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SPA Newsletter.
A factorial trial of six interventions for the prevention of postoperative nausea and vomitingChristian C. Apfel, MD, et al. IMPACT Investigators. N Engl J Med 2004;350:2441-51 International Multicenter Protocol to Assess the Single and Combined Benefits of Antiemetic Interventions in a Controlled Clinical Trial Untreated, one third of adult patients undergoing anesthesia will have postoperative nausea, vomiting, or both. With infants, children, and teens, probabilities are even higher. Since anesthetics are administered to more than 75 million surgical patients annually, the cost of PONV is high in terms of giving rise to medical and surgical complications, extending stays postoperatively, adding expenses to patient and system, and contributing to human misery. In the last decade alone, more than 1,000 randomized, controlled trials were performed to evaluate pharmacologic methods of preventing and treating PONV. Numerous additional studies focused on identifying emetogenic risk factors by patient profile, type of surgery, and anesthetic agent or technique. Most of these studies have been unifactoral: a single intervention versus placebo. Because none of the previous studies had sufficient scope or design to analyze multiple interventions simultaneously, it was recognized at a recent international conference that it was not yet possible to put forth a set of consensus guidelines for the prevention and management of postoperative nausea and vomiting. This recognition led to the decision to design IMPACT, the International Multicenter Protocol to Assess the Single and Combined Benefits of Antiemetic Interventions in a Controlled Clinical Trial. The IMPACT investigators took six well-established antiemetic strategies and combined them in a factorial fashion to compare not just the relative efficacies of individual strategies, but to analyze the extent to which efficacy could be improved further by combining two or three interventions. Three of the prophylactic interventions involved the use of an antiemetic drug: ondansetron, dexamethasone, or droperidol. The other three interventions consisted of using propofol instead of a volatile anesthetic; air (nitrogen) instead of nitrous oxide; and remifentanil rather than longer-acting fentanyl. Based on studies demonstrating optimal sufficiency, doses of the antiemetic drugs were uniform throughout the study: ondansetron 4 mg IV, dexamethasone 4 mg IV, and droperidol 1.25 mg IV. To study the 64 possible combinations (2x2x2x2x2x2, or 2 to the 6th power), as well as to have enough left over to analyze possible sub-populations, the study for statistical purposes had to contain approximately 5,000 patients. These were gathered from 28 participating international centers for surgery. Overall, patient enrollment was slanted towards those adults most at risk for PONV. Of the 5,161 patients, 81.5% were women, 81.2% were non-smokers, 54.5% had a history of postoperative nausea and vomiting or motion sickness, and 78.1% received postoperative opioids. Surgical procedures included hernia repair (2.8%), cholecystectomy (7.7%), hysterectomy (16.9%), thyroid surgery (5.9%), breast surgery (2.8%), hip replacement (3.5%), knee arthroscopy (2.2%), upper extremity (2.5%), head & neck & eye surgery (9.0%), and gynecologic surgery other than hysterectomy (11.7%). Consistent with previous studies on incidence, 34% of the complete set of randomized 5,161 patients experienced PONV. However, 59% of patients receiving the combination of volatile anesthetics, nitrous oxide, fentanyl and NO antiemetics developed PONV, while only 17% of the patients who had received the combination of propofol, air, remifentanil, ondansetron, dexamethasone, and droperidol experienced a problem. According to bivariate analyses, each antiemetic reduced the incidence of PONV by about 26%; propofol reduced it by about 19%, and avoidance of nitrous oxide reduced it by about 12%. Increasing the number of antiemetics administered reduced the incidence of PONV from 52% when no antiemetics were used, to 37%, 28%, and 22% when one, two, or three antiemetics were administered. This corresponded to a 26% reduction in the relative risk for PONV for each additional prophylactic antiemetic used. There were no significant differences among the three antiemetics. The use of remifentanil rather than fentanyl did not significantly reduce the incidence of PONV, but it was associated with an increased use of intraoperative vasoconstrictors and with more postoperative shivering. When interactions between treatments and potentially confounding factors (e.g., type of surgery) were analyzed, only one significant interaction was detected: the relationship between gender and the effectiveness of droperidol. Droperidol significantly reduced the incidence of PONV among women, but not among men. The beneficial effect of droperidol was entirely independent of the phase of the woman's menstrual cycle or whether or not menopause had occurred. The investigators acknowledged the Food and Drug Administration's recent "Black Box" warning that droperidol may be associated with torsade de pointes, but observed there was little evidence that antiemetic doses of droperidol could trigger this arrhythmia. Ondansetron and other 5-hydroxytryptamine type 3 antagonists have an insignificant risk of side effects, but they are the most expensive of the antiemetics. Droperidol, even in low-dose antiemetic ranges, can be associated with dysphoria and other side effects. The investigators concluded that dexamethasone at an effective antiemetic dose of 4 mg had the most attractive profile as a first-line agent for prophylaxis against postoperative nausea and vomiting. However, they caution, it works only when given near the beginning of surgery. Once PONV has occurred, management techniques such as total intravenous anesthesia are no longer options. Furthermore, postoperative "rescue" drugs are no longer effective when the same drug has already been used prophylactically. IMPACT investigators concluded that for patients at greatest risk for post-operative nausea and/or vomiting, or for associated complications, risks may be reduced most significantly and reasonably by using the combination of a propofol-based total intravenous anesthesia, air-oxygen rather than nitrous oxide-oxygen, plus a single intraoperative antiemetic. Prophylaxis for PONV was preferable to and more effective than treatment of it once it had started. They favored ondansetron (and its serotonin antagonist relatives) for the "rescue" drug role, while promoting dexamethasone 4 mg at the start of the surgery as the first-line prophylactic antiemetic. Reviewed by: Anne E. Dickison, MD Table of Contents
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