Focused Review Article

P6 Stimulation for the Prevention of Nausea and Vomiting Associated with Cesarean Delivery Under Neuraxial Anesthesia: A Systematic Review of Randomized Controlled Trials
Terrence K. Allen, MBBS, FRCA Ashraf S. Habib, MBBCh, MSc, FRCA
BACKGROUND: A number of studies investigated the use of P6 stimulation for the prevention of intraoperative and postoperative nausea and vomiting (IONV and PONV) in women having cesarean delivery under neuraxial anesthesia. We performed a systematic review to determine the overall efficacy of these techniques in preventing IONV and PONV in this patient population. METHODS: We performed a literature search of all randomized controlled trials (1966 2007) that compared different methods of P6 stimulation with placebo in women having cesarean delivery under neuraxial anesthesia. Data were extracted on the primary outcomes including the incidence of nausea, vomiting, and the need for rescue antiemetic therapy, both intraoperatively and postoperatively. RESULTS: Six studies involving 649 patients were included in this review. Five studies reported on intraoperative outcomes. Of these, two studies reported a significant reduction in the incidence of intraoperative nausea with P6 stimulation, and one study reported a significant reduction in rescue antiemetic requirement. However, none of the studies reported any differences between the treatment and control groups with respect to vomiting. Four studies reported postoperative outcomes. Of these, one study reported a significant reduction in postoperative nausea, two studies reported a significant reduction in postoperative vomiting, and one study reported a significant reduction in the need for postoperative rescue antiemetic therapy. CONCLUSIONS: While some studies showed a benefit of P6 stimulation, this finding was not consistent. The presence of heterogeneity and inconsistent results among the included trials prevents any definitive conclusions on the efficacy of P6 stimulation in reducing IONV and PONV associated with cesarean delivery performed under neuraxial anesthesia.
(Anesth Analg 2008;107:1308 12)

ausea and vomiting are common intraoperative and postoperative complications in women having cesarean delivery under neuraxial anesthesia.1,2 The etiology of intraoperative and postoperative nausea and vomiting (IONV and PONV) is multifactorial. The physiologic changes of pregnancy, intraoperative hypotension, increased vagal activity, visceral stimulation, as well as administration of neuraxial opioids and oxytocic drugs, may all play a role.3 Nonpharmacological techniques such as acupuncture, acupressure, and transcutaneous acupoint electrical stimulation of the
From the Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina. This study was presented in part at the 39th Annual Meeting of the Society for Obstetric Anesthesia and Perinatology, Alberta, Canada, May 16 19, 2007. Financial support: This study was supported by departmental funds. Address correspondence and reprint requests to Ashraf S. Habib, Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710. Address e-mail to habib001@mc.duke.edu. Copyright 2008 International Anesthesia Research Society
DOI: 10.1213/ane.0b013e31816d1864

pericardium 6 (P6) Neiguan point have been studied for the prevention of IONV and PONV.4 12 The increasing popularity of these modalities is, in part, due to their low cost and simplicity, and in obstetrics, concern about placental transfer and secretion in breast milk of drugs.13 Several physiological mechanisms have been proposed for the antiemetic effect of P6 stimulation. These include stimulation of the endogenous opioid system, serotonin release, increased vagal modulation, direct stimulation of gut smooth muscle, and stimulation of somatovisceral and somatosympathetic reflexes that affect lower esophageal sphincter and gastric relaxation.14 A number of studies have investigated P6 stimulation for preventing PONV and IONV in women undergoing cesarean delivery under neuraxial anesthesia. We performed this systematic review to assess the efficacy of P6 stimulation in this patient population.

METHODS
We followed the recommendations of the QUOROM statement.15
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13 publications identified and retrieved for screening 6 immediately excluded 3 review articles 2 studies in gynecological patients 1 case report

Figure 1. Flow-chart of retrieved, excluded and included publications. RCTrandomized controlled trials.

7 potentially relevant publications in obstetric patients 1 study excluded Not a RCT

6 RCTs investigating the effects of P6 stimulation techniques for the prevention of nausea and vomiting associated with neuraxial anesthesia for cesarean delivery analyzed

Literature Search
We searched MEDLINE (1966 2007), the Cochrane Central Register of Controlled Trials, Scopus and CINAHL for randomized controlled trials (RCTs) that investigated the perioperative use of P6 stimulation for the prevention of PONV and IONV in women having cesarean delivery under neuraxial anesthesia. The terms acupuncture, acupressure, electroacupuncture, and transcutaneous acupoint electrical stimulation were exploded as MeSH terms and combined with the search terms cesarean section, cesarean delivery, intraoperative, postoperative, nausea, vomiting, emesis, spinal anesthesia, and epidural anesthesia. The search was performed without language restrictions and limited to RCTs involving human subjects. The date of the last computer search was September 2007. In addition, the bibliographies of retrieved articles were searched for additional studies.

