Chewing gum for the treatment of postoperative nausea and vomiting: a pilot randomized controlled trial

British Journal of Anaesthesia, 118 (1): 83 9 (2017) doi: 10.1093/bja/aew375 Clinical Practice Chewing gum for the treatment of postoperative nausea and vomiting: a pilot randomized controlled trial J. N. Darvall 1,2,3, *, M. Handscombe 1 and K. Leslie 1,3,4,5 1 Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, Victoria, Australia, 2 Royal Melbourne Hospital Clinical School, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia, 3 Anaesthesia, Perioperative and Pain Medicine Unit, University of Melbourne, Melbourne, Victoria, Australia, 4 Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, Victoria, Australia and 5 Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia *Corresponding author. E-mail: jai.darvall@mh.org.au Abstract Background. A novel treatment, chewing gum, may be non-inferior to in inhibiting postoperative nausea and vomiting (PONV) in female patients after laparoscopic or breast surgery. In this pilot study, we tested the feasibility of a large randomized controlled trial. Methods. We randomized 94 female patients undergoing laparoscopic or breast surgery to 4 mg i.v. or chewing gum if PONV was experienced in the postanaesthesia care unit (PACU). The primary outcome was full resolution of PONV, with non-inferiority defined as a difference between groups of <15% in a per protocol analysis. Secondary outcomes were PACU stay duration, anti-emetic use, and acceptability of anti-emetic treatment. The feasibility of implementing the protocol in a larger trial was assessed. Results. Postoperative nausea and vomiting in the PACU occurred in 13 (28%) patients and 15 (31%) chewing gum patients (P¼0.75). Three chewing gum patients could not chew gum when they developed PONV. On a per protocol basis, full resolution of PONV occurred in five of 13 (39%) vs nine of 12 (75%) chewing gum patients [risk difference 37% (6.3 67%), P¼0.07]. There was no difference in secondary outcomes between groups. Recruitment was satisfactory, the protocol was acceptable to anaesthetists and nurses, and data collection was complete. Conclusions. In this pilot trial, chewing gum was not inferior to for treatment of PONV after general anaesthesia for laparoscopic or breast surgery in female patients. Our findings demonstrate the feasibility of a larger, multicentred randomized controlled trial to investigate this novel therapy. Clinical trial registration. Australian New Zealand Clinical Trials Registry: ACTRN12615001327572. Key words: chewing gum; ; postanaesthesia nursing; postoperative nausea and vomiting Postoperative nausea and vomiting (PONV) affects one-third of untreated patients after general anaesthesia. 1 2 It is a leading cause of admission after planned ambulatory surgery and may lead to dehydration, bleeding, surgical wound complications, and Editorial decision October 7, 2016; Accepted: October 7, 2016 VC The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com 83

84 Darvall et al. Editor s key points Chewing gum may be as effective as in inhibiting postoperative nausea and vomiting (PONV). Either 4 mg or chewing gum was randomly provided to female patients who had PONV after laparoscopic or breast surgery, to test the feasibility of a large randomized controlled trial. A large randomized controlled trial would be feasible, because recruitment was satisfactory, the protocol was acceptable to anaesthetists and nurses, and data collection was complete. aspiration of gastric contents. 3 4 Well-established guidelines for the pharmacological prophylaxis and treatment of PONV exist; however, medications such as the 5-hydroxytryptamine type 3 (5- HT) receptor antagonists are only partly effective and have sideeffects. 5 More recently, interest has emerged in nonpharmacological therapies, such as P6 stimulation with acupuncture modalities 6 and ginger, 7 which have advantages including low cost, favourable side-effect profile, and patient acceptability. Chewing gum has been prospectively evaluated as a therapy to reduce postoperative paralytic ileus after gastrointestinal surgery. Postulated mechanisms of its effect surround the principle of sham feeding, with chewing resulting in increased gastrointestinal activity via cephalic vagal stimulation. 8 Recent metaanalyses (the largest involving 272 patients across seven randomized controlled trials) have demonstrated a reduced time to first flatus and bowel motion, and a non-significant trend towards earlier hospital discharge. 