The New England Journal of Medicine

Numéro : Volume 350(24), 10 June 2004, p 2441-2451
Copyright : Copyright (C) 2004 Massachusetts Medical Society. All rights reserved.
Type de publication : [Original Articles]
DOI : 10.1056/NEJMoa032196
ISSN : 0028-4793
Accès : 00006024-200406100-00003

A Factorial Trial of Six Interventions for the Prevention of Postoperative Nausea and Vomiting

Apfel, Christian C.; Korttila, Kari; Abdalla, Mona; Kerger, Heinz; Turan, Alparslan; Vedder, Ina; Zernak, Carmen; Danner, Klaus; Jokela, Ritva; Pocock, Stuart J.; Trenkler, Stefan; Kredel, Markus; Biedler, Andreas; Sessler, Daniel I.; Roewer, Norbert
Informations sur l'auteur
For the IMPACT Investigators*
From Julius-Maximilians Universitat, Wurzburg, 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 Universitatsklinik 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 Universitatskliniken 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 [email protected].
*The International Multicenter Protocol to Assess the Single and Combined Benefits of Antiemetic Interventions in a Controlled Clinical Trial of a 2x2x2x2x2x2 Factorial Design (IMPACT) Investigators are listed in the Appendix.

Abstract

Background: Untreated, one third of patients who undergo surgery will have postoperative nausea and vomiting. Although many trials have been conducted, the relative benefits of prophylactic antiemetic interventions given alone or in combination remain unknown.

Methods: We enrolled 5199 patients at high risk for postoperative nausea and vomiting in a randomized, controlled trial of factorial design that was powered to evaluate interactions among as many as three antiemetic interventions. Of these patients, 4123 were randomly assigned to 1 of 64 possible combinations of six prophylactic interventions: 4 mg of ondansetron or no ondansetron; 4 mg of dexamethasone or no dexamethasone; 1.25 mg of droperidol or no droperidol; propofol or a volatile anesthetic; nitrogen or nitrous oxide; and remifentanil or fentanyl. The remaining patients were randomly assigned with respect to the first four interventions. The primary outcome was nausea and vomiting within 24 hours after surgery, which was evaluated blindly.

Results: Ondansetron, dexamethasone, and droperidol each reduced the risk of postoperative nausea and vomiting by about 26 percent. Propofol reduced the risk by 19 percent, and nitrogen by 12 percent; the risk reduction with both of these agents (i.e., total intravenous anesthesia) was thus similar to that observed with each of the antiemetics. All the interventions acted independently of one another and independently of the patients' baseline risk. Consequently, the relative risks associated with the combined interventions could be estimated by multiplying the relative risks associated with each intervention. Absolute risk reduction, though, was a critical function of patients' baseline risk.

Conclusions: Because antiemetic interventions are similarly effective and act independently, the safest or least expensive should be 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-risk patients.

N Engl J Med 2004;350: 2441-51.



Anesthesia is given to more than 75 million surgical patients annually, worldwide. Untreated, one third will have postoperative nausea, vomiting, or both. [1-3] Patients often rate postoperative nausea and vomiting as worse than postoperative pain. [4,5] It is not surprising, therefore, that prevention of postoperative nausea and vomiting improves satisfaction among patients who are likely to experience them. [6] Vomiting increases the risk of aspiration and has been associated with suture dehiscence, esophageal rupture, subcutaneous emphysema, and bilateral pneumothoraxes. [7,8] Postoperative nausea and vomiting frequently delay discharge from postanesthesia care units, and they are the leading cause of unexpected hospital admission after planned ambulatory surgery. [9] The annual cost of postoperative nausea and vomiting in the United States is thought to be several hundred million dollars. [10,11]

More than 1000 randomized, controlled trials have evaluated pharmacologic methods of preventing and treating postoperative nausea and vomiting. Most have compared a single intervention with placebo. Serotonin (5-hydroxytryptamine type 3) antagonists (e.g., ondansetron), dexamethasone (a corticosteroid), and droperidol (a neuroleptic drug) are among the best-studied antiemetic agents. Alternatively, the avoidance of emetogenic factors during anesthesia can reduce the baseline risk of postoperative nausea and vomiting. This strategy includes the use of propofol instead of volatile anesthetics, the substitution of nitrogen for nitrous oxide, and the use of remifentanil, an ultra-short-acting opioid, instead of fentanyl. [12,13]

The limited efficacy of treatment with single antiemetics [14] has prompted evaluations of several antiemetic strategies used in combination. [15] However, no previous study of postoperative nausea and vomiting has had an appropriate design or sufficient power to evaluate all the major pharmacologic interventions simultaneously or to determine the extent to which combining multiple interventions improves outcome. A recent consensus conference was thus unable to support a definitive statement on the benefits of combining antiemetic strategies. [16] We therefore conducted a large clinical trial of factorial design with sufficient power to compare the efficacy of six well-established antiemetic strategies and to determine the extent to which efficacy could be improved by combining two or three interventions.

