Nausea and vomiting are common and uncomfortable symptoms with a large number of underlying causes. Nausea is a subjective sensation, usually experienced in the epigastrium or throat when vomiting is imminent (although vomiting may or may not occur). Nausea may be followed by retching, which is repetitive active contraction of the abdominal musculature. Retching may occur in isolation without the forceful expulsion of gastric contents. In contrast, vomiting is a highly physical event that results in the evacuation of gastric contents. This should be distinguished from regurgitation, which is the effortless reflux of gastric or esophageal contents to the hypopharynx.
Studies have suggested that the act of vomiting is controlled by a central neurologic center. Borison and colleagues have studied the mechanism of vomiting in cats and found that vomiting can be induced by electrical stimulation of a “vomiting center” located in the dorsal portion of the medulla. These studies, however, have not yet been repeated in human subjects. Experimental studies have also suggested that a chemoreceptor trigger zone (CTZ) activates the vomiting center when stimulated.
Emetic stimuli can cause vomiting by one of two mechanisms. One mechanism is by activation of afferent vagal and sympathetic neural pathways within the gastrointestinal tract that act directly on the vomiting center. Ablation of these pathways in experimental animals prevents vomiting induced by copper sulfate, which is known to cause vomiting. The second mechanism by which emetic stimuli can cause vomiting is via the CTZ. Unlike the vomiting center, the CTZ is not responsive to electrical stimuli, but only to chemical stimuli from the circulation that crosses the blood–brain barrier. These stimuli include drugs, uremia, diabetic ketoacidosis (DKA), and toxins derived from gram-positive bacteria. The exact neurotransmitters that are involved are not known, but there is strong evidence that both dopamine and serotonin may mediate vomiting.
Regardless of the emetic stimulus or the mechanism by which the vomiting center is activated, the act of vomiting is initiated from the vomiting center. The efferent pathways are primarily somatic and involve the vagus, phrenic, and spinal nerves that supply the abdominal musculature.
Approach to Nausea and Vomiting
Three steps should be considered in approaching nausea and vomiting:
What is the etiology?
What are the consequences and/or complications that need to identified and corrected?
What therapy can be provided?
There are a vast number of causes of nausea and vomiting (Tables 95-1 and 95-2). The differential diagnosis can be approached with a careful history and physical examination. The acuity of symptoms should first be addressed. Acute nausea and vomiting are usually associated with acute infection (especially of the gastrointestinal tract), ingestion of toxins, gastrointestinal obstruction or ischemia, new medication, pregnancy, or head trauma/increased intracranial pressure. Chronic nausea and vomiting, which are usually defined as the persistence of symptoms for more than 1 month, suggest partial mechanical obstruction, intracranial pathology, motility disturbance as in gastroparesis, metabolic or endocrine etiology, or a psychologic disturbance.
Table 95-1 Differential Diagnosis of Nausea and Vomiting ||Download (.pdf)
Table 95-1 Differential Diagnosis of Nausea and Vomiting
|Abdominal Causes||Nervous System Causes|
|Mechanical obstruction||Autonomic system disorders|
| Gastric outlet obstruction||Demyelinating disorders|
| Small bowel obstruction||Hydrocephalus|
|Motility disorders|| Congenital malformations|
| Chronic intestinal pseudoobstruction|| High intracranial pressure|
| Functional dyspepsia|| Low pressure hydrocephalus|
| Gastroparesis|| Intracerebral lesions with edema|
| Irritable bowel syndrome||Labyrinthine disorders|
|Organic disorders|| Labyrinthitis|
| Acute appendicitis|| Meniere disease|
| Acute cholecystitis|| Motion sickness|
| Acute hepatitis||Meningitis|
| Crohn disease||Migraine headaches|
| Inflammatory intraperitoneal disease||Seizure disorders|
| Mesenteric ischemia||Visceral neuropathy|
| Mucosal metastases||Other Causes|
| Pancreatic cancer||Alcohol abuse|
| Pancreatitis||Anxiety and depression|
| Peptic ulcer disease||Cardiac disease|
| Retroperitoneal fibrosis|| Congestive heart failure|
|Drugs (See Table 95-2)|| Myocardial ischemia|
|Infectious Causes|| Radiofrequency ablation|
|Acute gastroenteritis||Cyclic vomiting syndrome|
| Bacterial||Eating disorders|
| Viral||Functional disorders|
|Nongastrointestinal infectious||Hypervitaminosis A|
| Otitis media||Intense pain|
| Systemic||Paraneoplastic syndrome|
|Metabolic and Endocrine Causes||Postoperative state|
| Acute intermittent porphyria||Postvagotomy|
| Addison disease||Radiation therapy|
| Diabetes mellitus||Rheumatologic disorders|
| Hypercalcemia|| Scleroderma|
| Hyperparathyroidism|| Sjögren syndrome|
| Hyperthyroidism|| Systemic lupus erythematosis|
| Hyponatremia||Rumination syndrome|
Table 95-2 Common Medications Associated with Nausea and Vomiting
The timing of vomiting in relation to meals can also be important in elucidating the etiology of symptoms. Patients with a pyloric peptic ulcer or psychogenic vomiting may present with vomiting during or soon after a meal. Patients with gastric outlet obstruction as in diabetic or postvagotomy gastroparesis are more likely to experience delayed vomiting of more than 1 hour after eating. The content of the vomitus can further provide important information. Old food in the vomitus may suggest gastroparesis, gastric outlet obstruction, or a proximal small bowel obstruction, while presence of bile indicates patency between the stomach and proximal duodenum.
