Nausea and Vomiting in Adolescents and Adults

Rahul Kuver, M.D. , John V. Sheffield, M.D. , and George B. McDonald, M.D.

1.0 Introduction

Nausea means feeling "sick to the stomach", a sensation that is associated with the urge to
vomit. Vomiting, the forceful discharge of gastric contents, may be a protective physiologic
mechanism that prevents entry of potentially harmful substances into the gastrointestinal tract
(1). Persistent vomiting can lead to dehydration, severe alkalosis, bleeding and rarely
esophageal perforation -- irrespective of the cause of vomiting.

Vomiting is to be differentiated from retching, regurgitation or rumination. Retching or dry

heaves involves the same physiological mechanisms as vomiting, but occurs against a closed
glottis; there is no expulsion of gastric contents. Regurgitation is the return of small amounts of
food or secretions to the hypopharynx in the context of mechanical obstruction of the
esophagus, gastroesophageal reflux disease or esophageal motility disorders. Rumination is
similar to regurgitation, except small amounts of completely swallowed food are returned to the
hypopharynx from the stomach and is often re-swallowed (2). Rumination is not associated with
nausea.

This review of nausea and vomiting is based on a MEDLINE literature search encompassing
1990-2000, using the MeSH headings Nausea and Vomiting with the subheadings
Complications, Diagnosis, Drug Treatment, Treatment, Etiology, Psychology and Radiography.
Certain articles, including placebo-controlled trials of therapy, comprehensive reviews and other
publications deemed seminal, were reviewed and are referenced. Certain articles prior to 1990
were also reviewed. The emphasis is placed on articles that provide evidence which can be
incorporated into guidelines for diagnosis and management.

Certain patients typically present with nausea and vomiting, such as cancer chemotherapy
patients, patients recovering from general anesthesia, pregnant women and patients whose
symptoms are related to motion. Many of these patients are seen in the primary care setting. In
most cases, the history can point to the etiology without the need for sophisticated diagnostic
testing or referral. In a minority of patients, unusual causes of nausea and vomiting may require
thorough diagnostic testing and referral to a specialist (1).

Assessment of the duration of nausea and vomiting is an important initial point in the history.
Symptoms present for less than a week may be due to conditions which are separable from
those causing symptoms over weeks, months or years.

For acute nausea and vomiting, the diagnostic algorithm is based on three key
questions (Table 1):

1. Whether immediate therapy is needed due to the consequences of nausea and vomiting
regardless of the underlying cause
2. Whether empiric treatment and reassurance are sufficient
3. Whether expeditious work-up is required to establish the cause.
For chronic nausea and vomiting, the diagnostic algorithm is based on history and physical
exam findings that point to the organ system involved: the gastrointestinal tract, the nervous
system or the endocrine system. Psychogenic causes are an important additional category to
consider in chronic nausea and vomiting. A subset of patients will have no cause identified
despite extensive diagnostic testing. This group of patients may benefit from referral to
specialized centers. Certain presentations prompt referral to a gastroenterologist (Table 12).

1.1 Associated Symptoms

Certain symptoms are typically associated with nausea and vomiting. Associated upper GI tract
complaints such as bloating, early satiety, dysphagia and odynophagia should be sought.
Dyspepsia can be associated with nausea. Lightheadedness, abdominal or chest pain, cough or
hematemesis are symptoms that should prompt an assessment for conditions that may require
immediate therapy regardless of the underlying cause of nausea and vomiting. A missed
menstrual period, vertigo, arthralgias, low grade fevers and nausea and vomiting associated
with motion are clues that suggest a condition that may be treated empirically . Symptoms that
are severe, such as chest or abdominal pain, CNS symptoms, fever with chills, a history of an
underlying systemic disease or of immunosuppression should prompt a diagnostic workup.