Methods

The design of the study, the recruitment of patients at each center, the acquisition and management of data, the statistical analyses, the interpretation of the data, and the writing and editing of the manuscript were performed independently of the sponsors. The contributions of the individual authors are listed in the Appendix.

After obtaining approval from the institutional review boards of the 28 participating centers, we enrolled 5199 adults who were scheduled to undergo elective surgery during general anesthesia that was expected to last at least one hour. All the patients had a risk of postoperative nausea and vomiting that exceeded 40 percent, according to a simplified risk score, [17] based on the presence of at least two of the following risk factors: female sex, nonsmoker status, previous history of postoperative nausea and vomiting or motion sickness, and anticipated use of postoperative opioids. [18,19] We excluded patients in whom any of the study drugs were contraindicated, those who had taken emetogenic or antiemetic drugs within the 24 hours before surgery, those who were expected to require postoperative mechanical ventilation, and those who were pregnant or lactating. All the patients provided their written informed consent.

Protocol

The antiemetic efficacy of six individual treatments and combinations of them was simultaneously evaluated according to a 2 [6] factorial design. [20] Three of the prophylactic interventions involved the use of an antiemetic drug: ondansetron, dexamethasone, or droperidol. The other three interventions consisted of the use of propofol instead of a volatile anesthetic, the omission of nitrous oxide, and the substitution of remifentanil for fentanyl. Thus, according to the study design, each patient was to be randomly assigned to one of each of the following six interventions: ondansetron (4 mg intravenously) or no ondansetron; dexamethasone (4 mg intravenously) or no dexamethasone; droperidol (1.25 mg intravenously) or no droperidol; propofol or a volatile anesthetic (i.e., isoflurane, desflurane, or sevoflurane) in a 2:1 ratio; nitrogen or nitrous oxide; and remifentanil or fentanyl.

These 6 treatments lead to a possible 64 (i.e., 2 [6]) different treatment combinations. However, propofol is associated with a reduced risk of postoperative nausea and vomiting, [21] so to ensure sufficient power to quantify the effect of antiemetics in the propofol subgroup, we assigned twice as many patients to propofol as to volatile anesthetics (for a 2:1 randomization ratio). Therefore, permuted blocks of 96 (2(3)) x 3 x 2(2))) patients were generated. Each center received four blocks with a unique computerized randomization, stored in sequentially numbered, sealed, opaque envelopes.

The envelopes were opened after consent was obtained, just before the induction of general anesthesia. The anesthesiologists responsible for intraoperative management were not blinded to the treatment, but they were not involved in the postoperative assessment. Supplemental oxygen may [22,23] or may not [24,25] have an antiemetic effect. Consequently, at three centers patients were randomly assigned to 30 percent oxygen in nitrous oxide, 30 percent oxygen in nitrogen, or 80 percent oxygen in nitrogen, in a randomization ratio of 1:1:1. As a result, a minimum of 144 (3x48) patients were required per block. To provide sufficient power, each center agreed to study 288 patients, twice as many as the minimum.

The patients were given premedication with a benzodiazepine. Three minutes before the induction of anesthesia, they received either a bolus of fentanyl (100 to 200 microg) or an infusion of remifentanil (0.25 microg per kilogram of body weight per minute), according to the treatment to which they had been assigned. Anesthesia was induced with intravenous propofol (Disoprivan or Diprivan, AstraZeneca) at a dose of 2 to 3 mg per kilogram, and tracheal intubation was facilitated with rocuronium.

Normocapnic mechanical ventilation was instituted with the assigned gas combination. Anesthesia was maintained with either propofol (starting at about 80 microg per kilogram per hour) or a standardized concentration of a volatile anesthetic. If the heart rate or blood pressure deviated by more than 20 percent from the preoperative value, an intravenous bolus of fentanyl (50 to 100 microg) was given or the rate of remifentanil infusion was increased slightly. In addition, the concentration of volatile anesthetics or the propofol infusion rate could be adjusted as clinically appropriate. In the designated patients, 4 mg of dexamethasone (if assigned) and 1.25 mg of droperidol (if assigned) were given intravenously within 20 minutes after the start of anesthesia, [10,26] and 4 mg of ondansetron (if assigned) was given intravenously during the last 20 minutes of surgery. [27]

Postoperatively, the patients received supplemental oxygen, and pain was ameliorated with the use of nonsteroidal antiinflammatory medications administered intraoperatively. The patients who had been assigned to receive intraoperative remifentanil were given 50 microg of morphine per kilogram or an equivalent opioid at the end of surgery. The need for a postoperative opioid was left to the discretion of the anesthesiologist, and the dose was adjusted according to clinical needs. Patients who requested antiemetic therapy or who had an emetic episode were given 4 mg of ondansetron; if symptoms persisted, 4 mg of dexamethasone and 1.25 mg of droperidol were added.

