The Effect of Acupuncture on Postoperative Nausea and Vomiting After Pediatric Tonsillectomy: A Meta-Analysis and Systematic Review

The Laryngoscope VC 2016 The American Laryngological, Rhinological and Otological Society, Inc. Systematic Review The Effect of Acupuncture on Postoperative Nausea and Vomiting After Pediatric Tonsillectomy: A Meta-Analysis and Systematic Review Hwang Cheol Shin, MD; Jong Seung Kim, MD; Sang Kyi Lee, MD, PhD; Sam Hyun Kwon, MD, PhD; Min Su Kim, MD; Eun Jung Lee, MD, PhD; Yong Joo Yoon, MD, PhD Objectives/Hypothesis: Tonsillectomy is one of the most frequently performed pediatric surgical procedures worldwide. The complications of this procedure include postoperative nausea and vomiting (PONV) and pain; therefore, both the treatment and prevention of PONV are important. Classical antiemetics include drug therapies such as ondansetron, which are undesirable because they often carry a high cost and several side effects. Therefore, in this study we aimed to evaluate the antiemetic effect of acupuncture after pediatric tonsillectomy. Methods: We searched for eligible articles that reported on the antiemetic effects of acupuncture after tonsillectomy using the three databases, MEDLINE, Embase, and Cochrane, through July 2015. We included full-length original articles with adequate data for evaluating the antiemetic effects on pediatric tonsillectomy in the form of a relative ratio. The Newcastle- Ottawa scale was used to assess the quality of case control and cohort studies, and the Cochrane risk of bias tool was employed for randomized controlled trials (RCTs). Results: The search identified 415 publications. After screening, we selected eight articles for review (4 RCTs, 3 prospective cohorts, and 1 pilot study). A meta-analysis of acupuncture in pediatric tonsillectomy revealed that the number of patients with PONV was significantly reduced with acupuncture compared to the control group, with a risk ratio of 0.77 (95% confidence interval: 0.63 0.94, P < 0.05). Conclusion: When acupuncture at PC6 (neiguan) was used to prevent PONV after pediatric tonsillectomy, the risk ratio was significantly lower compared to that of conventional drug therapy. Although further randomized controlled trials are needed, acupuncture at PC6 is considered an economic and effective treatment for emesis after pediatric tonsillectomy. Key Words: Postoperative nausea and vomiting, acupuncture, tonsillectomy. Laryngoscope, 126:1761 1767, 2016 INTRODUCTION Tonsillectomy is one of the most frequently performed pediatric surgical procedures in the world. Common complications include nausea, vomiting, pain, and bleeding. Postoperative nausea and vomiting (PONV) have adverse effects, including bleeding, aspiration pneumonia, electrolyte imbalance, and psychological From the Department of Anesthesiology and Pain Medicine (H.C.S., S.K.L.); the Department of Otolaryngology Head and Neck Surgery (J.S.K., S.H.K, Y.J.Y, E.J.L.), College of Medicine, Chonbuk National University; the Research Institute of Clinical Medicine of Chonbuk National University Biomedical Research Institute of Chonbuk National University Hospital (J.S.K., Y.J.Y. S.H.K., E.J.L.), Jeonju; and the Department of Otorhinolaryngology Head and Neck Surgery, Seoul National University College of Medicine and Seoul National University Hospital (M.S.K.), Seoul, Republic of Korea. Editor s Note: This Manuscript was accepted for publication December 27, 2015. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Jong Seung Kim, MD, Department of Otolaryngology Head and Neck Surgery, College of Medicine, Chonbuk National University, 20, Geonji-ro, Deokjin-Gu, Jeonju-si, Chonbuk, 561-712, Republic of Korea. E-mail address: kjsjdk@gmail.com DOI: 10.1002/lary.25883 stress. 1,2 Postoperative nausea and vomiting often result in extended hospital stays, unexpected admissions, and high medical costs. 3 Parents whose children experience both pain and vomiting after surgery often report PONV to be the most bothersome symptom, which indicates that PONV causes more discomfort and stress than pain for some patients. 