1.2 Physiology of nausea and vomiting

The vomiting reflex is triggered by stimulation of chemoreceptors in the upper GI tract and
mechanoreceptors in the wall of the GI tract which are activated by both contraction and
distension of the gut as well as by physical damage. A coordinating center in the central
nervous system controls the emetic response. This center is located in the parvicellular reticular
formation in the lateral medullary region of the brain. Afferent nerves to the vomiting center arise
from abdominal splanchnic and vagal nerves, vestibulo-labyrinthine receptors, the cerebral
cortex and thechemoreceptor trigger zone (CTZ).The CTZ lies adjacent in the area postrema
and contains chemoreceptors that sample both blood and cerebrospinal fluid. Direct links exist
between the emetic center and the CTZ. The CTZ is exposed to emetic stimuli of endogenous
origin such as hormones associated with pregnancy and to stimuli of exogenous origin such as
drugs (3). The efferent branches of cranial nerves V, VII, and IX, as well as the vagus nerve and
sympathetic trunk produce the complex coordinated set of muscular contractions,
cardiovascular responses and reverse peristalsis that characterizes vomiting (4).
The area postrema is rich in dopamine receptors and is a target for the antagonists haloperidol,
metoclopramide and the phenothiazines. Histamine-1 and muscarinic cholinergic receptors are
present in the nucleus ambiguus and lateral vestibular nucleus. 5-hydroxytryptamine (5HT)
receptors are present within the area postrema. 5HT can activate dopamine release. The new
5HT3 receptor antagonists have demonstrated efficacy against cytotoxic chemotherapy-induced
emesis (5). Drugs effective against motion sickness--such as promethazine, diphenhydramine
and scopolamine--have little effect against cytotoxic drug-induced emesis.

2.0 Acute nausea and vomiting

Symptoms present for less than a week are defined as acute. The causes of nausea and
vomiting of short duration are often separable from etiologies leading to more chronic
symptoms. In the initial evaluation of a patient presenting with acute nausea and vomiting,
assessment regarding the need for immediate therapeutic intervention regardless of the
underlying cause is important. If immediate therapeutic intervention to correct the consequences
of vomiting are not necessary, or has been performed, then the important questions are whether
empiric treatment of nausea and vomiting and reassurance are sufficient, and whether
expeditious diagnostic work-up to determine the underlying cause is necessary. These latter two
questions are linked, and key historical points can help determine the most appropriate
diagnostic testing and therapy. Referral for additional diagnostic tests and/or management
needs to be considered for a variety of situations.

2.1 Immediate therapeutic intervention is necessary regardless of the cause.

Vomiting with intravascular volume depletion requires immediate intervetion

Certain consequences of vomiting require immediate treatment regardless of the cause. The
diagnosis and treatment of conditions described in this section are outlined in (Table 2). If
vomiting has been severe and protracted, intravascular volume depletion may have occurred,
leading to orthostatic hypotension and renal insufficiency. Hypokalemic hypochloremic
alkalosisresults from loss of gastric hydrochloric acid, increased H+ loss due to renin-
angiotensin-aldosterone and volume contraction. In these situations, intravascular access
should be established and fluid resuscitation instituted prior to diagnostic studies.

Vomiting or retching can cause mucosal injury and bleeding

Either vomiting or retching can lead to mucosal injury (e.g. Mallory-Weiss tear), evident as
hematemesis and/or melena; excessive blood loss may contribute to intravascular volume
depletion. In the case of GI bleeding with a significant drop in hematocrit or signs of
intravascular volume depletion, consultation for upper endoscopy should be obtained. In certain
situations, depending on the findings on endoscopy and the effectiveness of endoscopic
therapy, surgical consultation may be necessary.
 Vomiting can lead to aspiration

Vomitus may be aspirated, leading to respiratory compromise which may be severe enough to
require endotracheal intubation and mechanical ventilation. A corollary to this is the
development of aspiration pneumonitis or pneumonia. In the case of aspiration and hypoxemia,
ensuring a patent airway is of paramount importance. The management of such patients
requires a multidisciplinary approach, and may include the services of an intensivist,
gastroenterologist and primary care physician.

Vomiting or retching can lead to esophageal rupture

Vomiting or retching may cause rupture of the esophagus (Boerhaave syndrome), a surgical
emergency. Boerhaave syndrome deserves special consideration because a high index of
suspicion is required to make a timely diagnosis and surgical intervention is necessary.
Spontaneous rupture of the esophagus is an intrathoracic disaster if left untreated. As noted in a
recent review of all published cases in the literature since 1980 and 18 additional cases (6),
non-specific symptoms such as chest and abdominal pain can lead to mistaken diagnoses such
as pulmonary embolus, myocardial infarction, aortic dissection, spontaneous pneumothorax,
pancreatitis or perforated peptic ulcer. Forty percent of patients had a history of alcoholism, and
41% had peptic ulcer disease. Pain (83%) and vomiting (79%), often associated with dyspnea
(39%) and shock (32%), were the major symptoms. Physical exam may detect crepitus due to
air in the soft tissues of the neck and thorax. Chest and abdominal X-rays may show
subcutaneous emphysema, pneumothorax, pneumomediastinum, pleural effusion and free
mediastinal air. However, up to a third of patients have normal routine X-rays initially (7).
Esophagograms with water-soluble contrast agents are diagnostic in most cases. Thoracic CT
scans may reveal mediastinal air or pleural fluid even when the esophagogram shows no leak
and should be obtained when there is a high degree of suspicion. In the series cited, the
mortality rate was 31%, an improvement on the 50% mortality rate noted prior to 1980.
 Intra-abdominal bleeding is a rare complication of vomiting

