The incidence of postoperative nausea and vomiting (PONV) is as high as 60% to 70% in patients undergoing major gynecologic surgery, and as high as 90% in patients receiving opioids through a patient-controlled analgesia (PCA) device.1–3 A variety of drugs are used to prevent or treat PONV.4,5 Nonpharmacologic techniques have also been used, such as electro-acupoint stimulation,6,7 acupressure,8 capsicum plaster,2 and 1-Hz single twitch (ST) stimulation9 at the Neiguan (P6) acupuncture point (acupoint), all with only minor adverse effects. The P6 acupoint lies between the tendons of the palmaris longus and the flexor carpi radialis muscles, 2 to 3 cm proximal to the distal wrist crease.10
It has been reported that electrical stimulation of a peripheral nerve at the P6 acupoint improves PONV while simultaneously measuring neuromuscular blockade.9 It has also been reported that the use of 1-Hz ST at the P6 acupoint decreased the incidence of PONV and achieved accurate monitoring of the neuromuscular blockade. However, the ST method of neuromuscular blockade monitoring is rarely used in clinical practice, because double-burst stimulation (DBS) and train-of-four (TOF) stimulation are more sensitive tools to assess residual neuromuscular blockade.11 There are few studies that examined the effects of a range of neuromuscular monitoring modes on PONV.
The aim of this study was to identify which neuromuscular monitoring modes (ST, TOF, DBS, or tetanus) at the P6 acupoint can prevent PONV after laparoscopic hysterectomy.
The protocol of this prospective, randomized, double-blind, placebo-controlled study was approved by the Hospital Ethics Committee (IRB) of Hanyang University Hospital, and written informed consent was obtained from all participants. Based on a preliminary study, 264 women (ASA physical status I–II) aged 31 to 67 years and scheduled for laparoscopic hysterectomy were randomly assigned to one of the following groups: control (n = 54), ST (n = 52), TOF (n = 53), DBS (n = 53), or tetanus (n = 52). Exclusion criteria included receiving antiemetic medications within 24 hours of surgery; obesity (weight >130% of ideal body weight); neuromuscular, hepatic, or renal diseases; or a history of allergic reactions to the medications used during anesthesia. Before the procedure, electrocardiographic monitoring, noninvasive arterial blood pressure monitoring, pulse oximetry, and a temperature probe were placed.
Without premedication, anesthesia was induced with 0.2 μg/kg/min remifentanil injected IV over 120 seconds, followed by sodium thiopental 3 to 5 mg/kg and rocuronium 0.6 mg/kg. Anesthesia was maintained with sevoflurane (1.0%–1.5%) and remifentanil at a dose of 0.05 μg/kg/min with nitrous oxide 50% in oxygen. Ventilation was controlled, and end-tidal PCO2 was maintained between 35 and 40 mm Hg. Rocuronium was given intraoperatively as required. A nasogastric tube was inserted orally in all patients after induction of anesthesia and the stomach was emptied. At the end of anesthesia, the residual neuromuscular block was antagonized with glycopyrrolate 0.4 mg and neostigmine 2.5 mg IV as necessary.
In the postanesthesia care unit, analgesia was begun with an initial dose of fentanyl 50 μg and ketorolac 30 mg IV in all patients. A PCA device (WalkMed PCA; McKinley Medical, Wheat Ridge, CO) was programmed to provide 1 mL/h as a basal infusion and a 1-mL bolus with a lockout interval of 15 minutes; the bolus contained fentanyl 12.5 μg/mL and ketorolac 1.8 mg/mL with saline (total volume 60 mL). Most patients felt comfortable with this regimen; however, if analgesia was judged to be inadequate by the patient or medical staff, the study was stopped and alternative analgesia was given.
In the control group, 2 surface electrodes (Cleartrode™, Ref. 1720-003; ConMed®, Utica, NY) were placed over the ulnar nerve on the dominant upper extremity before the anesthetic induction and removed after anesthesia at the operating room. The proximal positive electrode was placed approximately 3 cm proximal to the distal negative electrode, and each electrode was connected to a peripheral nerve stimulator (TOF-Watch®; Organon Ltd., Dublin, Ireland). An accelerometer was attached to the volar aspect of the thumb and connected to the stimulator. ST stimulation with 1 Hz (square-wave pulses of 0.2 millisecond) was applied throughout maintenance of anesthesia.9 The stimulating current was set at 50 mA, and the accelerometer functioned in the uncalibrated mode. The arm and hand were immobilized with tape, leaving only the thumb free. No special arm board was used, and no preload was applied to the thumb.
