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Possibilities and limitations in the pharmacological management of postoperative nausea and vomiting

Kranke, Peter; Eberhart, Leopold H.J.

European Journal of Anaesthesiology: November 2011 - Volume 28 - Issue 11 - p 758–765
doi: 10.1097/EJA.0b013e32834a4e1e
Review
Free
SDC

The incidence of postoperative nausea and vomiting (PONV) after a standard anaesthetic technique consisting of inhalational anaesthetics and opioids and no PONV prophylaxis is up to 30%. Being one of the most common complaints following surgery under general anaesthesia, it is not surprising that PONV is a considerable cause of dissatisfaction with recovery from anaesthesia and remains one of the most commonly used items in surveys assessing patient satisfaction with the perioperative period and in scoring systems for the quality of recovery following anaesthesia. The weakest link in the chain from research to patient benefit is the implementation of well proven strategies. Rather than simply following existing consensus guidelines, anaesthesiologists should critically assess whether the algorithms introduced produce the desired effect. Risk-adapted strategies may work, but recent implementation studies suggest that compliance with these algorithms may be poor and that high-risk patients often do not receive appropriate antiemetic prophylaxis. Multimodal prevention may represent a more simple approach and, thus, a more reliable strategy to reduce the incidence of PONV. Such an approach would circumvent the inherent weaknesses of the need to undertake a risk assessment for each individual patient. Anaesthesiologists need to know about the new agents available to manage PONV, such as the NK1-antagonists or the newer 5-HT3 antagonists, but should not forget the traditional and well established antiemetics that are valuable components in the current portfolio. The low cost of most of the currently available antiemetics and the low incidence of side-effects suggests that a liberal antiemetic prophylaxis regimen is a meaningful option in order to eliminate or substantially reduce the ‘big little problem’.

From the Department of Anaesthesia and Critical Care, University Hospital of Würzburg, Würzburg and the Department of Anaesthesia and Intensive Care, University Hospitals of Marburg and Gießen, Campus Marburg, Marburg, Germany

Correspondence to Professor Dr. Peter Kranke, Department of Anaesthesia and Critical Care, University Hospital of Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany E-mail: kranke_p@klinik.uni-wuerzburg.de

This review is based on a Refresher Course lecture given at the ESA European Anaesthesiology Congress, Amsterdam, June 2011.

Published online 5 October 2011

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Introduction

The incidence of postoperative nausea and vomiting (PONV) after a standard anaesthetic technique consisting of inhalational anaesthetics and opioids and no PONV prophylaxis is up to 30%.1,2 It is one of the most common complaints following surgery under general anaesthesia3 and is a considerable cause of dissatisfaction with recovery from anaesthesia.4 It remains one of the most commonly used items in surveys assessing patient satisfaction with the perioperative period as well as scoring systems for the quality of recovery following anaesthesia.5,6 It is estimated that anaesthesia is administered to approximately one in 10 of the population in France each year.7 It is reasonable to assume that these figures can be extrapolated to other European countries. This means that in a worst-case scenario (in which no prophylaxis is used), up to 22 million patients suffer from some degree of PONV every year in Europe (estimated population ∼731 million8).

Anaesthesia-related mortality and morbidity have fallen dramatically for healthy patients in recent decades,9,10 and outcome parameters focusing on ‘well being’ and ‘patient satisfaction’ are gaining importance. PONV can lead to a substantial prolongation of recovery room stay, prolonged hospital stay or unplanned overnight hospital admissions with associated increased costs for patient care. For paediatric patients, these consequences have been recently explored in detail using information in a large database. This revealed that PONV is one of the most common causes (about one quarter) of the observed 1–2% of unplanned hospital admissions following outpatient surgery.11 Despite their rarity, serious consequences secondary to vomiting may occur and are described in the anaesthesia literature every year. These include aspiration pneumonia, Boerhaave's syndrome, severe subcutaneous emphysema, pneumothorax, rupture of the trachea and loss of vision. Such complications may be considered the visible part of the iceberg and are a warning sign not to underestimate the scale of the problem.12–19

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Current guidelines and consensus statements

Despite the existence of recommendations on how to manage PONV on an international,20 national/European21 and national/local level,22 surveys published on guideline adherence or the use of institutional PONV policies in routine patient care suggest that implementation is poor.23–26 The existing consensus recommendations not only provide recommendations regarding the use of preventive measures, but sometimes give examples on how these recommendations can be implemented in terms of standard operating procedures.

