A Factorial Trial of Six Interventions for the Prevention of Postoperative Nausea and Vomiting
Christian C. Apfel, M.D., Kari Korttila, F.R.C.A., Ph.D., Mona Abdalla, Ph.D., Heinz Kerger, M.D., Alparslan Turan, M.D., Ina Vedder, M.D., Carmen Zernak, M.D., Klaus Danner, M.D., Ritva Jokela, M.D., Ph.D., Stuart J. Pocock, Ph.D., Stefan Trenkler, M.D., Markus Kredel, M.D., Andreas Biedler, M.D., Daniel I. Sessler, M.D., Norbert Roewer, M.D., for the IMPACT Investigators
Background Untreated, one third of patients who undergo surgerywill have postoperative nausea and vomiting. Although many trialshave been conducted, the relative benefits of prophylactic antiemeticinterventions given alone or in combination remain unknown.
Methods We enrolled 5199 patients at high risk for postoperativenausea and vomiting in a randomized, controlled trial of factorialdesign that was powered to evaluate interactions among as manyas three antiemetic interventions. Of these patients, 4123 wererandomly assigned to 1 of 64 possible combinations of six prophylacticinterventions: 4 mg of ondansetron or no ondansetron; 4 mg ofdexamethasone or no dexamethasone; 1.25 mg of droperidol orno droperidol; propofol or a volatile anesthetic; nitrogen ornitrous oxide; and remifentanil or fentanyl. The remaining patientswere randomly assigned with respect to the first four interventions.The primary outcome was nausea and vomiting within 24 hoursafter surgery, which was evaluated blindly.
Conclusions Because antiemetic interventions are similarly effectiveand act independently, the safest or least expensive shouldbe used first. Prophylaxis is rarely warranted in low-risk patients,moderate-risk patients may benefit from a single intervention,and multiple interventions should be reserved for high-riskpatients.
Source Information
From Julius-Maximilians Universität, Würzburg, Germany (C.C.A., M.K., N.R.); the University of Louisville, Louisville, Ky. (C.C.A., D.I.S.); Helsinki University Central Hospital, Helsinki, Finland (K.K., R.J.); the London School of Hygiene and Tropical Medicine, London (M.A., S.J.P.); the Universitätsklinik Mannheim, Mannheim, Germany (H.K.); Trakya University Hospital, Edirne, Turkey (A.T.); von Bodelschwingsche Anstalten Bethel, Bielefeld, Germany (I.V.); Kreiskrankenhaus Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany (C.Z.); Westpfalz-Klinikum, Kaiserslautern, Germany (K.D.); Reiman University Hospital, Presov, Slovakia (S.T.); and the Universitätskliniken des Saarlandes, Homburg, Germany (A.B.).
Address reprint requests to Dr. Apfel at Outcomes Research Institute, 501 East Broadway, Suite 210, Louisville, KY 40202, or at apfel{at}ponv.org.
Leslie, K., Myles, P. S., Chan, M. T. V., Paech, M. J., Peyton, P., Forbes, A., McKenzie, D., the ENIGMA Trial Group,
(2008). Risk factors for severe postoperative nausea and vomiting in a randomized trial of nitrous oxide-based vs nitrous oxide-free anaesthesia. Br J Anaesth
101: 498-505
[Abstract][Full Text]
Bonnet, M.-P., Marret, E., Josserand, J., Mercier, F. J.
(2008). Effect of prophylactic 5-HT3 receptor antagonists on pruritus induced by neuraxial opioids: a quantitative systematic review. Br J Anaesth
101: 311-319
[Abstract][Full Text]
Mraovic, B., Simurina, T., Sonicki, Z., Skitarelic, N., Gan, T. J.
(2008). The Dose-Response of Nitrous Oxide in Postoperative Nausea in Patients Undergoing Gynecologic Laparoscopic Surgery: A Preliminary Study. Anesth. Analg.
107: 818-823
[Abstract][Full Text]
Lichtor, J. L., Glass, P. S. A.
(2008). We're Tired of Waiting. Anesth. Analg.
107: 353-355
[Full Text]
Kovac, A. L., Eberhart, L., Kotarski, J., Clerici, G., Apfel, C., The Palonosetron 04-07 Study Group,
(2008). A Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Three Different Doses of Palonosetron Versus Placebo in Preventing Postoperative Nausea and Vomiting Over a 72-Hour Period. Anesth. Analg.
107: 439-444
[Abstract][Full Text]
Wittmann, M., Schaaf, T., Peters, I., Wirz, S., Urban, B. W., Barann, M.
