Management of post-operative nausea and vomiting in adults

The evidence base supporting pharmacological and non-pharmacological interventions for nausea and vomiting after surgery.

Patient with post operative vomiting

Post-operative nausea and vomiting (PONV) is an umbrella term that covers nausea and vomiting following any surgical procedures[1]
. Nausea and vomiting in combination are reflexes designed to protect against the absorption of toxins, but olfactory, visual, vestibular and psychogenic triggers also exist, which have implications for hospital ward environments where PONV can spread around the bay. 

This article describes the extent of PONV in adults, the risk prediction tools used and the interventions that reduce baseline risk. The importance of optimal management and prevention strategies are discussed in the context of the evidence base supporting pharmacological and non-pharmacological interventions in this field.

Physiology 

Complex physiological processes lie at the root cause of PONV and involve the chemoreceptor trigger zone (CTZ), located in the area postrema (a medullary structure), and the nucleus tractus solitarius (NTS), a series of purely sensory nuclei (clusters of nerve cell bodies) forming a vertical column of grey matter embedded in the medulla oblongata. The CTZ is outside the blood–brain barrier and can therefore be affected by opioids, anaesthetics and neurotransmitters (e.g. 5-hydroxytryptamine [5-HT]) that may be released during surgery.

 

Source: Adapted with permission from Borison HL et al. J Clin Pharmacol 1981;21:235–295.

The cerebellum may function as a second relay or gating mechanism in the link between labyrinth and CTZ (not shown). CNS: central nervous system; CTZ: chemoreceptor trigger zone; D2: dopamine; 5-HT3: 5-hydroxytryptamine type 3; H1: histamine; mACh: muscarinic acetylcholine

For clinical purposes, it is only necessary to be aware that drugs acting on a range of receptor sites (e.g. serotonin receptors [5-HT3], dopamine receptors [D2], histamine receptors [H1] and muscarinic acetylcholine receptors, along with neurokinin-1 receptors [NK1]) are utilised and effective in the prevention and treatment of PONV, and that combining drugs acting on the same receptor is not clinically rational (see Figure 1).

Avoidance of PONV has been shown to be important to patients and is underpinned by results of willingness-to-pay studies[2],[3]
. However, during a recent study of UK patient-related outcomes, anxiety was found to be the principal concern for patients and only a minority of respondents reported severe PONV[4]
. The main problem regarding PONV is impairment of well-being, followed by delayed recovery. Less frequently, PONV can lead to increased duration of hospital stay (including admission following day surgery) or further post-surgical complications (e.g. dehiscence [rupture] of the wound), adding financial to humanitarian grounds for optimal management of this symptom[5]
.

Despite attempts to reduce the incidence, around 30% of patients undergoing surgical procedures under general anaesthesia experience symptoms of PONV (around 50% experience nausea)[6]
. Hospital sites or centres that consistently achieve levels significantly below this (in the absence of adequate implementation of the policy measures described below) should check that they are recording the full incidence of PONV —from the recovery unit until discharge. Where patients are promptly discharged (e.g. in day surgery), consideration should be given to auditing post-discharge nausea and vomiting (PDNV), where a risk score has been developed[5]
.

This article is structured around consensus guidelines from the Society for Ambulatory Anesthesia on the management of PONV[6]
. The subheadings used correspond with this guidance and readers are encouraged to review this guidance for any relevant definitions. The main headings represent the steps to be followed for the prevention and management of PONV[6]
.

Identify patient’s risk for PONV

The simplest and mostly widely used risk-scoring system is the four-point scoring system developed by Apfel et al. for use in patients undergoing general anaesthesia, which uses four risk factors:

  • Female gender;
  • Non-smoking status;
  • Use of post-operative opioids; 
  • Previous history of either PONV or motion sickness[7]
    .

One point is gained for the presence of each factor. The listing (see Table) can then be used to determine the approximate incidence.

