Approach to the adult patient with nausea and vomiting

George F Longstreth, MD

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INTRODUCTION — Nausea, the unpleasant sensation of being about to vomit, can occur alone or can accompany vomiting (the forceful expulsion of gastric contents), dyspepsia, or other gastrointestinal symptoms. Retching differs from vomiting in the absence of expulsion of gastric content. In addition, patients may confuse vomiting with regurgitation, which is the return of esophageal contents to the hypopharynx with little effort [1]. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults").
The pathophysiology of nausea and vomiting and the overall approach to the patient with these symptoms will be reviewed here. Nausea usually lasts longer than vomiting and may therefore be more distressing; in some cases, vomiting partially relieves nausea. This topic is also discussed in an official guideline issued by the American Gastroenterological Association. (See "AGA guideline: Nausea and vomiting").
PATHOPHYSIOLOGY — Normal function of the upper gastrointestinal tract involves an interaction between the gut and the central nervous system. The motor function of the gut is controlled at three main levels: the parasympathetic and sympathetic nervous systems; enteric brain neurons; and smooth muscle cells (show figure 1). (See "Pathogenesis of delayed gastric emptying" for a discussion of the anatomy and physiology of gastric motor function).
Nausea — Studies that produce motion sickness in humans indicate how some of the physiologic interactions can cause nausea [2,3]. In one report, for example, gastric myoelectrical activity and endogenous neuroendocrine responses were compared in subjects with and without motion sickness elicited by vection (induced by rotating a drum with black and white vertical stripes around seated stationary subjects) [2]. Thirteen subjects developed tachygastria (an increase in gastric slow wave rhythm) and motion sickness during vection, while nine maintained normal gastric rhythms and remained symptom-free. Nausea followed within minutes of and was proportional to the degree of tachygastria. Anticipatory increases in plasma cortisol and beta endorphin occurred in subjects who developed nausea and gastric tachyarrhythmias; endogenous epinephrine and norepinephrine concentrations were also increased in these subjects.
Vomiting — Vomiting is a reflex that allows an animal to rid itself of ingested toxins or poisons. It can be activated by humoral or neuronal stimuli, or both [4]. Multiple afferent and efferent pathways exist which induce vomiting; the following are the major components of these pathways: The area postrema in the floor of the fourth ventricle which contains a "chemoreceptor trigger zone" that is sensitive to many humoral factors, including neurotransmitters, peptides, drugs, and toxins. An area in the medulla known as the nucleus tractus solitarius (NTS) which may serve as a central pattern generator for vomiting; information from humoral factors via the area postrema and visceral afferents via the vagus nerve may converge at this site [4]. The central pattern generator presumably projects to the various motor nuclei to elicit the sequential excitation and inhibition that controls the vomiting reflex.
Vagal afferent nerves from the gastrointestinal tract synapse in the NTS. From there, some neurons extend to the area postrema; other neurons from the NTS ascend to the paraventricular nuclei of the hypothalamus and the limbic and cortical regions, where gastric electromechanical events are perceived as normal sensations or symptoms such as nausea or discomfort. Afferent sympathetic neurons mediating nociceptive stimuli synapse in the spinal cord and ascend to brain stem nuclei and the hypothalamus, where vasopressin (antidiuretic hormone) and corticotropin releasing factor can be released (show figure 2).
Studies of vomiting in dogs reveal that gastric content is expelled as a result of gastric and lower esophageal sphincter relaxation, retrograde contraction in the proximal small bowel and antrum, abdominal muscle contraction, and initial cricopharyngeus contraction followed by relaxation seconds before vomiting [5]. Retching occurs when the glottis closes and respiratory muscles counteract abdominal muscle contraction to prevent the expulsion of gastric content.
APPROACH TO MANAGEMENT — As a general rule, the following three steps should be considered [1]. The consequences or complications of nausea and vomiting (eg, fluid depletion, hypokalemia and metabolic alkalosis) should be identified and corrected. The etiology should be sought Targeted therapy should be provided, when possible (eg, surgery for bowel obstruction or malignancy). In other cases, symptoms should be treated.