In the treatment groups (ST, TOF, DBS, or tetanus), the same electrodes described above were used to stimulate the median nerve at the P6 acupoint on the dominant upper extremity before the anesthetic induction and removed after anesthesia at the operating room. The proximal positive electrode was placed between the tendons of the palmaris longus and the flexor carpi radialis 1 cm proximal to the P6 acupoint. The distal negative electrode was placed 2 cm distal to the P6 acupoint. This distal electrode acts as a skin surface electrode to allow electrical current through the P6 acupoint.9 Each electrode was connected to a peripheral nerve stimulator with the same square-wave pulses (0.2 millisecond), constant current (50 mA), and uncalibrated mode as the control group. Throughout anesthesia maintenance, we automatically applied ST stimulation at 1 Hz in the ST group, TOF stimulation every 15 seconds in the TOF group, DBS every 20 seconds in the DBS group,12 and tetanic stimulation at 50 Hz for 5 seconds every 10 minutes in the tetanus group.13 Skin temperature over the adductor pollicis was kept above 32°C by wrapping the arm in cotton wool, and core temperature was kept above 35°C by applying forced air warming. Because most authors recommend the patient's dominant hand for P6 stimulation,7,9 we assessed handedness in the preanesthetic interview. The investigator who set up the neuromuscular monitoring was not involved with subsequent patient management or assessment. The patients, as well as the anesthesiologist and the nursing staff, were unaware of the patient grouping.
The risk for PONV was evaluated with a simplified Apfel score.14 This validated risk scoring system assigns 1 point for each of the following factors: (1) female gender, (2) nonsmoking status, (3) history of PONV or motion sickness, and (4) use of postoperative opioid analgesics.
Vomiting (including retching) and other symptoms were assessed at 6 hours and 24 hours, according to recommendations for PONV trials, by an independent observer who was unaware of the patient randomization and of the neuromuscular monitoring mode. Nausea was defined as the desire to vomit without the presence of expulsive muscular movements. Vomiting was defined as forceful expulsion of gastric contents from the mouth. Retching was defined as an active attempt to vomit without expulsion of gastric contents.15 PONV was assessed on a 3-point scale: 0 = no symptoms, 1 = only nausea, 2 = vomiting. The highest score reported during the study determined a patient's category. Patients who experienced both nausea and vomiting were included in the vomiting category. Ondansetron 4 mg was administered IV to any patient who experienced an episode of severe nausea, an episode of vomiting, or who requested the medication.
Pain was evaluated with a visual analog scale (0 = no pain to 10 = worst pain imaginable) in the postanesthesia care unit. We also recorded total opioid consumption and satisfaction rating (0 = very dissatisfied to 10 = most satisfied imaginable) on PONV management during the first 24 hours after surgery.
The predetermined sample size was calculated to be 50 patients per group using a power analysis based the incidence of PONV from a previous study.2 In our study, the incidence of PONV was 70% in the control group and 49% in the treatment group. We determined a 30% reduction in the total incidence of PONV (from 70% to 49%) to be clinically relevant (α = 0.05, β = 0.2, power = 80%). A series of 1-way analysis of variance was conducted to examine differences among the 5 groups with respect to parametric variables. If a significant difference was found, a comparison was conducted with the post hoc Bonferroni correction test for continuous variables. The Kruskal-Wallis test was used to determine differences in nonparametric variables among groups, and the Mann-Whitney rank sum test was then used to detect intergroup differences. The pain scores over time and their interaction with the intervention were analyzed by analysis of variance for repeated measures. Statistical analysis was performed using SPSS statistical software, version 17.0 (SPSS, Inc., Chicago, IL). Differences were considered statistically significant if P < 0.05. Values are reported as the mean ± SD (number or percentage).
A total of 264 women were recruited for this study (n >50 in each group) without any dropouts during the observation period. Baseline characteristics of study participants were similar, as were intraoperative variables (Table 1). No side effects were reported from the electrical stimulation.
Pain scores during the first 2 hours after surgery were not significantly different among the study groups (P = 0.219) (Table 2). In the first 6 hours after surgery, the need for opioids was significantly less in the tetanus group (P = 0.003) than in the control group, but not in the ST (P = 0.506), TOF (P = 0.854), or DBS (P = 0.273) groups (Table 2). Between 6 and 24 hours after surgery, however, there were no differences in pain scores between treatment and control groups (P = 0.993).
In the first 6 hours after surgery, the incidence of PONV was significantly lower in the tetanus group (15.4%), but not in the ST (40.4%), TOF (37.7%), or DBS (26.4%) groups, than that of the control group (53.7%) (P = 0.022). However, there was no difference in PONV incidence among groups during the late period (6–24 hours) (P = 0.728). There was no difference in the need for antiemetics among groups (P = 0.365). Overall satisfaction scores on PONV management were significantly higher in the tetanus group compared with the control group (P < 0.001) (Table 3).
This study found that tetanic stimulation applied to the P6 acupoint significantly reduced PONV (P = 0.022), requests for PCA (P = 0.009), and total PCA dose (P = 0.042) during the first 6 hours after laparoscopic hysterectomy, while it increased patient satisfaction. No differences were observed in the ST, TOF, and DBS groups compared with controls.
