Nausea: The unpleasant sensation of the imminent need to vomit, usually referred to the throat or epigastrium; a sensation that may or may not ultimately lead to the act of vomiting.

Retching: Spasmodic respiratory movements against a closed glottis with contractions of the abdominal musculature without expulsion of any gastric contents, referred to as ‘dry heaves’.

Vomiting: Forceful oral expulsion of gastric contents associated with contraction of the abdominal and chest wall musculature.

Regurgitation: The act by which food is brought back into the mouth without the abdominal and diaphragmatic muscular activity that characterises vomiting.

Rumination: Chewing and swallowing of regurgitated food that has come back into the mouth through an unconscious voluntary increase in abdominal pressure within minutes of eating or during eating.

Anorexia: Loss of desire to eat, that is, a true loss of appetite.

Sitophobia: Fear of eating because of subsequent or associated discomfort.

Early satiety: The feeling of being full after eating an unusually small quantity of food.

Adapted from Quigley EM, Hasler WL, Parkman HP. AGA technical review on nausea and vomiting. Gastroenterology 2001; 120:263–86.

PATHOGENESIS

Emetic stimuli are recognised in the vomiting centre in the dorsal medulla, which is linked to other centres controlling respiration and salivation. This area is innervated by vagal and sympathetic afferents from the gastrointestinal tract, the pharynx, vestibular system, heart, peritoneum and higher central nervous system centres such as the thalamus, hypothalamus and cerebral cortex. A second area in the brain, the area postrema, is home to the chemoreceptor trigger zone (CTZ). The blood–brain barrier is essentially absent in this location, permitting substances in the circulation to stimulate the CTZ, which in turn induces vomiting, probably via the vomiting centre.

Neurotransmission in the vomiting centre and CTZ appears to be mediated via dopaminergic, serotonergic, muscarinic and histaminergic receptors, and pharmacological therapies have been developed targeting each of these (see later).

CLINICAL CONSIDERATIONS

The differential diagnosis of nausea and/or vomiting is extensive and is presented in Table 5.2. The major causes include infection, medications (particularly chemotherapeutic agents) and toxins, central nervous system pathology, organic gastrointestinal disorders, endocrine and metabolic disorders including pregnancy, systemic illnesses, psychiatric disease, postoperatively and functional gastrointestinal disorders including the cyclical vomiting syndrome.

TABLE 5.2 Causes of nausea and/or vomiting

• Antibiotics/antivirals

– Erythromycin

– Tetracycline

– Sulfonamides

– Antituberculous drugs

– Aciclovir

• Gastrointestinal medications

– Sulfasalazine

– Azathioprine

• Central nervous system (CNS) active

– Nicotine

– Narcotics

– Antiparkinsonian drugs

Disorders of the gut and peritoneum

• Functional gastrointestinal disorders

– Functional nausea and vomiting disorders

– Cyclic vomiting syndrome

– Irritable bowel syndrome

• Mechanical obstruction

– Gastric outlet obstruction

– Small bowel obstruction

– Gastroparesis

– Chronic intestinal pseudo-obstruction

Endocrine and metabolic causes

• Pregnancy

• Other endocrine and metabolic

– Uraemia

– Diabetic ketoacidosis

– Hyperparathyroidism

– Hypoparathyroidism

– Hyperthyroidism

– Addison’s disease

– Acute intermittent porphyria

Infectious causes

• Gastroenteritis

– Viral e.g. Norwalk, rotavirus, adenoviruses

– Bacterial e.g. Staphylococcus aureus, Salmonella, Bacillus cereus, Clostridium perfringens

• Non-gastrointestinal infections

– Otitis media

– Urinary tract infection

– Jamaican vomiting sickness

CNS causes

• Migraine

• Increased intracranial pressure

– Congenital malformation

– Hydrocephalus

– Pseudotumour cerebri

• Labyrinthine disorders

– Fluorescein angiography

• Seizure disorders

• Demyelinating disorders

• Emotional responses

Psychiatric disease

• Functional vomiting

Miscellaneous causes

• Postoperative nausea and vomiting

• Radiation therapy

• Cardiac disease

– Myocardial infarction

– Congestive heart failure

– Radiofrequency ablation

• Hypervitaminosis

Adapted from Quigley EM, Hasler WL, Parkman HP. AGA technical review on nausea and vomiting. Gastroenterology 2001; 120:263–86.

