CHAPTER
15  
Nausea and Vomiting
JUAN-R. MALAGELADA AND CAROLINA MALAGELADA
CHAPTER OUTLINE
Pathophysiology.........................................................................207
Clinical Characteristics..............................................................208
Causes......................................................................................208
Acute Vomiting.......................................................................... 209
Chronic or Relapsing Vomiting................................................... 211
Nausea and Vomiting During Pregnancy..................................... 212
Functional Vomiting................................................................... 212
Cyclic Vomiting Syndrome......................................................... 213
Superior Mesenteric Artery Syndrome........................................ 213
Rumination Syndrome............................................................... 214
Evaluation..................................................................................214
Acute Vomiting.......................................................................... 214
Chronic Vomiting....................................................................... 215
Nausea, retching, and vomiting may occur separately or
together. When they occur together, they are often in sequence
as manifestations of the various physiologic events that inte-
grate the emetic reflex. Vomiting is a complex act that requires
central neurologic coordination, whereas nausea and retching
do not imply activation of the vomiting reflex. When nausea,
retching, or vomiting manifests as an isolated symptom, the
clinical significance may differ from the stereotypical picture
of emesis.1
Nausea is an unpleasant subjective sensation most people
have experienced at some point in their lives and usually
recognize as a feeling of impending vomiting in the epigas-
trium or throat.
Retching consists of spasmodic and abortive respiratory
movements with the glottis closed. When part of the emetic
sequence, retching is associated with intense nausea and
usually, but not invariably, culminates in the act of vomiting.
Vomiting is a partially voluntary act of forcefully expelling
gastric or intestinal content through the mouth. Vomiting must
be differentiated from regurgitation, an effortless reflux of
gastric contents into the esophagus that sometimes reaches the
mouth but is not usually associated with the forceful ejection
typical of vomiting (see Chapter 13).
PATHOPHYSIOLOGY
The mechanism of vomiting has been well characterized in
experimental animals and humans (Fig. 15-1).2,3 Neurologic
coordination of the various components of vomiting is pro-
vided by the emetic center (or vomiting center) located in the
medulla, specifically in the dorsal portion of the lateral reticu-
lar formation in the vicinity of the fasciculus solitarius. The
afferent neural pathways that carry activating signals to the
emetic center arise from many locations in the body. Afferent
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Complications............................................................................216
Emetic Injuries to the Esophagus and Stomach.......................... 216
Spasm of the Glottis and Aspiration Pneumonia.......................... 217
Fluid, Electrolyte, and Metabolic Alterations................................ 217
Nutritional Deficiencies.............................................................. 217
Treatment..................................................................................217
Correction of Metabolic Complications........................................ 217
Pharmacologic Treatment.......................................................... 217
Gastric Electrical Stimulation...................................................... 219
neural pathways arise from various sites along the digestive
tract—the pharynx, stomach, and small intestine. Afferent
impulses from these organs are relayed at the solitary nucleus
(nucleus tractus solitarius) to the emetic center. Emetic signals
arising from the GI tract are carried via vagal fibers, but
nausea may occur even in humans with bilateral abdominal
vagotomy; therefore, it is activated via other alternative
pathways, including hormones.4 Nausea and vomiting share
only in part the neural circuitry used to generate these symp-
toms, which explains why nausea and vomiting are clinically
and pharmacologically separable.4 In some patients, nausea
may be present continuously and become very troublesome.
Afferent pathways also arise from nondigestive organs like
the heart and testicles. Abdominal pain is a significant induc-
tor of nausea and vomiting.3 Pathways from the chemorecep-
tor trigger zone (CTZ) located in the area postrema on the
loor of the fourth ventricle also activate the emetic center.
Despite its central location, the CTZ is outside (at least in part)
the blood-brain barrier and serves primarily as a sensitive
detection apparatus for circulating endogenous and exoge-
nous molecules that may activate emesis. Finally, pathways
arise from other central nervous system (CNS) structures,
including the cortex, brainstem, and vestibular system via the
cerebellum.
The circuitry of the emetic reflex involves multiple recep-
tors.3 The following elements are the most relevant to clinical
issues:
1. Stimulation of brain 5-hydroxytryptamine3 (5-HT3) sero-
tonin receptors provokes release of dopamine, which
in turn stimulates dopamine D2 receptors in the emetic
center, thereby activating the emetic sequence. This
sequence is the basis for the pharmacodynamic action of
antiemetic agents like ondansetron, a 5-HT3 receptor inhib-
itor effective in treating acute (0 to 24 hours post drug)
chemotherapy-induced vomiting,5 and metoclopramide, a
dopamine D2-receptor antagonist (see later). Toxins and
207
208    Section III  Symptoms, Signs, and Biopsychosocial Issues

Drugs/chemicals: chemotherapeutic agents.3 Conversely, they may have less

dopamine agonists, potent antinausea effects.
cancer chemotherapy, When activated, the emetic center sets into motion, through
apomorphine, digoxin neural efferents, the various components of the emetic
Chemoreceptor Receptors for
trigger zone
sequence.3 First, nausea develops as a result of activation of
dopamine the cerebral cortex, the stomach relaxes concomitantly, and
(CTZ) (D2) and
antral and intestinal peristalsis is inhibited. Second, retching
serotonin
Emetic (5-HT3) occurs as a result of activation of spasmodic contractions of
Medulla center the diaphragm and intercostal muscles combined with closure
of the glottis. Third, the act of vomiting occurs when somatic
Vagal and visceral components are simultaneously activated. The
afferents components include brisk contraction of the diaphragm and
abdominal muscles, relaxation of the lower esophageal sphinc-
ter, and a forceful retrograde peristaltic contraction in the
jejunum that pushes enteric content into the stomach and
Sympathetic
Spinal afferents
from there toward the mouth.10 Simultaneously, protective
cord reflexes are activated. The soft palate is raised to prevent
gastric content from entering the nasopharynx, respiration is
momentarily inhibited, and the glottis is closed to prevent
Other trigger areas: pulmonary aspiration, which is a potentially serious complica-
Pharynx tion of vomiting. Other reflex phenomena that may accom-
Coronary arteries pany this picture include hypersalivation, cardiac arrhythmias,
Peritoneum and passage of gas and stool rectally. Emesis may alleviate
GI tract Bile ducts
Cortex, thalamus,
nausea.3
Stomach hypothalamus
Vestibular
apparatus CLINICAL CHARACTERISTICS
(motion sickness)
Certain clinical features may be characteristic of specific
Triggers causes of nausea and vomiting. Nausea and vomiting that
(e.g., staphylococcal occur in the morning or on an empty stomach and with emis-
enterotoxin)
sion of mucoid material (swallowed saliva) or gastroenteric
secretions are characteristic of direct activation of the emetic
FIGURE 15-1. Schematic representation of the proposed neural center or CTZ. This type of emesis is most typical of preg-
pathways that mediate vomiting. 5-HT, 5-hydroxytryptamine. nancy, drugs, toxins (e.g., alcohol), or metabolic disorders
(e.g., diabetes mellitus, uremia). Psychogenic vomiting may
also exhibit these characteristics. Clinical tradition holds that
excessive nocturnal postnasal drip may be responsible for this
drugs (including chemotherapeutic agents) acting on the type of vomiting, although direct evidence for this association
GI tract are detected by enteroendocrine cells that release is lacking. Vomiting that occurs outside the immediate post-
5-HT, which in turn activates 5-HT3 receptors on vagal prandial period and is characterized by evacuation of retained
afferents.4 and partially digested food is typical of slowly developing
2. Histamine H1 and muscarinic M1 receptors, which are gastric outlet obstruction or gastroparesis.11 Pseudovomitus,
abundant in the vestibular center and solitary nucleus, in which totally undigested food that has not been exposed to
constitute the preferred pharmacologic targets for inhibit- gastric juice is expelled, may occur in long-standing achalasia
ing motion sickness, vestibular nausea, and pregnancy- or with a large Zenker’s diverticulum. Bilious vomiting is
related emesis.6 commonly seen after multiple vomiting episodes occur in
3. Cannabinoid CB1 receptors in the dorsal vagal complex close succession because of retrograde entry of intestinal mate-
inhibit the emetic reflex.7 Cannabinoid agonists also modu- rial into the stomach. It is also characteristic of patients with
late 5-HT3 ion channels. The CB and 5-HT3 receptor systems a surgical enterogastric anastomosis, in whom the gastric con-
co-localize and interact in the brainstem.8 Activation of tents normally include bile-stained enteric refluxate. Vomitus
somatodendritic 5-HT1A autoreceptors in the dorsal raphe with a feculent odor suggests intestinal obstruction, ileus asso-
nucleus by cannabinoids reduces nausea and emesis pro- ciated with peritonitis, or long-standing gastric outlet obstruc-
voked by emetogenic drugs.9 tion. Vomiting that develops abruptly without preceding
4. Neurokinin-1 (NK-1) receptors located in the area pos- nausea or retching (projectile vomiting) is characteristic of, but
trema and the solitary nucleus bind to substance P and not specific for, direct stimulation of the emetic center, as may
are part of the terminal emetic pathways. Activation of occur with intracerebral lesions (tumor, abscess) or increased
NK-1 receptors by substance P constitutes the basis of intracranial pressure.12
chemotherapy-induced emesis (i.e., emesis 24 to 72 hours
after administration of chemotherapeutic drugs).5 NK-1
antagonists reduce emesis induced by peripherally and CAUSES
centrally acting emetogens. 5-HT3 receptors appear to be
involved to a greater extent in centrally induced emesis In clinical practice, promptly establishing the cause of nausea
than in peripherally induced emesis. Therefore, NK-1 and vomiting is critical because specific treatment may be
receptor antagonists appear to be more efficacious than feasible. Acute (<1 week) and chronic vomiting should be
5HT3-receptor inhibitors and other known antiemetic considered separately because the respective causes generally
drugs in reducing vomiting induced by a variety of causes differ. Patients with chronic vomiting tend to consult a special-
and are useful in preventing delayed emesis induced by ist after being symptomatic for some time, whereas patients