(2008). The Effects of Fentanyl-Like Opioids and Hydromorphone on Human 5-HT3A Receptors. Anesth. Analg.
107: 107-112
[Abstract][Full Text]
Coburn, M., Kunitz, O., Apfel, C. C., Hein, M., Fries, M., Rossaint, R.
(2008). Incidence of postoperative nausea and emetic episodes after xenon anaesthesia compared with propofol-based anaesthesia. Br J Anaesth
100: 787-791
[Abstract][Full Text]
Orhan-Sungur, M., Kranke, P., Sessler, D., Apfel, C. C.
(2008). Does Supplemental Oxygen Reduce Postoperative Nausea and Vomiting? A Meta-Analysis of Randomized Controlled Trials. Anesth. Analg.
106: 1733-1738
[Abstract][Full Text]
Grecu, L., Bittner, E. A., Kher, J., Smith, S. E., Rosow, C. E.
(2008). Haloperidol Plus Ondansetron Versus Ondansetron Alone for Prophylaxis of Postoperative Nausea and Vomiting. Anesth. Analg.
106: 1410-1413
[Abstract][Full Text]
Habib, A. S., Gan, T. J.
(2008). PRO: The Food and Drug Administration Black Box Warning on Droperidol Is Not Justified. Anesth. Analg.
106: 1414-1417
[Full Text]
Kapoor, R., Hola, E. T., Adamson, R. T., Mathis, A. S.
(2008). Comparison of two instruments for assessing risk of postoperative nausea and vomiting. Am J Health Syst Pharm
65: 448-453
[Abstract][Full Text]
Kooij, F. O., Klok, T., Hollmann, M. W., Kal, J. E.
(2008). Decision Support Increases Guideline Adherence for Prescribing Postoperative Nausea and Vomiting Prophylaxis. Anesth. Analg.
106: 893-898
[Abstract][Full Text]
Wyllie, A. R. J., Carvalhana, V. V., Burry, L. D., Teresi, J. E.
(2008). Sufficiency of data for resuming use of low-dose droperidol. Am J Health Syst Pharm
65: 201-201
[Full Text]
Chen, C.-C., Lin, C.-S., Ko, Y.-P., Hung, Y.-C., Lao, H.-C., Hsu, Y.-W.
(2008). Premedication with Mirtazapine Reduces Preoperative Anxiety and Postoperative Nausea and Vomiting. Anesth. Analg.
106: 109-113
[Abstract][Full Text]
Gan, T. J., Meyer, T. A., Apfel, C. C., Chung, F., Davis, P. J., Habib, A. S., Hooper, V. D., Kovac, A. L., Kranke, P., Myles, P., Philip, B. K., Samsa, G., Sessler, D. I., Temo, J., Tramer, M. R., Vander Kolk, C., Watcha, M.
(2007). Society for Ambulatory Anesthesia Guidelines for the Management of Postoperative Nausea and Vomiting. Anesth. Analg.
105: 1615-1628
[Abstract][Full Text]
Hohlrieder, M., Brimacombe, J., von Goedecke, A., Keller, C.
(2007). Postoperative nausea, vomiting, airway morbidity, and analgesic requirements are lower for the ProSeal laryngeal mask airway than the tracheal tube in females undergoing breast and gynaecological surgery. Br J Anaesth
99: 576-580
[Abstract][Full Text]
Phillips, T. W. Jr, Broussard, D. M., Sumrall, W. D. III, Hart, S. R.
(2007). Intraoperative Oxygen Administration Does Not Reduce the Incidence or Severity of Nausea or Vomiting Associated with Neuraxial Anesthesia for Cesarean Delivery. Anesth. Analg.
105: 1113-1117
[Abstract][Full Text]
Diemunsch, P., Gan, T. J., Philip, B. K., Girao, M. J., Eberhart, L., Irwin, M. G., Pueyo, J., Chelly, J. E., Carides, A. D., Reiss, T., Evans, J. K., Lawson, F. C., for the Aprepitant-PONV Protocol 091 International,
(2007). Single-dose aprepitant vs ondansetron for the prevention of postoperative nausea and vomiting: a randomized, double-blind Phase III trial in patients undergoing open abdominal surgery. Br J Anaesth
99: 202-211
[Abstract][Full Text]
Artukoglu, F., Asenjo, J. F.
(2007). 43631 - SINGLE DOSE DEXAMETHASONE INDUCED POSTOPERATIVE PSYCHOSIS: CASE REPORT or SERIES. Canadian J. Anesthesia
54: 43631-43631
[Abstract][Full Text]
Dinsmore, J.