9 11 To date, however, no study has examined the effect of gum chewing on PONV. We previously conducted a prospective cohort study to assess the safety and acceptability of chewing gum in the postanaesthesia care unit (PACU), enrolling 41 patients undergoing ambulatory gynaecological laparoscopy. 12 Thirty-one patients (76%) were awake enough to chew gum. Chewing gum was acceptable to patients and PACU nurses, with no identified safety concerns. Chewing gum has also been linked to lowered cortisol concentrations, improved stress and anxiety, and more positive 13 14 mood in the research setting. We therefore conducted a pilot randomized controlled noninferiority trial to test the hypothesis that chewing gum in the PACU would prove to be non-inferior to for the treatment of PONV in female patients after laparoscopic or breast surgery and to test the feasibility of a large multicentre randomized controlled trial using this protocol. The primary outcome was full resolution of PONV after either or chewing gum. Secondary outcomes were the duration of PACU stay, anti-emetic use in the PACU, and patient acceptability of anti-emetic treatment. Feasibility outcomes were recruitment rate, protocol compliance, incidence of PONV, ability to chew gum, and the primary outcome. Methods This pilot randomized controlled non-inferiority trial was conducted in the Department of Anaesthesia and Pain Management, Royal Melbourne Hospital. Approval was gained from the hospital Human Research and Ethics Committee (21 December 2015, HREC number 2015.230), and the trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615001327572; 3 December 2015). Female patients aged 18 yr and of ASA physical status I III undergoing laparoscopic or breast surgery were enrolled between January and June 2016, after being advised that the principal purpose of the study was to assess the feasibility of a larger randomized controlled trial and after written informed consent had been obtained. Patients were excluded if they had inadequate English comprehension, significant cardiorespiratory impairment, impaired pharyngeal or oesophageal function, phenylketonuria (contraindication to the sweetener aspartame in chewing gum), a full upper or lower denture (not feasible to chew gum), or a contraindication to any of the protocolized anti-emetic drugs. Patients were randomized to either chewing gum or after written informed consent had been obtained and before surgery. The randomization schedule was created via a computerized random number generator, with sequentially numbered envelopes used for allocation concealment until PONV developed in the PACU. Patients, anaesthetists, PACU nurses, and observers therefore were blind to group allocation until PONV developed in the PACU. Procedure Induction of general anaesthesia was accomplished with either fentanyl or alfentanil, propofol, and a non-depolarizing neuromuscular blocker if indicated. Midazolam premedication was permitted at the discretion of the attending anaesthetist. Anaesthesia was maintained with sevoflurane without nitrous oxide. Patient monitoring was established in accordance with the standards published by the Australian and New Zealand College of Anaesthetists. At the conclusion of anaesthesia, antagonism of neuromuscular block was accomplished with neostigmine and glycopyrrolate, or if the train of four count was zero with sugammadex 200 mg. Non-opioid analgesics and additional fentanyl or morphine were given at the discretion of the attending anaesthetist. Anti-emetic prophylaxis Intraoperative anti-emetic prophylaxis was protocolized according to simplified Apfel risk factors, commensurate with the Consensus Guidelines for the Management of Postoperative Nausea and Vomiting published by the Society for Ambulatory Anesthesia. 5 Risk factors were female gender, non-smoking status, past history of PONV or motion sickness, or anticipated requirement for postoperative opioids (defined as estimated requirement of at least 20 mg oral oxycodone equivalent in the first 24 h after surgery, consistent with the initial validation trials of the Apfel scoring system). 15 Patients with one risk factor ( low risk ) received no prophylaxis; patients with two or three risk factors ( medium risk ) received dexamethasone 4 mg i.v.; and patients with four risk factors ( high risk ) received dexamethasone 4 mg i.v. and 0.625 mg. Treatment of postoperative nausea and vomiting Patients randomized to chewing gum and experiencing PONV in the PACU, with an Observer s Assessment of Alertness/Sedation (OAA/S) rating scale of 5 16 ( responding readily to name spoken in normal tone ) and with the PACU nurse satisfied that the patient was not sleeping between observations, commenced gum chewing (Wrigley s Extra Sugarfree Gum VR, peppermint flavour), aiming for a period of 15 min. Patients randomized to, or those randomized to chewing gum who either refused it or were too drowsy, received 4 mg i.v. in the event of PONV. The feasibility of chewing gum was recorded (able; unable because of refusal; unable because of drowsiness). Rescue