In a recent analysis, even close and individual feedback for anaesthesiologists in conjunction with continuing medical education (CME) activities was unable to significantly improve compliance with PONV standard operating procedures and did not prevent insufficient therapy in medium or high-risk patients.26 In the high-risk group (patients with three risk factors1), in which – according to the standard of care in that particular hospital – patients should receive three antiemetics, only one-third received the scheduled treatment. In another survey, it was concluded that, irrespective of the existence of a carefully worded institutional policy to manage PONV that was published in multiple formats (intranet, print version, booklet), ‘… PONV in routine clinical care is likely to be underreported’.2 This may be an argument not to rely solely on treatment but that sufficient prophylactic antiemetics should be used ‘to reduce the incidence of PONV as much as possible’.27,28

These considerations may be viewed as an argument to critically re-assess the existing guidelines and recommendations, which mainly rely on a risk-adapted approach, with respect to their practicability. Guidelines frequently suggest that antiemetics should not be administered in low-risk patients. Some of the consensus guidelines advocate the use of risk models by stating that ‘the use of prophylactic antiemetics should be based on valid assessment of the patient's risk for postoperative vomiting (POV) or PONV’.20 Some anaesthesiologists interpret such statements as advice to use antiemetic prophylaxis only if the patient's individual risk is sufficiently high. Although such a recommendation seems to be convincing at first sight, actual clinical implementation is far less clear. There is no common consensus of the ideal threshold of when the risk for PONV is sufficiently high to warrant antiemetic prevention. Furthermore, the ideal way of performing an individual risk assessment remains unclear. One option consists of applying one of the numerous risk scores for PONV that have been developed. The plethora of available risk scores to predict PONV in adult patients witnesses the fact that, at least so far, none of the available tools seems to satisfy all needs. Although being excellent tools to educate colleagues regarding the most important risk factors for populations, recent analyses29 demonstrate that the predictive properties of such PONV scores are limited and it is unlikely that future scores will improve this.

Systematic research to elucidate risk factors for PONV has condensed the long list of supposed factors into a memorable number of important factors. This is important for both research questions (such as calculating the average expected risk in a group of patients) and for individual risk assessment in selected cases, and it facilitates evidence-based teaching. However, taking into account the results of recent research regarding the implementation of PONV scoring systems into clinical practice and the reluctance to act according to institutional standard operating procedures and to provide effective antiemetic prophylaxis, especially in high-risk patients,23–25,30 it may be concluded that too sophisticated algorithms (for example, a risk-adapted protocol) are among the most important hurdles to eliminating PONV. Provided guideline adherence is ensured, saving antiemetic interventions for those patients who need them most (high-risk patients) may be valid. But implementation studies have shown that with the intention to withhold antiemetics for low-risk patients, there is a constant threat that a considerable proportion of moderate-to-high-risk patients receive substandard care.31

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Barriers to the implementation of postoperative nausea and vomiting guidelines

It may be speculated that the most important hurdle to overcome is not the risk adaptation per se (which could mean the administration of two antiemetics to every patient and then to increase the number to three or more if the risk seems to be above average) but the fact that restricting antiemetics to patients at risk implicitly suggests that the currently available antiemetics put patients at risk of suffering side-effects. To fully implement such a laudable risk-benefit analysis using each individual patient's preferences would require extensive preoperative assessment. We know, for example by using conjoint analyses, willingness-to-pay investigations and other techniques frequently used for marketing management, that patients simply do not want to suffer from PONV and appreciate its avoidance.4,32 This, in the authors’ opinion, may be viewed as sufficient justification for a more liberal use of pharmacological management of PONV. Such reasoning may even be applied if the hurdles of insufficient guideline adherence and assessment of symptoms when using a traditional risk-adapted PONV algorithm33 are overcome in an institution.

Looking at the previously cited arguments to withhold effective antiemetic prevention such as acquisition costs, unknown efficacy and supposed adverse effects, we should take for granted that a large body of evidence suggests that these are no longer valid, provided that relevant contraindications are taken into account.

