Clinical manifestations

Presentation and course

	• Nausea and vomiting may be accompanied by autonomic disturbances, such as hypersalivation, skin pallor, and increased perspiration.
	• Vomiting may follow other symptoms of raised intracranial pressure, such as headache.
	• The prognosis of nausea and vomiting depends on etiology.

Apart from nausea and retching, autonomic disturbances such as hypersalivation, skin pallor, and increased perspiration may accompany vomiting. Other accompaniments include hypotension and bradycardia, like the manifestations of a vagovagal syndrome. Anorexia may also be present. Nausea and vomiting may be acute or chronic. Occasional acute nausea and vomiting are generally associated with a viral gastroenteritis or bacterial infection (usually as preformed food-borne enterotoxins). The symptom-complex starts with an uneasy feeling in the "pit" of the stomach, hypersalivation, breath-holding, a characteristic facial appearance of an open mouth, and an attempt to sit down or lie still. There is an urge to vomit to relieve the uncomfortable sensation in the abdomen. Most episodes of vomiting are short-lived and do not lead to any complications. Persistent or chronic nausea and vomiting are usually symptoms of an underlying organic disease.

Vomiting may follow other symptoms of raised intracranial pressure such as headache. Occasionally, vomiting may be the first sign of brain tumor in children.

Prognosis and complications

The prognosis of nausea and vomiting depends on the etiology. Nausea and vomiting due to chemotherapy, for example, disappears after cessation of therapy. The prognosis of neurologic disorders depends on the associated disease. For example, in long-term follow-up of patients with chronic cyclic vomiting, about half become asymptomatic, and those who remain symptomatic show an association with migraine.

Complications of uncontrolled chronic nausea and vomiting include electrolyte imbalance and malnutrition.

Biological basis

	• Vomiting is under the control of a "vomiting center" in the dorsal portion of the lateral reticular formation and a chemoreceptor trigger zone in the area postrema of the floor of the fourth ventricle.
	• Causes of vomiting include a large number of disorders, including gastrointestinal and neurologic, as well as adverse effects of drugs.
	• The act of vomiting involves raised intra-abdominal pressure due to contraction of the diaphragm and abdominal muscles combined with the contraction of the pylorus of the stomach.

Anatomic localization

Traditionally, vomiting has been under the control of 2 distinct centers: (1) a "vomiting center" in the dorsal portion of the lateral reticular formation, and (2) a chemoreceptor trigger zone in the area postrema of the floor of the fourth ventricle. The vomiting center receives afferent fibers from the gastrointestinal tract via the dorsal vagal complex, the brainstem, the higher cortical centers, and the chemoreceptor trigger zone. Various noxious substances stimulate the trigger zone to release neurotransmitters, which affect the vomiting center and the impulses received by it. The important efferent pathways for vomiting are the phrenic nerves to the diaphragm, the spinal nerves to the abdominal muscles, and the visceral efferent fibers in the vagus nerve, the larynx, pharynx, and esophagus.

Excitatory and inhibitory receptors for vomiting have been found in the thorax. Vagal section above the level of the heart causes an intractable vomiting syndrome, and central cervical vagal stimulation inhibits vomiting.

Pathophysiology

Common causes of nausea and vomiting are shown in Table 1. Pathophysiology of vomiting will be described in the following text.

