Postoperative Nausea and Vomiting—Can It Be Eliminated?

Postoperative nausea and vomiting (PONV) frequently complicates recovery from surgery. Before the 1960s, when older inhalational anesthetic agents such as ether and cyclopropane were widely used, the incidence of vomiting was as high as 60%.¹ Better anesthetic techniques, along with a new generation of antiemetics and shorter-acting anesthetic drugs, have reduced the overall incidence of PONV to approximately 30%.² However, PONV occurs in as many as 70% of high-risk patients,^{3 - 4} and pediatric populations are not spared. Although the overall incidence may be lower in children younger than 2 years,⁵ procedures such as tonsillectomies and strabismus surgery have a PONV incidence as high as 60%.^{6 - 7} Ambulatory patients appear to have a lower incidence of PONV compared with inpatients,⁸ but this incidence may be related to underrecognition of postdischarge nausea and vomiting. Although PONV is rarely fatal, it is an unpleasant postoperative symptom ( Article ). Even mild PONV can delay hospital discharge, decrease patient satisfaction, and increase use of resources.⁹ Avoiding PONV is important to patients, more so than avoiding postoperative pain.¹⁰ In one study, patients were willing to spend up to $100, at their own expense, for an effective antiemetic.¹¹

1. Identify high-risk patients (Figure 1)

2. Avoid emetogenic stimuli
Etomidate
Inhalational anesthetic agents
Opioids*

3. Multimodal therapy
Antiemetics (consider combination therapy)
Total intravenous anesthesia with propofol
Adequate hydration
Effective analgesia incorporating local anesthetics and inhibitors of cyclooxygenase 2
Anxiolytics (benzodiazepines)
Intraoperative supplemental oxygen (FIO₂≥0.8)
Nonpharmacologic techniques

*Although opioids are emetogenic, optimal analgesia should be the goal and can be achieved by incorporating preoperative education, local anesthetics, and inhibitors of cyclooxygenase 2. Optimal analgesia may include an opioid.

It is important to understand the underlying physiology of emesis and the factors involved while elimination of PONV is considered. The emetic center is an ill-defined area located in the lateral reticular formation of the medulla. It receives input from the chemoreceptor trigger zone, vestibular apparatus, cerebellum, solitary tract nucleus, and higher cortical center.¹² The receptor types implicated in nausea and vomiting include dopamine, acetylcholine (muscarine), histamine, and serotonin receptors. Opioid receptors have also been found in the chemoreceptor trigger zone.⁵

Pharmacologic agents acting as antagonists of these receptors have been the mainstay of PONV management. Among the dopamine antagonists, droperidol and metoclopramide are the most studied. Although metoclopramide has prokinetic effects that enhance gastric and upper intestinal motility, it is no more effective as an antiemetic than a placebo.¹³ Droperidol (0.625-1.25 mg) is an effective antiemetic in adults, with an adverse effect profile similar to that of the serotonin antagonists.¹⁴ Other dopamine antagonists, eg, promethazine and prochlorperazine, are effective but associated with sedation. Anticholinergics such as scopolamine, once widely used as an anesthetic premedication, have recently received renewed interest as antiemetics in the form of a transdermal patch. Among the commonly used antihistamines, cyclizine is effective, although it may contribute to sedation and dry mouth because of its anticholinergic properties.¹⁵ Serotonin antagonists (eg, ondansetron, dolasetron, and granisetron, introduced a decade ago and brought into clinical use in 1991, 1997, and 1993, respectively) have proven effective with minimal adverse effects.^{16 - 17} It is important to distinguish between symptoms of nausea and vomiting, since some drugs are more effective against nausea (eg, droperidol), while others are more effective against vomiting (eg, serotonin antagonists).¹⁸

Postoperative nausea and vomiting is a multifactorial entity, comprising patient, surgical, and anesthetic factors. Attempts have been made to identify the risk factors. A recent study concluded that female sex, a history of motion sickness or PONV, nonsmoking status, and use of postoperative opioids were most predictive. The incidence of PONV with the presence of 0, 1, 2, 3, or all 4 of these risk factors were 10%, 21%, 39%, 61%, and 79%, respectively.³ Some surgical procedures are associated with a higher incidence of PONV: craniotomy; ear, nose, throat procedures; major breast procedures; strabismus surgery; laparoscopy; and laparotomy. Agents used during anesthesia, including opioids, nitrous oxide, and volatile inhalational anesthetics, are emetogenic. Pain, anxiety, and dehydration may also increase the incidence of PONV.¹² Suggested guidelines for antiemetic prophylaxis of PONV, based on published data of risk factors, are presented in Figure 1.