(2007). Anaesthesia for elective neurosurgery. Br J Anaesth
99: 68-74
[Abstract][Full Text]
Thibault, M., Girard, F., Moumdjian, R., Chouinard, P., Boudreault, D., Ruel, M.
(2007). Craniotomy site influences postoperative pain following neurosurgical procedures: a retrospective study: [Le site de craniotomie influence la douleur postoperatoire suite aux procedures neurochirurgicales : une etude retrospective]. Canadian J. Anesthesia
54: 544-548
[Abstract][Full Text]
Jackson, C. W., Sheehan, A. H., Reddan, J. G.
(2007). Evidence-based review of the black-box warning for droperidol. Am J Health Syst Pharm
64: 1174-1186
[Abstract][Full Text]
White, P. F., Kehlet, H., Neal, J. M., Schricker, T., Carr, D. B., Carli, F., the Fast-Track Surgery Study Group,
(2007). The Role of the Anesthesiologist in Fast-Track Surgery: From Multimodal Analgesia to Perioperative Medical Care. Anesth. Analg.
104: 1380-1396
[Abstract][Full Text]
Kim, M. S., Cote, C. J., Cristoloveanu, C., Roth, A. G., Vornov, P., Jennings, M. A., Maddalozzo, J. P., Sullivan, C.
(2007). There Is No Dose-Escalation Response to Dexamethasone (0.0625-1.0 mg/kg) in Pediatric Tonsillectomy or Adenotonsillectomy Patients for Preventing Vomiting, Reducing Pain, Shortening Time to First Liquid Intake, or the Incidence of Voice Change. Anesth. Analg.
104: 1052-1058
[Abstract][Full Text]
Gan, T. J., Apfel, C. C., Kovac, A., Philip, B. K., Singla, N., Minkowitz, H., Habib, A. S., Knighton, J., Carides, A. D., Zhang, H., Horgan, K. J., Evans, J. K., Lawson, F. C., The Aprepitant-PONV Study Group,
(2007). A Randomized, Double-Blind Comparison of the NK1 Antagonist, Aprepitant, Versus Ondansetron for the Prevention of Postoperative Nausea and Vomiting. Anesth. Analg.
104: 1082-1089
[Abstract][Full Text]
White, H., Black, R. J., Jones, M., Mar Fan, G. C.
(2007). Randomized comparison of two anti-emetic strategies in high-risk patients undergoing day-case gynaecological surgery. Br J Anaesth
98: 470-476
[Abstract][Full Text]
Ahonen, J., Jokela, R., Uutela, K., Huiku, M.
(2007). Surgical stress index reflects surgical stress in gynaecological laparoscopic day-case surgery. Br J Anaesth
98: 456-461
[Abstract][Full Text]
Edler, A. A., Mariano, E. R., Golianu, B., Kuan, C., Pentcheva, K.
(2007). An Analysis of Factors Influencing Postanesthesia Recovery After Pediatric Ambulatory Tonsillectomy and Adenoidectomy. Anesth. Analg.
104: 784-789
[Abstract][Full Text]
Paech, M. J., Rucklidge, M. W.M., Lain, J., Dodd, P. H., Bennett, E.-J., Doherty, D. A.
(2007). Ondansetron and Dexamethasone Dose Combinations for Prophylaxis Against Postoperative Nausea and Vomiting. Anesth. Analg.
104: 808-814
[Abstract][Full Text]
White, P. F., Kehlet, H.
(2007). Postoperative Pain Management and Patient Outcome: Time to Return to Work!. Anesth. Analg.
104: 487-489
[Full Text]
Habib, A. S., Reuveni, J., Taguchi, A., White, W. D., Gan, T. J.
(2007). A Comparison of Ondansetron with Promethazine for Treating Postoperative Nausea and Vomiting in Patients Who Received Prophylaxis with Ondansetron: A Retrospective Database Analysis. Anesth. Analg.
104: 548-551
[Abstract][Full Text]
Jokela, R., Ahonen, J., Valjus, M., Seppala, T., Korttila, K.
(2007). Premedication with controlled-release oxycodone does not improve management of postoperative pain after day-case gynaecological laparoscopic surgery. Br J Anaesth
98: 255-260
[Abstract][Full Text]
Nichols, D. G., Yaster, M.
(2007). Victims of Our Own Success or Quo Vadis Pediatric Anesthesia?. Anesth. Analg.
