Postoperative nausea and vomiting (PONV) is defined as nausea and/or vomiting occurring within 24 hours of surgery. Along with pain, PONV is the most important complaint patients report following surgery under anesthesia and is the leading cause of unanticipated hospital admission following outpatient surgery. Without prophylaxis, nausea occurs in up to 40% of patients who undergo general anesthesia but can be as high as 80% in high-risk patients.1There have been thousands of studies examining ways to prevent PONV and to effectively treat it when it does develop. Likewise, several anesthesia societies and organizations have developed guidelines on how to best address the problem. There have been a number of nonpharmacologic methods used to prevent and/or attenuate this disorder but this chapter will focus on the pharmacologic therapies used as prophylaxis and treatment of PONV.
Definition
PONV, recognized by the National Library of Medicine as a single medical subject heading term, actually refers to two distinct entities. Although nausea and emesis are intimately related, one can have one without the other or vice versa. Some drugs are more effective in treating one than the other. A patient who experiences nausea or has emesis within 24 hours of a surgical procedure that required anesthesia meets the criteria for the diagnosis of PONV. The classification is further divided into early PONV (within 6 hours of emergence from anesthesia) or late PONV (6 to 24 hours after the procedure).
Incidence
As mentioned previously, PONV occurs in 30% to 40% of all patients who undergo general anesthesia, but among patients with identified risk factors for developing PONV, it can occur in 70% to 80%. From a patient satisfaction point of view, PONV is a major issue. In a study of 195 surgical patients who were given a standardized questionnaire during the preoperative period, 130 questionnaires were returned prior to surgery. The patients rated emesis as the most important clinical anesthesia outcome to avoid, ahead of gagging on the tracheal tube (2), pain (3), nausea (4), and intraoperative recall (5). Independent of patient perception, PONV has been associated with morbidity including dehydration, electrolyte abnormalities, wound dehiscence, bleeding, esophageal rupture (Boerhaave’s syndrome), and airway compromise.
Pathophysiology
Patients with nausea have a subjective feeling of the need to vomit; the sensation is very, very unpleasant. The nauseated patient does not necessarily vomit or retch, however. Emesis, which is the expulsion of stomach contents up the esophagus to the mouth, may or may not be preceded by nausea. The process often begins with antiperistalsis or muscular contractions within the ileum and jejunum, moving luminal contents back towards the stomach. The process of expelling these gastric contents involves closure of the glottis and contraction of the diaphragm, creating negative intrathoracic pressure at the same time that pharyngeal sphincters relax. Almost simultaneously, abdominal muscles contract creating increased intraabdominal pressure, which is transferred to the stomach; the stomach contents follow the path of least resistance and emesis occurs. If there are no stomach contents, the person may retch—the same events take place but no particulate or liquid material is expelled from the mouth. Emesis is different from regurgitation in which acidic gastric material passively reflexes into the esophagus because of an incompetent esophageal sphincter and elevated abdominal pressure.
The sequence of events that occur during emesis are controlled by the so-called vomiting “center,” which lies in the medulla oblongata and consists of the nucleus of the tractus solitarius and parts of the reticular formation. A number of neurotransmitters modulate the activity of the vomiting center (Fig. 34-1); agonists and antagonists of these neurotransmitters are used to prevent nausea and vomiting. Slightly cephalad to the vomiting center is the chemoreceptor trigger zone (CRTZ), which detects noxious chemicals in the bloodstream, for example, ethanol at high concentration sends signals via neural networks, which activate the vomiting center. Other anatomic sites that can activate the vomiting center include the vestibular apparatus, the thalamus and cerebral cortex, and neurons within the gastrointestinal tract itself. The latter would occur for example if a small bowel obstruction triggered antiperistalsis, and as small intestinal contents were forced backwards filling the stomach, afferent signals would be transmitted to the vomiting center.
Upon activation, the vomiting center sends efferent signals via the cranial nerves V, VII, IX, X, and XII through the vagal parasympathetic fibers and sympathetic chain and to skeletal muscle through α motor neurons. Signals from the vomiting center via these nerves trigger the complex motor process resulting in emesis.
