Zárate, Eduardo MD*,; Mingus, Melinda MD†,; White, Paul F. PhD, MD*,; Chiu, Jen W. MD*,; Scuderi, Phillip MD‡,; Loskota, William MD§,; Daneshgari, Venus MD*
Laparoscopic cholecystectomy is associated with a frequent risk of postoperative nausea and vomiting (PONV). The incidence of PONV in this patient population varies from 46% to 68%(1,2). Many different pharmacologic approaches have been investigated with varying degrees of success in an attempt to minimize PONV. However, concerns regarding the side effects associated with traditional antiemetics (3–5) and the large cost of the newer drugs (6–8) have increased interest in the use of nonpharmacologic techniques [e.g., acupuncture (9), electroacupuncture (10), transcutaneous electrical nerve stimulation (TENS) (10,11), acupoint stimulation (12), and acupressure (13)].
Transcutaneous acupoint electrical stimulation (TAES) at the Nei-Guan P6 acupoint may be a useful alternative to antiemetic drugs (14). It is effective in the treatment of both motion sickness and pregnancy-induced nausea and vomiting (15), as well as emesis associated with chemotherapy (16). Unfortunately, the results of published studies regarding the effectiveness of TAES for the prevention of PONV are inconclusive because of inadequate blinding of the patients, investigators, or both (17); insufficient time of stimulation (10,18); or poorly defined outcome measures (11).
Therefore, we designed a multicenter, randomized, double-blinded, placebo- and sham-controlled study to test the hypothesis that TAES at the P6 acupoint is effective in reducing PONV in patients undergoing laparoscopic cholecystectomy procedures.
Two-hundred-fifty healthy adults scheduled for laparoscopic cholecystectomy procedures were enrolled in this study after we obtained IRB approval and written informed consent at four university medical centers. Outpatients who had been fasted overnight were randomly assigned to one of three treatment groups (Groups T, S, and P) with a computer-generated random number table. The TAES group (Group T) had active electrical stimulation applied at the P6 acupoint. The Sham group (Group S) had an inactive device positioned at the P6 acupoint, with similar pressure applied at the P6 site as Group T. In the Placebo group (Group P), an inactivated device was positioned at the dorsal aspect of the wrist directly opposite from the P6 acupoint.
Patients who had taken an antiemetic, glucocorticosteroids, or psychoactive medication within 24 h before the operation; were pregnant; had an implanted cardiac pacemaker or defibrillator device; or had experienced vomiting or retching within 24 h before surgery were excluded. Patient demographic information and any history of PONV or motion sickness were recorded. Before surgery, a baseline visual analog scale for nausea was obtained by using a 7-point Functional Living Index—Emesis (FLIE) scale (19) (1 = none to 7 = maximum [worst imaginable]).
The ReliefBand® (Woodside Biomedical, Inc, Carlsbad, CA) is a noninvasive, portable (34 g), battery-powered (two 3V lithium coin cells), watchlike acustimulation device (Fig. 1). The skin contact surface has two metal electrodes through which TAES is applied. After a hypoallergic conductive gel is applied to the skin surface, the acustimulation unit is attached around the wrist with an adjustable Velcro strap. For the purpose of this study, the device was set to deliver a 25 mA (setting 1) stimulus at 31 Hz. The cost of the 48-h disposable ReliefBand device is approximately US$30, whereas the reusable model costs $125.
At each of the four participating centers, one individual was trained in the proper positioning of the ReliefBand device. The IV catheter was inserted in the nondominant arm to avoid interfering with the acustimulation device, which was applied to the dominant arm. An inactive ReliefBand was applied before surgery to familiarize the patients with the position of the device on their lower arm after surgery. The P6 acupuncture point was located between the tendons of the flexor carpi radialis and palmaris longus muscles, one-sixth of the distance between the distal transverse wrist crease and the antecubital crease, along the course of the median nerve (15).
