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.11 Conversely, 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
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