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Improving prevention of postoperative nausea and vomiting

The most important question, therefore, is how can we ensure that patients benefit from the large number of studies performed on PONV? In a provocative and prominent statement, Scuderi28 recently concluded that ‘… given the extremely low cost of all the currently available generic antiemetics and the extremely low incidence of adverse side effects, I would suggest that all patients might benefit from three or more antiemetics during the course of surgery to reduce the incidence of PONV as much as possible’. This change in attitude, from questioning the value of prophylactic antiemetics in terms of improved patient satisfaction27 to the advocacy of a liberal use of antiemetic agents without individual risk calculation, is based on changing environmental conditions (perception of PONV as a relevant outcome, decreasing costs of antiemetics, increasing demand for a smooth and predictable recovery, well investigated drugs in terms of their efficacy and effectiveness, as well as their side-effect profile) and may be viewed as a shift in the paradigm of PONV prevention.

Irrespective of the ‘ideal implementation strategy’, which depends on the population and institution being studied, it is reasonable to conclude that all patients undergoing a general anaesthetic consisting of inhalational anaesthetics and opioids should be eligible to receive at least two antiemetics. This liberal assumption should then be modified in the light of previous experience (no previous nausea or vomiting), patient specific contraindications (such as Parkinson's disease) and patient preferences (for example, the patient always has PONV following anaesthesia and wishes to avoid this symptom).

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Strategies to reduce the incidence of postoperative nausea and vomiting

In addition to the use of antiemetics, an important part of PONV prevention is the reduction in baseline risk by avoiding pro-emetic factors. In patients reporting previous PONV, regional anaesthesia should be considered and can be used either alone or in conjunction with general anaesthesia as an opioid-sparing and anaesthetic-sparing strategy. Regional anaesthesia, including both central neuraxial anaesthesia and peripheral nerve blocks or local anaesthesia techniques,34 is associated with a significantly lower risk of PONV in adults than general anaesthesia. Such an effect is likely to be due to the avoidance of both opioid and inhalational anaesthetics.35 If general anaesthesia cannot be avoided, using propofol rather than inhalational anaesthetics is a better choice to reduce the incidence of PONV. The relative risk (RR) reduction of this intervention together with the avoidance of nitrous oxide is equivalent to using antiemetics with well documented efficacy such as those described below.36–39 As opioids are among the most potent intraoperative and postoperative triggers for PONV, strategies that allow a dose reduction or even avoidance decrease the incidence of PONV.1,35,38,40,41

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Pharmacological and non-drug-based prevention

A huge variety of antiemetic molecules, grouped into different drug classes, are available for drug-based PONV prevention. Most of these agents antagonise the action of emetogenic substances at specific receptors, for example in the area postrema or on the free nerve endings of the vagus nerve (Table 1).

Table 1

Table 1

Increasing the inhaled oxygen concentration may have some effect on the incidence of PONV, but, according to the results of a recent meta-analysis, this effect is not clinically relevant for many PONV-related outcomes.42 The same holds true for ginger and ginger extracts.43 The effects of aromatherapy, for example with isopropyl alcohol, are not convincing so far and the study designs used are inferior to those used for established pharmacological agents. Fluid replacement strategies are thought to play a significant role in the occurrence of PONV. However, studies that have investigated the effect of fluid replacement on the incidence of PONV are heterogeneous (for example with respect to the definition of a ‘liberal’ versus a ‘restrictive’ fluid replacement strategy and the type of surgery) rendering them unsuitable to serve as a reliable basis for valid recommendations. Acupuncture or acupressure at point Pericardium 6 (Neiguan) on the wrist has been associated with better PONV prevention than placebo (sham acupuncture or acupressure).44 There is an ongoing debate about the importance that should be attributed to such non-pharmacological techniques in view of well proven pharmacological interventions.45 The most controversial discussion is that many different techniques and application modes have been investigated so far and have been grouped together in meta-analyses. This means that irrespective of the significant reduction in nausea [RR 0.71; 95% confidence interval (CI): 0.61–0.83] and vomiting (RR 0.7; 95% CI: 0.59–0.83) when compared with placebo in adults and children in a recent Cochrane Review, these conclusions must be interpreted with caution.46 However, these techniques may be the first choice if pharmacological management is contraindicated or the number of available agents is decreased, for example in pregnant patients.