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 Chapter 15  Nausea and Vomiting    209

BOX 15-1 Principal Causes of Nausea and Vomiting

Abdominal Causes Tamoxifen Hydrocephalus

Mechanical obstruction Vinblastine Congenital malformations
Gastric outlet obstruction Cardiovascular drugs Increased intracranial pressure
Small bowel obstruction Antiarrhythmics Low-pressure hydrocephalus
Motility disorders Antihypertensives Intracerebral lesions with edema
Chronic intestinal Beta blockers Abscess
pseudo-obstruction Calcium channel blockers Hemorrhage
Functional dyspepsia Digoxin Infarction
Gastroparesis Diuretics Neoplasm
Other intra-abdominal causes Central nervous system drugs Labyrinthine disorders
Acute appendicitis Antiparkinsonian drugs (levodopa Labyrinthitis
Acute cholecystitis and other dopamine agonists) Ménière’s disease
Acute hepatitis Anticonvulsants Motion sickness
Acute mesenteric ischemia GI medications Meningitis
Crohn’s disease Azathioprine Migraine headaches
Gastric and duodenal ulcer disease Sulfasalazine Otitis media
Pancreatitis and pancreatic Narcotics Seizure disorders
neoplasms Oral contraceptives Visceral neuropathy
Peritonitis and peritoneal Theophylline
carcinomatosis Other Causes
Retroperitoneal and mesenteric Infectious Causes Anxiety and depression
pathology Acute gastroenteritis Cannabinoid hyperemesis syndrome
Viral Cardiac disease
Drugs* Bacterial Heart failure
Aspirin and other NSAIDs Nongastrointestinal (systemic) infections Myocardial infarction, ischemia
Antidiabetic agents Metabolic and Endocrine Causes Radiofrequency ablation for
Antigout drugs Acute intermittent porphyria arrhythmias
Antimicrobial agents Addison’s disease Collagen vascular disorders
Acyclovir Diabetic ketoacidosis Scleroderma
Antituberculosis drugs Diabetes mellitus Systemic lupus erythematosus
Erythromycin Hyperparathyroidism and other causes Cyclic vomiting syndrome
Sulfonamides of hypercalcemia Eating disorders
Tetracycline Hyperthyroidism Ethanol abuse
Cancer chemotherapy Hyponatremia Functional disorders
Cisplatin Hypoparathyroidism Hypervitaminosis A
Cytarabine Pregnancy Intense pain
Dacarbazine Paraneoplastic syndrome
Etoposide Nervous System Causes Postoperative state
5-Fluorouracil Demyelinating disorders Postvagotomy
Methotrexate Disorders of the autonomic nervous Radiation therapy
Nitrogen mustard system Starvation

*Partial list.

with severe acute vomiting require immediate medical atten-
tion. Causes of nausea and vomiting are listed in Box 15-1.
Acute Vomiting
In the patient with acute vomiting, the following 2 questions
must be answered immediately:
1. Is emergency action required? The patient must be assessed
for shock, hypokalemia, other serious electrolyte distur-
bances, hollow viscus perforation, organ infarction, cere-
bral edema, and poisoning.
2. Is the female patient pregnant? In fertile women, preg-
nancy must be considered first.
Once these 2 issues are addressed, a number of potentially
emergent diagnostic possibilities should be considered.
Acute Intestinal Obstruction
Vomiting may be a presenting feature of intestinal obstruction
due to an incarcerated hernia or stool impaction; the latter
entity is seen in older, debilitated, or mentally challenged
persons. Distal duodenal and proximal jejunal neoplasms
(adenocarcinoma, lymphoma, leiomyosarcoma, carcinoid)
may cause gastric outlet or intestinal obstruction that mani-
fests as acute or chronic vomiting. Proximal intestinal obstruc-
tion may be particularly difficult to diagnose because the
obstructing lesion may be overlooked or unreachable by con-
ventional upper GI endoscopy and yet may present without
the typical picture of dilated fluid-filled loops of small bowel
(air-fluid levels) on plain abdominal films (see Chapter 123).
Gastric Outlet Obstruction
In the past, PUD was a major cause of gastric outlet obstruc-
tion (see Chapter 53). Obstruction due to a pyloric channel
peptic ulcer or impaction at stenotic scarring of the antroduo-
denal junction can manifest abruptly with acute vomiting or
insidiously, mimicking the clinical picture of gastroparesis
(see Chapter 49). The incidence of PUD has declined sharply,
and patients are treated early and more effectively in the
course of the disease, so PUD has become a much less frequent
cause of gastric outlet obstruction. Gastric volvulus is a rela-
tively uncommon but important cause of acute vomiting;
symptoms may be relapsing because of intermittent volvulus
formation and spontaneous resolution (Fig. 15-2) (see Chapter
26). Excessive splenic mobility (i.e., wandering spleen)13 and

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210    Section III  Symptoms, Signs, and Biopsychosocial Issues
FIGURE 15-2. Plain abdominal film showing marked gastric
dilatation in a patient with a mesenteroaxial gastric volvulus.
(Courtesy Dr. Anna Accarino, Barcelona, Spain.)
outlet obstruction by a pseudopolypoid antral mass (e.g., het-
erotopic pancreas)14 are other uncommon but well-described
causes. Paraesophageal and post-traumatic diaphragmatic
hernias also predispose to acute vomiting secondary to
obstruction (see Chapter 26).15
Both acute and chronic pancreatitis, with associated inflam-
matory masses, necrosis, pseudocysts, or secondary infection,
may lead to gastric outlet obstruction at the duodenum or, less
commonly, the antrum and pylorus (see Chapters 58 and 59).
Similarly, gastric, duodenal, or pancreatic malignancies (ade-
nocarcinoma, lymphoma, cystic pancreatic neoplasms) may
cause gastric outlet obstruction, sometimes manifesting as
acute vomiting (see Chapters 31 to 33, 54, 60, and 125).
Intestinal Infarction
A diagnosis of intestinal infarction should be considered in
any patient with acute vomiting.16 Intestinal infarction may
occur with a paucity of physical signs but requires expeditious
management. The diagnosis is more common in patients with
vascular disorders and thrombotic diatheses and in older
adults (see Chapter 118).
Extraintestinal Causes
Extraintestinal causes of vomiting do not usually present
a challenging diagnostic problem, because the primary
condition is generally clinically apparent. Myocardial infarc-
tion may manifest initially as acute vomiting because of affer-
ent connections between the heart and emetic center. Similarly,
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renal colic and biliary pain may manifest with intense vomit-
ing, although localization of the pain and other characteristic
features usually make these diagnoses evident (see Chapter
65). Ovarian or testicular torsion may initially manifest with
intense vomiting.
Intraperitoneal or retroperitoneal inflammatory con­
ditions (e.g., acute appendicitis, bowel perforation, acute
pancreatitis—in general, any cause of acute abdominal pain)
may be associated with vomiting. Vomiting is occasionally so
intense (and rarely, the only symptom) that it causes diagnos-
tic confusion (see Chapters 11, 58, and 120).
Toxins and Drugs
Vomiting caused by toxins and drugs is common but usually
not difficult to diagnose. Alcohol abuse and various types of
poisoning should be considered.
Cancer chemotherapy is associated with a high likelihood
of nausea and vomiting, which motivates routine preventive
administration of antiemetic agents. Chemotherapeutic agents
and combinations of agents vary in their propensity to cause
nausea and vomiting, and patient-related factors are relevant
(see Box 15-1).17 As many as 50% to 80% of patients under­
going radiotherapy may experience nausea and vomiting,
depending on the site of irradiation, patient susceptibility, and
radiotherapy protocol.18
The list of drugs that can induce nausea and vomiting is
lengthy (see Box 15-1). Some drug classes and individual
agents are particularly common culprits in clinical practice,
especially aspirin and other nonsteroidal anti-inflammatory
drugs (NSAIDs; their emetic effect is partially attenuated by
coadministration of a proton pump inhibitor [see Chapter 52]),
cardiovascular drugs (digitalis, antiarrhythmics), antibiotics,
levodopa and its derivatives, theophylline, opiates, and aza-
thioprine. Patients on multidrug regimens pose a special chal-
lenge in identifying the culprit drug(s).
Metabolic Causes
Metabolic causes of vomiting include diabetic ketoacidosis,
hyponatremia, and hypercalcemia. Diabetic gastroparesis
associated with visceral neuropathy is usually associated with
chronic relapsing nausea and vomiting (see later), but the
clinical onset of diabetic gastroparesis may be abrupt (see
Chapter 49). Addison’s disease may also manifest clinically
with acute vomiting.
Infectious Causes
Vomiting may be due to acute gastritis or gastroenteritis
caused by viruses like norovirus (a common cause of epidemic
or sporadic gastroenteritis) or bacteria, including bacterial
toxins like that produced by Staphylococcus.19 Enterotoxin stim-
ulation of enterochromaffin cells that release 5-HT and acti-
vate vagal afferent pathways is the principal mechanism.20
During the early stages of illness, nausea and vomiting may
be the predominant or even exclusive clinical manifestation
(see Chapters 52, 110, and 111).
Neurologic Causes
Nausea and vomiting may be the sole or predominant
manifestation of a neurologic disorder. Meningeal inflamma-
tion is a potential cause. Nausea and vomiting may be associ-
ated with vertigo in patients with vestibular or cerebellar
disorders. Motion sickness is another well-known cause, and
its mechanism involves 5-HT1B and 5-HT1D receptors expressed
in the vestibular aparatus.21 Migraine headaches may be

