Definition

Vomiting (emesis) is a complex reflex behavioral response to a variety of stimuli (see later discussion). The emetic reflex has three phases: (1) a prodromal period consisting of the sensation of nausea and signs of autonomic nervous system activation, (2) retching, and (3) vomiting or forceful expulsion of the stomach contents through the oral cavity. Although the overall sequence of these three phases is stereotypical, each can occur independently of the others. For example, nausea does not always progress to vomiting, and pharyngeal stimulation can induce vomiting without a prodrome of nausea. It is important to note that vomiting and regurgitation (defined as effortless reflux of the intragastric contents into the esophagus) are not synonymous. Clinically, vomiting can be distinguished from regurgitation, because regurgitation is not preceded by prodromal events, retching does not occur, and gastric contents are not forcibly expelled. The differentiation between vomiting and regurgitation is critical because each has different causes and is produced by distinct physiologic mechanisms. Furthermore, retching and vomiting, commonly thought to occur in tandem, can also occur independently of one another.

Physical Description

The events that herald the onset of the act of vomiting are nausea and several autonomic manifestations. Nausea is a subjective experience that is difficult to define. It is usually described as an unpleasant, but painless sensation associated with the feeling that vomiting is imminent. This wavelike, aversive feeling, is usually referred to the stomach, but some individuals perceive it in the back of the throat or head. The autonomic signs include cutaneous vasoconstriction, sweating, dilation of pupils, increased salivation, and tachycardia. Several gastrointestinal (GI) motor events characterize the emetic prodrome. There is inhibition of spontaneous contractions within the GI tract and dilation of the proximal stomach. The esophageal skeletal muscle shortens longitudinally, pulling the relaxed proximal stomach (hiatus and cardia) into the thoracic cavity, with loss of the abdominal segment of the esophagus. These anatomic changes result in the free flow of gastric contents into the esophagus. Soon after, a single large-amplitude contraction is initiated in the jejunum and propagates toward the stomach at 8 to 10 cm/s. This retropulsive event is termed the retrograde giant contraction (RGC). It propels the duodenal contents into the stomach before the onset of retching. The RGC is followed by a brief period of moderate-amplitude contractions in the distal small intestine and a second period of inhibition lasting several minutes.

The two major somatic motor components of vomiting (retching and expulsion) are produced by the coordinated action of the respiratory, pharyngeal, and abdominal muscles, resulting in rhythmic changes in intrathoracic and intraabdominal pressures. During each cycle of retching, the glottis closes and the diaphragm, external intercostal muscles, and abdominal muscles contract, producing large negative intrathoracic and positive intraabdominal pressure spikes. The esophagus dilates and the atonic proximal stomach continues to be displaced into the thoracic cavity. The antireflux mechanisms are overcome, and the gastric contents move back and forth into the esophagus with each cycle of retching.

Sometime after the onset of retching, expulsion or vomiting occurs. During this event the external intercostal muscles and the diaphragmatic crura relax and the abdominal muscles and costal diaphragm contract violently, producing positive pressures in both abdomen and thorax, resulting in orad propulsion of the gastric contents. Retrograde contraction of the cervical esophagus assists in oral expulsion. After expulsion, antegrade peristalsis in the esophagus clears the lumen of residual material and the proximal stomach returns to its normal intraabdominal position, restoring the normal antireflux anatomy.

Gastrointestinal Motor Activity During Nausea and Vomiting

GI motor activity during the emetic reflex is mediated by the vagus nerve. Vagal preganglionic parasympathetic fibers activate both inhibitory and excitatory pathways in the enteric nervous system. A wide range of stimuli induce nausea and vomiting. However, these GI motor events do not appear to be the cause of the sensation of nausea, which may be a physiologic process separate from vomiting. Moreover, the programmed somatic pattern of retching and vomiting continues even when the GI motor correlates of vomiting are prevented by disruption of the vagal efferents.

Although GI motor activity is not necessary for retching and vomiting, the motor changes that do occur may serve a significant role. As a defense against noxious ingested agents, relaxation of the stomach can confine a toxin before it is expelled, and the RGC can move toxins and alkaline duodenal secretions to the stomach to buffer and dilute gastric irritants (e.g., vinegar, hypertonic saline) in preparation for expulsion. The buffering of the gastric contents can also serve to protect the esophagus from acid injury. Finally, changes in the position of the stomach can place it in an advantageous position for compression by the abdominal musculature.