Chewing gum and PONV 85 anti-emetics if the first-line therapy was not fully successful consisted of the following: first line, 4 mg i.v. (if not already administered); second line, 0.625 mg i.v.; third line, promethazine 6.25 mg i.v.; fourth line, dexamethasone 4 mg i.v.; fifth line, prochlorperazine 12.5 mg i.v.; and sixth line, propofol 20 mg i.v. bolus. Observers recorded the number of episodes of nausea, retching, and vomiting and the time when each one occurred. Relief of PONV was graded on a four-point verbal descriptive scale: worse, no change, partial resolution, or full resolution. At readiness for discharge from the PACU, patients graded their acceptability of both anti-emetic treatment and anaesthetic care using a five-point Likert scale ranging from completely unacceptable to completely acceptable. Antiemetic and analgesic requirements for the first 24 h after surgery were recorded. Sample size calculation The primary outcome was full resolution of PONV after the randomized treatment. The target sample size for a definitive non-inferiority randomized controlled trial was computed. A non-inferiority trial using a hypothesized difference for equivalence of 15% (i.e. effective treatment of PONV in 60 75% of chewing gum-treated patients considered equivalent to treatment) at a power of 80% and a¼0.05 would require 204 patients, 102 in each group. This clinically relevant margin for equivalence was chosen as, if achieved, it was considered likely to result in acceptance and potentially practice change by anaesthetists. In our previous cohort study, 12 85% of patients achieved an OAA/S score of 5 and were thus deemed sufficiently awake to chew gum, and 40% of patients experienced PONV despite appropriate prophylaxis. On the assumption that 40% of randomized patients would experience PONV, of whom 85% would be sufficiently awake to chew gum, a total of 600 patients would be required, 300 in each group. To guide a future large randomized controlled trial, we conducted an initial pilot trial on a targeted convenience sample of 100 patients. The feasibility objectives for this pilot trial were as follows: (i) to refine and test the trial protocol for a large multicentre study; (ii) to assess acceptability of the trial protocol to our patients and anaesthetic and nursing staff, because a high recruitment and participation rate will be required for a viable definitive study; (iii) to confirm the high rates of PONV despite prophylaxis seen in our previous study, to inform sample size estimates for a definitive trial; (iv) to assess the proportion of patients meeting criteria for chewing gum in the PACU, to guide the external validity of this trial; and (v) to assess the event rates using the protocol developed. Feasibility outcomes were recruitment rate, protocol compliance, incidence of PONV, ability to chew gum, and the primary outcome. Statistical analysis Continuous data were tested for normality. Normally distributed data were summarized using the mean (SD) and compared using Student s unpaired two-tailed t-tests. Skewed data were summarized using the median (interquartile range) and Enrolment Assessed for eligibility (n=155) Excluded (n=53) Patient declined (n=25) Anaesthetist declined (n=7) Direct to theatre from radiology (n=6) Other reasons (n=15) Consented (n=102) Excluded (n=8) Anaesthetist declined (n=5) Other reasons (n=3) Randomized (n=94) Allocated to chewing gum (n=48) Received allocated intervention (n=12) Did not receive allocated intervention (n=36) No PONV (n=33) Too sleepy to chew (n=2) Refused gum (n=1) Allocation Allocated to (n=46) Received allocated intervention (n=13) Did not receive allocated intervention (n=33) No PONV (n=33) Lost to follow-up (n=0) Discontinued intervention (n=0) Follow-up Lost to follow-up (n=0) Discontinued intervention (n=0) Analysed for primary outcome (n=12) Excluded from analysis (n=0) Analysis Analysed for primary outcome (n=13) Excluded from analysis (n=0) Fig 1 CONSORT diagram. PONV, postoperative nausea and vomiting.

