By Zheng Cheng Zhu
Key reference:
Gan, T. J., Belani, K. G., Bergese, S., Chung, F., Diemunsch, P., Habib, A. S., Jin, Z., Kovac, A. L., Meyer, T. A., Urman, R. D., Apfel, C. C., Ayad, S., Beagley, L., Candiotti, K., Englesakis, M., Hedrick, T. L., Kranke, P., Lee, S., Lipman, D., Minkowitz, H. S., … Philip, B. K. (2020). Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting. Anesthesia and analgesia, 131(2), 411–448. https://doi.org/10.1213/ANE.0000000000004833
You are performing your usual pre-anaesthetic check for an elective laparoscopic cholecystectomy. You meet Ms. Jones, who is an otherwise well 45yo lady, with no allergies, regular medications, and is a non-smoker. She appears highly anxious, and through your prompting, she asks if she will experience the same terrible nausea and vomiting she endured after her emergency caesarean 20 years ago following her general anaesthesia.
What is Ms. Jones referring to?
Post-operative nausea and vomiting (PONV) is defined as:
-
Nausea, the unpleasant sensation pertaining to desire to vomit;
And/or,
-
Vomiting, the expulsion of gastrointestinal content through the mouth,
in the post-anaesthetic care unit (PACU) or 24 hours in the immediate post-operative period
How common is PONV, and should you be worried about Ms. Jones’ concerns?
-
PONV is the second most common post-operative adverse event after post-operative pain.
-
Incidence has been reported to be 30% in the general surgical population.
-
Has been reported as high as 80% in high-risk cohorts.
-
Highly distressing symptoms that can result in adverse sequelae including:
| Logistical/cost | Patient |
| Prolonged PACU stay
Delayed discharge
Unexpected (re-)admission
Delayed return to work and daily activities
--> Increased healthcare and societal costs |
High psychological distress
Often compounded by post-operative pain Reduced patient satisfaction
Respiratory aspiration
Wound dehiscence (increase abdominal pressure)
Post-operative hypovolaemia
Acid-base and electrolyte disturbance Metabolic alkalosis Hypokalaemia, hypomagnesaemia |
How does PONV occur?
The pathophysiology of PONV involves complex interplay of multiple afferent pathways and neurotransmitters inputting into the “vomiting centre”, an ill-defined region within the reticular formation of the brainstem.
The types of surgery, anaesthetic agents used and patient-specific factors can all trigger or augment these afferent pathways to elicit nausea and/or vomiting response
| Afferent pathways | Stimulants / triggers | Chemoreceptor involved |
Chemoreceptor trigger zone
|
Emetogenic drugs, toxins, catecholamines
|
5-HT3, H1, M, D2 |
| Vagal mucosal afferent pathway | GIT local toxins/irritants, surgical manipulation
|
5-HT3, H3, M3 |
| Vestibular afferent pathway | Position change, motion sickness, vestibular apparatus manipulation
|
H1, M |
| Pharyngeal gag reflex | Disruption / irritation of oropharynx
|
CN IX -> nucleus solitarius -> CN X |
| Cortical afferent pathway | Obnoxious sensory stimuli inputting to vomiting centre
|
How do we manage PONV?
Management should primarily focus on the prevention, risk minimisation and prophylaxis against PONV, with rescue therapy provided to patients experiencing PONV to alleviate symptoms and reduce adverse outcomes. This forms the framework set out by the Fourth Consensus Guideline for management of PONV using the following stepwise approach:
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Risk stratification – identification of high-risk groups
-
Risk modification – patient-centered strategies to reduce risk
-
PONV prophylaxis – non-pharmacological and pharmacological options to prevent or reduce severity of PONV
-
PONV treatment – rescue therapy for patients with PONV who did not receive or failed prophylaxis
Risk stratification: is Ms. Jones a “high risk” patient?
The following table outlines the patient, surgical and anaesthetic factors associated with high risk of PONV:
| Patient factors | Surgical factors | Anaesthetic factors |
| Female sex
Age <50 Non-smoker Hx of PONV and/or motion sickness
|
Type of surgery
Duration of surgery / duration of anaesthesia > 1hr
|
Volatile anaesthetics
> Nitric oxide
Post-operative opioids
|
| Paediatric:
Age >= 3 PMHx and/or FHx of PONV or motion sickness Post-pubertal female
|
Paediatric:
Type of surgery
Duration >30min
|
Paediatric:
Volatile anaesthetics Anticholinesterase Post-operative opioids |
The Apfel score is a validated risk assessment tool that provides an objective measure in predicting PONV incidence and hence informs clinicians of the prophylaxis regime required based on the risk
The Apfel score utilises 4 predictors, whereby each score 1 point:
-
Female gender
-
Non-smoker
-
History of PONV and/or motion sickness
-
Post-operative opioids
The score corresponds with the following risk:
|
0 |
10% |
Low risk |
|
1 |
20% |
|
|
2 |
40% |
Medium risk |
|
3 |
60% |
High risk |
|
4 |
80% |
Applying the Apfel score to Ms. Jones, who is female, non-smoker, with lived history of PONV and is likely to require post-operative opioid analgesia, she scores 4 which puts her at high risk of PONV. Her age and type of surgery also puts her at a higher risk not included in the Apfel score.
