Prospective randomized, double‐blind comparative study of dexamethasone, ondansetron, and ondansetron plus dexamethasone as prophylactic antiemetic therapy in patients undergoing day‐case gynaecological surgery
2001; Elsevier BV; Volume: 87; Issue: 4 Linguagem: Inglês
10.1093/bja/87.4.588
ISSN1471-6771
Autores Tópico(s)Cardiac, Anesthesia and Surgical Outcomes
ResumoDexamethasone alone and in combination with selective 5‐hydroxytryptamine receptor antagonists is of benefit in the prophylaxis of post‐operative nausea and vomiting. In this study, the effectiveness of such a combination in comparison to either drug alone is investigated in day case gynaecological surgery. A total of 177 patients were randomized to three treatment groups: dexamethasone 8 mg, ondansetron 4 mg, and dexamethasone 8 mg plus ondansetron 4 mg. The only significant difference between groups was seen in the first 3 h when failure of prophylaxis was more frequent in patients who had received dexamethasone alone (P=0.0085; Fisher’s exact probability test). Confidence interval analysis indicates a modest treatment effect for the combination and the decision whether to perform a larger study depends upon whether such an effect is clinically relevant. Dexamethasone alone and in combination with selective 5‐hydroxytryptamine receptor antagonists is of benefit in the prophylaxis of post‐operative nausea and vomiting. In this study, the effectiveness of such a combination in comparison to either drug alone is investigated in day case gynaecological surgery. A total of 177 patients were randomized to three treatment groups: dexamethasone 8 mg, ondansetron 4 mg, and dexamethasone 8 mg plus ondansetron 4 mg. The only significant difference between groups was seen in the first 3 h when failure of prophylaxis was more frequent in patients who had received dexamethasone alone (P=0.0085; Fisher’s exact probability test). Confidence interval analysis indicates a modest treatment effect for the combination and the decision whether to perform a larger study depends upon whether such an effect is clinically relevant. A recent meta‐analysis examined the role of dexamethasone for the prevention of postoperative nausea and vomiting. 1Henzi I Walder B Tramer MR. Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review.Anesth Analg. 2000; 90: 186-194Crossref PubMed Scopus (634) Google Scholar It concluded that ‘it is very likely that the best prophylaxis of postoperative nausea and vomiting (PONV) currently available is by combining dexamethasone with a selective 5‐hydroxytryptamine type 3 (5‐HT3) receptor antagonist’. Such combinations are both safe and efficacious in paediatric, 2Fujii Y Tanaka H Toyooka H. Granisetron and dexamethasone provide more improved prevention of postoperative emesis than granisetron alone in children.Can J Anaesth. 1996; 43: 1229-1232Crossref PubMed Scopus (36) Google Scholar, 3Fujii Y Saitoh Y Tanaka H Toyooka H. Prophylactic therapy with combined granisetron and dexamethasone for the prevention of post‐operative vomiting in children.Eur J Anaesthesiol. 1999; 16: 376-379Crossref PubMed Google Scholar obstetric, 4Fujii Y Saitoh Y Tanaka H Toyooka H. Granisetron/dexamethasone combination for reducing nausea and vomiting during and after spinal anesthesia for cesarean section.Anesth Analg. 1999; 88: 1346-1350Crossref PubMed Google Scholar breast, 5Fujii Y Tanaka H Toyooka H. Prophylactic antiemetic therapy with granisetron‐dexamethasone combination in women undergoing breast surgery.Acta Anaesthesiol Scand. 1998; 42: 1038-1042Crossref PubMed Scopus (34) Google Scholar middle ear, 6Fujii Y Tanaka H Toyooka H. Prophylactic antiemetic therapy with granisetron‐dexamethasone in patients undergoing middle ear surgery.Br J Anaesth. 