Table 1. Common Causes of Nausea and Vomiting

Inflammatory or vascular disorders of the gastrointestinal tract
	Acquired immunodeficiency enteropathy Esophagitis Gastritis Gastroenteritis due to infections Hemorrhage in esophagus, stomach, or duodenum Inflammatory bowel disease Intestinal infarction Peptic ulcer
Mechanical disorders of the gastrointestinal system
	Chronic intestinal pseudo-obstruction Gastric stapling procedure Intestinal adhesions Pyloric stenosis
Neurogastroenterological disorders
	Gastroparesis Hollow visceral neuropathy Following bilateral vagotomy or vagal injury
Diseases of abdominal viscera
	Cholecystitis Hepatitis Pancreatitis
Neurologic disorders
	Abdominal migraine Autonomic epilepsy Benign intracranial hypertension Encephalopathy Hemorrhagic stroke Hydrocephalus Ménière disease Meningitis Raised intracranial pressure due to mass brain lesions Subarachnoid hemorrhage Traumatic brain injury
Drugs
	Alcohol Anesthetics: postoperative vomiting Antibiotics Anticonvulsant medications Apomorphine Cardiac drugs, eg, digitalis Chemotherapeutic agents Dopamine agonists: ropinirole Nonsteroidal anti-inflammatory drugs Opioid analgesics
Cancer and radiotherapy
	Gastric carcinoma Paraneoplastic syndrome Radiation sickness Colon cancer
Metabolic disorders
	Diabetes mellitus with ketoacidosis Uremia Hypercalcemia
Hormonal disorders
	Adrenal insufficiency Hyperparathyroidism Hypoparathyroidism Hyperthyroid crisis
Cardiovascular disorders
	Syncope Myocardial ischemia
Psychological disturbances
	Anorexia nervosa Anxiety and panic disorder Bulimia Psychogenic vomiting
Miscellaneous causes
	Acute systemic infections with fever Hyperemesis gravidarum Motion sickness Systemic lupus erythematosus

General mechanism of vomiting. The act of vomiting involves raised intra-abdominal pressure due to contraction of the diaphragm and abdominal muscles, which combined with the contraction of the pylorus of the stomach, leads to expulsion of the gastric contents into the esophagus. Raised intrathoracic pressure and reverse esophageal peristalsis lead to further movement of the contents into the mouth. Reflex elevation of the palate prevents entry of the expelled material into the nasopharynx.

The objection to the classical concept of a vomiting center is that it would have to receive all emetic stimuli that enter the brain through several routes (visual, olfactory, auditory, gustatory, visceral, and somatic), which show no tendency to converge to a single center. Similarly, the gastric, esophageal, laryngeal, abdominal, diaphragmatic, and autonomic effector systems have no common input from a single nucleus that could coordinate the precise sequence of various components of the act of vomiting.

Mechanism of cyclic vomiting syndrome. The cyclic vomiting syndrome is characterized by discrete episodes of relentless vomiting separated by asymptomatic intervals and is associated with migraine headaches. It bears considerable similarities to abdominal migraine. Cyclic vomiting syndrome usually occurs in children, but many characteristics of this syndrome are similar irrespective of age at onset, suggesting a uniform pathogenesis.

Cyclic vomiting syndrome is an intense and prolonged activation of protective vomiting reflex. The role of peripheral receptors or peripherally released agents in the etiology of cyclic vomiting is unknown. Possible mechanisms for the induction of the cyclic vomiting syndrome are:

	• Defects in intrinsic pathways that modulate the brain stem emetic mechanisms.
	• Defects in the regulation of cellular mechanisms (eg, cAMP, ion channels) in cells at overactivation of hypothalamic-pituitary-adrenal axis and autonomic dysfunction seem to be involved.
	• Identified multiple pathways that can form a brain-gut interaction to provide a possible mechanism of cyclic vomiting.

Next generation DNA sequencing in cyclic vomiting syndrome has revealed a significant association with the stress-induced calcium channel (RYR2), which is the basis of the proposed mechanism in which RYR2 sequence variants result in aberrant calcium release into the mitochondria of autonomic neurons, resulting in an increased risk of developing this autonomic or functional disease and related conditions, such as migraine and gut dysmotility (16).

Genomics of nausea and vomiting. A genome-wide association study on motion sickness revealed 35 single-nucleotide polymorphisms associated with motion sickness at a genome-wide-significant level, and many of these single-nucleotide polymorphisms are near genes involved in balance and are involved in eye, ear, and cranial development (11).