4 Proper management can reduce the incidence of PONV and pain. Classical treatments include ondansetron, palonosetron, midazolam, dimenhydrate, and metoclopramide. Although 5-hydroxytryptamine type 3-antagonists such as ondansetron are effective for preventing PONV, they can cause adverse effects such as headache, constipation, abdominal cramps, transient elevations of plasma aminotransferase and bilirubin levels, and anaphylactic reactions. 1,5 9 For centuries, acupuncture has been used to improve pain and quality of life, and it has the added benefit of having a low cost. 10 Acupuncture at PC6 (neiguan) has also been used to prevent nausea and vomiting. 11 In this study, our purpose was to evaluate the efficacy of acupuncture to prevent PONV in children after tonsillectomy using a systematic review and meta-analysis. 1761

MATERIALS AND METHODS Search Strategy Institutional review board approval and patient consent were not required due to the nature of this study. The metaanalysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. 12 Two authors independently searched for eligible articles using the MEDLINE, EMBASE, and Cochrane databases for all studies published up to July 2015. The following search formula was used for MEDLINE: (( tonsillectomy [MeSH Terms] OR tonsillectomy [All Fields]) AND ( vomiting [MeSH Terms] OR vomiting [All Fields]) AND ( acupuncture [MeSH Terms] OR acupuncture [All Fields] OR acupuncture therapy [MeSH Terms] OR ( acupuncture [All Fields] AND therapy [All Fields]) OR acupuncture therapy [All Fields])) OR (( tonsillectomy [MeSH Terms] OR tonsillectomy [All Fields]) AND ( child [MeSH Terms] OR child [All Fields]) AND ( acupuncture [MeSH Terms] OR acupuncture [All Fields] OR acupuncture therapy [MeSH Terms] OR ( acupuncture [All Fields] AND therapy [All Fields]) OR acupuncture therapy [All Fields])). We used similar search words for the other databases. Selection Criteria Eligible studies met the following inclusion criteria: 1) fulllength original article providing adequate data for evaluating the antiemetic effects of acupuncture on pediatric tonsillectomy in the form of a relative ratio and 2) prospective or retrospective trial or randomized controlled trial. Studies were excluded if 1) the patient group contained adults; 2) the study had no control group; 3) the article described fewer than 10 cases because as we regarded these articles as being case series rather than trials or cohort studies; 4) the article was in a language other than English; or 5) the study had no relation to tonsillectomy. Group Selection All of the acupuncture groups met the following criterion: the acupuncture was unilaterally or bilaterally performed at the point of PC6, which is located at the wrist between the tendons of the palmaris longus and the flexor carpi radialis, 2 cm proximal from the distal palmar crease. Statistical Analysis The ratio of PONV in the experimental group was obtained by dividing the number of PONV cases by the total number of patients in the study. The proportion of PONV cases in the control group was calculated using the same method. The effect size was represented by the risk ratio, which was compared between the acupuncture group and the control group. The standard error of the proportion was then calculated for each clinical outcome measure. Hedge s g and standard error were determined for each treatment outcome measure. The 95% confidence interval (CI) was then computed for each type of therapy. Cochrane Review Manager (RevMan 5.3; The Cochrane Collaboration, Oxford, England) and R 3.1.2 software were also utilized to analyze and graphically display the meta-analysis data. We calculated the relative risk with the 95% CI for the treatment outcome. Heterogeneity between studies was assessed using the I 2 statistic, and P < 0.10 and I 2 > 50% indicated evidence of heterogeneity. A potential publication bias was investigated using a funnel plot. If a publication bias was suspected, Duval s trim-and-fill method was used to correct for the bias using R 3.1.2. 13,14 1762 RESULTS Study Search The combined electronic and manual search initially resulted in 415 potentially eligible publications. The initial screening process of the title and abstracts for relevance excluded 383 studies because as they did not meet our inclusion criteria. Duplicate records of 12 articles were also excluded. The remaining 20 articles that qualified for full-text reading were systematically reviewed. After reviewing the full text, 12 publications were excluded because they failed to meet our eligibility criteria. Thus, eight articles were finally included in our qualitative analysis (Table I). 