Measurements

Our primary outcome measure was the incidence of any nausea, emetic episodes (retching or vomiting), or both (i.e., postoperative nausea and vomiting) during the first 24 postoperative hours. After the 2nd and 24th postoperative hours, trained investigators who were fully blinded to the intraoperative management and random treatment assignments recorded the number of emetic episodes and the time each one occurred. At both these time points, patients orally rated their worst nausea episode during the preceding interval on an 11-point scale, where 0 represented no nausea and 10 the most severe nausea possible.

Statistical Analysis

Different sample-size estimations were performed and indicated that about 5000 patients would be needed for the analysis of interactions involving as many as three factors, whereas the number of patients required for the analysis of two-factor interactions or of single factors was considerably smaller. [20] An interaction was defined as present if the effect of two factors in combination was significantly different from the separate effects of each factor multiplied together on an odds-ratio scale.

For each of the six randomized treatments, the numbers of patients who had postoperative nausea and vomiting were compared with the use of chi-square tests for each main effect, and reductions in the relative risk of nausea and vomiting were estimated. Logistic-regression analyses were used to quantify the relative effects of the six interventions as odds ratios and to identify potential two- or three-factor interactions by a stepwise forward-inclusion algorithm. This analysis was repeated to compensate for the specified covariates (female sex, nonsmoking status, age, a history of postoperative nausea and vomiting or motion sickness, use of postoperative opioids, type of surgery, and study center). A two-sided P value of less than 0.05 was considered to indicate statistical significance.

Results

Patients were recruited from February 2, 2000, until July 30, 2002, at 28 centers; 5199 patients underwent factorial randomization to ondansetron or no ondansetron, dexamethasone or no dexamethasone, droperidol or no droperidol, and propofol or a volatile anesthetic. Outcome data were incomplete for 38 patients, leaving 5161 patients (99 percent) for whom complete outcome data were available. One center each did not randomize with respect to carrier gas (424 patients), use of remifentanil or fentanyl (191 patients), or both of these factors (181 patients). Three centers randomly assigned a total of 280 patients to 80 percent oxygen in nitrogen (as a third alternative to 30 percent oxygen in nitrogen or in nitrous oxide). A total of 4123 patients were thus randomly assigned with respect to all six primary factors, and outcome data were incomplete in 37 of them (1 patient with incomplete data was among those not randomly assigned with respect to carrier gas), leaving 4086 patients (99 percent) for whom complete outcome data could be analyzed (Figure 1).

Figure 1 Figure 1 Opens a popup window Opens a popup window Opens a popup window

Of the 5161 patients, 81.5 percent were women, 81.2 percent were nonsmokers, 54.5 percent had a history of postoperative nausea and vomiting or motion sickness, and 78.1 percent received postoperative opioids. Hernia repair was performed in 2.8 percent of the patients, cholecystectomy in 7.7 percent, hysterectomy in 16.9 percent, thyroid surgery in 5.9 percent, breast surgery in 2.8 percent, hip replacement in 3.5 percent, knee arthroscopy in 2.2 percent, arm or hand surgery in 2.5 percent, head and neck surgery (including ophthalmic surgery) in 9.0 percent, gynecologic surgery other than hysterectomy in 28.2 percent, other bone surgery in 6.6 percent, and other types of general surgery in 11.7 percent. The baseline characteristics were similar among the patients randomly assigned to each intervention; more detailed information can be found in Table S1of the Supplementary Appendix 1 (available with the full text of this article at http://www.nejm.org).