104: 255-257
[Full Text]
White, P. F., Tang, J., Song, D., Coleman, J. E., Wender, R. H., Ogunnaike, B., Sloninsky, A., Kapu, R., Shah, M., Webb, T.
(2007). Transdermal Scopolamine: An Alternative to Ondansetron and Droperidol for the Prevention of Postoperative and Postdischarge Emetic Symptoms. Anesth. Analg.
104: 92-96
[Abstract][Full Text]
Piper, S. N., Rohm, K. D., Boldt, J., Faust, K. L., Maleck, W. H., Kranke, P., Suttner, S. W.
(2006). Inspired oxygen fraction of 0.8 compared with 0.4 does not further reduce postoperative nausea and vomiting in dolasetron-treated patients undergoing laparoscopic cholecystectomy. Br J Anaesth
97: 647-653
[Abstract][Full Text]
McKay, R. E., Bostrom, A., Balea, M. C., McKay, W. R.
(2006). Airway Responses During Desflurane Versus Sevoflurane Administration via a Laryngeal Mask Airway in Smokers. Anesth. Analg.
103: 1147-1154
[Abstract][Full Text]
Chan, M. T. V., Choi, K. C., Gin, T., Chui, P. T., Short, T. G., Yuen, P. M., Poon, A. H. Y., Apfel, C. C., Gan, T. J.
(2006). The Additive Interactions Between Ondansetron and Droperidol for Preventing Postoperative Nausea and Vomiting. Anesth. Analg.
103: 1155-1162
[Abstract][Full Text]
Tominaga, K., Nakahara, T.
(2006). The Twenty-Degree Reverse-Trendelenburg Position Decreases the Incidence and Severity of Postoperative Nausea and Vomiting After Thyroid Surgery. Anesth. Analg.
103: 1260-1263
[Abstract][Full Text]
Sweeney, B.
(2006). Postoperative nausea and vomiting. BMJ
333: 313-314
[Full Text]
Wallenborn, J., Gelbrich, G., Bulst, D., Behrends, K., Wallenborn, H., Rohrbach, A., Krause, U., Kuhnast, T., Wiegel, M., Olthoff, D.
(2006). Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind multicentre trial. BMJ
333: 324-
[Abstract][Full Text]
Gan, T. J., Coop, A., Philip, B. K.
(2006). Clinical Experience with Small-Dose Granisetron and Dexamethasone for Prevention of Postoperative Nausea and Vomiting. Anesth. Analg.
103: 511-511
[Full Text]
Komatsu, R., Orhan-Sungur, M., In, J., Podranski, T., Bouillon, T., Lauber, R., Rohrbach, S., Sessler, D.
(2006). Ondansetron does not reduce the shivering threshold in healthy volunteers. Br J Anaesth
96: 732-737
[Abstract][Full Text]
Gan, T. J.
(2006). Risk factors for postoperative nausea and vomiting.. Anesth. Analg.
102: 1884-1898
[Abstract][Full Text]
Kovac, A. L
(2006). Meta-Analysis of the Use of Rescue Antiemetics Following PONV Prophylactic Failure with 5-HT3 Antagonist/Dexamethasone Versus Single-Agent Therapies. The Annals of Pharmacotherapy
40: 873-887
[Abstract][Full Text]
Leslie, J. B, Gan, T. J
(2006). Meta-Analysis of the Safety of 5-HT3 Antagonists with Dexamethasone or Droperidol for Prevention of PONV. The Annals of Pharmacotherapy
40: 856-872
[Abstract][Full Text]
White, P. F., Tang, J., Hamza, M. A., Ogunnaike, B., Lo, M., Wender, R. H., Naruse, R., Sloninsky, A., Kariger, R., Cunneen, S., Khalili, T.
(2006). The use of oral granisetron versus intravenous ondansetron for antiemetic prophylaxis in patients undergoing laparoscopic surgery: the effect on emetic symptoms and quality of recovery.. Anesth. Analg.
102: 1387-1393
[Abstract][Full Text]
Hadzic, A., Kerimoglu, B., Loreio, D., Karaca, P. E., Claudio, R. E., Yufa, M., Wedderburn, R., Santos, A. C., Thys, D. M.
(2006). Paravertebral Blocks Provide Superior Same-Day Recovery over General Anesthesia for Patients Undergoing Inguinal Hernia Repair.. Anesth. Analg.