Midazolam 20–30 μg/kg IV was administered for premedication, and anesthesia was induced with fentanyl 1–3 μg/kg IV and propofol, 1.5–2.5 mg/kg IV. Maintenance of anesthesia consisted of isoflurane 0.6%–1.8% (inspired concentration) in combination with nitrous oxide 50%–70% in oxygen. Supplemental bolus doses of fentanyl 0.5 μg/kg IV were administered, if needed, to treat persistent tachycardia caused by inadequate intraoperative analgesia. An oral gastric tube was inserted after tracheal intubation and removed at the end of surgery. Residual neuromuscular blockade was antagonized with neostigmine 40–60 μg/kg IV and glycopyrrolate 6–12 μg/kg IV. No prophylactic antiemetic medication was administered during the perioperative period.
Approximately 5–10 min before the end of surgery (upon completion of electrocautery use), the acustimulation device was placed at the P6 acupoint (Groups T and S) or at the dorsal side of the wrist (Group P). The devices were carefully secured in the proper location on the wrist with tape. All patients wore the ReliefBand device continuously for 9 h after surgery. Although the ReliefBand devices used in all three groups were identical in appearance, the devices used in Groups S and P had been altered by the manufacturer such that only the devices used in Group T produced any electrical stimulation. To minimize bias resulting from the presence or absence of the electrical stimulation, all patients were told before the operation that the ReliefBand produces a sensation which “they might or might not feel.”
The durations of surgery and anesthesia, as well as the length of the recovery room and hospital stays, were recorded. Postoperative evaluations of nausea with the FLIE scale were performed upon admission to the postanesthesia care unit (PACU) and subsequently at 45 and 90 min and 2-, 4-, 6-, and 9-h intervals after surgery. All episodes of vomiting and retching, as well as needed-for-rescue antiemetic and analgesic medications, were also recorded during the 9-h observation period. Antiemetic drug usage was evaluated at four different postoperative time intervals: 0–2 h, 2–4 h, 4–6 h, and 6–9 h. The recovery room nursing staff were unaware of the acustimulation treatment group to which the patient had been assigned.
An emetic episode was defined as a vomiting or retching event, or a combination of these events, that occurred in a rapid sequence (<1 min between events). If episodes of retching or vomiting were separated by >1 min, they were considered separate episodes. In the PACU, droperidol 0.625 mg IV was administered as the initial rescue medication if the patient experienced repeated episodes of emesis or moderate to severe nausea (FLIE score ≥ 4) persisting for more than 15 min. If a rescue antiemetic drug was required, the patient was considered to be a treatment failure. If emesis or nausea persisted for more than 15 min after droperidol was given, ondansetron 4 mg IV was administered. Postoperative pain in the PACU was treated with fentanyl 25–50 μg IV or morphine 2–5 mg IV. After discharge from the PACU, pain was treated with either a combination of hydrocodone 5 mg and acetaminophen 500 mg PO, or ibuprofen 400–800 mg PO.
When patients were discharged from the hospital before completion of the study, they were allowed to take the device home and given a diary to record emetic events and FLIE nausea scores at the specified time intervals. Follow-up telephone calls were made at 9 h after admission to the PACU. If the follow-up call could not be made before 9 pm, patients were telephoned at 8 am the following morning to inquire about the FLIE nausea scores and number of episodes of vomiting or retching during the remainder of the 9-h study interval. Any antiemetic and analgesic medications taken during the time interval from discharge to completion of the study were also recorded in the diary.
Assuming a 60% PONV rate after laparoscopic cholecystectomy, a sample size of 100 patients in the TAES group and another 50 patients in each of the Sham and Placebo groups were determined by an a priori power analysis to provide 80% power for detecting a 20% reduction in the incidence of PONV. Repeated-measures analysis of variance with general linear models procedure in the Statistical Analysis System (SAS) software version 6.12 (SAS Institute, Inc., Gary, NC) was used to compare nausea FLIE scores, number of emetic episodes, antiemetic usage, and center-by-treatment interaction. Because time-by-time comparisons are statistically invalid because of repeated measures, a longitudinal analysis based on logistic regression of the repeated measurements of moderate to severe nausea with the method of generalized estimating equations was adopted. Each of the observations for a given patient was treated as a binomial repeated measure (with a score of 1–3 = none or mild nausea, and 4–7 = moderate to severe nausea). The standard link function (logit) and exchangeable correlation matrix were used to linearize the variables to be estimated. The χ2 test was used to compare sex differences, the proportion of patients with nausea, the proportion of patients having one or more emetic episodes, and the percentage of patients receiving at least one dose of rescue antiemetic medication in each time period. In cases where expected frequencies were small, Fisher’s exact test was used. Unless otherwise indicated, data are presented as mean ± sd, and a value of P < 0.05 was considered significant.
