Preventive Effect of Preoperative Administration of Hange-Shashin-To on Postoperative Sore Throat: A Prospective,Double-Blind,Randomized Trial

Abstract

Objectives:

The present study aimed to determine the efficacy of Hange-Shashin-To (HST), a Kampo medicine, in treating postoperative sore throat and nausea.

Design:

This randomized, controlled, double-blind study was conducted among two groups of adult female patients who were scheduled to undergo benign laparoscopic surgery under general anesthesia. All patients in each group had a physical status of either 1 (normal, healthy patient) or 2 (patient with a mild systemic disease), according to the American Society of Anesthesiologists. Patients were randomly assigned to either the HST group or the placebo (control) group.

Intervention:

Before surgery, the HST group received HST (5.0 g) mixed with jelly, while the placebo group received only jelly. Patients and the evaluator were blinded to the treatment status.

Outcome measures:

At 0, 3, and 24 hours after anesthesia recovery, an investigator (also blinded to the treatment status) recorded incidence and severity using the Numeric Rating Scale for sore throat and nausea.

Results:

Incidence and severity of sore throat were significantly lower in the HST group than in the control group immediately and 3 hours after surgery (p<0.05). In contrast, incidence and severity of nausea did not differ significantly between the HST and control groups.

Conclusions:

HST administration before general anesthesia did not alleviate postoperative nausea, but effectively decreased the incidence and severity of postoperative sore throat in female patients undergoing laparoscopic surgery.

Introduction

Postoperative sore throat (POST) and nausea is common complaint among patients receiving general anesthesia following tracheal intubation,^1,2 likely due to the irritation and inflammation of the airway.^3,4 Several agents have been used to decrease both the incidence and severity of POST, with varying success rates,^5,6 but a definitive method for prevention has not yet been established. Postoperative nausea and vomiting (PONV) are also critical complications that can adversely influence patient recovery following general anesthesia.^7,8 These major complications after general anesthesia with tracheal intubation decrease the comfort level for patients during recovery.

Hange-Shashin-To (TJ-14) (HST) is a Japanese Kampo medicine that has been used as an empirical treatment for mouth inflammation pain, acute and chronic gastroenteric catarrh, fermentative diarrhea, and acute gastroenteritis.^9,10 Recent reports indicate that HST alleviates inflammatory pain by suppressing molecules such as prostaglandin E₂.¹¹ Based on this evidence, we hypothesized that preoperative administration of HST may alleviate POST or nausea after general anesthesia. We then performed a prospective randomized clinical trial to test this hypothesis.

The primary objective of the present study was to determine the efficacy of HST in reducing POST. The secondary objective was to evaluate its efficacy for nausea alleviation. To this end, a double-blinded, controlled trial was conducted to examine the effects of preoperative HST administration on POST or nausea.

Materials and Methods

This study was approved by the Institutional Review Board of the Daiichi Towakai Hospital. From January to September 2014, adult women with an American Society of Anesthesiologists physical status of either 1 (normal, healthy patient) or 2 (patient with a mild systemic disease), who were scheduled to undergo benign gynecological laparoscopic surgery under general anesthesia and who were expected to be hospitalized for at least 24 hours after surgery, were eligible for this study. Patients who were pregnant or those who used analgesics, anti-inflammatory drugs, or another Kampo formulation were excluded. A document explaining the purpose, procedure, and risks involved in the proposed study was given to each patient and written consent was obtained.

Eligibility was assessed for a total of 74 patients. Randomization was performed by the envelope method. Patients in the HST group were given two oral doses (2.5 g each) of HST (TJ-14; Tsumura Co, Tokyo, Japan) just before falling asleep the night before surgery and on the morning of the operation. Drug or placebo was mixed with jelly in the pharmaceutical department, ensuring that patients, anesthesiologists, and nurses were all blind to the HST administration status.

Premedication was not provided. Routine monitoring was performed, and included percutaneous oxygen saturation, noninvasive blood pressure, heart rate, electrocardiography, and end-tidal carbon dioxide measurements. Anesthesia was induced with propofol 1–2 mg/kg and remifentanil 0.3–0.5 μg/kg/min. Rocuronium 0.8–1.0 mg/kg was administered as a muscle relaxant. Tracheal intubation was performed by experienced anesthesiologists with more than 8 years of clinical experience, who were also blinded to the patient status for HST administration. Tracheal tube size was calculated using the “height per 20” formula to minimize tube size effects.¹² The cuff of the tracheal tube was sufficiently lubricated with medical jelly without local anesthetics. Anesthesia maintenance was performed using sevoflurane 1.5–2% and remifentanil 0.1–0.3 μg/kg/min. At the phase of sample out, 200 μg of fentanyl was administered as postoperative analgesia. At the end of the operation, remifentanil and sevoflurane administration was attenuated. A gastric tube was inserted before the beginning of surgery and removed at the end of anesthesia. The presence of the gastric tube was confirmed by X-ray. To reverse the neuromuscular blockade, sugammadex (2 mg/kg) was administered. The patient was extubated after confirming recovery of awareness.