102: 1076-1081
[Abstract][Full Text]
Janicki, P. K., Schuler, H. G., Jarzembowski, T. M., Rossi, M. II
(2006). Prevention of Postoperative Nausea and Vomiting with Granisetron and Dolasetron in Relation to CYP2D6 Genotype.. Anesth. Analg.
102: 1127-1133
[Abstract][Full Text]
Romundstad, L., Breivik, H., Roald, H., Skolleborg, K., Haugen, T., Narum, J., Stubhaug, A.
(2006). Methylprednisolone Reduces Pain, Emesis, and Fatigue After Breast Augmentation Surgery: A Single-Dose, Randomized, Parallel-Group Study with Methylprednisolone 125 mg, Parecoxib 40 mg, and Placebo. Anesth. Analg.
102: 418-425
[Abstract][Full Text]
Liu, S. S., Strodtbeck, W. M., Richman, J. M., Wu, C. L.
(2005). A Comparison of Regional Versus General Anesthesia for Ambulatory Anesthesia: A Meta-Analysis of Randomized Controlled Trials. Anesth. Analg.
101: 1634-1642
[Abstract][Full Text]
Gan, T. J., Coop, A., Philip, B. K., the Kytril Study Group,
(2005). A Randomized, Double-Blind Study of Granisetron Plus Dexamethasone Versus Ondansetron Plus Dexamethasone to Prevent Postoperative Nausea and Vomiting in Patients Undergoing Abdominal Hysterectomy. Anesth. Analg.
101: 1323-1329
[Abstract][Full Text]
Pirat, A., Tuncay, S. F., Torgay, A., Candan, S., Arslan, G.
(2005). Ondansetron, Orally Disintegrating Tablets Versus Intravenous Injection for Prevention of Intrathecal Morphine-Induced Nausea, Vomiting, and Pruritus in Young Males. Anesth. Analg.
101: 1330-1336
[Abstract][Full Text]
Roberts, G. W., Bekker, T. B., Carlsen, H. H., Moffatt, C. H., Slattery, P. J., McClure, A. F.
(2005). Postoperative Nausea and Vomiting Are Strongly Influenced by Postoperative Opioid Use in a Dose-Related Manner. Anesth. Analg.
101: 1343-1348
[Abstract][Full Text]
Cheng, C.-R., Sessler, D. I., Apfel, C. C.
(2005). Does Neostigmine Administration Produce a Clinically Important Increase in Postoperative Nausea and Vomiting?. Anesth. Analg.
101: 1349-1355
[Abstract][Full Text]
Bonnet, F., Marret, E.
(2005). Influence of anaesthetic and analgesic techniques on outcome after surgery. Br J Anaesth
95: 52-58
[Abstract][Full Text]
Golembiewski, J., Chernin, E., Chopra, T.
(2005). Prevention and treatment of postoperative nausea and vomiting. Am J Health Syst Pharm
62: 1247-1260
[Abstract][Full Text]
Rusch, D., Eberhart, L., Biedler, A., Dethling, J., Apfel, C. C.
(2005). Prospective application of a simplified risk score to prevent postoperative nausea and vomiting: [L'application prospective d'un score de risque simplifie pour prevenir les nausees et les vomissements postoperatoires]. Canadian J. Anesthesia
52: 478-484
[Abstract][Full Text]
Kuhne, J., Vanarase, M. Y., Pandit, H. G., Dodd, C. A. F., Murray, D. W., Popat, M. T., Davies, A. F.
(2005). Perioperative analgesia for knee arthroplasty. Br J Anaesth
94: 393-395
[Full Text]
White, P. F., Hamza, M. A., Recart, A., Coleman, J. E., Macaluso, A. R., Cox, L., Jaffer, O., Song, D., Rohrich, R.
(2005). Optimal Timing of Acustimulation for Antiemetic Prophylaxis as an Adjunct to Ondansetron in Patients Undergoing Plastic Surgery. Anesth. Analg.
100: 367-372
[Abstract][Full Text]
Sneyd, J. R.
(2004). Recent advances in intravenous anaesthesia. Br J Anaesth
93: 725-736
[Abstract][Full Text]
Yalcyn, S., Yalcyn, B., Buyukcelik, A., Hartig, F., Pechlaner, C., Apfel, C. C., Sessler, D. I.
(2004). Prevention of Postoperative Nausea and Vomiting. NEJM
351: 1458-1459
[Full Text]
(2004). Other articles noted. Evid. Based Med.
9: e5-e5
[Full Text]
(2004). Combinations of antiemetics are better for post-operative nausea and vomiting. BMJ
329: -
[Full Text]