Table: Apfel risk scoring tool to determine patient incidence of post-operative nausea and vomiting
Risk factors (number) Incidence (approximate %)
 Source: Adapted from Anesthesiology 1999;91(3):693–700[7]
 0 10
 1 20
 2 40
 3 60
 4 80

The Apfel score has been widely adopted as it is relatively simple to use in everyday clinical practice. Other risk scores have been developed but are often complicated and are more suited for research purposes.

In terms of non-modifiable risk factors, a longer duration of the surgical procedure has been identified to increase the risk of PONV, with one observational study showing that each 30-minute increase in the duration of surgery increased the risk of PONV by 60%[8]
.

Reduce baseline risk for PONV

In the IMPACT trial, the combination of using propofol and avoiding nitrous oxide (i.e. total intravenous anaesthesia [TIVA]) reduced the incidence of PONV by the same proportion as use of an anti-emetic agent (26%)[9]
.

Other ways to minimise PONV include:

  • Using regional rather than general anaesthesia;
  • Using opioid-free or opioid-sparing analgesia, particularly post-operatively, while providing appropriate multimodal analgesia;
  • Keeping the patient well hydrated.

Administer PONV prophylaxis using one or two interventions in adults at moderate risk of PONV or administer prophylactic therapy with combination (≥2) interventions/multimodal therapy in patients at high risk of PONV

The Society for Ambulatory Anesthesia guidelines on the management of PONV define patients as being at moderate risk if they have two of the risk factors present from the Apfel score or at high risk if they have three or more risk factors present[6]
. The following section describes the evidence base used to guide prophylactic treatment in patients at moderate risk and high risk of PONV.

Evidence from clinical trials

IMPACT trial

Most PONV trials have historically fallen into the conventional trial design of pitching a single intervention (sometimes two drugs or two doses of a single drug) against placebo and measuring the effect on a PONV outcome (e.g. nausea and/or vomiting for a defined period post-operatively or requirement for rescue antiemetics). However, the IMPACT trial demonstrated the effect of six independent interventions (including three different anti-emetics) in a multi-factorial trial design on a large number of high-risk patients (n=5,161 with 4,123 patients randomised to all six interventions)[9]
. The primary outcome was PONV within 24 hours, which was blindly evaluated and all patients were at high risk for PONV (Apfel score ≥2)[9]
.

Three anti-emetics were tested individually (ondansetron, dexamethasone and droperidol) and independently reduced the incidence of PONV by around 26%[9]
. No statistical difference was found between any of the anti-emetics or, indeed, any pair of anti-emetics tested. As noted previously, propofol reduced the incidence of PONV by 19% and nitrogen (compared with nitrous oxide) by a further 12%[9]
. TIVA (combining the two) reduced PONV with a similar risk reduction to the individual anti-emetics. The effect of all interventions were shown to be additive[9]
. Adding a second agent (or TIVA), and indeed a third agent on top of this, reduced the incidence by a further 26%, although the absolute reduction would clearly be less (as the baseline risk is already reduced). Accordingly, the absolute risk reduction in individual patients is the highest in patients with a high baseline risk[8]
.

DREAMS trial

The DREAMS trial was designed to address the impact of addition of a single dexamethasone dose (8mg intravenous) to a single antiemetic agent (labelled standard care, regardless of risk scoring) in 1,350 patients undergoing gastrointestinal surgery[10]
. Despite the lack of risk scoring, the two groups were balanced when comparing the four factors used in the Apfel score and, contrary to the protocol, more than one pre-operative routine antiemetic was given to 20% of patients in the standard care group compared with 8% in the dexamethasone group[10]
. The primary outcome was vomiting reported within 24 hours. Dexamethasone reduced the incidence of PONV and the need for rescue antiemetics, along with hastening return to diet. However, the study authors note that, in terms of antiemetic effects, these would have been expected given the results around combination antiemetics described previously (and elsewhere in the literature)[10]
.

Anti-emetic prophylaxis

The take-home message from the IMPACT trial is that it does not matter which agent is selected for PONV prophylaxis, it is the number of agents administered that is important (provided that each agent exerts its pharmacological effect via a different receptor site; known as multimodal prophylaxis).