15 22 A flow diagram of the study selection progress and the main reasons for exclusion are shown in Figure 1. All eligible studies were published between 1990 and 2014, and the enrolled articles were of moderate to high quality. We used the type of treatment to divide all participants into two groups: an acupuncture group and a control group. The control group contained either no treatment with antiemetic group or a classical antiemetic treatment group. When the control group was the classical antiemetic drug treatment group, the acupuncture group was treated with acupuncture and a classical antiemetic drug. Data on treatment outcomes were dichotomized into two categories: PONV and no such symptoms. Meta-Analysis of All Studies Eight studies were included and analyzed using meta-analysis (Table I). A random effect model metaanalysis of the eight studies involving 800 patients yielded a pooled relative risk of PONV of 0.77 (95% CI: 0.63 0.94, P 5 0.010) (Fig. 2A) with small to modest heterogeneity (I 2 5 43%, P < 0.10). We found that acupuncture reduced the risk of PONV by about 23% compared to the control group. The pooled risk difference was calculated to be 0.17 (Fig. 2B). The number needed to treat to prevent PONV was 5.88 (95% CI: 3.57 16.67, P < 0.01). Evaluation of Publication Bias In a funnel plot of acupuncture treatments, the studies were distributed almost to the center and top of the funnel plot, which suggests minimal publication bias (Fig. 3A). Duval s trim-and-fill method estimated the presence of one potentially unreported cohort. After this one potentially unpublished cohort was filled, the pooled risk ratio improved to 0.79 (95% CI: 0.69 0.90, P 5 0.0004) (Fig. 3B). Subgroup Analysis We performed a subgroup analysis using modality and methodology. In the modality subgroup, we divided patients into two groups: the acupuncture and electrostimulation groups. The risk ratio of the electrostimulation group was 0.59, which was lower than the acupuncture group risk of 0.87 (Fig. 4A).

TABLE I. Summary of Acupuncture Characteristics. Study Age (years) Acupuncture Group Control Group Events Total Events Total Stimulation Modality Methodology Quality Score Other Drugs Used to Reduce PONV Kabalak 4 12 1 30 11 30 Electrostimulation RCT Unclear risk Ondansetron group 2005 15 20 Hz, 5 min 0.15 mg/kg Liodden 1 11 36 77 51 77 Acupuncture RCT Low risk All pts : 4 mg dexa iv 2011 16 Postinduction, tens of minutes, wristband 24 hr Liodden 1 11 61 138 69 144 Acupuncture RCT Low risk All pts: dexamethasone 2015 17 Postinduction, intravenously (0.25 mg/kg) 15 20 min Norheim 2 8 5 10 10 10 Electrostimulation Pilot study 6* No antiemetic drug 2010 18 Postinduction, 20 min Rusy 2002 19 4 18 25 40 37 40 Electrostimulation Postinduction, after Randomized prospective study tonsillectomy 4 Hz, 20 min Shenkman 2 12 28 47 31 53 Acupressure and 1999 20 Acupuncture Pre and post induction, tens of minutes Randomized prospective study 8* Sham P2: chonchon ondansetron (0.15 mg/kg up to 4 mg x1), 7* Midazolam 0.5 1.0 mg/kg Acetaminophen 10 20 mg/kg Codeine 0.5 1.0 mg/kg No antiemetic drug Tsao 2015 21 3 12 5 30 7 29 Electrostimulation RCT Low risk All pts: propofol 2 4 mg/kg 4100 Hz hydromorphone 3 mcg/kg dexamethasone 0.5 mg/kg Yentis 2 11 8 22 9 23 Acupuncture Randomized 1991 22 Postinduction, prospective study tens of minutes 6* Thiopental 5 mg/kg Atropine 0.02 mg/kg Codeine 1.5 mg/kg *Newcastle-Ottawa scale. Cochrane risk of bias tool. Pts 5 patients. In the methodology subgroup, we divided the subgroups into randomized controlled trial (RCT) and prospective study groups. The risk ratio of the RCT group was 0.74, which was lower than that of the prospective study group (0.83) (Fig. 4B). Sensitivity Analysis A sensitivity analysis to evaluate the stability of the results was performed by removing each study one by one. The pooled risk ratio in the overall comparison and the stratified analyses were not significantly changed, indicating a stable and robust outcome (Fig. 4C). DISCUSSION Postoperative nausea and vomiting after tonsillectomy is a complication that, along with postoperative pain, can significantly compromise the patient s quality of life. Many studies have shown that drugs such as ondansetron, palonosetron, metoclopramide, dexamethasone, and midazolam can reduce PONV. 23 27 However, the exact mechanism of action of midazolam and dexamethasone is unknown. The mechanisms of serotonin receptor antagonists on PONV are both central and peripheral. Serotonin receptor antagonists bind competitively and selectively to serotonin receptors in the central nervous system, and they also block receptors in the digestive tract. 