Intra-abdominal bleeding is a rare complication of vomiting. Hemoperitoneum has been

described following vomiting. Splenic laceration secondary to persistent emesis in a pregnant
patient was diagnosed at laparotomy (8). Hepatic laceration caused by vomiting leading to
massive intra-abdominal hemorrhage was described (9). In both cases, abdominal pain in the
context of nausea and vomiting was the chief complaint. Surgical intervention is necessary for
diagnosis and treatment. Rectus sheath hematoma, diagnosed by ultrasound or CT, may lead
to abdominal pain, and needs to be considered in the patient who is anti-coagulated (10).
Anticoagulation or low platelet counts may lead to intramural hematomas of the esophagus after
vomiting. The presentation is one of severe substernal or intrascapular pain, hematemesis and
dysphagia.
2.2. Empiric treatment and reassurance are sufficient

If the patient does not have complications of vomiting that require immediate attention, and if the
underlying cause of the nausea and vomiting as suggested by the history does not require
expeditious work-up and therapy, then the patient can be reassured and treated empirically with
anti-emetic agents (Table 11). Before such a decision is made, however, symptoms and signs
that favor a self-limited illness should be reviewed and compared with findings that favor serious
underlying disease. Such a comparison is provided in (Table 3).

Key questions can help identify conditions that can be treated empirically. Certain presentations
and etiologies are sufficiently characteristic as to be identifiable as self-limited. In these
situations, no specific treatment is necessary, or, if specific therapy is available, the benign
nature of the condition precludes the need for an extensive diagnostic evaluation. A majority of
patients seen in the ambulatory care setting falls into this category.

2.2.1 Early pregnancy

If the patient is a woman of child-bearing age, a pregnancy test should be done. Pregnancy-
related nausea and vomiting is common, reported in 70-90% of pregnancies (11)(123). Rising
estrogen and progesterone levels during pregnancy have been implicated, as has maternal
serum prostaglandin E2 levels (124). The onset is usually shortly after the first missed
menstrual period, and symptoms may begin before the woman recognizes that pregnancy has
occurred. Symptoms typically begin by four to six weeks of gestation, peaking in severity by
eight to twelve weeks, and resolving spontaneously by the 20th week (11). Nausea, sometimes
accompanied by vomiting, is noted especially in the morning. In one prospective study of 160
pregnant women, however, "morning sickness" occurred in only 1.8%, whereas 80% reported
nausea lasting all day (125). Symptoms usually disappear by the fourth month of pregnancy,
although they may persist into the third trimester. Babies born to a mother with nausea and
vomiting of pregnancy have birth weights similar to babies born to mothers without these
symptoms. Thus, the prognosis for mother and baby is generally excellent. However, in one
study a higher than normal incidence of antepartum hemorrhage was noted (12). Vomiting
during pregnancy is not teratogenic (13).

If pregnancy-related nausea and vomiting are not characteristic of morning sickness (for
example, has its onset in the second or third trimester and is severe), then other potentially
more serious conditions such as hyperemesis gravidarum, acute fatty liver of pregnancy,
and HELLP syndrome need to be considered.
In general, referral to an obstetrician for management of nausea and vomiting of pregnancy is
indicated for these more serious conditions.

Treatment of Pregnancy-related nausea and vomiting

For typical pregnancy-related nausea and vomiting, reassurance is often all that is needed,
although an anti-emetic may be necessary. Traditionally, dietary advice such as dry toast in the
morning and avoiding fatty foods was offered. Antacids for reflux symptoms associated with
nausea and vomiting may be used. If an anti-emetic is necessary, then antihistamines may be
used and are considered safe for use during pregnancy. The efficacy or safety of
phenothiazines or metoclopramide have not been established for nausea and vomiting of
pregnancy in controlled trials despite their widespread use (11).