86 Darvall et al. compared using ranksum tests. Categorical data were summarized using the number (%) and compared using the v 2 test or Fisher s exact test where applicable. Survival data were summarized using the median (interquartile range) and compared using log-rank tests. Statistical analyses were performed using Stata 14.1 (Stata Corporation, College Station, TX, USA). A value of P <0.05 was considered statistically significant. Table 1 Baseline characteristics of patients. Values are expressed as the mean (SD), median (interquartile range), or n (%). PONV, postoperative nausea and vomiting; postoperative opioid requirement is defined as at least 20 mg oral oxycodone equivalent requirement in first 24 h after surgery Variable Control group (n¼46) Chewing gum group (n¼48) Age (yr) 46 (14) 46 (16) BMI (kg m 2 ) 29 (24 36) 25 (22 30) ASA physical status I 15 (33) 19 (40) II 29 (63) 24 (50) III 2 (4) 5 (10) Non-smoker 41 (89) 41 (85) PONV/motion sickness 21 (46) 29 (60) Postoperative opioid 2 (4) 3 (6) Apfel score 1 2 (4) 2 (4) 2 25 (54) 19 (40) 3 18 (39) 27 (56) 4 1 (2) 0 (0) Type of surgery Laparoscopic 21 (46) 27 (56) Breast surgery 25 (54) 21 (44) Table 2 Intraoperative characteristics (intention to treat). Values are expressed as the mean (SD), median (interquartile range), or n (%) Variable Ondansetron group (n¼46) Chewing gum group (n¼48) P-value Midazolam 13 (28) 12 (25) 0.72 Dose (mg) 2.0 (0.6) 1.8 (0.2) 0.47 Morphine equivalents 13 (10 20) 13 (7 17) 0.83 (mg) Propofol (mg) 184 (40) 177 (40) 0.38 Neuromuscular block 23 (50) 28 (58) 0.42 Neostigmine 14 (30) 23 (48) 0.08 Sugammadex 9 (20) 5 (10) 0.21 Sevoflurane 2.0 (1.8 2.2) 2.0 (1.8 2.2) 0.50 (% end-tidal) I.V. fluid 45 (98) 47 (98) 0.98 Dose (litres) 0.6 (0.4 1.0) 0.7 (0.5 1.0) 0.43 Anti-emetic 44 (96) 47 (98) 0.53 Dexamethasone 44 (96) 47 (98) 0.53 Droperidol 1 (2) 0 (0) 0.49 Duration of anaesthesia (min) 57 (31 75) 62 (34 91) 0.39 We used a per protocol analysis for the primary outcome, because intention-to-treat analyses, with usually smaller differences in efficacy between treatments than per protocol analyses, make it easier to establish non-inferiority by rejecting the null hypothesis of no difference between treatments. 17 Risk differences with 90% confidence intervals (CIs) were calculated. 17 We also conducted intention-to-treat and per treatment analyses, because expert guidance suggests performing these analyses, with equivalence or non-inferiority established when both intention-to-treat and per protocol analyses agree. 17 Results A total of 155 patients were screened for inclusion in this pilot trial. After exclusions, 94 patients were enrolled and followed to the final analysis, 46 randomized to and 48 to chewing gum (Fig. 1) between 5 February 2016 and 23 June 2016. There were no protocol violations. The two groups were similar in terms of patient characteristics, PONV risk factors, and surgery and anaesthesia details (Tables 1 and 2). Table 3 Postoperative characteristics (intention to treat). Values are expressed as the mean (SD), median (interquartile range), or n (%). OAA/S, Observers Assessment of Alertness/Sedation Score; PACU, postanaesthesia care unit; PONV, postoperative nausea and vomiting Variable OndansetronChewing group gum group (n¼46) (n¼48) P-value Duration of PACU stay (min) 42 (30 63) 46.5 (34 68.5) 0.22 PACU opioid 25 (54) 28 (58) 0.70 Morphine equivalents (mg) 6.7 (5.0 9.3) 6.7 (4.0 8.9) 0.94 PACU nausea First event 12 (26) 15 (31) 0.58 Second event 2 (4) 4 (8) 0.43 Third event 1 (2) 0 (0) 0.30 PACU vomiting First event 3 (7) 3 (6) 0.96 Second event 1 (2) 3 (6) 0.33 Third event 0 (0) 1 (2) 0.33 PACU PONV 13 (28) 15 (31) 0.75 PACU PONV initial treatment Ondansetron 13 (100) 3 (20) Chewing gum 0 (0) 12 (80) <0.001 Full resolution after initial 5 (38) 9 (60) 0.26 treatment Time to full resolution (min) 7 (4 7) 10 (7 15) 0.08 PACU PONV subsequent treatment 4 (9) 7 (15) 0.52 Acceptability (PONV treatment) Neither acceptable nor 1 (8) 0 (0) unacceptable Mildly acceptable 3 (23) 7 (47) Completely acceptable 9 (69) 8 (53) 0.32 Ward treatment of PONV patients Anti-emetic 8 (62) 7 (47) 0.43 Opioid 9 (69) 12 (80) 0.43 Morphine equivalents (mg) 10 (7.7 12.7) 7.7 (5.0 40.5) 0.62