1998; 81: 754-756Crossref PubMed Scopus (41) Google Scholar and other 7Janknegt R Pinckaers JW Rohof MH et al.Double‐blind comparative study of droperidol, granisetron and granisetron plus dexamethasone as prophylactic anti‐emetic therapy in patients undergoing abdominal, gynaecological, breast or otolaryngological surgery.Anaesthesia. 1999; 54: 1059-1068Crossref PubMed Scopus (44) Google Scholar surgery associated with a high risk of PONV. Despite work demonstrating the benefits of such combination therapy in major gynaecological surgery, 8Fujii Y Tanaka H Toyooka H. The effects of dexamethasone on antiemetics in female patients undergoing gynecological surgery.Anesth Analg. 1997; 85: 913-917Crossref PubMed Google Scholar, 9Fujii Y Tanaka H Toyooka H. Granisetron‐dexamethasone combination reduces postoperative nausea and vomiting.Can J Anaesth. 1995; 42: 387-390Crossref PubMed Scopus (48) Google Scholar, 10McKenzie R Tantisira B Karambelkar DJ Riley TJ Abdelhady H. Comparison of ondansetron with ondansetron plus dexamethasone in the prevention of postoperative nausea and vomiting.Anesth Analg. 1994; 79: 961-964Crossref PubMed Scopus (140) Google Scholar, 11Lopez‐Olaondo L Carrascosa F Pueyo FJ Monedero P Busto N Saez A. Combination of ondansetron and dexamethasone in the prophylaxis of postoperative nausea and vomiting.Br J Anaesth. 1996; 76: 835-840Crossref PubMed Scopus (133) Google Scholar little evidence exists regarding the use of an ondansetron and dexamethasone combination in a day‐surgical gynaecological population. 12Rajeeva V Bhardwaj N Batra YK Dhaliwal LK. Comparison of ondansetron and dexamethasone in prevention of PONV in diagnostic laparoscopy.Can J Anaesth. 1999; 46: 40-44Crossref PubMed Scopus (66) Google Scholar PONV occurs frequently after day case gynaecological surgery. 13Cholwill JM Wright W Hobbs GJ Curran J. Comparison of ondansetron and cyclizine for prevention of nausea and vomiting after day‐case gynaecological laparoscopy.Br J Anaesth. 1999; 83: 611-614Crossref PubMed Scopus (40) Google Scholar, 14McKenzie R Kovac A O’Connor T et al.Comparison of ondansetron versus placebo to prevent postoperative nausea and vomiting in women undergoing ambulatory gynecological surgery.Anesthesiology. 1993; 78: 21-28Crossref PubMed Scopus (182) Google Scholar, 15Malins AF Field JM Nestling PM Cooper GM. Nausea and vomiting after gynaecological laparoscopy: comparison of premedication with oral ondansetron, metoclopramide and placebo.Br J Anaesth. 1994; 72: 231-233Crossref PubMed Scopus (81) Google Scholar Both 5‐HT3 receptor antagonists 14McKenzie R Kovac A O’Connor T et al.Comparison of ondansetron versus placebo to prevent postoperative nausea and vomiting in women undergoing ambulatory gynecological surgery.Anesthesiology. 1993; 78: 21-28Crossref PubMed Scopus (182) Google Scholar, 16Paxton LD McKay AC Mirakhur RK. Prevention of nausea and vomiting after day case gynaecological laparoscopy. A comparison of ondansetron, droperidol, metoclopramide and placebo.Anaesthesia. 1995; 50: 403-406Crossref PubMed Scopus (103) Google Scholar and dexamethasone 17Wang JJ Ho ST Liu YH et al.Prophylactic antiemetic effect of dexamethasone in women undergoing ambulatory laparoscopic surgery.Br J Anaesth. 2000; 84: 459-462Crossref PubMed Scopus (80) Google Scholar are superior to placebo in the prophylaxis of PONV in this setting. Our study has compared the efficacy of ondansetron plus dexamethasone with each antiemetic alone for the prevention of PONV in patients undergoing day case gynaecological surgery. After obtaining approval from the local research ethical committee and written informed consent, we studied 177 ASA I or II pre‐menopausal female patients, aged 19–53 yr, undergoing day case gynaecological surgery. Patients with gastrointestinal, liver, or renal diseases, those who had received any antiemetic medication within 24 h before surgery or complained of pre‐operative nausea or vomiting, and those who were pregnant, lactating