accompanied by nausea and vomiting with little or no head-
ache, making the diagnosis difficult. Ictal vomiting is a rare
manifestation, most often associated with right temporal lobe
epilepsy.22 A rare autoimmune condition associated with anti-
bodies against a brain water channel may cause severe nausea
and vomiting.23 Intracerebral lesions associated with increased
intracranial pressure, interference with intracerebral fluid
flow, or direct compression of the emetic center may manifest
with nausea and vomiting. Projectile vomiting is a common
but not invariable feature of intracerebral lesions. Exercise-
induced nausea and vomiting may provide a clue to the diag-
nosis of pheochromocytoma or paraganglioma.
Postoperative Nausea and Vomiting
Postoperative nausea and vomiting is generally a therapeutic
rather than a diagnostic problem. At least a third of patients
who do not receive antiemetic prophylaxis will experience
nausea and vomiting after surgery. The risk is highest with
abdominal, gynecologic, strabismus, and middle ear surgery
and is 3 times as common in women as in men. General and
epidural anesthesia carry a similar risk,24 whereas the risk is
much lower for intravenous anesthesia.25 The differential diag-
nosis includes complications of surgery, such as intestinal per-
foration, peritonitis, and electrolyte disturbances. Cardiac
disease (“silent” myocardial infarction, heart failure) may also
manifest as nausea and vomiting in the postoperative period.
Chronic or Relapsing Vomiting
In patients with chronic or relapsing vomiting, the same
causes of acute vomiting discussed earlier must be considered,
but with important differentiating features. Additional consid-
erations include pregnancy, functional vomiting, cyclic vomit-
ing syndrome, and pseudovomiting.
Partial Intestinal Obstruction
In contrast to acute complete intestinal obstruction, partial
intestinal obstruction may be associated with relapsing vomit-
ing over long periods of time. Abdominal pain and distention
may accompany the clinical picture but wax and wane as
intestinal flow is intermittently interrupted and spontane-
ously restored. The clinical presentation of long-standing
partial intestinal obstruction and chronic intestinal pseudo-
obstruction (an intestinal motor disorder) may be similar.
Excluding occult partial intestinal obstruction is a prerequisite
for the diagnosis of pseudo-obstruction (see Chapters 123 and
124). Stenosing Crohn’s disease, neoplasms of the intestine,
postradiation enteric injury, and ischemic strictures are the
main causes of partial mechanical intestinal obstruction (see
Chapters 40, 115, 118, and 123). Adhesions from surgery or
pelvic inflammatory disease are a frequent cause of intestinal
obstruction, although establishing their pathogenic role is
sometimes difficult. Advanced intra-abdominal cancer is
another important cause of intestinal obstruction. In older,
debilitated, and mentally challenged persons, constipation
may lead to a picture of intestinal obstruction when the colon
becomes impacted with stool and ileal outflow is partially
impeded (see Chapter 19).26
Gastric Outlet Obstruction
When partial and sustained over time, gastric outlet obstruc-
tion is an important cause of chronic vomiting. In the past, this
presentation was common in patients with PUD (see earlier).
With the advent of early endoscopic diagnosis and effective
treatment of peptic ulcer and endoscopic management of
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Chapter 15  Nausea and Vomiting    211
gastric outlet obstruction, this presentation of peptic ulcer is
now uncommon.
GI Motility Disorders
Gastroparesis and chronic intestinal pseudo-obstruction
may produce chronic vomiting (see Chapter 49).27,28 Recurrent
vomiting, sometimes with symptom-free periods, is a major
component of the clinical picture of gastroparesis. It may lead
to food aversion, poor oral intake, and malnutrition.29 As in
partial gastric outlet obstruction, abdominal pain is absent, the
stomach may become markedly dilated, and the vomitus
may contain partially digested food, but these findings are not
constant. Delayed gastric emptying is the hallmark of gastro-
paresis, but there is controversy as to whether the degree
of impairment is an indicator of refractoriness to therapy30,31
and negative health outcomes.32 Diminished accommodation
of the proximal stomach may better determine the symptom-
atology than delayed emptying.33 Marked gastric stasis,
however, tends to be associated with more severe vomiting
and satiety.34 In idiopathic gastroparesis, sometimes develop-
ing after an acute viral illness in both children35 and adults,36
abdominal pain is a prominent feature.34 Cytomegalovirus and
Epstein-Barr virus have been identified as potential culprits.37
Demyelination, similar to that found in Guillain-Barré syn-
drome, has been observed.38 Postviral gastroparesis is often
self-limited.36
Diabetes mellitus is a major cause of gastroparesis with
chronic nausea and vomiting that may also be associated with
abdominal pain.39 In this context, diminishing gastric stasis
may improve symptoms.40 Extrinsic denervation was once
considered the predominant pathogenesis, but as in idiopathic
gastroparesis, gastric cellular abnormalities such as loss of
growth factors for the interstitial cells of Cajal (which generate
pacemaker activity), enteric nerve abnormalities, and increased
immune cells have been reported.34,41-43 Iatrogenic gastropare-
sis may occur in patients with diabetes mellitus treated with
incretins (pramlintide or exenatide).39
Chronic gastroparesis with recurrent nausea and vomiting,
long recognized as a sequela of vagotomy for peptic ulcer
surgery (see Chapter 53), is now occasionally observed tran-
siently after fundoplication for gastroesophageal reflux or
after bariatric surgery and is possibly due to vagal nerve
injury and other factors (see Chapters 8 and 44).44 Gastropare-
sis may also develop after pulmonary45 or combined heart-
lung46 transplantation.
A distinct group of patients with chronic nausea and
vomiting, clinically indistinguishable from those with idio-
pathic gastroparesis but with normal gastric emptying, has
been described.43 Nausea and vomiting may be presenting
features of intestinal pseudo-obstruction, but other symptoms
and signs associated with small bowel dysmotility (e.g.,
abdominal pain, distention) are usually present (see Chapter
124). The distinction between primary and secondary forms
of gastroparesis and chronic intestinal pseudo-obstruction
often requires specific diagnostic tests (see later and Chapters
49 and 124).
Neurologic Disorders
Neurologic disorders are an important and sometimes diag-
nostically elusive source of chronic nausea and vomiting, even
after the various neuropathies that may be responsible for
gastroparesis and chronic intestinal pseudo-obstruction are
excluded. Foremost among neurologic causes of chronic or
relapsing vomiting is migraine, particularly atypical forms
without an aura or family history and with delayed or no
headache. Hydrocephalus and lesions that compress or irritate
212    Section III  Symptoms, Signs, and Biopsychosocial Issues
the emetic center in the base of the brain may also account for
chronic vomiting.
Nausea and Vomiting During Pregnancy
Nausea occurs in more than half of all normal pregnancies and