Vomiting in motion sickness. Nausea and vomiting are well-known components of motion sickness. Anatomic and physiologic evidence show an extensive convergence of vestibular and autonomic information in the brain stem. Autonomic manifestations of vestibular dysfunction and motion sickness are well recognized. Autonomic responses to vestibular stimulation in experimental animals are regionally selective, supporting the concept of a “vestibulosympathetic reflex.” However, the role of vestibular inputs in autonomic regulation is unclear because of inadequate controls for secondary factors, such as affective-emotional responses and cardiovascular responses.

Role of the neuroendocrine system in nausea and vomiting. Three hormones (corticotropin-releasing factor, vasopressin, and progesterone) play an important role in nausea and vomiting.

Corticotropin-releasing factor. Corticotropin-releasing factor is produced in the paraventricular nuclei of the hypothalamus and controls the production and secretion of pro-opiomelanocortin by the anterior pituitary. This prohormone subsequently gives rise to adrenocorticotropic hormone, beta-endorphins, and beta-melanocyte stimulating hormone. Adrenocorticotropic hormone stimulates the adrenal glands to release cortisol and catecholamines (ie, epinephrine and norepinephrine), which inhibit the stomach and the small intestine and may produce nausea. A1-adrenergic receptor agonists such as ephedrine can produce nausea by mimicking the adrenal response of catecholamine release. Oversecretion of adrenocorticotropic hormone in response to persistent stress can produce chronic nausea and vomiting. Acute nausea activates the hypothalamo-pituitary-adrenal axis and the neurohypophyseal system. Nausea can, thus, be the cause as well as an effect of neurohypophyseal disturbances. Production and release of beta-endorphins can have the same effect as an injection of morphine or another opioid (ie, nausea and vomiting).

Vasopressin. Vasopressin is produced in the supra-optic portion of the hypothalamus and transported to the posterior pituitary; it is an important hormonal mediator of nausea and vomiting. Serum levels of vasopressin are raised in motion sickness, following stimulation of the vagal afferents and after injection of apomorphine.

Progesterone. Progesterone is 1 of the important hormones responsible for nausea and vomiting. Its major site of action is the GABAA receptor. The secretion of progesterone is determined by the hypothalamic-pituitary-gonadal axis. Gonadotropin-releasing hormone from the arcuate nucleus of the hypothalamus controls the release of the follicle-stimulating hormone and the luteinizing hormone in the anterior pituitary. This part of the reproductive cycle in women is characterized by nausea and vomiting. Luteinizing hormone is responsible for the maturation of corpus luteum, which becomes an endocrine organ and secretes 17-hydroxyprogesterone and later progesterone. Both these hormones are key factors in the occurrence of nausea and vomiting in the irritable bowel syndrome.

Dopamine agonist-induced nausea and vomiting. Ropinirole, a non-ergoline dopamine agonist, is commonly associated with nausea and vomiting in patients being treated for restless legs syndrome. Nausea and vomiting represented nearly 50% of all adverse events reported for ropinirole (15).

Chemotherapy-induced nausea and vomiting. Nausea and vomiting as an adverse reaction to chemotherapy is common and well recognized. The gastrointestinal tract and the cerebral cortex are identified as sources of afferent input to the vomiting center in chemotherapy. The chemoreceptor trigger zone, which lacks the protective blood-brain barrier, is exposed to substances in the systemic circulation in addition to those circulating in the cerebrospinal fluid of the brain. Various neurotransmitters involved in chemotherapy-induced nausea and vomiting are dopamine, acetylcholine, histamine, and serotonin. Receptors for each of these neurotransmitters are found in the vomiting center, the chemoreceptor trigger zone, and the gastrointestinal tract. Activation of these receptors by chemotherapy, metabolites, or neurotransmitters can be responsible for nausea and vomiting. Serotonin (5-HT), which is released from the chromaffin cells in the intestinal mucosa following chemotherapy, binds to 5-HT3 receptors that are found both in the peripheral vagal nerve terminals in the gastrointestinal tract and in high concentration in the area postrema of the brain where chemoreceptor trigger zone is located. 5-HT3 antagonists do not prevent release of serotonin but bind to 5-HT3 receptors and prevent chemotherapy-induced nausea and vomiting by preventing agonism of the 5-HT3 receptors by serotonin.