Clinical trials assessing the efficacy of anti-emetic therapy are of varialbe quality. An analysis of
such trials showed that anit-histamines, pyridoxine, and P6 acupressure appeared to reduce the
frequency of nausea in early pregnancy (126). A risk-benefit assessment of drug therapy for
nausea and vomiting of pregnancy show that controlled trials demonstrated the safety and
efficacy of dicyclomine, anti-histamine H1 receptor antagonists, and phenothiazines (127). The
pooled data, however, were not homogenous.

A prospective trial comparing pregnancy outcomes in women given metoclopramide in the first
trimester for the treatment of nausea and vomiting in pregnancy compared to women who
received nonteratogenic drugs, showed no increased risk of fetal malformations, spontaneous
abortions, or decreased birth weight of the infants in the metoclopramide group (135).

The effectiveness of pyridoxine (vitamin B6) for nausea and vomiting of pregnancy has been
studied in a randomized, double-blind placebo-controlled trial. Patients in the treatment group
received 30 mg/day of pyridoxine hydrochloride for 5 days. A significant decrease in post-
therapy nausea in the treatment group was noted (14). Similar results were noted for vomiting in
another study over a 3-day duration (15). Acupressure at the P6 point located on the wrist has
also been studied in a randomized, double-blind placebo-controlled study and found to reduce
nausea, but not vomiting, in pregnant patients (16). Sixty women were assigned to two
treatment groups: one to a group receiving P6 acupressure, and a control group receiving
pressure at another anatomic location. Symptom scores after 5-7 days of treatment were used
to judge efficacy. Nausea scores improved over time in both groups, achieving statistical
significance in the acupressure group. In another study, 161 pregnant symptomatic women
were assigned to three groups: P6 acupressure treatment, placebo (acupressure band placed in
an inappropriate location) or control. Improvement in nausea and vomiting or retching was noted
in all three groups, with no statistically significant differences noted in the acupressure group
(17).

2.2.2 Vertigo

Nausea or vomiting associated with vertigo suggests another set of causes. Vertigo is a
sensation of the environment spinning around, often described as dizziness by the patient.
Evaluation of the dizzy patient begins with a thorough history, which can identify the cause in
many patients. If a characteristic change in head position brings on vertigo, benign positional
vertigo is usually the cause, which does not usually lead to nausea and vomiting. Associated
aural symptoms such as hearing loss, fullness in the ears and tinnitus should be ascertained.
Neurologic symptoms such as headache, visual changes or loss of sensation are important to
determine. Loss of consciousness associated with vertigo should be determined.

Peripheral causes of vertigo, such as benign positional vertigo, vestibular neuronitis,

Meniere's disease and acoustic neuroma need to be distinguished from central causes of
vertigo, such as multiple sclerosis, brainstem ischemia and central nervous system tumor. The
physical examination is often helpful in determining whether a peripheral or central cause of
vertigo is present. A complete head and neck exam including examination of the tympanic
membranes is advised. Cranial nerves should be tested, including assessment of extraocular
muscle function. Nystagmus can aid in diagnosis. Nystagmus of peripheral origin is rotatory or
horizontal. Vertical nystagmus is pathognomonic for brain stem disease, as is nystagmus that is
more pronounced in one eye.

Nystagmus may be tested by having the patient look ahead, then 30 degrees to the left and to
the right. Pausing at each position allows evaluation of nystagmus. Induced nystagmus is done
by rapidly changing the position of the head. The Hallpike-Dix (or Nylen-Barany) maneuver is
performed by making the patient undergo a rapid change from the erect sitting position to a
supine position with the head hanging to the left, right or center. A positive test is present when
paroxysmal nystagmus is induced after a brief delay. A positive test is diagnostic for either
benign positional vertigo, which is seldom associated with nausea and vomiting; or a central
nervous system disorder. In order to distinguish the two, the following characteristics of
nystagmus are noted. For benign positional vertigo, a 3-20 second latency, rotatory nystagmus
and adaptation (i.e. less response to repeat testing) is seen. For a central nervous system
cause, no latency is seen, the nystagmus can be vertical or horizontal and can last longer than
60 seconds and there is no adaptation.