Although most NHS hospital trusts with guidelines for PONV have included the agents discussed previously, it is likely that certain other antiemetics available in the UK (e.g. cyclizine[11]
) would have a similar efficacy. Haloperidol has also been used at a dose between 0.5mg and 1.0mg as an alternative to droperidol[12]
. However, in the UK, both cyclizine and haloperidol have become relatively expensive options for use in this indication and many trusts avoid using these from a financial perspective. Cyclizine is not recommended in the consensus guidelines (although dimenhydrinate and meclizine are mentioned)[6]
. It must also be remembered that metoclopramide 10mg is largely ineffective (with a number needed to treat [NNT]=30) for prophylaxis[13]
 and should not be included in local guidelines. Higher doses are more effective[14]
 but the drug tends to be avoided (unless a prokinetic effect is also desirable) in favour of the other dopaminergic agents outlined earlier.

In clinical practice, many trust guidelines recommend using a 5-HT3 antagonist and dexamethasone as first-line agents, largely because steroids are longer acting, negating the need for repeat administration and 5-HT3 antagonists (usually ondansetron) are the gold standard because they have been widely studied. Longer-acting 5-HT3 antagonists (e.g. granisetron) may also share the above advantage but are slightly more expensive. A network meta-analysis showed granisteron to be significantly better in prevention of PONV than ondansetron (although the studied 5-HT3 antagonists were comparable in the prevention of post-operative vomiting)[15]
. Palonosetron is much longer acting (half-life around 40 hours), with evidence supporting its use in PONV[16]
, but it currently costs in excess of £50 per dose, limiting its use in this indication. 

Administration of prophylactic doses

Most prophylactic agents, with the exception of dexamethasone, should be administered 20–30 minutes before the planned end of surgery in order to achieve optimal effect. Dexamethasone should instead be administered shortly after induction and, as its administration is associated with perianal pruritis, it should not be administered to patients while they are awake. Perianal pruritis may be reduced by diluting dexamethasone with 50ml of normal saline or glucose 5%, and administering slowly over 5–10 minutes. Pragmatically, this can be simplified to giving dexamethasone at the start of the procedure and other prophylactic anti-emetics at the end.

Side effects of prophylactic anti-emetics are rarely troublesome given that single administrations are required, often at low dose, but should always be considered. Combining droperidol with a 5-HT3 antagonist has not been shown to prolong the QT interval[6]
. Recent studies have raised concerns about the effect of dexamethasone on post-operative infection and blood glucose levels 6–12 hours post-operatively, and should be avoided in labile patients with diabetes[6]
.

Non-pharmacological measures

The P6 acupuncture point stimulation is effective in preventing early PONV in adults (NNT of around 4), although there is no benefit in children or in patients with late vomiting[17]
.

Administering prophylactic anti-emetic therapy to children at increased risk for PONV

Paediatric PONV management is beyond the scope of this article; however, as noted in the consensus guidance above, the principles are similar to management in adults and the use of combination therapy is most effective. A four-point risk factor system is available using duration of surgery; age over three years; history of PONV in patient, sibling or parent; and strabismus surgery as factors[18]
. Age over three years is used because post-operative vomiting is rare in children aged under two years, while rates are higher than for adults above this age. After puberty, rates then normalise. Strabismus surgery has a PONV rate of around 70%. Further information on drugs, dose ranges and the level of evidence can be found in recent consensus guidelines[6]
.

Provide anti-emetic treatment to patients with PONV who did not receive prophylaxis or in whom prophylaxis failed

There is a sparsity of evidence to guide the management of established PONV occurring, despite the use of antiemetic prophylaxis. In a recent systematic review, 5-HT3 antagonists were shown to prevent further vomiting, with little evidence of dose-responsiveness[19]
. Effects on nausea were less marked[19]
. Little evidence is available that supports the use of other antiemetics.

Guidelines recommend using an agent acting on a different receptor to that used for prophylaxis (repeated administration should only be undertaken after drug levels have depleted)[6]
. This would appear to be rational and in one randomised, double-blind, placebo-controlled study in 2,199 patients, ondansetron was ineffective for the treatment of PONV that occurred within two hours after discontinuation of inhaled anaesthesia where ondansetron had been administered for prophylaxis[20]
. Use of combination treatment for PONV would seem rational, although evidence that supports this approach is limited.

