Management of Postoperative Nausea And

Anesthesiology Clin N Am 21 (2003) 347 – 365

Management of postoperative nausea and vomiting in ambulatory surgery
David Cameron, MD, Tong Joo (TJ) Gan, MB*
Department of Anesthesiology, Duke University Medical Center, Erwin Road, Suite 3414, PO Box 3094, Durham, NC 27710, USA

In the United States, over 60% of the 79 million surgical procedures performed each year occur in an ambulatory care setting [1]. Minimizing patient morbidity and maximizing patient satisfaction is an important goal for health care providers. Postoperative nausea and vomiting (PONV) is a complex condition that assumes greater importance as major mortality relating to surgery decreases. PONV costs have been estimated at $1.2 billion a year in the United States alone [2]. In the ‘‘ether era,’’ incidence of PONV was reported as high as 80%. The replacement of older anesthetic agents with shorter-acting and less emetogenic agents in conjunction with surgical refinements has reduced the overall incidence to 20% to 30%, which has been remarkably consistent over the past two decades [3]. The introduction of the 5-hydroxytrytamine type 3 (5HT3) receptor antagonists greatly improved chemotherapy-associated emesis [4] and generated much enthusiasm that the ‘‘big little problem’’ [5] in perioperative care might be eliminated. The clinical consequences of PONV include wound hematoma, suture disruption and dehiscence, potential aspiration of gastric contents, and esophageal rupture (Boerhaave’s syndrome) [6]. Some patients will experience prolonged intractable symptoms, which if left untreated can result in electrolyte and dehydration disruption [7]. The challenge in current clinical practice is to evaluate the available evidence and formulate an anesthetic plan appropriate for the individual patient within each institution.

Mechanism of emesis Current understanding of the basic integrated neuroanatomy and physiology of the emetic process is largely the result of electrical stimulation and ablative surgical procedures performed by Wang and Borrison [8] in the 1950s.
* Corresponding author. E-mail address: [email protected] (T.J. Gan). 0889-8537/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved. doi:10.1016/S0889-8537(03)00017-8

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Vomiting is a natural reflex action to many different stimuli involving complex coordinated activity of the gastrointestinal, diaphragm, and respiratory and airway muscles. Nausea is often associated with vomiting, but the two do not necessarily occur together and therefore should be evaluated separately. The physiology of nausea is poorly understood and is difficult to study in animal models. The physical act of the expulsive phase of vomiting raises intraabdominal pressure above the intrathoracic pressure. Relaxation of the lower esophageal junction tone and retrograde waves result in removal of gastric contents past a previously closed glottis in awake subjects [9]. The neuroanatomical site coordinating these actions are found in an ill-defined area in the lateral reticular formation situated in the brainstem (Fig. 1) [10]. This area is referred to as the ‘‘vomiting center’’ and receives multiple afferent inputs from many areas, including the higher cortical centers, cerebellum, vestibular apparatus, vagal, and glossopharyngeal nerve afferents [3]. Communication also exists with the surrounding nucleus tractus soltarius and chemoreceptor trigger zone (CTZ) [11]. The latter area lies in the floor of the IV ventricle, in the area postrema, outside the blood brain barrier and in contact with cerebrospinal fluid (CSF). The CTZ appears to play an important communicating role for substances within blood and CSF, but direct stimulation does not result in vomiting. Immunochemical studies of the central nervous system have identified these anatomical areas to be rich in histamine, serotonin, cholinergic, neurokinin-1, and

Fig. 1. Mechanism of nausea and vomiting.

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D2 dopamine receptors [12]. To date, no anesthetic agent has been found to be a direct trigger agent to the vomiting center.

Predicting PONV To identify those patients who may benefit from antiemetic medication, predictive models of PONV have been investigated. Surgical, anesthetic, and patient factors have been identified as predictive of PONV. Studies have attempted to rank the relative importance of the risk factors using logistical regression analysis. In a two-center inpatient study, Apfel et al [13] found four highly predictive factors: female gender, history of motion sickness or PONV, nonsmoker, and the use of perioperative opioids. If none, 1, 2, 3, or 4 of these risk factors were present, the incidences of PONV were 10%, 21%, 39%, 61%, and 79%, respectively. This simplified risk score was found favorable when compared with other predictive models [14]. One large study that specifically tried to identify PONV risk factors in ambulatory surgical patients has been reported by Sinclair et al [15]. This 3-year study enrolled 17,638 consecutive patients. The study had an overall reported PONV incidence of 4.6% and 9.1% in the PACU and at a 24-hour follow-up, respectively. The authors confirmed the above four risk factors and suggested in addition: Type of anesthesia (11-fold increase with general anesthesia compared with regional) Duration of anesthesia (59% increase for each 30-minute increase in duration of anesthesia) Type of surgery (sixfold increase in patients undergoing plastic, ophthalmologic, and orthopedic surgery; twofold increase in ENT, dental, general orthopedic, and gynecologic surgery when compared with reference groups) Pediatric patients are not spared from postoperative vomiting, with peak incidences in schoolchildren of 34% to 50% [16]. Nausea is often not recorded in smaller children because of their difficulty describing this symptom. Younger children have some protection with incidence of 5% to 20% reported in infants and preschool children. Preoperative anxiety state does not appear to be of predictive value [17], whereas female gender does not increase risk until after puberty. Children undergoing adenotonsillectomy, strabismus repair, orchiopexy, herniorrapy, middle ear surgery, and laparotomy appeared to be at increased risk of emetic events [16].

Antiemetics in clinical practice Different classes of drugs have been used in the management of PONV. Many of these drugs possess activity at one or more of the receptors implicated in the

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emetic neurosignaling process. To date, no drug capable of blocking all receptors has been found. Many older antiemetic drugs have been used in clinical practice for years before what is now regarded as adequate study design, including power analysis, blinding, and randomization, was considered. In contrast, antiemetics of the 5HT3 antagonist class have been subject to extensive investigation. Meta-analysis has been used to further examine areas of PONV management [18]. The number needed to treat (NNT) and number needed to harm (NNH) are often reported. The NNT indicates the number of patients needed to be exposed to a particular intervention for one patient to benefit had they received placebo or no treatment. The NNT is a useful estimate of the clinical relevance of treatment effect. Table 1 represents the NNT for the commonly used antiemetics. The NNH is an estimate of the frequency of drug-related adverse effects [19]. Cholinergic antagonists The anticholinergic agents are among the oldest antiemetic agents. Scopolamine (hyoscine) and atropine have peripheral and central actions with ability to cross the blood brain barrier as tertiary amines. The intraoperative use of atropine is a potentially confounding factor in assessing PONV trials. Atropine is not often used in the postoperative period because of its cardiovascular effects.

