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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 $1.2 billion a year in the United States alone [2].
In the ‘‘ether era,’’ incidence of PONV was reported as high as 80%. The
replacement of older anesthetic agents with shorter-acting and less emetogenic
agents in conjunction with surgical refinements has reduced the overall incidence
to 20% to 30%, which has been remarkably consistent over the past two decades
[3]. The introduction of the 5-hydroxytrytamine type 3 (5HT3) receptor antagonists
greatly improved chemotherapy-associated emesis [4] and generated much enthu-
siasm that the ‘‘big little problem’’ [5] in perioperative care might be eliminated.
The clinical consequences of PONV include wound hematoma, suture
disruption and dehiscence, potential aspiration of gastric contents, and esoph-
ageal rupture (Boerhaave’s syndrome) [6]. Some patients will experience pro-
longed intractable symptoms, which if left untreated can result in electrolyte and
dehydration disruption [7]. The challenge in current clinical practice is to
evaluate the available evidence and formulate an anesthetic plan appropriate
for the individual patient within each institution.
Mechanism of emesis
Current understanding of the basic integrated neuroanatomy and physiology of
the emetic process is largely the result of electrical stimulation and ablative
surgical procedures performed by Wang and Borrison [8] in the 1950s.
0889-8537/03/$ – see front matter D 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) 347–365
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 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 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.
D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365348
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
D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365 349
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 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 estimate
of 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 5
Combination 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. [34,38,43,79–81].
D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365350
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 sedation—dry 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 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 electrocardio-
graphic 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].
D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365 351
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, 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 (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 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 1–2 mg/kg) and inappropriate timing of dose. Metoclopra-
mide 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.
D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365352
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 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 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 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.
D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365 353
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 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 quantitative
systematic review in 1997 where 84 randomized controlled studies were
identified involving 6069 patients, 3098 of which received propofol [57]. Studies
with a PONVevent 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
D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365354
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 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
D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365 355
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 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 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 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
D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365356
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
D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365 357
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.)
D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365358
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 prophylactic
antiemetic 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 incidenceof PONV
1. Identify high-risk patients2. Avoid emetogenic stimuli
� Etomidate� Inhalational anesthetic agents� Opioids (although opioids are emetogenic, optimal analgesiashould be the goal and can be achieved by incorporatingpreoperative education, local anesthetics, and inhibitors ofcyclooxygenase 2.Optimal analgesiamay include an opioid.)
3. Multimodal therapy� Antiemetics (consider combination therapy)� Total intravenous anesthesia with propofol� Adequate hydration� Effective analgesia incorporating local anesthetics andinhibitors 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 AmericanMedical Association; with permission.
6
D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365 359
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 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
D. Cameron, T.J. Gan / Anesthesiology Clin N Am 21 (2003) 347–365360
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 high-
risk populations should reduce these unpleasant symptoms and help direct
appropriate clinical strategies. Treatment following failure of prophylactic antie-
metic therapy requires knowledge of previously used antiemetics and the time of
their administration.
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