A different pattern of GI motor activity is observed in circumstances in which nausea is induced by motion. Before the onset of nausea, an increase occurs in the gastric slow waves from 3 to 9 cycles/min. This phenomenon, known as tachygastria , is controlled by central cholinergic and α-adrenergic pathways. In motion-induced nausea, the GI motor activity appears to play a role in the induction of symptoms.

Emetic Reflex

The emetic reflex consists of an afferent limb (receptor and pathway), central integration and control, and an efferent limb (pathway and effector) ( Figure 8-1 ). This reflex can be induced by visceral pain and inflammation, toxins, motion, pregnancy, radiation exposure, postoperative states, and unpleasant emotions. The diverse afferent receptors and pathways may originate within the gut, oropharynx, heart, vestibular system, or central nervous system (e.g., area postrema, hypothalamus, and cortical regions). These multiple afferent pathways are integrated within the brainstem, and the emetic reflex is completed through a common integrated efferent limb consisting of multiple pathways and effectors.

Schematic representation of the afferent limb and central integration of the emetic reflex. Receptors known to be involved in each pathway are listed within ovals . The region of central integration is designated by a dashed box to indicate that no single central locus exists as a “vomiting center.” The nucleus of the solitary tract (NTS) and the dorsal motor vagal nucleus (DMVN) may each play a role in central integration. Receptor abbreviations: 5-HT, 5-Hydroxytryptamine (serotonin); D, dopamine; M, acetylcholine muscarinic; H, histamine; NK, neurokinin.

Within the GI tract, multiple receptors are capable of initiating the emetic reflex. Mechanoreceptors present within the muscularis are activated by changes in tension and may be stimulated by passive distension or active contraction of the bowel wall. These conditions are present in bowel obstruction, a clinical state that causes vomiting. Chemoreceptors within the mucosa of the stomach and proximal small bowel respond to a wide range of chemical irritants (hydrochloric acid [HCl], copper sulfate, vinegar, hypertonic saline, syrup of ipecac) and are involved in radiation and chemotherapy-induced emesis. The afferent pathways from the GI tract are mediated principally via the vagus nerves; the splanchnic nerves play a minor role. Vagal afferent fibers project centrad principally to the dorsomedial portion of the nucleus of the solitary tract (NTS), and to a lesser extent to the area postrema and the dorsal motor vagal nucleus.

Circulating toxins can trigger the emetic reflex. The major detector of blood-borne noxious agents is the chemoreceptor trigger zone (CTZ), which is located within the area postrema on the floor of the fourth ventricle, outside of the blood–brain barrier. Substances in the cerebrospinal fluid and bloodstream can be detected by the cells of this region. Several types of receptors for endogenous neurotransmitters and neuropeptides have been localized to the CTZ. Intravenous infusion or direct application of these neuroactive agents (dopamine, acetylcholine, enkephalin, peptide YY, and substance P) to the CTZ can induce vomiting. Stimulation of the CTZ is essential for the induction of vomiting by these and other agents (apomorphine, cisplatin), but not for that induced by the stimulation of abdominal vagal afferents or motion. In addition to playing a role in vomiting, the area postrema is involved in taste aversion, control of food intake, and fluid homeostasis.

Activation of the afferent limb of the vomiting reflex may also occur through real or apparent motion of the body. Motion-induced vomiting is the result of a sensory mismatch involving the visual, vestibular, and proprioceptive systems, although an intact vestibular system is a necessary component. Histamine (H ₁ ) and cholinergic muscarinic receptors are involved in the afferent limb of this pathway. In addition to the foregoing afferent pathways, higher cortical centers can also activate the emetic reflex, when stimulated by unpleasant situations or in instances of conditioned vomiting (e.g., anticipatory vomiting in chemotherapy).