or with a body mass index of greater than 35 were excluded. Patients were allocated randomly to receive one of three treatment regimens: ondansetron 4 mg, dexamethasone 8 mg, or ondansetron 4 mg with dexamethasone 8 mg. A randomization list was prepared using a mechanical randomization device. The drugs were administered by slow i.v. injection immediately after induction of anaesthesia. Personnel not involved in the study prepared identical syringes containing the study drug(s). The drug(s) were diluted with normal saline to achieve a volume of 5 ml. The study drugs are known to be compatible when mixed. 18Trissel LA. Handbook of Injectable Drugs. 11th edn. Special Publishing Department of the American Society of Health‐System Pharmacists, 2001Google Scholar A standardized anaesthetic technique was used. This was administered by one of the two investigators who were unaware of which treatment the patient had been given. Patients received no pre‐anaesthetic medication. Anaesthesia was induced with 2.0–2.5 mg kg–1 propofol and 1 µg kg–1 fentanyl and maintained with 2.0–3.0% sevoflurane (inspired concentration) and 66% nitrous oxide in oxygen. Ventilation was controlled mechanically via a laryngeal mask airway (LMA †LMA® is the property of Intavent Limited. ) and adjusted to maintain end‐tidal carbon dioxide concentration at 4.5–5.3 kPa throughout surgery. Neuromuscular relaxation was achieved with mivacurium 0.1–0.2 mg kg–1 and was not reversed. All patients received a 100 mg diclofenac suppository before surgery started. In addition, tramadol 100 mg i.v. was administered to those patients who underwent laparoscopic procedures. Patients were transferred to the recovery area once adequate spontaneous respiration was established and the LMA was removed once the patient was awake. Whilst in recovery, rescue analgesia was provided by a further dose of tramadol 100 mg i.v. if required. If patients experienced PONV whilst in hospital, cyclizine 50 mg i.m. was administered as rescue antiemesis. On discharge home, patients were provided with cyclizine 50 mg tablets to be taken if needed. All patients were discharged with a 3‐day supply of analgesics. Those who had undergone laparoscopic procedures were provided with diclofenac 50 mg and codeine phosphate 30 mg/paracetamol 500 mg tablets. Other patients were provided with dextropropoxyphene 32.5 mg/paracetamol 325 mg tablets. Patients were advised to take their analgesic medication regularly for the first 24 h post‐discharge. Patients were interviewed on discharge from the day surgical unit (3 h post‐surgery) by blinded nursing staff and by phone at 24 h post‐surgery by one of the two blinded investigators. The patients were asked if retching or vomiting had occurred, whether rescue antiemetics had been used and if they had felt nauseated in three time periods: 0–3, 3–12, and 12–24 h post‐surgery, with only two possible answers (yes/no). Nausea was defined as the unpleasant sensation associated with awareness of the urge to vomit; retching was defined as laboured, spasmodic, rhythmic contraction of the respiratory muscles without expulsion of gastric contents; vomiting was defined as the forceful expulsion of gastric contents from the mouth. 19Watcha MF White PF. Postoperative nausea and vomiting. Its etiology, treatment, and prevention.Anesthesiology. 