Balance testing such as the Romberg test and assessment of the gait should also be
performed. Vertigo can also be an early symptom in multiple sclerosis. Lesions in the lower
midbrain and pons produce internuclear ophthalmoplegia. This is checked for by having the
patient follow the finger of the examiner from side to side horizontally. In this type of nystagmus
the eye on the side to which the gaze is directed participates strongly with a horizontal
nystagmus, whereas the opposite eye will show less nystagmus and weakness of internal
rotation. A careful cardiac examination is also necessary, as arrhythmias can produce
symptoms which are confused with vertigo (18).

Spontaneous and Induced Nystagmus and their Causes

Spontaneous Nystagmus

Symptom/Sign Peripheral Central

Direction Usually horizontal-rotatory Any direction

Never purely vertical May be purely vertical

Direction of fast component Away from side with disease Toward side with disease
 (or direction changing)

Effect of visual fixation Suppressed Not suppressed

Usual anatomical location of Labyrinth or vestibular nerve Brainstem or cerebellum

problem

Induced Nystagmus

Feature Peripheral (BPV) Central

Time to onset after 3-20 seconds Immediate

quick position change
(latency)

Duration Less than 1 minute Persists longer than 1 minute

Fatigability Marked None

Vertigo may be a symptom of a more serious underlying disorder , such as vertebro-basilar

vascular insufficiency or a cerebellopontine-angle tumor. In order to determine which vertiginous
patient needs further diagnostic testing and possible referral, several items in the history are
helpful. Are there associated neurologic symptoms such as headache, visual changes or loss of
sensation and strength, suggesting cortical or brain stem disorders? Is there a history of
seizures? Has the patient lost consciousness with the episode of vertigo? Is there antecedent
cranial or cervical trauma? If the answer is affirmative to any of these questions, then empiric
therapy is not advised.

Referral to a neurologist and possibly a neurosurgeon may be necessary in patients with CNS
symptoms suggestive of a brain stem lesion, vertebro-basilar insufficiency or cortical lesions.
Additionally, in patients with vertigo associated with seizures, referral to a neurologist is
appropriate. If vertigo is associated with syncope, a thorough cardiac evaluation by a
cardiologist may be indicated to rule out arrhythmias or other cardiac causes.

2.2.2.1 Vestibular neuronitis

The sudden onset of vertigo with nausea and vomiting, increasing in severity over several
hours with resolution over a similar span of time, is characteristic of vestibular neuronitis.
Patients may awaken from sleep with vertigo. There is often a history of a recent or concurrent
upper respiratory tract infection, and clusters of cases may be seen. The etiology is probably
viral, and the condition is often diagnosed in adolescents and young adults. Following the acute
episode, prolonged dizziness similar to motion sickness may be noted, lasting weeks to months.
No new associated auditory deficits, fullness in the ear, or tinnitus are noted. Persistent
nystagmus toward the affected side may be noted. Clinical and histopathologic studies implicate
an isolated lesion of the vestibular nerve (19).

In cases where there is doubt about the diagnosis based on the signs and symptoms, additional
diagnostic tests to consider include audiologic assessment, electronystagmography with caloric
testing and head CT. Referral to an otolaryngologist should be considered for refractory or
atypical cases.

Treatment

Treatment for nausea and vomiting is symptomatic, similar to that for motion sickness (Table
11).

2.2.2.2 Acute labyrinthitis

Acute labyrinthitis symptomatically is similar to vestibular neuronitis, except hearing loss on the
involved side is also noted. The cause may be viral, bacterial or due to a toxin (18). A history of
recent or concurrent upper respiratory tract infection is often given. Most patients improve over
1-2 weeks, although recurrent episodes have been described. Most report an upper respiratory
tract illness 1-2 weeks prior to the onset of vertigo. Several members of the patient's family may
be affected, and it is seen more often in spring and early summer. In most cases a viral etiology
is likely.

A subgroup of patients may have herpes zoster oticus (Ramsay-Hunt syndrome), with vertigo
and periauricular vesicles or facial paralysis. Vesicles may be seen on the pinna and on the face
in the distribution of the sensory branch of the seventh cranial nerve. Vertigo may last days to
weeks.

