|Remifentanil for general anaesthesia: a systematic review
|Komatsu R, Turan A M, Orhan-Sungur M, McGuire J, Radke O C, Apfel C C
This generally well-conducted review compared remifentanil with fentanyl, alfentanil or sufentanil for analgesia during general anaesthesia. The authors concluded that remifentanil induced deeper analgesia and anaesthesia. Patients given remifentanil showed faster recovery times but needed post-operative analgesia more frequently. The review included a large number of patients and, despite some concerns about the synthesis, the authors' conclusions are likely to be reliable.
To evaluate the intra-operative and post-operative efficacy and safety of remifentanil as an analgesic supplement during general anaesthesia compared with other currently used opioids.
MEDLINE, an ISI index and the Cochrane Library were searched; the search terms were reported, but not the search dates. No language restrictions were employed. The reference lists of all identified studies were checked.
Randomised controlled trials (RCTs) that enrolled adult patients aged at least 18 years undergoing general anaesthesia were eligible for inclusion. Studies had to compare remifentanil with fentanyl, alfentanil or sufentanil during general anaesthesia using tracheal intubation or a laryngeal mask airway. Where rigid bronchoscopy or laryngoscopy were conducted under general anaesthetic without intubation, studies were also included. Studies using remifentanil for sedation in monitored anaesthesia care, to provide adjuvant analgesia to local anaesthetic without general anaesthetic or as sedation and analgesia for intensive care unit patients, were excluded from the review. Concomitant use of anaesthetic agents was required to be controlled or demonstrated to have equal distribution between patient groups.
Studies that reported either dichotomous outcomes or means with standard deviations (SDs) for the following outcomes were eligible for inclusion: intra-operative awareness with recall; muscle rigidity; hypertensive, hypotensive, tachycardic or bradycardic episodes during the anaesthesia period; inadequate anaesthesia response at any point; requirement for vasopressor, anticholinergic or antihypertensive drugs during anaesthesia; systolic blood-pressure and heart rate at induction, intubation, skin incision, skin closure and extubation. Studies reporting the following post-operative outcomes were also eligible: requirement for post-operative rescue analgesics; nausea and vomiting; shivering; respiratory depression or requirement for naloxone administration; time taken for patient to obey verbal command, initiate spontaneous ventilation, and to have adequate ventilation.
Two reviewers selected the papers for the review.
Assessment of study quality
Studies were assessed for validity using the Oxford scale, which gives studies a score of between 0 and 5 based on the criteria of randomisation, blinding and the reporting of study withdrawals. Blinding was assessed separately for intra-operative and post-operative periods within studies.
It appears that at least two reviewers assessed the studies for validity.
Data were extracted on the number of patients in each group experiencing dichotomous outcomes, the mean and SD of each group for continuous outcomes, and the doses employed of remifentanil and comparator opioids. Where remifentanil was compared with two different opioids, the number of remifentanil patients was divided by two for each comparison. Where several doses of remifentanil were used, only data from the lowest dose group were included in the analysis. Where multiple doses of a comparator opioid were employed, only data from that closest to the other studies in the analysis were included. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated for dichotomous data, while weighted mean differences (WMDs) with 95% CIs were calculated for continuous data.
One reviewer extracted the data, which a second reviewer checked.
Methods of synthesis
The studies were combined in random-effects meta-analysis for each outcome.
Subgroup analyses were conducted for each comparator opioid. Statistical heterogeneity between studies was assessed using the χ2 test. Where a p-value of less than 0.05 indicated such heterogeneity, outlier studies with point estimates outside twice the 95% CI of the combined outcome of the remaining studies were excluded from the analysis. I2 tests also appear to have been conducted.
Results of the review
Eighty-five RCTs (n=13, 057) were included in the review. The study sizes ranged from 18 to 4789.
The median quality score of the trials was 3 out of a possible 5 for both intra-operative and post-operative periods.