is frequently associated with vomiting. These symptoms tend
to develop early in pregnancy, peak around 9 weeks’ gesta-
tion, and rarely continue beyond 22 weeks’ gestation. Nausea
with vomiting is more common in women with multiple ges-
tations than in those with a single gestation. The origin of
nausea and vomiting during pregnancy remains unclear,
although hormonal and psychological influences appear to
contribute.47 In particular, increased human chorionic gonado-
tropin (HCG) levels during the first trimester may have causal
effects via stimulation of gastric cholecystokinin (CCK) recep-
tors.48 Gastric dysrhythmias have been documented by elec-
trogastrography (EGG [see Chapter 49]). Because symptoms
may occur even before a woman realizes she is pregnant, a
pregnancy test must be obtained in any fertile woman with a
complaint of nausea and vomiting.
Nausea and vomiting tend to occur primarily, although
not exclusively, in the morning before food is ingested. The
symptoms may warrant pharmacotherapy to alleviate the dis-
comfort they produce but must be regarded as a normal mani-
festation of pregnancy. The prognosis for mother and child is
excellent. Drugs that may be used safely to treat nausea and
vomiting during pregnancy (on the basis of published data)
include ondansetron and related 5-HT3 antagonists, metoclo-
pramide, and doxylamine-pyridoxine, an antihistamine with
antiemetic properties available in some European countries.49
Other antiemetics may also be safe, but specific evidence in
support of their use is not available. Ancillary nonpharmaco-
logic measures may be helpful.
Hyperemesis gravidarum refers to unusually severe nausea
and vomiting that leads to complications (e.g., dehydration,
electrolyte imbalance, Mallory-Weiss tears, malnutrition).50
Multiparous overweight women are at increased risk. The
syndrome appears to represent an exaggeration of the common
nausea and vomiting of pregnancy, and hormonal and psy-
chological factors are also thought to contribute to the patho-
genesis. Hyperthyroidism has been reported in some affected
persons. Liver dysfunction may be present (see Chapter 39).51,52
Manifestations generally develop in, and may continue
beyond, the first trimester. Fluid and electrolyte replacement
therapy may be required, together with antiemetic drugs; 1%
to 5% of affected women may require hospitalization. Gluco-
corticoids, dopamine antagonists, phenothiazines, histamine
receptor blockers, erythromycin, and powdered ginger root
have been reported to be helpful in patients with hyperemesis
gravidarum.53 Behavior modification and other psychothera-
peutic techniques have been reported to be helpful as well.
Small and frequent low-fat, protein-rich meals may be helpful,
as is avoidance of unpleasant odors and foods that precipitate
vomiting.53 Occasionally, enteral or parenteral nutrition may
have to be prescribed to prevent severe malnutrition.54 Patients
with hyperemesis gravidarum do not have an increased risk
of toxemia of pregnancy or spontaneous abortion, and
although the condition may be associated with low fetal
weight at term, it does not lead to an increased rate of adverse
fetal consequences.55
Severe vomiting may accompany acute fatty liver of
pregnancy, a serious but uncommon condition that occurs
in the third trimester (in contrast to hyperemesis gravi-
darum). Headache, general malaise, and manifestations of
preeclampsia (hypertension, edema, proteinuria) are common
accompanying features. Progression to hepatic failure and dis-
seminated intravascular coagulation may occur rapidly, so
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measurement of serum liver biochemical test levels is advis-
able in women in whom severe nausea and vomiting develop
late in pregnancy. Liver biopsy, which characteristically dis-
closes microvesicular steatosis, is rarely required to establish
the diagnosis. The differential diagnosis of acute fatty liver
of pregnancy includes fulminant viral hepatitis and drug-
induced hepatitis. If the diagnosis of acute fatty liver is con-
firmed, the neonate should be delivered immediately to
prevent maternal and fetal death (see Chapter 39). The syn-
drome may recur in subsequent pregnancies. The hemolysis,
elevated liver enzymes, low platelets (HELLP) syndrome also
occurs in the third trimester and may include nausea and
vomiting.
Functional Vomiting
Consensus criteria for functional vomiting by the Rome III
Consensus Committee on Functional Gastrointestinal Disor-
ders include 1 or more episodes of vomiting per week for 3
months, with the onset of symptoms at least 6 months prior
to diagnosis. Eating disorders, rumination, self-induced vom-
iting, major psychiatric disorders, chronic cannabinoid use,
and organic causes of vomiting (i.e., with a definable struc-
tural or physiologic basis) should be excluded (see later and
Chapters 9 and 22).56
Epidemiologic studies have suggested that occasional
vomiting is not uncommon in otherwise healthy persons. Spe-
cifically, population-based data indicate that vomiting once a
month or more occurs in 2% to 3% of the general population.
Only a small minority of these persons probably fulfill the
criteria for functional vomiting.
Evaluation of a patient with suspected functional vomiting
should be directed toward excluding the usual organic causes
of vomiting. Special motility tests are typically necessary to
differentiate functional vomiting from gastroparesis or intes-
tinal pseudo-obstruction.57 In our experience, a radionuclide
gastric emptying test and GI manometry are useful because a
normal or minimally affected gastric emptying test result
excludes gastroparesis. Unfortunately, the reverse is not true;
gastric emptying may be abnormally prolonged when the test
is performed in a patient with severe nausea of any cause.
If GI manometry is performed in a patient with protracted
vomiting, detection of strong antral phasic waves and a
normal intestinal pressure pattern during fasting and post-
prandially makes the diagnosis of unrecognized intestinal
pseudo-obstruction almost untenable. Electrogastrography
(EGG), another technique that has been applied to the evalu-
ation of GI dysmotility, may be of limited usefulness in
patients with otherwise unexplained vomiting, because the
test may not establish whether gastric dysrhythmias are a
cause or consequence of nausea and vomiting; furthermore,
gastric dysrhythmias may occur in patients with a normal
gastric emptying rate (see Chapter 49). Vomiting is an uncom-
mon manifestation of gastroesophageal reflux, which may or
may not be detected at endoscopy, depending in part on
whether or not esophagitis is present (see Chapter 44).
The definition of functional vomiting excludes major psy-
chiatric disorders, but underlying anxiety or depression often
play important roles in the patient’s illness and may have to
be addressed. Nutritional deficiencies and metabolic imbal-
ances, if present, must be corrected, but antiemetic medica-
tions tend to be ineffective in these patients if an underlying
major eating disorder is present. Specific dietary therapy adds
little to management, because patients are already likely to
avoid offending foods that may worsen their symptoms.
Psychosocial support is essential, and reports suggest that
cognitive and social skills training may be helpful. Psycho-
therapy, behavioral therapy, and psychotropic agents are all