Table 1 Number needed to treat (NNT) for commonly used antiemetics NNT a Agent or strategies Prophylaxis Ondansetron 4 mg IV Ondansetron 8 mg IV Ondansetron 16 mg oral Dexamethasone, adults 8 – 10 mg IV Dexamethasone, children 1.5 mg/kg IV Propofolb Acupuncture Droperidol 0.625 – 1.25 mg Metoclopramide 10 mg Transdermal scopolamine Avoiding nitrous oxide Combination therapy, ondansetron and droperidol Treatment Ondansetron 1 – 8 mg
a

Nausea 5.6

Vomiting 5.5

PONV

5 6 Early 5 Late 4.3 4.7 5 16 6 7.1 3.8 4.9 5 7 9 6 All patients 13 High-risk 5 2.2 3.4 Early 4.8 Late 4.1

NNT < 5 is equivalent to a 20% absolute risk reduction. Baseline event rate 20% to 60% PONV, introduction and maintenance Data from refs. [34,38,43,79 – 81].
b

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Scopolamine has been used for many years as a premedication often administered with an opioid [20]. Only the L-isomer is pharmacologically active and, because of its short elimination half-life and dose-dependent side effects, has proven efficacy [21]. It seems that antiemetic effect is gained at low concentrations with many of the well-recognized side effects of sedation—dry mouth, blurred vision, mydriasis, memory loss, urinary retention, and confusion occurring usually, but not exclusively, at higher concentrations. Kranke et al [22] investigated the efficacy and safety of transdermal scoplamine for the prevention of PONV in a quantitative systematic review. This study identified 23 trials with 979 patients receiving transdermal scopolamine. Of 100 patients who receive transdermal scopolamine, approximately 17 will not experience PONV who would have done so had they received placebo. However, 18 of 100 patients will have visual disturbances, eight will report dry mouth, two will report dizziness, and nine will be classified as being agitated. The timing of the application does not seem to alter efficacy. A role may exist for transdermal scopolamine as an antiemetic to be used in conjunction with PCA in decreasing nausea scores and antiemetic rescue [23]. However, the noted side effects and concerns over central cholinergic syndrome, particularly in the elderly, may limit its widespread use.

Dopamine antagonists Three drug groups with strong D2 antagonist properties have been widely used as antiemetics—butyrophenones, benzamides, and the phenothiazines. Butyrophenones The main agents in this group include haloperidol and droperidol, the latter of which has been subject to most investigation in PONV. As a group, they have alpha-blocking characteristics and can cause extrapyramidal side effects. Until the US Food and Drug Administration (FDA) placed a highly controversial ‘‘black box’’ warning on the use of droperidol, it was one of the most commonly used drugs in the United States and Europe. This warning, the most serious for an FDA-approved drug, draws attention to the potential for cardiac arrhythmias and urges consideration in the use of alternative medications. The FDA decision was based on nine case reports of sudden cardiac death when lower doses of droperidol (  1.25 mg) were administered in the perioperative period. The FDA recommends all elective surgery patients undergo 12 lead electrocardiographic monitoring before droperidol administration to determine whether QTc prolongation is present, which can lead to potentially fatal torsades de pointes. The EKG should be continuously monitored for 2 to 3 hours after administration. These recommendations create practical difficulties, especially in ambulatory patients when the anesthesiologist has to choose appropriate PONV therapy [24]. Haloperidol has demonstrated antiemetic properties with a faster onset and shorter duration of action when compared with droperidol [25].

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The efficacy of droperidol compared with placebo has been demonstrated in many patient populations, including general, gynecologic, and ophthalmic [26 –30]. Pandit et al [31] reported an increased efficacy of droperidol 20 mg/kg compared with droperidol 10 mg/kg (approximately 1.25 mg and 0.625 mg for a 70-kg person, respectively) with no increase in the incidence of side effects. Delayed side effects even with low-dose droperidol (0.625 –1.25 mg) doses have been reported, including the extrapyramidal effects of acute dystonias, Parkinsonism features, and akathasia [32]. A follow-up study of patients discharged after ambulatory surgery found 23% given droperidol 1.25 mg had developed anxiety and restlessness after discharge and cautioned its routine use [20]. However, in a 2061 adult surgical outpatient study comparing ondansetron 4 mg with droperidol 0.625 mg and droperidol 1.25 mg in PONV prevention, Fortney et al [33] established all antiemetic to be superior to placebo with droperidol 1.25 mg more efficacious in the early recovery period (0 –2 hours) and associated with reduced incidence of nausea over the first 24 hours postoperatively compared with ondansetron 4 mg and droperidol 0.625 mg. There were no increased incidences of adverse events in the droperidol groups compared with ondansetron. In a systematic review, Henzi et al found an NNT of 5 for early nausea and an NNT of 7 for early and late vomiting in adults using 0.25 mg and 2.5 mg, respectively. Children demonstrated dose responsiveness with 75 mcg/kg with an NNT of 4 to prevent early and late vomiting [34]. Benzamides Metoclopromide was the most commonly used compound in this group. This procainamide derivative, which is capable of blocking central and peripheral dopamine receptors and promotes gastric motility while increasing lower esophageal tone, is theoretically useful with concurrent opoid administration. In high doses it has been shown to have weak serotonin receptor antagonistic effect. However, clinical investigation has failed to show its usefulness in PONV management, with 50% of trials showing no more effect than placebo [35]. Systematic review of randomized placebo trials found no significant antinausea effect with NNT for early (0 –6 hours) and late vomiting (within 48 hours), 9.1 and 10, respectively. Domino et al [36] examined the comparative efficacy and safety of ondansetron, droperidol, and metclopramide for preventing PONV in a metaanalysis of 54 studies and found ondansetron and droperidol to be more effective than metclopramide. This finding may be the result of inadequate dosing (effective chemotherapy doses 1 – 2 mg/kg) and inappropriate timing of dose. Metoclopramide has a short duration of action (1– 2 hours with a profile), which may suggest more appropriate dosing at the end of surgery or on arrival in the recovery facility. Antihistamines Antihistamines (diphenhydramine and cyclizine) act by blocking the histamine H1 receptor in the nucleus of the solitary tract. The blockade of acetylcholine receptors is responsible for side effects, including sedation and dry mouth.