Overall, 1731 of 5161 patients (34 percent) had postoperative nausea and vomiting. This reflects the average incidence among all 64 possible combinations of interventions, which ranged from 59 percent among patients who were given volatile anesthesia, nitrous oxide, fentanyl, and no antiemetics (26 of 44 of these patients had nausea and vomiting) to 17 percent among patients who received propofol, nitrogen, remifentanil, ondansetron, dexamethasone, and droperidol (17 of 102 of these patients had nausea and vomiting). Nausea occurred in 1617 patients (31 percent) and vomiting in 734 (14 percent). Among the patients who had symptoms, the median and mean ratings for the maximal nausea level were 5 and 5.7, respectively, and the median and mean numbers of emetic episodes were 1 and 1.5, respectively. According to bivariate analyses, each antiemetic reduced the incidence of postoperative nausea and vomiting by about 26 percent, propofol reduced it by about 19 percent, and nitrogen reduced it by about 12 percent (Table 1). The rates of hypotension, use of intraoperative vasoconstrictors, and shivering were similar with each antiemetic. Propofol was associated with less frequent use of intraoperative vasoconstrictors (15 percent) than were volatile anesthetics (20 percent, P=0.001). The use of remifentanil rather than fentanyl did not significantly reduce the incidence of postoperative nausea and vomiting, but it was associated with increased use of intraoperative vasoconstrictors (21 percent, vs. 13 percent with fentanyl; P<0.001) and an increased incidence of shivering (6.7 percent, vs. 3.3 percent with fentanyl; P<0.001).

Table 1 Table 1 Opens a popup window Opens a popup window Opens a popup window

Increasing the number of antiemetics administered reduced the incidence of postoperative nausea and vomiting from 52 percent when no antiemetics were used to 37 percent, 28 percent, and 22 percent when one, two, and three antiemetics, respectively, were administered (Figure 2). This corresponds to a 26 percent reduction in the relative risk of nausea and vomiting for each additional antiemetic used (95 percent confidence interval, 23 percent to 30 percent). Furthermore, there were no significant differences among the antiemetics (chi-square=0.01, 2 df; P=1.00) or among any pair of antiemetics (chi-square=0.42, 2 df; P=0.81).

Figure 2 Figure 2 Opens a popup window Opens a popup window Opens a popup window

The effects of the anesthetic interventions and their combinations were explored in the 4086 patients who were randomly assigned with respect to all six interventions. The average incidence of postoperative nausea and vomiting was 41 percent among those given a volatile anesthetic and nitrous oxide, 34 percent among those given a volatile anesthetic and nitrogen, 32 percent among those given propofol and nitrous oxide, and 29 percent among those given propofol and nitrogen. Figure 3 shows these incidences broken down according to the number of antiemetics. There was no significant interaction between propofol and nitrogen (chi-square=0.94, 2 df, by the likelihood ratio test; P=0.33). Although the type of volatile anesthetic (isoflurane, sevoflurane, or desflurane) was not a randomized factor, it had no significant effect on the incidence of postoperative nausea and vomiting in a multivariate model (P=0.30). The incidence of postoperative nausea and vomiting was 31 percent among the patients who received 80 percent oxygen in nitrogen and 24 percent among those who received 30 percent oxygen in nitrogen (P=0.07).

Figure 3 Figure 3 Opens a popup window Opens a popup window Opens a popup window

Multivariate logistic analyses of data from all 5161 patients and of data from the 4086 patients assigned with respect to all six treatments are shown in Table 2. This analysis found no significant interactions among the treatments. When the interactions between treatments and potentially confounding factors (e.g., the type of surgery) were analyzed, only one significant interaction was detected: an interaction between droperidol and sex (P=0.003). Droperidol significantly reduced the risk of postoperative nausea and vomiting among women, but not among men: 910 of the 2106 women who did not receive droperidol had nausea or vomiting (43 percent), as compared with 662 of the 2101 women who did receive this agent (32 percent) (odds ratio, 0.61; 95 percent confidence interval, 0.53 to 0.69; P<0.001), and the effect was independent of menstrual-cycle phase or whether menopause had occurred; in contrast, 79 of the 482 men who did not receive droperidol had nausea or vomiting (16 percent), as compared with 80 of the 472 men who did receive this agent (17 percent) (odds ratio, 1.04; 95 percent confidence interval, 0.74 to 1.46; P=0.82).

Table 2 Table 2 Opens a popup window Opens a popup window Opens a popup window

The results based on analyses of data from 4086 patients remained essentially unchanged when data from all 5161 patients were considered or when potential confounders were included in the statistical models (Table 2). Detailed results for the 4086 patients in the 64 groups are given in Table S2of the Supplementary Appendix 1. Given the finding that total intravenous anesthesia or the use of any antiemetic independently reduced the risk of postoperative nausea and vomiting by about 26 percent, the incidence of postoperative nausea and vomiting for five different initial risks was calculated for as many as four interventions (Table 3).

