Prevention of Postoperative Nausea and Vomiting

Sheila M. Wilhelm, PharmD; Michelle L. Dehoorne-Smith, PharmD; Pramodini B. Kale-Pradhan, PharmD

The Annals of Pharmacotherapy. 2007;41(1):68-78. 

Abstract and Introduction

Objective: To review the literature on the prevention of postoperative nausea and vomiting (PONV) in adults.
Data Sources: Literature retrieval was accessed through MEDLINE (1966-December 2006) using the terms postoperative nausea and vomiting, prevention and treatment. Article references were hand-searched for additional relevant articles and abstracts.
Study Selection and Data Extraction: All studies published in English were evaluated. Those dealing with prevention and treatment of PONV in adults were included in the review.
Data Synthesis: Evidence suggests that providing prophylactic antiemetic medications in high-risk surgical patients is warranted. 5-HT3 receptor antagonists are widely used, with no one agent being clearly superior. However, studies have shown other types of agents to be more cost-effective.
Conclusions: The first step in the prevention of PONV is assessment and reduction of risk factors. Although nonpharmacologic therapies may play a role in the treatment of PONV, the mainstay of therapy for PONV is pharmacologic modalities. Patients at moderate to high risk for PONV need prophylactic antiemetic therapy. High-risk patients may require combination therapy with 2 or 3 agents from different antiemetic classes. Rescue antiemetic therapy is needed by patients who actually develop PONV. The agents of choice in such cases should be from antiemetic classes different from those used for prophylaxis of PONV.

Nausea and vomiting are caused by complex interactions of the gastrointestinal (GI) system, the vestibular system, and various parts of the brain. Postoperative nausea and vomiting (PONV) occurs in 30% of surgical patients overall and in up to 70% of high-risk patients.[1,2] Recognizing and understanding risk factors of PONV guide the decision regarding early prophylaxis versus later treatment of PONV. This review focuses on the prevention of PONV in adults.

Data Sources

Relevant studies were accessed through MEDLINE (1966-December 2006) using the terms postoperative nausea and vomiting, prevention and treatment. Article references were hand-searched for additional relevant articles and abstracts. All studies published in English were evaluated. Those dealing with prevention and treatment of PONV in adults are reviewed here.

Pathophysiology

Nausea and vomiting consists of 3 stages: nausea, retching, and vomiting. Nausea is the subjective feeling of a need to vomit.[3] Autonomic symptoms such as pallor, tachycardia, diaphoresis, and salivation often accompany this feeling. Retching consists of rhythmic contractions of the diaphragm, abdominal wall, and chest wall muscles and follows nausea. Vomiting is a reflexive, rapid, and forceful oral expulsion of upper GI tract contents due to powerful and sustained contractions in the abdominal and thoracic musculature.

Various areas in the brain and the GI tract are involved in the process of nausea and vomiting. These areas include the chemoreceptor trigger zone (CTZ) in the brain, the vestibular system, visceral afferents from the GI tract, and the cerebral cortex.[4] These stimulate the central vomiting center in the brain stem, which sends impulses to the salivation center, the respiratory center, and the pharyngeal, GI, and abdominal muscles that lead to vomiting.[5] Figure 1 illustrates the pathways involved in the pathophysiology of nausea and vomiting.

Pathophysiology of nausea and vomiting. Receptors for each pathway are indicated in parentheses. D2 = dopamine type 2 receptor; GI = gastrointestinal; H1 = histamine type 1 receptor; 5-HT3 = serotonin type 3 receptor; NK1 = neurokinin type 1 receptor.

The CTZ, located outside the blood-brain barrier, is exposed to cerebrospinal fluid and blood. The CTZ has many serotonin 5 hydroxytryptamine type 3 (5-HT3), neurokinin-1 (NK1) and dopamine (D2) receptors.[6] Visceral vagal nerve fibers are rich in 5-HT3 receptors, and these respond to GI distention, mucosal irritation, and infection.

