Introduction
Postoperative nausea and vomiting (PONV) are among the most common side effects associated with anesthesia and surgery. Currently, the overall incidence of PONV for all surgeries and patient populations is estimated to be 25% to 30%. Furthermore, it is estimated that approximately 0.18% of all patients may experience intractable PONV, leading to a delay in postanesthesia care unit (PACU) discharge, unanticipated hospital admission, or both, thereby increasing medical costs. Symptoms of PONV are also among the most unpleasant experiences associated with surgery and one of the most common reasons for poor patient satisfaction ratings in the postoperative period. In one survey, surgical patients were willing to pay up to $100 to avoid PONV.
Because only 25% to 30% of the surgical patient population overall will experience PONV, not all patients will require antiemetic prophylaxis. Identification of patients at high risk for PONV is therefore important. Anesthesia-, patient-, and surgery-related risk factors have been identified ( Table 38-1 ). Apfel et al developed a simplified risk score consisting of four predictors: female gender, history of motion sickness or PONV, nonsmoking status, and the use of opioids for postoperative analgesia. If none, one, two, three, or four of these risk factors were present, the incidences of PONV were 10%, 21%, 39%, 61%, and 79%, respectively.
| Anesthetic Factors | Patient Factors | Surgical Factors |
|---|---|---|
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|
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Therapies
Pharmacologic Agents
Pharmacologic agents available for the prevention of PONV can be summarized as follows:
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Conventional antiemetics
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Dopamine (D 2 ) receptor antagonists: phenothiazines (e.g., promethazine, prochlorperazine), butyrophenones (e.g., droperidol, haloperidol), benzamides (e.g., metoclopramide)
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Antihistamines (e.g., dimenhydrinate, cyclizine)
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Anticholinergics (e.g., scopolamine)
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Serotonin receptor antagonists (e.g., ondansetron, dolasetron, granisetron)
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Neurokinin-1 receptor antagonists (e.g., aprepitant)
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Nonconventional antiemetics
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Steroids, propofol
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Other therapies shown to be of benefit
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Benzodiazepines, ephedrine, aggressive intravenous hydration
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Nonpharmacologic Techniques
Nonpharmacologic techniques include P6 stimulation with the use of acupuncture, acupressure, electroacupuncture, transcutaneous acupoint electrical stimulation, or laser, as well as hypnosis.
Evidence
There are hundreds of published randomized controlled trials (RCTs) investigating the efficacy of different antiemetic interventions. This plethora of data has resulted in a number of systematic reviews being published in this area. Although systematic reviews are a powerful tool to further our understanding of the efficacy of interventions and likelihood of harm when there are data from many small trials, they are not a substitute for a well-conducted large prospective RCT. In this chapter, the evidence reported is based on the results of RCTs and systematic reviews. Four issues will be addressed in providing evidence for the best strategy for prevention of PONV:
- 1.
Evidence for selecting a single antiemetic.
- 2.
Is combination antiemetic therapy better than monotherapy?
- 3.
What is the best available combination of antiemetics?
- 4.
Evidence for the use of a multimodal approach to prevent PONV.
Evidence for Selecting a Single Antiemetic
There are at least five major receptor systems involved in the etiology of PONV: dopaminergic (D 2 ), cholinergic (muscarinic), histaminergic (H 1 ), serotonergic (5-HT 3 ), and the neurokinin-1 (NK-1) receptors. Traditionally, antagonists at these receptors have been the mainstay of PONV management. Metoclopramide and droperidol are the most commonly studied dopamine receptor antagonists. Although metoclopramide has prokinetic effects, its antiemetic efficacy when used in a dose of 10 mg is uncertain. Two studies, however, suggested that higher doses of metoclopramide (20 to 50 mg) might be efficacious. Droperidol, on the other hand, has been shown to be an effective antiemetic and has been widely used. In a meta-analysis of RCTs involving droperidol, the number needed to treat (NNT) was found to be five to seven. However, after the U.S. Food and Drug Administration (FDA) black box warning on droperidol, a significant decline has been seen in the use of this cost-effective agent. Some studies suggested that 1 to 2 mg intravenous (IV) haloperidol might be a suitable alternative, but large well-conducted studies investigating its use for this purpose are lacking.
