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ANESTHETIC PHARMACOLOGY

A Randomized Comparison of a Multimodal Management Strategy Versus Combination Antiemetics for the Prevention of Postoperative Nausea and Vomiting

Ashraf S. Habib, MBBCh MSc, FRCA^*, William D. White, MPH^*, Steve Eubanks, MD, Theodore N. Pappas, MD, and Tong J. Gan, MB FRCA, FFARCS(I)^*

Departments of *Anesthesiology and Surgery, Duke University Medical Center, Durham, North Carolina

Address correspondence and reprint requests to Tong J. Gan, MB, FRCA, FFARCS(I), Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710. Address e-mail to Gan00001{at}mc.duke.edu

	Abstract

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A multimodal management strategy for the prevention of postoperative nausea and vomiting (PONV) appears to be superior to single-drug prophylaxis. We tested the hypothesis that a multimodal PONV prophylaxis regimen incorporating total IV anesthesia (TIVA) with propofol and a combination of ondansetron and droperidol is more effective than a combination of these antiemetics in the presence of an inhaled anesthetic. Ninety patients undergoing laparoscopic cholecystectomy were randomized to one of three groups. Group 1 (multimodal group) received TIVA with propofol, droperidol, and ondansetron. Group 2 (combination group) received droperidol and ondansetron with isoflurane and nitrous oxide for the maintenance of anesthesia. Group 3 (TIVA group) received propofol for the induction and maintenance of anesthesia. The complete response rate (no PONV and no rescue antiemetic) at 2 h after surgery was 90%, 63%, and 66% in Groups 1, 2, and 3, respectively (P < 0.05, Group 1 versus Group 2). At 24 h, the complete response rate was 80%, 63%, and 43% in Groups 1, 2, and 3, respectively (P < 0.05, Group 1 versus Group 3). Patient satisfaction was also greater in the multimodal group than in the other two groups in the postanesthesia care unit (P < 0.05). In conclusion, the multimodal management strategy for PONV was associated with a higher complete response rate and greater patient satisfaction when compared with similar antiemetic prophylaxis with inhaled anesthesia or TIVA with propofol.

IMPLICATIONS: A multimodal management strategy for postoperative nausea and vomiting was superior to combination antiemetic prophylaxis with inhaled anesthetic or total IV anesthesia with propofol.

	Introduction

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Postoperative nausea and vomiting (PONV) are common after laparoscopic cholecystectomy, with a reported incidence from 53% to 72% (1–4). Because of the multifactorial etiology of PONV, there has been increasing interest in using a combination of antiemetics from different classes for PONV prophylaxis. Total IV anesthesia (TIVA) with propofol has also been shown to be associated with less PONV compared with inhaled drugs, especially in the early postoperative period (5–7). The use of a multimodal approach incorporating both TIVA and a combination of antiemetic drugs was reported to be associated with an incidence of PONV less than 10%. To date, all the studies that investigated a multimodal approach for PONV prophylaxis compared the multimodal regimen with standard balanced anesthesia using a volatile anesthetic with or without single-drug antiemetic prophylaxis (8,9). No studies have compared this technique with a combination of two antiemetics in the presence of volatile anesthetics or with TIVA with propofol.

Therefore, we designed this prospective double-blinded randomized controlled trial to test the hypothesis that a multimodal PONV prophylaxis regimen incorporating TIVA with propofol and a combination of ondansetron and droperidol is more effective than a combination of the same antiemetics in the presence of an isoflurane/nitrous oxide-based anesthetic or TIVA with propofol in ambulatory patients undergoing laparoscopic cholecystectomy.

	Methods

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Ninety adult patients scheduled for laparoscopic cholecystectomy were enrolled in this study after we obtained IRB approval and written, informed patient consent. Exclusion criteria were ASA physical status IV or V; antiemetic or glucocorticosteroid use within 24 h of surgery; allergy to ondansetron, droperidol, or propofol; pregnancy; breast-feeding; obesity (body mass index >34 kg/m²); mental retardation; or psychiatric illness. For women of childbearing potential, a negative serum ß-human chorionic gonadotropin test was confirmed before enrollment.