used in practice, even in the absence of formal studies dem-
onstrating their efficacy.
Cyclic Vomiting Syndrome
First recognized in the 19th century, cyclic vomiting syndrome
is characterized by clustered episodes of vomiting that last
from 1 day to 3 weeks (average, 6 days). The vomiting epi-
sodes tend to be stereotypical, with a predictable onset and
duration separated by asymptomatic or almost asymptomatic
intervals that range from 2 weeks to 6 months; sometimes,
mild to moderate dyspeptic symptoms persist between epi-
sodes of vomiting. Some patients describe a prodromal phase
resembling that associated with a migraine. The Rome III Con-
sensus Committee’s definition of cyclic vomiting syndrome
requires 3 or more discrete episodes of vomiting (with no
apparent explanation) during the preceding year.56
A personal or family history of migraine is supportive of
the diagnosis of cyclic vomiting syndrome, particularly in chil-
dren. In the pediatric age group, various mitochondrial, ion
channel, and autonomic disorders have also been associated
with intermittent episodes of vomiting and may have to be
excluded. Similarly, food allergy (sensitivity to cow’s milk,
soy, or egg white protein) or food intolerances (to chocolate,
cheese, nuts, or monosodium glutamate) may manifest with
vomiting spells and should be excluded (see Chapter 10).
Cyclic vomiting syndrome can occur at any age, although
it is particularly common in children58 and relatively uncom-
mon in older adults. There is no gender predilection. A per-
sonal or family history of migraines is elicited in up to 25% to
40% of patients.58,59 Abdominal pain may be an accompanying
feature in two thirds of affected persons. Transient fever and
diarrhea may also occur. In some women, the vomiting epi-
sodes are linked to the menstrual cycle. Anxiety or depression
are found in one third of patients.58,60 Although cyclic vomiting
syndrome has features that suggest an episodic CNS disorder
(e.g., migraine, cluster headaches), studies have suggested
that a high percentage of these patients have underlying intes-
tinal motor disturbances, but counterintuitively, gastric emp-
tying tends to be rapid in about 60% of cases (instead of
delayed as in gastroparesis).61 Electrogastrographic abnormal-
ities, chiefly tachygastria, have been noted,60 as has autonomic
nerve dysfunction, predominantly sympathetic.59,62 An asso-
ciation between chronic cannabis abuse and cyclic vomiting
has been well documented, at least in male patients in com-
munity studies, and the so-called cannabinoid hyperemesis
syndrome has been described in long-term users of cannabis.63
A useful diagnostic feature is the associated urge to take
hot baths or showers during the active phase of the illness.
Patients who discontinue cannabis recover completely.
Diagnostic evaluation of cyclic vomiting should proceed
along the lines described for chronic vomiting (see later), with
an emphasis on excluding neurologic diseases, chronic partial
small bowel obstruction, and disordered gastric emptying.
Testing for mitochondrial disorders (chiefly mitochondrial
neurogastrointestinal encephalopathy [MNGIE]; see Chapter
36) and food allergies or intolerances (see Chapter 10) should
also be considered. Identification of factors that trigger attacks
may help prevent them.
The psychological aspects of cyclic vomiting syndrome
require special consideration. Clinicians should refrain from
the temptation to attribute cyclic vomiting to purely psycho-
logical factors. Careful studies have shown that only 1 in 5
adult patients with cyclic vomiting syndrome has an anxiety
disorder or other psychiatric disease, but patients may note
that tension and stress precipitate episodes of vomiting.
Treatment of cyclic vomiting syndrome is mostly empiri-
cal; formal therapeutic trials have not been conducted.
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Chapter 15  Nausea and Vomiting    213
Dehydration and metabolic complications may require admis-
sion to the hospital and intravenous corrective measures. Con-
ventional antiemetics are used but rarely abort an episode of
vomiting. Intravenous ondansetron may be useful, at least in
children.64
That some patients have a personal or family history of
migraines has stimulated the use of antimigraine drugs, espe-
cially serotonin 5-HT1 agonists (e.g., sumatriptan) given by a
subcutaneous, transnasal, or oral route. Such drugs are rela-
tively contraindicated in patients with a history of ischemic
heart disease, ischemic stroke, and uncontrolled hypertension.
Similarly, β-adrenergic receptor blockers like propranolol have
been used as preventive therapy and have reportedly helped
some patients by reducing the frequency of or abolishing
vomiting spells. Tricyclic antidepressants are effective in about
two thirds of both adults and children, according to non–
placebo-controlled cohort studies.58,65 Other agents anecdot-
ally reported to help include serotonin reuptake inhibitors,
cyproheptadine, naloxone, carnitine, valproic acid, and eryth-
romycin. Even though habitual cannabis abuse may appar-
ently induce cyclic vomiting syndrome, other reports have
emphasized the therapeutic value of marijuana smoking in
patients with the syndrome. Nevertheless, the best option
seems to be to discourage cannabis use. Spontaneous resolu-
tion of the syndrome after long periods of activity (7 years, on
average) has been observed.66
Superior Mesenteric Artery Syndrome
Although some objective basis exists for superior mesenteric
artery (SMA) syndrome, the diagnosis tends to be applied
inappropriately to patients with functional vomiting or cyclic
vomiting syndrome, who then are unfortunately subjected to
unnecessary surgery.67 The SMA branches off the aorta at an
acute angle, travels in the root of the mesentery, and crosses
over the duodenum, usually just to the right of the midline
(see Chapter 118). In some persons, possibly because the angle
between the aorta and the SMA is or becomes more acute than
normal, the duodenum is partially obstructed and the patient
becomes symptomatic, usually when precipitating factors
accentuate vascular compression of the duodenum.68 Such
precipitating factors include increased lordosis (as may occur
with a body cast), loss of abdominal muscle tone, rapid weight
loss (which may be precipitated by a psychiatric condition),
and abdominal surgery followed by prolonged bed rest. A
somewhat analogous situation has been described in conjunc-
tion with PUD, acute pancreatitis, or other intra-abdominal
inflammatory conditions that may compress the mesenteric
vessels.
Symptoms associated with SMA syndrome include epigas-
tric fullness and pressure after meals, nausea and vomiting
(often bilious because the obstruction occurs distal to the
ampulla of Vater), and midabdominal pain. Some patients
obtain relief from adopting a prone or knee-chest position.
The diagnosis is supported by imaging tests (upper GI
barium contrast study or CT) that show dilatation and stasis
proximal to the duodenum where the SMA crosses it. The
appearance may be misleading, however, because duodenal
dilatation may be caused by atony rather than mechanical
obstruction.67 As noted earlier, SMA syndrome is often over-
diagnosed. Before surgical correction is considered, stasis
proximal to the site of duodenal obstruction should be dem-
onstrated on contrast studies and, in some cases, scintigraphic
tests. In specialized centers, intestinal manometry may be per-
formed and demonstrates characteristic patterns that distin-
guish mechanical obstruction from a motility disorder. Finally,
a feeding catheter should be passed across the obstruction into
the proximal jejunum (with endoscopic assistance if required)
214    Section III  Symptoms, Signs, and Biopsychosocial Issues
to demonstrate that vomiting does not occur when the obstruc-
tion is bypassed and, if necessary, to replete the patient’s
nutritional status.
If SMA syndrome has been precipitated by any of the
factors noted, the precipitating factor should be corrected
if possible. If the syndrome has developed acutely, patience
is required because the condition may self-correct with
gastric decompression combined with intravenous fluid
replacement. Only infrequently in well-investigated patients
with chronic relapsing episodes of SMA syndrome should
corrective surgery be undertaken. The surgical technique most
commonly recommended is a laparoscopic proximal duode-
nojejunostomy69; a gastrojejunostomy may not be effective
because the proximal duodenum is not decompressed by this
approach.
Rumination Syndrome
Rumination resembles vomiting but does not involve an inte-
grated somatovisceral response coordinated by the emetic
center. Rather, it consists of repetitive effortless regurgitation
of small amounts of recently ingested food into the mouth,
followed by rechewing and reswallowing or expulsion.70
Characteristically, nausea and autonomic manifestations (e.g.,
hypersalivation, cutaneous vasoconstriction, sweating) that
usually accompany vomiting are absent. In many ruminators,
the process begins while the person is eating or immediately
following completion of a meal. In some ruminators, rumina-
tion ceases when the regurgitated material becomes noticeably
acidic. Others continue to ruminate for hours, however. In
infants, in whom rumination was first described, rumination
is relatively common and typically develops between 3 and 6
months of age. The rumination process occurs without appar-
ent distress to the ruminator and ceases when the baby is
distracted by other events or sleeps, but undernutrition and
dehydration that can lead to serious complications may occur.
In adults, rumination occurs in men and women with equal
frequency and at any age. According to the Rome III commit-
tee,56 rumination constitutes a distinct and unique category of
functional gastroduodenal disorders.
The clinical significance of rumination varies. Some other-
wise healthy persons ruminate frequently without consider-
ing the practice abnormal. Others, under pressure from family
or friends, consult a health care provider, who may mistakenly
interpret rumination as habitual vomiting. Some ruminators
seek medical attention because of the concern that they are
unable to control the process. Physicians unaware of rumina-
tion may mistakenly attribute the symptoms to gastroesopha-
geal reflux, achalasia, or gastroparesis and thereby delay
making the correct diagnosis and instituting appropriate man-
agement. Alternatively, rumination is frequently associated
with heartburn, epigastric discomfort, and changes in bowel
habits in patients who have concomitant GERD, functional
dyspepsia, or irritable bowel syndrome, respectively. Weight
loss may occur and suggest a possible eating disorder.
Diagnosis of rumination involves several steps. First,
typical features of rumination, as described earlier, should be
confirmed by careful history taking. Second, organic diseases,
chiefly achalasia or other esophageal motility disorder, gastric
outlet obstruction, and gastroparesis, should be excluded (see
earlier). Detection of esophagitis at endoscopy does not
exclude rumination. Third, diagnostic tests for rumination can
be performed (see later). Fourth, the coexistence of rumination
with another functional disorder should be considered.
Rumination may be diagnosed in most patients by its
typical clinical features, but in equivocal cases the diagnosis
may be confirmed by special tests. Combined upper GI
manometry and esophageal pH testing may show rapid
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declines in esophageal pH in concurrence with sharp phasic
pressure spikes recorded in the antrum and duodenum on
manometry. The spikes correspond to abrupt increments in
intra-abdominal pressure as the patient involuntarily or vol-
untarily forces subdiaphragmatic intragastric content toward
the esophagus through a relaxed lower esophageal sphincter.
High-resolution esophageal manometry and impedance
testing after a meal may help differentiate rumination from
other belching and regurgitation disorders.71,72
An association between rumination and anorexia nervosa
or bulimia has been reported. In 1 study, 20% of patients with
bulimia were found to ruminate, although they tended to
expel rather than reswallow the regurgitated portion of the
meal. In patients with bulimia, rumination may be a learned
behavior used for controlling weight without resorting to (or
in addition to) frank vomiting (see Chapter 9).
The pathophysiology of rumination syndrome has been
elucidated only partially. Most likely, rumination represents
an adaptation of the belch reflex. During the spurting retro-
grade movement of gastric content, the gastroesophageal junc-
tion appears to move into the thorax, thereby creating a
“pseudohernia” that facilitates opening of the lower esopha-
geal sphincter.73 A distinct subgroup of ruminators have
“reflux-related” rumination with abdominogastric strain that
is synchronized with gastroesophageal common cavity reflux
events.74
Treatment of rumination involves several steps. Patients
with heartburn and endoscopic evidence of esophagitis should
be treated with a proton pump inhibitor. Reassurance and
careful explanation of the phenomenon may permit some
patients to control rumination on their own. Behavior modifi-
cation is the most effective therapy and may be accomplished
by teaching the patient special diaphragmatic breathing tech-
niques75 or with the help of biofeedback training. The rumina-
tion behavior is eliminated by these habit reversal techniques
because rumination and the competing response (diaphrag-
matic breathing) cannot be performed at the same time. Phar-
macologic treatment includes baclofen, a γ-aminobutyric acid
(GABA) agonist that increases lower esophageal sphincter
pressure and decreases the swallowing rate. The standard
adult dose is 10 mg orally 3 times daily.76
EVALUATION
Acute Vomiting
A number of diagnostic tests can be used to evaluate acute
vomiting.
Basic Tests
As noted earlier, evaluation of a patient with acute vomiting
should begin with a carefully obtained history and a physical
examination that focuses on the patient’s volume status. An
algorithm for management of the patient with acute vomiting
is shown in Figure 15-3. A urine pregnancy (HCG) test should
be performed in all women of childbearing potential who have
acute vomiting. Routine blood studies should include a com-
plete blood count, tests of kidney function, thyroid function
tests, liver biochemical tests, electrolyte, glucose, serum
amylase and lipase levels, and in some cases, arterial blood
gases to assess the patient’s acid-base status.
Imaging
Plain abdominal radiographs, lying and standing, should
be obtained. If the films suggest small bowel obstruction,
 Chapter 15  Nausea and Vomiting    215