Treatment

No specific therapy is recommended. Symptomatic treatment with anti-vertigo medications as

for motion sickness may be used if symptoms are severe (Table 11). If there is suspicion of a
bacterial etiology, with fever, chills and a purulent middle ear, then medical therapy with
antibiotics and possibly surgical therapy is indicated to prevent meningitis. In this case, referral
to an otolaryngologist should be considered. For the Ramsay-Hunt syndrome, acyclovir is
effective in the treatment of facial paralysis, but is ineffective for vertigo (18).
2.2.2.3 Meniere's disease

Severe nausea and vomiting may be a manifestation of endolymphatic hydrops, or Meniere's

disease. Symptoms characteristically include episodic aural fullness, tinnitus, hearing loss
andvertigo. If vertigo is associated with hearing loss or tinnitus, an audiogram is needed to
diagnose Meniere's disease or acoustic neuroma. The onset is abrupt, and usually no
precipitating factors are identified. Attacks of vertigo can last a few hours to 24 hours, and
subside gradually. Horizontal or horizonto-rotatory nystagmus may be observed.

Treatment

Treatment is with restriction of salt intake and anti-vertigo drugs. Symptomatic relief of vertigo
can be obtained with anticholinergic agents (e.g. scopolamine orally or by transdermal patch),
orantihistamines (e.g. diphenhydramine, meclizine or cyclizine). Diazepam 2-5 mg orally q 6-
8h is effective in suppressing the vestibular system (Table 11). In severe cases, referral to an
otolaryngologist is appropriate.

2.2.3 Motion sickness

Motion sickness is a form of physiologic vertigo. Perspiration, increased salivation, yawning

and malaise are described by patients with motion sickness. Hyperventilation can lead to
hypocapnia, and venous pooling can predispose to hypotension and syncope. The sight and
smell of food can exacerbate nausea. Motion sickness is readily diagnosed by history. This is a
common syndrome that can occur in an automobile, airplane or at sea. Exaggerated self-
generated movement, in fact, can cause motion sickness by forcing rapid and inappropriate
changes of vestibular function (20).
Treatment

The treatment of vertigo associated with motion sickness is empirical (21). Transdermal
scopolamine can prevent motion sickness. The patch must be placed several hours prior to the
anticipated onset of motion sickness. Anti-histamines such as dymenhydrinate, meclizine,
cyclizine, promethazine and diphenhydramine can be used
(Table 11) The main side effect of this drug class is drowsiness.

Acupressure on the P6 point located on the wrist, which has been used in traditional Chinese
medicine to treat nausea and vomiting of pregnancy, has been evaluated in a randomized,
placebo-controlled double-blind study. Sixty-four subjects were randomly divided into 4
groups (P6 acupressure, dummy-point acupressure, sham P6 acupressure, and control) and
subjected to optokinetic drum rotation which elicits motion sickness in normal volunteers.
Subjects in the P6 acupressure group reported significantly less nausea and the incidence of
gastric tachyarrhythmia was reduced in this group (22). In another blinded placebo-controlled
study on 36 patients, however, acupressure provided no protection (23).

2.2.4 Viral syndrome

Acute infections with viruses such as Norwalk agent or other enteric viruses can be
accompanied by headache, fever, arthralgias and non-bloody diarrhea as well as nausea and
vomiting. These symptoms, suggestive of a viral etiology, are an indication that no specific
diagnostic testing is necessary.

Treatment

Empiric therapy with liberal fluid intake, anti-emetics and antipyretics may suffice. Empiric
therapy should only be instituted in immunocompetent patients with symptoms that are mild and
typical for a viral syndrome. Signs such as protracted fever with chills, bloody diarrhea and
clinically evident fluid depletion should be handled with proper diagnostic studies and
appropriate specific therapy.

A randomized, double-blind comparison of treatment of uncomplicated nausea and vomiting due

to viral gastroenteritis with prochorperazine (Compazine) or promethazine (Phernergan) was
published. The results showed that prochoroperazine was significantly better in terms of
symptom relief compared to promethazine (119).

2.2.5 Post-operative

Post-operative nausea and vomiting is common, but is unlikely to be encountered in the primary
care setting. In a prospective evaluation of 101 patients admitted for abdominal surgery, the
overall incidence of nausea and vomiting was 42% (24). These symptoms are generally
attributed to the general anesthetic agents or analgesics used. In the immediate post-operative
setting, these patients are often treated empirically. However, the possibility of other causes of
nausea and vomiting must be kept in mind. Vomiting in the post-operative period following
laparoscopy may lead to pneumomediastinum and bilateral pneumothoraces (25). Congestion
of the eye secondary to phakomorphic glaucoma can lead to intractable nausea and vomiting in
the post-operative state (26).