The physical examination may be helpful in determining the underlying etiology and is important in assessing the consequences of nausea and vomiting. The general examination can detect important findings such as increase in pulse rate or postural decrease in blood pressure, which would suggest dehydration. Examination may also reveal jaundice, abdominal masses, or features suggestive of an endocrinologic process like thyrotoxicosis or Addison disease. Abdominal examination should focus on presence or absence of bowel sounds, tenderness, distention, as well as evidence of masses, hernias, or prior surgical procedures.
The history and physical examination should direct which lab tests and radiologic studies to order. Basic laboratory testing includes a complete blood count and electrolyte panel. Sustained vomiting resulting in loss of water and electrolytes may lead to dehydration and a hypokalemic metabolic alkalosis. In women, a pregnancy test should be obtained not only to determine if pregnancy is the cause of vomiting, but also as a prerequisite for any radiologic studies. Further laboratory testing may include serum drug levels in patients who are taking certain medications, as well as thyroid function tests.
Flat radiographs of the abdomen or a computed tomographic (CT) scan may reveal mechanical obstruction. An upper gastrointestinal series or endoscopy is particularly helpful in making the diagnosis when the history and physical examination suggest that peptic ulcer disease or gastric outlet obstruction is likely. It is important to recognize that the serial imaging included with a small bowel series adds important diagnostic information that a single image obtained during a CT scan may not. The absence of obvious obstructive pathology on a CT scan should not dissuade the clinician from obtaining a small bowel series. In patients with chronic nausea and vomiting who have a normal upper gastrointestinal series and endoscopy, further evaluation with a radionuclide gastric emptying study can be considered. Electrogastrography and antroduodenal manometry can also be considered if available; however, the clinical utility of these studies in most patients with chronic nausea is not well established, and these procedures are not offered at most facilities. In patients with normal gastric emptying and motility studies, evaluation with CT or ultrasonography may provide valuable information if a gallbladder, pancreatic, or hepatobiliary etiology is suspected. In addition, given that central nervous system processes can result in nausea, one should have a low threshold to perform neurologic imaging in the appropriate clinical context. Finally, a psychiatric consultation should also be considered if studies do not indicate any organic pathology.
When vomiting arises in the hospital, often it is medications that are to blame. Opiates, in particular, slow gastrointestinal transit and have additional direct emetogenic effects in some patients. Chemotherapeutic medications, antibiotics, and general anesthesia are also common precipitants of nausea in hospitalized patients. Abdominal procedures are also well known to result in nausea and delayed gut motility, independent of the anesthesia received. In many instances in which a clear precipitant is apparent, there is not a need to pursue aggressive diagnostic interventions; supportive care is adequate. However, if the symptoms are out of proportion to the clinical scenario or unusually prolonged (eg, persistent nausea and vomiting 4 days after general anesthesia for a nonabdominal procedure), diagnostic evaluation is wise. Additionally, other signs and symptoms such as fever or focal neurologic deficits should be sought out, and if present, should lead to prompt diagnostic evaluation. Finally, myocardial ischemia (particularly right-sided myocardial infarction) should be considered in hospitalized patients with cardiovascular risk factors. Diaphoresis, dyspnea, and changes in heart rate or blood pressure may suggest a cardiac etiology.