The 5-HT 3 receptor antagonists are highly specific and selective for nausea and vomiting. Their antivomiting efficacy is better than their antinausea efficacy. Members of this group exert their effects by binding to the 5-HT 3 receptor in the chemoreceptor trigger zone and vagal afferents in the gastrointestinal tract. Their favorable side effect profile and, in particular, the lack of sedation make them particularly popular and suitable for ambulatory surgery. Currently available first-generation 5-HT 3 receptor antagonists include ondansetron, granisetron, and dolasetron. There is no evidence that the efficacy or side effect profiles of the various 5-HT 3 receptor antagonists differ when appropriate doses are used for the management of PONV. Therefore acquisition cost is the main factor that differentiates the 5-HT 3 compounds from one another. It is of note that ondansetron, the most commonly studied agent in this group, has become generic. The NNT for the prevention of PONV with ondansetron is five to six. Palonosetron is a more recent 5-HT 3 receptor antagonist. It has a unique pharmacokinetic profile with a duration of action of up to 72 hours. In two placebo-controlled multicenter studies, a dose of 0.075 mg IV reduced the incidence of nausea and vomiting for up to 3 days after surgery. Two recent studies suggested that palonosetron might be more effective than 8 mg ondansetron and 3 mg granisetron for PONV prophylaxis. Ramosetron is another recent 5-HT 3 receptor antagonist, available mainly in Japan and Korea, with a more potent and longer antagonistic effect at the 5-HT 3 receptor compared with the first-generation members of this group. Some studies have suggested that 0.3 mg IV ramosetron might provide better antiemetic prophylaxis compared with ondansetron.
Dexamethasone has also proved to be an effective antiemetic. In a meta-analysis of 17 studies (1946 patients), dexamethasone was reported to be especially effective against late PONV. When 8 or 10 mg IV was used in adults or 1 to 1.5 mg/kg IV was used in children, the NNT to prevent early and late vomiting compared with placebo was 7.1 and 3.8, respectively. In adults, the NNT to prevent late nausea was 4.3. There were no reports of dexamethasone-related side effects when it was used in a single dose for PONV prophylaxis. However, more recent studies have suggested that antiemetic doses can cause elevations in blood sugar levels, particularly in obese and diabetic patients. Smaller doses (4 mg) of dexamethasone also proved to be effective for PONV prophylaxis.
In a large multicenter study involving patients having at least a 40 % risk of PONV, 4 mg ondansetron, 1.25 mg droperidol, and 4 mg dexamethasone were reported to produce a similar reduction in the incidence of PONV of approximately 26%. Any of these antiemetics could therefore be recommended for use as a first-line agent.
Scopolamine (hyoscine) is an anticholinergic agent with antiemetic properties. A 1.5-mg transdermal patch can be applied for up to 72 hours. Its efficacy is similar to that of 4 mg ondansetron and 1.25 mg droperidol. A recent systematic review confirmed the efficacy of transdermal scopolamine for the prophylaxis of PONV for 24 hours after surgery, regardless of whether it was applied the night before or on the morning of surgery. The incidence of anticholinergic adverse events (e.g., dry mouth, sedation, and urinary retention) was no different from placebo. However, the incidence of visual disturbances was significantly higher with scopolamine at 24 to 48 hours postoperatively compared with placebo (relative risk, 3.35; 95% confidence interval, 1.78 to 6.32).
The antihistamines include the ethanolamines (i.e., dimenhydrinate and diphenhydramine) and the piperazines (i.e., cyclizine, hydroxyzine, and meclizine). Their major disadvantages are sedation, dry mouth, blurred vision, urinary retention, and delayed recovery room discharge. Promethazine is an effective antiemetic with a long duration of action. In a dose of 12.5 to 25 mg given toward the end of surgery, it has been shown to be effective for PONV management. Its use, however, is limited by sedation and prolonged recovery from anesthesia. One study did not show increased awakening time or duration of PACU stay when compared with ondansetron and placebo in patients undergoing middle ear surgery. The use of low-dose promethazine (6.25 mg) was shown to be as effective as higher doses and might be associated with less sedation. Another antihistamine, dimenhydrinate, appears also to be effective for PONV prophylaxis.