Risk modification: how can we reduce Ms. Jones’ risk?
Examining our risk factor table, there are two modifiable factors targetable in our anaesthetic plan to minimise PONV risk: the judicious use or avoidance of:
-
Volatile anaesthetics
This can be achieved, when permitted by the type of surgery and patient’s anaesthetic risk profile, through the preferential use of regional anaesthesia or total intravenous anaesthesia (TIVA) using propofol induction and maintenance. It has been demonstrated that PONV risk associated with TIVA is comparable to the use of volatile general anaesthetia with single agent prophylaxis with 5-HT3 antagonist or droperidol, and the risk is further reduced when TIVA is used in combination with prophylaxis.
-
Peri-operative and post-operative opioids
In optimising analgesia in the peri- and post-operative setting, a multimodal regimen should be used to limit the use of opioids while achieving adequate pain relief. It is therefore best practice to provide concurrent simple analgesia (examples IV paracetamol, NSAIDS) as well as adjuncts such as alpha-2 agonists.
Peri-operative alpha-2 agonists, including dexmedetomidine and clonidine, acts as opioid –sparing analgesia and short-term direct anti-emetic. Dexmedetomidine given at skin incision at 1microgram/kg has been demonstrated to be similarly effective in PONV prevention compared to 8mg dexamethasone, with added benefit of superior pain relieve in the immediate 24 hours after laparoscopic cholecystectomy.
Beyond pharmacological strategies, simple measures to maintain patient’s hydration status can also be effective. Limiting fasting time and providing IV crystalloid pre-operatively at 10-30ml/kg are effective in reducing PONV risk and need for rescue therapy.
| Modifiable factors | Strategy |
| Volatile anaesthetic | Regional | Neuraxial anaesthesia
Limit / avoid use of GA all together E.g.
Propofol total intravenous anaesthesia (TIVA)
|
| Opioid use | Multimodal analgesia regimen
for post-operative pain in reducing opioid requirement
Peri-operative alpha-2 agonist Short-acting direct anti-emetic and opioid-sparing analgesia
|
| Non-pharmacological | Maintaining clinical euvolaemia
|
PONV prophylaxis: what agents and combinations are available for Ms. Jones to prevent PONV?
There is a wide array of antiemetic agents available to anaesthetists in preventing PONV, largely classed based on the specific chemoreceptors targeted in the afferent pathways involved in eliciting the nausea and vomiting response:
-
5-hydroxytryptamine 3 (5-HT3) receptor antagonists
-
Neurokinin-1 (NK-1) receptor antagonists
-
Dopamine receptor antagonists | antidopaminergics
-
Histamine receptor antagonists | antihistamines
-
Muscarinic receptor antagonists | anticholinergics
-
Corticosteroids
Corticosteroids, namely dexamethasone, do not target specific chemoreceptor pathways, and its antiemetic property remains poorly understood despite large body of empirical evidence supporting its efficacious use in preventing PONV since 1990s. Mechanisms proposed include its anti-inflammatory effects in limiting emetogenic cytokine production, genomic effects in reducing expression of 5-HT3 receptors, direct action at the nucleus solitarius, and indirect benefits in reducing post-operative pain and therefore the use of opioids.
The following table summarises an antiemetic from each class, some of which form the cornerstone of PONV prophylaxis:
| Antiemetic | Dose | Adverse reactions | Comments |
| Aprepitant
NK-1 antagonist |
40mg, 80mg, 125mg PO
On induction |
Mild ADRs predominate: headache, anorexia, hiccup | More effective in preventing vomiting than nausea at all dosages
Efficacy as monotherapy comparable to several combination therapies
Useful for patients where PONV is best avoided; e.g. gastric (anastomotic leak) and neurosurgery (raised intracranial pressure) |
| Ondansetron
5-HT3 antagonist |
4mg IV, 8mg PO
End of surgery |
Headache, constipation, deranged LFT, prolonged QT (at 32mg dose) | “Gold standard” of PONV prophylaxis, and most-well studied agent
Efficacious in prophylaxis and rescue therapy for PONV
Similarly effective compared to dexamethasone 4 – 8mg
Comparatively less efficacious versus second-generation 5-HT3 antagonists ramosetron and palonosetron |
| Dexamethasone
Corticosteroid |
4 – 8mg IV | See comments | Recent Cochrane review and PADDI trial demonstrated as single dose, dexamethasone does NOT increase risk of post-operative wound infection
Current evidence also does not suggest association with increased risk of anastomotic leak, bleeding or clinically significant hyperglycaemia |
| Droperidol
Antidopaminergic |
0.625mg IV | Extrapyramidal side effect, prolonged QT, sedation | Dosage <1mg effective in PONV, whilst ADRs are dose dependent |
| Dimenhydrinate
Antihistamine |
1mg/kg IV | Dry mouth, sedation, visual disturbance | |
| Scopolamine
Anticholinergic |
Transdermal patch | Dry mouth, sedation, visual disturbance, dizziness |
Non-pharmacologically, acupuncture at the pericardium 6 point (PC6) has been well documented to have efficacy in preventing PONV and need for rescue therapy that is non-inferior to single-agent ondansetron, dexamethasone, or droperidol. This possibly provides a viable option for patients who wish to avoid the adverse effects/reactions towards common antiemetics.