Chewing gum and PONV 87 Postoperative nausea and vomiting in the PACU occurred in 13 (28%) of the group patients and 15 (31%) of the chewing gum group patients (P¼0.75; Table 3 and Fig. 2). Three patients randomized to chewing gum did not proceed with gum chewing (two patients were too drowsy; one refused) and received instead. Therefore, 13 group patients and 12 chewing gum group patients were included in the per protocol analysis (the primary analysis), 13 group patients and 15 chewing gum group patients were included in the intention-to-treat analysis, and 16 group patients and 12 chewing gum group patients were included in the per treatment analysis (Fig. 3). The median (interquartile range) time for which the gum was chewed was 31.5 (17 36) min. Full resolution of PONV was seen in five of 13 (39%) group patients and nine of 12 (75%) chewing gum group patients [per protocol risk difference (90% CI): 37% (6.3 67%), P¼0.07; confirming non-inferiority]. Both intention-to-treat risk difference (90% CI) of 22% ( 8.9 to 52.0%), P¼0.22 and per treatment risk difference (90% CI) of 44% (15.7 71.8%), P¼0.02 confirmed non-inferiority (Fig. 3). There was no difference in the time to full resolution of PONV between groups (Table 3). Recurrence of PONV in the PACU after full resolution was seen in one -treated patient (39 min after initial full resolution, requiring ) and two chewing gumtreated patients (one patient 24 min after initial full resolution, resolving completely with further chewing gum requested by the patient, and one patient 34 min after full resolution, requiring ). Rescue PONV treatment, duration of PACU stay, and requirement for ward anti-emetic treatment did not differ between groups (Table 3). All sticks of chewing gum were retrieved from patients, with no safety concerns identified. No differences in acceptability of PONV treatment were found, with all patients finding chewing gum either completely or mildly acceptable. Discussion In this randomized controlled pilot trial, we demonstrated the feasibility of conducting a large randomized controlled trial. We showed that chewing gum was not inferior to in the treatment of PONV in the PACU in female patients after laparoscopic or breast surgery. The incidence of PONV, acceptability of chewing gum, and effect size for full resolution recorded in this study will be valuable in planning the definitive study. This is the first randomized controlled trial assessing this novel treatment for PONV. Strengths of our study include a high recruitment rate, complete protocol adherence, and complete data collection, including follow-up of anti-emetic and opioid requirements for 24 h after surgery. Our study has several limitations. This study was planned as a pilot rather than a definitive randomized controlled trial, using a sample based on convenience rather than a sample size calculation. We did not measure nausea severity, merely recorded it as present or absent. We therefore cannot report whether the severity of nausea was similar in the two groups. Twenty per cent of the chewing gum group patients were unable to chew gum because of either Ondansetron group PONV = 13 Chewing gum group PONV = 15 1 (2 too drowsy, 1 refused gum) 12 received gum 5 fully 7 partially 1 no change 3 partially 9 fully 3 partially 1 recurrent event (fully after ) 1 received further promethazine 2 recurrent PONV episodes (1 fully after 2nd gum) (1 fully after ) 1 received further Fig 2 Flowchart of patients with postoperative nausea and vomiting (PONV) in the postanaesthesia care unit (PACU).