The NK-1 receptor antagonists belong to a new class of antiemetics that may act on the final common pathway to the emetic center. This group of compounds has a long half-life, is not associated with sedation, and appears to be particularly effective against vomiting. In females undergoing abdominal surgery, the incidence of no vomiting (0 to 24 hours) was significantly higher with 40 mg aprepitant (84% to 90%) and 125 mg aprepitant (86% to 95%) versus ondansetron (71% to 74%) ( p < 0.001 for both comparisons). Both aprepitant doses also had higher incidences of no vomiting over 0 to 48 hours ( p < 0.001). The 40 mg dose of aprepitant was approved for the prophylaxis of PONV. Similar results were also reported in patients undergoing craniotomy when the antiemetics were used in combination with dexamethasone. More recently rolapitant, another NK-1 antagonist with a very long half-life of up to 180 hours, was effective for PONV prophylaxis compared with placebo and at doses of 70 and 200 mg was associated with a higher incidence of no vomiting compared with ondansetron at 72 and 120 hours postoperatively.
Total intravenous anesthesia (TIVA) with the use of propofol has also been shown to reduce the incidence of PONV and to be as efficacious as 4 mg ondansetron in reducing postoperative nausea. The protective effect of propofol against PONV was not evident when it was used as an induction agent only. A dose-response relationship of propofol for improvement of nausea has also been established.
A recent meta-analysis concluded that P6 stimulation with 10 different acupuncture modalities reduced nausea, vomiting, and the need for rescue antiemetics compared with sham stimulation. The efficacy of P6 stimulation was similar to that of prophylactic antiemetics, such as ondansetron, droperidol, metoclopramide, cyclizine, and prochlorperazine. In subgroup analysis, there was no difference in effectiveness in adults compared with children or invasive versus noninvasive modalities for P6 stimulation.
Some studies suggested that this modality was particularly effective for prophylaxis against nausea. The benefits and side effects of the main classes of agents used for the prophylaxis of PONV are summarized in Table 38-2 .
| Class of Antiemetics | Benefits | Side Effects |
|---|---|---|
| Dopamine receptor antagonists: | ||
| Phenothiazines (e.g., promethazine, prochlorperazine) | Long duration of action | Sedation, extrapyramidal side effects, hypotension, restlessness, anticholinergic syndrome |
| Butyrophenones (e.g., droperidol, haloperidol) | Improved prophylaxis against nausea | Sedation with high doses, hypotension, extrapyramidal side effects, neuroleptic malignant syndrome, droperidol has an FDA black box warning regarding prolongation of QTc, although the risk is considered minimal with antiemetic doses |
| Benzamides (e.g., metoclopramide) | Have prokinetic effects | Sedation, restlessness, extrapyramidal side effects |
| Anticholinergics (e.g., scopolamine) | Effective against motion sickness Transdermal preparation with a long duration of action available | Sedation, blurred vision, dry mouth, restlessness, central cholinergic syndrome |
| Antihistamines (e.g., dimenhydrinate, cyclizine) | Effective against motion sickness Effective for PONV after middle ear surgery | Sedation, dry mouth, restlessness |
| 5-HT 3 receptor antagonists (e.g., ondansetron, dolasetron, granisetron) | Specific for PONV Do not have sedative side effects | Headache, constipation, elevated liver enzymes |
| NK-1 receptor antagonists (e.g. aprepitant) | Long duration of action Improved efficacy against vomiting Do not have sedative side effects | Headache, constipation |
| Corticosteroids (e.g., dexamethasone) | Do not have sedative side effects Long duration of action | Few data available regarding side effects after single dose for PONV prophylaxis; may cause hyperglycemia in diabetic and obese patients |
| Acupuncture (P6 stimulation) | Improved efficacy against nausea | None reported when used for PONV prophylaxis |
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