(iv) duration of therapy, (v) incidence of intraoperative hypotension and use of vasopressors, (vi) exteriorization of the uterus, and (vii) intraoperative and postoperative outcome measures including the incidence and severity of nausea and vomiting, need for rescue antiemetics, and complete response to therapy (no nausea, vomiting, or need for rescue antiemetics). It was our initial intention to combine the data using classic methods of meta-analysis and report summary estimates with 95% confidence intervals. However, because the relevant trials were clinically heterogeneous, meta-analysis was deemed inappropriate. Instead the primary outcome data extracted from the original studies were compared qualitatively. The results of statistical significance between the intervention and control groups were reported as in the original manuscripts.

RESULTS
Thirteen publications were initially identified. All studies were in English. Seven publications were subsequently excluded (Fig. 1). The remaining 6 RCTs yielded 649 patients for analysis. Of these, 326 patients received P6 stimulation and 323 sham or placebo. The characteristics of the included studies are shown in Table 1. The minimum Oxford scale score of an included trial was 4 and the maximum score was 6. Bilateral acupressure was used in four studies,5,9,11,18 unilateral acupressure in one study,8 and unilateral transcutaneous acupoint electrical stimulation in one study.19 Interventions in the control and treatment groups were instituted preoperatively 5 to 60 min before the induction of neuraxial anesthesia. Placebo bands were used as the control in all the
2008 International Anesthesia Research Society

Methodological Quality Assessment

Both authors reviewed the abstracts of retrieved articles and excluded those that did not meet the selection criteria. Both reviewers then independently read the selected articles and assessed their methodological quality using the 7 point modified Oxford scale.16,17 Any discrepancies were resolved by discussion.

Data Handling and Analyses

We designed a data collection form and collected data from the included studies on: (i) type of nonpharmacological technique, (ii) unilateral versus bilateral application, (iii) timing of administration of therapy,
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Table 1. Characteristics of Studies Included in the Systematic Review

Quality score
18

Study Ho (1996)

Participants 60 patients A (n 30) C (n 30)

Type and duration of P6 stimulation Bilateral application P6 Acupressure bands (Sea-Band) applied immediately preoperatively and for up to 46 h postoperatively Bilateral application P6 Acupressure bands (Sea-Band) applied 15 min preoperatively and intraoperatively only Bilateral application P6 Acupressure bands (Sea-Band) applied immediately preoperatively and for a minimum of 10 h postoperatively Unilateral application P6 Acupressure bands (Sea-Band) applied 5 min preoperatively and for 6 h postoperatively

Duration of study 048 h postoperatively

Neuraxial technique/ neuraxial opioids (dose) CSE Postoperative epidural morphine (612 mg)

Outcome of P6 stimulation ION, IOV, IOR: NR PON: A (3%), C (43%), P 0.05 POV: A (0%), C (27%), P 0.05 POR (metoclopramide): A (0%), C (0.6%), P NS ION: A (24%), C (76%), P 0.001 IOV: A (12%), C (24%), P NS IOR, PON, POV, POR: NR

Stein (1997)11

50 patients* A (n 25) C (n 25)

Intraoperative only

SAB Intrathecal fentanyl (10 g)

Duggal (1998)5

244 patients A (n 122) C (n 122)

Intraoperative 010 h postoperatively

SAB Intrathecal fentanyl (10 g)/morphine (250 g)

ION: A (27%), C (30%), P NS IOV: A (7%), C (7%), P NS IOR: A (26%), C (13%), P NS PON: A (57%), C (66%), P NS POV: A (41%), C (46%), P NS POR: A (40%), C (51%), P NS ION: A (15%), C (36%), P 0.018 IOV: A (9%), C (17%), P NS IOR (ondansetron): only mean dose reported: A (0.08 mg), C (0.5 mg), P 0.002 PON: A (9%), C (17%), P NS POV: A (28%), C (36%), P 0.011 POR (cyclizine): only mean dose reported: A (13 mg), C (25 mg), P 0.002 IOR POR: A (25%), C (50%), P 0.01 ION: A (30%), C (43%), P NS IOV: A (13%), C (9%), P NS IOR (ondansetron): A (23%), C (18%), P NS PON: A (23%), C (41%), P NS POV: A (26%), C (37%), P NS POR (ondansetron): A (34%), C (39%), P NS ION: A (64%), C (71%), P NS IOV: A (22%), C (27%), P NS IOR (metoclopramide): A (2%), C (4%), P NS PON, POV, POR: NR

