Fifth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting: Executive Summary

Novel PONV Risk Factors

Literature since the last PONV consensus guideline reported several novel risk factors for PONV. A retrospective study of 160,000 patients identified a strong association between lower preoperative physical fitness (ASA classification 3) and decreased likelihood of developing PONV (SDC 3, Table S1, https://links.lww.com/AA/F570 B1).⁷ A smaller retrospective analysis demonstrated that higher hemoglobin and hematocrit (Hct) were associated with less PONV (B1),⁸ with Hct level >39.3% being optimal. Both elevated neutrophil/lymphocyte ratio and platelet/lymphocyte ratio were associated with increased PONV risk (B1).⁹

Avoiding intraoperative hypotension (B1)¹⁰ and goal directed hemodynamic management (A1)¹¹ may reduce the risk of PONV. Kim et al found that propensity matching, overweight and obese patients [body mass index (BMI) > 25 kg/m² and > 30 kg/m² respectively] had significantly lower incidence of PONV than patients with lower BMI (B1).¹²

Type of Surgery

Patients undergoing bariatric surgery have higher rates of PONV (B1).¹³ Other higher risk surgeries include laparoscopic cholecystectomy, urological procedures, and knee arthroplasty (B1).¹⁴ Breast, gynecologic and obstetric surgeries are also associated with increased risk.¹⁵

At the population level, adding more risk factors to the prediction model is unlikely to improve model performance. Additional factors should be considered on a case-by-case basis if vomiting poses a significant medical risk, such as an increased intracranial pressure or in conjunction with wired jaws in the postoperative phase.

PDNV Risk Evaluation

PDNV presents a significant risk as patients no longer have access to fast-onset intravenous (IV) antiemetics or direct care. A simplified PDNV score included 5 risk factors: female gender, age <50 years, history of PONV, opioid use in the post-anesthesia care unit (PACU), and nausea in the PACU (Figure 1B),¹ the incidence of PDNV with 0 to 5 risk factors to be about 10%, 20%, 30%, 50%, 60%, and 80%, respectively. Other risk factors may include previous PDNV, length of surgery, antiemetic use in the PACU and postdischarge pain.¹

Genomics, Genetics, and Polymorphism

Emerging evidence suggests that PONV risk and antiemetics efficacy may be influenced by genetic polymorphisms and variation in gene expression (epigenetics). This includes genetic determinants of cytochrome P450 (CYP 2D6), serotonin, dopamine and acetylcholine receptor activities (SDC 3, Table S2, https://links.lww.com/AA/F570).¹⁶ It is however unclear how this may influence PONV risk stratification in the future.¹⁷

The Impact of Sex/Race/Gender/Social Determinants on PONV

Social determinants, such as sex, gender, race, and socioeconomic status may lead to disparities in health care access, treatment, and outcomes but are infrequently considered in randomized controlled trials (RCTs) related to PONV management.¹⁸ Patients with lower socioeconomic status are less likely to receive antiemetics after correcting for potential confounders.

The interaction between race/ethnicity and PONV risk is a topic of ongoing debate. It has been observed that African American patients are more frequently undertreated when compared to white patients.¹⁹ High-risk Hispanic patients were more likely to experience PONV than white patients.¹⁹ Racial disparity in PONV management can be avoided through standardization of care. Sex and gender may impact the perioperative management of PONV, and transgender patients represent a potentially vulnerable population. Transgender patients undergoing facial gender affirming surgery (GAS) were found to have significantly higher risk of PONV than cisgender patients undergoing oral and maxillofacial surgery.²⁰

Gravid women who underwent non-obstetric procedures with general anesthesia have comparable PONV incidence compared to non-gravid patients.²¹ Fewer prophylactic antiemetics were given among gravid patients, which may be related to the lack of specific recommendations for PONV prophylaxis during pregnancy.