Table 3 Table 3 Opens a popup window Opens a popup window Opens a popup window

Discussion

The large enrollment and the factorial design of our trial allowed simultaneous evaluation of the antiemetic efficacy of three antiemetic interventions and three anesthetic interventions and of all possible combinations of two or three interventions. All the tested antiemetics appeared to be similarly effective. Ondansetron and other 5-hydroxytryptamine type 3 antagonists are considered relatively safe, but they are more expensive than droperidol and dexamethasone. However, low-dose droperidol can cause dysphoria, [28,29] and the Food and Drug Administration recently added a "black box" warning to the drug's labeling to indicate that it may be associated with torsade de pointes; however, there is little evidence that antiemetic doses trigger this condition. [30] No studies have identified complications associated with the antiemetic dose of dexamethasone, although even meta-analyses may have insufficient power to detect rare complications. [31] The combination of low cost and apparent safety makes dexamethasone at a dose of 4 mg an attractive first-line agent for prophylaxis against postoperative nausea and vomiting.

Bivariate analysis indicated that substituting propofol for a volatile anesthetic reduced the risk of postoperative nausea and vomiting by about 19 percent, whereas substituting nitrogen for nitrous oxide reduced the risk by about 12 percent. Combining these two anesthetic management strategies (i.e., total intravenous anesthesia) thus reduced the risk by about as much as any single antiemetic. In contrast, the use of remifentanil instead of fentanyl did not significantly reduce the risk of nausea and vomiting.

The relative risk reduction associated with each intervention was apparently independent for a wide range of absolute risks. Thus, interventions that reduce the relative risk to a similar extent will provide the greatest absolute risk reduction in patients most likely to have postoperative nausea and vomiting. For example, a single intervention in a patient with an 80 percent risk of postoperative nausea and vomiting will reduce the risk to 59 percent; the absolute risk reduction is 21 percent, which translates into a number needed to treat of about five to prevent nausea and vomiting in one patient. Conversely, the absolute risk reduction in a patient with a baseline risk of 10 percent is only about 3 percent; this corresponds to a number needed to treat of about 40, which would probably not justify the expense and risk of prophylactic treatment. The efficacy of an intervention thus depends critically on patients' baseline risk.

Interestingly, there were no significant interactions among the antiemetic interventions, among the anesthetic interventions, or among the antiemetics and the anesthetics. The resulting relative risk of nausea and vomiting associated with a combination of interventions can thus be directly calculated as the product of the individual relative risks. As a consequence, the absolute risk reduction provided by a second or third intervention is less than that provided by the initial intervention (irrespective of which combination is chosen). A 70 percent reduction in the relative risk of postoperative nausea and vomiting is thus the best that can be expected, even when total intravenous anesthesia is used in combination with three antiemetics.

Because each tested antiemetic agent and the use of total intravenous anesthesia reduced the relative risk of nausea and vomiting to a similar extent, the logical sequence is to use the least expensive or safest intervention first. Additional interventions that cost more or that are associated with a greater chance of adverse effects will further reduce the absolute risk, but to a lesser extent than will the initial intervention. Combining prophylactic interventions therefore markedly increases costs and the likelihood of adverse effects while providing progressively less additional absolute benefit. Multiple interventions should thus generally be reserved for patients at high risk for postoperative nausea and vomiting or those in whom nausea and vomiting would be especially dangerous.

In analyses based on the entire study population, droperidol decreased the risk of postoperative nausea and vomiting as much as did the other antiemetics, but when sex was considered, no significant benefit was found in men. Such a finding has not been described in previous studies, presumably because many studies have been restricted to women and because studies that included both sexes were too small to detect the interaction. Estrogen or other hormonal factors seem unlikely to be the cause, since the effectiveness of droperidol was independent from menstrual-cycle phase and menopause (data not shown). It is possible that dopamine is a more important trigger in women than in men. It is also possible that the lack of efficacy of droperidol in men is simply a spurious finding resulting from multiple testing.

It is well known that the incidence of postoperative nausea and vomiting varies considerably according to the type of surgery conducted. However, with the exception of hysterectomy and possibly cholecystectomy, the relative risk was similar for all types of surgery when corrected for major risk factors including sex, nonsmoking status, a history of postoperative nausea and vomiting, and the use of postoperative opioids. As a consequence, risk models that include the type of surgery [1,32] do not provide greater predictive power than a simplified model. [18,19] Since no interactions were detected between the interventions and the type of surgery, it is not necessary to repeat studies of postoperative nausea and vomiting for various types of surgery. [14,33]

Management techniques such as total intravenous anesthesia cannot be used once postoperative nausea and vomiting have begun. Dexamethasone, similarly, prevents postoperative nausea and vomiting only when given near the beginning of surgery, probably by reducing surgery-induced inflammation. [34] Moreover, "rescue" treatments are ineffective when the same drug has already been used prophylactically. [35] Postoperative treatment options are thus limited when compared with the broader range of prophylactic options, suggesting that prophylaxis may be preferable to the treatment of established postoperative nausea and vomiting. A reasonable treatment strategy would be to use dexamethasone and total intravenous anesthesia as first-line and second-line methods of prophylaxis against postoperative nausea and vomiting and to reserve serotonin antagonists as a rescue treatment.