Treatment

While post-operative nausea and vomiting is unlikely to be encountered in the primary care
setting, treatment regimens have been studied in this patient population. Therefore, it is useful
to be aware of this literature. For example, the efficacy, safety and cost-effectiveness
of ondansetron (4 mg intravenously) was compared to droperidol (0.625 mg or 1.25 mg
intravenously) in a randomized, double-blind placebo-controlled trial for the prevention of
postoperative nausea and vomiting after outpatient gynecologic surgery in 161 women.
Droperidol 0.625 mg iv provided antiemetic prophylaxis comparable to that of ondansetron 4 mg
iv without an increased incidence of side effects and in the most cost-effective manner (27). In
another randomized, double-blind, placebo-controlled trial conducted on patients undergoing
laparoscopic cholecystectomy, prophylactic anti-emetic therapy with ondansetron, tropisetron,
granisetron or metoclopramide was studied. Ondansetron prophylaxis resulted in a lower
incidence of post-operative nausea and vomiting compared to metoclopramide or placebo.
There were no statistically significant differences among the three 5-HT3 receptor
antagonists(28). A review of published controlled trials comparing 5-HT3 receptor antagonists
to traditional anti-emetic agents (including metoclopramide, perphenazine, prochlorperazine,
cyclizine and droperidol) for prophylaxis of postoperative nausea and vomiting showed the 5-
HT3 receptor antagonists to be superior (128).

2.3 Diagnostic workup required

Experienced physicians triage patients based on the patients history and presentation as well as
on clinical instincts that factor in severity of illness and familiarity with the patient (Table 3). Most
causes of acute vomiting are self-limited illnesses, but nausea and vomiting can be symptoms
of conditions that require expeditious diagnostic workup and treatment (Table 4). Guidelines for
referral are included in each section.

2.3.1 Abdominal or chest pain

A history of pain may indicate that nausea and vomiting is a consequence of a pathophysiologic
process in the thoracic cavity or abdomen. Abdominal pain preceding nausea and vomiting
indicates an organic lesion. Pain following vomiting may be due to tenderness of the abdominal
musculature, an abdominal wall or esophageal hematoma, (especially in patients who are anti-
coagulated) or esophageal perforation.

2.3.1.1 Coronary artery disease

Acute and chronic myocardial ischemia, as well as myocardial infarction, may present with
nausea and vomiting. These symptoms may be accompanied by abdominal bloating or fullness.
Often, concomitant substernal chest pain is present, or the patient may give a history of angina
pectoris. Even in the absence of classic signs and symptoms of myocardial ischemia, the
physician must keep an open mind to the possibility of a cardiac source of symptoms. At a
minimum, an electrocardiogram should be obtained in such patients. Further diagnostic
evaluation and therapy depend on the clinical impression. Cardiac enzymes to rule out
myocardial infarction and electrocardiographic monitoring may be necessary. Management in
consultation with a cardiologist should be considered.

2.3.1.2 Intra-abdominal inflammation

A variety of inflammatory conditions within the abdomen may present with nausea and vomiting
including cholecystitis, appendicitis, pancreatitis, inflammatory bowel disease, cholangitis and
peritonitis. The duration, location, quality, radiation and pattern of abdominal pain, and factors
that exacerbate or ameliorate the pain, may help distinguish between these possibilities. A
history of biliary colic or gallstones suggests cholecystitis or gallstone pancreatitis. Pain in the
periumbilical area which moves to the right lower quadrant over time classically suggests
appendicitis. On physical exam, certain findings are suggestive of a particular diagnosis.
Murphy's sign (tenderness and inspiratory arrest with palpation in the right upper quadrant of
the abdomen) may be elicited in acute cholecystitis. Rebound tenderness on abdominal exam
suggests peritonitis, and in the context of free air on X-ray, warrants laparotomy. In acute
pancreatitis, diffuse tenderness to palpation of the abdomen may be elicited, making this
diagnosis a difficult one to make on physical findings alone (29). Nausea and vomiting in the
context of intra-abdominal inflammation are symptoms that should respond to treatment of the
underlying inflammatory process.