Propofol Total Intravenous Anesthesia

Propofol total intravenous anesthesia (TIVA) alone has comparable PONV risk to volatile anesthesia plus 5-hydroxytryptamine 3 (5-HT₃) receptor antagonists or droperidol (A1). Both propofol TIVA and subhypnotic dose propofol infusion are effective in combination with other antiemetics (A2).¹

Multimodal Systemic Analgesia

Effective analgesic interventions for minimizing PONV risk include acetaminophen (A1), intraoperative ketamine (A1), and esmolol infusion (A2). Lidocaine infusion can reduce PONV risk in laparoscopic abdominal procedures, but not in other surgery types (A1).¹ Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 inhibitors (A1) are also effective for reducing PONV risk. However, nonselective NSAIDs may be associated with anastomotic leak in gastrointestinal (GI) surgery and their use should be carefully considered.¹ A large systematic review and meta-analysis (SRMA) found that low dose gabapentinoids (<300 mg pregabalin/day or <900 mg gabapentin/day) reduced the risk of PONV despite demonstrating no significant analgesic efficacy (A1).²² While opioid-free anesthesia reduces PONV when compared to opioid-based anesthesia (A1),²³ it is unclear if this is comparable with multimodal opioid-sparing analgesia.

Neuraxial and Regional Anesthesia

Epidural analgesia reduces the risk of PONV (A1), opioid-containing epidural mixture is associated with higher risk of PONV than plain local anesthetic preparations (B1).²⁴ Other effective regional anesthesia techniques include transversus abdominis plane (TAP) block before abdominal surgery (A1), quadratus lumborum block (A1) and continuous wound infiltration (A3).^1,25

Other Risk Reduction Interventions

N₂O as maintenance anesthesia increases the risk of PONV (A1). In contrast, N₂O administered only during emergence did not affect PONV risk (A3).²⁶ Sugammadex reduces the incidence and severity of PONV (A1),²⁷ especially in PACU.

Supplemental crystalloids reduced the risk of early and late PONV (A1).¹ Colloids may be more effective in major surgeries >3 hours (A1).²⁸ Stroke volume-guided fluid therapy reduced the risk of PONV and antiemetic requirement in patients undergoing gastrectomy (A3).²⁹ Notably, carbohydrate drink was no more effective than clear liquids in reducing PONV risk (C1).³⁰ A SRMA of RCTs showed that supplemental oxygen did not reduce PONV risk (C1).³¹

5-HT₃ Receptor Antagonists

Serotonin receptor antagonists generally have better anti‐vomiting than anti‐nausea efficacy,³² headache is a common side effect.

Ondansetron

Ondansetron was one of the first 5-HT₃ receptor antagonists approved by the U.S. Food and Drug Administration (FDA),¹ recommended dose was 4mg by slow intravenous (IV) injection or 16mg oral disintegrating tablets (given 1 hour before induction). Ondansetron monotherapy is more effective than dexamethasone for PONV prophylaxis,³³ while having less side effects than prochlorperazine³⁴ and droperidol.³⁵

A retrospective study of 32,737 patients reported that no patients died or developed torsades de pointes as a direct result of ondansetron, this included 4,331 patients whose baseline QTc was >450msec.³⁶

Palonosetron

Palonosetron has a longer half-life of 40 hours than other 5-HT₃ receptor antagonists.³⁷ It is more effective than single dose ondansetron in reducing 24-hour PONV,³⁸ and comparable to ondansetron being regularly redosed at 8-hour intervals.³⁹ While the recommended dose of palonosetron is 0.075mg, it has been suggested that weight-adjusted dose of 1mcg/kg may be more efficacious in obese patients, without an increase in side effects.⁴⁰

Other 5-HT₃ Receptor Antagonists

Granisetron 1mg was approved by the FDA for PONV. More recently an adult dosing range of 0.1 to 3 mg IV at the end of surgery has been suggested for preventing PONV.³² At doses of 2 to 3 mg, granisetron was more effective than ondansetron,⁴¹ particularly for late PONV.⁴²

Both ramosetron and tropisetron are not available in the United States but are available in parts of Asia and Europe.^1,32 Ramosetron may have longer duration of action than other first generation 5-HT₃ antagonists. A dose of 0.3 mg ramosetron was superior to 4 mg ondansetron,⁴³ while being comparable or superior to ondansetron 8 mg.⁴⁴ It is somewhat less effective than granisetron⁴⁵ and palonosetron.⁴⁶ Tropisetron was more effective at preventing POV than ondansetron (A1),⁴⁷ but less effective than palonosetron for later PONV.⁴⁸

Dexamethasone

The recommended PONV dose of dexamethasone is 4 to 8 mg. It was one of the five most effective single drugs for POV prevention in the large network meta-analysis (A1),³² and 8 mg dose seemed to have the optimal antiemetic and analgesic efficacy.