Obtain relevant medical history, basic blood tests,

and pregnancy test, if applicable

Chemotherapy, Suspicion of Suspicion of drug- Neurologic Electrolyte

radiotherapy, gastrointestinal or toxin-induced or vestibular or glucose
or surgery? or systemic emesis? manifestations? imbalance?
infection?
Yes Yes Yes

Standard management Remove offending agent. Correct metabolic

with 5-HT3 antagonist, If uncertain, perform derangements.
glucocorticoids toxicology screen or Consider testing for
measure drug level. adrenal insufficiency
Central antiemetics Antiemetic agent, e.g.,
metoclopramide
0.1-1 mg/kg/6 hr
intravenously
Yes No Yes

Confirm by cultures, MRI/CT of the brain,

serologic testing, imaging other neurologic and ENT
studies, as appropriate. studies, if necessary
Antiemetic agent, e.g.,
metoclopramide
0.1-1 mg/kg/6 hr
intravenously
Motion sickness:
No Gastrointestinal No Yes antihistamine or
obstruction muscarinic M1 blockers
suspected? Other neurologic disorder :
central antiemetics
No
Yes

Abdominal CT,
upper endoscopy, or UGI
series

Investigate possible No Mechanical obstruction Yes

motility disorder, other confirmed? Specific treatment
less common causes

FIGURE 15-3. Algorithm for management of a patient with acute vomiting. Possible treatments are italicized. ENT, ear, nose, and throat;
5-HT, 5-hydroxytryptamine; UGI, upper GI. Potential treatments are shown in italics.

further testing to ascertain the cause of obstruction (includ-
ing abdominal exploration) should be undertaken (see
Chapter 123).
If plain abdominal films are negative, additional tests can
be considered. Upper endoscopy can be performed to look
for mucosal lesions, ulcer, neoplasia, and gastric outlet or duo-
denal obstruction. CT of the abdomen can be performed to
look for painless appendicitis, acute intestinal ischemia,
obstruction, or pseudo-obstruction. US may substitute for CT
but tends to be less revealing in this setting. MRI of the brain
can be performed to look for a mass lesion or other neurologic
cause of vomiting.
Additional Tests
If the results of the aforementioned tests are negative, further
testing can be considered, including blood levels of drugs and
toxins (specifically digoxin, opiates, theophylline, ethanol, and
carbamazepine), cultures of blood or body fluids if an infec-
tion is suspected, analysis of cerebrospinal fluid following
lumbar puncture, and serologic tests for viral hepatitis if indi-
cated. If appropriate, blood levels of cortisol, corticotropin-
releasing factor, and catecholamines can be determined.
Chronic Vomiting
A detailed clinical history and careful physical examination
(primarily to exclude other diagnoses) are central to diagnos-
ing functional dyspepsia, functional vomiting, cyclic vomiting
syndrome, and rumination syndrome. Upper GI endoscopy
or an upper GI barium study (often both) are the tests of
choice for partial gastric outlet obstruction and partial duode-
nal obstruction. Barium contrast studies may suggest a diag-
nosis of achalasia, gastroparesis (missed by endoscopy), or
neoplasm. CT of the abdomen is particularly useful for estab-
lishing the presence of partial intestinal obstruction secondary

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216    Section III  Symptoms, Signs, and Biopsychosocial Issues
to an intrinsic intestinal lesion or an intra-abdominal disease
that can cause intestinal obstruction. CT enterography pro-
vides information on the degree of bowel dilatation, bowel
wall thickness, and point of transition of the caliber of the
intestinal lumen. Intra-abdominal masses and retroperitoneal
pathology (e.g., pancreatitis, appendicitis, peritonitis, infarc-
tion) can be detected by CT.77 By contrast, plain films of the
abdomen are often unreliable, particularly in the presence of
fluid-filled loops of bowel. MR enterography is an alternative
to CT enterography and has the advantage of not exposing
patients to radiation.78
MRI of the head is used to diagnose CNS lesions that may
cause vomiting, including slow-growing tumors, hydrocepha-
lus, and inflammatory, vascular, and ischemic lesions.
Motility tests are useful for evaluating motor disorders like
gastroparesis and chronic intestinal pseudo-obstruction, rela-
tively uncommon but important causes of nausea and vomit-
ing. Various tests are available (see Chapters 49, 99, and 124).
Esophageal Manometry
Esophageal manometry, preferably high-resolution manome-
try, is used to assess esophageal motor activity. Patients with
esophageal motility disorders may occasionally present with
vomiting. Achalasia may produce pseudovomiting and prog-
ress unrecognized for years. Similarly, manometry may detect
distal esophageal spasm and other motor disturbances of the
smooth muscle portion of the esophagus that may present
with or without characteristic symptoms (see Chapter 43).
Measurement of Gastric Emptying
Radioscintigraphy is the preferred and most accurate method
of assessing gastric emptying. Ideally, dual markers (1 for
solids, 1 for liquids) should be used and the test performed
with a dual-headed gamma camera. Symptoms of gastropare-
sis are primarily associated with delayed solid emptying.79
Alternative but less precise methods of assessing gastric emp-
tying include gastric 3-dimensional US80 to assess emptying of
a liquid meal and the 13C breath test with octanoate acid, a
fatty acid that is labeled with a stable isotope and incorporated
into a test meal. The rate at which 13CO2 is exhaled reflects the
rate of gastric emptying and subsequent duodenal absorption
of the lipid marker, but the diagnostic reliability of this breath
test is not firmly established (see Chapter 49).81 Other potential
diagnostic modalities are a wireless motility capsule, MRI, and
single photon emission CT.80,82
Cutaneous Electrogastrography
EGG with cutaneously placed electrodes identifies dysrhyth-
mia (e.g., bradygastria or tachygastria) of the gastric pace-
maker and changes in the frequency of pacemaker activity
in response to feeding. Potential advantages of this test are
its noninvasiveness and relative simplicity. Disadvantages
include its unreliability (although multichannel EGG and
computerized spectral analysis have boosted its potential
value37,83) and a lack of correlation with clinical symptoms;
identified abnormalities may or may not be related to the
patient’s symptoms. Certain EGG anomalies may be second-
ary to nausea rather than the cause of nausea, although this
issue is still subject to debate (see Chapter 49).
GI Manometry
GI manometry is probably the most reliable physiologic test
for assessing motor disturbances of the upper GI tract. Intra-
luminal pressure changes are recorded via a pressure-sensitive
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catheter at sites located in the antrum and small bowel. The
test is cumbersome, expensive, technically challenging to
perform, and available at only a few centers that specialize in
GI motility disorders. Manometry may distinguish myogenic
from neurogenic forms of pseudo-obstruction and may help
detect partial small bowel obstruction on the basis of wave
pattern analysis (see Chapters 49, 123, and 124). If GI mano-
metric studies are abnormal, a laparoscopic full-thickness
biopsy of the small bowel should be considered to diagnose
genetic and acquired myogenic or neurologic causes of chronic
intestinal pseudo-obstruction.
Autonomic Function Tests
Autonomic function tests can be used to assess sympathetic
function, as with the tilt table test (an orthostatic challenge
to blood pressure and cardiac rate regulation) and the cold
hand test (a pain reflex test in which the hand is immersed
in cold water to produce vasoconstriction and, normally, a
significant increase in systolic arterial pressure). Parasympa-
thetic function may also be assessed by measuring variations
in the RR interval on the electrocardiogram in response
to bradycardia induced by deep respiration (via a vasovagal
reflex) and by a voluntary Valsalva maneuver. Results of
such tests can help distinguish visceral autonomic neuropa-
thies (e.g., due to amyloidosis or diabetes mellitus) from a
central autonomic disorder (e.g., Shy-Drager syndrome,
pandysautonomia).
Histopathologic Studies
In some patients, a further diagnostic step may involve histo-
pathologic study of mucosal biopsies for quantification of
nerve density and morphology to search for evidence of auto-
nomic neuropathy.84
COMPLICATIONS
Vomiting, particularly when protracted or recurring, can lead
to a number of potentially life-threatening complications.
Emetic Injuries to the Esophagus and Stomach
Chronic protracted vomiting often produces esophagitis.
The endoscopic severity may range from mild erythema to
erosions and ulcerations. Characteristically the esophagitis
extends uniformly throughout the body of the esophagus,
as opposed to esophagitis associated with gastroesophageal
reflux disease, which tends to be more pronounced distally.
Patients often experience heartburn or retrosternal pain
after an acute bout of vomiting. By contrast, patients with
chronic vomiting rarely complain of chest symptoms, and the
esophagitis associated with long-standing vomiting is often
asymptomatic.
Abrupt retching or vomiting episodes may also induce
longitudinal mucosal and even transmural lacerations at the
level of the gastroesophageal junction. When the lacerations
are associated with acute bleeding and hematemesis, the clini-
cal picture is described as Mallory-Weiss syndrome (see Chapter
20). Boerhaave’s syndrome refers to spontaneous rupture of the
esophageal wall, with free perforation and secondary medias-
tinitis, and carries a high mortality rate.85 It is more common
in alcoholics, although esophageal rupture may develop in
any person during vomiting (see Chapter 46).
Multiple purpuric lesions may appear on the face and
upper neck after prolonged episodes of vomiting, probably