Harmon (2000)8

94 patients A (n 47) C (n 47)

Intraoperative 024 h postoperatively

SAB Intrathecal morphine (200 g)

Habib (2006)19

91 patients A (n 47) C (n 44)

Unilateral application P6 Transcutaneous Acupoint Electrical Stimulation bands (ReliefBand) applied 3060 min preoperatively and for 24 h postoperatively Bilateral application P6 Acupressure bands (Sea-Band) applied approximately 30 min preoperatively and intraoperatively only

Intraoperative 024 h postoperatively

SAB Intrathecal fentanyl (20 g)/morphine (200 g)

Ho (2006)9

110 patients A (n 55) C (n 55)

Intraoperative only

SAB No intrathecal opioids

* This study had an additional group that received placebo bands and metoclopramide. Only data on the acupressure group and placebo group without metoclopramide were included in this review. CSE combined spinal epidural; SAB subarachnoid block; P6 pericardium 6 Neiguan point; A active group; C control group; ION intraoperative nausea; IOV intraoperative vomiting; IOR intraoperative rescue antiemetic; PON postoperative nausea; POV postoperative vomiting; POR postoperative rescue antiemetic; NR not reported; NS not statistically signicant.

included studies. In two studies, the stimulating buttons were removed in the placebo group.5,11 In another two studies, these buttons were blunted.9,18 In the two remaining studies, the placebo groups received stimulation at nonacupuncture points.8,19 Neuraxial opioids were used in all studies except one. The latter study only reported intraoperative outcomes.9 In four studies, opioids were administered intrathecally5,8,11,19 and, in one study, opioids were administered via an epidural catheter postoperatively for pain relief.18 The included studies reported no difference between the P6 stimulation and control groups in the rate of uterine exteriorization,5,11,19 or the incidence of intraoperative opioid supplementation,5,8,9,19 postoperative opioid consumption,5,8,18,19 intraoperative vasopressor use,5,8,9,11,19 or intraoperative hypotension.5,8,11
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Side effects were reported in five of the six studies with no differences between the active and control groups.5,8,9,18,19 In two studies, no adverse effects were reported.9,18 In the remaining studies, application of bands caused localized discomfort, itching, swollen hands, and problems with IV infusions.5,8,19 The outcomes are as follows: Nausea: Five studies reported on the incidence of intraoperative nausea.5,8,9,11,19 Two studies reported a significant reduction in intraoperative nausea with P6 stimulation,8,11 whereas the remaining three studies reported no difference compared with the control group.5,9,19 The incidence of postoperative nausea was reported by four studies.5,8,18,19 Only one study reported a significant
ANESTHESIA & ANALGESIA

P6 Stimulation for Antiemetic Prophylaxis in Cesarean Delivery

reduction in the incidence of postoperative nausea with P6 stimulation.18 However, in a subgroup analysis in one of the other studies, Duggal et al.5 demonstrated that P6 acupressure significantly reduced the incidence of postoperative nausea in patients with a history of PONV. The only study reporting nausea scores found no differences between the treatment and control groups.19 Vomiting: Of the five studies reporting on the incidence of intraoperative vomiting, none were able to demonstrate an improvement with P6 stimulation.5,8,9,11,18,19 Of the four studies reporting the incidence of postoperative vomiting,5,8,18,19 only two reported a significant reduction with P6 stimulation.8,18 Again Duggal et al.,5 in a subgroup analysis, reported a statistically significant reduction in the incidence of postoperative vomiting with P6 stimulation in women who had a history of PONV. Use of Rescue Antiemetics: The need for intraoperative rescue antiemetics was reported in four studies.5,9,19 Only one study reported a significant reduction in antiemetic requirement during surgery with P6 simulation.8 Four studies reported on the need for postoperative antiemetic rescue.5,8,18,19 Of these, only one was able to demonstrate a significant reduction in the need for rescue antiemetic therapy in the P6 stimulation group.8 Complete Response to Therapy: Only one study reported on the rate of intraoperative and postoperative complete response to P6 stimulation, but found no differences between the treatment and control groups.19