A Cochrane reviews of 38 studies, as well as a subsequent large RCT reported that a single dose of up to 8mg dexamethasone did not increase the risk of postoperative (wound or systemic) infections, including in patients with diabetes mellitus (A1).¹

Dexamethasone can cause transient postoperative hyperglycemia in patients with diabetes mellitus, but the magnitude of hyperglycemia is small (2 mmol/L or 36 mg/dL).⁴⁹ Dexamethasone administration and the transient hyperglycemia was not associated impaired wound healing.⁴⁹

Dopamine Receptor Antagonists

Neurokinin-1 Receptor Antagonists

Aprepitant is a neurokinin-1 (NK-1) receptor antagonist with a half-life of approximately 40 hours. A 40 mg oral formulation is available in the US, while an 80 mg formulation is common in other countries. It is also available as a prodrug for slow IV infusion (fosaprepitant) and injectable lipid emulsion (Aponvie^®).¹ Aponvie^®, is available in a 32 mg dose and administered as a 30-second IV injection, with 97% of receptor occupancy achieved within 5 min of administration.⁵⁶ It is the only IV formulation with the FDA indication for PONV prophylaxis.

Aprepitant appears to be more effective for preventing vomiting over nausea.¹ In recent years, there has been an increased focus on 80 mg dosing, likely due to availability in particular geographic regions, but there is absence of direct head to head comparisons of 40 mg to 80 mg.¹ Aprepitant alone⁵⁷ or added to a multimodal regimen⁵⁸ significantly reduced the risk of PONV. Aprepitant monotherapy is more effective compared to 5-HT₃ receptor antagonists, and is comparable with some combination therapy for prevention of POV (A1).³²

Rolapitant is a long-acting, NK-1 receptor antagonists with a half-life of 180 hours.¹ There is limited evidence regarding its efficacy.³² Vestipitant is thought to have similar efficacy to other NK-1 receptor antagonists.¹ Casopitant is removed from recommendations due to a lack of widespread global availability.

Antihistamines

Dimenhydrinate is effective for PONV prophylaxis (A1).³² The optimal dose, time of administration, and side-effect profile when used for PONV prophylaxis are unclear. Side effects associated with the use of dimenhydrinate include drowsiness/ sedation, dizziness, headache and dry mouth.³² It is also effective in combination with ondansetron.⁵⁹

Low dose (6.25mg) promethazine is effective for both the prophylaxis³² and treatment⁵¹ of PONV. Side effects associated with promethazine include drowsiness/sedation, and potential for skin necrosis with IV extravasation, particularly at high concentrations.

Anticholinergics

Transdermal scopolamine can be applied on the day of surgery or the night before surgery, and reduces the risk of PONV for 24 hours after surgery (A1). Side effects include visual disturbances, dry mouth, and dizziness.¹ Recent evidence suggests that transdermal scopolamine may increase the risk of postoperative urinary retention, especially following urogynecologic procedures.⁶⁰

Other Pharmacological Options

Dexmedetomidine administration decreases the risk of PONV (A1)⁶¹ and also reduces postoperative pain. Side effects include bradycardia, hypotension and sedation, which may delay PACU discharge.⁶² Interestingly, dexmedetomidine was associated with reduced risk of oculocardiac reflex following strabismus surgery.⁶¹

When given towards the end of surgery, ephedrine 0.5 mg/kg IM was effective for PONV prophylaxis, particularly in the early postoperative period.¹ It may be less effective than antiemetics such as dexamethasone in preventing PONV.⁶³

Perioperative benzodiazepine administration reduces the risk of PONV, but the optimal dosing and timing is not clear (A1).⁶⁴ Given the risk of sedation, the panel does not recommend the use of benzodiazepines solely for the indication of PONV prophylaxis.