Substance P is 1 of the 4 mammalian tachykinins found in neurons, which innervate the brain stem nucleus tractus solitarius and area postrema in the region of the vomiting center. Substance P produces vomiting when applied to cells of tractus solitarius. The biological actions of substance P are mediated through the neurokinin 1 (NK1) receptor, a G protein receptor coupled to the inositol phosphate signal-transduction pathway. NK1 receptors are highly concentrated in the brain and bind the neurokinin substance P. Activation of NK1 receptors plays a central role in nausea and vomiting induced by emetogenic stimuli, including certain cancer chemotherapies. NK1 receptor antagonists have been demonstrated to improve the management of nausea and vomiting experienced by cancer patients undergoing chemotherapy.

Radiotherapy-induced nausea and vomiting. As many as 40% to 80% of patients undergoing radiotherapy will experience nausea or vomiting, depending on the site of irradiation, dose, radiotherapy techniques, and recent chemotherapy.

Postoperative nausea and vomiting. Some degree of nausea and vomiting occurs invariably following operations under general anesthesia. This is a multifactorial issue involving many physiological and biological mechanisms. Incidence of postoperative nausea and vomiting is 55% to 70% in patients undergoing craniotomy. Gabapentin plus dexamethasone significantly reduced the 24-hour incidence of post-operative nausea and vomiting in these patients (18).

Complications of vomiting. Although vomiting is a protective mechanism for removing harmful material from the stomach, repeated emesis may have deleterious effects:

	• Forceful vomiting may rupture the esophagus.
	• Prolonged vomiting can lead to dehydration with metabolic alkalosis and malnutrition.
	• Severe, persistent vomiting can produce neurologic disorders. For example, patients with severe vomiting following gastric banding can develop Wernicke encephalopathy, which can be treated successfully by thiamine treatment.
	• Vomiting in patients with impaired consciousness can lead to aspiration pneumonia.

Differential diagnosis

Confusing conditions

In the differential diagnosis, various causes of nausea and vomiting have been considered and are listed in Table 1. The first step is to sort out the category of causes (eg, gastrointestinal disorders, neurologic disorders, or drug-induced). The following points help in the differential diagnosis:

Temporal relation of vomiting to eating. Vomiting in the early morning is often seen in uremia, alcoholic gastritis, and hyperemesis gravidarum. Vomiting following a meal may suggest peptic ulcer or psychogenic vomiting. Vomiting that occurs several hours after eating suggests gastroparesis or pyloric obstruction.

Nature of vomiting. Projectile vomiting (ie, intensely forceful vomiting with or without nausea) usually suggests increased intracranial pressure due to central nervous system lesion. In the absence of increased intracranial pressure, symptoms may result from the direct effects of a small mass lesion in the floor of the fourth ventricle, which may irritate the chemoreceptor trigger zone.

Nature of the vomitus. Hydrochloric acid in the vomited material suggests a gastric outlet obstruction, gastric ulcer, or a hypersecretory state. Absence of hydrochloric acid is compatible with gastric malignancy. A fecal odor suggests distal intestinal obstruction with bacterial action on intestinal contents. The presence of blood suggests a bleeding from the esophagus, stomach, or the duodenum.

Drug-induced vomiting. Temporal relation with drug ingestion is the most important clue. The drugs may have a central emetic action or local irritant action on the gastric mucosa. Drug-induced vomiting should be differentiated from that associated with the primary disease, such as cancer.

Chronic idiopathic nausea. This term applies to patients with bothersome nausea occurring several times a week, and it is usually not associated with vomiting.

Cyclical vomiting. This has been reported as a presenting symptom in a prepubertal female suffering from lymphocytic hypophysitis, an autoimmune-mediated chronic inflammation of the pituitary gland, which should be considered in differential diagnosis of cyclical vomiting (14).

