Department of Anaesthetics, North Hampshire Hospital, Aldermaston Road, Basingstoke, Hampshire RG24 9NA, UK*Corresponding author: Shackleton Department of Anaesthetics, Southampton General Hospital, Tremona Road, Southampton, Hampshire SO16 6YD, UK
LMA® is the property of Intavent Limited.
Accepted for publication: June 12, 2001
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Abstract |
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Br J Anaesth 2001; 87: 58892
Keywords: vomiting, antiemetics; vomiting, incidence; vomiting, nausea
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Introduction |
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PONV occurs frequently after day case gynaecological surgery.1315 Both 5-HT3 receptor antagonists14 16 and dexamethasone17 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.
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Patients and methods |
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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.18
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 2.02.5 mg kg1 propofol and 1 µg kg1 fentanyl and maintained with 2.03.0% sevoflurane (inspired concentration) and 66% nitrous oxide in oxygen. Ventilation was controlled mechanically via a laryngeal mask airway (LMA) and adjusted to maintain end-tidal carbon dioxide concentration at 4.55.3 kPa throughout surgery. Neuromuscular relaxation was achieved with mivacurium 0.10.2 mg kg1 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: 03, 312, and 1224 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.19 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 (Wilson20) 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 Fishers exact test (StatXact v. 3.0, Cytel Software Corporation, MA, USA).
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Results |
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Discussion |
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As PONV is recognized to be a common complication of gynaecological surgery performed under general anaesthesia,24 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 studies8 10 13 24 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.25 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.26 27
Our study demonstrated a significant difference between the ondansetron/dexamethasone combination and either drug alone in the 03 h period. Although this difference failed to maintain significance overall (024 h), or during the 312 or 1224 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 (024 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 alone28 or in combination,1 12 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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References |
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