Nonpharmacological Options

A Cochrane systematic review of aromatherapy as PONV rescue treatment found overall low quality of evidence.¹ Peppermint aromatherapy was no more effective than placebo, while isopropyl alcohol reduced the need for additional rescue treatment (A1). A recent study reported that lemon aromatherapy started the morning of surgery was effective in reducing PONV (A3).⁶⁵ An SRMA found that ginger root preparation may reduce the risk of PON, but did not reduce the risk of POV.⁶⁶

Acupoint stimulation at the 6^th point of the pericardial meridian (PC6) stimulation is comparable to pharmacological PONV prophylaxis. Application of the neuromuscular function electrodes over the median nerve is effective in reducing the incidence of early PONV, especially when tetanic stimulation is used.¹

Limited evidence suggest that chewing gum may be effective as a rescue treatment,¹ but it does not appear to be effective for PONV prophylaxis.⁶⁷

Combination Therapy

The panel continues to recommend the use of general multimodal PONV prevention in adults. There is robust evidence that appropriate use of combination therapy is likely to be more effective than monotherapy (Table 2). There is currently limited data regarding whether antiemetics could be administered at lower doses when used as a part of multimodal prophylaxis.

A network meta-analysis NMA by Weibel et al reviewed an extensive number of monotherapy and combination options for the prevention of PONV.³² Based on the primary outcome of 24-hour POV, options which demonstrated efficacy included NK-1 receptor antagonist plus 5-HT₃ receptor antagonist, NK-1 receptor antagonist plus dexamethasone, and 5-HT₃ receptor antagonist plus dexamethasone. Some antiemetic combinations are noted to be more effective than others for PONV prevention.³² This provides an evidence-based approach to designing combination antiemetic regimens beyond using agents from a different pharmacologic class.

Published evidence on combination therapy with 3 or more agents remains limited. Aprepitant 40 mg PO is effective in addition to ondansetron, dexamethasone and propofol TIVA.⁵⁸ Olanzapine 10 mg PO is effective in addition to ondansetron and dexamethasone.⁵⁵ Haloperidol in addition to ondansetron and dexamethasone is also effective.⁶⁸ More research is required on the efficacy of adding a third or fourth antiemetic in high-risk patients.

Since the last consensus guideline, there has been an exponential increase in the number of different antiemetic combinations reported within the literature. A list of other experimental combinations antiemetics is summarized in SDC 3, Table S5, https://links.lww.com/AA/F570. Evaluation of antiemetics used in conjunction with risk reduction interventions is summarized in SDC 3, Table S6, https://links.lww.com/AA/F570.

Acupoint stimulation (including acupuncture and electrostimulation) consistently demonstrated efficacy when used in addition to 5-HT₃ receptor antagonists and dexamethasone (A1).¹ This may be particularly useful in high-risk patients or procedures who require 3 or more prophylactic interventions.

Algorithmic Approach to PONV Management in Adults

We continue to recommend an algorithmic approach to risk assessment, mitigation, PONV prophylaxis and rescue treatment (Figure 2). Risk mitigation strategies should be considered and implemented if appropriate. Since most adult patients undergoing surgery and anesthesia will have at least one risk factor for PONV, a general multimodal approach is recommended for administering PONV prophylaxis. In patients with 3 or more PONV risk factors, there is a paucity of clinical data on the use of 3 or more prophylactic interventions. We therefore recommend maximizing the use of risk mitigation strategies. Institutions and providers are encouraged to weigh the costs of risk mitigation strategies (such as monetary cost, equipment and personnel requirements) against the impact of PONV in high-risk patients. Patients who develop PONV despite prophylaxis should receive rescue treatment from a different pharmacological class to the prophylactic agents administered.

Post-Discharge Nausea and Vomiting

Post-discharge nausea and vomiting presents a significant risk to discharged postoperative patients who no longer have access to fast onset IV antiemetics or direct care after being discharged from the hospital or medical facility. Patients at high risk of PDNV should be given prophylactic, long acting antiemetics before discharge (B1).⁶⁹

Palonosetron, a long-acting antiemetic, significantly reduced the incidence of PDNV and use of rescue antiemetics on POD 1 and 2.⁷⁰ Another long-acting antiemetic option is oral olanzapine, which reduced the risk of PDNV but was associated with higher risk of sedation.⁵⁵ Alternatively, orally disintegrating tablet (ODT) could be given to patients on discharge for self-administration at home. Ramosetron ODT taken regularly at home on POD 1 and 2 significantly reduced PDNV (A3).⁷¹

Risk Mitigation

Fluid Therapy and Dextrose Loading

A SRMA reported that compared to a “standard” fluid therapy, a “liberal” fluid therapy reduced POV and PONV (A1).⁷³ However, heterogeneity in the definitions of both “liberal” and “standard” therapy across studies limits generalizability, and the optimal fluid regimen remains unclear.