- In many instances in which a clear precipitant is apparent, there is no need to pursue aggressive diagnostic interventions; supportive care is adequate. However, if the symptoms are out of proportion to the clinical scenario or unusually prolonged (eg, persistent nausea and vomiting 4 days after general anesthesia for a nonabdominal procedure), diagnostic evaluation is wise.
Treatment of nausea and vomiting involves correction of fluid and electrolyte imbalance if present, identification and treatment of the underlying cause if one exists, and relief of symptoms either by suppression or by elimination if the primary cause cannot be promptly identified and removed. Patients with long-standing chronic nausea and vomiting are at risk for developing malnutrition, and it is important to monitor for this in the hospital setting. If a patient is not able to tolerate adequate oral caloric intake after a 5-day period, consideration should be given for enteral or parenteral feeding. Enteral feeding is usually the first option; however, dislodgment of enteral feeds with acute vomiting is not uncommon and occasionally parenteral feeding may be required.
There are many commonly employed antiemetic agents, and these medications can be divided into two main categories: central antiemetic agents and peripheral prokinetic agents. In practice, many drugs employ both mechanisms and many of the specific pathways by which these medications exert benefit are still being elucidated. The main antiemetics are detailed in the next sections.
Dopamine D2 receptor antagonists Metoclopramide is the classic agent in this category and exerts a central antiemetic effect through antagonism of dopamine D2 receptors as well as a peripheral prokinetic effect through stimulation of peripheral 5-HT4 receptors. Common indications include postoperative nausea and vomiting, chemotherapy and radiation therapy-induced nausea, and gastroparesis. The standard dose is 5–10 mg orally or intravenously three to four times daily. Metoclopramide is associated with significant side effects, including restlessness, anxiety, somnolence, extrapyramidal effects, QT interval prolongation, and, if used for a month or more, tardive dyskinesia (which in some cases is irreversible). Metoclopramide is currently the only U.S. Food and Drug Administration (FDA)-approved medication for gastroparesis; however, due to side effects it has a black box warning against use of greater than 12 weeks based on the risk of tardive dyskinesia.
Domperidone is a second agent in this category that crosses the blood–brain barrier poorly and is believed to act primarily through prokinetic function as a peripheral D2 receptor antagonist. Domperidone is a weaker antiemetic than metoclopramide, but as it is better tolerated, higher doses can be employed and the risk of anxiety and dystonia is significantly reduced. Domperidone is not approved for use in the United States; however, it can be obtained by filing an investigational new drug application with the FDA.
Phenothiazines Phenothiazines (chlorpromazine, promethazine) block D2 dopaminergic receptors in addition to muscarinic M1 receptors and histamine H1 receptors. These drugs induce relaxation and somnolence and are generally used parenterally or as suppositories in patients with acute intense vomiting of central origin (such as with migraine headaches and motion sickness). Although effective, side effects can be significant and often limit use. Of note, promethazine does have a black box warning from the FDA due to severe tissue injury; as a vesicant, if promethazine extravasates into subcutaneous tissues or is accidentally infused intra-arterially, severe local necrosis may occur.
Butyrophenones Butyrophenones block D2 dopaminergic receptors and muscarinic M1 receptors and are believed to affect nausea through central antiemetic effects. Commonly used agents in this category include droperidol and haloperidol. As with the phenothiazines already mentioned, side effects and safety concerns have limited routine use of these agents, although they may be of benefit on an adjunct basis.
Antihistamines and antimuscarinic agents These agents work primarily through blockage of histamine H1 receptors and muscarinic M1 receptors at a central level. Commonly used antihistamines are diphenhydramine, meclizine, and cyclizine. The most commonly used antimuscarinic agent is scopolamine. In addition, promethazine also has both antihistamine and antimuscarinic effects. Somnolence and drowsiness are the main limiting factors with these agents; however, anticholinergic effects can also be problematic—particularly for older patients. These agents are commonly used for treatment of motion sickness and nausea associated with vestibular disease.
Serotonin antagonists Serotonin 5-HT3 receptors seem to play a key role in nausea, and selective antagonists (such as ondansetron) are particularly effective through central nausea mediation. In addition, these agents may have a mild gastric prokinetic function. These agents are primarily used for postoperative nausea and after chemotherapy and radiation therapy; however, given their efficacy they are often used for refractory nausea related to other conditions. Of note, headache is a common side effect.