Prophylaxis
Preventing PONV is easier than treating it2 but the side effects of the antiemetic drugs are such that the American Society of Anesthesiologists has recommended that antiemetic agents should be used for the prevention and treatment of nausea and vomiting when indicated but not routinely. In order to determine whether prophylaxis is indicated, it is important to assess a patient’s propensity to develop PONV according to risk factors that increase or decrease a patient’s chances of experiencing PONV. These risk factors are traditionally divided into patient, surgical, and anesthetic risk factors.
Patient Factors
Women, nonsmokers3, and those with a history of motion sickness4 or of previous episodes of PONV are at an increased risk of experiencing PONV if they undergo a surgical procedure under anesthesia. Women most likely are at increased risk for PONV because of the effects of progesterone and/or estrogen on the CRTZ or on the vomiting center itself as evidenced by the fact that the incidence of PONV varies within the menstrual cycle and is reduced after menopause.5 Obese patients, because of exposure to greater amount of emetogenic lipophilic drugs such as the inhalational anesthetic agents stored in their adipose tissue, were once thought to have a higher incidence of PONV but a subsequent investigation did not show this to be true.6
Surgical Factors
The longer the surgical procedure, the greater is the risk for a patient to develop PONV, perhaps because of prolonged exposure to emetogenic lipophilic drugs.7 Independent of duration, certain surgical procedures have been associated with an increased incidence of PONV, for example, laparotomies; gynecologic surgeries; laparoscopic procedures; as well as ear, nose, throat, breast, plastic, and orthopedic surgical procedures.8 Age is only weakly associated with PONV; for pediatric patients having surgery under general anesthesia, the greatest association is with the surgical procedure itself. Herniorrhaphy, tonsillectomy, and adenoidectomy; strabismus procedures; and surgical procedures on male genitalia have the highest risk.9 Among adults, risk is reduced with aging.
Anesthetic Factors
There have been a number of anesthetic-related factors that investigators have assessed for their relationship to the development of PONV. The inhalation anesthetic agents nitrous oxide, neostigmine, and opioids have all been implicated in the genesis of PONV. However, correlation is limited and most scoring systems used to identify patients at risk of PONV do not use anesthetic factors as risk factors.
Pharmacologic Interventions
A multimodal approach for prophylaxis in patients at high risk for developing PONV and as rescue therapy in patients who develop PONV in the postanesthetic care unit works well because of the complexity of systems involved in the pathogenesis of PONV. The drugs that modulate activity in the vomiting center and CRTZ are listed in Table 34-1 and will be discussed in the following sections.
Anticholinergics
Scopolamine
Prevention of Motion-Induced Nausea and of Postoperative Nausea and Vomiting
Transdermal absorption of scopolamine provides sustained therapeutic plasma concentrations, which protect against motion-induced nausea usually without introducing prohibitive side effects such as sedation, cycloplegia, or drying of secretions. For example, a postauricular application of scopolamine delivers the drug at about 5 µg per hour for 72 hours (total absorbed dose is <0.5 mg). Protection against motion-induced nausea is greatest if the transdermal application of scopolamine is initiated at least 4 hours before the noxious stimulus. Administration of transdermal scopolamine after the onset of symptoms is less effective than prophylactic administration. Similar protection against motion-induced nausea by oral or intravenous (IV) administration of scopolamine would require large doses, resulting in undesirable side effects and subsequent poor patient acceptance.
Transdermal application of a scopolamine patch has been shown to exert significant antiemetic effects in patients experiencing motion sickness and in those treated with patient-controlled analgesia or epidural morphine for the management of postoperative pain.10 It is well known that motion sickness is caused by stimulation of the vestibular apparatus. It has also been shown that morphine and synthetic opioids increase vestibular sensitivity to motion. It is presumed that scopolamine blocks transmission to the medulla of impulses arising from overstimulation of the vestibular apparatus of the inner ear. Indeed, application of a transdermal scopolamine (TDS) patch before the induction of anesthesia protects against nausea and vomiting after middle ear surgery, which is likely due to altered function of the vestibular apparatus.10 Furthermore, prophylactic TDS applied the evening before surgery decreases but does not abolish the occurrence of nausea and vomiting after outpatient laparoscopy using general anesthesia.11Conversely, not all reports describe an antiemetic effect in patients treated with TDS who are undergoing general anesthesia.12 However, Apfel and colleagues13 performed a meta-analysis of 25 studies of TDS used to treat PONV and found that TDS was associated with significant reductions in PONV with both early and late application during the first 24 hours after the start of anesthesia. TDS was associated with a higher prevalence of visual disturbances at 24 to 48 hours after surgery, but no other adverse events were noted.13 Some of the visual disturbances may be due to anisocoria, which has been attributed to contamination of the eye after digital manipulation of the TDS patch.14 More than 90% of unilateral dilated pupils occur on the same side as the patch. This diagnosis is confirmed by history and failure of the mydriasis to respond to topical installation of pilocarpine.