Evidence for preoperative carbohydrate loading in children is limited. Preoperative carbohydrate drinks reduce PONV when compared to standard fasting protocols,⁷⁴ but not when compared to a similar volume of flavored water. Intraoperative 5% dextrose maintenance infusion is less effective than ondansetron (A3).⁷⁵ Finally, a small RCT indicated that early, early oral fluid intake in the PACU reduced opioid requirement and PONV (A3).⁷⁶

Neuraxial and Regional Anesthesia

The efficacy and utility of neuraxial and regional anesthesia in minimizing opioid use and preventing PONV is uncertain due to heterogeneous study designs.⁷⁷ These techniques may offer variable protection against PONV, their role should be tailored to the surgical procedure and individual patient risk factors.

Adjuvant Therapies

A recent meta-analysis found “very low” grade evidence that perioperative lidocaine reduced POV, but not PONV.⁷⁸ Notably, lidocaine bolus plus infusion may be more effective for preventing POV in children, the efficacy is comparable to dexamethasone monotherapy prophylaxis.

Intravenous acetaminophen reduces PONV in children undergoing strabismus surgery (A2), though data outside this population are limited.¹

Premedication with intranasal dexmedetomidine reduces PONV rates compared to intranasal midazolam or clonidine (A1).¹ Intravenous dexmedetomidine reduces both PONV and risk for the oculocardiac reflex during strabismus procedures (A1).⁷⁹ Oral clonidine is also more effective than midazolam or placebo for premedication (A1). Notably, these findings are largely derived from strabismus surgery and require broader validation Miscellaneous Factors

Higher intraoperative fractional inspired oxygen (FiO2) did not result in differences in PONV.⁸⁰ In adenotonsillectomy, timing of fentanyl administration 10 to 15 minutes prior to, versus at the conclusion of the procedure were associated with comparable PONV risk.⁸¹ Hypopharyngeal packing during adenotonsillectomy also did not reduce the risk of PONV.⁸²

Efficacy of pharmacological Agents in Children

The effectiveness and safety of 5-HT₃ receptor antagonists, particularly ondansetron (0.05 mg/kg to 0.1 mg/kg) in children are well established (A1, Table 3).¹ Ondansetron (0.2 mg/kg) resulted in lower incidence of POV compared to dexamethasone (0.1 mg/kg) in children, without notable differences in QTc changes, although caution continues to be advised in patients with existing cardiac conduction issues.⁸³

Dexamethasone (0.1–0.5 mg/kg) is a highly effective antiemetic in pediatric patients (A1).⁸⁴ Higher dose of dexamethasone did not confer clinically significant benefit. Doses beyond 0.15 mg/kg up to a 4 mg maximum do not provide additional benefit.

There is limited clinical data on the use of aprepitant in children. Pharmacokinetic data suggest that weight-based dosing in adolescents results in plasma concentrations comparable to those achieved with standard fixed-dose adult regimens (A3).⁸⁵

TIVA is effective as PONV prophylaxis in children. Sub hypnotic doses of propofol infusion may also serve as a risk mitigation strategy.

Combination Therapy

Combination prophylaxis in children is more effective than single agents in children (Table 3). Dexamethasone plus ondansetron is the best-studied combination (A1), while data on dexamethasone plus tropisetron or ondansetron plus droperidol are more limited (A3).¹ Dexamethasone plus droperidol is less effective than dexamethasone plus ondansetron (A3).⁸⁶

In high-risk pediatric groups (3+ risk factors), a single retrospective study suggests a benefit when adding a third agent (scopolamine or diphenhydramine) to ondansetron and dexamethasone.⁸⁷ This finding from a retrospective analysis using historical controls necessitates cautious interpretation.