25 Although the potency of these drugs differ, these drug therapies have a limited effect on PONV and also have adverse effects, such as headache, sedation, and extrapyramidal reactions. 4,28,29 Acupuncture is an alternative therapy for the prevention of PONV. The studies we reviewed included acupuncture, acupressure, and electrostimulation. Acupuncture and acupressure have existed for thousands of years in Oriental medicine. The effectiveness of acupuncture and acupressure is similar, and these methods can also reduce the intraoperative anesthetic requirement and perioperative demand for drugs. 30 Acupressure involves the use of firm pressure to massage an acupoint. In acupuncture, a needle such as a Seirin needle (Seirin Corporation, Shizuoka, Japan) is inserted into the acupoint. Electrostimulation applies electric 1763

Fig. 1. Flow chart of the study literature search (n 5 number of studies). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.] stimulation to acupoints and is a widely used method in anesthesiology and rehabilitative medicine. The target of acupuncture is the P6 or PC6 between the wrist and elbow, as previously described. The clinical effects of acupuncture on PC6 are digestive effects, including mitigation of nausea and vomiting. 30 32 Increased use of acupuncture has reduced the need for opioids in the ear, nose, and throat field. 33 35 The aim of the current study was to determine the effect of acupuncture on PONV after pediatric tonsillectomy. Four RCTs and three cohort studies were included in the final meta-analysis according to the inclusion criteria. The relative ratio presented in our study was 0.77 (95% CI: 0.63 0.94, P < 0.05), which indicates that acupuncture therapy reduced PONV by about 23% after pediatric tonsillectomy. The subgroup analysis revealed that RCTs carried a lower risk ratio than the prospective study (Fig. 4B). Another subgroup analysis indicated that the electrostimulation group had a significantly lower risk ratio than the acupuncture group. Although the electrostimulation group included the outlier study of Kabalak et al., 15 the sensitivity analysis indicated that the risk ratio was robust (0.787) when the Kabalak study was omitted. A common method for handling an outlier study is to remove it from the effect size distribution; however, the risk ratio calculated from this method (0.787) was no different than the presented risk ratio (0.77). The first reason that Kabalak et al. 15 was an outlier study was that those researchers used electrostimulation (20 Hz, 5 minutes); this method had a greater effect on reducing PONV than other studies. In contrast, Norheim et al. 18 and Rusy 19 et al. used the electrostimulation method for a 1764 duration of 20 minutes with both an unclear and a 4 Hz frequency of electrostimulation, which may have created a large enough difference to make Kabalak et al. 15 an outlier. The third explanation for this outlier result is related to the correct localization of the acupuncture point and to adequate administration of the stimulus. Kabalak et al. 15 suggested that an optimal frequency of 10 to 20 Hz produced the maximal benefit and emphasized that a duration greater than 5 minutes had no effect. Moreover, these authors reported that correct localization of the acupuncture point and adequate administration of the stimulus are vital for antiemetic effectiveness. They used cunometers (a special measuring device commonly employed in traditional Chinese medicine) and a single generating feature of the electroacupuncture device to identify the correct acupoints. For these reasons, the outlier study of Kabalak et al. 15 needs to be included in our meta-analysis. The I 2 statistic results of P < 0.10 and I 2 < 50% indicated little evidence of heterogeneity, which led us to use the fixed effects method. To account for variation across studies, we also included the random-effects model in our meta-analysis, which estimates the mean size of effects that may differ across interventions, populations, or programs. 