Central Anticholinergic Syndrome
Scopolamine and atropine can enter the central nervous system (CNS) and produce symptoms characterized as the central anticholinergic syndrome. Symptoms range from restlessness and hallucinations to somnolence and unconsciousness. Presumably, these responses reflect blockade of muscarinic cholinergic receptors and competitive inhibition of the effects of acetylcholine in the CNS. Glycopyrrolate does not easily cross the blood–brain barrier and thus is not likely to cause central anticholinergic syndrome. Nevertheless, central anticholinergic syndrome has been attributed to the IV administration of anticholinergic drugs before the induction of anesthesia.15
Physostigmine, a lipid-soluble tertiary amine anticholinesterase drug administered in doses of 15 to 60 µg/kg IV, is a specific treatment for the central anticholinergic syndrome. Treatment may need to be repeated every 1 to 2 hours. Edrophonium, neostigmine, and pyridostigmine are not effective antidotes because their quaternary ammonium structure prevents these drugs from easily entering the CNS. The central anticholinergic syndrome is often mistaken for delayed recovery from anesthesia. Ventilation may be depressed. Differentiation of this syndrome from other causes of perioperative confusion is possible with slow IV administration of physostigmine, 0.4 mg/kg.
Overdose
Deliberate or accidental overdose with an anticholinergic drug produces a rapid onset of symptoms characteristic of muscarinic cholinergic receptor blockade. The mouth becomes dry, swallowing and talking is difficult, vision is blurred, photophobia is present, and tachycardia is prominent. The skin is dry and flushed, and a rash may appear especially over the face, neck, and upper chest (blush area). Even therapeutic doses of anticholinergic drugs sometimes may selectively dilate cutaneous vessels in the blush area. Body temperature is likely to be increased by anticholinergic drugs, especially when the environmental temperature is also increased. This increase in body temperature largely reflects inhibition of sweating by anticholinergic drugs, emphasizing that innervation of sweat glands is by sympathetic nervous system nerves that release acetylcholine as the neurotransmitter. Small children are particularly vulnerable to drug-induced increases in body temperature, with “atropine fever” occurring occasionally in this age group after administration of even a therapeutic dose of anticholinergic drug. Minute ventilation may be slightly increased due to CNS stimulation and the impact of an increased physiologic dead space due to bronchodilation. Arterial blood gases are usually unchanged. Fatal events due to an overdose of an anticholinergic drug include seizures, coma, and medullary ventilatory center paralysis.
Small children and infants seem particularly vulnerable to developing life-threatening symptoms after an overdose with an anticholinergic drug. Physostigmine, administered in doses of 15 to 60 µg/kg IV, is the specific treatment for reversal of symptoms. Because physostigmine is metabolized rapidly, repeated doses of this anticholinesterase drug may be necessary to prevent the recurrence of symptoms.
Decreased Barrier Pressure
Barrier pressure is the difference between gastric pressure and lower esophageal sphincter pressure. Administration of atropine, 0.6 mg IV, or glycopyrrolate, 0.2 to 0.3 mg IV, decreases lower esophageal sphincter pressure and thus decreases barrier pressure and the inherent resistance to reflux of acidic fluid into the esophagus.16 This effect may persist longer with glycopyrrolate (60 minutes) than after administration of atropine (40 minutes).