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Cholwill et al [37] reported equal reduction in severe nausea and antiemetic rescue in ambulatory laparoscopic gynecologic patients who received either ondansetron 4 mg or cyclizine 50 mg intravenously. Ahmed et al [38] recently found no patient requiring admission using an ondansetron and cyclizine combination compared with ondansetron or saline (placebo). Serotonin antagonists Serotonin antagonists were introduced in the early 1990s following successful reduction of chemotherapy-induced nausea and vomiting [4]. These compounds were discovered when metoclopramide analogs were noted to have antiemetic effects not related to dopamine receptor antagonism. Sanger [39] subsequently showed this action to be secondary to antagonism of a serotonin receptor. At least seven different types of 5HT receptors have been identified, each with different actions. The 5HT3 receptor unit is unique in belonging to a multisubunit ligandgated ion channel group of receptors that have been detected peripherally and within the nucleus tractus soltarius and area postrema centrally [40]. Ondansetron has been widely studied as the prototype for this new drug group, which also includes dolasetron, granisetron, and tropisetron. It is available in oral (tablets, elixir, and orally disintegrating tablet), intravenous, and suppository form. Though differing in their duration of action, published studies suggest that all the 5HT3 antagonists seem to have a similar efficacy and safety profile with similar side effects of constipation, headache, and liver enzyme elevation [19]. Ondansetron does not affect gastric emptying (small intestinal transit time) but appears to delay colonic transit [41 – 43]. Dolasetron and ondansetron currently have FDA approval for use in PONV. Granisetron has recently been approved for perioperative use. Early clinical investigations established the efficacy and safety of ondansetron [44]. Bodner et al [45] demonstrated ondansetron to be superior to placebo (51% and 92% respectively) in patients requiring outpatient laparoscopic surgery. A European multicenter trial enrolled about 1000 patients with oral ondansetron 1 mg, 8 mg, 16 mg, or placebo 1 hour before the induction of anesthesia. This study reported frequency of nausea (55%, 56%, 55%, and 75%, respectively) and vomiting (55%, 37%, 37%, and 60%) and concluded that 16 mg conferred no greater benefit and recommended 8 mg as a prophylactic dose [46]. A new freezedried oral preparation of ondansetron has been evaluated. This orally disintegrating tablet (ODT) formulation was found to be effective but noted to have a bitter aftertaste [47]. Dershwitz et al [48] investigated the dose-response relationship of ondansetron. This study found patients receiving ondansetron 4 mg required less rescue medication than those receiving lower doses (0.5 mg, 1 mg, 2 mg) and no benefit from increased doses (8 mg, 16 mg). The timing of administration of serotonin antagonists has also been investigated. Sun et al [49] found a significant decrease in the incidence of nausea, vomiting, and the need for recovery room antiemetic rescue in patients who received ondansetron 4 mg at the end of surgery.

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Dolasetron (12.5 mg IV) has been found to be well tolerated and more effective than placebo [50]. Though dolasetron has a short serum half-life of 9 minutes, its major metabolite hydrodolasetron is 1000 times more potent than the parent compound with a half-life of 8 hours. Single oral doses given 1 to 2 hours before surgery has been shown to be safe and effective with maximal antiemetic response achieved with 50 mg orally in major gynecologic surgery [51]. A recent study suggested that dolasetron 12.5 mg IV used for prophyiaxis was as effective as the higher dose (25 mg) and was no different from ondansetron 4 or 8 mg IV [52]. In a quantitative systematic review of randomized placebo-controlled trials involving ondansetron, Tramer et al [19] found an NNT of 5 and 6 for intravenous 8 mg and oral 16 mg ondansetron, respectively, in PONV prevention. The NNT for early outcome (0 –6 hours) for ondansetron 4 mg was 5.6 for nausea and 5.5 for vomiting. The antinausea effect was reported as less pronounced. The side effect profile showed significantly increased risk for elevated liver enzymes (NNH 31) and headache (NNH 36). Steroids Dexamethasone has been shown to be effective in reducing the incidence of PONV in various surgical groups. The precise mechanism of action is unknown but it has been postulated to deplete tryptophan, the biochemical precursor to 5-hydroxytryptomine, or have an anti-inflammatory action on the gut, reducing the release of serotonin [53]. Wang et al [54] found the administration of intravenous dexamethasone to be most effective at induction rather than at the end of surgery. The same group in a dose-ranging study compared dexamethasone 10 mg, 5 mg, 2.5 mg, and 1.25 mg with saline in female patients requiring thyroidectomy. This study found dexamethasone 5 mg to be the minimum effective dose in decreasing PONV [55]. Henzi et al [53] identified 17 trials suitable for examination in a quantitative systematic review involving 1946 patients, 598 of whom had received dexamethasone. Studies most frequently tested 8 mg to 10 mg in adult and 1.5 mg/kg in children without noted adverse reactions. The review reported overall NNT of 7.1 and 3.8 for adults and children, respectively, in prevention of early and late vomiting. In adults, the NNT to prevent late nausea was 4.3. Propofol Propofol was found to decrease emetic events after its introduction to clinical practice [56]. The role of propofol in PONV was the subject of a quantitative systematic review in 1997 where 84 randomized controlled studies were identified involving 6069 patients, 3098 of which received propofol [57]. Studies with a PONV event rate between 20% and 60% were included. This review found a decrease in early PONV when propofol was used as the induction and maintenance agent with an NNT of 5 but found this effect to be lost in late events (generally considered after 6 hours). Propofol seems to have an influence

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on nausea at much lower plasma level (343 ng/mL) than that required for sedation (900 –1300 ng/mL) and maintenance of general anesthesia (3000 – 5000 ng/mL or 3 –5 mg/mL) [58]. Clinical investigation has demonstrated that a 20 mg bolus dose of propofol is effective for treating established PONV in the early postoperative period [59]. The mechanism of propofol as an antiemetic is yet to be fully explained. The lipid emulsion carrier (intralipid) for propofol has been shown to have no effect on incidence of nausea or vomiting [60], and recent published evidence shows subhypnotic doses of propofol are unlikely to have a peripheral mechanism and cannot be considered a gastric prokinetic agent [61]. At a receptor level, no direct action has been demonstrated at either the dopamine or serotonin site. Recent animal experiments using immunohistochemistry, high-performance liquid chromatography, and electrophysiology have examined the effect of propofol on rat brain stem [62]. They demonstrated a reduced area postrema activity and lower concentrations of serotonin and its metabolites, 5-hydroxy-indoleacetic acid (5-HIAA), versus control (intralipid) in the rats sliced brain when propofol was administered.