Ensure PONV prevention and treatment is implemented in the clinical setting

PONV guidelines

Seemingly irrespective of content (and the anti-emetic agents selected), guideline implementation reduces the incidence of PONV[21]
. Documentation of PONV incidences is helpful for highlighting issues and for auditing purposes. Recording on observation charts focuses attention on PONV and should promote prompt treatment for nausea and/or vomiting.

Guidance from the Royal College of Anaesthetists suggests that practice should be audited against local guidelines for PONV and provides relevant audit standards[22]

Any policy should include (as a minimum):

  • Risk scoring;
  • Combination anti-emetic prophylaxis;
  • Treatment of PONV;
  • Other mechanisms to reduce risk.

It suggests auditing compliance to any local guidance but many authors, including Kumar et al., have demonstrated that achieving high compliance with any protocol can be challenging[23]
.

Use general multimodal prevention to facilitate implementation of PONV policies

As with all treatments, it is necessary to balance benefit against potential risks. For some patients at low PONV risk it may be appropriate to administer anti-emetic prophylaxis. The guidance algorithm from Doncaster and Bassetlaw Hospitals suggests that all patients should receive one prophylactic anti-emetic, given the low cost and potential for adverse effects/interactions with ondansetron, and that those patients scoring 2 or more risk factors should receive combination anti-emetic prophylaxis[24]
. Nottingham University Hospitals use the sticker shown in Figure 2.

 

Source: Nottingham University Hospitals

IV: intravenous; NUH: Nottingham University Hospitals; PONV: post-operative nausea and vomiting; S/C: subcutaneous

Over a decade ago, Glass & White went as far as stating: “Given the high efficacy, low cost and excellent safety profiles of the most commonly used anti-emetic drugs (e.g. droperidol, dexamethasone and ondansetron), in our view these drugs should be routinely administered for anti-emetic prophylaxis of all patients receiving general anaesthesia irrespective of their risk classification”[25]
. Consensus guidelines state: “The goal, therefore, is for anti-emetic multimodal prevention to become an integral part of anaesthesia”[6]
. One centre using an aggressive prophylactic approach has achieved impressive reductions (using triple anti-emetic prophylaxis and modifiable risk reduction) in PONV rates for those undergoing day-case surgery[26]
.

German language recommendations discuss the advantages and disadvantages of a risk-dependent and a risk-independent approach, suggesting that a risk-independent approach may be easier to implement[27]
. One recent trial examined the effect of further simplifying guidance and giving all male patients dexamethasone and ondansetron, and adding either a target-controlled infusion with propofol or droperidol to the two anti-emetics in female patients. This simplification resulted in improved compliance with the guidance and a reduction in the incidence of PONV[28]
.

Summary

PONV remains a significant clinical problem. New anti-emetic molecules continue to emerge (e.g. aprepitant, palonosetron, rolapitant), potentially offering minor advances over widely available (and inexpensive) therapies. However, the evidence guiding how to significantly reduce PONV rates already exists — using combinations of ‘traditional’ antiemetics.

Pharmacists working in the surgical environment should be aware that influencing PONV management is largely protocol-driven, requiring both input and ‘buy-in’ from all members of the multidisciplinary teams caring for perioperative patients, and attempts to manage this at ward level alone without these changes will be largely futile. Regular audit is necessary to monitor changes in practice.

Financial and conflicts of interest disclosure

The authors have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. No writing assistance was used in the production of this manuscript.

References

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[24] Wilson LJ & Graham D. Doncaster and Bassetlaw Hospitals NHS Foundation Trust formulary post-oerative nausea and vomiting (PONV) guidance. Available at: http://www.dbth.nhs.uk/wp-content/uploads/2018/06/PONV-Lee-wilson.pdf (accessed November 2018)

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Citation
Clinical Pharmacist, CP, November 2018, Vol 10, No 11;10(11):DOI:10.1211/PJ.2018.20205652