Benzamides
Metoclopramide
The benzamides stimulate the gastrointestinal tract via cholinergic mechanism, which results in (a) contraction of the lower esophageal sphincter and gastric fundus, (b) increased gastric and small intestinal motility, and (c) decreased muscle activity in the pylorus and duodenum when the stomach contracts. Metoclopramide and domperidone are the two benzamides currently in use, but domperidone is not available in the United States because the U.S. Food and Drug Administration (FDA) was concerned about its use in lactating women (increases milk production). This review will therefore focus on metoclopramide, which presumably has either a peripheral effect as just described or because it readily crosses the blood–brain barrier may have direct effects on the CRTZ and/or vomiting center because of its antidopaminergic effect.
A meta-analysis of 30 trials evaluating 10 mg of systemic metoclopramide on PONV outcomes concluded that compared to placebo metoclopramide, the incidence of 24-hour PONV was reduced with an odds ratio of .58 with a 95% confidence interval of 0.43 to 0.78. The number needed to treat was 7.8.17
Because of its antidopaminergic activity, metoclopramide should be used with caution if at all in patients with Parkinson’s disease, restless leg syndrome, or who have movement disorders related to dopamine inhibition or depletion.18 In patients with no known movement disorders, dystonic extrapyramidal reactions (oculogyric crises, opisthotonus, trismus, torticollis) occur in less than 1% of patients treated chronically with metoclopramide. Although usually a problem if large oral doses (40 to 80 mg daily) are administered chronically, there are reports of neurologic dysfunction related to the preoperative administration of metoclopramide.19 These extrapyramidal reactions are identical to the Parkinson’s syndrome evoked by antipsychotic drugs that antagonize the CNS actions of dopamine.20 Akathisia, a feeling of unease and restlessness in the lower extremities, may follow the IV administration of metoclopramide, sometimes so severe that it can result in cancellation of surgery21 or which may manifest in the postanesthesia care unit.18,22
Benzodiazepines
Midazolam
The activity of the benzodiazepines is relatively well known but with respect to a possible mechanism of action in PONV, benzodiazepines may decrease synthesis and release of dopamine within the CRTZ.23,24 Because many, if not a majority of patients, receive benzodiazepines administered as part of general and regional anesthetics and for monitored anesthesia care, a lengthy discussion of their role in the prophylaxis and for rescue therapy of PONV is probably not warranted. However, in patients for whom the administration of benzodiazepine is not planned but who are at risk of PONV, if midazolam is used for its antiemetic effect, it should be administered IV toward the end of the surgical procedure25 or by continuous infusion in intubated and ventilated patients in the intensive care unit.26
Butyrophenones
Droperidol and Haloperidol
After the FDA placed black box restrictions on droperidol due to its association with prolonged QT syndromes, many physicians stopped using droperidol. However, the FDA’s restriction on droperidol was for a result of case reports with higher doses than are necessary for the treatment of PONV. Because of its efficacy at low dose, the use of droperidol has increased over the last several years for prophylaxis and as rescue therapy as an antiemetic. Prophylactic doses of droperidol of 0.625 to 1.25 mg IV are effective for the prevention and treatment of PONV. Haloperidol also has antiemetic properties when used in low doses, 0.5 to 2 mg IV. At these doses, sedation does not occur. Extrapyramidal symptoms, however, are a risk of all medications that involve dopamine receptor blockade in the brain and therefore, these drugs should be used with caution if at all in patients with Parkinson’s disease, restless leg syndrome, and other diseases related to dopaminergic activity. For patients in whom dopamine antagonism is not a concern, droperidol is as effective as dexamethasone or ondansetron in preventing and treating PONV.27
Corticosteroids
Dexamethasone
Dexamethasone has been shown to be useful in the management of PONV but the mechanism of antiemetic activity is unclear. Corticosteroids are proposed to centrally inhibit prostaglandin synthesis and control endorphin release. As discussed already, dexamethasone has efficacy similar to ondansetron and droperidol27 and with a minimal side effect profile associated with one-time use. Obese and diabetic patients are at increased risk for perioperative hyperglycemia when they receive a single dose of dexamethasone.
5-HT3 Receptor Antagonists
The 5-HT3 receptors are excitatory ligand-gated nonselective cation. The ion channel is a pentamer consisting of five monomers that form a central pore, which can be readily permeated by small cations. The 5-HT3 receptors are extensively distributed on enteric neurons in the gastrointestinal tract and brain. Serotonin is released from the enterochromaffin cells of the small intestine, stimulates the vagal afferents through 5-HT3 receptors, and initiates the vomiting reflex. Antagonism of 5-HT3 receptors results in an antiemetic effect. Clinically used 5-HT3 receptor antagonists are selective for these receptors with almost no significant binding with other 5-HT receptor subtypes.
