Before the 1990s, patients with cancer often withdrew from potentially life-saving chemotherapy regimens due to adverse side effects. Two major treatment-limiting side effects were nausea and vomiting. While incurring fewer long-term effects than other complications (eg, pulmonary fibrosis, peripheral neuropathies, renal dysfunction), chemotherapy-induced emesis (CIE) was a significant source of apprehension in patients. Antiemetic regimens were better known for their complexity, lack of efficacy, and toxicity. The introduction of the serotonin antagonists, however, has changed this view.

The cause of nausea and vomiting must be determined prior to formulating a plan to prevent these effects in a cancer patient. The fact that a cancer patient is receiving chemotherapy does not necessarily indicate that the patient is suffering from CIE. Nausea and vomiting can be caused by a physical condition such as a brain metastasis or a bowel obstruction, which requires different therapy. Metabolic complications such as hypercalcemia, as well as causes such as gastroenteritis or a gastric ulcer, also need to be excluded. This exclusionary process will determine whether CIE is the cause of nausea and vomiting.

Various neurotransmitters (eg, dopamine, endorphin, serotonin, substance P) have receptors in the chemoreceptor trigger zone of the area postrema that transmit impulses to the vomiting center in the brain stem. Their involvement in producing CIE has led to the development of a variety of medications to treat CIE: dopaminergic antagonists (eg, phenothiazines, butyrophenones), cannabinoids (eg, dronabinol), corticosteroids (eg, dexamethasone, methylprednisone), and benzodiazepines (eg, lorazepam, alprazolam). However, serotonin antagonists have dominated CIE treatment protocols for the past decade. Cytotoxic agents release serotonin from enterochromaffin cells in the gut. These stimulate intestinal mucosal 5-HT₃ receptors and, via the vagus, stimulate the chemoreceptor trigger zone that sends impulses to the vomiting center.

While the superiority of one 5-HT₃ receptor antagonist agent over another is often debated, the three agents available in the United States — dolasetron, granisetron, and ondansetron (tropisetron and itasetron are presently under study) — appear to be similar in efficacy and side effects. Although the half-lives of granisetron and dolasetron are two to three times longer than that of ondansetron, serotonin receptor blockade does not correlate with elimination half-life, and all three possess similar antiemetic duration of action. Antiemetic effect correlates with receptor blockade rather than with plasma levels. All three agents can be administered as a single daily dose. The choice of agent should rest on cost differences. Since acquisition costs of the different serotonin antagonists may vary among institutions, the choice varies depending on locale.

The most commonly used prophylactic regimen for moderately and highly emetogenic chemotherapy includes a corticosteroid and a serotonin antagonist. A recommended regimen may include granisetron (10µg/kg IV), tropisetron (5 mg), ondansetron (16 to 32 mg IV), or dolasetron (1.8 mg/kg IV) plus dexamethasone (8 to 10 mg IV).⁵ Low emetogenic chemotherapy may be treated on an as-needed basis. Delayed emesis may be treated with metoclopramide (20 mg PO twice daily for 3 days) plus dexamethasone (16 mg PO on day 1, 8 mg PO on day 2; 4 mg PO on day 3).⁵

Impact of CIE Control

Preventing or controlling CIE improves patients’ quality of life and allows greater tolerance of chemotherapeutic regimens, which in turn may improve outcomes by preventing premature withdrawal from treatment. Metabolic derangements associated with intractable emesis and the physical complications previously seen (eg, Mallory-Weiss tears) are decreased. Persistent CIE can interfere with oral feedings, which leads to intravenous alimentation. Effective CIE control also decreases the costs of managing the patient with cancer and allows the patient to be treated on an ambulatory basis.

Postoperative Nausea and Vomiting

Postoperative nausea and vomiting (PONV) is a frequent and bothersome complication after anesthesia and surgery. It is often cited as the most common reason for unexpected admission to the hospital after outpatient surgery.⁸ While the metabolic complications associated with PONV mirror those seen with CIE, other concerns are specific to the postoperative setting. Persistent retching may cause tension of skin sutures. PONV may also cause venous hypertension that increases the incidence of wound hematomas and bleeding under skin flaps. The risk of pulmonary aspiration of gastric contents is increased.⁹ While the prophylactic administration of antiemetics has been recommended, a variety of perioperative factors can be modified to reduce the incidence of PONV.

Several factors influence the occurrence of PONV (Table 2). As in CIE, the incidence of PONV is more common in women and younger patients, and medical conditions such as uremia or pregnancy increase its incidence.

The use of mask ventilation may cause gastric inflation, which has been shown to trigger PONV. The use of a laryngeal mask airway is increasing. The onset of passive gastric regurgitation is higher with a laryngeal mask airway than with a mask (due to "food bolus" sensation in the pharynx with relaxation of lower gastroesophageal sphincter). However, a higher incidence of PONV has not been observed. Postoperative hypotensive states contribute to an increase in the incidence of PONV. In a recent prospective study evaluating 500 patients undergoing otolaryngologic or ophthalmologic surgery, the incidence of PONV was lower in smokers than in nonsmokers.¹²

Medications that are known emetogenics should be avoided in the postoperative setting in order to decrease PONV incidence. While opioids can induce nausea and vomiting, pain is a more potent trigger of PONV. Anderson and Krohg¹³ demonstrated that relieving pain in the postanesthesia care unit also relieved nausea, and only 10% of patients with adequate pain relief complained of nausea. Nonetheless, the vagotonia associated with most opioids causes delayed gastric emptying and sets the stage for nausea and vomiting. Also, there may be a significant vestibular component in patients receiving opioids, since the incidence of nausea and vomiting is markedly higher in ambulatory patients.

The treatment of PONV should begin with the preoperative interview. Explaining the planned procedure with the patient and answering all questions will help to relieve the anxiety that increases nausea and vomiting. Particularly in patients medicated with opioids, movements should be slow and deliberate to minimize the possibility of motion sickness. PONV may be prevented with relatively simple measures such as modifying the anesthetic regimen (for example, using propofol rather than nitrous oxide).

Pretreatment with antiemetics is recommended for patients who will undergo procedures at high risk for PONV. The most commonly used medications are droperidol (0.625 to 1.25 mg IV) and the 5-HT₃ antagonists — dolasetron (50 mg), granisetron (3 mg), tropisetron (5 mg), and ondansetron (4 mg). Agents such as metoclopramide that have been documented in several studies are no more effective than placebo in preventing PONV. While preoperative administration of agents was recommended initially, evidence now indicates that dose timing may influence efficacy. A recent study involving otolaryngologic surgeries reported that ondansetron was more effective in preventing PONV when administered during the last hour of surgery than preoperatively.¹⁴ Similar to the effect described in CIE patients, patients at high risk for developing PONV should be considered for combination dosing with corticosteroids such as dexamethasone or betamethasone to increase efficacy.¹⁵

Efforts to identify and prophylactically treat patients at risk for PONV should continue, since surgical results and patient comfort may be significantly enhanced when PONV is prevented. Improved PONV control may decrease indirect costs (eg, work absenteeism of the patient and/or caregiver). Direct hospital-related costs might be also be reduced by decreasing postanesthesia care unit time and thus the length of hospital stay.

References

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