The meta-analysis summarises data from 14 prospective randomised trials and a total of more than 2000 patients. In our primary analysis, there was no difference in the overall risk of PONV, POV, need for rescue medication and early PONV in patients receiving TIVA compared with patients receiving IA + AE. However, patients receiving TIVA were more likely to suffer from PONV in the late postoperative phase than patients receiving IA + AE. Also, we found evidence of a publication bias with smaller trials favouring TIVA.
When considering PONV prophylaxis with antiemetics, potential side-effects warrant discussion: high dosages of most available antiemetics prolong cardiac QT interval.47 For these reasons, the antiemetic droperidol was labelled with a black box warning by the American Food and Drug Administration in 2001. This was followed by an intense debate, with the result that now the dose administered for prophylaxis and treatment of PONV is considered to be well tolerated as it is some 10-fold lower than the doses given historically for neurolept anaesthesia.48–50 Other side-effects are characteristic of specific drugs,7 e.g. headache after 5-hydroxytryptamine (5-HT3) antagonists or sedation after droperidol or dimenhydrinate.51 Although slight increases in blood glucose concentration may be observed after dexamethasone administration in nondiabetic patients,52 low doses of dexamethasone are proven not to increase the risk of surgical site infection.53,54 To add to this discussion, we identified six studies which investigated perioperative adverse events, including dizziness, headache, myalgia, drowsiness and shivering. Except for a trend towards increased postoperative shivering following IA + AE, which has been known for decades to be associated with inhalational anaesthetics,42 we did not find any difference between the two groups. We acknowledge that for the individual side-effects, the data came from only one or two studies and we could not include two of the six studies in the analysis as no data on adverse events were given. Nevertheless, despite the small number of studies, we feel that our findings do not contradict the general notion that the use of low-dose antiemetics for PONV prophylaxis is well tolerated.
Our funnel plot analysis showed significant asymmetry, suggesting a publication bias favouring TIVA. This observation is supported by our subgroup analysis stratifying studies by study size: studies involving more than 100 patients favoured IA + AE, whereas smaller studies tended to favour TIVA. Although other reasons for funnel plot asymmetry exist,16 we decided to extended our analysis to assess the implications for our findings: when heterogeneity is high and random-effects modelling is applied then smaller studies are weighted disproportionately higher than larger studies, so we re-examined our primary analysis using a fixed effect model.16 With fixed effect modelling, TIVA was actually inferior to IA + AE in preventing overall PONV (Fig. 2). We would like to emphasise that this analysis was conducted a posteriori, and its results are merely explorative. To exclude any further bias because of poor study quality, individual risk of bias for each study was assessed, revealing an overall moderate risk. Excluding studies with high risk of bias did not change the results of our primary analysis. Finally, in the face of significant heterogeneity in our primary analysis, we estimated the overall quality of evidence19 to be ‘moderate’.
Even with antiemetic prophylaxis, PONV still occurred in a high proportion (39%) of patients across all studies. Thus, irrespective of their relative effectiveness, neither strategy in isolation reduced patients’ risk of PONV sufficiently. Accordingly, we would emphasise that only a multimodal approach, including administration of multiple prophylaxes, reduces the incidence of PONV satisfactorily in high-risk patients undergoing general anaesthesia. Thus, adding one or more additional antiemetic- to both strategies will further decrease the incidence of PONV. However, the aim of our analysis was to establish the relative effect of single pharmacological prophylaxis compared with TIVA, which is why we excluded studies investigating multiple prophylaxes.
Secondly, it has been shown that titration of inhalational anaesthesia to higher levels of bispectral index (BIS) with avoidance of unnecessary deep anaesthesia reduces the incidence of postoperative vomiting.55 Unfortunately, only one study controlled for anaesthesia depth,31 making a sensitivity analysis impossible. In the IMPACT trial, the BIS level was one of the randomised factors,56 but these data were not published.1 Therefore, it is possible that the relative effectiveness of pharmacological prophylaxis might be even more pronounced when anaesthetic depth is controlled; however, our data do not allow us to make any assumption about this effect.
Third, we pooled groups with different antiemetic classes and subclasses in our main analysis. Therefore, our primary findings are limited to the comparison of TIVA versus ‘uncontrolled’ pharmacological antiemetic prophylaxis and the results might differ between antiemetic classes. As most of the included studies investigated 5-HT3 antagonists, it might be concluded that our findings are more or less restricted to that class. However, as has been shown in the IMPACT trial,1 as well as many others, the prophylactic effect of antiemetics from different classes is comparable when adequate doses are used.7
In summary, our meta-analysis shows that when substitution of TIVA for inhalational anaesthetics to reduce a patient's risk of PONV is not an option, then the PONV risk can be compensated to an equivalent degree by the use of a single-drug pharmacological prophylaxis. Finally, as neither strategy alone decreases PONV sufficiently in high-risk patients, the use of multiple prophylactic methods should be instituted to minimise the incidence of PONV and improve surgical outcome.
Assistance with the study: none.
Financial support and sponsorship: this work was supported by departmental funding of the Department of Anaesthesiology, University Hospital Düsseldorf, Germany and the Department of Anaesthesiology and Critical Care, University Hospital Würzburg, Germany.
Conflicts of interest: PeKr has conducted funded Research by Acacia Ltd. and has received fees for lectures by Fresenius Kabi, Baxter GmbH, Germany and ProStrakan and is co-author of the cited consensus guideline on the management of PONV (SAMBA-Guideline), published by TJ Gan et al. PeKi has been consulting for Baxter GmbH Germany and Air Liquide Medical GmbH Germany, has received lecture fees and travelling expenses from both companies and is an associated editor of BMC Anesthesiology.
Presentation: preliminary data for this study have been presented at the European Society of Anaesthesiology meeting, 28 to 30 May 2016, London.
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