The latest Fourth Consensus Guideline on PONV now recommends the use of multimodal prophylaxis instead of single agents for patients with one or more risk factors, based on robust data demonstrating its superiority in preventing PONV and adverse reactions associated with high-dose single agents.
The most common combinations include:
-
5-HT3 antagonist with dexamethasone
-
Remains most well studied and used clinically
-
-
5-HT3 antagonist with aprepitant
-
Aprepitant with dexamethasone
-
Superior in preventing PONV compared to ondansetron + dexamethasone or ondansetron single agent, particularly useful in high-risk groups such as neurosurgery
-
-
5-HT3 antagonist with droperidol
Recent data is emerging for the use of more than 2 agents. For example, triple therapy using aprepitant 80mg + dexamethasone 4 – 8mg + ondansetron 4mg in elective laparoscopy patients undergoing TIVA combined with neuromuscular blockade was superior compared to dual dexamethasone and ondansetron.
In the case of Ms. Jones, who is a high-risk patient, we can utilise many of the risk minimisation and prophylaxis strategies in a shared decision-making basis. A combination of TIVA, multimodal analgesia, peri-operative alpha 2 agonist, combination ondansetron + dexamethasone, and judicious post-op opioid use may be a suitable option.
What can we do if Ms. Jones still gets PONV after her operation?
When PONV prophylaxis fails, Ms. Jones should receive an antiemetic that acts via different chemoreceptor pathway.
Further doses of same agent given within 6 hours does not provide additional benefit
In patients who did not receive antiemetic prophylaxis, then 5-HT3 antagonists remain first-line for established PONV, exampled include:
-
Ondansetron 4mg IV or PO
-
Ramosetron 0.3mg
-
Granisetron 0.1mg
-
Tropisetron 0.5mg
Other rescue therapies demonstrated to have effect include:
-
Promethazine 6.25mg IV
-
Vestipitant 4-36mg
-
Droperidol 0.625mg
-
PC6 acupuncture
Importantly, in PONV that persists despite adequate rescue therapy, it is imperative to rule out organic pathology such as post-operative infection, wound dehiscence, bowel obstruction, or oropharyngeal trauma.
References
Chu, C. C., Hsing, C. H., Shieh, J. P., Chien, C. C., Ho, C. M., & Wang, J. J. (2014). The cellular mechanisms of the antiemetic action of dexamethasone and related glucocorticoids against vomiting. European journal of pharmacology, 722, 48–54. https://doi.org/10.1016/j.ejphar.2013.10.008
Corcoran, T. B., Myles, P. S., Forbes, A. B., Cheng, A. C., Bach, L. A., O’Loughlin, E., Leslie, K., Chan, M. T. V., Story, D., Short, T. G., Martin, C., Coutts, P., Ho, K. M., PADDI Investigators, Australian and New Zealand College of Anaesthetists Clinical Trials Network, & Australasian Society for Infectious Diseases Clinical Research Network (2021). Dexamethasone and Surgical-Site Infection. The New England journal of medicine, 384(18), 1731–1741. https://doi.org/10.1056/NEJMoa2028982
Gan, T. J., Belani, K. G., Bergese, S., Chung, F., Diemunsch, P., Habib, A. S., Jin, Z., Kovac, A. L., Meyer, T. A., Urman, R. D., Apfel, C. C., Ayad, S., Beagley, L., Candiotti, K., Englesakis, M., Hedrick, T. L., Kranke, P., Lee, S., Lipman, D., Minkowitz, H. S., … Philip, B. K. (2020). Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting. Anesthesia and analgesia, 131(2), 411–448. https://doi.org/10.1213/ANE.0000000000004833
Shaikh, S. I., Nagarekha, D., Hegade, G., & Marutheesh, M. (2016). Postoperative nausea and vomiting: A simple yet complex problem. Anesthesia, essays and researches, 10(3), 388–396. https://doi.org/10.4103/0259-1162.179310
Weibel, S., Rücker, G., Eberhart, L. H., Pace, N. L., Hartl, H. M., Jordan, O. L., Mayer, D., Riemer, M., Schaefer, M. S., Raj, D., Backhaus, I., Helf, A., Schlesinger, T., Kienbaum, P., & Kranke, P. (2020). Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: a network meta-analysis. The Cochrane database of systematic reviews, 10(10), CD012859. https://doi.org/10.1002/14651858.CD012859.pub2
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