in each case. The patients were told that the study involved 2 different sweet solutions for prevention of postextubation sore throat.
Exclusion criteria were tracheal pathology including tracheostomy, surgery within the previous month, upper respiratory tract infection, body mass index exceeding 40 kg/m2 , known or suspected allergy to licorice, use of nonsteroidal anti-inflammatory drug medication within 24 hours, chronic opioid use, preoperative pain ≥2 on an 11-point Likert scale (0 = no pain; 10 = worst pain), and known or suspected difficult airway.
Protocol
Patients were premedicated 2 hours before surgery with up to 7.5 mg oral midazolam, per routine. Patients were randomly assigned to 1 of 2 groups: (1) Extractum Liquiritiae Fluidum (licorice 0.5 g); or, (2) Sirupus Simplex (sugar 5 g), which is a solution with a similar degree of sweetness.
Randomization (1:1) to licorice or placebo was assigned by a Web-based system that was accessed just before treatment by an independent researcher who was not involved in data collection; no stratification was used.
Licorice or sugar (placebo) was diluted in 30 mL water and placed in small brown opaque bottles by an independent apothecary. The respective bottles were opened just before use; the investigator was blinded to the preparation used for gargling, and the patient was not told which solution was provided. Patients were asked to gargle at least 1 minute in sitting position, but without swallowing, under supervision and direct observation of a researcher who was not subsequently involved in data collection.
Five minutes after gargling, general anesthesia was induced with fentanyl approximately 3 µg/kg, propofol approximately 1.5 mg/kg, and rocuronium approximately 0.6 mg/kg. After complete neuromuscular block, which was confirmed by absence of palpable twitches in response to supramaximal train-of-four stimulation of the ulnar nerve at the wrist, direct laryngoscopy was performed with a Macintosh laryngoscope, and the trachea was intubated as gently as possible by experienced physicians. We used a 37-cm left-sided unlubricated double-lumen tube for women and a 39-cm left-sided unlubricated double-lumen tube for men. The double-lumen tubes we used did not have a hook; they were inserted with a stylet which was removed as soon as the tube passed the vocal cords. The endotracheal tube cuff was inflated with air to 20 mm Hg immediately after intubation with a standard syringe. Cuff pressure was measured immediately after inflation and again after patients were positioned laterally, and adjusted as necessary to maintain pressure at 20 mm Hg.
General anesthesia was maintained with sevoflurane, and patients’ lungs were ventilated with oxygen and air as deemed appropriate by the attending anesthesiologist. End-tidal PCO2 was maintained between 32 and 35 mm Hg to the extent clinically practical. Hypnotic depth was guided by the Bispectral Index (Covidien, Dublin, Ireland), targeted between 40 and 50.
Small amounts of opioid were given per clinical judgment. At the end of surgery, an intercostal plexus block, using up to 20 mL ropivacaine 0.1%, was performed by the thoracic surgeon who was otherwise not involved in this study. Paracetamol, 1000 mg, was given IV 10 minutes before end of surgery. Patients were tracheally extubated, while still anesthetized, after confirmation of adequate spontaneous breathing and 4 twitches in response to supramaximal train-of-four stimulation of the ulnar nerve at the wrist. Postoperative pain was treated using fractional piritramid (Dipidolor) 3 mg IV as required.
Measurements
Thirty minutes and 1.5 hours after arrival in the postanesthesia care unit (PACU), and 4 hours after extubation, sore throat using an 11-point Likert scale (0 = no pain; 10 = worst pain) was assessed. Thirty minutes after arrival in the PACU, pain with swallowing was assessed with the same 11-point Likert scale. Sore throat was defined as a visual analog scale score exceeding 0.
Postextubation coughing was assessed by clinical observation and questioning the patient immediately after extubation, 0.5 and 1.5 hours after arrival in the PACU and 4 hours after extubation. We used an established scoring system: (1) none; (2) mild (less than a common cold); (3) moderate (similar to a common cold); and (4) severe (more than a common cold).19
Patients were asked whether they experienced any side effects related to the use of the gargle solution, including allergic reactions, discomfort, and mucosal burning. All examinations in the PACU were performed by the same independent, blinded, and experienced nurses who were not present when the patient gargled and were not involved in anesthetic management. On the first postoperative morning, sore throat pain and coughing were assessed, again by an independent and blinded investigator by clinical observation and questioning the patient using the scoring systems mentioned above.
Statistical Analysis
The 2 randomized groups (licorice and sugar-water) were compared for balance on demographics and baseline characteristics using standard summary statistics and the standardized difference (STD), defined as the difference in means or proportions divided by the pooled standard deviation. We prespecified a criterion of >0.20 absolute STDs as an indication of imbalance. All analyses were conducted on the conservative intention-to-treat basis.