Antiemetics with potential clinical use Cannabinoids Cannabinoids are the active constituents of cannibis (marijuana). The potential antiemetic effects from the Cannabis Sativa L have been used for centuries in India. Dronabinol-tetrahydrocannabinol, a component of cannabis and nabilone, a synthetic cannabinoid are available as a prescription drug in some countries. Tramer et al [63] examined the available evidence for control of chemotherapyinduced nausea and vomiting with cannabinoids. This systematic analysis identified 30 studies: oral nablone was used in 16 studies; oral dronabinol in 13 studies; and intramuscular levonantradol in one study. The cannabinoids were shown to have a high degree of patient acceptability with antiemetic profiles superior to prochlorperazine or metoclopramide with NNT of 6 and 8 to control nausea and vomiting, respectively. The side effect profile of these compounds is not surprising given the well-known psychotropic activity of cannabis in the smoked form. NNTs of side effects include feeling ‘‘high’’, 3; depression, 8; sedation, 5; euphoria, 7; paranoia, 20; hallucination, 17; dizziness, 3; and arterial hypotension, 7. These side effects are unlikely to be acceptable. Other synthetic compounds already tested in animal models without the cannabimimetic activity may prove more useful [64]. Neurokinin-1 antagonists Substance P is an important neuropeptide found in many neuronal structures including the nucleus tractus soltarius and is responsible for a wide variety of biological responses. It is thought to play an important part in the transmission of

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sensory information, including noxious stimuli from peripheral to central nervous system, stimulation of gastrointestinal smooth muscle activity, and exocrine gland secretion. It is the natural ligand for the neurokinin-1 (NK-1) receptor. The NK-1 receptor antagonists may be useful, depending on their ability to penetrate the CNS and block central emetic stimuli. Initial investigations in ferret model using cisplatin-induced emesis suggested these novel agents were more effective than the serotonin antagonists and worthy of clinical investigation [65]. The safety and antiemetic efficacy of CP-122,721 was evaluated when administered alone or in combination with ondansetron in PONV [50]. This randomized double-blind, placebo-controlled trial included 243 women undergoing abdominal hysterectomy. An oral dose of CP-122,721 (NK-1 antagonist) 200 mg 60 to 90 minutes preoperatively decreased the emetic episodes in the first 24 hours, similar to intravenous ondansetron 4 mg given 15 to 30 minutes before the end of surgery. The combination of ondansetron and NK-1 receptor antagonist significantly prolonged the time to first-rescue antiemetic compared with either drug alone. No difference in patient satisfaction was noted. This may represent the initial pathway for a useful new class of antiemetic drug. Oxygen The use of supplemental oxygen to reduce the incidence of PONV has been reported in a study whose primary objective was to observe the effects of two different oxygen concentrations on surgical wound infections [66]. Patients undergoing colonic/rectum resections lasting over 2 hours were randomly selected to receive 30% O2 or 80% O2 with balanced nitrogen in the background of an opoid (fentanyl) and isoflurane anesthetic. This was continued for 2 hours in the postoperative care areas with the increased concentration as required to maintain saturation above 95%. Supplemental oxygen reduced the incidence of PONV from 30% to 17% when low oxygen (30%) was compared with high oxygen (80%), P = 0.027. This may indicate a potential role for oxygen in PONV reduction. Goll et al [67] found that supplemental oxygen at 80% given intraoperatively and continued for 2 hours postoperatively to be as effective as ondansetron 8 mg when administered with 30% oxygen for reduction of PONV.

Nonpharmacologic techniques The lack of a clear pharmacologic agent capable of preventing PONV has led to the investigation of many nonpharmacologic alternatives. The most widely studied have been in the areas of acupuncture. Many different stimulating techniques have been used, including electroacupuncture, transcutaneous electrical nerve stimulation, acupoint stimulation, and acupressure. The basis of these techniques is the balanced and free flow of Qi (pronounced as chee) or ‘‘life energy,’’ found in traditional Chinese medicine dating back over 3000 years and an important concept associated with good health. The ‘‘life energy’’ is postulated

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to flow through the body in channels or pathways called meridians, which have a complex interaction with each other and body organ systems. Acupuncture at a particular point or set of points can restore the deficiency or blockage of Qi flow. Stimulation of pericardium (P6) acupuncture point (4 cm proximal from the wrist crease between the tendons of palmaris longus and flexor carpii radialias muscles) can reduce postoperative nausea and vomiting, motion sickness, and pregnancy-induced nausea and vomiting [68]. There are many diverse invasive and noninvasive techniques used to stimulate the P6 point, with the precise point of stimulation more important than the method. The mechanism by which PONV may be prevented is unknown. Dundee is credited with early work in this field, refining study design and highlighting that acupuncture may be less effective under general anesthesia [69]. The application of transcutaneous acupoint electrical stimulation (TAES) at the end of surgery and continued for 9 hours in patients undergoing laparoscopic cholecystectomy resulted in a decreased incidence of nausea (73% versus 41% and 49% for TAES, sham, and placebo groups, respectively). No difference was found between the groups in incidence of vomiting and rescue medication requirements [70]. The meta-analysis by Lee et al [71] concluded that there is a significant reduction in early PONV (0– 6 hours) in adults, and the effects of nonpharmacologic methods were comparable to antiemetics (metclopramide, cyclizine, droperidol, and prochloperizine). A recent study by our group suggests electroacupuncture appears to be as effective as prophylactic ondansetron [72]. The NNT for acupuncture for the prevention of PONV is 4 to 5 in adults. Studies involving pediatric patients to date have failed to show any benefit. Ginger The use of ginger (Zingiber officinale) has been used in traditional Chinese and Indian medicine, though data remains limited. 6-Gingerol has been identified as the active ingredient and has been shown to enhance animal gastrointestinal transport. Conflicting reports on the antiemetic effects of ginger in PONV have been reported with doses between 0.5 and 1 g given preoperatively. In a review of double-blinded placebo-controlled trials for all indications of ginger as an antiemetic, Ernst was unable to find sufficient data to drawn conclusions about the clinical efficacy of ginger and could only conclude that further trials were necessary [73].