Associated or underlying disorders

Associated symptoms. Vertigo and tinnitus suggest Ménière disease, and relief of abdominal pain after vomiting may suggest peptic ulcer. Viral or bacterial gastroenteritis is usually accompanied by diarrhea as well. Longstanding nausea and vomiting without significant loss of weight or any other signs suggest psychogenic causes. However, significant weight loss may occur in bulimia.

Diagnostic workup

Key tests and procedures

	• Baseline laboratory investigations of blood and stools for infectious organisms
	• Pregnancy test in women
	• Further investigations, such as brain imaging, if there are neurologic signs

The initial diagnostic workup of a patient with nausea and vomiting varies according to the associated constellation of signs and symptoms. In general, the baseline laboratory investigations should include a complete blood count, liver profile, and amylase and lipase levels. If the patient has abdominal pain or diarrhea, a stool sample should be examined for leukocytes and pathogenic organisms. A pregnancy test should be done in women.

If the accompanying signs and symptoms point to a neurologic disease, further neurologic investigations and brain imaging studies should be carried out if intracranial lesions are suspected. Suspicion of meningitis, subarachnoid hemorrhage, or benign intracranial hypertension may indicate a diagnostic lumbar puncture.

Headache in children after minor head injury may be due to intrinsic factors other than increasing intracranial pressure. In 1 study on children with minor head injury that compared vomiters with nonvomiters, the only identified associated factors were history of recurrent vomiting and motion sickness, rather than a specific feature of head injury.

Nausea associated with chronic unexplained abdominal pain may require special gastrointestinal investigations starting with an x-ray of the abdomen and proceeding to ultrasonography, CT scan, barium studies, and endoscopy. If endocrine disturbances are suspected, various endocrine tests such as thyroid function tests and morning cortisol level may be ordered. A psychiatric consultation may be indicated in cases with psychogenic causes. Emetophobia is an intense, irrational fear or anxiety of or pertaining to vomiting (28).

If the above investigations do not reveal any abnormality in patients with nausea and vomiting associated with chronic unexplained abdominal pain, a referral should be made to a neurogastroenterologist. Other tests that may be carried out include an antroduodenal manometry to assess mechanical function, a hydrogen breath test to assess bacterial growth, and an electroenterography to assess the movement disorder of the stomach and the small intestine.

Management

	• Several pharmacological approaches are available for controlling nausea and vomiting according to the cause.
	• Nonpharmacological approaches, such as acupressure, biofeedback, and relaxation techniques, are also used.
	• Innovative therapies, such as bioelectric neuromodulation, are also in development.

Pharmacological approach: the management of nausea and vomiting varies according to the cause. Symptomatic treatments are shown in Table 2:

Table 2. Pharmacological Management of Nausea and Vomiting

Category: Phenothiazines
	Site of action: Mainly on D2 receptors and H1 receptors in the dorsal vagal complex Examples of drugs: Chlorpromazine, prochlorperazine, diphenylhydramine Comments: Main side effect is hypotension
Category: Anticholinergics
	Site of action: M1 receptors in the dorsal vagal complex Examples of drugs: Scopolamine Comments: Available as transdermal patch
Category: Butyrophenones
	Site of action: D2 receptors in the dorsal vagal complex Examples of drugs: Haloperidol Comments: Prevention of postoperative nausea and vomiting
Category: Substituted benzamides
	Site of action: Mainly on D1 receptors. Cisapride acts on 5-HT4 Examples of drugs: Metoclopramide, domperidone, cisapride, amisulpride Comments: Metoclopramide crosses the blood-brain barrier and is safe for use in pregnancy
Category: Serotonin antagonists
	Site of action: 5-HT3 antagonists Examples of drugs: Ondansetron granisetron, tropisetron, dolasetron, palonosetron Comments: For prevention of nausea and vomiting associated with chemotherapy and surgery
Category: Benzodiazepines
	Site of action: GABAA receptors on enteric neurons to inhibit the production of progesterone Examples of drugs: Diazepam, alprazolam, clonazepam, clorazepate, lorazepam Comments: Used for cyclical vomiting and hyperemesis gravidarum, but caution is required because the effect on developing fetus is unknown
Category: Gonadotropin-releasing hormone antagonists
	Site of action: Downregulates the hypothalamic-pituitary-gonadal axis to inhibit the production of progesterone Examples of drugs: Leuprolide acetate Comments: Induces menopause in women and impotence in men
Category: Human substance P/neurokinin 1 (NK1) receptors antagonist
	Site of action: Selective high-affinity antagonist of human substance P/NK1 receptor and acts by blocking responses in the brain that are triggered by chemotherapy. It has no affinity for 5-HT3, dopamine, and corticosteroid receptors. Examples of drugs: Aprepitant Comments: Used for preventing chemotherapy-induced nausea and vomiting in combination with standard antiemetic therapy (a 5-HT3 receptor antagonist plus a corticosteroid)