The administration of an antiemetic acting on 1 receptor type typically reduces the incidence of PONV by about 30%. Using a combination of antiemetics acting on different receptors can further reduce this incidence. Many antiemetic combinations have been investigated, most often a serotonin antagonist with a dopamine antagonist or a corticosteroid (dexamethasone).¹⁹ Combination antiemetic therapy in general exhibits greater effectiveness than a single agent.²⁰ Specifically, ondansetron and droperidol combined can achieve at least a 90% response rate (no nausea, vomiting, or rescue antiemetics).^{21 - 22} Evidence suggests similar effectiveness when a serotonin antagonist is combined with droperidol or dexamethasone.²³

Although a single dose of dexamethasone (<8 mg) appears to be safe, larger doses and prolonged use may cause adverse effects. Avascular necrosis of the femoral head is a recognized complication of prolonged glucocorticoid therapy and can develop following relatively brief courses (7 days) of orally administered corticosteroids.²⁴ In a recent warning by the Food and Drug Administration (FDA), droperidol, when used in antiemetic doses, was associated with prolongation of QTc interval and fatal arrhythmias in a number of anecdotal reports.²⁵ The FDA recommended that droperidol not be used as a first-line therapy, and electrocardiographic monitoring should be performed before treatment and continued for 2 to 3 hours afterward to monitor for arrhythmias. The Medicines Control Agency, part of the Department of Health in the United Kingdom, did not mandate electrocardiographic monitoring with the use of droperidol perioperatively.²⁶ In the 31 years of droperidol use, there has not been a single case report in a peer-reviewed journal in which droperidol used for the management of PONV has been associated with QTc prolongation, arrhythmias, or cardiac arrest.

Although it may be logical to extrapolate that use of multiple (>2) drug combinations will further enhance effectiveness, published evidence is scarce. Scuderi et al²⁶ showed that multimodal management incorporating combination antiemetics and propofol resulted in a 98% complete response rate. A high concentration of oxygen as an antiemetic is a use that few appreciate.^{27 - 28} Greif et al²⁷ used intraoperative oxygen and continued oxygen administration 2 hours after surgery, while Goll et al²⁸ used it only intraoperatively. The use of 80% oxygen intraoperatively as a component of general anesthesia significantly reduced the incidence of PONV compared with 30% oxygen. However, it is unclear whether the antiemetic effect was due to the increase in oxygen concentration or the decrease in nitrous oxide concentration.

There is mounting evidence to suggest that total intravenous anesthesia with propofol reduces the incidence of PONV.²⁹ A dose-response relationship of propofol for improvement of nausea has been established.³⁰ A recent study on anesthesia use (comparing propofol with isoflurane) demonstrated a reduction of absolute risk of PONV by 18% among outpatients (from 46% to 28%) up to 72 hours after surgery, as well as a shorter postanesthesia care unit stay. However, the propofol anesthetic was more expensive.⁸ Used as an induction agent only, propofol is not as protective against PONV, probably because of its short duration of action.^{4 ,29} The mechanism for propofol's action as an antiemetic has not been conclusively elucidated; however, recent evidence suggests that propofol may act by reducing serotonin levels in the area postrema.³¹

Compared with placebo, acupuncture in various forms (acupressure, laser acupuncture, manual acupuncture, and transcutaneous acupoint stimulation) effectively reduced PONV.³² These studies used the acupuncture point Pericardium 6 (Neiguan), the sixth point on the pericardial meridian, located about 5 cm proximal to the palmar aspect of the wrist between flexor carpi radialis and palmaris longus tendons. Other acupuncture points may also possess antiemetic properties.³³ Perioperative hypnosis has been demonstrated to reduce emesis following breast surgery.³⁴ The perioperative use of ginger, however, has not been found to be effective for PONV prevention.³⁵