1992; 77: 162-184Crossref PubMed Scopus (1483) Google Scholar Failure of prophylaxis was defined as any episode of nausea, retching, vomiting or use of rescue antiemetic. The nursing staff and investigators recorded details of adverse events using an open questioning technique. The patients were asked about analgesic consumption after leaving hospital and pain was scored at 3 and 24 h using a simple scoring system (1, no pain; 2, mild pain; 3, moderate pain; 4, severe pain). A sample‐size of 174 patients (58 in each of three treatment groups) was required to detect a difference in response rates of 0.25 from a baseline prevalence of 0.5, with 80% power at a two‐sided significance level of 5%. Sample size was determined using the software package nQuery Advisor v 3.0 (Statistical Solutions Ltd, Cork, Ireland). The progress of the study was monitored by an independent third party who kept a record of numbers per treatment group and terminated the study when a minimum of 58 patients in each group was obtained. The statistical significance of observed differences in the treatment outcomes was assessed using the recommended method (Wilson 20Wilson EB. Probable inference, the law of succession, and statistical inference.J Am Stat Assoc. 1927; 22: 209-212Crossref Scopus (2495) Google Scholar) for comparing two proportions in the software package Confidence Interval Analysis v. 2.0.0 (BMJ Books, 2000). To make allowances for multiple testing, all differences found to be significant at the 5% level were re‐tested at the 1% level (using 99% confidence interval). Thence, the exact probability of any differences surviving such tests was obtained using Fisher’s exact test (StatXact v. 3.0, Cytel Software Corporation, MA, USA). Patient characteristics and surgical procedures were similar in each group (Table 1). Failure of prophylaxis during the first 3 h (0–3 h) after surgery was recorded in 22, 28.3, and 8.6% of patients who had received ondansetron, dexamethasone, and ondansetron/dexamethasone, respectively. The incidences during the next 9 h (3–12) were 30.5, 35, and 24.1%, respectively. The incidences during the following 12 h (12–24) were 13.5, 15, and 15.5%, respectively. The overall incidences for the 24 h post surgery were 42.4, 48.3, and 34.5%, respectively.Table 1Patient characteristics. Values are numbers or means (sd)GroupDexamethasoneOndansetronCombinationn605958Age (yr)34.9 (20–50)36.2 (21–53)36.0 (19–53)Body mass index25.1 (4.2)23.8 (3.5)24.1 (3.3)Past history of PONV or travel sickness353433Non‐smokers404132Migraine sufferers201818Menstruation498Duration of anaesthesia (min)30.5 (9.94)29.7 (7.41)30.2 (9.3)Laparoscopic procedure333338Laparoscopic sterilization131814Procedure involving cervical dilation535255Rescue analgesia provided in recovery (tramadol)346 Open table in a new tab Thus, only in the first 3 h was failure of prophylaxis seen significantly less often in patients who had received a combination of ondansetron and dexamethasone than in those who had received dexamethasone alone: exact probability P=0.0085. For ondansetron, the difference was significant at the 5% level, but not by our stricter 1% criterion (see Table 2). No patient required hospital admission for PONV. The most frequently reported adverse events were fatigue, headache, and dizziness, but there were no differences between groups (Table 3). There were no differences with respect to analgesic consumption and the incidence and severity of pain (Table 4).Table 2Incidence of nausea, retching, vomiting, use of rescue antiemetics and patients in whom prophylaxis failed. Values are numbers (proportions)DexamethasoneOndansetronCombinationGroup 0–3 hNausea16135Retching511Vomiting401Rescue antiemetic872Overall proportion of subjects classified as ‘failures’17/60 (0.283)13/59 (0.22)5/58 (0.086)Combination vs dexamethasone: 0.2 (95% CI: 0.06 to 0.33, 99% CI: 0.01 to 0.37)Combination vs ondansetron: 0.13 (95% CI: 0.01 to 0.27)Ondansetron vs dexamethasone: 0.063 (95% CI: –0.09 to 0.22)Group 3–12 hNausea201614Retching411Vomiting643Rescue antiemetic161212Overall proportion of subjects classified as ‘failures’21/60 (0.35)18/59 (0.305)14/58 (0.241)Combination vs dexamethasone: 0.11 (95% CI: –0.06 to 0.27)Combination vs ondansetron: 0.064 (95% CI: –0.10 to 0.22)Ondansetron vs dexamethasone: 0.045 (95% CI: –0.12 to 0.21)Group 12–24 hNausea768Retching000Vomiting010Rescue