After activation, the afferent systems project centrad. Although no single central locus has been identified as a “vomiting center,” two models of central coordination of the emetic reflex have been proposed: (1) a group of nuclei (paraventricular system of nuclei, defined by their connection to the area postrema) form a linked neural system whose activation can account for all of the phenomena associated with vomiting; and (2) vomiting is produced by the sequential activation of a series of discrete effector (motor) nuclei as opposed to being activated in parallel by a single locus. Furthermore, the concept of a localized “vomiting center” has been refuted by recent anatomic studies implicating multiple groups of neurons within the medulla (nucleus ambiguus) activated in sequence by a “central pattern generator” that controls the emetic reflex.

Neurochemical Basis

A wide variety of neurotransmitters, neuroactive peptides, and hormones are involved in the emetic reflex. As investigations proceed into the physiology of vomiting and the pharmacology of antiemetic agents, the role of these and other mediators will continue to be defined.

Dopaminergic pathways have long been known to participate in the emetic reflex. Apomorphine, a commonly used experimental emetic agent, acts through the dopamine (D ₂ subtype) receptor. Furthermore, several clinically effective antiemetic agents (e.g., metoclopramide) are D ₂ receptor antagonists. The site of action of these agents (agonists and antagonists) is the CTZ, where a high density of D ₂ receptors is present. These receptors participate in the emetic reflex induced by several, but not all, noxious agents acting through the CTZ. In addition to this subclass of receptors, recent evidence has implicated D ₃ receptors within the area postrema as having a role in the emetic reflex.

The importance of serotonin (5-hydroxytryptamine or 5-HT) and serotonin receptors in the emetic reflex has been demonstrated by the observation that cisplatin-induced vomiting can be prevented by blockade of 5-HT ₃ receptors. In addition to its involvement in mediating the emetic response to several chemotherapeutic agents, 5-HT ₃ receptors play an important role in vomiting induced by radiation therapy and noxious substances in the GI tract. The 5-HT ₃ receptors are present on vagal afferent fibers in the GI tract and the presynaptic vagal afferent terminals within the central nervous system, specifically in the NTS, and CTZ in the area postrema. Current evidence indicates that chemotherapeutic agents, irradiation, and various noxious substances act directly on the GI mucosa, inducing release of serotonin from enterochromaffin cells. Terminal vagal afferents in proximity are stimulated, producing afferent activation of the emetic reflex. The precise role of the 5-HT ₃ receptors on the presynaptic vagal afferents within the central nervous system has not been fully elucidated, but they appear to facilitate the emetic reflex induced by some afferent pathways (e.g., cranial irradiation, chemotherapeutic agents within the cerebrospinal fluid). Other members of the 5-HT receptor family also may be involved in the emetic reflex. The 5-HT ₄ receptor has been shown to be necessary in the afferent limb of the emetic reflex induced by at least one GI irritant. Blockade of central 5-HT _1A receptors, located primarily in the NTS, prevents emesis induced by a broad range of stimuli.

Animal studies have convincingly linked physical and psychological stress to gastric stasis via central corticotropin-releasing factor (CRF) acting on CRF-R2 at the dorsomotor nucleus of the vagus. During exposure to stress, CRF initiates the hypothalamic-pituitary-adrenal (HPA) axis and could play an initiating role in emesis. The role of CRF in humans remains to be established, but its effects can produce the behavioral, neuroendocrine, autonomic, immunologic, and visceral responses to stress. Given its link between stress and GI motility, CRF may also be responsible for stress-induced nausea and dyspepsia.

Substance P (a member of the neurokinin family of peptides) and its receptor neurokinin NK ₁ (tachykinin) are widely distributed in the central nervous system and peripheral neural and extraneural tissues. Evidence in animal models of vomiting has demonstrated that this ligand and receptor are critical to the emetic response produced by a wide range of stimuli. NK ₁ receptor antagonists prevent vomiting produced by intravenous (morphine) and intragastric toxins (ipecac, copper sulfate), chemotherapeutic agents (cisplatin), and motion. The site of action of these antagonists is believed to be NK ₁ receptors located in the central nervous system (NTS, dorsal motor vagal nucleus). Because blockade of this receptor prevents emesis induced by both peripheral and central-acting agents, it has been suggested that NK ₁ receptors are critical elements in the central integration or effector pathway common to all emesis-inducing stimuli. Tachykinin receptor antagonists (aprepitant and its newer intravenous prodrug fosaprepitant) are now included in clinical treatment guidelines for moderate to highly emetogenic chemotherapy-induced vomiting.