Risk Factors

Risk factors for PONV consist of both patient and surgical factors. Patient-related risk factors include female gender, history of motion sickness or PONV, nonsmoking status, and use of opioids in the postoperative period.[7] Females have a two- to fourfold higher incidence of PONV compared with males, possibly due to circulating gonadotropin levels.[8] A previous history of PONV or motion sickness, negative smoking history, or postoperative opioid use approximately doubles the risk of experiencing PONV.[7] Obese patients may have an increased incidence of PONV.[8] This may be due to pharmacokinetic parameters of lipophilic anesthetic agents having prolonged half-lives in these patients. Surgical factors that increase the risk of PONV include the type of surgery performed and the anesthetic used. The risk of PONV increases with abdominal, gynecological, orthopedic, ear, nose, and throat procedures.[3,8] Certain anesthetic agents contribute to PONV.[1] Volatile and inhalational agents such as isoflurane, enflurane, and nitrous oxide are highly emetogenic. Regional anesthesia causes less PONV than general anesthesia.[3] Lengthy surgeries are also associated with a higher incidence of PONV.[9]

Risk Assessment

Apfel et al.[7] found that the incidence of PONV was 10-21% in patients with not more than 1 risk factor. This incidence increased to almost 80% in patients with 2 or more risk factors. Tramer[10] developed a similar scheme of risk assessment in which a prior history of PONV automatically places a patient at moderate to high risk of requiring prophylactic antiemetic agents. As the number of risk factors increases, it is beneficial to administer prophylactic antiemetics rather than treat established PONV.

Prevention of PONV

The first step in preventing PONV is to reduce baseline risk factors when appropriate.[1] Regional anesthesia rather than general anesthesia should be used when possible. Nitrous oxide and volatile inhaled anesthetics should be replaced with intravenous agents such as propofol. Opioid-sparing techniques, including the use of other analgesics such as nonsteroidal antiinflammatory drugs and regional blocks, should be implemented. Additionally, the use of high-dose neostigmine (≥2.5 mg) should be minimized.[11] Hydration with 20 mL/kg of appropriate intravenous fluid preoperatively significantly decreases postoperative nausea on day 1 (p < 0.05).[12] Providing 80% oxygen postoperatively and intraoperatively also decreases PONV.[13,14] Nonpharmacologic and pharmacologic modalities may also be helpful in the prevention of PONV.

A variety of effective pharmacologic treatments exist for nausea and vomiting, but they all have the potential to cause unwanted effects. For this reason, nonpharmacologic treatment options may be considered in selected patients.

Acupressure has been investigated as a preventive tool for PONV. Acupressure wristbands may be effective in preventing PONV after short surgical procedures when applied prior to emetic stimulus exposure such as anesthetic agents (PONV incidence 23% in treatment group, 41% in placebo group; p = 0.0058).[15] A meta-analysis included 19 studies on acupuncture, electroacupuncture, transcutaneous electrical nerve stimulation, acupoint stimulation, and acupressure.[16] These techniques were similar to pharmacologic agents in preventing early and late vomiting (number needed to treat [NNT] = 63 and 25, respectively). White et al.[17] compared acustimulation with ondansetron and found that the 2 therapies were similar for preventing PONV. However, the combination of acustimulation and ondansetron was better than ondansetron alone in preventing nausea and vomiting (20% vs 50% for nausea; p < 0.05 and 0% vs 20% for vomiting; p < 0.05, respectively). When compared with placebo, Korean acupressure, when using points on the fingers rather than the wrists, significantly reduced nausea and vomiting (40% vs 70%, p = 0.006; 22.5% vs 50%, p = 0.007, respectively).[18]