36 Publication bias, which was corrected by Duval s trim-and-fill method, 13 showed a very minimal study effect. In conclusion, the risk ratio calculated by the random effect model was robust and indicated that acupuncture reduced the risk of PONV by about 23% compared to the control group. Reports of side effects of acupuncture are rare. Possible adverse events in children are numbness at the acupuncture site, mild dizziness, and needle pain. 37 The

Fig. 2. Forest plot of the effect of acupuncture on postoperative nausea and vomiting. (A) The pooled risk ratio of 0.77 was calculated using the M-H method and random effects. (B) The pooled risk difference was calculated to be 0.17. The risk of bias in this randomized controlled study is also shown. CI 5 confidence interval; M-H 5 Mantel-Haenszel. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.] Fig. 3. Study funnel plot. (A) In the funnel plot, the studies were spread almost from the top of the pyramid, with only one study in the left lower corner, suggesting a small study effect. (B) Duval s trim- and-fill method estimated the presence of one potentially unreported cohort. After this one cohort was filled, the pooled RR improved to 0.79 (95% CI: 0.69 0.90, P 5 0.0004). CI 5 confidence interval; RR 5 risk ratio. 1765

Fig. 4. (A) Subgroup analysis by modality. The risk ratio of the electrostimulation group was 0.59, which was lower than the acupuncture group risk of 0.87. (B) Subgroup analysis by methodology. The risk ratio of the randomized controlled trials group (0.74) was lower than that of the prospective study group (0.83). (C) Sensitivity analysis. The pooled risk ratio in the overall comparison and the stratified analyses were not significantly changed, indicating a stable and robust outcome. CI 5 confidence interval; RR 5 risk ratio. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.] 1766

use of acupuncture did not increase the operation time for any patient. Typical application of acupuncture or electrostimulation was initiated after induction of anesthesia. The Kabalak 15 method had the shortest duration of electrostimulation, whereas the others in the electrostimulation group continued for 20 minutes. The durations of the acupuncture group varied depending on the length of the surgery. All studies stopped the acupuncture before the end of surgery. Therefore, acupuncture resulted in no added time for pediatric tonsillectomy. CONCLUSION One limitation of the current meta-analysis is that there were no conclusive results according to sex or age due to the absence of uniform information in the included studies. Further studies that include these data will help to address these limitations and enable moderator analysis or multiple meta-regression analysis. Another limitation of the present analysis was that it included non-rct studies with low-quality scores. A meta-analysis including only RCTs would have been more powerful but was not possible in the present study due to the limited number of published RCT studies. Although this study included a small number of RCT studies, meta-analyses using observational studies have recently become more widely accepted. 38 In spite of these limitations, we believe that our study the first meta-analysis to examine the effects of acupuncture on PONV after pediatric tonsillectomy provides the foundation and motivation for future studies. Acupuncture is an effective alternative therapy for the prevention of PONV. Well-designed future clinical studies should overcome the present limitations and provide additional clinical support for our results. Acknowledgment This article was supported by a fund of the Biomedical Research Institute at Chonbuk National University Hospital, Jeonju, Republic of Korea. BIBLIOGRAPHY 1. Watcha MF, White PF. Postoperative nausea and vomiting. 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