Several previous studies have examined the efficacy of stimulation at the P6 acupoint for PONV prophylaxis after general anesthesia.2,6–8 Arnberger et al.9 found that 1-Hz ST at the P6 acupoint during surgery significantly reduced the incidence of PONV during the early postoperative period (0–6 hours) (33% vs 51%), whereas no difference was found for the late postoperative period (6–24 hours). In another report, electroacupuncture with TOF at the P6 acupoint decreased emetic symptoms.16 In the present study, we also found that stimulation at the P6 acupoint reduced PONV in the early period after surgery (15.4%/53.7% vs 11.5%/20.4%) (Table 3). We further identified that tetanic stimulation specifically reduced PONV, whereas ST, TOF, and DBS did not.
The difference in effectiveness of the stimulation modes may be related to a gap in the maximal intensity of electrical stimulation, as previously reported in the literature.17,18 Researchers of one study reported that high electroacupuncture (100 Hz every 3 seconds) applied at the Hegu (LI-4) acupoint decreased opioid requirements by 65% and reduced PCA duration, as well as the incidence of nausea, dizziness, and pruritus.17 They also found that low electroacupuncture (2 Hz every 3 seconds) produced a 34% decrease in the opioid requirement compared with only 23% by sham electroacupuncture. Another study found that preoperative electroacupuncture applied at the Zusanli (ST-36) acupoint decreased the total amount of morphine required by 21%, 43%, and 61% in the sham, low-intensity (2-Hz), and high-intensity (100-Hz) groups, respectively.18
The primary difference between 1-Hz and 50-Hz stimulation is the number of electrical pulses per unit time. Tetanic stimulation at 50 Hz results in highly variable responses, with up to 2-fold–higher forces and longer contraction times than an ST in the medial gastrocnemius muscle of rats.19 DBS consists of 2 short bursts with 3 impulses (DBS3,3) of 50-Hz tetanic stimulation, separated by 750 milliseconds. The first response to DBS was demonstrated when the number of posttetanic responses was >5 after atracurium for muscle relaxation, related to a gap in the maximal intensity of electrical stimulation.20 Stimulation at specific acupoints has been hypothesized to modulate serotonin, substance P, and endorphins in several pathways of the central nervous system in rabbits.21 Differences in electrical stimulation may achieve distinct neuronal sensitization and characteristic spatial processes in the central nervous system. Nonetheless, the neurochemical basis for electroacupuncture's effect on PONV is unknown. Future neurophysiologic and neurochemical investigations may help us to further understand the complexity of emesis and to broaden the current approach to its treatment.
Studies have found that when electroacupuncture was used at the P6 acupoint for the prevention of PONV, a greater degree of patient satisfaction and better analgesia resulted compared with placebo.22 In the present study, we also found that despite similar postoperative pain scores, patients who received tetanic stimulation had less average postoperative opioid consumption than the control group during the first 6 hours after surgery. These results demonstrate that tetanic stimulation of the P6 acupoint provides additional pain relief and contributes to the prevention of PONV. We also believe that the higher satisfaction rate in the tetanus group was attributable to the antiemetic efficacy of this modality. We carefully assessed possible side effects from the repeated electrical stimulation (ST, TOF, DBS, and tetanus) during the perioperative and postoperative period, but we did not find any side effects.
White et al.23 found that the antiemetic efficacy of P6 acustimulation with the ReliefBand® (Woodside Biomedical Systems, Inc., Carlsbad, CA) was enhanced when administered in the postoperative (versus preoperative) period, and the efficacy of perioperative stimulation was not significantly better than postoperative stimulation alone. In the present study, electrical stimulation at the P6 acupoint was performed during the perioperative period, as previously reported in the literature.9 The discrepancy of the stimulation period is attributable to pain when electrical stimulation (ST, TOF, DBS, or tetanus) is used during the postoperative period.
The large variability in the control event rate of PONV may be attributable to differences in the study population (female gender, nonsmoking status, history of PONV or motion sickness, lengthy or emetogenic surgery, or administration of nitrous oxide, volatile anesthetics, or postoperative opioids).15 The incidence of PONV after laparoscopic gynecologic procedures has been reported to be 65% at 24 hours, similar to the incidence in our study (59.3%).1
There is limited information available regarding the optimal timing of median nerve stimulation to optimize its antiemetic effect. Thus, we chose clinical time intervals for the consecutive measurements of ST, TOF, DBS, and tetanus.9,12,13 It remains to be shown whether stimulation of the ulnar and median nerves can be widely used for accurate neuromuscular monitoring in the future. One limitation of our study design was the use of a continuous basal infusion of fentanyl in the postoperative period. This does not allow patients to demand analgesic as they require it and hence the results on pain and opioid requirement may not be reliable. Another limitation of our study was that our results lacked the sensitivity to detect an antiemetic effect because we did not use a verbal rating scale with 0 = none to 10 = worst imaginable to evaluate the severity of nausea and vomiting, and it was difficult to administer tetanus every 10 minutes during the duration of the study.
We found that tetanic stimulation applied at the P6 acupoint reduced the incidence of PONV in the first 6 hours after laparoscopic hysterectomy and increased patient satisfaction compared with our control treatment of simple ST stimulation of the ulnar nerve.
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