The anesthetic technique was standardized. All patients received midazolam up to 2 mg IV and fentanyl up to 100 µg as premedication. Patients were randomly assigned to one of three treatment groups. Randomization was achieved by using a sealed envelope technique and was prepared by independent personnel not associated with the study. In Group 1 (multimodal group), propofol 1.5–2.5 mg/kg was used for the induction and propofol 50–150 µg · kg^–1 · min^–1 for maintenance of anesthesia with 50% oxygen in air (no nitrous oxide). Droperidol 0.625 mg was given IV at the induction of anesthesia, and ondansetron 4 mg was given IV at the end of surgery. In Group 2 (combination group), propofol 1.5–2.5 mg/kg was used for the induction of anesthesia, followed by maintenance with 0.5%–2.5% inspired isoflurane and 50% nitrous oxide in oxygen. Droperidol 0.625 mg was given IV at the induction of anesthesia, and ondansetron 4 mg was given IV at the end of surgery. Patients in Group 3 (TIVA group) received propofol 1.5–2.5 mg/kg for induction and propofol 50–150 µg · kg^–1 · min^–1 for maintenance of anesthesia with 50% oxygen in air (no nitrous oxide). The patients’ tracheas were intubated by using a muscle relaxant of the anesthesiologist’s choice. An orogastric tube was inserted for suction of gastric contents after the induction of anesthesia and was removed at the end of surgery. Intraoperative analgesia was provided by fentanyl up to 5 µg · kg^–1 · h^–1. Ketorolac 30 mg IV was also given at the end of surgery. Local infiltration with 10 mL of bupivacaine 0.5% was administered around the trocar incision sites. Muscle relaxation was reversed with neostigmine 70 µg/kg and glycopyrrolate 10 µg/kg.

Data were collected by an independent research nurse who was unaware of the patients’ randomization. The duration of surgery and anesthesia, as well as the length of postanesthesia care unit (PACU) stay, were recorded. Postoperative assessments were made at 0, 30, 60, 90, and 120 min in PACU and at 24 h by telephone interview with a trained interviewer blinded to the patient’s group. Nausea, emetic episodes, nausea score (11-point, linear numeric scale from 0 to 10, where 0 represents no nausea and 10 represents the worst nausea; this concept was explained to the patients before surgery), sedation scores (0–5; a modified Observer’s Assessment of Alertness/Sedation Scale) (10), and rescue antiemetic use were recorded during these time intervals. The time to readiness for PACU discharge—when patients were fully awake and oriented, had stable vital signs and minimal pain (<3 on a 0–10 scale), were able to ambulate, and were not experiencing any side effects—was recorded. Patients rated their satisfaction with the control of PONV by using a five-point scale (1 = very satisfied; 2 = somewhat satisfied; 3 = neither satisfied nor dissatisfied; 4 = somewhat dissatisfied; 5 = very dissatisfied) just before discharge from the hospital and at 24 h.

Nausea was defined as a feeling of the urge to vomit, as solicited by the investigators during assessments. Vomiting was defined as expulsion of stomach contents through the mouth. Retching was defined as an attempt to vomit that was not productive of stomach contents. An emetic episode was defined as a single vomit or retch or any number of continuous vomits or retches. A complete response was defined as no PONV and no need for rescue antiemetics. In the PACU, ondansetron 4 mg was used as the initial rescue medication for PONV. This was given if nausea was intractable and lasted for at least 15 min, if 3 emetic episodes occurred within 15 min, or at any time at the patient’s request. Postoperative pain in the PACU was treated with IV fentanyl 25–50 µg.

Previous studies performed by our group demonstrated an incidence of nausea and or vomiting of 65% in this population under general anesthesia without a prophylactic antiemetic. A sample size of 30 patients per group was determined to be adequate to demonstrate a 30% reduction in the incidence of PONV (from 65% to 35%) with = 0.05 and ß = 0.8. Descriptive statistics were used to summarize the demographic characteristics of patients. Because subjects were randomly assigned to treatment, no differences in these variables were expected across the treatment groups at baseline. Fisher’s exact test and ² procedures for categorical data and Wilcoxon’s ranked sum test and the Kruskal-Wallis test for continuous variables were performed for comparisons among the treatment groups. Three treatment group comparisons were performed: the multimodal group versus the combination and the TIVA groups. P < 0.05 was accepted as statistically significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Ninety patients were enrolled in the study. The three groups were similar with respect to age, weight, height, sex, ASA status, race, history of PONV or motion sickness, duration of surgery, the amount of preoperative midazolam used, and the amount of fentanyl used during surgery and in the PACU (Table 1).

The number of patients who were very satisfied with PONV management before discharge from the hospital was significantly larger in the multimodal group (97%) compared with both the combination and TIVA groups (70%) (P = 0.01). At 24 h, the number of patients who were very satisfied with PONV management was not different between the groups.

	Discussion

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Our data suggest that a multimodal management strategy for the prevention of PONV that incorporated TIVA with propofol and a combination of two antiemetics was superior to the use of a similar combination in the presence of an inhaled anesthetic or TIVA with propofol. Routine PONV prophylaxis has been recommended for patients at high risk for PONV (11,12). This approach has been found to be more cost-effective and associated with a higher degree of patient satisfaction compared with treatment of established symptoms (13). The optimal prophylactic antiemetic regimen has not yet been established. A combination of antiemetic drugs acting at different receptor sites was found to be more effective compared with prophylaxis with a single drug (14). The use of a multimodal approach was also found to have improved efficacy and has been advocated for patients at high risk for PONV (15).