Clinical Uses
The 5-HT3 receptor antagonists represent (ondansetron, tropisetron, granisetron, dolasetron) a significant advance in the prophylaxis and treatment of nausea and vomiting because they are highly specific and evoke minimal side effects. Drugs that act as competitive antagonists at 5-HT3 receptors are useful antiemetics in the prophylaxis and treatment of chemotherapy- and radiation therapy–induced nausea and vomiting.28 Furthermore, these 5-HT3 receptor antagonists have proved to be highly effective in the prevention and treatment of PONV. Serotonin receptor antagonists are not effective in the treatment of motion-induced nausea and vomiting nor are they effective treatment for PONV caused by vestibular stimulation because the vestibular apparatus and the nucleus of the tractus solitarius are rich in muscarinic and histamine receptors that would not be blocked by a 5-HT3 receptor antagonist.
The convenience of use, efficacy, and safety profile are some of the reasons for the popularity of 5-HT3 receptor antagonists for management of PONV.
Comparison with Other Antiemetics
Ondansetron (4 mg), dexamethasone (4 mg), and droperidol (1.25 mg) administered IV as prophylactic therapy before induction of general anesthesia are equally effective in decreasing the incidence of PONV by about 26%.27However, a cost–benefit analysis did not support the use of 5-HT3 receptor antagonists for routine antiemetic prophylaxis when studied in the early 2000s.29 Now that some 5-HT3antagonists are available as lower cost generic preparations, the balance may have shifted.
Pharmacokinetics
The 5-HT3 receptor antagonists are readily absorbed after oral administration and readily cross the blood–brain barrier. Following IV administration, the maximum brain concentration is achieved quickly. These antagonists are moderately bound to protein (60% to 75%). Metabolism is by different subtypes of cytochrome P450 enzymes and metabolites undergo principally renal excretion.
Ondansetron
Ondansetron is a carbazalone derivative that is structurally related to serotonin and possesses specific 5-HT3 subtype receptor antagonist properties without altering dopamine, histamine, adrenergic, or cholinergic receptor activity.30As a result, ondansetron is free of neurologic side effects common to droperidol and metoclopramide.31 Ondansetron is effective when administered orally or IV and has an oral bioavailability of about 60% with therapeutic blood concentrations appearing 30 to 60 minutes after administration. Metabolism to inactive metabolites occurs predominantly in the liver and the elimination half-time is 3 to 4 hours.
The most commonly reported side effects from treatment with ondansetron are headache and diarrhea. Transient increases in the plasma concentrations of liver transaminase enzymes have been observed only in patients receiving chemotherapy and may be due to these drugs rather than ondansetron. Cardiac arrhythmias and conduction disturbances (atrioventricular block) have been reported after the IV administration of ondansetron and metoclopramide.28Ondansetron and other 5-HT3 receptor antagonists can cause slight prolongation of the QTc interval on the electrocardiogram of treated patients but this has not created the same level of concern as that ascribed to droperidol for unclear reasons.
It is estimated that for every 100 patients who receive ondansetron for the prevention of PONV, 20 patients will not vomit who would have vomited without treatment (“number needed to treat”), and three of those 100 patients will develop a headache who would have not had this adverse effect without the drug (“number needed to harm”).32 Ondansetron, 4 to 8 mg IV (administered over 2 to 5 minutes immediately before the induction of anesthesia), is highly effective in decreasing the incidence of PONV in a susceptible patient population (ambulatory gynecologic surgery, middle ear surgery). Oral (0.15 mg/kg) or IV (0.05 to 0.15 mg/kg) administration of ondansetron is effective in decreasing the incidence of postoperative vomiting in preadolescent children undergoing ambulatory surgery, including tonsillectomy and strabismus surgery.