Management of nausea and vomiting in the emergency department. Antiemetic agents are among the most frequently used medications in the emergency department. Ondansetron is recommended as a first-line agent for relief of nausea or vomiting for most patients in this setting (23). Ondansetron use in children with a head injury who are discharged to home after CT scan is relatively safe, does not appear to mask any significant conditions, and reduces return visits to the emergency department (29).

Management of postoperative nausea and vomiting. Several antiemetic interventions have been used for preventing or relieving postoperative nausea and vomiting, eg, ondansetron, dexamethasone, droperidol, and propofol. A meta-analysis of controlled clinical trials indicates that a preoperative intravenous dose of ondansetron 4 mg in adults is required to prevent nausea and vomiting during the first postoperative 24 hours following craniotomy (05). Another meta-analysis of clinical trials has shown that dexmedetomidine, a selective alfa 2-adrenoceptor agonist administrated by continuous infusion, prevents postoperative nausea and vomiting in addition to reduction of side effects such as bradycardia and hypotension (13). A systematic review of several studies provides moderate-certainty evidence that supplemental perioperative intravenous crystalloid administration reduces postoperative nausea and vomiting in patients receiving general anesthesia for ambulatory surgical procedures (12).

Droperidol has been used for several years to prevent or treat postoperative nausea and vomiting. Significant restrictions have been placed on its administration because of reports of sudden cardiac death in patients receiving this drug. Haloperidol is a safe substitute for droperidol in the prevention and treatment of postoperative nausea and vomiting. Serotonin receptor antagonists are the preferred antiemetic drugs for prophylaxis of postoperative vomiting in children. Serotonin receptor antagonists reduce incidence of vomiting in postoperative neurosurgical patients but do not affect nausea. Further investigations continue to find more effective agents for control of nausea. Positive results of initial studies showing reduction of the risk for postoperative nausea and vomiting by inhalation of 80% oxygen were not confirmed by any of the subsequent trials, and this method is not recommended.

The incidence of postoperative nausea and vomiting is 50% to 80% after neurosurgery. According to the results of a retrospective case-control study, acoustic neuroma surgery and microvascular decompression of cranial nerves increase the risk of postoperative nausea and vomiting compared with craniotomies performed for other tumors (30). A prospective, double-blind, randomized study found that the combination of aprepitant and dexamethasone was more effective than the combination of ondansetron and dexamethasone for the prevention of postoperative nausea and vomiting in patients undergoing craniotomy (08). The common prophylactic treatment for postoperative nausea and vomiting is a triple therapy of droperidol, promethazine, and dexamethasone. More effective methods of prophylaxis are being investigated. A prospective, double-blind, single-center study is comparing the efficacy of ondansetron, a NK1 antagonist, and aprepitant, as a substitute for droperidol, in the prophylaxis of postoperative nausea and vomiting after neurosurgery (02).

A multifaceted approach to the management of postoperative nausea and vomiting includes promotion of an evidence-based guideline, and provision of individualized prescribing and patient outcome data to anesthetists (24). Prior to this intervention, 9% of moderate- and high-risk patients received antiemetic prophylaxis consistent with the guideline. Postintervention, the rate of guideline adherence was 19.3% and in the high-risk postoperative nausea and vomiting group, the time in postanesthesia care units was significantly reduced. However, further efforts would be required to ensure fuller compliance with the current extensive evidence base for management of higher-risk patients.