Differential diagnosis — A variety of disorders can produce nausea with or without vomiting (show table 1A-1B). Gastroesophageal reflux disease can also cause chronic nausea [6].
The diverse differential diagnosis of nausea and vomiting should be approached initially with a careful history and physical examination. Laboratory evaluation and other testing should be guided by the symptom duration, frequency and severity, as well as the characteristics of vomiting episodes and associated symptoms. The following features can be helpful in diagnosis: Abdominal pain with vomiting usually indicates an organic etiology (eg, cholelithiasis). Abdominal distension and tenderness suggest bowel obstruction. Vomiting of food eaten several hours earlier and a succussion splash detected on abdominal examination suggest gastric obstruction or gastroparesis. Early morning vomiting is characteristic of pregnancy. Feculent vomiting suggests intestinal obstruction or a gastrocolic fistula. Vertigo and nystagmus are typical of vestibular neuritis. Bulimia is associated with dental enamel erosion, parotid gland enlargement, lanugo-like hair, and calluses on the dorsal surface of the hand [7]. Neurogenic vomiting may be positional, projectile, and is usually associated with other neurologic signs or symptoms. (See "Clinical presentation and diagnosis of brain tumors").
Most patients with acute nausea and vomiting can be diagnosed from the history, physical examination and directed laboratory/radiological testing. As in patients evaluated for chronic dyspepsia, which often overlaps with nausea and vomiting, most patients with chronic nausea and vomiting that is unexplained after routine evaluation should undergo esophagogastroduodenoscopy to identify disorders that should have specific therapy.
However, endoscopy and other routine tests are often normal, suggesting an idiopathic (functional) etiology. (See "Functional dyspepsia"). Gastric motor dysfunction can be identified by special tests (such as gastric scintigraphy) in a large proportion of these patients, although the relationship to symptoms is not always clear. A non-invasive method of recording gastric myoelectrical activity or slow waves from cutaneous leads placed over the stomach (electrogastrography) reveals abnormalities in some patients. There is no evidence that correction of these abnormalities improves symptoms; thus, the role of this procedure in management is uncertain [8]. (See "Etiology and diagnosis of delayed gastric emptying").
Therapy — Few high-quality therapeutic trials have compared the efficacy of different drugs in specified types of nausea and vomiting. However, acute or chronic nausea and vomiting can often be helped by antiemetic or prokinetic drugs [9]. The recommended antiemetic drug varies according to the etiology (show table 2). Side effects also vary by antiemetic class.
Prokinetic drugs can also be useful [1]. The dopamine antagonist, metoclopramide, has combined antiemetic and prokinetic properties. However, it can be associated with extrapyramidal side-effects. Another dopamine antagonist, domperidone, penetrates the blood-brain barrier poorly; hence, anxiety and dystonia are much less common than with metoclopramide. However, domperidone is not approved for use in the United States. Agents with mainly prokinetic properties include erythromycin (motilin receptor agonist) and bethanechol (muscarinic receptor agonist).
Erythromycin has a narrow therapeutic window, above which abdominal pain and nausea are common. Thus, it can improve gastric emptying without improving nausea. A systematic review of published clinical trials of erythromycin therapy for various types of gastroparesis revealed that all studies were methodologically weak and that symptom improvement occurred in fewer than 50 percent of patients [10]. The side effects of bethanechol are similar to those of erythromycin, and trial data are even more limited. Thus, the role of prokinetic drugs for patients with gastroparesis is undefined.
Surgical therapy (gastrostomy, jejunostomy, and gastrectomy) has been performed in patients with postsurgical, diabetic, and idiopathic gastroparesis, but the reports were uncontrolled, unblinded, and retrospective, and benefit was unconvincing, except possibly for completion gastrectomy in patients with postsurgical gastroparesis [10].
Gastric electrical stimulation via implanted electrodes has been applied to highly selected patients with gastroparesis that is refractory to conventional therapy. (See "Electrical stimulation for gastroparesis").
