Management of Postoperative Nausea And

8/2/2019 Management of Postoperative Nausea And

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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 enthu-

siasm 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 esoph-

ageal rupture (Boerhaaves syndrome) [6]. Some patients will experience pro-

longed 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 ablativesurgical procedures performed by Wang and Borrison [8] in the 1950s.

0889-8537/03/$ see front matterD 2003, Elsevier Inc. All rights reserved.

doi:10.1016/S0889-8537(03)00017-8

* Corresponding author.

E-mail address: [email protected] (T.J. Gan).

Anesthesiology Clin N Am

21 (2003) 347365


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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 notnecessarily 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 intra-

abdominal 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 inputsfrom 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.

D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347365348


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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 com-

pared with other predictive models [14].

One large study that specifically tried to identify PONV risk factors in ambu-

latory 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, ophthalmo-

logic, 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 inci-

dences 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 yearsbefore 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 in-

tervention 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 estimateof the frequency of drug-related adverse effects [19].

Cholinergic antagonists

The anticholinergic agents are among the oldest antiemetic agents. Scopol-

amine (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

NNTa

Agent or strategies Nausea Vomiting PONV

Prophylaxis

Ondansetron 4 mg IV 5.6 5.5

Ondansetron 8 mg IV 5

Ondansetron 16 mg oral 6

Dexamethasone, adults 8 10 mg IV Early 5 7.1

Late 4.3

Dexamethasone, children 1.5 mg/kg IV 3.8

Propofolb 4.7 4.9

Acupuncture 5

Droperidol 0.625 1.25 mg 5 7

Metoclopramide 10 mg 16 9

Transdermal scopolamine 6 6

Avoiding nitrous oxide All patients 13

High-risk 5Combination therapy, ondansetron and droperidol 2.2 3.4

Treatment

Ondansetron 1 8 mg Early 4.8

Late 4.1

a NNT < 5 is equivalent to a 20% absolute risk reduction.b Baseline event rate 20% to 60% PONV, introduction and maintenance

Data from refs. [34,38,43,7981].



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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 concen-

trations with many of the well-recognized side effects of sedationdry mouth,

blurred vision, mydriasis, memory loss, urinary retention, and confusion occur-

ring 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 iden-

tified 23 trials with 979 patients receiving transdermal scopolamine. Of 100 pa-

tients who receive transdermal scopolamine, approximately 17 will not experience

PONV who would have done so had they received placebo. However, 18 of100 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 antiemeticsbutyrophenones, 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. Untilthe 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 electrocardio-

graphic monitoring before droperidol administration to determine whether QTcprolongation 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

[2630]. Pandit et al [31] reported an increased efficacy of droperidol 20 mg/kgcompared 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 (0.6251.25 mg) doses have

been reported, including the extrapyramidal effects of acute dystonias, Parkin-

sonism 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]. How-

ever, 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 (02 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 inci-

dences 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 esoph-

ageal 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 meta-

analysis 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 12 mg/kg) and inappropriate timing of dose. Metoclopra-

mide has a short duration of action (12 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] recentlyfound 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] subsequentlyshowed 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 ligand-

gated 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 thatall 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 [4143]. 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. AEuropean 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 freeze-

dried oral preparation of ondansetron has been evaluated. This orally disinte-

grating tablet (ODT) formulation was found to be effective but noted to have a

bitter aftertaste [47]. Dershwitz et al [48] investigated the dose-response relation-

ship of ondansetron. This study found patients receiving ondansetron 4 mg re-quired 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 ad-

ministration 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 parentcompound 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 (06 hours) for ondansetron 4 mg was 5.6 for nauseaand 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 to5-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 dexameth-asone. 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 quantitativesystematic 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

(9001300 ng/mL) and maintenance of general anesthesia (30005000 ng/mL or

3 5 mg/mL) [58]. Clinical investigation has demonstrated that a 20 mg bolusdose of propofol is effective for treating established PONV in the early post-

operative 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 chro-matography, 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 chemotherapy-

induced nausea and vomiting with cannabinoids. This systematic analysis iden-

tified 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-1receptor 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 under-

going 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 first24 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 widelystudied have been in the areas of acupuncture. Many different stimulating

techniques have been used, including electroacupuncture, transcutaneous elec-

trical 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]. Theapplication 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 (06 hours) in adults, and the effects of

nonpharmacologic methods were comparable to antiemetics (metclopramide,

cyclizine, droperidol, and prochloperizine). A recent study by our group suggestselectroacupuncture 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 eventsnumber 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 tonormal 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 [7678]. 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;287:12336.

CopyrightD 2002 American Medical Association; with permission.)



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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 consid-

erations 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 prophylacticantiemetic was more effective in preventing PONV and achieved greater satis-

faction 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.

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 elimi-

nated? JAMA 2002;287:1233 6 Copyright C 2002 American

Medical Association; with permission.

6



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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 gyneco-

logic procedures. No benefit was conferred with an increased dose of dexame-

thasone 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 laparo-

scopic 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 man-

agement 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 incitingfactorspain, current medication, and mechanical factorsneed 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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Management of Postoperative Nausea And