Management strategy It is clear that no single intervention can completely prevent PONV. A multimodal approach similar to that employed in pain management is advocated. Patients differ in their risk of developing PONV. Risk stratification attempts to identify those in whom intervention will bring the most benefit. Many studies have concentrated on the absolute decrease in emetic events—number of

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vomiting episodes, time to rescue antiemetic administration, and assessment of nausea severity. Controversy remains that these so-called ‘‘surrogate’’ end points are less important than patient satisfaction, time to discharge, and return to normal daily activities [74]. Baseline risk reduction Many patient and surgical variables are fixed (eg, gender and type of surgery), but the anesthesiologist has options to lower the baseline risk. The choice of regional anesthesia, when appropriate, can offer an alternative to general anesthesia and avoid exposure to factors that increase PONV [75]. Avoiding nitrous oxide in five high-risk patients can prevent one episode of postoperative vomiting with potential awareness in 1 in 46 patients [76 –78]. The incidence of nausea remains unchanged. The volatile agents and larger doses of neostigmine (greater than 2.5 mg) have all been associated with increased emetic episodes [79]. Though opioids remain important emetogenic stimuli, the provision of ade-

Fig. 2. Risk factors for PONV and guidelines of prophylactic antiemetic therapy. PONV indicates postoperative nausea and vomiting. Percentages denote risk of developing PONV. Consideration should be given to avoid risk factors associated with PONV and other strategies (see Box 1 in article) to further reduce the incidence. Serotonin antagonists may be preferred antiemetics in operative settings where nursing labor costs are directly related to the length of postanesthesia care unit stay (From Gan TJ. Postoperative nausea and vomiting: can it be eliminated? JAMA 2002;287:1233 – 6. Copyright D 2002 American Medical Association; with permission.)

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Box 1. Recommended strategies for minimizing the incidence of PONV 1. Identify high-risk patients 2. Avoid emetogenic stimuli  Etomidate  Inhalational anesthetic agents  Opioids (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.) 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 From Gan TJ. Postoperative nausea and vomiting: can it be elimiC nated? JAMA 2002;287:1233 – 6 Copyright 6 2002 American Medical Association; with permission.

quate pain relief is important. However, the incorporation of NSAIDs and COX-2 inhibitors should be encouraged (Fig. 2) [80]. Prophylaxis and cost-effectiveness The increasing awareness of cost-effectiveness is important in an era of growing economic constraint on health care delivery [75,81]. Hill et al [82] compared the cost-effectiveness of four prophylactic intravenous regimens for PONV: ondansetron 4 mg, droperidol 0.625 mg, droperidol 1.25 mg, and placebo in over 2000 ambulatory surgical patients at high risk for PONV. Cost considerations included drug acquisition, the cost of wasted drug, the need for adjuvant drugs to manage side effects, nursing labor costs, and costs associated with unanticipated hospital stay. The report concluded the use of prophylactic antiemetic was more effective in preventing PONV and achieved greater satisfaction at a lower cost compared with placebo. The use of droperidol 1.25 mg intravenously was associated with greater effectiveness, lower costs, and similar patient satisfaction compared with droperidol 0.625 mg and ondansetron 4 mg. The exclusion of nursing labor costs, which vary for each institution and are semifixed, from the calculation did not alter the overall conclusion.

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Combination therapy The use of a single antiemetic agent typically reduces the incidence of PONV by up to 30% [2]. No single agent can block all the receptors involved in the emetic process [83,84]. The use of combination therapy has been shown to be effective, and combination antiemetic therapy with a 5HT3 antagonist avoids many of the cumulative side effect profile of the older antiemetics. Most studies have combined ondansetron and droperidol and found this to be more effective than placebo or single agent [85,86]. Droperidol may protect against postoperative headache, a side effect observed with the 5HT3 antagonists [34]. Dexamethosone 8 mg in combination with ondansetron 4 mg has been found effictive in females undergoing diagnostic laparoscopy [87] and major gynecologic procedures. No benefit was conferred with an increased dose of dexamethasone 20 mg [87]. The combinations of 5HT3 antagonists with droperidol and dexamethasone, respectively, have been compared where 29 trials involving 1551 patients were analyzed. A total of 658 patients received 5HT3 antagonist (ondansetron, granisetron, tropisetron) combination with droperidol and 893 patients received a combination with dexamethasone. There was no difference between the two combinations in the incidence of early or late PONV when all studies were combined, but the incidence of dizziness and headache was significantly less in the droperidol group [88]. The adjunctive use of dolasetron and dexamethasone was found to shorten the time to achieve discharge criteria and improve the quality of recovery and patient satisfaction after outpatient laparoscopic cholecystectomy [89]. Scuderi et al [90] investigated a predefined multimodal management algorithm in outpatient laparoscopy patients. Anesthetic regimen involved total intravenous anesthesia (propofol and remifentanil); avoiding nitrous oxide and reversal of neuromuscular blockade; intravenous fluid hydration 25 mL/kg; triple antiemetic combination (ondansetron, droperidol, and dexamethasone); and ketorolac, whereas the control group received ondansetron or placebo. Multimodal management resulted in 98% complete response rate and 0% incidence of vomiting before discharge. However, no difference in patient satisfaction was found between the multimodal approach and monotherapy prophylaxis. Rescue treatment Despite the reduction of baseline risks and the administration of prophylactic antiemetics, some patients will still develop PONV [80,91]. Before initiating pharmacologic intervention for treating established PONV, the potential inciting factors—pain, current medication, and mechanical factors—need to be excluded [75]. The first choice recommendation in a patient with no previous prophylaxis should be a 5HT3 antagonist. A lower dose (eg, ondansetron 1 mg) seemed as effictive as the higher dose of 4 mg [90]. The NNT for ondansetron when used for rescue treatment is about 4 [92]. Children also benefit from ondansetron in established emesis [93]. In patients who have received a 5HT3 antagonist as

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prophylactic, no further benefit is conferred with further dosing within 6 hours, and another drug from a different class of antiemetic should be used instead [94]. Repeat doses of dexamethasone are not beneficial within 24 hours of dosing. A recommended strategy for minimizing the risks and the management of PONV is presented in Box 1 and Figure 2.