SPECIFIC DISORDERS
Acute Disorders
Acute gastroenteritis — Acute gastroenteritis is a common cause of acute care seeking and is second only to the common cold as a cause of lost work time [11]. Bacterial, viral, and parasitic pathogens cause this illness which is characterized by diarrhea and/or vomiting. Vomiting is especially common with infections caused by rotaviruses, enteric adenovirus, and Norwalk agent (See "Epidemiology of viral gastroenteritis in adults").
Laboratory testing usually is unnecessary in adults with domestically acquired illness. One study, for example, evaluated 163 patients, 57 percent of whom had vomiting and diarrhea [12]. There was no association between abnormal laboratory results and the requirement for intravenous hydration, antibiotic treatment with the stool culture being positive, or hospitalization. Stool cultures had higher yields in patients with fever or diarrhea of more than two days' duration.
Postoperative nausea and vomiting — About one third of surgical patients have nausea, vomiting or both after receiving general anesthesia. Risk factors include female sex, nonsmoker status, previous history of postoperative nausea and vomiting or motion sickness, and unanticipated use of postoperative opioids. Most research has been directed toward prevention rather than therapy of established symptoms [13]. In a large trial, intravenous doses of1.25 mg of droperidol and 4 mg of dexamethasone within 20 minutes after the start of anesthesia or 4 mg of ondansetron during the last 20 minutes of surgery each reduced postoperative nausea and vomiting by about 26 percent [13]. Combining drugs had an additive effect, and the combination of the inexpensive drugs, droperidol and dexamethasone, was more beneficial than the expensive drug, ondansetron.
Vestibular neuritis — This acute labyrinthine disorder is the second most common cause of peripheral vertigo, and nausea is a common symptom. The assumed cause is reactivation of herpes simplex virus type 1 infection. A placebo-controlled clinical trial found that methylprednisolone was more effective than placebo or valacyclovir; the combination of the methylprednisolone and valacyclovir was not superior to the drug methylprednisolone alone [14]. The 22-day therapy comprised methylprednisolone in a daily dose of 100 mg for three days, followed by three days each of 80 mg, 60 mg, 40 mg, 20 mg, and 10 mg and, finally, 10 mg every other day for two doses.
Patients receiving chemotherapy — Nausea and vomiting are common side effects of cancer chemotherapy, and anticipatory antiemetic therapy is indicated when highly emetogenic chemotherapy regimens are given. A multidisciplinary approach at the Memorial Sloan-Kettering Cancer Center has classified the emetogenic potential of chemotherapy programs into five categories and has identified effective oral antiemetic therapy (show table 3) [15]. The use of specified antiemetic guidelines for each category has resulted in the treatment of more patients at lower overall cost. The recommended prophylactic regimen for the most emetogenic chemotherapy consists of an oral 5-HT3 receptor antagonist plus dexamethasone (20 mg PO). (See "Prevention and treatment of chemotherapy-induced nausea and vomiting").
Drugs — Multiple drugs are associated with nausea and thus a careful medication history is mandatory. The history should include non-prescription drugs. Use of marijuana has been associated with recurrent vomiting with features similar to cyclic vomiting syndrome. Compulsive bathing behavior may be a clue to identifying cannabinoid hyperemesis. (See "Cyclic vomiting syndrome").
Chronic disorders
Nausea and vomiting of pregnancy — About 70 to 85 percent of pregnant women suffer nausea and/or vomiting; 50 percent have both nausea and vomiting, and 25 percent have nausea only. Risk factors include increased placental mass (eg, advanced molar gestation, multiple gestation), family history of hyperemesis gravidarum or a personal history of the disorder in a previous pregnancy, female fetus, and a history of motion sickness or migraine headaches.
This disorder nearly always begins within the first nine weeks of pregnancy; onset after the initial nine weeks should direct especially careful evaluation for another cause within the differential diagnosis of nausea and vomiting in nonpregnant patients. The diagnosis of hyperemesis gravidarum is applied to the most severely affected patients, approximately 0.5 to 2 percent of pregnancies. (See "Hyperemesis gravidarum").
Functional vomiting — A subset of patients with functional gastroduodenal disorders has nausea. (See "Functional dyspepsia").