Ernst et al.[19] performed a systematic review of the use of ginger in prevention of nausea and vomiting. In 2 of the 3 PONV studies, ginger 1 g was better than placebo and equivalent to metoclopramide 10 mg in preventing PONV. The third study found that ginger was no better than placebo. The pooled analysis of these studies suggests that there is a nonsignificant absolute risk reduction of PONV (0.052; 95% CI -0.082 to 0.186) when ginger is used. A randomized, placebo-controlled trial evaluated ginger treatment in 184 women undergoing gynecologic laparoscopies.[20] The patients received ginger 300 mg, ginger 600 mg, or placebo. Ginger was no better than placebo in preventing PONV, and the study was discontinued after interim analysis. PONV occurred in 49% of the placebo group compared with 58% and 53% in the ginger 300 mg and 600 mg groups, respectively (p = 0.69). Overall, ginger does not appear to be beneficial in preventing PONV.

Another trial evaluated 33 surgical patients who received either peppermint oil, isopropyl alcohol, or placebo aromatherapy.[21] The investigators assessed nausea scores at baseline and 2 and 5 minutes posttreatment with a visual analog scale. There was no difference among the groups (p value not provided). Overall, nausea scores decreased from baseline for the 3 groups combined (p < 0.005 and p < 0.00001 for the 2- and 5-min assessments, respectively). The authors concluded that aromatherapy is effective for reducing nausea in surgical patients. This may be due to controlled breathing patterns rather than the scent of the aromatherapy.

There are 8 classes of antiemetic agents that are typically used for PONV: phenothiazines, anticholinergics, anti-histamines, butyrophenones, substituted benzamides, corticosteroids, 5-HT3 receptor antagonists, and NK1 receptor antagonists. Clonidine, an α2-receptor agonist, has shown some efficacy, although it is not routinely used for PONV.[22] lists the most commonly used drugs for treatment of PONV, as well as the usual adult dosages and common adverse effects.[1,3,5]

Phenothiazines. Stimulation of D2 receptors in the CTZ leads to nausea and vomiting. Phenothiazine antiemetics act primarily via a central antidopaminergic mechanism in the CTZ.[3] Common phenothiazines used for PONV include prochlorperazine and promethazine. A double-blind randomized trial compared ondansetron with prochlorperazine for the prevention of PONV in 78 patients undergoing orthopedic procedures.[23] The patients received either ondansetron 4 mg or prochlorperazine 10 mg intravenously at the end of surgery. Prochlorperazine was significantly more effective in preventing nausea compared with ondansetron (OR = 3.4; 95% CI 1.2 to 9.4; p = 0.02). A similar trend was noted with vomiting; however, it did not reach statistical significance (OR = 2; 95% CI 0.8 to 5.0; p = 0.13). There were more patients with moderate-to-high risk of PONV (history of PONV) in the ondansetron group than the prochlorperazine group (40% vs 27%), which may have affected the results. Khalil et al.[24] found promethazine to be more effective than placebo for preventing nausea and vomiting 24 hours after middle ear surgery (p < 0.05).

Phenothiazines are available as oral, parenteral, and rectal formulations. These drugs may cause extrapyramidal symptoms (EPS) such as dystonia, tardive dyskinesia, and akathisia.[3,25,26] Single doses may cause EPS, although they are more commonly seen with chronic use.[27] Akathisia is disturbing for patients and can be disruptive to patient care. The incidence of akathisia may be reduced if diphenhydramine is administered with prochlorperazine; however, the combination increases the risk of sedation.[28] Slowing the intravenous infusion rate of prochlorperazine does not decrease the incidence of akathisia.[26,27]

Anticholinergics. The anticholinergic agent scopolamine blocks muscarinic receptors in the vestibular system, thereby halting the signaling to the central nervous system and central vomiting center. It may be effective for preventing PONV (NNT = 3.8; 95% CI 2.9 to 5.6).[29] Scopolamine is available as an adhesive transdermal patch and should remain in place for 24 hours after application. This may be beneficial for patients unable to tolerate oral medications. Transdermal scopolamine's onset of action is approximately 2-4 hours; therefore, it should be applied the evening before surgery.[1] Other anticholinergic agents, such as atropine and glycopyrrolate, are generally not used for PONV.[30] However, there is some evidence to support the use of glycopyrrolate.[31]

Antihistamines. Antihistamines are used to prevent and treat PONV.[1,4] Their efficacy is presumably due to the high concentration of histamine (H1) and muscarinic cholinergic receptors within the vestibular system. These agents are considered drugs of choice for surgeries related to the middle ear.