More than 60% of all US surgery is performed in the ambulatory setting, and this trend is increasing.³⁶ Postoperative nausea and vomiting may continue after discharge from the ambulatory surgery unit, with a reported incidence of 30% to 50%.^{37 - 38} Many of these patients did not have symptoms while in the surgical center. It is important to prevent nausea and vomiting beyond discharge for 2 reasons: patients' resumption of normal activities and readiness to return to work may be delayed if PONV is prolonged,³⁷ and ambulatory patients are not under direct medical supervision after their discharge. Hence, the presence of PONV may be distressing because patients cannot easily request an antiemetic. Most antiemetics have short half-lives and may not be effective after discharge. There is a lack of effective over-the-counter antiemetics. The prophylactic use of the ondansetron orally disintegrating tablet beyond discharge appears to reduce emetic symptoms.³⁸ Other options include transcutaneous acupoint electrical stimulation on Pericardium 6³⁹ (Relief Band, Woodside Biomedical Inc, Carlsbad, Calif) or a transdermal scopolamine patch (Transderm Scop, Novartis Consumer Health Inc, Summit, NJ).⁴⁰

The cost-effectiveness of antiemetics is increasingly scrutinized in this era of limited resources. With PONV prophylaxis, some patients will receive antiemetic therapy prophylactically without actually needing it, while others will have PONV despite receiving prophylaxis. Confining attention to drug acquisition costs without considering direct and indirect costs may lead to an inefficient use of resources.⁴¹ In a cost-incremental analysis (cost per additional patient who benefits from a change in clinical practice), prophylaxis with ondansetron in all patients is less cost-effective than treatment with the same drug.¹⁶ In this context, ondansetron (1 mg intravenous) appears to be effective when patients with established PONV are treated.⁴² However, the use of prophylactic antiemetic therapy in selected high-risk surgical patients (history of PONV and having emetogenic procedures) is cost-effective and associated with greater patient satisfaction.⁹ In that study, droperidol (1.25 mg) was associated with greater effectiveness and less cost compared with droperidol (0.625 mg) and ondansetron (4 mg). Most of the costs (70%-80%) were from nursing labor costs from prolonged postanesthesia care unit stay as a result of persistent nausea and vomiting or adverse effects of antiemetics. Hence, the cost-effectiveness of prophylactic antiemetic therapy will depend on where the procedure is performed. For example, nursing labor costs are more likely to be directly related to the duration of postanesthesia care unit stay in an office-based setting and, to a lesser extent, an ambulatory surgery unit, whereas prolonged postanesthesia care unit stay may not have a significant impact in nursing labor costs in an inpatient hospital setting, unless nursing staff can be reduced. In light of the recent FDA advisory on droperidol, further investigation of the cost-effectiveness of other therapies is required.

The natural ligand of the neurokinin 1 (NK-1) receptor, substance P, is found in the nucleus tractus solitarius and the area postrema, as well as in the peripheral nervous system.⁴³ A recent study suggests that NK-1 receptor antagonists may effectively prevent PONV.⁴⁴ Combining this new class of antiemetics with a serotonin antagonist may eliminate PONV. Use of the combination of an NK-1 receptor antagonist and ondansetron significantly prolonged the time to administration of rescue antiemetic compared with the use of either drug alone and almost completely abolished emesis.⁴⁵ The discovery and development of nonopioid analgesics will help reduce opioid-induced nausea and vomiting. Selective inhibitors of cyclooxygenase 2 (eg, parecoxib, celecoxib, and rofecoxib) can reduce opioid requirement or may be used as an opioid substitute.

Although PONV management has advanced significantly, PONV still occurs too frequently in high-risk patients. Inquiring about each patient's history and educating patients regarding their risk for developing PONV should be a preoperative routine. Because there are many factors involved in PONV, a multimodal approach to its prevention should be adopted: preoperative risk factors should be identified, avoidable risk factors should be reduced, and the use of combination antiemetics should be considered ( Article ). Adopting these practices should serve as the best strategy to minimize and even eliminate PONV.