Supported by a grant (1518 TG 72) from the Klinik fur Anaesthesiologie, Julius-Maximilians Universitat, Wurzburg, Germany; a Helsinki University Central Hospital State Allocation grant (TYH 0324) from Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland; AstraZeneca, Wedel, Germany; GlaxoSmithKline, Hamburg, Germany; the Gheens Foundation, Louisville, Ky.; the Joseph Drown Foundation, Los Angeles; the Commonwealth of Kentucky Research Challenge Trust Fund, Louisville, Ky.; and a Health Grant (GM 061655) from the National Institutes of Health, Bethesda, Md.

Presented in part at meetings of the European Society of Anaesthesiologists, Glasgow, Scotland, June 2003; the German Society of Anesthesiologists, Munich, Germany, April 2003; and the American Society of Anesthesiologists, San Francisco, October 2003.

Dr. Apfel reports having served as a paid speaker for and having received grant support from AstraZeneca (Wedel, Germany) and GlaxoSmithKline (Munich, Germany), having served as a consultant for GlaxoSmithKline, and having served as a consultant for Merck (Whitehouse, N.Y.) and Helsinn Healthcare (Lugano, Switzerland) with respect to antiemetics unrelated to the products discussed in this article. Dr. Korttila reports having served as a consultant for Pharmacia/Pfizer (New London, Conn.) and Helsinn Healthcare and as a paid speaker for Pharmacia/Pfizer. Dr. Apfel and Dr. Sessler report having received a grant from Pharmacia/Pfizer for a grant-writing workshop. Dr. Sessler reports having received grants from Progenics (Tarrytown, N.Y.), Cardinal Health (McGraw Park, Ill.), Pfizer (New London, Conn.), Ocean Optics (Dunedin, Fla.), and Scott Laboratories (Lubbock, Tex.) for work unrelated to the field of antiemetic interventions.

We are indebted to Nancy L. Alsip, Ph.D., University of Louisville, for editorial assistance.

