Postoperative Nausea and Vomiting

Kok-Yuen Ho

Tong Joo Gan

CASE SUMMARY

A 40-year-old, 65 kg, female nonsmoker was scheduled for an elective laparoscopic cholecystectomy. She volunteered a history of postoperative vomiting after an elective cesarean section under general anesthesia 2 years ago. The anesthesiologist performed induction with 2 mg per kg of intravenous (IV) propofol. Muscle paralysis was obtained with rocuronium, 0.6 mg per kg IV, and the patient was intubated with an oral endotracheal tube. Intermittent positive-pressure ventilation was employed. Anesthesia was maintained with 1% isoflurane in 1 L per minute of oxygen and 2 L per minute of nitrous oxide. A total of 3 µg per kg of IV fentanyl was given intraoperatively for analgesia. At the end of surgery, the anesthesiologist administered glycopyrrolate and neostigmine to reverse muscle relaxation and prophylactically gave ondansetron, 4 mg IV, to prevent postoperative vomiting. The patient developed significant nausea and vomited twice in the recovery room. Rescue medication consisting of an additional 4 mg of ondansetron was administered intravenously. She had persistent vomiting despite the prophylactic and rescue doses of ondansetron.

What Baseline Knowledge Is Relevant?

▪ DEFINITIONS

Nausea is defined as a subjectively unpleasant sensation of having the urge to vomit. Vomiting is the reflex forceful expulsion of gastric contents through the esophagus and out of the mouth. Retching is physiologically similar to vomiting and describes the labored, spasmodic, rhythmic contractions of the respiratory and abdominal muscles without expulsion of gastric contents.

▪ INCIDENCE

The estimated overall incidence of postoperative nausea and vomiting (PONV) for all surgeries and patient populations ranges between 25% and 30%, with severe, intractable PONV estimated to occur in approximately 0.18% of all patients.¹ In high-risk groups, PONV occurs in as many as 70% of patients. PONV can delay patient discharge from the recovery room and prolong hospital stay. It may even be more distressing to patients than the postoperative pain itself.²,³ It is not uncommon for patients to develop PONV after discharge from the surgical center in the postdischarge period. The incidence of postdischarge nausea and vomiting was found to be as high as 35%, with more than 70% of this group having had no PONV in the recovery room.⁴

▪ ANATOMY AND PHYSIOLOGY OF VOMITING

The vomiting center, situated in the lateral reticular formation of the medulla oblongata, mediates the vomiting reflex (see Fig. 39.1). It is closely related to the nucleus tractus solitarius and the area postrema. The chemoreceptor trigger zone (CTZ) is located in the area postrema. Peripheral and central stimuli can affect both the vomiting center and the CTZ. Afferents from the pharynx, gastrointestinal tract, mediastinum, renal pelvis, peritoneum, and genitalia can stimulate the vomiting center. Central stimulation from the cerebral cortex, higher cortical and brainstem centers, nucleus tractus solitarius, CTZ, vestibular system of the inner ear, and the visual
centers also affects the vomiting center. Because the area postrema has no effective blood-brain barrier, drugs or chemicals present in the blood or cerebrospinal fluid (CSF) can directly stimulate the CTZ.

FIGURE 39.1 Central and peripheral afferent input to the vomiting center.

Receptors such as the 5-hydroxytryptamine type 3 (5-HT₃), dopamine type 2 (D₂), opioid and neurokinin-1 (NK-1) are found in the CTZ. The nucleus tractus solitarius has high concentrations of enkephalin, histaminergic (H₁), and muscarinic (M) cholinergic receptors. These receptors transmit messages to the vomiting center when stimulated. Recently, NK-1 receptors were also found to be present in the vomiting center.⁵,⁶ The vomiting center coordinates efferent impulses through the vagus, phrenic, and spinal nerves of the respiratory and abdominal musculature to initiate the vomiting reflex.

TABLE 39.1 Nonanesthetic Factors Associated with Postoperative Nausea and Vomiting

Patient Factors
▪	Young age
▪	Female gender
▪	Obesity
▪	History of motion sickness or postoperative nausea and vomiting
▪	Nonsmoking history
▪	Anxiety
▪	Gastrointestinal disease
▪	Concurrent therapy (chemotherapy, radiation therapy)
▪	Pregnancy
Surgical Factors
▪	Type of procedure
▪	Length of procedure

TABLE 39.2 Anesthetic Factors Associated with Postoperative Nausea and Vomiting

Preoperative	Premedication
Intraoperative	Inhalational anesthetic agents
		▪	Volatile anesthetic gases
		▪	Nitrous oxide
	Intravenous anesthetic agents
	Reversal agents for neuromuscular blockade
	Regional anesthesia
Postoperative	Pain
	Movement and ambulation

What Are the Factors Associated with Postoperative Nausea and Vomiting?

Given the diverse nature of afferent impulses that can stimulate the vomiting center, there are a variety of factors that are associated with PONV (see Tables 39.1 and 39.2).