Temporal Patterns

There are three temporal patterns of vomiting: one acute and two recurrent, chronic and cyclic ( Figure 8-2 ). Because of its frequent association with infections of childhood such as viral gastroenteritis, the acute form is the most common and is characterized by an episode of vomiting of moderate to high intensity. Recurrent vomiting is also a common problem encountered by pediatricians and gastroenterologists. Over a 5-year period, we evaluated 106 consecutive cases that could be further subclassified: two-thirds as chronic , a low-grade (1 to 2 times/day) daily pattern; and one-third as cyclic , an intensive but intermittent one ( Table 8-1 ). Those with the chronic pattern were mildly ill, whereas those with the cyclic pattern tended to have severe bouts (6 times/hour) associated with stereotypic pallor, listlessness, and dehydration. Because both the acute and cyclic patterns can produce intense vomiting, until the repetitive nature (more than three episodes) becomes evident, the cyclic pattern is understandably misclassified as an acute one and thus is typically misdiagnosed as a bout of viral gastroenteritis or food poisoning.

Representation of acute, chronic, and cyclic patterns of vomiting. Three temporal patterns of vomiting are depicted: acute — , chronic —, and cyclic —. The number of emeses per day is plotted on the vertical axis over a 2-month period. The acute pattern is represented by a single episode of moderate vomiting intensity; the chronic pattern by a recurrent low-grade vomiting pattern that occurs on a daily basis; and the cyclic pattern by recurrent, discrete episodes of high-intensity vomiting that occur once every several weeks with normal health in between.

Differential Diagnosis

The diagnostic profile varies according to the temporal pattern of vomiting ( Table 8-2 ). The acute pattern is dominated by infections both in and outside the GI tract. Other causes include food poisoning, obstruction of the GI tract, and increased intracranial pressure resulting from neurologic injury. Among those with the chronic pattern, GI disorders outnumbered extraintestinal ones by a ratio of 7 : 1; the most common were peptic, infectious ( Helicobacter pylori –induced) and allergic inflammation (eosinophilic esophagitis) of the upper GI tract. In contrast, the diagnostic profile in those with the cyclic pattern was reversed; extraintestinal disorders exceeded GI ones by a ratio of 5 : 1. Although the hallmark of idiopathic cyclic vomiting syndrome is the cyclic pattern of vomiting, episodic vomiting is also the central manifestation of a number of renal (e.g., acute hydronephrosis from ureteropelvic junction obstruction), endocrine (e.g., Addison’s disease), and metabolic disorders (e.g., disorders of fatty acid oxidation).

Causes of vomiting also vary with the age of the child ( Table 8-3 ). Although most congenital anomalies of the GI tract present in the neonatal period, webs and duplications can be discovered throughout childhood. Malrotation or nonfixation of the small intestine complicated by intermittent volvulus can cause episodic vomiting at any age and results in catastrophic small bowel necrosis, short bowel syndrome, and extended parenteral alimentation. Duodenal obstruction from superior mesenteric artery syndrome is associated with acute weight loss, resulting from anorexia nervosa, extensive burns, and immobilization in a body cast. Duodenal hematoma typically follows accidental trauma to the abdomen in bicycling children but can result from abuse of toddlers.

Although peptic and infectious injuries of the upper GI tract are most common, allergic (eosinophilic esophagitis) and inflammatory (Crohn’s disease) disorders also occur. Two unusual forms that affect toddlers include chronic granulomatous disease–induced antral obstruction and cytomegalovirus–associated Ménétrier gastropathy associated with hypoalbuminemia and anasarca. Typhlitis, a necrotizing inflammation of the cecum, principally affects children with acute lymphocytic leukemia during chemotherapy-induced neutropenia. In addition to a congenital form of intestinal dysmotility (chronic idiopathic intestinal pseudoobstruction), acquired viral and diabetes-induced gastroparesis can begin during adolescence.

Addison’s disease can mimic cyclic vomiting syndrome at all ages, manifesting itself with recurring bouts of vomiting and hyponatremic dehydration, even before hyperpigmentation appears. Pheochromocytoma (as part of a multiple endocrine neoplasia type 2b ), carcinoid syndrome, and gastrinoma are rare in children and adolescents. Although metabolic disorders usually present in infants and toddlers with vomiting and failure to thrive, medium-chain acyl-CoA (coenzyme A) dehydrogenase deficiency, partial ornithine transcarbamylase deficiency, and acute intermittent porphyria can present with episodic vomiting in older children and adolescents.