Patients were monitored for POST and nausea for the first 24 hours after surgery, and the severity of sore throat or nausea was recorded at three timepoints immediately after anesthesia recovery: immediately, 3 hours, and 24 hours after anesthesia recovery. A blind investigator (nurse) recorded incidences and severity of sore throat and nausea was 11 points utilizing the Numeric Rating Scale (0 was no pain or nausea, and 10 was the worst imaginable).

Statistical analysis was performed utilizing JMP^® 11 (SAS Institute Inc., Cary, NC). Statistical tests included Mann–Whitney's U-test and Fisher's exact test. Data were expressed as mean±SD. The level of significance for both tests was set at p<0.05. In the preliminary study, the incidence of POST was 60% in the group that received no HST, but only 20% in the group treated with HST. In order to detect significant differences (p<0.05) at a power of 80%, a sample size of 64 (32 in each group) was deemed necessary. Therefore, we planned to recruit 35 patients for each group to account for the possibility of missing data.

Results

Figure 1 shows the CONSORT flowchart of recruited patients. Seventy-four patients were assessed as eligible, three patients refused to participate in the study, and the operation was canceled for one patient. Ultimately, 70 patients were enrolled in the study (HST group, 35 patients; control group, 35 patients). No patients were lost to follow-up throughout the entire evaluation, and all patients completed the study.

FIG. 1.

CONSORT flowchart for patient recruitment. HST, Hange-Shashin-To.

Table 1 shows the demographic data of patients in the HST and control groups. A comparison between groups revealed no significant difference in demographic variables such as height, weight, BMI, age, duration of operation, duration of anesthesia, or American Society of Anesthesiologists classification.

Table 1.

Patient Background (Hange-Shashin-To Group vs. Control Group)

	HST group, N=35	Control group, N=35	p
Age (years)	46.3±14.9	42.5±12.8	0.34
Weight (kg)	52.0±9.9	51.5±6.7	0.26
Height (cm)	155.7±5.9	157.2±6.5	0.91
BMI (kg/m²)	21.4±3.9	20.9±2.8	0.86
Duration of surgery (min)	116.1±70.4	122.5±65.6	0.46
Duration of anesthesia (min)	168.5±70.5	175.4±68.3	0.52
ASA classification 1/2	18/17	20/15	0.81

Data are presented as mean±SD or number of patients. Data were analyzed utilizing Mann–Whitney's U-test or Fisher's exact test.

ASA, American Society of Anesthesiologists; BMI, body mass index; HST, Hange-Shashin-To.

Comparison of POST between HST and control groups

Table 2 shows the incidence and severity of POST. Upon recovery from anesthesia, 10 patients in the HST group and 19 patients in the control group complained of POST. Three hours after anesthesia recovery, only 3 patients in the HST group complained of POST, while 10 did so in the control group. The incidence of POST was significantly higher in the control group than in the HST group soon after anesthesia recovery and 3 hours after recovery (p<0.05). According to the NRS, severity of POST was significantly less in the HST group than in the control group, both immediately and 3 hours after anesthesia recovery (p<0.05).

Table 2.

Comparison of Postoperative Sore Throat Between Hange-Shashin-To and Control Groups

	HST group, N=35	Control group, N=35	p
Number of patients with sore throat immediately after anesthesia recovery	10	19	0.03^*
Number of patients with sore throat 3 hrs after anesthesia recovery	3	11	0.03^*
Number of patients with sore throat 24 hrs after anesthesia recovery	2	3	1.00
NRS of sore throat immediately after anesthesia recovery	1.0±2.2	2.2±2.8	0.03^*
NRS of sore throat 3 hrs after anesthesia recovery	0.3±1.0	0.9±1.8	0.02^*
NRS of sore throat 24 hrs after anesthesia recovery	0.1±0.2	0.3±1.4	0.63

Data are presented as mean±SD or number of patients. Data were analyzed utilizing Mann–Whitney's U-test or Fisher's exact test, ^* p<0.05. NRS, Numeric Rating Scale.