▪ PATIENT CONSIDERATIONS

Patient-related risk factors for PONV include female gender, nonsmoking status, and history of PONV or motion sickness.⁷ Patients with preexisting gastrointestinal diseases such as hiatus hernia, gastroesophageal reflux disease, or metabolic diseases such as diabetes mellitus, uremia, and electrolyte abnormalities may also be at higher risk for PONV. Pregnancy and preoperative anxiety increase the risk of PONV, as well as patients undergoing chemotherapy or radiation therapy.¹

▪ SURGICAL CONSIDERATIONS

Ear, nose, and throat surgery, dental surgery, breast augmentation surgery, orthopedic shoulder surgery, laparoscopy, gynecologic surgery, and varicose veinstripping procedures are all associated with a higher risk of PONV. Others at increased risk are pediatric patients undergoing strabismus surgery, adenotonsillectomy, and orchiopexy.⁸ The risk of PONV increases with the duration of the operative procedure; long surgeries increase the exposure time to emetogenic anesthetic drugs.¹

▪ ANESTHETIC CONSIDERATIONS

Anesthetic factors implicated in the incidence of PONV include premedication, anesthetic technique, choice of anesthetic drugs (nitrous oxide, volatile anesthetics, IV induction agents, opioids, and reversal agents), adequacy of hydration, and postoperative pain management. Hypotension during induction and surgery has been associated with increased risk of PONV as well.⁹

Premedication

Benzodiazepines are commonly used to reduce anxiety and produce amnesia. Several studies have shown that midazolam is effective in reducing postoperative vomiting.¹⁰,¹¹ In addition to its anxiolytic effect, midazolam probably enhances the inhibitory effects of γ-amino butyric acid and decreases dopaminergic activity and 5-HT release in the brain.

Inhalational Anesthetic Agents

General anesthesia in conjunction with inhalational anesthetic gases is strongly associated with the development of postoperative vomiting.¹² The PONV associated with inhalational anesthetic agents appears to be restricted to the first few hours after surgery, although this depends on the duration of exposure to these agents. A higher incidence of PONV is observed with the use of nitrous oxide.¹³,¹⁴ Nitrous oxide directly stimulates the vomiting center and interacts with opioid receptors. It also distends air spaces both in the middle ear and gastrointestinal tract, thereby affecting the vestibular system and increasing visceral input to the vomiting center, respectively.

Intravenous Anesthetic Agents

There is strong evidence to suggest that compared to inhalational anesthesia, total intravenous anesthesia (TIVA) with propofol reduces the incidence of PONV.¹⁴,¹⁵,¹⁶,¹⁷ The mechanism of action is not clear, but it appears that propofol may act by reducing 5-HT levels in the area postrema.¹⁸ Interestingly, propofol given for induction alone has no relevant effect on PONV.¹⁶ The antiemetic effect of propofol is dose-dependent, and better control of PONV can be achieved when patients receive a continuous IV propofol infusion as the maintenance agent.¹⁹,²⁰ Therefore, the lack of antiemetic effect with propofol induction is probably due to the fact that the plasma concentration of propofol in the early recovery period is below the effective concentration for preventing PONV.²¹

Nondepolarizing Muscle Relaxants

Nondepolarizing muscle relaxants are commonly used in general anesthesia. The use of cholinesterase inhibitors to antagonize residual neuromuscular blockade is a well-accepted practice and, theoretically, may increase PONV. However, with the use of short- and intermediate-acting muscle relaxants, spontaneous recovery from neuromuscular blockade may be preferred to minimize the PONV associated with reversal agents. The role that neostigmine plays in causing PONV remains unresolved; there are studies that implicate neostigmine as a culprit, and there are as many studies that show otherwise.²²,²³,²⁴,²⁵ These differences may be related to confounding factors such as age of patients (adult vs. child), type of surgery (peripheral vs. gynecologic), IV induction agents (thiopental vs. propofol), and doses of neostigmine and anticholinergic agents (glycopyrrolate vs. atropine). Women and children are more prone to PONV, and laparoscopic surgery is associated with a higher risk. Atropine, unlike the quaternary anticholinergic glycopyrrolate, crosses the blood-brain barrier and is known to possess antiemetic properties. A recent meta-analysis maintains that there is inconclusive evidence to suggest that neostigmine, administered either with glycopyrrolate or atropine, increases the incidence of PONV.²⁶ In the interest of patient safety, reversal drugs should be used in appropriate doses when clinically indicated.