Although 250 patients were enrolled in this multicenter study, 29 were excluded because of protocol violations. The three treatment groups were comparable demographically and with respect to their histories of PONV and motion sickness, baseline nausea score, duration of surgery, and the time the acustimulation device was applied before the end of surgery (Table 1). The times to discharge from the PACU and the hospital were also similar in the three treatment groups. No significant differences were found among the groups with respect to intraoperative and postoperative opioid analgesic doses (data not reported).
The incidence and severity of PONV and requirements for rescue antiemetics are summarized in Table 2. The average nausea FLIE scores across the study time intervals for Group T were significantly lower than Group S (P < 0.01) and Group P (P < 0.05) values (Fig. 2). The prevalence of moderate to severe nausea at any given time interval was also statistically lower in Group T (5%–11%) versus Groups S and P (16%–38% [P < 0.05] and 15%–26% [P < 0.05], respectively) (Fig. 3). Group T also had a larger proportion of patients who were completely free from moderate to severe nausea (73% vs 41% and 49% for Groups S and P, respectively). There were no differences between Group S and Group P with respect to the incidence and severity of nausea, incidence of vomiting, and the need for rescue antiemetic medication.
The only side effect noted in this study was mild cutaneous irritation with erythema in two patients, which resolved spontaneously within 24 h after removing the ReliefBand.
The antiemetic effectiveness of electrical stimulation at the P6 acupuncture point when used in adults at high risk for PONV is controversial. However, in a recent systematic review, Lee and Done (20) concluded that acustimulation appears to prevent PONV in adults. Similarly, Vickers (21) concluded from an analysis of 21 controlled trials in adults that P6 acupuncture point stimulation decreased emetic symptoms. The problems with many of the studies that have evaluated the efficacy of acustimulation relate to inadequate power (i.e., small group sizes), failure to include placebo or sham control groups, the absence of a relevant comparator, or a combination of these.
Perhaps the clinical benefits of these nonpharmacologic therapeutic techniques are related in part to nonspecific psychological mechanisms (14). Therefore, failure to include inactive (sham) devices constitutes a major deficiency in many of the earlier studies. In some studies, patients in the control group either had the device turned off or unattached, thus compromising patient blinding (11,17). In the current study, we attempted to minimize bias by using identical acustimulation units, which were inactivated to produce a sham effect at the P6 acupoint (Group S) and a placebo effect at a nonacupoint (Group P). In addition, all patients were told that the ReliefBands produce a sensation which they “might or might not feel.”
A cross-over design was not used for this study because subjects could have become aware of the differences in the sensation produced by the electrical stimulation in the active treatment group. The failure to include a bilateral P6 acupoint stimulation group, as well as a second control group having an active band at a “dummy point” (nonacupoint site), may also be considered deficiencies in the study design. However, previous studies have demonstrated efficacy with unilateral stimulation (20,21), and application of an active device at the nonacupoint chosen for the Placebo group could have transmitted electrical impulses through the wrist to the P6 acupoint. Furthermore, applying an active device at a more remote nonacupoint site (i.e., the upper arm) would be difficult because of the design of the device (e.g., limited strap length), and it might not produce an equivalent electrical sensation. Of interest, in studies evaluating the postoperative opioid-sparing effects of TENS, nonacupoint stimulation was significantly less effective than acupoint stimulation (22).