Gastroparesis — Nausea may be a feature of gastroparesis but there is a poor correlation among symptoms, gastric dysrhythmias and gastric emptying rate. (See "AGA technical review: Evaluation of dyspepsia" and see "Treatment of delayed gastric emptying").
Gastroesophageal reflux — Nausea can occasionally be the presenting symptom of gastroesophageal reflux disease.
Gastric outlet obstruction — Pyloric stenosis can occur from malignancy or peptic ulcer disease. Inflammatory edema associated with ulcers may respond to acid suppression therapy and nasogastric suction. However, fibrotic strictures may persist after ulcer healing. Treatment of benign fibrotic strictures can be accomplished surgically or endoscopically. The endoscopic approach is the least invasive, however there is a risk of perforation and recurrence is common after long-term follow-up. Because of the risk of perforation and high long-term recurrence rate, endoscopic dilation may be most appropriate for patients at high risk for surgery. (See "Complications of peptic ulcer disease").
Eosinophilic gastroenteritis — Benign eosinophilic infiltration of the gut is uncommon, but its diagnosis is especially important as steroid therapy is usually effective (See "Eosinophilic gastroenteritis"). The disease can occur from the esophagus to the colon, and the symptoms dependent upon the area and tissue layer of bowel involved [16,17]. Gastric mucosal disease is typically associated with nausea and vomiting. This disorder should be suspected in patients with a history of allergy or peripheral eosinophilia; however, these features may be absent in 50 and 33 percent of cases, respectively [17]. Endoscopic biopsy is needed for diagnosis.
Cyclic vomiting syndrome — Cyclic vomiting syndrome is characterized by repeated episodes of nausea and vomiting that last for hours to days and are separated by symptom-free periods of variable length. It has been most often described in children, in whom symptoms often begin in the early school years and stop spontaneously at puberty [18,19]. In adults, the disorder consists of episodes of nausea and vomiting lasting for three to six days in a patient-specific stereotypic pattern [20,21]. In one report, the average cycle length was approximately three months [19]. The etiology is unknown, although many hypotheses have been proposed. Treatment has been largely supportive. In a series of 17 adult patients, tricyclic antidepressants therapy was associated with a complete remission or a partial response in 18 and 59 percent, respectively [21]. (See "Cyclic vomiting syndrome").
Chronic idiopathic intestinal pseudo-obstruction — Chronic intestinal pseudo-obstruction is usually secondary to an underlying disorder affecting neuromuscular function that suggests mechanical bowel obstruction of the small or large bowel in the absence of an anatomic lesion that obstructs the flow of intestinal contents [22,23]. One study of 42 patients with this disorder found that nausea and vomiting were prominent clinical manifestations in 83 percent of patients [23]. Prokinetic drugs usually provide little benefit [22]. (See "Chronic intestinal pseudo-obstruction").
Rumination syndrome — The rumination syndrome is a behavioral disorder that is most commonly identified among mentally-disadvantaged children, although it is increasingly recognized among adolescents and adults of normal mental capacity. The behavior consists of daily, effortless regurgitation of undigested food within minutes of starting or completing ingestion of a meal. (See "Etiology and diagnosis of delayed gastric emptying" section on rumination syndrome).
SUMMARY AND RECOMMENDATIONS
We suggest the following three steps in patients who present with nausea and vomiting: The consequences or complications of nausea and vomiting (eg, fluid depletion, hypokalemia, and metabolic alkalosis) should be identified and corrected. The etiology should be sought. A variety of disorders can produce nausea with or without vomiting (show table 1A-1B). The diverse differential diagnosis of nausea and vomiting should be approached initially with a careful history and physical examination. Laboratory evaluation and other testing should be guided by the symptom duration, frequency, and severity as well as the characteristics of vomiting episodes and associated symptoms. Targeted therapy should be provided, when possible (eg, surgery for bowel obstruction or malignancy). In other cases symptoms should be treated. Few high-quality therapeutic trials have compared the efficacy of different drugs in specified types of nausea and vomiting. However, acute or chronic nausea and vomiting can often be helped by antiemetic or prokinetic drugs depending upon the underlying cause. (See "Therapy" above).
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