Pharmacological agents, such as the second-generation 5-hydroxytryptamine 3 receptor antagonists, a dopamine antagonist, and neurokinin 1 receptor antagonists as well as several novel combination therapies are recommended in the fourth consensus guidelines for the management of postoperative nausea and vomiting (06).

Management of radiation-induced nausea and vomiting. Granisetron, a potent and highly selective 5-HT3 receptor antagonist, has been shown to be effective in reducing radiation-induced nausea and vomiting in clinical trials. Other serotonin receptor antagonists for radiation-induced vomiting include ondansetron, dolasetron, palonosetron, and tropisetron. These drugs may be useful in both the radiotherapy patient as well as persons who are accidentally exposed to ionizing radiation. A systematic review of controlled clinical trials has shown that 5-hydroxytryptamine-3 receptor antagonists are superior to placebo and other antiemetics for prevention of emesis, but little benefit was identified for nausea prevention (27).

Management of opioid-induced nausea and vomiting. Approximately 40% of patients experience nausea and 15% to 25% of patients may suffer from vomiting after opioid administration. Nausea often precedes vomiting, although they can occur separately. Several medications can be used to treat opioid-induced nausea and vomiting including serotonin receptor antagonists, dopamine receptor antagonists, and neurokinin 1 receptor antagonists (17).

Management of chemotherapy-induced nausea and vomiting. The 5 main forms of chemotherapy-induced nausea and vomiting (ie, acute, delayed, anticipatory, breakthrough, and refractory) require different treatment regimens, which often include 5-HT3 receptor antagonists, neurokinin 1 receptor antagonists, and corticosteroids (07). Selective 5-HT3 antagonists, neurokinin 1 antagonists, and corticosteroids are the most effective therapeutic agents for chemotherapy-induced nausea and vomiting. A systematic review has shown that there is no significant difference between a short or long course of dexamethasone for preventing nausea or vomiting, but a short course was associated with fewer adverse effects (25).

Considerable progress has been made in the prophylaxis of chemotherapy-induced nausea and vomiting with the introduction of NK1 inhibitors. Dolasetron, granisetron, palonosetron, ondansetron, and tropisetron are agents with a high therapeutic index. Delayed nausea and vomiting after chemotherapy are best prevented by a combination of ondansetron with dexamethasone if given within the first 24 hours after start of chemotherapy. Another method is a single dose of 0.25 mg of palonosetron hydrochloride, a next generation 5-HT3 antagonist, by intravenous injection approximately 30 minutes before the start of chemotherapy. Further clinical studies of palonosetron have shown prolonged half-life and high receptor affinity, making it an effective antiemetic agent against chemotherapy-induced nausea and vomiting. Oral formulation of palonosetron is also available. A pilot study has shown the efficacy of gabapentin for controlling chemotherapy-induced nausea and vomiting (04). Rolapitant, a potent and orally active neurokinin NK1 receptor antagonist, is approved by the U.S. Food and Drug Administration for prevention of delayed chemotherapy-induced nausea and vomiting in adults. Data from randomized clinical trials support the use of an olanzapine for the treatment of breakthrough chemotherapy-induced nausea and vomiting (10). In a randomized, double-blind, placebo-controlled phase 3 trial, olanzapine significantly improved nausea prevention as well as the complete-response rate among previously untreated patients who were receiving highly emetogenic chemotherapy (22). Cannabidiol, a nonpsychotropic cannabinoid, reduces nausea and vomiting during chemotherapy (19).

Multiple approaches with varying degree of efficacy for management of nausea and vomiting are available. The most effective approach is administration of a 5-HT3-receptor antagonist, which reduces or prevents emesis in 50% of patients, and it increases to 70% when the agent is given in combination with dexamethasone with further increase to approximately 84% when an NK1-receptor antagonist is added (20).