Important aspects in the history that may assist in identifying the cause include:

• Associated symptoms

– Alarm symptoms such as weight loss, fevers or family history of cancer: suggest malignancy must be excluded

– Abdominal pain: usually suggests an organic process such as obstruction. Subacute bowel obstruction, which can be missed on barium studies, may be secondary to adhesions from previous abdominal surgery

– Neurological symptoms, e.g. neck stiffness, focal neurological deficit

– Menstruation: pregnancy must always be considered in the differential.

Physical examination should be directed by the history obtained, however, abdominal examination is essential and should include assessing for tenderness with some emphasis on localisation, presence or absence of bowel sounds and a succussion splash, evidence of previous abdominal surgery, hernias and masses. Subsequently several additional areas may need review including, but not limited to, assessment for lymphadenopathy, central or peripheral neurological deficits, evidence of connective tissue disease or thyroid dysfunction, and review of fingernails and tooth enamel for signs of acid damage from recurrent vomiting.

Investigations

The choice of investigations will depend predominantly on the conclusions drawn from the history and physical examination.

Assessment of the consequences of vomiting must be performed, in particular looking for evidence of dehydration, electrolyte disturbances and the presence of a hypokalaemic metabolic alkalosis. Initial evaluation should include a full blood count, electrolytes and liver function tests, pH, an erythrocyte sedimentation rate or C-reactive protein and β-hCG in females of child-bearing age. More specific screening, such as thyroid function tests, should be performed as considered appropriate.

Further diagnostic evaluation may include erect and supine abdominal X-rays if the history suggests intestinal obstruction and an abdominal ultrasound if hepatobiliary, pancreatic or gall bladder pathology is suspected. Gastroscopy may also be considered if a mucosal lesion such as peptic ulcer disease or reflux oesophagitis is suspected, and is more sensitive and specific than radiographic studies. Visualisation of the small intestine is commonly obtained with a small bowel follow-through (SBFT) examination. Some centres advocate enteroclysis (or small intestine enema), which is more sensitive but may require the use of sedation as the technique requires placement of a nasoduodenal or oroduodenal tube. Computed tomography (CT) enterography is preferable with oral and intravenous contrast when intestinal obstruction is suspected and provides additional information about the pancreas and hepatobiliary system and can also identify the presence of abdominal masses or retroperitoneal pathology.

The commonest causes of gastroparesis are idiopathic (possibly post-viral) and diabetes mellitus. Systemic diseases such as scleroderma, systemic lupus erythematosus, polymyositis, dermatomyositis and amyloidosis may also cause gastroparesis, which is also seen after vagotomy and in association with pancreatic adenocarcinoma. Gastroparesis results in abnormal gastric emptying, however this also may be seen in up to 40% of patients with functional gastroduodenal disorders (Table 5.3).

TABLE 5.3 Functional nausea and vomiting disorders

Diagnostic criteria^*for chronic idiopathic nausea

Must include all of the following:

1. Bothersome nausea, occurring at least several times per week

2. Not usually associated with vomiting

3. Absence of abnormalities at upper endoscopy or metabolic disease that explains the nausea

Diagnostic criteria^*for functional vomiting Must include all of the following:

1. On average, one or more episodes of vomiting per week

2. Absence of criteria for an eating disorder, rumination or major psychiatric disease according to DSM-IV

3. Absence of self-induced vomiting and chronic cannabinoid use and absence of abnormalities in the central nervous system or metabolic diseases to explain the recurrent vomiting

Diagnostic criteria^*for cyclic vomiting syndrome Must include all of the following:

1. Stereotypical episodes of vomiting regarding onset (acute) and duration (less than 1 week)

2. Three or more discrete episodes in the prior year

3. Absence of nausea and vomiting between episodes

Supportive criterion History or family history of migraine headaches

* Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.

Abnormal gastric emptying may be assessed using a radionuclide gastric emptying study in which serial images of the retention or disappearance of a radiolabelled meal from the stomach are captured by a γ-camera. Solid meals are more sensitive for detecting gastroparesis compared with liquid meals. Delayed gastric emptying is considered present if the gastric retention at 4 hours is greater than 40% of the radiolabelled meal (sensitivity 100%, specificity 70%).

Antroduodenal manometry, which can differentiate between neuropathy (abnormal contractile response with normal amplitude contractions) or myopathy (low amplitude contractions), is available in some specialised centres. It may also detect missed bowel obstruction.