88 Darvall et al. Intention-to-treat 21.5% (90% CI: 9 52%); P=0.22 Ondansetron = 13; success = 5 (38.5%) Chewing gum = 15; success = 9 (60.0%) Per protocol 36.5% (90% CI: 6 67%); P=0.07 Ondansetron = 13; success = 5 (38.5%) Chewing gum = 12; success = 9 (75.0%) Per treatment 44% (90% CI: 16 72%); P=0.02 Ondansetron = 16; success = 5 (31.3%) Chewing gum = 12; success = 9 (75.0%) 15 0 15 30 45 60 Risk difference (%) 75 Fig 3 Difference between percentage full resolution of postoperative nausea and vomiting (PONV) in chewing gum group vs group via intention-totreat, per protocol and as-treated analyses. CI, confidence interval. drowsiness or a preference to avoid it. The treatment is therefore not universally applicable to postoperative patients. Although chewing gum represented a potential PONV treatment for patients in this trial, whether it would be suitable for patients undergoing more major surgery, with higher opioid requirements and potentially longer emergence times, requires further research. We used a flavoured (peppermint) gum, which may have confounded the association between chewing and PONV treatment. Peppermint has been shown to have effects on gastric emptying, although literature is conflicting (evidence of both increasing and decreasing gastric motility). 18 19 Some evidence also exists for aromatherapy as a treatment for PONV, with blends including ginger found to be efficacious. 20 A recent Cochrane review, however, suggests no benefit from peppermint aromatherapy for PONV. 21 Finally, PONV beyond the PACU was not measured in our study, although anti-emetic requirements were used as a surrogate marker for its incidence. This pilot study has potentially important implications for practice, if the results are confirmed in a definitive trial. Chewing gum is a readily accessible therapy, of negligible cost and without storage considerations. It is also familiar to patients and can be self-administered. In contrast, the requirement for equipment and training in some non-pharmacological techniques (e.g. acupressure or transcutaneous electrical nerve stimulation) limits applicability for the majority of anaesthetists. Chewing gum has been acceptable to patients and PACU staff in two studies by this group at different sites, which lends support to the external validity of our findings. Our protocol was simple to implement and acceptable to anaesthetists and nurses, and would be generalizable to a multicentred study. The non-inferiority margin remains appropriate, but the sample size calculation for the main study might need to be modified in light of the lower than expected incidence of PONV (30% instead of 40%). Inclusion of a flavourless gum group may also bear consideration. Measurement of the severity of PONV using a previously validated ordinal instrument will improve cross-study comparability, as will tracking rates of PONV and efficacy of treatment beyond the PACU. A future trial design may also benefit from randomization of patients when experiencing PONV, making analysis of end points simpler. Conclusion In summary, chewing gum was not inferior to for the treatment of PONV in this pilot, randomized controlled trial of female patients undergoing general anaesthesia for laparoscopic or breast surgery. Our findings demonstrate the feasibility of a larger, multicentred randomized controlled trial to investigate this novel therapy. Authors contributions Study conception: J.N.D. Study design, study coordination data analysis, manuscript preparation: J.N.D., K.L. Patient recruitment: M.H. Data collection: J.N.D., M.H. Data analysis: J.N.D., K.L. Manuscript review: M.H. Declaration of interest None declared. Funding Australian and New Zealand College of Anaesthetists (project grant 16/040). References 1. Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004; 350: 2441 51 2. Gan TJ. Postoperative nausea and vomiting can it be eliminated? JAMA 2002; 287: 1233 6