DISCUSSION
The trials included in this review reported inconsistent results regarding the efficacy of P6 stimulation for the prevention of IONV and PONV in women undergoing cesarean delivery under neuraxial anesthesia. Of note, of the three studies reporting some benefit of P6 stimulation, two were the smallest studies included in this review.11,18 These results should be interpreted with caution, since small trials may detect a beneficial treatment effect by random chance.20 Additionally, one of the included studies suggested that the negative finding might have been due to inadequate power.19 While our original intent was to perform a metaanalysis, this was deemed inappropriate because of clinical heterogeneity among the included trials. For instance, intraoperative hypotension, a known risk factor for IONV, might have been managed differently in the included studies as reflected by the difference in the incidence of pre-delivery hypotension and need for vasopressors (40%76%). While fluid preloading was used in all the studies, prophylactic ephedrine was used in addition in one study,8 and bilateral leg wrapping was used in another study.9 Furthermore,
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while ephedrine was the primary vasopressor for the treatment of intraoperative hypotension for all five studies investigating IONV,5,8,9,11,19 phenylephrine was also used either alone or in combination with ephedrine in one study.5 The control event rates were also different among the included studies. For instance, intraoperative nausea in the control group ranged from 30% to 76%. Two of the included studies investigating IONV failed to describe the technique for uterine repair despite the fact that uterine exteriorization is a major risk factor for IONV.8,9 While the studies reporting postoperative outcomes used mostly intrathecal morphine 200 250 g,5,8,19 one study18 involved the administration of multiple boluses of epidural morphine postoperatively. The duration of P6 stimulation also varied among the different studies. There are currently no data comparing the efficacy of different P6 stimulation techniques. It is also not clear if bilateral P6 stimulation offers advantages compared with unilateral stimulation. Of interest, of the four trials using bilateral stimulation, two reported a beneficial effect of P6 stimulation,11,18 and of the two trials using unilateral stimulation, one reported better results with the active intervention.8 It is also not known whether continuous stimulation of the P6 point is needed to maintain the antiemetic effect of these techniques or whether a brief period of stimulation would be adequate. For instance, in a previous study in patients undergoing breast surgery under general anesthesia, intraoperative P6 stimulation produced an antiemetic effect for 24 h.7 A larger number of studies have investigated the antiemetic effect of P6 stimulation in the general surgical population, and generally found it to be effective at reducing PONV.21,22 P6 stimulation might be particularly effective for prophylaxis against nausea.7,23,24 The antiemetic efficacy of modalities stimulating the P6 point was reported to be comparable to currently available drugs,7,25 and resulted in enhanced prophylaxis when combined with antiemetics.25 This review highlights several areas where future research in the obstetric population is needed. Future large trials comparing different P6 stimulation modalities are needed. In a post hoc analysis, Duggal et al. reported an increased efficacy of P6 stimulation in reducing PONV in patients with a history of PONV, and this requires further investigation. The efficacy of unilateral versus bilateral P6 stimulation, as well as the optimal duration of P6 stimulation, also need to be established. The efficacy of P6 stimulation in combination with other acupuncture points with known antiemetic effects such as the St36 point and the Korean K9 point also requires further investigation. Finally, because IONV and PONV are multifactorial, and multimodal therapy is more effective than singlemode therapy, the efficacy of nonpharmacological techniques used in combination with drug therapy for reducing the incidence and severity of IONV and
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PONV in obstetric anesthesia practice is another area of future research. In conclusion, while some studies showed improved antiemetic prophylaxis with P6 stimulation, this finding was not consistent. The heterogeneity among the trials and the inconsistent results prevent any definitive conclusions on the efficacy of perioperative P6 stimulation as a method of prophylaxis for IONV and PONV in women having cesarean delivery under neuraxial anesthesia. REFERENCES
1. Lussos SA, Bader AM, Thornhill ML, Datta S. The antiemetic efficacy and safety of prophylactic metoclopramide for elective cesarean delivery during spinal anesthesia. Reg Anesth 1992;17:126 30 2. Nortcliffe SA, Shah J, Buggy DJ. Prevention of postoperative nausea and vomiting after spinal morphine for Caesarean section: comparison of cyclizine, dexamethasone and placebo. Br J Anaesth 2003;90:66570 3. Balki M, Carvalho JC. Intraoperative nausea and vomiting during cesarean section under regional anesthesia. Int J Obstet Anesth 2005;14:230 41 4. Chen HM. Effect of acupressure on nausea, vomiting, anxiety and pain among post-cesarean section women in Taiwan. Kaohsiung J Med Sci 2005;21:34150 5. Duggal KN, Douglas MJ, Peteru EA, Merrick PM. Acupressure for intrathecal narcotic-induced nausea and vomiting after caesarean section. Int J Obstet Anesth 1998;7:231 6 6. Fan CF, Tanhui E, Joshi S, Trivedi S, Hong Y, Shevde K. Acupressure treatment for prevention of postoperative nausea and vomiting. Anesth Analg 1997;84:8215 7. Gan TJ, Jiao KR, Zenn M, Georgiade G. A randomized controlled comparison of electro-acupoint stimulation or ondansetron versus placebo for the prevention of postoperative nausea and vomiting. Anesth Analg 2004;99:1070 5 8. Harmon D, Ryan M, Kelly A, Bowen M. Acupressure and prevention of nausea and vomiting during and after spinal anaesthesia for caesarean section. Br J Anaesth 2000;84:4637 9. Ho CM, Tsai HJ, Chan KH, Tsai SK. P6 Acupressure does not prevent emesis during spinal anesthesia for cesarean delivery. Anesth Analg 2006;102:900 3 10. Kotani N, Hashimoto H, Sato Y, Sessler DI, Yoshioka H, Kitayama M, Yasuda T, Matsuki A. Preoperative intradermal acupuncture reduces postoperative pain, nausea and vomiting, analgesic requirement, and sympathoadrenal responses. Anesthesiology 2001;95:349 56 11. Stein DJ, Birnbach DJ, Danzer BI, Kuroda MM, Grunebaum A, Thys DM. Acupressure versus intravenous metoclopramide to prevent nausea and vomiting during spinal anesthesia for cesarean section. Anesth Analg 1997;84:3425