This multicenter study demonstrated that TAES at the P6 acupoint significantly reduced the incidence and severity of nausea, but not vomiting or retching, after laparoscopic cholecystectomy. Because rescue antiemetic drug usage was similar among the three groups, the decrease in nausea in the TAES group cannot be attributed to these drugs and suggests that TAES may augment the clinical efficacy of commonly used antiemetic medications. The lack of a significant antiemetic effect with this acustimulation device may have been related to an inadequate sample size (because the prevalence of postoperative vomiting is much less than postoperative nausea), the failure to use the maximal intensity of electrical stimulation (23), and the limited time interval (six to seven minutes) that the electrical stimulation was applied before the end of surgery. Application of the device near the end of surgery while the patient was still under anesthesia may also account for the apparent lack of an antinausea effect in the initial postoperative period, because the timing of P6 acupoint stimulation has been alleged to be crucial in preventing PONV. Dundee and Ghaly (24) demonstrated that P6 stimulation must be administered preemptively before the emetic stimulus to be effective. Analogous to our current findings, Ho et al. (10) reported that postoperative application of TENS at the P6 acupoint failed to reduce the incidence of emesis in outpatients undergoing laparoscopic procedures. In future prophylaxis studies, TAES with the ReliefBand should be applied in a preemptive manner before the start of the surgical procedure because anesthetic drugs may mask the antiemetic effect of acupoint stimulation.
In previous studies involving the use of TENS for preventing PONV, it enhanced the effectiveness of prophylactic antiemetic drugs (18). Fassoulaki et al. (11) also conducted a prophylaxis study involving TENS applied at the P6 acupoint for a duration of six hours commencing 30–45 minutes before the induction of anesthesia in patients undergoing hysterectomy and found a significantly infrequent incidence of postoperative vomiting in the TENS group at all observation intervals. However, they did not evaluate the incidence and severity of nausea, nor the need for rescue antiemetic medications. In a metaanalysis of studies involving pediatric patients (20), nonpharmacologic therapies were unsuccessful in reducing the incidence of PONV. These findings were supported by a recently published acupressure-acupuncture study involving children undergoing tonsillectomy procedures (25).
Studies in adults have also demonstrated that acupressure may be effective in reducing PONV when administered prophylactically (13,20,26). In this study, it might be expected that the inactivated device placed at the P6 acupoint had the potential to reduce PONV because of the constant pressure applied at the wrist. However, the incidences and severity of nausea and vomiting, as well as antiemetic drug requirements, were similar in the Sham and Placebo groups. The most likely explanation for the failure of the ReliefBand to exert an acupressurelike effect relates to the fact that the area of the posterior surface of the ReliefBand is flat, with two narrow longitudinally shaped stimulating electrodes protruding only one millimeter from its surface, thereby minimizing the pressure effect at the P6 acupoint. This finding is also consistent with the results when sham wrist bands were used in the acupressure studies (13,26).
Another concern with the ReliefBand relates to the ease of displacement from the acupoint site, a factor that may have reduced its antiemetic activity. New acustimulation devices should be designed to be more compact, allow for more localized acupressure, and be compatible with the use of electrocautery during surgery. Future studies should be designed to evaluate the relative cost-effectiveness of acustimulation and prophylactic antiemetic therapies when they are administered separately or in combination (14). Given the inherent cost associated with the use of the disposable ReliefBand device (US$30), it should also be evaluated as a rescue therapy in patients developing PONV after receiving standard antiemetic prophylaxis or after removal of the patient’s IV catheter.
In conclusion, the application of TAES at the P6 acupoint at the end of surgery and for nine hours after surgery reduced the overall incidence and severity of postoperative nausea but not vomiting in outpatients undergoing laparoscopic cholecystectomy procedures. Because the commonly used antiemetic drugs have limited efficacy in preventing nausea (3), the use of combined pharmacologic (e.g., antiemetic) and nonpharmacologic (e.g., TAES) therapies may offer advantages over either modality alone in high-risk surgical populations.
The authors thank the residents and CRNAs, as well as the PACU and Day Surgery nurses at all of the participating institutions, for their cooperation during this study. The statistical assistance of Mr. Steve Lewis in analyzing these data was appreciated.
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