The Invited Commentary accompanies the following original article:
Bataille A, Letourneulx J-F, Charmeau A, et al. Impact of a prophylactic combination of dexamethasone–ondansetron on postoperative nausea and vomiting in obese adult patients undergoing laparoscopic sleeve gastrectomy during closed-loop propofol–remifentanil anaesthesia. A randomised double-blind placebo-controlled study. Eur J Anaesthesiol 2016; 33:898–905.
It has been more than 12 years since the first international recommendations for the prophylaxis and treatment of postoperative nausea and vomiting (PONV) were published.1 During the subsequent decade these guidelines were updated twice to incorporate new knowledge and trends from thousands of clinical trials on this important field of outcome research. Despite some criticisms concerning their applicability and the ease of implementing their complex risk score-based anti-PONV algorithms,2 the last version of the Society for Ambulatory Anesthesia PONV-guidelines were commended as a ‘leapfrog towards a PONV-free hospital.’3
‘Well done’, ‘everything is said,’ ‘why are we doing new trials on PONV?’ were frequently made comments from PONV researchers like us, of the first generation, who felt that there was no longer a question that could not be answered by the knowledge database that now existed on this topic. What arrogance! We should have known better and remembered Sokrates and his famous quote: ‘I know that I know nothing.’ Our problem is the clinical trial published in this issue of the European Journal of Anaesthesiology that destroys our self-confidence and tells us that we still do not have the answers, especially for the questions this study raises.4
Our first problem concerns the type of patients: younger, morbidly obese non-Caucasian women. We already know that there is a highly significant difference in PONV incidences between black and white South African patients surveyed within the same department (black 27 vs. white 45%).5 The authors concluded that black South African ethnicity was an independent protective factor against PONV. The present study does not report ethnicity among the included patients in detail, but assuming a comparable proportion of New Caledonian inhabitants among the patients, not more than one-third were Caucasians.
In addition to a varying susceptibility of different patients against emetogenic effects of anaesthesia and surgery, another source of heterogeneity may come from variable pharmacogenetics. A recently published report in this journal highlighted examples of great variation in the pharmacodynamics and pharmacokinetics of certain drugs.6
Another terra incognita is the appropriate dose of antiemetics in morbidly obese patients. The question here is whether conventional doses of antiemetics (dexamethasone and ondansetron 4 mg intravenously) provide high enough plasma levels to protect against PONV. The only group of patients where weight-adjusted doses of antiemetics are recommended so far are children. In this group of patients, current guidelines recommend 0.15 mg/kg body weight for dexamethasone and 0.1 mg/kg for ondansetron. Depending on what counts when pharmacokinetics of rather lipophilic drugs like dexamethasone are used – actual (115 to 120 kg) or calculated ideal body weight (57 to 59 kg) one may conclude that 4 mg of dexamethasone represents an under dose. Taking into account that larger doses of dexamethasone also show additional effects on quality of recovery (less opioid requirement, less nausea, sore throat, muscle pain, and difficulty falling asleep one would intuitively advocate at least the double dose, 8 mg of dexamethasone.7 We must acknowledge, though, that there is no clear evidence for this hypothesis, but one might argue that it is meaningless to start a scientific discussion on the dosage of a drug considering that the underlying molecular mechanism for the antiemetic action is not understood, even now. However, considering the almost perfect ratio of effects and adverse effects,8,9 a larger dose of dexamethasone would be the more rational choice in obese patients once the question of dose-responsiveness, of it and other well proven anti-emetic drugs, has been evaluated in future clinical trials in a more convincing way.
One more thing we can learn from this clinical trial is that it is not enough to simply calculate supposed incidences that are based on theoretical data on the risk of PONV in a cohort of patients and the presumed efficacy of anti-emetics. Just that approach was correctly used in the study to calculate power, assuming that in the placebo-group about half of the patients would suffer from PONV when anaesthetised with propofol-nitrous oxide. Using data from Caucasian patients with normal weights, anaesthetised with volatile anaesthetics, it was assumed that the addition of either of two well proven antiemetics would reduce this incidence by 25% each. Accordingly, the authors powered the study to demonstrate a reduction of PONV from 50 to 30%. As the incidence of PONV was only reduced from 54 to 45% the study results were not statistically significant.
The failure of this antiemetic strategy would have happened regardless of the risk classification. This is just one of several examples confirming that in many groups risk assessment for PONV may only help as a rough guide; with such high incidences in all risk groups, stratifying into ‘high,’ ‘very high,’ and possibly ‘extremely high risk’ is of no value.
The high incidence of PONV in the investigated cohort of patients also demonstrates the urgent need to verify assumptions we make based on theoretical calculations and a gut feeling that we are ‘doing the right things’ to improve patient outcomes. This holds true for PONV or any other sequelae. ‘Only if you can measure it, you can improve it’ is one basic message from quality assurance theory. For this reason, every one of us should perform surveys on our patients to find out whether PONV is a problem or not. If the result is ‘yes, we still have a problem’ (as demonstrated by the study results with an incidence of PONV of 45% and with every fifth patient suffering from severe symptoms) the anaesthetic regime needs to be modified. The lessons to be learnt may be that a triple antiemetic approach (anaesthesia maintenance with propofol and adding dexamethasone plus ondansetron) can be still too little. Whilst we should accept this, we should not accept that no more can be done. There are many other measures that can be added: increasing doses (as discussed before) or adjusting dose according to patients body weight;10 adding alternative measures, such as benzamides,11 potent dopamine antagonists like droperidol, or emerging alternatives like amisulpiride,12 antihistamines,13 and/or the new neurokinin 1-receptor antagonists;14 further reducing the emetogenic effects of anaesthesia and postoperative analgesic therapy.15
All these measures might improve the situation. It is crucial to stress the term ‘might improve’ as one of the key facts we learn from the presented trial is that we can only be sure if we have measured it. Kaizen, continuous improvement, was a term used in quality management in the automobile industry for decades. It is time to transfer this approach to improve outcomes of our patients and also to kaizen the problem of PONV. In summary, PONV should not be viewed as the ‘the big little problem’ but as a ‘big little opportunity.’ Just as anaesthesiologists have come to regard postoperative pain as undesirable and treatable, we should strive to do the same for PONV. Along with further single-agent and dose-finding studies, we advocate implementation studies reporting attempts to achieve the ‘PONV-free hospital’ and also to highlight the gaps in our knowledge (such as proper dose–response) that we should aim to close in the near future and thus improve the recovery of our patients.
Acknowledgements relating to this article
Assistance with the commentary: none.
Financial support and sponsorship: none.
Conflicts of interest: LHJE received honorarium for lectures from Baxter GmbH, Fresenius GmbH, Grunenthal GmbH, Sintetica GmbH, and Ratiopharm GmbH, Germany. He is a member of advisory board of Grunenthal GmbH and Ratiopharm GmbH, Germany. PK was a member of the consensus panel of the international guideline on the management of PONV. He has been primary investigator of various clinical studies on the prevention and treatment of PONV, including phase II and III trials of Acacia Pharma Inc., UK, GlaxoSmithKline, US, and FreseniusKabi, Germany. He has received lecture fees from FreseniusKabi Germany and Merck.
Comment from the editor: this article was checked and accepted by the Editors, but was not sent for external peer-review. PK is an Associate Editor of the European Journal of Anaesthesiology.
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