Remifentanil groups showed fewer responses to noxious stimuli (RR 0.65, 95% CI: 0.48, 0.87, p=0.004) and, although episodes of intra-operative awareness were not significantly different from comparators, they favoured remifentanil (RR 0.45, 95% CI: 0.15, 1.33, p=0.15). They also demonstrated other signs of deeper analgesia and anaesthesia, with more episodes of bradycardia (RR 1.46, 95% CI: 1.04, 2.05, p=0.03) and hypotension (RR 1.68, 95% CI: 1.36, 2.07, p<0.001) and fewer episodes of hypertension (RR 0.60, 95% CI: 0.46, 0.78, p=0.0002) than patients treated with comparator opioids. Rigidity did not differ between the groups (RR 1.07, 95% CI: 0.65, 1.75, p=0.80).
Remifentanil groups showed a faster recovery time on all four measures: extubation (WMD -2.03, 95% CI -2.92, -1.14, p<0.001), obeying command (WMD -2.51, 95% CI: -3.57, -1.45, p<0.001), spontaneous ventilation (WMD -0.94, 95% CI: -1.80, -0.08, p=0.03) and adequate ventilation (WMD -1.34, 95% CI: -2.58, -0.10, p=0.03). They also showed fewer requirements for naloxone treatment of respiratory events (RR 0.25, 95% CI: 0.14, 0.47, p<0.001). However, patients in the remifentanil groups also more frequently required post-operative analgesia (RR 1.36, 95% CI: 1.21, 1.53, p<0.001) and had more episodes of shivering (RR 2.15, 95% CI: 1.73, 2.69, p<0.001). There was no difference between the groups in the number of episodes of post-operative nausea (RR 1.03, 95% CI: 0.97, 1.09, p=0.34) and vomiting (RR 1.06, 95% CI: 0.96, 1.17, p=0.27).
There was generally no evidence of statistically significant heterogeneity in any of the analyses. The exceptions were the requirement for post-operative analgesia (p=0.005) and all measures of recovery time (p<0.001 in all cases).
Remifentanil was associated with signs of deep intra-operative analgesia and generally faster recovery, with less respiratory depression and requirement for naloxone. However, it was associated with a higher requirement for post-operative analgesia and significantly more shivering, although there was no increase in nausea and vomiting.
The review question and the inclusion criteria were clear. The authors searched three relevant databases. The lack of language restrictions reduced the chance that some relevant studies were not included in the review; however, it is not clear whether the authors sought unpublished studies. The authors used appropriate measures to minimise bias and error in the study selection, validity assessment and data extraction processes. Appropriate criteria were used to assess validity, although the results of the assessment were not used to inform the synthesis. The decision to use meta-analyses with subgroup analyses based on the comparator opioid seems appropriate, and some suitable sensitivity analyses were carried out where statistically significant heterogeneity was detected. The handling of studies with multiple comparator groups is potentially problematic. Whilst dividing a common group is a recognised approach, the decision to only use the lowest of multiple remifentanil dose groups will have been conservative only with respect to efficacy, but would favour remifentanil in the evaluation of safety. Likewise, it is probably not reasonable to select trial groups on the basis of the doses used in other included studies. If this approach is to be used, sensitivity analyses should be undertaken to establish the effect of the decisions. However, this was a generally well-conducted review which included a substantial number of trials and a large number of patients. The authors' conclusions are likely to be reliable.
Implications of the review for practice and research
Practice: The authors stated that remifentanil may be useful for patients deemed at risk of intra-operative awareness or obstructive sleep apnoea, or where early ambulation is desirable. They also indicated that it might be best used in short out-patient procedures which are unlikely to require more extensive post-operative analgesia.
Research: The authors did not state any implications for further research.
University of Louisville, Department of Anaesthesia and the Outcomes Research Institute; University of California at San Francisco, Department of Anaesthesia and Perioperative Care.
Komatsu R, Turan A M, Orhan-Sungur M, McGuire J, Radke O C, Apfel C C. Remifentanil for general anaesthesia: a systematic review. Anaesthesia 2007; 62(12): 1266-1280
Subject indexing assigned by NLM
Analgesics, Opioid /adverse effects; Anesthesia Recovery Period; Anesthesia, General /methods; Evidence-Based Medicine; Humans; Intraoperative Complications /chemically induced; Piperidines /adverse effects; Postoperative Complications /chemically induced; Randomized Controlled Trials as Topic
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.