Summary The management of PONV has improved significantly over the years but remains a frequent occurrence in postoperative patients. Evaluation of individual patient risk and the consideration for prophylactic antiemetic in highrisk populations should reduce these unpleasant symptoms and help direct appropriate clinical strategies. Treatment following failure of prophylactic antiemetic therapy requires knowledge of previously used antiemetics and the time of their administration.

References
[1] Vital and health statistics. Ambulatory and inpatient procedures in the US. Atlanta (GA): Centers for Disease Control; 1996. [2] Habib AS, Gan TJ. Combination therapy for postoperative nausea and vomiting—a more effective prophylaxis? Ambul Surg 2001;9:59 – 71. [3] Watcha MF, White PF. Postoperative nausea and vomiting: its aetiology, treatment and prevention. Anesthesiology 1992;77:162 – 84. [4] Bountra C, Gale JD, Gardner CJ. Towards understanding the aetiology and pathophysiology of the emetic reflex: novel approaches to antiemetic drugs. Oncology 1993;53(Suppl 1):102 – 9. [5] Kapur PA. The big ‘‘little problem’’. Anesth Analg 1991;73:243 – 5. [6] Davis C. Emesis research: a concise history of the critical concepts and experiments. J R Nav Med Serv 1997;83:31 – 41. [7] Kovac A. Prevention and treatment of postoperative nausea and vomiting. Drugs 2000;59: 213 – 38. [8] Wang SC, Borison HL. A new concept of organization of the central emetic mechanism: recent studies on the sites of action of apomorphine, copper sulphate and cardiac glycosides. Gastroenterology 1952;22:1 – 12. [9] Andrews PLR. Physiology of nausea and vomiting. Br J Anaesth 1992;69(Suppl 1):2S – 19S. [10] Wang SC, Borison HL. The vomiting center. Archives of Neurology and Psychiatry 1950;63: 928 – 41. [11] Leslie RA. Neuroactive substances in the dorsal vagal complex of the medulla oblongata: nucleus of the tractus solitarius, area postrema, and dorsal motor nucleus of the vagus. Neurochem Int 1985;7:191 – 211. [12] Leslie RA, Shah Y, Thejomayen M, et al. The neuropharmacology of emesis: the role of receptors in neuromodulation of nausea and vomiting. Can J Physiol Pharmacol 1990;68:279 – 88. [13] Apfel CC, Laara E, Koivuranta M, et al. A simplified risk score for predicting postoperative nausea and vomiting. Anaesthesiology 1999;91:693 – 700. [14] Apfel CC, Krane P, Eberhart LHJ, et al. Comparison of predictive models for postoperative nausea and vomiting. Br J Anaesth 2002;88:234 – 40. [15] Sinclair DR, Chung F, Mezei G. Can postoperative nausea and vomiting be predicted? Anesthseiology 1999;91:109 – 18.

362

D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365

[16] Rose JB, Watcha MF. Postoperative nausea and vomiting in paediatric patients. Br J Anaesth 1999;83:104 – 17. [17] Wang SM, Kain ZN. Preoperative anxiety and postoperative nausea and vomiting in children: is there an association? Anesth Analg 2000;90:571 – 5. [18] White PF, Mehernoor WF. Has the use of meta-analysis enhanced our understanding of therapies for postoperative nausea and vomiting? Anesth Analg 1999;88:1200 – 2. [19] Tramer M, Reynolds DJM, Moore RA, et al. Efficacy, dose-response, and safety of ondansetron in prevention of postoperative nausea and vomiting. Anaesthesiology 1997;87:1277 – 87. [20] Melnick B, Sawyer R, Karambelkar D, et al. Delayed side effects of droperidol after ambulatory general anesthesia. Anesth Analg 1989;69:748 – 51. [21] Honkavaara P, Saarnivaara L, Klemola UM. Effect of transdermal hyoscine on nausea and vomiting after surgical correction of prominent ears under general anaesthesia. Br J Anaesth 1995;74:647 – 50. [22] Kranke P, Morin AM, Roewer N, et al. The efficacy and safety of transdermal scopolamine for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg 2002;95:133 – 43. [23] Williams OA, Clarke FL, Harris RW, et al. Addition of droperidol to patient-controlled analgesia: effect on nausea and vomiting. Anaesthesia 1993;48:881 – 4. [24] Gan TJ, White PF, Scuderi PE, et al. FDA ‘‘black box’’ warning regarding use of droperidol for postoperative nausea and vomiting: is it justified? Anaesthesiology 2002;97:287 – 90. [25] Loeser EA, Bennett G, Stanley TH, et al. Comparison of droperidol, haloperidol and prochlorperazine as postoperative anti-emetics. Can Anaesth Soc J 1979;26:125 – 7. [26] Abramson S. The anti-emetic effect of droperidol following outpatient strabismus surgery in children. Anesthesiology 1983;59:579 – 83. [27] Grond S, Lynch J, Diefenbach C. Comparison of ondansetron and droperidol in the prevention of nausea and vomiting after inpatient minor gynecological surgery. Anesth Analg 1995;81: 603 – 7. [28] Kreisler NS, Spiekermann BF, Ascari CM, et al. Small-dose droperidol effectively reduces nausea in a general surgical adult patient population. Anesth Analg 2000;91:1256. [29] Patton C, Moon M, Dannemiller F. The prophylactic antiemetic effect of droperidol. Anesth Analg 1974;53:361 – 4. [30] Tang J, Watcha M, White P. A comparison of costs and efficacy of ondansetron and droperidol as prophylactic antiemetic therapy for elective outpatient gynecologic procedures. Anesth Analg 1996;83:304 – 13. [31] Pandit SK, Kothary SP, Pandit UA, et al. Dose response study of droperidol and metoclopromide as antiemetics for outpatient surgery. Anesth Analg 1989;68:798 – 802. [32] Melnick BM. Extrapyramidal reactions to low-dose droperidol. Anaesthesiology 1998;69:424 – 6. [33] Fortney JT, Gan TJ, Graczyk S, et al. A comparison of the efficacy, safety, and patient satisfaction of ondansetron versus droperidol as antiemetics for elective outpatient surgical procedures. Anesth Analg 1998;86:731. [34] Henzi I, Sonderegger J, Tramer MR. Efficacy, dose-response, and adverse effects of droperidol for prevention of postoperative nausea and vomiting. Can J Anaesth 2000;47:537 – 51. [35] Rowbotham DJ. Current management of postoperative nausea and vomiting. Br J Anaesth 1992; 69(Suppl 1):46S. [36] Domino KB, Anderson EA, Polissar NL, et al. Comparative efficacy and safety of ondansetron, droperidol, and metoclopromide for preventing postoperative nausea and vomiting: a metaanalysis. Anesth Analg 1999;88:1370 – 9. [37] Cholwill JM, Wright W, Curran J. Comparison of ondansetron and cyclizine for the prevention of nausea and vomiting after day-case gynaecological laparoscopy. Br J Anaesth 1999; 83:611 – 4. [38] Ahmed AB, Hobbs GJ, Curran JP. Randomised, placebo-controlled trial of combination antiemetic prophylaxis for day-case gynaecological laparoscopic surgery. Br J Anaesth 2000;85:678 – 82. [39] Sanger GJ. New antiemetic drugs. Can J Physiol Pharmaceut 1990;68:314 – 24.