Ondansetron, although highly effective in decreasing the incidence and intensity of PONV, does not totally eliminate this complication. The most significant feature of ondansetron prophylaxis and treatment is the relative freedom from side effects as compared with other described classes of antiemetic drugs. Use of propofol for induction and maintenance of anesthesia is almost as effective as ondansetron in preventing PONV (19% vs. 26%, respectively) and ondansetron continues to have antiemetic effects when used in propofol-based anesthetic.27
Tropisetron
Tropisetron is an indoleacetic acid ester of tropine that possesses highly selective 5-HT3 receptor blocking effects. Compared with ondansetron, tropisetron has the benefit of a longer elimination half-time (7.3 hours vs. 3.5 hours). Overall, the beneficial effects and side effects of tropisetron resemble ondansetron.33 This drug is also effective in the treatment of symptoms related to carcinoid syndrome and may also possess gastrokinetic properties. As an antiemetic, tropisetron is effective in prevention of chemotherapy- and radiotherapy-induced emesis and in the prevention of PONV when administered (2 to 5 mg IV) before the induction of general anesthesia.34 Rescue treatment using a single dose of tropisetron is often effective in decreasing further nausea and vomiting.35 Tropisetron did not prevent PONV associated with epidural morphine, whereas dexamethasone (5 mg IV) was effective.36
Granisetron
Granisetron is a more selective 5-HT3 receptor antagonist than ondansetron. Like ondansetron, granisetron is effective orally and IV. Doses as low as 0.02 to 0.04 mg/kg IV have been described as effective in prevention of chemotherapy-induced emesis and prevention of PONV.28 Concomitant administration of dexamethasone significantly improved the acute antiemetic efficacy of granisetron.37,38 Metabolism to inactive metabolites occurs in the liver with only about 10% of the drug excreted unchanged by the kidneys. The elimination half-time of granisetron (9 hours) is 2.5 times longer than that of ondansetron and thus may require less frequent dosing. For example, a single dose of granisetron may be effective for 24 hours. Side effects are mild and include headache, sedation, and diarrhea.
Dolasetron
Dolasetron is a highly potent and selective 5-HT3 receptor antagonist that is effective in the prevention of chemotherapy-induced nausea and vomiting and PONV following either oral or IV administration. After its administration, dolasetron is rapidly metabolized to hydrodolasetron, which is responsible for the antiemetic effect. Hydrodolasetron has an elimination half-time of approximately 8 hours and is approximately 100 times more potent as a serotonin antagonist than the parent compound.
A single IV dose of dolasetron, 1.8 mg, is equivalent to ondansetron, 32 mg IV, and granisetron, 3 mg IV, in preventing chemotherapy-induced nausea and vomiting. Established PONV is effectively blunted by treatment with dolasetron, 12.5 mg IV.39 Oral dolasetron, 25 to 50 mg, is effective as prophylaxis for decreasing PONV. Although serotonergic pathways are involved in the development of postoperative shivering, dolasetron was not effective in preventing this complication.40 Side effects include headache, dizziness, and increased appetite. It is unclear if an increased heart rate attributed to dolasetron is different from the incidence observed in placebo-treated patients.28
Histamine Receptor Antagonists
The effects of histamine are mediated via histamine receptors, and at least three histamine receptors subtypes have been identified and classified as H1, H2, and H3. Histamine acting through H1 receptors and inositol phospholipid hydrolysis evokes smooth muscle contraction in the gastrointestinal tract. Nonspecific antihistamines, likely acting on H1 receptors including diphenhydramine, dimenhydrinate, cyclizine, and promethazine are used as antiemetics.
Dimenhydrinate (marketed as Dramamine) has been used to treat PONV as well as motion sickness. It is speculated that the efficacy of dimenhydrinate in motion sickness and inner ear diseases may be due to inhibition of the integrative functioning of the vestibular nuclei by decreasing vestibular and visual input. Manipulation of the extraocular muscles as in strabismus surgery may trigger an “oculoemetic” reflex similar to the well-described oculocardiac reflex. If the afferent arc of this reflex is also dependent on the integrity of the vestibular nuclei apparatus, then dimenhydrinate may attenuate or block this reflex and decrease the incidence of PONV. Administration of dimenhydrinate, 20 mg IV, in adults decreases vomiting after outpatient surgery.41 In children, dimenhydrinate, 0.5 mg/kg IV, significantly decreases the incidence of vomiting after strabismus surgery.42
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