antiemetic778Overall proportion of subjects classified as ‘failures’9/60 (0.15)8/59 (0.135)9/58 (0.155) Open table in a new tab Table 3Incidence of adverse effects. Values are numbersGroupDexamethasoneOndansetronCombinationFatigue142Dizziness123Headache121Pruritis110Flushing003Cough001Diarrhoea010Transient chest pain200Heartburn100 Open table in a new tab Table 4Incidence and severity of pain and use of opiate analgesia after hospital discharge. Values are numbersDexamethasoneOndansetronCombinationGroup at 3 hNo pain253028Mild pain242122Moderate pain1178Severe pain010Group at 24 hNo pain212221Mild pain252526Moderate pain141011Severe pain010Use of opiate analgesia after hospital discharge in first 24 hrs (either codeine phosphate or dextropropoxyphene )474346 Open table in a new tab The aetiology of PONV after gynaecological surgery performed under general anaesthesia remains elusive, but is probably multifactorial. Age, gender, smoking habits, past history of previous PONV and/or motion sickness, surgical procedure, length of procedure, and use of postoperative opioids are of importance in predicting PONV. 21Toner CC Broomhead CJ Littlejohn IH et al.Prediction of postoperative nausea and vomiting using a logistic regression model.Br J Anaesth. 1996; 76: 347-351Crossref PubMed Scopus (70) Google Scholar, 22Apfel CC Greim CA Haubitz I et al.The discriminating power of a risk score for postoperative vomiting in adults undergoing various types of surgery.Acta Anaesthesiol Scand. 1998; 42: 502-509Crossref PubMed Scopus (97) Google Scholar, 23Sinclair DR Chung F Mezei G. Can postoperative nausea and vomiting be predicted?.Anesthesiology. 1999; 91: 109-118Crossref PubMed Scopus (484) Google Scholar In our study, these factors were well balanced between groups and, therefore, differences between groups may be attributed to differences in the antiemetic drugs administered. We decided to include a heterogeneous group of operations in our study to increase the ability to generalize our findings. Although theoretically, the baseline incidences of and mechanisms for PONV may be different for different operations, evidence for this is lacking in the group of operations we included. 23Sinclair DR Chung F Mezei G. Can postoperative nausea and vomiting be predicted?.Anesthesiology. 1999; 91: 109-118Crossref PubMed Scopus (484) Google Scholar We did specifically exclude the procedures of dilation and curettage and termination of pregnancy, as the incidence of PONV is lower. 23Sinclair DR Chung F Mezei G. Can postoperative nausea and vomiting be predicted?.Anesthesiology. 1999; 91: 109-118Crossref PubMed Scopus (484) Google Scholar As PONV is recognized to be a common complication of gynaecological surgery performed under general anaesthesia, 24Koivuranta M Laara E Snare L Alahuhta S. A survey of postoperative nausea and vomiting.Anaesthesia. 1997; 52: 443-449Crossref PubMed Scopus (486) Google Scholar we did not believe it to be ethical to include a placebo arm in our study. We based our choice of a baseline prevalence for PONV of 0.5 on the findings of other studies 8Fujii Y Tanaka H Toyooka H. The effects of dexamethasone on antiemetics in female patients undergoing gynecological surgery.Anesth Analg. 1997; 85: 913-917Crossref PubMed Google Scholar, 10McKenzie R Tantisira B Karambelkar DJ Riley TJ Abdelhady H. Comparison of ondansetron with ondansetron plus dexamethasone in the prevention of postoperative nausea and vomiting.Anesth Analg. 1994; 79: 961-964Crossref PubMed Scopus (140) Google Scholar, 13Cholwill JM Wright W Hobbs GJ Curran J. Comparison of ondansetron and cyclizine for prevention of nausea and vomiting after day‐case gynaecological laparoscopy.Br J Anaesth. 1999; 83: 611-614Crossref PubMed Scopus (40) Google Scholar, 24Koivuranta M Laara E Snare L Alahuhta S. A survey of postoperative nausea and vomiting.Anaesthesia. 