D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365

363

[40] Costall B, Naylor RJ. Neuropharmacology of emesis in relation to clinical response. Br J Cancer 1992;66(Suppl 19):S2. [41] Andrews PLR. The 5-hydroxytryptamine receptor antagonists as anti-emetics: preclinical evaluation and mechanism of action. Eur J Cancer 1993;29A(Suppl 1):S11 – 6. [42] Hesketh PJ, Gandara DR. Serotonin antagonists: a new class of antiemetic agents. J Natl Cancer Inst 1991;83:613 – 20. [43] Mitchelson F. Pharmacological agents affecting emesis: a review (part II). Drugs 1992;43: 443 – 63. [44] McKenzie R, Kovac A, O’Connor T, et al. Comparison of ondansetron versus placebo to prevent postoperative nausea and vomiting in women undergoing ambulatory gynaecologic surgery. Anaesthesiology 1993;78:21 – 8. [45] Bodner M, White PF. Antiemetic efficacy of ondansetron after outpatient laparoscopy. Anesth Analg 1991;73:250 – 4. [46] Kenny GNC, Oates JDL, Leeser J, et al. Efficacy of orally administered ondansetron in the prevention of postoperative nausea and vomiting: a dose ranging study. Br J Anaesth 1992;68: 466 – 70. [47] Gan TJ, Franiak R, Reves JBS. Ondansetron orally disintegrating tablet versus placebo for the prevention of post discharge nausea and vomiting after ambulatory surgery. Anesth Analg 2002; 94:1199 – 200. [48] Dershwitz M, Conant JA, Chang Y, et al. A randomised, double blind, dose response study of ondansetron in the prevention of postoperative nausea and vomiting. J Clin Anesth 1998;10: 314 – 20. [49] Sun R, Klein KW, White PF. The effect of timing of ondansetron administration in outpatients undergoing otolaryngologic surgery. Anesth Analg 1997;84:31 – 6. [50] Gesztesi Z, Scuderi PE, White PF, et al. Substance P (neurokinin-1) antagonist prevents postoperative vomiting after abdominal hysterectomy procedures. Anesthesiology 2000;93:931 – 7. [51] Diemunsch P, Korttila K, Leeser J, et al. Oral dolasetron mesylate for prevention of postoperative nausea and vomiting: a multicenter, double-blind placebo-controlled study. J Clin Anesth 1998; 10:145 – 52. [52] Zarate E, Watcha MF, White PF, et al. A comparison of the costs and efficacy of ondansetron versus dolasetron for antiemetic prophylaxis. Anesth Analg 2000;90:1352 – 8. [53] Henzi I, Walder B, Tramer M. Dexamethasone for the prevention of postoperative nausea and vomiting: A quantatitive systemic review. Anesth Analg 2000;90:186 – 94. [54] Wang JJ, Ho ST, Tzeng JI, et al. The effect of timing of dexamethasone administration on its efficacy as a prophylactic antiemetic for postoperative nausea and vomiting. Anaesth Analg 2000;91:136 – 9. [55] Wang JJ, Ho ST, Lee SC, et al. The use of dexamethasone for preventing postoperative nausea and vomiting in females undergoing thyroidectomy: a dose-ranging study. Anesth Analg 2000; 91:1404 – 7. [56] Campbell NN, Thomas AD. Does propofol have antiemetic effect? A prospective study of the antiemetic effect of propofol following laparoscopy. Anaesthesia and Intensive Care 1991;19:385 – 7. [57] Tramer M, Moore A, McQuay H. Propofol anesthesia and postoperative nausea and vomiting: quantitative systematic review of randomised controlled studies. Br J Anaesth 1997;78:247 – 55. [58] Gan TJ. Determination of plasma concentrations of propofol associated with 50% reduction in postoperative nausea. Anesthesiology 1997;87:779 – 84. [59] Gan TJ, El-Molem H, Ray J, et al. Patient-controlled antiemesis: a randomised, double-blind comparison of two doses of propofol versus placebo. Anesthesiology 1999;90:1564. [60] Ostman PL, Faure E, Glosten B, et al. Is the antiemetic effect of the emulsion formulation of propofol due to the lipid emulsion? Anesth Analg 1990;71:536 – 40. [61] Chassard D, Lansiaux S, Duflo F, et al. Effects of subhypnotic doses of propofol on gastric emptying in volunteers. Anesthesiology 2002;97:96 – 101. [62] Cechetto DF, Diab T, Gibson CJ, et al. The effects of propofol in the area postrema of rats. Anesth Analg 2001;92:934 – 42.