Appendix

The IMPACT investigators are as follows: Steering Committee - C.C. Apfel (Outcomes Research Institute and Department of Anesthesiology, University of Louisville, Louisville, Ky., and the Klinik und Poliklinik fur Anaesthesiologie, Universitat Wurzburg, Wurzburg, Germany); K. Korttila (Department of Anesthesiology and Intensive Care, University of Helsinki, Helsinki, Finland); and A. Biedler (Klinik fur Anasthesiologie und Intensivmedizin, Universitatskliniken des Saarlandes, Homburg, Germany). Data Management and Monitoring - C.C. Apfel, E. Kaufmann, M. Kredel, A. Schmelzer, and J. Wermelt (Klinik und Poliklinik fur Anaesthesiologie, Universitat Wurzburg, Wurzburg, Germany); and G. Link (Database Engineering, Rimpar, Germany). Manuscript Preparation and Data Analyses - C.C. Apfel (Outcomes Research Institute and Department of Anesthesiology, University of Louisville, Louisville, Ky., and the Klinik und Poliklinik fur Anaesthesiologie, Universitat Wurzburg, Wurzburg, Germany); D.I. Sessler (Outcomes Research Institute and Departments of Anesthesiology and Pharmacology, University of Louisville, Louisville, Ky.); S.J. Pocock and M. Abdalla (Statistics Unit, London School of Hygiene and Tropical Medicine, London). Site Investigators - A. Turan (Department of Anesthesiology and Reanimation, Trakya University, Edirne, Turkey); E. Kaufmann, P. Kranke, M. Kredel, N. Roewer, A. Schmelzer, and J. Wermelt (Klinik und Poliklinik fur Anasthesiologie, Julius-Maximilians Universitat, Wurzburg, Germany); R.M. Jokela, A. Soikkeli, and K. Korttila (Department of Anesthesiology and Intensive Care, Helsinki University Central Hospital, Helsinki, Finland); C. Isselhorst, B. Fritz, and H. Kerger (Klinik fur Anasthesiologie und Intensivmedizin, Universitatsklinik Mannheim, Mannheim, Germany); O. Danzeisen, C. Heringhaus, I. Schramm, and S. Spieth (Department of Anesthesiology, Universitat Freiburg, Freiburg, Germany); L. Eberhart and K. Werthwein (Department of Anesthesiology, Universitat Ulm, Ulm, Germany); W. Leidinger, J.N. Meierhofer, U. Ruppert, and C. Zernak (Abteilung fur Anasthesiologie, Operative Intensivmedizin, und Blutprodukte, Kreiskrankenhaus Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany); A. Bacher (Klinik fur Anasthesie und Allgemeine Intensivmedizin, Universitat Wien, Vienna); H. Bartsch and H. Forst (Department of Anesthesiology and Surgical Intensive Care, Zentralklinikum Augsburg, Augsburg, Germany); B. Book, W. Hoeltermann, and C. Prause (Department of Anesthesiology, Klinikum Lingen, Lingen, Germany); E. Palencikova and S. Trenkler (Department of Anesthesiology, Reiman University Hospital, Presov, Slovakia); H. Bause, H. Bordon, and K. Stoecklein (Department of Anesthesiology, Allgemeines Krankenhaus Altona, Hamburg-Altona, Germany); F. Bach, D. Buschmann, F. Mertzlufft, and I. Vedder (Klinik fur Anasthesiologie und Operative Intensivmedizin, von Bodelschwingsche Anstalten Bethel, Bielefeld, Germany); C. Frenkel and A. Paura (Department of Anesthesiology, Klinikum Luneburg, Luneburg, Germany); K. Danner, C. Madler, and B. Steinbrecher (Institut fur Anasthesiologie und Notfallmedizin, Westpfalz-Klinikum, Kaiserslautern, Germany); A. Kimmich, E. Schneider, and M. Trick (Department of Anesthesiology, Universitatsklinik Tubingen, Tubingen, Germany); A. Biedler, D. Detzel, and W. Wilhelm (Klinik fur Anasthesiologie und Intensivmedizin, Universitatskliniken des Saarlandes, Homburg, Germany); M. Koivuranta (Department of Anesthesiology, Central Lapland Hospital, Rovaniemi, Finland); M. Hinojosa, M. Lucas, S. Munoz, R. Rincon, and P. Vila (Department of Anesthesiology, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, Spain); M. Hergert and F. Liebenow (Department of Anesthesiology and Intensive Care, Klinikum Schwerin, Schwerin, Germany); H.-B. Hopf and S. Pohl (Department of Anesthesiology, Kreisklinik Langen, Langen, Germany); G. Frings (Anesthesiology Unit, Wedau-Kliniken, Duisburg); G. Fritz and C. Hoehne (Department of Anesthesiology, Charite, Campus Virchow-Klinikum, Berlin); H. Feierfeil and J. Motsch (Department of Anesthesiology, Universitat Heidelberg, Heidelberg, Germany); A. Goebel (Department of Anesthesiology, Eichhof Krankenhaus, Lauterbach, Germany); S. Alahuhta, T. Kangas-Saarela, and P. Karjaleinen (Department of Anesthesiology, Oulu University Hospital, Oulu, Finland); R. Sneyd (Department of Anaesthetics, Derriford Hospital, Plymouth, United Kingdom); and U. Koschel and M. Lange (Department of Anesthesiology, Waldkrankenhaus Rudolf Elle, Eisenberg, Germany).

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7. Schumann R, Polaner DM. Massive subcutaneous emphysema and sudden airway compromise after postoperative vomiting. Anesth Analg 1999;89:796-7. Buy Now [Context Link]

8. Bremner WG, Kumar CM. Delayed surgical emphysema, pneumomediastinum and bilateral pneumothoraces after postoperative vomiting. Br J Anaesth 1993;71:296-7. Full Text [Context Link]

9. Gold BS, Kitz DS, Lecky JH, Neuhaus JM. Unanticipated admission to the hospital following ambulatory surgery. JAMA 1989;262:3008-10. [Context Link]

10. Hill RP, Lubarsky DA, Phillips-Bute B, et al. Cost-effectiveness of prophylactic antiemetic therapy with ondansetron, droperidol, or placebo. Anesthesiology 2000;92:958-67. Buy Now [Context Link]

11. Watcha MF. The cost-effective management of postoperative nausea and vomiting. Anesthesiology 2000;92:931-3. [Context Link]

12. Apfel CC, Kranke P, Katz MH, et al. Volatile anaesthetics may be the main cause for early but not delayed postoperative nausea and vomiting: a randomized controlled trial of factorial design. Br J Anaesth 2002;88:659-68. Full Text [Context Link]

13. Divatia JV, Vaidya JS, Badwe RA, Hawaldar RW. Omission of nitrous oxide during anesthesia reduces the incidence of postoperative nausea and vomiting: a meta-analysis. Anesthesiology 1996;85:1055-62. Buy Now [Context Link]

14. Tramer MR. A rational approach to the control of postoperative nausea and vomiting: evidence from systematic reviews. I. Efficacy and harm of antiemetic interventions, and methodological issues. Acta Anaesthesiol Scand 2001;45:4-13. Buy Now [Context Link]