12. White PF, Hamza MA, Recart A, Coleman JE, Macaluso AR, Cox L, Jaffer O, Song D, Rohrich R. Optimal timing of acustimulation for antiemetic prophylaxis as an adjunct to ondansetron in patients undergoing plastic surgery. Anesth Analg 2005; 100:36772 13. Balki M, Kasodekar S, Dhumne S, Carvalho JCA. Prophylactic granisetron does not prevent postdelivery nausea and vomiting during elective cesarean delivery under spinal anesthesia. Anesth Analg 2007;104:679 83 14. Streitberger K, Ezzo J, Schneider A. Acupuncture for nausea and vomiting: an update of clinical and experimental studies. Auton Neurosci 2006;129:10717 15. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 1999;354:1896 900 16. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:112 17. Elia N, Tramer MR. Ketamine and postoperative pain-a quantitative systematic review of randomised trials. Pain 2005; 113:6170 18. Ho CM, Hseu SS, Tsai SK, Lee TY. Effect of P-6 acupressure on prevention of nausea and vomiting after epidural morphine for post-cesarean section pain relief. Acta Anaesthesiol Scand 1996;40:3725 19. Habib AS, Itchon-Ramos N, Phillips-Bute BG, Gan TJ. Transcutaneous acupoint electrical stimulation with the ReliefBand for the prevention of nausea and vomiting during and after cesarean delivery under spinal anesthesia. Anesth Analg 2006; 102:581 4 20. Moore RA, Gavaghan D, Trame ` r MR, Collins SL, McQuay HJ. Size is everything-large amounts of information are needed to overcome random effects in estimating direction and magnitude of treatment effects. Pain 1998;78:209 16 21. Scuderi PE. P6 stimulation: a new approach to an ancient technique. Anesthesiology 2007;107:870 2 22. Chernyak GV, Sessler DI. Perioperative acupuncture and related techniques. Anesthesiology 2005;102:1031 49; quiz 77 8 23. Zarate E, Mingus M, White PF, Chiu JW, Scuderi P, Loskota W, Daneshgari V. The use of transcutaneous acupoint electrical stimulation for preventing nausea and vomiting after laparoscopic surgery. Anesth Analg 2001:629 35 24. Arnberger M, Stadelmann K, Alischer P, Ponert R, Melber A, Greif R. Monitoring of neuromuscular blockade at the P6 acupuncture point reduces the incidence of postoperative nausea and vomiting. Anesthesiology 2007;107:903 8 25. White PF, Issioui T, Hu J, Jones SB, Coleman JE, Waddle JP, Markowitz SD, Coloma M, Macaluso AR, Ing CH. Comparative efficacy of acustimulation (ReliefBand) versus ondansetron (Zofran) in combination with droperidol for preventing nausea and vomiting. Anesthesiology 2002;97:1075 81

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