The most common antihistamines used for PONV include hydroxyzine and dimenhydrinate. Hydroxyzine is a desirable agent for several reasons. First, hydroxyzine has anxiolytic properties as well as bronchodilatory effects. Second, it has a long duration of action (4-6 h). Third, it is not associated with circulatory or respiratory compromise. Finally, it has the ability to supplement analgesic effects in patients receiving opioids. In patients who have not received prophylactic antiemetic agents, intramuscular hydroxyzine 100 mg, administered upon induction of anesthesia, was shown to be better than droperidol 2.5 mg for the prevention of PONV.[32] The dose of hydroxyzine was selected to ensure adequate sedation. The surprising finding of droperidol's inferior response may be attributed to inadequate absorption following intramuscular administration.

Kothari et al.[33] evaluated dimenhydrinate in 128 patients undergoing elective laparoscopic cholecystectomy in a randomized prospective trial. Dimenhydrinate was as effective as ondansetron in preventing postoperative nausea (p = 0.422) and postoperative vomiting (p = 0.228). Also, the percent of patients requiring rescue antiemetics was similar between the 2 groups (34% with ondansetron vs 29% with dimenhydrinate; p = 0.376). While more adverse effects (headache, dizziness, drowsiness) were reported in the dimenhydrinate group than the ondansetron group (14 vs 2; p = 0.05), the authors were not able to draw more detailed conclusions due to the small number of events. In a meta-analysis of 18 trials involving more than 3000 patients, dimenhydrinate was as effective as 5-HT3 receptor antagonists and droperidol in preventing PONV.[34] Antihistamines are available in a variety of dosage forms, including parenteral and oral formulations.

Butyrophenones. Droperidol, a butyrophenone derivative, is a centrally acting antidopaminergic agent effective in preventing PONV and treating opioid-induced nausea and vomiting.[1,3] According to Kreisler et al.,[35] intravenous droperidol 0.625 mg is effective in preventing PONV compared with placebo (p < 0.001). Droperidol was as effective as ondansetron 4 mg and promethazine 12.5 mg in preventing PONV, with no significant differences in adverse events. A systematic review found that droperidol doses less than 1 mg were effective for the prevention of nausea, but not vomiting.[36] However, doses between 1 mg and 2.5 mg improved antiemetic efficacy. Droperidol 1-1.25 mg had efficacy similar to that of ondansetron 4-8 mg. Droperidol should be administered at the end of surgery to patients at high risk for developing PONV.[1]

Droperidol carries a Food and Drug Administration (FDA) black box warning regarding the potential for QT interval prolongation and cardiac arrhythmias that may result in torsade de pointes and sudden cardiac death.[37] According to the warning, droperidol should not be used in patients with a prolonged QT interval or in those who are at risk for developing a prolonged QT interval (eg, heart failure, electrolyte abnormalities, or concurrent medications that may prolong the QT interval). A 12-lead electrocardiogram (ECG) is recommended prior to treatment with droperidol.

Nineteen cases reporting droperidol in 10 mg or less dosages that resulted in prolonged QT interval and were involved in the development of the black box warning have been reviewed.[38] The author concluded that evidence is not sufficient to warrant elimination of the use of droperidol at low dosages as used for PONV. Similarly, Gan et al.[39] stated that there have been no case reports published in medical journals regarding PONV doses of droperidol leading to QT prolongation, arrhythmias, or cardiac arrest. Additionally, they argued that droperidol, when used for PONV, is often administered in the setting of continuous electrocardiographic monitoring, which should negate the need for the FDA-recommended 12-lead ECG. PONV guidelines continue to list droperidol 0.625-1.25 mg as an IA recommendation and state that, if the black box warning were not present, droperidol would be the consensus panel's first-choice agent for PONV prophylaxis.[1]

Buttner et al.[40] conducted a meta-analysis of 4 randomized trials of haloperidol used for PONV. They noted that the 1 mg and 2 mg doses were superior to placebo in preventing PONV (NNT = 6 and 4, respectively). The intravenous and intramuscular routes were equally effective.