A technique incorporating TIVA with propofol—a combination of antiemetics acting at different receptors, avoiding nitrous oxide and large inspired oxygen concentrations—was described in two previous studies. In the first, Scuderi et al. (8) compared the multimodal approach with standard outpatient anesthesia with or without ondansetron 4 mg in women undergoing outpatient laparoscopy. The multimodal group received TIVA with propofol and remifentanil; a triple antiemetic combination with droperidol 0.625 mg, dexamethasone 10 mg, and ondansetron 1 mg; adequate hydration; no nitrous oxide; 80% oxygen; and no neuromuscular blockade. The other two groups received sevoflurane, nitrous oxide, and muscle relaxation with reversal at the end of the procedure. Patients in one group received antiemetic prophylaxis with ondansetron 4 mg, and patients in the other group received placebo. The multimodal management resulted in a complete response rate of 98% in the PACU, compared with 76% in the ondansetron group and 59% in the placebo group. In the second study, in women undergoing gynecological and breast surgery, Eberhart et al. (9) also found that a multimodal approach consisting of TIVA with propofol, no nitrous oxide, 80% oxygen, dexamethasone 8 mg, haloperidol 10 µg/kg, and tropisetron 2 mg was associated with a 7% incidence of PONV over 24 hours, compared with 41% in the control group (desflurane, nitrous oxide, and no antiemetic prophylaxis).

Although these two studies demonstrated the excellent efficacy of the multimodal approach for PONV management, the contribution of TIVA and avoidance of volatile anesthetics and nitrous oxide to the success of the technique could not be evaluated because there was no TIVA-only group. Furthermore, these studies compared the multimodal approach with an inhaled technique with or without antiemetic prophylaxis using a single drug. Because improved PONV prophylaxis with a combination of different antiemetics compared with prophylaxis using a single drug has previously been shown (14), we decided to compare the multimodal approach with prophylaxis by using a combination of two antiemetics.

In this study, we found that a multimodal approach consisting of TIVA with propofol, a combination of ondansetron and droperidol, and avoidance of nitrous oxide was associated with a higher complete response rate during the first two postoperative hours compared with isoflurane/nitrous oxide-based anesthesia with a similar antiemetic combination. Patient satisfaction was also higher in the multimodal group. There was, however, no difference between the two groups in the duration of PACU stay. At 24 hours, there was also no difference between groups in either the complete response rate or patient satisfaction. This finding confirms that the antiemetic effect of propofol is short lived, because the improved PONV prophylaxis in the multimodal group did not extend into the postdischarge period. The limitation of the antiemetic effect of propofol to the early postoperative period has been previously reported (16). The use of TIVA is also associated with an increase in drug cost compared with maintenance of anesthesia with a volatile anesthetic (17). The use of the multimodal approach might therefore be suitable only for patients at a very high risk for PONV.

When compared with the TIVA group, patients in the multimodal group had a significantly less frequent incidence of nausea, had lower nausea scores, required fewer rescues, and were more satisfied with PONV management during the first two hours after surgery. This superiority in the multimodal group also extended into the postdischarge period, with a significantly higher complete response rate at the 24-hour assessment.

In a meta-analysis, Tramer et al. (18) reported that omitting nitrous oxide from general anesthesia decreased postoperative vomiting significantly if the baseline risk of vomiting was high. In this study, however, there was no difference in the incidence of emesis between patients who received nitrous oxide (the combination group) and those who did not receive nitrous oxide (the multimodal and the TIVA groups). This might have been due to the administration of a combination of two antiemetics to patients who were receiving nitrous oxide and suggests that omitting nitrous oxide might not confer any additional benefit in patients receiving prophylaxis with a combination of antiemetic drugs. However, this conclusion cannot be drawn from our study, because there was no control group receiving the inhaled technique without nitrous oxide.

This study has its limitations. Although it was powered to detect an overall difference among the groups in the incidence of PONV, it was not adequately powered for intergroup comparisons. We therefore failed to achieve statistical significance for some of the intergroup comparisons. Another criticism might arise because of the absence of a placebo group in our study. However, because laparoscopic cholecystectomy is associated with a high risk of PONV in these ambulatory patients, we believed that it was ethically inappropriate to include a placebo group. Another concern might relate to the Food and Drug Administration "black box" warning regarding the use of droperidol for antiemetic prophylaxis. However, this warning has been challenged by many anesthesiologists (19,20). Most experts in the field would agree that small-dose droperidol has been proven to be a safe and cost-effective antiemetic for more than 30 years (21).

In summary, we found that, in patients undergoing laparoscopic cholecystectomy, a multimodal approach incorporating TIVA with propofol, a combination of ondansetron and droperidol, and omission of nitrous oxide was associated with a higher complete response rate and greater patient satisfaction in the PACU, compared with similar antiemetic prophylaxis with isoflurane/nitrous oxide-based anesthesia. The multimodal group also had a significantly less frequent incidence of PONV at 24 hours after surgery and greater patient satisfaction in the PACU when compared with the TIVA group.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999