Electrogastrography (EGG) measures the electrical activity of the stomach with surface electrodes in both the fasting and the postprandial states. The normal pacemaker rhythm of gastric myoelectrical activity is three cycles per minute. A reduction in or absence of the expected postprandial increase in the EGG amplitude correlates with delayed gastric emptying and antral hypomotility. Unfortunately, gastric dysrhythmias (both bradygastria and tachygastria) have been observed in the absence of altered gastric emptying, limiting its application to clinical practice.

Although uncommon in the absence of localising signs, intracranial lesions should be considered in those with severe, unexplained nausea and vomiting. Magnetic resonance imaging (MRI) is the investigation of choice to permit optimal imaging of the posterior fossa.

Assessment for an eating disorder (e.g. bulimia) or psychiatric illness (e.g. major depression) should be undertaken if organic causes prove elusive or when other factors indicate this may be the underlying cause.

Functional vomiting

Once common organic and psychiatric causes for chronic nausea and vomiting have been excluded, functional nausea and vomiting disorders need to be considered as a possible diagnosis. These are summarised in Table 5.3. The essential difference between functional and cyclic vomiting disorders is the pattern and frequency of vomiting; functional vomiting occurs at least weekly (on average), whereas cyclic vomiting syndrome (CVS) consists of stereotypical episodes of vomiting regarding onset (acute) and duration (less than 1 week), with the additional requirement for three or more discrete episodes in the prior year and the absence of nausea and vomiting between episodes. CVS is commonly associated with irritable bowel syndrome, motion sickness and, less frequently, migraine; family histories of these conditions are present in approximately 50% of patients.

MANAGEMENT

Initial management should include appropriate replacement of fluids either orally or intravenously as tolerated, with correction of any electrolyte (e.g. potassium, bicarbonate) or nutritional deficiencies that may have resulted from vomiting itself or the food aversion that may accompany these symptoms (Figure 5.1). Symptomatic management of the nausea and/or vomiting may be required while the underlying cause of the symptoms is identified and eliminated where possible. Placement of a nasogastric tube may also be required to relieve gastric distension if gastrointestinal obstruction is the cause.

AXR = abdominal X-ray; CNS = central nervous system; CT = computed tomography; CTx = chemotherapy; EEG = electroencephalogram; EGD = endoscopic gastroduodenoscopy; EGG = electrogastrography; FT₄ = free thyroxine; GI = gastrointestinal; GORD = gastrooesophageal reflux disease; ICP = intracranial pressure; K = potassium; LP = lumbar puncture; MRI = magnetic resonance imaging; MS = multiple sclerosis; NA = sodium; PPI = proton pump inhibitor; PTH = parathyroid hormone; PUD = peptic ulcer disease; RTx = radiotherapy; SBS = small bowel series.

Adapted from Quigley EM, Hasler WL, Parkman HP. AGA technical review on nausea and vomiting. Gastroenterology 2001; 120:263–86.

Pharmacological

A variety of agents display antiemetic properties including serotonin (5-HT) antagonists, anticholinergics, H₁-receptor antagonists, phenothiazines, butyrophenones, benzamides, which also have prokinetic effects, neurokinin-1 antagonists, cannabinoids, and adjunctive agents such as benzodiazepines and corticosteroids. Examples of these agents are given in Table 5.4, which also outlines their common uses.

TABLE 5.4 Pharmacological agents effective in treating organic nausea and vomiting

Agent	Use	Formulation
Phenothiazines e.g. promethazine, prochlorperazine	PONV, PCNV	Oral, PR, IV
	Severe nausea and vomiting
	Vertigo, motion sickness, migraine
5-HT₃ antagonists e.g. ondansetron, tropisetron	PONV, PCNV	Oral, wafers, IV
Prokinetics e.g. metoclopramide, domperidone	Gastroparesis PONV, PCNV	Oral, IV (not domperidone)
Butyrophenones e.g. droperidol, haloperidol	Anticipatory and acute chemotherapy related nausea and vomiting PONV	Oral, IM, IV
Benzodiazepines e.g. lorazepam	Adjunctive in treatment of chemotherapy related nausea and vomiting	Oral, S/L, IV
Neurokinin-1 antagonists	Acute and delayed PCNV, adjunct in combination with 5-HT₃ antagonist and dexamethasone	Oral
Corticosteroids e.g. dexamethasone	Adjunctive in treatment of chemotherapy related nausea and vomiting	Oral, IV

5-HT = 5-hydroxytryptamine or serotonin; IM = intramuscular; IV = intravenous; PCNV = post-chemotherapy nausea and vomiting; PONV = post-operative nausea and vomiting; PR = per rectum; S/L = sublingual.