Substituted Benzamides. The substituted benzamide metoclopramide acts as a D2 antagonist both centrally in the CTZ and peripherally in the GI tract.[1,4] It also displays cholinergic activity, which increases lower esophageal sphincter tone and promotes gastric motility. Metoclopramide at high doses has anti-serotonergic properties as well. The drug is available in injectable and oral dosage forms, allowing for its use in both hospitalized and ambulatory patients.

According to a meta-analysis of 54 studies, metoclopramide is as effective as ondansetron in preventing postoperative nausea (59% vs 48%, respectively; p = 0.125).[41] However, metoclopramide prevented postoperative vomiting in only 35% of patients compared with 50% of those using ondansetron (p < 0.001). In addition, metoclopramide was inferior to droperidol in preventing both postoperative nausea and vomiting. The incidence of nausea was 41% for droperidol and 52% for metoclopramide (p < 0.008); the incidence of vomiting was 26% for droperidol versus 34% for metoclopramide (p < 0.001).

A prospective, randomized, double-blind parallel-group study evaluated the efficacy of intravenous ondansetron 4 mg, intravenous metoclopramide 10 mg, and placebo for treatment of PONV in 175 women undergoing gynecological laparoscopic surgery.[42] The primary outcome was early antiemetic effect (elimination of vomiting within 10 min and nausea within 30 min after administration of study drugs during the first hour). While metoclopramide's early antiemetic efficacy was significantly better than that of placebo, ondansetron performed significantly better than metoclopramide (p < 0.001). In addition, the probability of remaining PONV-free for 48 hours after treatment with ondansetron was 0.59 (95% CI 0.45 to 0.71), with metoclopramide was 0.45 (95% CI 0.29 to 0.60), and with placebo was 0.33 (95% CI 0.15 to 0.53). These differences were statistically significant (p = 0.003).

Metoclopramide crosses the blood-brain barrier and has centrally mediated adverse effects. Young children and the elderly are especially susceptible to these effects, which include somnolence, reduced mental acuity, anxiety, depression, and EPS.[43] The overall incidence of adverse effects is estimated to be between 10% and 20%.[3] In light of metoclopramide's adverse effect profile and because of the availability of more effective antiemetics in the setting of PONV, metoclopramide is not routinely recommended for the prevention or treatment of PONV.

Corticosteroids. Dexamethasone is used for preventing and treating PONV.[44] The mechanism of action of dexamethasone is not fully elucidated. There are 2 theories: prostaglandin antagonism and release of endorphins. Dexamethasone was shown in a systematic review to be better than placebo in preventing postoperative vomiting (relative benefit 1.50; 95% CI 1.07 to 2.09; p < 0.01).[44] However, there is a trend toward 5-HT3 receptor antagonists being superior to dexamethasone in preventing vomiting (relative benefit 0.82; 95% CI 0.71 to 0.95; p value not reported). Dexamethasone is not significantly different from droperidol in preventing vomiting (relative benefit 0.98; 95% CI 0.91 to1.05; p value not reported). Tzeng et al.[45] enrolled 120 postcesarean section women in a randomized, double-blind, placebo-controlled study. Participants received dexamethasone 8 mg, droperidol 1.25 mg, or placebo. The investigators found that dexamethasone was significantly better than placebo in preventing nausea and vomiting (18% vs 51%, respectively; p < 0.01). Also, significantly fewer patients in the dexamethasone group required rescue antiemetics compared with those in the placebo group (11% vs 41%; p < 0.05). Dexamethasone and droperidol were not directly compared in this study.