1997; 52: 443-449Crossref PubMed Scopus (486) Google Scholar and on local audit data. The high incidence of PONV in this population may justify the use of prophylactic antiemetics. Using antiemetics in this way, however, does raise cost‐effectiveness issues. 25Watcha MF. The cost‐effective management of postoperative nausea and vomiting.Anesthesiology. 2000; 92: 931-933Crossref PubMed Scopus (137) Google Scholar At the drug dosages used, we found that ondansetron and dexamethasone performed similarly, despite an approximate 7‐fold price differential. Our selection of drug dosages was based on previous work that demonstrated that these doses were effective. 26Pearman MH. Single dose intravenous ondansetron in the prevention of postoperative nausea and vomiting.Anaesthesia. 1994; 49: 11-15Crossref PubMed Scopus (119) Google Scholar, 27Liu K Hsu CC Chia YY. The effect of dose of dexamethasone for antiemesis after major gynecological surgery.Anesth Analg. 1999; 89: 1316-1318Crossref PubMed Scopus (103) Google Scholar Our study demonstrated a significant difference between the ondansetron/dexamethasone combination and either drug alone in the 0–3 h period. Although this difference failed to maintain significance overall (0–24 h), or during the 3–12 or 12–24 h periods, the 95% confidence intervals show a trend suggesting that the combination has some benefit over the individual drugs. This is probably a result of underpowering of our study for the size of the actual difference observed. In designing this study, we had to choose an arbitrary reduction in PONV that we believed clinically important. We based this upon a reduction of 50% in the incidence of PONV in the combination group when compared with either of the single treatment groups. We believed this to be a reasonable and clinically important effect that would lead to anaesthetists using the ondansetron/dexamethasone combination in preference to either drug alone. Our failure to demonstrate significance overall (0–24 h) may be because of other reasons. It could be argued that our base line prevalence for PONV of 0.5 was too high, in the absence of a placebo group. This would result in an underestimation of sample size. The fact that the dexamethasone treatment group demonstrated a PONV rate of 0.48 would argue against this, however. Additionally, we may have reduced the likelihood of a significant result by our decision to include a heterogeneous group of operations. This decision has been discussed above. It may be that a smaller than 50% reduction in PONV as a result of using the combination therapy in preference to single agent therapy is still clinically valuable. This is in the context of a day case gynaecological population as a whole or for certain high risk patients within it. We estimate that 1565 patients per group would be required in an identical study of the same power investigating a 10% difference between treatment groups. Other work has suggested that dexamethasone alone 28Rothenberg DM McCarthy RJ Peng CC Normoyle DA. Nausea and vomiting after dexamethasone versus droperidol following outpatient laparoscopy with a propofol‐based general anesthetic.Acta Anaesthesiol Scand. 1998; 42: 637-642Crossref PubMed Scopus (31) Google Scholar or in combination, 1Henzi I Walder B Tramer MR. Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review.Anesth Analg. 2000; 90: 186-194Crossref PubMed Scopus (634) Google Scholar, 12Rajeeva V Bhardwaj N Batra YK Dhaliwal LK. Comparison of ondansetron and dexamethasone in prevention of PONV in diagnostic laparoscopy.Can J Anaesth. 1999; 46: 40-44Crossref PubMed Scopus (66) Google Scholar may be particularly efficacious in preventing late or delayed PONV. Our results do not support this, but this may be because of problems associated with our study design as discussed above.
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