Serotonin agonists Serotonin 5-HT4 receptors seem to play a key role in gastric motility, and agonists of these receptors (such as metoclopramide, cisapride, and tegaserod) have significant prokinetic capabilities. Of these agents, cisapride has the most potent function and demonstrated efficacy for nausea associated with gastroparesis, pseudoobstruction, or other motility cause; however, cisapride was removed from the market due to QT-prolongation complicated by the risk of lethal ventricular arrhythmias. Tegaserod was also removed from the market due to increased associated cardiac events. At the moment, the only medication available in the United States that works through this mechanism is believed to be metoclopramide, and, as detailed earlier, this is but one mechanism by which metoclopramide is believed to exert benefit.
Motilin receptor agonists The classic motilin receptor agonist is the antibiotic erythromycin, which acts as a motilin receptor ligand on smooth muscle cells and enteric nerves, increasing gastric and intestinal peristaltic motor activity. In clinical practice, erythromycin may be used to treat acute nausea and vomiting associated with delayed gastric emptying and is also used to clear the stomach of retained food and blood prior to endoscopy. Erythromycin is best used acutely and is, unfortunately, not a good agent for chronic use in most patients as it is associated with tachyphylaxis. Erythromycin also induces nausea in a significant subset of patients and is associated with QT interval prolongation. New synthetic motilin agonists devoid of antibacterial activity are in development; however, none are ready for clinical use at the present time.
Ghrelin is a peptic structurally similar to motilin that also accelerates gastric emptying. Ghrelin receptor agonists are under development and may play a role in the future; however, they are not available at present for clinical use.
Glucocorticoids The antiemetic mechanism of glucocorticoids is not clear and numerous hypotheses have been raised, including inhibition of central prostaglandin synthesis, altered serotonin processing, and enhanced endorphin release. Regardless, glucocorticoids do appear to have an antiemetic effect and are often used for postoperative nausea or for treatment of nausea in the context of chemotherapy or radiation. In most cases, this use is as an adjunct therapy in combination with other agents rather than as a sole treatment modality.
Cannabinoids Synthetic cannabinoids have entered the therapeutic armamentarium for treatment of nausea. Two oral formulations, dronabinol and nabilone, are approved by the FDA for chemotherapy-induced nausea and vomiting refractory to conventional antiemetic therapy. While attractive to many patients, use of these agents is often limited by hypotension and psychotropic reactions.
Neurokinin-1 receptor antagonists Neurokinin-1 (NK) receptor antagonists inhibit substance P/NK-1 and are potent antiemetics. These agents (aprepitant, fosaprepitant) appear to be particularly effective for treatment of postoperative vomiting and may be used as adjunct therapy for patients not responding to the foregoing measures.
Benzodiazepines Although not proven nor approved as therapy for nausea, anecdotal experience supports the use of benzodiazepines in patients with refractory nausea, particularly when there appears to be a psychological or anticipatory component (ie, the patient reports nausea at the smell or sight of food prior to ingestion).
Alternative and Surgical Treatment
For patients with refractory nausea despite the pharmacologic options already detailed, it is occasionally necessary to explore alternative and surgical options. Acupuncture has been studied for treatment of nausea in select clinical situations and has shown benefit. Gastric electrical stimulation has also been explored for chronic nausea associated with gastroparesis. The concept is that an implantable neurostimulator delivers brief, low-energy impulses to the stomach, which alters afferent sensation, particularly with regard to nausea. This is approved for humanitarian use by the FDA; however, the procedure is not without risk, and clinical improvement is not universal—with most studies suggesting approximately a 40% response rate. At the moment, this is only approved for chronic nausea in the context of gastroparesis; however, studies are ongoing that may broaden this indication. Other surgical options for chronic nausea do not appear to have sufficient data to pursue further at the present time, except for perhaps completion gastrectomy in patients with nausea in the context of postsurgical gastroparesis.
Case 95-1 (Continued)
The patient was admitted for intravenous fluids and started on erythromycin, while being continued on the remainder of her regimen. She declined supplemental enteral or parenteral nutrition and after stabilization was discharged home. As an outpatient she was started on domperidone and seen in consultation by surgery for gastric stimulator placement, which she underwent later that year. Following gastric stimulator placement, she had a difficult postoperative recovery period and was discharged home on parenteral nutrition, which she was able to eventually taper off. She did well for a period of 3 months with marked improvement in nausea and significant weight gain, but unfortunately developed recurrent debilitating nausea and progressive weight loss, leading to a jejunal tube placement for enteral nutrition. At present, nausea remains a significant ongoing issue despite the efforts detailed here.