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Combination treatment

After the benefit of single interventions had been established, research moved towards combining antiemetics for improved efficacy. Many combinations have been analysed and the take-home message was that the combination was better than a single intervention. If the finding that most of the different classes of antiemetic agent exert their effects independently of each other38 can be confirmed, then it is reasonable to conclude that the overall effect of such a bundle of interventions can be computed by simply adding up the relative effect of each single component.47,48 For many commonly used pharmacological interventions, the additive effect has been formally established.49–51 Good clinical evidence exists for the combination of a 5-HT3 receptor antagonist with dexamethasone or droperidol52 and for the combination of droperidol with dexamethasone.38

The next step is to combine several interventions into a ‘multimodal approach’ or ‘balanced antiemesis’.53 One of the early investigations using multimodal prevention was able to show that even in a high-risk setting, it is possible to almost completely eliminate PONV.54 The majority of the trials using a multimodal approach combined different interventions and strategies with various targets,55 such as reducing the emetic potency of the anaesthesia itself (for example by using propofol), the combination of several pharmacological and non-pharmacological techniques to prevent PONV or the use of other measures to decrease the incidence of PONV such as using regional analgesia techniques or peripherally acting analgesics or non-opioid analgesics in order to minimise the need for opioid analgesics. The extent to which each of the components contributed to the overall benefit remains speculative, as a factorial design36 that would have allowed the description of relative benefits was rarely used.

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Practical aspects of the management of postoperative nausea and vomiting

Dexamethasone, droperidol and ondansetron have been shown to have comparable antiemetic efficacy, with a RR reduction for PONV of about one-third in large clinical trials.36,38 The same reduction holds true for changing the anaesthetic technique and using total intravenous anaesthesia (TIVA) with propofol together with air instead of nitrous oxide. A combination of these measures (dexamethasone, droperidol, ondansetron and TIVA) is associated with a cumulative effect. It is reasonable to conclude that the cumulative effect is also valid for other drug-based measures described in Table 1, provided that the chosen interventions for combined prophylaxis act at different receptors.

There is no evidence that specific antiemetics work particularly well in conjunction with a specific patient profile (for example female versus male patients) or a particular surgical procedure (for example laparoscopy or middle ear surgery). Thus, patient or procedure-related (relative) contraindications or previous drug-related side-effects in a specific patient should be taken into account when choosing antiemetics. Using a multimodal approach, it is possible to achieve a significant reduction of the incidence of PONV in high-risk patients. In patients with a previous bad experience of PONV, such a success is usually associated with a substantial increase in patient satisfaction.54,55

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Postoperative nausea and vomiting treatment

An early trial comparing single agent prevention with treatment after the onset of PONV concluded ‘although PONV is unpleasant, the data indicate little difference in outcomes when routine prophylactic medications are administered versus simply treating PONV should symptoms occur’.27 Considering the currently available antiemetic substances in conjunction with the knowledge that the assessment of PONV symptoms in the postoperative care unit (PACU) and on the ward is usually less than optimal,2 better efforts should be made to prevent PONV. If PONV occurs despite prevention or in patients who have not received any prophylactic antiemetics, prompt treatment is indicated as the likelihood of PONV persisting or recurring is approximately 65%.56 The use of 5HT3-receptor antagonists, particularly ondansetron, for this indication has been extensively investigated and confirmed as being effective.57,58 Provided that no previous prophylactic antiemetics have been used these agents may be considered first-line drugs for the treatment of PONV. The data available on other pharmacological and non-pharmacological methods are less extensive. However, other drugs, such as dexamethasone, haloperidol, dimenhydrinate and promethazine, have been shown to be effective agents in the treatment of PONV.59,60

So far, there is no evidence that agents that are effective for prevention fail to work when administered as treatment. Therefore, taking into account some basic pharmacokinetic considerations, it is reasonable to extrapolate data and results from trials investigating the prevention of PONV. Interventions associated with a slow onset of action (such as dexamethasone, or transdermal scopolamine) should not be used in isolation, but should be used in combination with a fast-acting agent. For some drugs, such as ondansetron, the minimum effective dose for treatment is less than that used for prevention.57,58 However, for practical reasons, the same doses as those used for prevention are usually recommended for treatment.22 When PONV occurs despite preventive measures, it is recommended that drugs from another class should be administered. This is particularly true in the immediate postoperative phase.61,62 We have to rely on empirical pharmacokinetic considerations when re-administering a specific drug in order to prolong its antiemetic effect as reliable data do not exist. Combination therapy should be considered and promising data exist supporting the use of dexamethasone with dolasetron or haloperidol.59 Such treatments are supported by a recurrence rate of PONV over the subsequent 24 h in the range of 35–50% after intervention using a single agent.