364

D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365

[63] Tramer MR, Carroll D, Campbell FA, et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systemic review. BMJ 2001;323:16 – 21. [64] Feigenbaum JJ, Richmond SA, Weissman Y, et al. Inhibition of cisplatin-induced emesis in the pigeon by a non-psychotropic synthetic cannabinoid. Eur J Pharmacol 1989;169:159 – 65. [65] Watson JW, Gonsalves SF, Fossa AA, et al. The antiemetic effects of CP-99,994 in the ferret and the dog: role of the NK1 receptor. Br J Pharmacol 1995;115:84 – 94. [66] Greif R, Laciny S, Rapf B, et al. Supplemental oxygen reduces the incidence of postoperative nausea and vomiting. Anesthesiology 1999;91:1246 – 52. [67] Goll V, Akca O, Grief R, et al. Ondansetron is no more effective than supplemental intraoperative oxygen for prevention of postoperative nausea and vomiting. Anesth Analg 2001; 92:112 – 7. [68] Mayer DJ. Acupuncture: an evidence based review of the clinical literature. Annu Rev Med 2000;51:49 – 63. [69] Dundee JW, Ghaly RG, Fitzpatrick KT, et al. Does the timing of P6 acupuncture influence its efficacy as a postoperative antiemetic? Br J Anaesth 1989;63:630P. [70] Zarate E, Mingus M, White PF, et al. The use of transcutaneous acupoint electrical stimulation for preventing nausea and vomiting after laparoscopic surgery. Anesth Analg 2001;92:629. [71] Lee A, Done M. The use of nonpharmacologic techniques to prevent postoperative nausea and vomiting: a meta-analysis. Anesth Analg 1999;88:1362 – 9. [72] Gan TJ, Parrillo S, Fortney J, Georgiade G. Comparison of electroacupuncture and ondansetron for the prevention of postoperative nausea and vomiting [abstract]. Anesthesiology 2001; 95:A22. [73] Ernst E, Pittler MH. Efficacy of ginger for nausea and vomiting: a systemic review of randomised clinical trials. Br J Anaesth 2000;84:367 – 71. [74] Fisher DM. Surrogate outcomes: meaningful not. Anaesthesiology 1999;90:355 – 6. [75] Scuderi P, Wetchler B, Sung YF, et al. Treatment of postoperative nausea and vomiting after outpatient surgery with the 5 – HT3 antagonist ondansetron. Anesthesiology 1993;78:2 – 5. [76] Hartung J. Twenty-four of twenty-seven studies show a greater incidence of emesis associated with nitrous oxide than with alternative anesthetics. Anesth Analg 1996;83:114 – 6. [77] Tramer MR, Moore A, McQuay H. Omitting nitrous oxide in general anaesthesia: meta-analysis of intraoperative awareness and postoperative emesis in randomized controlled trials. Br J Anaesth 1996;76:186 – 93. [78] Tramer M, Moore A, McQuay H. Meta-analytic comparison of prophylactic antiemetic efficacy for postoperative nausea and vomiting: propofol anaesthesia vs omitting nitrous oxide vs total i.v. anaesthesia with propofol. Br J Anaesth 1997;78:256 – 9. [79] Joshi GP, Garg SA, Hailey A, et al. The effects of anatgonising residual neuromuscular blockade by neostigmine and glycopyrrolate on nausea and vomiting after ambulatory surgery. Anesth Analg 1999;89:628 – 31. [80] Gan TJ. Postoperative nausea and vomiting: can it be eliminated? JAMA 2002;287:1233 – 6. [81] Meheroor WF. The cost-effective management of postoperative nausea and vomiting. Anesthesiology 2000;92:931. [82] Hill R, Lubarsky D, Phillips-Bute B, et al. Cost-effectiveness of prophylactic antiemetic therapy ondansetron, droperidol, or placebo. Anesthesiology 2000;92:958 – 67. [83] Tramer MR. A rational approach to the control of postoperative nausea and vomiting: evidence from systematic reviews. Part I. Efficacy and harm of antiemetic interventions, and methodological issues. Acta Anaesthesiol Scand 2001;45:4 – 13. [84] Tramer MR. A rational approach to the control of postoperative nausea and vomiting: evidence from systematic reviews. Part II. Recommendations for prevention and treatment, and research agenda. Acta Anaesthesiol Scand 2001;45:14 – 9. [85] Pueyo FJ, Carrascosa F, Lopez L, et al. Combination of ondansetron and droperidol in the prophylaxis of postoperative nausea and vomiting. Anesth Analg 1996;83:117 – 22. [86] McKenzie R, Lim Uy NT, Riley TJ, et al. Droperidol/ondansetron combination controls nausea and vomiting after tubal banding. Anesth Analog 1996;83:1218 – 22.

D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365

365

[87] McKenzie R, Riley TJ, Tantisira B, et al. Effect of propofol for induction and ondansetron with or without dexamethasone for the prevention of nausea and vomiting after major gynaecologic surgery. J Clin Anesth 1997;9:15 – 20. [88] Habib AS, El-Moalem HE, Gan TJ. Should 5 – HT3 receptor antagonists be combined with droperidol or dexamethasone for postoperative nausea and vomiting prophylaxis? A metanalysis of randomised controlled trials. Anesthesiology 2001;92:A20. [89] Coloma M, White PF, Markowitz S, et al. Dexamethasone in combination with dolasetron for prophylaxis in the ambulatory setting after laparoscopic cholecystectomy. Anesthesiology 2002;96:1346 – 50. [90] Scuderi PE, James RL, Harris L, et al. Multimodal antiemetic prevents early postoperative vomiting after outpatient laparoscopy. Anesth Analg 2000;91:1408 – 14. [91] White PF, Mehernoor WF. Postoperative nausea and vomiting: prophylaxis versus treatment. Anesth Analg 1999;89:1337 – 9. [92] Kovac A, Scuderi PE, Boerner TF, et al. Treatment of postoperative nausea and vomiting with single intravenous doses of dolasetron mesylate: a multicenter trial. Anesth Analg 1997;85: 546 – 52. [93] Khalil S, Rodarte A, Weldon BC, et al. Intravenous ondansetron in established postoperative emesis in children. Anesthesiology 1996;85:270 – 6. [94] Kazemi-Kjellberg F, Henzi I, Tramer MR. Treatment of established postoperative nausea and vomiting: a quantitative systematic review. BMC Anesthesiology 2001;1(2):1 – 11. Available at: http://www. biomedcentral.com/1471-2253/1/2.