Although most studies have used between 8 and 10 mg of dexamethasone, there is evidence that lower doses (2.5-5 mg) are effective.[46-48] Dexamethasone is administered intravenously as a single dose prior to induction of anesthesia.[44] Because treatment for PONV is generally of short duration, long-term adverse effects (eg, reduction in bone mineral density, corticosteroid-related diabetes, cataracts) are not usually seen.

Serotonin Antagonists. Selective 5-HT3 receptor antagonists (ondansetron, granisetron, dolasetron) are approved to prevent and treat PONV.[1] These agents antagonize 5-HT3 receptors in the CTZ and the vagal afferents in the GI tract.[49] Fifty-three randomized placebo-controlled trials of ondansetron for PONV were reviewed.[50] The incidence of PONV in the control group was 40% and 60% in the early and late stages, respectively, indicating that the patients were at high risk for PONV. The investigators found that 8 mg (intravenous) and 16 mg (oral) were the most effective doses for ondansetron. The NNT for these regimens was between 5 and 6. The NNT was consistently lower for vomiting than for nausea, indicating the drug's better efficacy in preventing vomiting compared with nausea.

Zarate et al.[51] compared dolasetron 12.5 mg, dolasetron 25 mg, ondansetron 4 mg, and ondansetron 8 mg. No significant differences were found with respect to incidence of nausea or vomiting or failure of complete response to antiemetic agents (26%, 27%, 25%, and 30%, respectively) in the first 24 postoperative hours. A retrospective study found no significant difference between single doses of intravenous dolasetron 12.5 mg and ondansetron 4 mg in the prevention of PONV.[52] A randomized, double-blind trial compared dolasetron 25 mg, dolasetron 50 mg, ondansetron 4 mg, and placebo.[53] Dolasetron 50 mg was found to be equivalent to placebo and ondansetron 4 mg was found to be superior to placebo for all efficacy measures. Complete response (no emetic episodes and no rescue medication) rates were 49%, 51%, 71%, and 64% for placebo, dolasetron 25 mg, dolasetron 50 mg, and ondansetron 4 mg, respectively. These results generated discussion regarding the appropriate dose of dolasetron.

Graczyk et al.[54] studied 635 high-risk patients undergoing laparoscopic gynecologic surgery. The patients received dolasetron 12.5 mg, 25 mg, or 50 mg, or placebo. The complete response (no emetic episodes, no escape medication within 24 h after study drug) rates for dolasetron 12.5, 25, or 50 mg, or placebo were 50%, 52%, 56%, and 31%, respectively (p ≤ 0.0003). The study's recommended dose of dolasetron is 12.5 mg, as the 3 dosages were similarly effective.

A dose-ranging study evaluated use of intravenous granisetron in 200 women following gynecologic surgery.[55] Doses of 5, 10, and 20 µg/kg were significantly better than did 2 µg/kg or placebo (p < 0.05) in preventing all emetic episodes in these patients. In addition, doses of 5, 10, and 20 µg/kg prevented postoperative nausea better than 2 µg/kg of granisetron or placebo (p < 0.05). These doses are equivalent to 0.35, 0.7, and 1.4 mg in a typical patient weighing 70 g.

Wilson et al.[56] administered intravenous granisetron 0.1 mg, granisetron 1 mg, granisetron 3 mg, or placebo to 527 patients undergoing abdominal surgery or vaginal hysterectomy. Doses of 1 mg and 3 mg prevented nausea and vomiting for the first 24 hours significantly better than placebo (p < 0.001). It was also found that the 0.1 mg dose was no better than placebo in preventing nausea and vomiting. These data led to the investigators' recommendation of between 0.35 and 1 mg of granisetron for the prevention of PONV.