Primary Analysis
The primary aim of the study was to assess the effect of licorice gargle on the occurrence of sore throat at rest after intubation with double-lumen endotracheal tubes compared with sugar-water gargle after surgery through the first 4 postextubation hours (i.e., measured at 0.5 and 1.5 hours after arrival in the PACU and 4 hours after surgery). The overall treatment effect across the 3 measurements was our primary analysis, with use of the modified Mantel-Haenszel test adjusting for the within-patient correction.20
Secondary Analyses
We assessed the effect of licorice on the incidence of sore throat at rest assessed at postoperative day (POD) 1 morning, and the incidence of sore throat during swallowing assessed at 0.5 hours after arrival in the PACU using χ2 tests.
The overall mean difference in the sore throat pain between licorice and sugar-water groups across the 2 conditions (i.e., at rest and during swallowing) at 0.5 hours after arrival at the PACU and across 4 measurement times during the initial POD was evaluated by a linear mixed effects model with autoregressive covariance matrix.
The licorice and sugar-water groups were compared on the incidence of coughing over the 5 measurement times (i.e., immediately after extubation, 0.5 and 1.5 hours after arrival in the PACU, 4 hours after surgery, and on the first POD morning) with use of the modified Mantel-Haenszel test1
Sample Size Consideration
We expected the incidence of postoperative sore throat at 30 minutes, 1.5 hours, and 4 hours to be approximately 0.70, 0.70, and 0.55, respectively, in our control group, based on Agarwal et al.14 N = 236 was needed, adjusting for 2 interim analyses and a final analysis.
All results are reported with an interim-adjusted confidence interval (CI), estimated using the Z-statistic efficacy criterion of 2.284 (i.e., corresponding to an α of 0.0224). For each repeat measures outcome, the treatment effect at each specific time was reported for descriptive purposes, regardless of the significance of the corresponding treatment-by-time interaction, using χ2 test, student t test, or a multivariate GEE model, as appropriate. The corresponding CI was further adjusted for multiple comparisons by Bonferroni correction, using the Z-statistic criteria of 2.675, 2.770, and 2.842 for the outcomes with 3, 4, and 5 measurement times, respectively. All tests were 2-tailed. The significance level for each hypothesis was 0.05 for the main effect and 0.10 for the treatment-by-time interaction, if applicable.
Sample size calculations were based on work by Dahmen et al.21
RESULTS
Two hundred thirty-six patients (118 patients in each group) were included in this study. One patient, assigned to the sugar-water group, was withdrawn due to surgery schedule changes (emergency surgery) and was not included in the analysis (Fig. 1 ). In addition, 2 patients (1 patient in each group) did not have any outcome assessments, because they were still intubated at the assessment times. These 2 patients were included in the analysis using a conservative intention-to-treat basis; we assigned the observed worst and best outcomes to the patient in the licorice group and in the sugar-water group, respectively. Progression of the interim analyses toward efficacy and futility is shown in Figure 2 .
Figure 1: Trial diagram.
Figure 2: Plot of standardized effect size Z for 2 interim analyses (at N = 79 and N = 179) and the final analysis (at N = 235), which are shown by the solid line (+) with Z-statistics of 2.66, 3.48, and 4.25, respectively. The 3 regions from top to bottom correspond to efficacy, futility, and harm, respectively. At the second interim analysis, the study crossed the efficacy boundary. However, the study executive committee decided to continue the study to obtain a more precise estimate of the treatment effect and because there was little if any risk to participants.
The licorice and the sugar-water groups were well balanced (absolute value of STD ≤0.2) on demographics and baseline characteristics (Table 1 ). We thus did not adjust for any baseline variables when comparing the licorice gargle users and the sugar-water gargle users on the outcomes.
Table 1: Demographics and Baseline Characteristics (N = 235)
Primary Analysis
The observed incidences of postoperative sore throat at rest in the licorice and the sugar-water groups were 19% and 36% at 0.5 hours after arrival in the PACU, 10% and 35% at 1.5 hours after arrival, and 21% and 45% at 4 hours after surgery, respectively (Table 2 ).
Table 2: Primary Results—Treatment Effect of Preoperative Gargling with Licorice on Incidence of Sore Throat at Rest Through the First 4 Postextubation Hours
The estimated treatment effects (relative risk [RR]) of licorice versus sugar-water on reducing the incidence of sore throat at rest were 0.54 (95% CI, 0.30–0.99), 0.31 (0.14–0.68), and 0.48 (0.28–0.83), at 0.5 and 1.5 hours after arrival in the PACU and 4 hours after surgery, respectively (Table 2 ). Although the above estimated treatment effect varied from 0.31 to 0.54 (treatment-by-time interaction: P = 0.02), preoperative gargling with licorice significantly reduced the incidence of sore throat at all 3 measurement times. The overall RR of experiencing sore throat across the 3 measurements during the first 4 hours after surgery was estimated as 0.46 (95% CI, 0.29–0.72, licorice versus sugar-water; P < 0.001), as analyzed with repeated-measures analysis of variance.