Acute hydronephrosis resulting from obstruction of the ureteral-pelvic junction can present as a cyclic vomiting pattern, so-called Dietl’s crisis. Increased intracranial pressure can result not only from structural subtentorial lesions (brainstem glioma, cerebellar medulloblastoma, and Chiari malformation) but also from pseudotumor cerebri associated with obesity, corticosteroid taper, vitamin A deficit or excess, tetracycline use, and hypophosphatasia. Both migraine headache and abdominal migraine are associated with vomiting in 40% of affected patients. Epilepsy as a cause of recurrent abdominal pain and vomiting without evident seizure activity remains a controversial entity.

Functional vomiting and Munchausen by proxy (ipecac poisoning) should be considered when the clinical pattern does not fit known disorders, the laboratory testing is negative, and psychosocial stresses are evident (see the later section on functional vomiting). Because of its lipid solubility, ipecac can be detected on a toxicology screen up to 2 months after administration.

Clinical Clues to Diagnosis

Clinical clues to aid in differential diagnosis are presented in Table 8-4 . Hematemesis more commonly results from peptic esophagitis, prolapse gastropathy, and Mallory-Weiss injury, and less often from allergic injury, Crohn’s disease, and vasculitis involving the upper GI tract. In the face of nonspecific gastric petechiae, vomiting occasionally originates from a bleeding diathesis such as that of von Willebrand disease. Of the causes of morning vomiting upon wakening, the most worrisome is a neoplasm in the posterior fossa. More common causes of early morning nausea and vomiting include environmental allergies and chronic sinusitis associated with a history of congestion, postnasal drainage, and cough-and-vomit sequence, as well as cyclic vomiting syndrome. Vertigo is commonly associated with a migraine headache or middle ear dysfunction (e.g., Ménière syndrome).

Unlike adults, for whom eating often provides pain relief, children more often experience postprandial exacerbation of their abdominal pain and vomiting. Malodorous breath may be associated with chronic sinusitis, H. pylori gastritis, giardiasis, and small bowel bacterial overgrowth. Although seen infrequently, visible peristalsis in infants and a succussion splash in children are indications of a gastric outlet obstruction that is causing gastric distension and retention of fluid. Abdominal masses can be seen in congenital (e.g., mesenteric cyst) or acquired non-neoplastic (e.g., ovarian cysts) and neoplastic (e.g., Burkitt’s lymphoma) lesions. In a sexually active female adolescent, pregnancy should always be considered as a cause of morning nausea and vomiting and excluded by a human chorionic gonadotropin level.

Repetitive, stereotypical, intense bouts of vomiting that begin abruptly in the early morning hours and resolve rapidly are characteristic of cyclic vomiting syndrome (see the later sections on cyclic vomiting syndrome and abdominal migraine). Chronic vomiting with possible aspiration can be associated with neurologic injury such as cerebral palsy or a metabolic disorder that affects muscle tone (e.g., mitochondriopathy).

Evaluation

Evaluation of the child with acute vomiting is usually the purview of the primary care or emergency department physician. A clinical assessment of dehydration without laboratory confirmation is usually a sufficient basis to begin intravenous rehydration ( Table 8-5 ). Viral testing and bacterial cultures in stool in presumed gastroenteritis or colitis can identify the infectious risk to others. If the physical examination reveals acute abdominal signs, abdominal radiographs and surgical consultation are indicated. When the emesis is voluminous and frequent, empiric antiemetic therapy (ondansetron) may forestall progression to dehydration and the need for intravenous therapy.

In a child presenting with chronic vomiting, screening laboratory tests (e.g. celiac panel, complete metabolic panel, hepatic transaminases, amylase, and lipase), and empiric treatment with H ₂ receptor antagonists or proton pump inhibitors can precede more definitive testing. If the condition does not improve with therapy, definitive tests may be considered: an esophagogastroduodenoscopy to detect suspected peptic, allergic, infectious, and inflammatory mucosal injuries; small bowel radiography or contrast imaging (magnetic resonance [MR] enterography) to identify possible anatomic lesions and Crohn’s disease; an abdominal ultrasound to assess potential cholelithiasis, pancreatic pseudocyst, or hydronephrosis; and sinus computed tomography (CT) to document chronic sinusitis. Radiographic sinus evaluation has a 10% yield in chronic vomiting.