When used in equipotent doses, 5-HT3 receptor antagonists are equally effective in the prevention of PONV.[1] These drugs should be administered at the end of surgery to patients at high risk for developing PONV.

Palonosetron, the most recently available 5-HT3 receptor antagonist, is not FDA approved for prophylaxis or treatment of PONV. In 218 women undergoing hysterectomies, intravenous palonosetron 30 µg/kg did not reduce PONV in high-risk patients (those with a history of PONV).[57]

Neurokinin-1 Receptor Antagonists. Aprepitant 40 mg was the first NK1 receptor antagonist approved for PONV. NK1 receptors in the central and peripheral nervous systems are blocked by this drug, thus preventing emesis. In one study, oral aprepitant alone or in combination with intravenous ondansetron led to significantly fewer emetic episodes than did ondansetron alone (p < 0.05).[58] However, the time for receiving a rescue antiemetic agent was not different between the groups. Diemunsch et al.[59] found that in patients with established PONV, aprepitant significantly controlled nausea and vomiting compared with placebo (p < 0.05) for up to 24 hours after major gynecological surgery. In a report of combined data from 2 large trials, oral aprepitant 40 mg was superior to intravenous ondansetron 4 mg for the prevention of PONV.[60] Complete response (no nausea, vomiting, or need for rescue therapy) was achieved in 37.9% of the aprepitant group compared with 31.2% of the ondansetron group (OR 1.3; p = 0.027).

Combination Therapy. Numerous neurotransmitters are involved in the pathogenesis of PONV. A combination of pharmacologic agents that work on different receptors contributing to PONV may exhibit better efficacy with fewer adverse events. Using combinations of antiemetics may be the most effective method of preventing PONV for high-risk patients.[2,10] Dexamethasone plus a 5-HT3 receptor antagonist is an effective combination.[44] This combination was superior to placebo in preventing early and late nausea and vomiting. The early nausea and vomiting rates with placebo were 33% (95% CI 22 to 44) and 34% (95% CI 28 to 40), respectively. The early nausea and vomiting rates with the combination therapy were 3.9% (95% CI 1 to 7) and 1.4% (95% CI 0.2 to 3), respectively. The late nausea and vomiting incidences were 45% (95% CI 36 to 54) and 48% (95% CI 42 to 54), respectively, for placebo. The late nausea and vomiting incidences were 25% (95% CI 18 to 32) and 17% (95% CI 13 to 21), respectively, for the combination therapy. The use of 5-HT3 receptor antagonists with dexamethasone was more effective than the use of 5-HT3 receptor antagonists or dexamethasone alone, and 5-HT3 receptor antagonists or dexamethasone were better than placebo in preventing PONV. No statistical information was provided for these data.

Another combination that has been evaluated is droperidol with 5-HT3 receptor antagonists. Eight studies were included in a meta-analysis.[61] The combination of droperidol with a 5-HT3 receptor antagonist was not significantly better than either agent alone in preventing PONV. Three-drug combinations, such as dexamethasone, droperidol, and a 5-HT3 receptor antagonist, have not been formally studied but may be a reasonable approach for patients at high risk for PONV.[10]

Treatment of PONV

Postoperative patients who experience nausea and vomiting should be assessed for contributing factors including opiate use, abdominal obstruction, or surgical complications.[1] Rescue antiemetic therapy is initiated once the above factors are addressed. If a patient has not previously received an antiemetic agent, a low-dose 5-HT3 receptor antagonist should be used.[62] Due to the lack of dose response with 5-HT3 receptor antagonists, minimal effective doses should be used (dolasetron 12.5 mg, granisetron 0.1 mg, ondansetron 1 mg). Patients who have already received 5-HT3 receptor antagonists for prophylaxis should receive an agent from another class for treatment.[1] Some options are intravenous formulations of droperidol 0.625 mg, dexamethasone 2-4 mg, prochlorperazine 10 mg, promethazine 12.5 mg, or propofol 0.5-1 mg/kg.