Incidence and severity of POST diminished to under 10% of patients after 24 hours in both groups, and no difference in severity was noted between the 2 groups.

Comparison of postoperative nausea between HST and control groups

Table 3 shows the incidence and severity of postoperative nausea in the HST and control groups. During the follow-up period, neither incidence nor severity of nausea differed significantly between the two groups.

Table 3.

Comparison of Postoperative Nausea Between Hange-Shashin-To and Control Groups

	HST group, N=35	Control group, N=35	p
Number of patients with nausea immediately after anesthesia recovery	11	10	0.80
Number of patients with nausea 3 hrs after anesthesia recovery	6	7	1.00
Number of patients with nausea 24 hrs after anesthesia recovery	1	1	1.00
NRS of nausea immediately after anesthesia recovery	1.6±2.9	1.5±2.7	0.92
NRS of nausea 3 hrs after anesthesia recovery	0.4±1.0	0.3±0.7	0.92
NRS of nausea 24 hrs after anesthesia recovery	0.1±0.5	0.3±1.4	0.31

Data are presented as mean±SD or number of patients. Data were analyzed utilizing Mann–Whitney's U-test or Fisher's exact test.

During this clinical trial, there was no significant side effect related to HST such as edema, hepatic impairment, interstitial pneumonia, or hypokalemia.

Discussion

POST is a common side effect of general anesthesia. The likelihood of POST varies with the diameter and cuff pressure of the endotracheal tube used.¹² If intubation is essential, prophylactic drug administration may be helpful for POST alleviation. Local anesthetics and steroids have been used for this purpose. In a previous study, aspirin and benzydamine hydrochloride gargles significantly reduced the incidence and severity of POST.⁸ Other studies have evaluated steroids for this purpose, and demonstrated the utility of belcomethasone inhalation or intravenous dexamethasone for POST alleviation.^13
–15 These reports suggest that anti-inflammatory drugs may reduce POST.

HST is prepared from seven crude herbs, Pinelliac tuber, Scutellariae radix, Zingiberis rhizome, Ginseng radix, Glycyrrhizae radix, Zizuph fructus, and Coptidis rhizome.¹⁶ Pharmacologically, HST upregulates the neuropeptide calcitonin gene-related peptide (CGRP), which is essential for pain generation and conduction.^17,18 Another study revealed that HST suppressed increases in plasma neuropeptide Y-immunoreactive substances.¹⁹ Furthermore, HST reportedly suppresses plasma prostaglandin E₂, a key molecule involved in inflammatory pain.^11,20 This indicates that HST might be beneficial in inflammation-related pain.

In the present study, roughly 55% of women in the control group showed POST immediately after anesthesia recovery, while HST diminished this incidence to less than 30%. At 3 hours after anesthesia recovery, only 3 of 35 women complained of POST in the HST group. Furthermore, no side effect was seen after HST medication was admitted. These results suggest that HST is clinically effective against POST safely.

In contrast, the HST did not alleviate postoperative nausea. As HST regulates the upper and lower gastrointestinal tract, we anticipated an antiemetic effect of HST,^21,22 but this was not observed. One probable explanation for this is that postoperative nausea is induced by the central nervous system, in which the utility of antipsychotic drugs such as droperidol has been validated.^23,24 Another possibility is that a larger dose of HST is needed to induce an antiemetic effect. Previously, we reported the utility of Go-Rei-San in preventing PONV.²⁵ Future studies should compare the components and pharmacological activities of HST and Go-Rei-San.

This study has some limitations worth noting. First, we used a relatively low dose of HST (total dose of 5.0 g preoperatively), and thus a higher amount of HST may enhance the effect. Second, pharmacologically, administration of HST for a longer duration (e.g., 1 week) may enhance its effects. Third, we performed anesthesia maintenance with sevoflurane. Total intravenous anesthesia with propofol may provide different results. Finally, this study was performed at a single institute. A multicenter large-scale clinical study may be needed in the future.

For future direction, as analgesic and anti-inflammatory effect of HST for POST has been suggested, it is interesting to evaluate the effect of HST on postoperative pain of surgical site. Furthermore, as POST may be correlated with hoarseness, examination of HST effect on postoperative hoarseness is also needed in the next study.

Conclusions

Our results demonstrate that preventive administration of HST before general anesthesia can effectively reduce the occurrence of POST in female patients undergoing laparoscopic surgery.

Footnotes

Acknowledgments

Financial support for the study was provided by our institution and department.

Author Disclosure Statement

No competing financial interests exist.

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