because of repetitive increases in intrathoracic pressure and
rupture of blood vessels. Dental caries and erosions may result
from chronic vomiting.
Spasm of the Glottis and Aspiration Pneumonia
Spasm of the glottis and transient asphyxia may develop
during vomiting as a result of irritation of the pharynx by
acidic or bilious material. Similarly, vomiting during insertion
of a nasogastric tube or during endoscopy, when the patient’s
consciousness is diminished, or in an older person or patient
with a depressed cough reflex may be associated with aspira-
tion of gastric contents into the bronchi, with resulting acute
asphyxia and a subsequent risk of aspiration pneumonia.
Aspiration is more likely to occur when the stomach contains
food or enteric secretions than when it is empty.
Fluid, Electrolyte, and Metabolic Alterations
Fluid, electrolyte, and metabolic abnormalities may develop
rapidly after protracted vomiting. The clinical picture is that
of dehydration, hypotension, hemoconcentration, oliguria,
muscle weakness, and cardiac arrhythmias. Hypochloremic
alkalosis is usually the first metabolic abnormality to develop
and is due to loss of fluid and hydrogen and chloride ions.
Hypokalemia is usually present as a result of loss of potassium
ions in the vomitus and renal potassium wasting secondary to
alkalosis. Hyponatremia may occur in severe cases because of
loss of sodium and release of antidiuretic hormone in an
attempt to conserve intravascular volume. This pattern of
metabolic derangements associated with chronic vomiting
should alert the clinician to the possibility of chronic func-
tional or self-induced vomiting, despite the patient’s denial. A
diagnostic clue is that metabolic alkalosis secondary to vomit-
ing is typically associated with low urinary chloride excretion,
which suggests extrarenal loss of chloride.
Nutritional Deficiencies
Nutritional deficiencies may result from reduced caloric intake
or loss of nutrients in the vomitus. Regardless of cause, nausea
and vomiting can result in malnutrition, weight loss, and defi-
ciency states that require correction (see Chapter 5).
TREATMENT
Effective management of the patient with nausea and
vomiting requires correction of clinically relevant metabolic
complications, pharmacologic therapy, and treatment of the
underlying cause.
Correction of Metabolic Complications
Patients with acute, severe, or repeated vomiting may become
rapidly dehydrated and experience metabolic imbalances, sec-
ondary circulatory collapse, and kidney failure. If oral intake
is not possible, intravenous fluids and electrolytes should be
administered promptly. Adequate replacement generally con-
sists of a normal saline solution in volumes sufficient to correct
deficits (and in addition to maintenance fluids) with potas-
sium supplementation (60 to 80 mEq/24 hr). The saline can be
administered with glucose (e.g., 5% dextrose in normal saline),
and in some cases a 10% glucose solution may be required.
When oral intake can be resumed, glucose-containing fluids
are preferred because they are easily absorbed from the intes-
tine. A split-meal, low-fat, and low-fiber solid diet can be
gradually introduced.
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Chapter 15  Nausea and Vomiting    217
Patients with long-standing chronic vomiting are at risk of
developing malnutrition, so enteral or parenteral feeding
should be considered when the patient is unable to resume
adequate oral nourishment after 5 to 8 days. Although enteral
nutrition is a good option, even orogastrojejunal catheters
placed with guidewires may be dislodged during episodes of
vomiting. For long-term treatment, home parenteral nutrition
may be required (see Chapter 6).
Pharmacologic Treatment
Drugs used to treat nausea and vomiting belong to 1 of 2 main
categories: central antiemetic agents and peripheral prokinetic
agents. Some drugs share both mechanisms of action, with
variable predominance of 1 or the other. (Doses indicated are
for adult patients.)
Central Antiemetic Agents
Central antiemetic agents are classified according to the pre-
dominant receptor on which the drug acts. Virtually all may
be administered orally or parenterally (either single, repeat
boluses or continuous intravenous infusion).86 Some have
transdermal formulations.
Dopamine D2 Receptor Antagonists
Benzamides.  The main antiemetic effect of benzamides (e.g.,
metoclopramide, clebopride) is exerted centrally in the emetic
center through antagonism of the dopamine D2 receptor.
These agents also stimulate peripheral 5-HT4 receptors,
thereby facilitating acetylcholine release and acting as antro-
duodenal prokinetic agents.
Side effects limit the use of these drugs. Metoclopramide,
if administered rapidly by the intravenous route, may cause
acute restlessness and anxiety. Repeated oral administration
may induce somnolence in some patients. In about 1% of
treated patients, distressing extrapyramidal effects, including
dystonic reactions and tremor, may appear and limit their use,
particularly at high doses. Older patients are at particular risk
of tardive dyskinesia.87 Metoclopramide may prolong the QT
interval and thus has an arrhythmogenic potential.
The most common indications for these drugs are nausea
and vomiting of pregnancy, postoperative nausea and vomit-
ing, and chemotherapy- and radiotherapy-induced nausea
and vomiting. Because of their associated gastric prokinetic
action, the drugs can be used for gastroparesis related to dia-
betes mellitus, prior vagotomy, and prior partial gastrectomy.
The standard dose of metoclopramide is 10 to 20 mg 3 or 4
times daily orally or intravenously.
Benzimidazole Derivatives.  Domperidone is the chief representa-
tive of this class of antiemetics.88 The drug crosses the blood-
brain barrier poorly and acts primarily as a peripheral
dopamine D2 receptor antagonist. It blocks the receptors cen-
trally in the area postrema (which is partly outside the blood-
brain barrier) and in the stomach, where D2 receptor inhibition
decreases proximal gastric relaxation and facilitates gastric
emptying. Although domperidone is a weaker antiemetic than
metoclopramide, it may be particularly useful for the manage-
ment of nausea and vomiting secondary to treatment with
levodopa in patients with Parkinson’s disease, because it
antagonizes the proemetic side effects of levodopa without
interfering with its antiparkinsonian action in brain centers
protected by the blood-brain barrier. The standard dose is 10
to 20 mg 3 or 4 times daily orally. A review of domperidone
use in the treatment of diabetic gastroparesis has concluded
that the drug is probably useful but has not been properly
evaluated by well-designed controlled trials. Responses may
218    Section III  Symptoms, Signs, and Biopsychosocial Issues
be influenced by genetic characteristics.89 Domperidone (as
well as benzamides) may increase the release of prolactin and
is occasionally associated with breast tenderness and galactor-
rhea. It has also been noted to prolong the QT interval on the
electrocardiogram.
Phenothiazines and Butyrophenones
The phenothiazines (chlorpromazine, perphenazine, prochlor-
perazine, promethazine, and thiethylperazine) and butyro-
phenones (droperidol and haloperidol) also block D2
dopaminergic receptors and, in addition, block muscarinic M1
receptors. Phenothiazines also block histamine H1 receptors.
These drugs tend to induce relaxation and somnolence and are
generally used parenterally or as suppositories in patients
with acute intense vomiting of central origin, as occurs with
vertigo, migraine headaches, and motion sickness. They are
also useful for patients with vomiting secondary to toxic
agents and chemotherapy and after surgery.90,91 Safety con-
cerns, including not uncommon extrapyramidal effects, have
limited the use of all these agents to some degree.92 For this
reason, the dose of droperidol should not exceed 1 mg. Olan-
zapine, a second-generation neuroleptic agent is an attractive
alternative because of its strong antinausea and antiemetic
action and lack of extrapyramidal side effects.93,94 It may also
be used in combination with other agents like dexamethasone
or an NK-1 antagonist.
Antihistamines and Antimuscarinic Agents
Antihistamines and antimuscarinic agents primarily act by
blocking histamine H1 receptors (cyclizine, dimenhydramine,
cinnarizine, meclizine, hydroxyzine) and muscarinic M1
receptors (scopolamine, which may be applied transdermally)
at a central level.95 The last agent may be associated with
annoying visual accommodation disturbances.96 Prometha-
zine belongs to the phenothiazine class but acts as an antihis-
taminic H1 and antimuscarinic agent with strong sedative
properties. Cyclizine and diphenhydrinate are commonly
used to treat motion sickness and have been shown to decrease
gastric dysrhythmia, so their antiemetic effect may be medi-
ated in part by their peripheral action. A standard antiemetic
dose of cyclizine is 50 mg given 3 times daily orally or 100 mg
as a suppository. The main indication is nausea and vomiting
associated with motion sickness and vestibular disease. Cycli-
zine is useful for postoperative and other forms of acute vom-
iting. Some of these drugs are also used as antipruritic agents.
Drowsiness is the major limiting side effect, particularly for
the older agents, but this effect may be advantageous in the
treatment of acute vomiting. Anticholinergic effects are poten-
tially troublesome in patients with glaucoma, prostatic hyper-
plasia, and asthma.
Serotonin Antagonists
Serotonin 5-HT3 receptor antagonists (ondansetron, granise-
tron, dolasetron, tropisetron) are potent antiemetics that selec-
tively block 5-HT3 receptors in the emetic center and in gastric
wall receptors that relay afferent emetic impulses through the
vagus nerve. In addition to their antiemetic effect, they have
a modest gastric prokinetic action. The main indication for this
class of drugs is nausea and vomiting associated with chemo-
therapy or radiation therapy or following surgery. They are
often prescribed in combination therapy with haloperidol and
dexamethasone, with or without an NK-1 antagonist.97 Head-
ache is a common side effect. Ondansetron appears to be safe
in pregnancy. It may be given as a single dose of 8 to 32 mg,
intravenously in a dose of 0.15 mg/kg every 8 hours, or orally
in a dose of 12 to 24 mg every 24 hours in 3 divided doses.
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There is a risk of QT prolongation with high doses of ondan-
setron.98 Granisetron is available in a transdermal patch form.99
Palonosetron, a second-generation agent, exhibits unique
interactions with the 5HT3 receptor100 and appears to be more
effective than first-generation 5HT3 receptor antagonists101-103
and the only effective agent for preventing delayed nausea
and vomiting.104
Glucocorticoids
The antiemetic mechanism of glucocorticoids is not well
understood. It may relate to inhibition of central prostaglandin
synthesis, release of endorphins, or altered synthesis or release
of serotonin. The principal indication is treatment of nausea
and vomiting in the postoperative period or as a result of
chemotherapy or radiation. Glucocorticoids may also be used
to reduce cerebral edema and hence alleviate vomiting sec-
ondary to increased intracranial pressure. Dexamethasone is
the formulation used acutely, in doses ranging from 8 to 20 mg
intravenously and 4 mg every 6 hours orally. Side effects are
uncommon because treatment is usually administered for
short periods. In diabetic patients, however, careful monitor-
ing of blood glucose levels is required. In patients with a
history of peptic ulcer or with a gastroenteric anastomosis,
concurrent administration of a gastric antisecretory agent is
advisable. In practice, dexamethasone is often used in combi-
nation with another antiemetic agent, such as haloperidol,
olanzapine, metoclopramide, or a 5-HT3 antagonist.105
Cannabinoids
Synthetic cannabinoids are becoming part of the standard
therapeutic armamentarium. Two oral formulations are avail-
able: nabilone and dronabinol. Both are approved by the U.S.
Food and Drug Administration (FDA) for use in chemotherapy-
induced nausea and vomiting refractory to conventional anti-
emetic therapy. The combination of a dopamine antagonist
and a cannabinoid may be particularly effective in preventing
nausea that has a major negative impact on a patient’s quality
of life.106,107 Mood-enhancing properties make cannabinoids
attractive to patients, but these drugs are potentially more
toxic than conventional antiemetic agents. Hypotension and
psychotropic reactions are relatively common side effects.
These drugs should be used with caution in older adults and
in patients with a history of mental illness. Side effects and
more attractive alternatives have removed cannabinoids as
first-line agents in the management of chemotherapy-induced
emesis, although they may remain useful for breakthrough
nausea and vomiting.108
Neurokinin-1 Receptor Antagonists
NK-1 receptor antagonists, which inhibit substance P and
NK-1, are potent antiemetic agents. Two formulations are
available, aprepitant (oral) and fosaprepitant (parenteral),109
and others (e.g., rolapitant)110 are undergoing evaluation.
These drugs appear to provide better protection against post-
operative vomiting but not nausea when compared with
5-HT3 antagonists. NK-1 receptor antagonists may be particu-
larly useful when combined with other drugs like 5-HT3
antagonists and dexamethasone and are FDA approved for
use in preventing vomiting in patients undergoing cancer
chemotherapy.97
Adjuvant Agents and Therapies
Patients with acute nausea and vomiting associated with
chemotherapy, radiotherapy, and surgery often have anxiety
that may exacerbate their symptoms. The anxiolytic effects