Cost-Effectiveness

PONV may occur shortly after surgery and in turn may cause complications leading to an increase in direct and indirect healthcare costs.[4] Direct costs are associated with drug acquisition cost, nursing time, and delayed release from the postanesthesia care unit. Indirect costs include delayed discharge, hospital readmission, and loss of income for the patient. Several cost-effectiveness analyses have been performed. Tramer et al.[63] concluded that treatment of PONV with lower doses of ondansetron (1 mg) is more cost-effective than was prophylaxis with higher doses of ondansetron (4-8 mg). However, it has been shown that high-risk patients who do not receive prophylaxis may incur costs 100 times greater than those associated with use of a single generic antiemetic agent.[64] Similarly, in another study of high-risk patients, droperidol and dolasetron were more cost-effective than no prophylaxis.[65] Thus, the cost of providing prophylactic antiemetic medications in high-risk surgical patients is warranted. Additionally, Hill et al.[64] and Tang et al.[66] have shown that droperidol is more cost-effective than ondansetron as a prophylactic agent. Tang et al. also found that droperidol did not increase adverse events or delay discharge. Due to the concern of prolonging QT intervals with droperidol, prochlorperazine may be an alternative. One study found that prochlorperazine is more cost-effective than ondansetron for the prevention of PONV.[67]

5-HT3 receptor antagonists are still widely used, even though studies have shown that there are more cost-effective alternatives. According to the consensus guidelines, the different drugs in this class have comparable efficacy and favorable adverse effect profiles.[1] Therefore, the choice of which 5-HT3 receptor antagonist to use depends primarily on the acquisition cost. However, Wang et al.[68] found that fewer patients who received ondansetron needed rescue medication compared with those receiving dolasetron or granisetron or a combination of the 2 (11.8% vs 23.6%, p = 0.05; 11.8% vs 24%, p < 0.04; 11.8% vs 23.8%, p < 0.02, respectively). They also noted a significant reduction in the length of stay in the recovery room for patients who received ondansetron compared with those who received dolasetron or granisetron (2, 3.3, and 3 h, respectively; p < 0.0001 by Kruskal-Wallis analysis). On this basis, ondansetron may be more cost-effective. Aprepitant, the newest agent for PONV, does not yet have cost-effectiveness data available. However, its acquisition cost is relatively high, making it less appealing as a first-line agent at this time.

Recommendations

The first step in managing PONV is to assess the patient's risk factors. Patients with no more than 1 risk factor do not need prophylaxis. Those who have 2 or more risk factors or who have a history of PONV are considered to be in the moderate-to-high risk category. In such patients, risk factors may be reduced by using regional anesthetic agents or intravenous anesthetic agents such as propofol. Also, nitrous oxide and volatile inhaled anesthetic agents, as well as large doses of neostigmine, should be avoided. Hydrating a patient and providing supplemental oxygen also decrease the incidence of PONV. Finally, when possible, opioid-sparing techniques should be employed. Moderate-to-high risk patients will require prophylactic management of their PONV. In these patients, clinicians may consider monotherapy with any of the antiemetic agents that have been reviewed here. Some patients may require dual, or even triple, therapy.

For low-risk patients who develop PONV, low-dose 5-HT3 receptor antagonists are indicated. Moderate-to-high risk patients who fail prophylaxis should receive a rescue antiemetic from a different class than what was previously administered. Figure 2 summarizes the recommendations for prevention and treatment of PONV. As experience is gained with newer agents such as aprepitant, recommendations for prevention of PONV will need to be modified. Currently, aprepitant should be considered only in high-risk patients, due to lack of data and the high cost associated with it.

Management of PONV. 5HT3RA = 5-HT3receptor antagonist; PONV = postoperative nausea and vomiting.

Summary

Nonpharmacologic and pharmacologic measures are available for the prevention of PONV. High-risk patients may require combination therapy. If a rescue antiemetic is required, a drug from a class not previously administered should be used.


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