Nonpharmacologic Interventions

A recent SRMA⁸⁸ found “very low” grade evidence for that acupuncture and acupressure reduces early POV (A1), particularly when acupuncture was administered before surgery. A Cochrane review reported a tentative benefit of aromatherapy such as isopropyl alcohol, though evidence is of low to moderate quality.¹

PONV Management in Children: An Algorithmic Perspective

For evidence-based prevention of POV/PONV in children, we propose a multi-step, algorithmic approach as outlined in Figure 4. This begins with baseline risk assessment, considering both patient and procedural details, which in turn determines the approach to baseline risk mitigation (SDC 3, Table S7, https://links.lww.com/AA/F570) and administration of prophylactic agents (Table 3).

Recent findings indicate low-risk patients appear to benefit from prophylaxis that aligns with guideline recommendations, while high-risk patients do not show improvement from additional prophylactic measures.⁸⁹ Major pediatric risk prediction models show a negligible difference in the predicted POV risk between patients with zero and one risk factors, while there is limited evidence supporting prophylactic regimens with greater than two pharmacologic agents. Additionally, clinicians’ adherence to risk-based adjustments in PONV prophylaxis is suboptimal.⁴

Given the existing data and the favorable safety profiles of widely researched antiemetics such as ondansetron and dexamethasone, we recommend the use of a single prophylactic agent (preferably ondansetron or dexamethasone) in pediatric patients without risk factors. For patients with one or two risk factors, escalating to a two-agent regimen (typically combining ondansetron and dexamethasone) is advisable.

For patients presenting with three or more risk factors, the current evidence does not conclusively favor the routine addition of a third agent. Instead, emphasis should be placed on modifying baseline risk factors through various interventions (such as elimination of nitrous oxide, use of propofol-based total intravenous anesthesia, administration of local and regional anesthesia techniques, and incorporation of multimodal analgesia).

Economic Considerations of PONV Management

Healthcare economics considerations include quality (patient safety, experience of care), patient-reported outcomes (quality of life, functional outcomes), and operational efficiency (personnel/space/operational outcomes).⁹⁰ Furthermore, it is also important to evaluate costs from the patient perspective. These include direct costs (cost of additional visits) and indirect costs (lost income and caregiver costs). When implementing PONV management pathways, one must ensure evidence-based and equitable provision of care. Racial disparities in perioperative care can led to increase in direct and indirect healthcare costs.⁹¹ Provider awareness can be increased by presenting cost data to the department, which increases the likelihood that providers consider costs of PONV medications.⁹² Conversely, providers’ practice habits may be determined by considerations of availability and cost.

Enhanced recovery pathways can improve PONV guideline compliance, thereby reducing PONV incidence and cost of care.⁹³ This also highlights the role of PONV prophylaxis as an important part of the larger perioperative pathways.

Current evidence suggests that the efficacy of non-pharmacological interventions is clinically modest in many cases, these may be cost-effective and potentially underutilized tools for managing PONV.⁹⁴

Professional Society Endorsements

This set of guidelines have been officially endorsed by the following professional organizations:

• American Society for Enhanced Recovery
• American Academy of Anesthesiologist Assistants
• American Association of Nurse Anesthesiology
• American Academy of Ambulatory Care Nursing (AAACN)
• American College of Clinical Pharmacy
• American Society of Health Systems Pharmacists
• American Society of Peri Anesthesia Nurses
• Australian and New Zealand College of Anesthetists
• Australian Society of Anesthetists
• Canadian Anesthesiologists’ Society
• College of Anesthesiologists of Ireland
• European Society of Anesthesiology
• German Society of Anesthesiology
• Hong Kong College of Anesthesiologists
• Indian Society of Anesthesiology
• Indonesian Society of Anesthesiologists and Intensive Therapy
• Japanese Society of Anesthesiologists
• Korean Society of Anesthesiologists
• Malaysian Society of Anesthesiologists
• Royal College of Anesthesiologist Thailand
• Royal College of Anaesthetists United Kingdom
• Singapore Society of Anesthesiologists
• Society for Ambulatory Anesthesia
• Society for Pediatric Anesthesia
• South African Society of Anesthesiologists