15. Scuderi PE, James RL, Harris L, Mims GR III. Multimodal antiemetic management prevents early postoperative vomiting after outpatient laparoscopy. Anesth Analg 2000;91:1408-14. Buy Now [Context Link]

16. Gan TJ, Meyer T, Apfel CC, et al. Consensus guidelines for management of postoperative nausea and vomiting. Anesth Analg 2003;97:62-71. Buy Now [Context Link]

17. Apfel CC, Laara E, Koivuranta M, Greim CA, Roewer N. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology 1999;91:693-700. Buy Now [Context Link]

18. Pierre S, Benais H, Pouymayou J. Apfel's simplified score may favourably predict the risk of postoperative nausea and vomiting. Can J Anaesth 2002;49:237-42. [Context Link]

19. Apfel CC, Kranke P, Eberhart LHJ, Roos A, Roewer N. Comparison of predictive models for postoperative nausea and vomiting. Br J Anaesth 2002;88:234-40. Full Text [Context Link]

20. Apfel CC, Korttila K, Abdalla M, et al. An international multicenter protocol to assess the single and combined benefits of antiemetic interventions in a controlled clinical trial of a 2x2x2x2x2x2 factorial design (IMPACT). Control Clin Trials 2003;24:736-51. [Context Link]

21. Sneyd JR, Carr A, Byrom WD, Bilski AJ. A meta-analysis of nausea and vomiting following maintenance of anaesthesia with propofol or inhalational agents. Eur J Anaesthesiol 1998;15:433-45. [Context Link]

22. Greif R, Laciny S, Rapf B, Hickle RS, Sessler DI. Supplemental oxygen reduces the incidence of postoperative nausea and vomiting. Anesthesiology 1999;91:1246-52. [Context Link]

23. Goll V, Akca O, Greif R, et al. Ondansetron is no more effective than supplemental intraoperative oxygen for prevention of postoperative nausea and vomiting. Anesth Analg 2001;92:112-7. Buy Now [Context Link]

24. Purhonen S, Turunen M, Ruohoaho U-M, Niskanen M, Hynynen M. Supplemental oxygen does not reduce the incidence of postoperative nausea and vomiting after ambulatory gynecologic laparoscopy. Anesth Analg 2003;96:91-6. Buy Now [Context Link]

25. Joris JL, Poth NJ, Djamadar AM, et al. Supplemental oxygen does not reduce postoperative nausea and vomiting after thyroidectomy. Br J Anaesth 2003;91:857-61. Full Text [Context Link]

26. Liu K, Hsu CC, Chia YY. The effect of dose of dexamethasone for antiemesis after major gynecological surgery. Anesth Analg 1999;89:1316-8. Buy Now [Context Link]

27. Tang J, Wang B, White PF, Watcha MF, Qi J, Wender RH. The effect of timing of ondansetron administration on its efficacy, cost-effectiveness, and cost-benefit as a prophylactic antiemetic in the ambulatory setting. Anesth Analg 1998;86:274-82. Buy Now [Context Link]

28. Melnick B, Sawyer R, Karambelkar D, Phitayakorn P, Uy NT, Patel R. Delayed side effects of droperidol after ambulatory general anesthesia. Anesth Analg 1989;69:748-51. [Context Link]

29. Lim BS, Pavy TJ, Lumsden G. The antiemetic and dysphoric effects of droperidol in the day surgery patient. Anaesth Intensive Care 1999;27:371-4. Buy Now [Context Link]

30. Gan TJ, White PF, Scuderi PE, Watcha MF, Kovac A. FDA "black box" warning regarding use of droperidol for postoperative nausea and vomiting: is it justified? Anesthesiology 2002;97:287. Buy Now [Context Link]

31. Henzi I, Walder B, Tramer MR. Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg 2000;90:186-94. Buy Now [Context Link]

32. Sinclair DR, Chung F, Mezei G. Can postoperative nausea and vomiting be predicted? Anesthesiology 1999;91:109-18. Buy Now [Context Link]

33. Apfel CC, Roewer N, Korttila K. How to study postoperative nausea and vomiting. Acta Anaesthesiol Scand 2002;46:921-8. Buy Now [Context Link]

34. Wang JJ, Ho ST, Tzeng JI, Tang CS. The effect of timing of dexamethasone administration on its efficacy as a prophylactic antiemetic for postoperative nausea and vomiting. Anesth Analg 2000;91:136-9. Buy Now [Context Link]

35. Kovac AL, O'Connor TA, Pearman MH, et al. Efficacy of repeat intravenous dosing of ondansetron in controlling postoperative nausea and vomiting: a randomized, double-blind, placebo-controlled multicenter trial. J Clin Anesth 1999;11:453-9. [Context Link]



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