Chewing gum and PONV 89 3. Meeks GR, Waller GA, Meydrech EF, Flautt FH Jr. Unscheduled hospital admission following ambulatory gynecologic surgery. Obstet Gynecol 1992; 80: 446 50 4. Apfel CC, Heidrich FM, Jukar-Rao S, et al. Evidence-based analysis of risk factors for postoperative nausea and vomiting. Br J Anaesth 2012; 109: 742 53 5. Gan TJ, Diemunsch P, Habib AS, et al. Consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg 2014; 118: 85 113 6. Frey UH, Scharmann P, Löhlein C, Peters J. P6 acustimulation effectively decreases postoperative nausea and vomiting in high-risk patients. Br J Anaesth 2009; 102: 620 5 7. Chaiyakunapruk N, Kitikannakorn N, Nathisuwan S, Leeprakobboon K, Leelasettagool C. The efficacy of ginger for the prevention of postoperative nausea and vomiting: a meta-analysis. Am J Obstet Gynecol 2006; 194: 95 9 8. Person B, Wexner SD. The management of postoperative ileus. Curr Prob Surg 2006; 43: 6 65 9. Fitzgerald JE, Ahmed I. Systematic review and meta-analysis of chewing-gum therapy in the reduction of postoperative paralytic ileus following gastrointestinal surgery. World J Surg 2009; 33: 2557 66 10. Chan MK, Law WL. Use of chewing gum in reducing postoperative ileus after elective colorectal resection: a systematic review. Dis Colon Rectum 2007; 50: 2149 57 11. de Castro SM, van den Esschert JW, van Heek NT, et al. A systematic review of the efficacy of gum chewing for the amelioration of postoperative ileus. Dig Surg 2008; 25: 39 45 12. Darvall JN, Simmons SW, Leslie K. Acceptability of chewing gum for postoperative nausea and vomiting prevention in high risk patients: a pilot study. Anaesth Intensive Care 2011; 39: 515 6 13. Scholey A, Haskell C, Robertson B, Kennedy D, Milne A, Wetherell M. Chewing gum alleviates negative mood and reduces cortisol during acute laboratory psychological stress. Physiol Behav 2009; 97: 304 12 14. Smith A. Effects of chewing gum on cognitive function, mood and physiology in stressed and non-stressed volunteers. Nutr Neurosci 2010; 13: 7 16 15. Apfel CC, L a ar a E, Koivuranta M, Greim CA, Roewer N. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from crossvalidations between two centers. Anesthesiology 1999; 91: 693 700 16. Chernik D, Gillings D, Laine H, et al. Validity and reliability of the Observer s Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol 1990; 10: 244 51 17. Walker E, Nowacki AS. Understanding equivalence and noninferiority testing. J Gen Intern Med 2011; 26: 192 6 18. Inamori M, Akiyama T, Akimoto K, et al. Early effects of peppermint oil on gastric emptying: a crossover study using a continuous real-time 13 C breath test (BreathID system). J Gastroenterol 2007; 42: 539 42 19. Hiki N, Kurosaka H, Tatsutomi Y, et al. Peppermint oil reduces gastric spasm during upper endoscopy: a randomized, double-blind, double-dummy controlled trial. Gastrointest Endosc 2003; 57: 475 82 20. Hunt R, Dienemann J, Norton HJ, et al. Aromatherapy as treatment for postoperative nausea. A randomized trial. Anesth Analg 2013; 117: 597 604 21. Hines S, Steels E, Chang A, Gibbons K. Aromatherapy for treatment of postoperative nausea and vomiting. Cochrane Database Syst Rev 2012; 4: CD007598 Handling editor: T. Asai