In evaluating a child with cyclic or episodic vomiting, laboratory test results are typically abnormal only during the symptomatic attack; therefore, blood and urine screening for metabolic disorders must be obtained early on during the episode . The serum chemistry profile can detect hyperglycemia in diabetes mellitus or hypoglycemia in disorders of fatty acid oxidation, hyponatremia in Addison’s disease, an anion gap and low bicarbonate in organic acidemias, elevated hepatic transaminases in hepatobiliary disorders, and elevated lipase in pancreatic disorders. Blood is analyzed for elevations of ammonia in urea cycle defects, lactic acid in mitochondriopathies, amino acids in aminoacidemias, and deficiency of carnitine in disorders of fatty acid oxidation. After screening children for pyuria (infection) and hematuria (stones), the urine is analyzed for elevations in organic acids, carnitine esters, δ-aminolevulinic acid, and porphobilinogen, respectively, in organic acidurias, disorders of fatty acid oxidation, and acute intermittent porphyria. Positive results on screening tests necessitate appropriate definitive testing. For example, the absence of ketones, presence of dicarboxylic aciduria, and elevated urinary esterified free carnitine ratio of greater than 4 : 1 implicate a disorder of fatty acid oxidation, and diagnosis entails definitive plasma acylcarnitine, urinary acyl glycine profiles, and genetic testing. Definitive evaluation of GI tract involvement includes contrast imaging for anatomic or inflammatory disorders, an esophagogastroduodenoscopy for mucosal inflammation, and an abdominal ultrasound for renal, gallbladder, pancreatic, and ovarian lesions. With a history suggestive of increased intracranial pressure (e.g., headache, onset upon wakening), magnetic resonance imaging (MRI) of the brain is the best imaging modality to visualize the subtentorial region. In the absence of laboratory, radiographic, or endoscopic findings, if the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) consensus criteria for cyclic vomiting syndrome are fulfilled, an empiric trial of prophylactic antimigraine therapy may be initiated.

Complications

The two principal complications of acute or cyclic vomiting (during the episode) include dehydration with electrolyte derangement and hematemesis from prolapse gastropathy or Mallory-Weiss injury. The electrolyte disturbance resulting from varying losses of gastric HCl, pancreatic HCO ₃ , and GI NaCl is generally corrected with standard intravenous replacement. Hypochloremic, hypokalemic alkalosis results from high-grade gastric outlet obstruction and predominant loss of gastric H ⁺ and Cl ⁻ ions. Risk factors for development of alkalosis in pyloric stenosis include female gender, African American race, longer duration of illness, and more severe dehydration. Preoperative restoration of electrolyte balance reduces the perioperative morbidity.

Prolapse gastropathy occurs more commonly than the Mallory-Weiss injury at the gastroesophageal junction. The former injury results from repeated mechanical trauma resulting from herniation of the cardia through the gastroesophageal junction. No therapy or short-term acid suppression suffices.

Complications of persistent peptic injury to the esophagus (e.g., stricture formation and Barrett’s metaplasia) and bronchopulmonary aspiration are more likely to occur with long-standing chronic vomiting associated with gastroesophageal reflux disease in which the esophageal mucosa undergoes prolonged acid exposure. Growth failure as a complication of chronic vomiting can be caused by loss of calories, inflammatory burden, or protein-losing enteropathy. Aggressive nutritional rehabilitation may require continuous nasogastric or transpyloric feedings.

Pharmacologic Treatment

Although the therapy should be directed toward the cause, empiric therapy of the vomiting symptom may be indicated when the severity of the acute or cyclic vomiting places the child at risk of dehydration and other complications. Although laboratory confirmation of cyclic vomiting syndrome is not possible, a positive response to the antimigraine therapy can support the diagnosis. A comprehensive listing of therapeutic agents by pharmacologic category is presented in Table 8-6 .

TABLE 8-6

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