Management of cyclic vomiting syndrome. Ondansetron or prochlorperazine can be used to control nausea and vomiting. Antimigraine therapies, including the 5-HT1D receptor agonist sumatriptan, reduce the severity of cyclic vomiting attacks. Combination therapy with valproate sodium and phenobarbital may be useful in management of vomiting in patients with intractable cyclic vomiting syndrome. Amitriptyline is also used for the management of cyclic vomiting syndrome. A randomized clinical trial showed that amitriptyline is a better choice for reducing the severity of cyclic vomiting attacks compared to topiramate in a short-term evaluation, but studies with a longer follow-up are required to confirm this (01).

Nonpharmacological approaches. These approaches consist of dietary modifications, acupuncture, and biofeedback techniques. Acupuncture can control unexplained nausea in some patients. Biofeedback, relaxation techniques, and meditation probably work via limbic mechanisms to control unexplained chronic nausea. Foods with tyramine can induce nausea in susceptible patients, and the withdrawal of foods such as cheese can improve nausea.

Acupressure has been recommended as an effective, nonpharmacologic adjuvant intervention for chemotherapy-induced nausea and vomiting. Acupuncture seems to be effective in preventing nausea and vomiting in pediatric cancer patients receiving chemotherapy. Electroacupuncture combined with granisetron can relieve the nausea in chemotherapy patients at a delayed stage (33). Hypnosis could be a clinically valuable intervention for anticipatory and chemotherapy-induced nausea and vomiting in children with cancer.

Novel approaches to the management of nausea and vomiting. Some of the novel pharmacological approaches to the treatment of nausea and vomiting include the following:

	• Tricyclic antidepressant drugs have shown efficacy in long-term treatment of functional nausea.
	• Gastric 5-HT4 and motilin receptors, which accelerate gastric emptying and relieve vomiting due to gastroparesis.
	• Gastric electrical pacing (patients with refractory gastroparesis may benefit especially).
	• 5-HT1A receptor agonists protect against a broad spectrum of emetic challenges and presumably act on central emetic mechanisms. They are used for combating nausea and vomiting associated with cyclic vomiting syndrome.
	• A double-blind, placebo-controlled, randomized clinical trial conducted on outpatients with advanced cancer who had persistent nausea/vomiting without having had chemotherapy or radiotherapy in the prior 14 days showed that olanzapine was effective in controlling nausea and emesis and in improving other symptoms and quality-of-life parameters in the study population (21).
	• A systematic review of controlled clinical trials shows that low-dose, intravenous amisulpride, an atypical antipsychotic and antiemetic, is safe and effective for the prevention and treatment of postoperative nausea and vomiting compared to placebo, but further studies are needed to explore the optimal dose and timing (32).
	• Traditional management of nausea and vomiting may be inadequate in some patients. Moreover, safety concerns and controversies with established pharmaceuticals have led to newer immunotherapies, bioelectrical neuromodulation (including gastric electrical stimulation), and surgical therapies (09).

Concluding remarks on management of nausea. Review of literature on nausea due to different disorders indicates that the mechanism appears to be similar, and the use of antiemetics can be individualized, depending on patient-reported efficacy and adverse effects as well as preferences (31).

Devices for the management of chronic nausea and vomiting. The Food and Drug Administration has approved an abdominal implant for the treatment of chronic drug refractory nausea and vomiting secondary to gastroparesis of diabetic or idiopathic etiology. The implant's mechanism of action is like that of a cardiac pacemaker.

Outcomes

The prognosis of nausea and vomiting depends on the etiology. Nausea and vomiting due to chemotherapy, for example, disappears after cessation of therapy. The prognosis of neurologic disorders depends on the associated disease. For example, in long-term follow-up of patients with chronic cyclic vomiting, about half become asymptomatic, and those who remain symptomatic show an association with migraine.

Complications of uncontrolled chronic nausea and vomiting include electrolyte imbalance and malnutrition.