Secondary Analyses
Preoperative gargling with licorice significantly reduced sore throat pain during the first initial POD (P < 0.001); the overall mean reduction in the pain score was estimated as 0.55 on a 0 to 10 scale (95% CI, 0.27–0.84; Table 3 ). The treatment effect of licorice on sore throat pain score was consistent between the 2 conditions (i.e., at rest and during swallowing) at 30 minutes after arrival at the PACU (treatment-by-condition interaction: P = 0.11) and across 4 measurement times during the initial POD (treatment-by-time interaction: P = 0.15).
Table 3: Secondary Results—Treatment Effects of Preoperative Gargling Licorice on Secondary Outcomes
Compared with sugar-water, preoperative gargling with licorice significantly reduced the incidence of sore throat during swallowing at 0.5 hours after arrival in the PACU (RR [95% CI]: 0.53 [0.32–0.88], P = 0.003); and the incidence of sore throat at rest on the first POD morning: 0.54 [0.33–0.87], P = 0.003.
Preoperative gargling with licorice significantly reduced the incidence of coughing across all 5 assessment times (i.e., immediately after extubation, 0.5 and 1.5 hours after arrival in PACU, 4 hours after surgery, and on the first POD morning) as compared with sugar-water (P = 0.01, Table 3 ). The estimated overall RR during the first initial POD was 0.68 (95% CI, 0.48–0.96, licorice versus sugar-water, Table 3 ). No treatment-by-time interaction was observed for the incidence of coughing (P = 0.94).
Patients in the licorice group were 1.7 times (95% CI, 1.1–2.7) more likely to rate a lower (better) coughing score during the first POD as compared with patients in the sugar-water group (P < 0.001, Table 3 ). The effect of licorice on amount of coughing did not vary over the 5 measurements (treatment-by-time interaction: P = 0.91). Severe coughing was only reported by 2 patients, 1 in each group, on the first POD morning. No side effects related to the use of licorice, including allergic reactions, discomfort, or mucosal burning were observed.
DISCUSSION
Postextubation coughing and sore throat are minor but common postoperative complaints. In general, our patients reported only mild sore throat which is in distinct contrast to previous reports.7 , 22–24 7 , 22–24 22 , 24 , 25 13 , 26 27 27–29
Our primary result is that preoperative gargling with licorice significantly reduces the incidence of early postoperative sore throat compared with gargling sugar solution in patients intubated with double-lumen tubes. The overall treatment effect was a factor-of-2 reduction in sore throats: RR 0.46 (95% CI, 0.29–0.77; P < 0.001). Furthermore, benefit was sustained during coughing and over time. That such a simple, inexpensive, and low-risk prophylactic intervention so effectively prevents a common and annoying complication of intubation is remarkable, and seems well worth implementing into routine clinical practice.
Small studies reporting large treatment effects are often subsequently proven wrong or have substantially overestimated actual benefit.30 14
While preoperative gargling with licorice might seem unlikely to reduce the risk of postoperative sore throat, we note that others have demonstrated benefit with ketamine,31 , 32 8 13 , 33 34 35 36 10
Unlike many airway studies that evaluated patients having minor procedures, most of our patients had thoracotomies, which are among the most painful operations. Furthermore, our patients were given opioids which simultaneously diminishes the intensity of all pain, including sore throat pain. It is thus unsurprising that they rated sore throat pain as being of modest intensity. But even pain of modest intensity contributes to overall patient discomfort and deserves consideration.
The sweetness of each gargling solutions used in this study was considered subjectively equal by an independent pharmacist. Nevertheless, based on its distinctive taste, patients could potentially tell which was licorice. However, patients were told that 2 different solutions for prevention of postextubation sore throat were used, but were not told what flavors were being tested. It is thus unlikely that their knowledge of being given licorice would provide any substantial placebo effect over the control sugar gargle. Furthermore, all outcomes were evaluated by independent and blinded investigators.
In summary, licorice gargling halved the incidence of sore throat over the first POD. Preinduction gargling with licorice appears to be a simple way to prevent a frequent and unpleasant postoperative complication.
DISCLOSURES
Name: Kurt Ruetzler, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Kurt Ruetzler has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Michael Fleck, MD.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Attestation: Michael Fleck has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Sabine Nabecker.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Sabine Nabecker has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Kristina Pinter.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Kristina Pinter has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Gordian Landskron.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Gordian Landskron has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Andrea Lassnigg, MD.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Attestation: Andrea Lassnigg has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Jing You, MS.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Jing You has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Daniel I. Sessler, MD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Daniel I. Sessler has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Peter S. A. Glass, MB, ChB.
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