Regional Anesthesia

Regional anesthesia techniques have advantages over general anesthesia in that the use of nitrous oxide, volatile anesthetic gases, and even opioids is avoided; nonetheless, PONV can still occur if opioids are administered intravenously or into the epidural or intrathecal space. The use of highly lipophilic opioids such as fentanyl or sufentanil limits the cephalad spread of opioids and can lower the risk of subsequent opioid-induced emesis.²⁷ Hypotension secondary to sympathetic blockade in central neuraxial blocks can also contribute to PONV. It is postulated that hypotension leads to brain stem ischemia, which then activates the vomiting center in the medulla. Hypotension can also cause gut ischemia, which releases emetogenic substances from the intestines.²⁷ These various hypotheses that link hypotension and PONV still need to be clarified and the mechanism linking hypotension to nausea and vomiting defined.

POSTOPERATIVE FACTORS

Postoperative pain, especially visceral or pelvic pain, is often overlooked as a cause of PONV. Pain can prolong gastric-emptying time and, thereby, contribute to emesis after surgery. A multimodal approach to pain management can reduce postoperative pain by utilizing a combination of systemic opioids, nonsteroidal anti-inflammatory drugs, neuraxial blocks, regional nerve blocks, and through local infiltration of the surgical wound. A conscious attempt to use the lowest possible dose of opioid to achieve adequate analgesia is important to limit the nausea and vomiting that opioids can cause.

Sudden movements, changes in position during patient transfer, and ambulation can also precipitate nausea and vomiting, particularly in patients who have received opioids. The vestibular apparatus may become sensitized to motion-induced nausea and vomiting by opioids or by nitrous oxide diffusion into the middle ear.

TABLE 39.3 Classification of Antiemetics

Class	Receptor Site of Action	Drugs	Side Effects
Anticholinergics	Muscarinic, histaminergic (H₁)	Atropine Scopolamine	Dry mouth, visual disturbances, confusion, hallucination, sedation
Antihistamines	Histaminergic (H₁)	Cyclizine Dimenhydrinate Diphenhydramine	Sedation
Butyrophenones	D₂	Droperidol	Sedation, agitation, extrapyramidal effects, QT prolongation.
Phenothiazines	D₂	Promethazine Prochlorperazine Perphenazine	Sedation, agitation, extrapyramidal effects
Benzamides	D₂, 5-HT₃	Metoclopramide	Dystonia, extrapyramidal effects
Serotonin antagonists	5-HT₃	Ondansetron Dolasetron Granisetron	Headache, dizziness, QT prolongation
D₂, dopamine type 2; 5-HT₃, 5-hydroxytryptamine type 3.

What Drugs Can Be Given for the Prevention of Postoperative Nausea and Vomiting?

Traditional antiemetic drugs used for prevention of PONV include the anticholinergics (atropine, scopolamine), antihistamines (cyclizine, diphenhydramine, dimenhydrinate), butyrophenones (droperidol), phenothiazines (promethazine, prochlorperazine), and benzamides (metoclopramide) (see Table 39.3). Many of these antiemetics, although effective, are associated with undesirable side effects such as restlessness, dry mouth, sedation, hypotension, dystonia and extrapyramidal symptoms, and even QT prolongation.

▪ METOCLOPRAMIDE

Metoclopramide has been widely used in clinical practice for many decades. It blocks dopamine D₂ receptors centrally (vomiting center, CTZ) and peripherally (gastrointestinal tract). However, it has fallen out of favor because of its weak antiemetic efficacy. A systematic review of 66 studies showed that prophylactic metoclopramide was not effective in preventing PONV in either adults or children at the commonly used doses of 10 to 20 mg (adults) and 0.25 mg per kg (children).²⁸ Metoclopramide is more effective, when given in the immediate postoperative period, in treating established vomiting in children.²⁹

▪ DROPERIDOL

Droperidol acts by the antagonism of dopamine D₂ receptors centrally, and is as effective as ondansetron when given prophylactically.³⁰ It was reported to be more effective when given at the end of surgery than at induction.³¹ At IV doses of ≤1.25 mg, the incidence of central nervous system side effects for droperidol was comparable to that of ondansetron. A 0.625-mg dose of droperidol was effective when compared with placebo, although a 1.25-mg dose demonstrated enhanced efficacy.³⁰ In contrast to adults, droperidol is less effective than ondansetron in pediatric patients.³²

The U.S. Food and Drug Administration (FDA) issued a “black box” warning in 2001 on droperidol based on a number of anecdotal reports (FDA Med Watch) of QTc prolongation and torsades de pointes associated with its use.³³ This has, unfortunately, led to the withdrawal of droperidol in some countries. No adverse cardiac events related to droperidol have ever been reported in the medical literature since its introduction for the management of PONV.³⁴ Moreover, the dose used for PONV prevention and treatment is considerably lower than the doses reported with cardiac arrhythmias. The minimum FDA-approved dose for droperidol is 2.5 mg; hence, the doses routinely used for antiemesis (≤1.25 mg) are actually substantially lower than the FDA-approved dose range. The authors believe that droperidol still has an important role in the prophylaxis and therapy of PONV. The antiemetic doses (0.625 to 1.25 mg) are below the minimum FDA-approved doses in the package insert (2.5 mg and above).

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