of benzodiazepines (e.g., lorazepam, alprazolam) may potenti-
ate the antiemetic action of agents like 5-HT3 receptor antago-
nists and glucocorticoids that are devoid of psychotropic
effects. Gabapentin may help prevent delayed nausea and
vomiting after chemotherapy.111 Ginger has shown some
useful antinausea effects.112 Acupuncture, acustimulation, aro-
matherapy, and acupressure have also been shown to decrease
the nausea associated with motion sickness induced by illu-
sory self-motion and nausea associated with cancer radio-
therapy and chemotherapy, but the evidence is somewhat
controversial.113,114
Gastric Prokinetic Agents
Serotonin 5-HT4 Receptor Agonists
Drugs in the benzamide class share the peripheral 5-HT4
agonist effect of metoclopramide (also a benzamide) without
the dopamine D2 antagonist action that is primarily respon-
sible for the potentially troublesome central side effects of
metoclopramide. Only prucalopride, an agent primarily
intended for treatment of constipation but with some proki-
netic effects in the upper GI tract as well, is currently available
in the United States (see Chapter 19).115
Cinitapride is another agent with pharmacodynamic prop-
erties quite similar to those of cisapride, an older drug that
was associated with cardiac arrhythmias and withdrawn from
the market. At a dose of 1 mg orally 3 times daily, cinitapride
appears to be free of cardiac side effects but is not yet available
in the United States.
The main indication for 5-HT4 agonist drugs is the man-
agement of nausea and vomiting associated with gastropare-
sis, intestinal pseudo-obstruction, and functional dyspepsia.
Motilin Receptor Agonists
Motilin receptor agonists include the antibiotic erythromycin
and other agents—none of which is commonly available—
that act as motilin receptor ligands on smooth muscle cells
and enteric nerves. The pharmacodynamic effects in humans
are dose dependent. In low doses (0.5 to 1 mg/kg as an intra-
venous bolus), erythromycin induces sweeping gastric and
intestinal peristaltic motor activity that resembles phase III of
the interdigestive migrating motor complex but may empty
the stomach inefficiently (see Chapters 49 and 99). In higher
doses (3 mg/kg every 8 hours given as a slow intravenous
infusion), antral activity becomes intense and empties the
stomach rapidly, although the burst of motility does not
always migrate down the small intestine. A simultaneous
increase in small bowel contractions may induce abdominal
cramps and diarrhea. When used clinically as an antibiotic,
generally at higher doses, erythromycin may cause nausea
and vomiting.
In clinical practice, erythromycin may be used to treat
acute nausea and vomiting associated with gastroparesis (dia-
betic, postsurgical, or idiopathic) and to clear the stomach of
retained food, secretions, and blood prior to endoscopy (see
Chapter 20). Although the prokinetic effect is well established,
its symptom-relieving effects have been questioned116; there
is evidence erythromycin modulates vagal nerve traffic,117 a
potential antinausea mechanism. Erythromycin may be
administered intravenously in boluses of 200 to 400 mg every
4 to 5 hours. The lower doses are more appropriate for patients
with pseudo-obstruction, which is associated with reduced
interdigestive sweeping motor activity in the small bowel.
Erythromycin is not suitable for prolonged treatment, first
because of relatively prompt tachyphylaxis and second
because its efficacy by the oral route is uncertain and its
inherent antibiotic properties carry the potential risk of
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Chapter 15  Nausea and Vomiting    219
complications, including pseudomembranous colitis and QT
prolongation. Azithromycin, a structurally similar drug, has
been proposed for the treatment of gastroparesis in slowly
administered intravenous boluses of 250 or 500 mg,118 but
an FDA warning has alerted the public of the potential danger
of azithromycin use in patients with heart disease. New syn-
thetic motilin agonists devoid of antibiotic activity are in
development.
Ghrelin is a peptide structurally and functionally related
to motilin that acts to accelerate postprandial gastric empty-
ing. Ghrelin receptor agonists (e.g., ulimorelin, atilmolin,
mitemcinal) have prokinetic action and may have a future
therapeutic role as prokinetic agents to treat nausea and vom-
iting in patients with gastroparesis.119,120
Gastric Electrical Stimulation
There are 2 main technical approaches to gastric electrical
stimulation. The first is low-frequency/high-energy stimula-
tion (“gastric pacing”) that involves application of high-energy
currents to entrain the gastric slow waves and generate phasic
contractions. This technique may achieve correction of gastro-
paresis and amelioration of nausea and vomiting but requires
external energy sources that limit the autonomy of the
patient. A more recent technical variation, “2-channel gastric
pacing,” has achieved some success in normalizing gastric
dysrhythmia and delayed emptying.121 A second approach,
“gastric neurostimulation,” delivers high-frequency/low-
energy impulses to the stomach with the use of an implantable
neurostimulator like the Enterra system, similar to devices
used to control chronic pain. The gastric neurostimulator does
not entrain slow-wave activity and does not consistently accel-
erate emptying, but it appears to relax proximal gastric tone,
reduces discomfort associated with gastric distension,122 and
produces significant improvement in nausea and vomiting, as
well as the patient’s nutritional status and quality of life,123
even in patients with normal gastric emptying.124 In respond-
ers, symptoms may be ameliorated for at least 5 years, on
average.125 Addition of a pyloroplasty has been proposed to
boost the effectiveness of neurostimulation in patients with
nausea and vomiting associated with gastroparesis.126
Gastric neurostimulation is not without risk123; commonly
reported complications include electrode dislodgement, infec-
tion, and bowel obstruction. The device is also expensive and
may be recommended with caution only for long-standing (at
least 1 year’s duration) refractory gastroparesis. A trial of tem-
porary neurostimulation via endoscopically placed electrodes
is feasible.127
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Chapter 15  Nausea and Vomiting    220.e3
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