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Postoperative nausea and vomiting in children

The incidence of PONV is strongly age-dependent. Whereas children less than 3 years of age are rarely affected, the incidence of PONV increases from this age upwards and reaches a peak between 5 and 9 years of age.63 Nausea is much more difficult to assess in infants and studies of PONV in this patient population are usually restricted to the incidence of POV. As in adults, a simplified prognostic system that is based on the most dominant risk factors (the Postoperative Vomiting in Children, or POVOC, score) can be used to predict vomiting in children.64,65 However, the same restrictions and limitations apply to individual risk prediction in children as described above for an adult population. Therefore, the aim should be to prevent PONV in this patient population.

In children, the same interventions for PONV prophylaxis and treatment can be used as for adults. Table 1 provides an overview of recommended body weight adjusted dosing regimens in children. TIVA using propofol in conjunction with the avoidance of nitrous oxide should be used at an early stage in the antiemetic protocol in children, as the overall armamentarium is restricted compared with that for adults due to limitations regarding the use of D2-antagonists (such as metoclopramide, droperidol or haloperidol) in children,66 and the fact that transdermal scopolamine and NK1-antagonists are not available in paediatric doses. Irrespective of recent concern regarding the administration of dexamethasone in children undergoing tonsillectomy, the current recommendations of the Task Force for Pediatric Anesthesia of the German Society of Anesthesia state that it is too early to draw meaningful conclusions regarding potentially harmful effects and the administration of 0.15 mg kg−1 dexamethasone is considered useful in preventing PONV in children.67,68

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Prevention and treatment algorithms

The effectiveness of specific algorithms depends on the risk distribution in a given population. Thus, no recommendations can be given about a single ‘ultimate’ prevention algorithm being universally effective and efficient.48 The underlying rationale for using a risk-adapted approach is to save resources in certain patients (those who do not need antiemetic prevention) and concentrate resources for patients who need multimodal prevention. Inherent limitations regarding risk prediction and reported problems in the enduring implementation of a risk-adapted individual approach clearly support easy-to-use and simple algorithms. Being easy to use is a vital prerequisite to facilitate their use becoming as routine as providing analgesia during and after the surgical procedure. The acquisition costs and the side-effect profile of many of the available antiemetics should not present a major obstacle with respect to widespread use. In simulation studies, the efficacy of prevention regimens is usually comparable with risk-adapted approaches,48 without being hampered by a dependency on the accuracy of strategies used to determine those patients who would not benefit from preventive measures.29

It appears that it is more important to monitor local factors and ensure sufficient prophylactic administration of antiemetics than to decide upon the most sophisticated antiemetic prophylactic strategy.69,70 At this time, there are insufficient data to justify specific recommendations based on pharmacogenetic considerations (‘tailored antiemesis’). All the pharmacological interventions listed in Table 1 have been investigated in many clinical trials and have demonstrated a convincing risk to benefit ratio. Thus, a liberal and multimodal prophylaxis regime is justified in high-risk patients. However, as the potential of antiemetic interventions to cause specific adverse events is variable, patient-specific considerations must be included in an overall risk-benefit analysis in the light of the patient's individual profile and his or her preferences.

The costs of the different antiemetics are varied. This may allow some opportunities for cost-savings. However, the purchase prices of antiemetics for different institutions vary to such an extent that general pharmaco-economic analyses are unreliable. Simulation analyses using institutional data on the local population may help overcome these limitations and facilitate an a priori assessment of the most suitable algorithm.48 However, the decision for, or against, specific antiemetics should be based primarily on medical reasoning.

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Conclusion

In summary, all practicing anaesthesiologists should be invited to join the antiemetic crusade to make actual change happen. It is up to each individual anaesthesiologist to decide whether PONV will eventually stop or whether it will remain a ‘never-ending story’. The weakest link in the chain from research to patient benefit is clearly the implementation of well proven strategies. To this end, we should be familiar with the new pharmacological agents to cope with PONV, such as the NK1-antagonists or newer 5-HT3, but we should not forget the traditional and well established antiemetics that remain valuable components in our current portfolio and may contribute to a (nearly) PONV-free hospital.71–73

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Acknowledgements

The present work was supported by the Department of Anaesthesia and Critical Care, University Hospitals of Würzburg, Germany.

P.K. and L.H.J.E. have both received speaker's fees from Fresenius Kabi (Germany) and ProStrakan (Germany).

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Keywords:

antiemetics; patient satisfaction; postoperative complications; postoperative nausea and vomiting

© 2011 European Society of Anaesthesiology