Referral to a gastroenterologist should be considered in severe cases of pancreatitis, in those

whom choledocholithiasis is suspected as a cause of pancreatitis or cholangitis, and in cases
where the diagnosis is uncertain. For patients with inflammatory bowel disease (IBD) presenting
with nausea and vomiting, symptoms may be due to a flare of IBD or the presence of bowel
obstruction (see below). Management of IBD with the aid of a gastroenterologist should be
considered. Referral to a general surgeon is warranted in cases of acute cholecystitis,
appendicitis or peritonitis.
2.3.1.3 GI tract obstruction

Obstruction of the stomach or intestine can present with nausea, vomiting and abdominal pain.
When abdominal pain precedes nausea and vomiting, obstruction of the GI tract should be
strongly considered. Gastric outlet obstruction may be due to peptic ulcer disease in the
pyloric channel or duodenal bulb, or benign or malignant gastric tumor. Patients may complain
of early satiety and bloating. Abdominal pain is generally postprandial. Symptoms may be worse
after a solid meal compared to a liquid one. These symptoms may be resolved with vomiting as
the stomach is decompressed. The volume of gastric contents expelled may be large. The
vomitus may be foul-smelling, containing food ingested more than 12 hours previously.
Heartburn due to reflux of acidic gastric contents may be a complaint. Physical exam findings
include a distended abdomen with tympany and, in some cases, epigastric tenderness. A
succussion splash heard with the stethoscope after gently rocking the patient from side to side
implicates retention of liquid contents in the stomach.

Diagnostic tests include upright abdominal X-rays showing an enlarged gas-filled stomach,
contrast radiographs and endoscopy. Water soluble contrast X-rays are helpful when a
gastric bezoaris suspected, or when a tight stenosis is present. Endoscopy is in many cases the
procedure of choice, as histologic diagnosis and in some cases therapy can be provided.
Referral to a gastroenterologist is appropriate in cases of acute nausea and vomiting suspected
to be due to gastric outlet obstruction.

In the small bowel, a history of prior abdominal surgery may predispose to small bowel
obstruction caused by adhesions. Eighty percent of small bowel obstructions are due to post-
operative adhesions. Other etiologies include primary or metastatic carcinoma, benign tumor,
internal and external hernias and Crohns disease. Less commonly, prior abdominal radiation,
intussusception, endometriosis, volvulus and congenital abnormalities can lead to small bowel
obstruction. The patient can present with intestinal colic, which may be intermittent initially,
progressing to sustained abdominal pain centered in the midline of the abdomen at or cephalad
to the umbilicus. Vomiting is a cardinal feature, with complete obstruction leading to vomiting of
liquid material which may be feculent if the obstruction is in the distal small intestine. Physical
findings include a distended abdomen; dilated, palpable loops of bowel; and high-pitched,
intermittent bowel sounds.

An important aspect of the diagnostic evaluation is the differentiation of incomplete from

complete small bowel obstruction. Complete obstruction should be considered if the patient is
not able to pass flatus. Abdominal radiographs (supine and upright views) should be obtained.
Complete obstruction is suggested by dilated loops of small bowel with air-fluid levels without
gas in the large bowel. In partial obstruction, gas is noted in the colon and rectum, although air-
fluid levels and dilated loops of small bowel are present. If the differentiation between partial and
complete obstruction is still uncertain, contrast radiography may help differentiate these
conditions and rule out a paralytic ileus.

If the diagnostic evaluation suggests partial obstruction, nasogastric suction and IV fluids should
be instituted. Lack of clinical improvement in 48 hours warrants operative treatment.
Completesmall bowel obstruction is an indication for laparotomy. Resuscitation pre-
operatively includes correction of hypoxemia, replacement of intravascular volume and
correction of serum electrolyte abnormalities.

Primary small bowel malignant tumors presented with abdominal pain (83%), nausea and/or
vomiting (54%) and weight loss (53%) in a retrospective review of 69 patients (30). Lymphoma
was the most common tumor (42%), followed by adenocarcinoma (38%), carcinoid (10%) and
leiyomyosarcoma (10%). In 41%, the tumor was located in the jejunum, in the ileum in 33%, in
the duodenum in 22% and in multiple sites in 4%. Of the 65 symptomatic patients, 43%
presented as surgical emergencies.

Metastases to the GI tract can present with abdominal pain and nausea and vomiting.
Melanoma and breast cancer can metastasize to the small bowel. In a review of 68 patients with
metastatic melanoma, sites commonly involved were the small bowel (75%), large intestine
(25%) and stomach (16%) (31).
2.3.2 Drug, toxin or environmental exposure

2.3.2.1 Drugs as a Cause of Nausea and Vomiting

2.3.2.1.1 Drugs associated with nausea and vomiting at prescribed dosages

Many drugs routinely used in clinical practice can cause nausea and vomiting when taken at the
prescribed dose. Therefore a careful drug history, including the use of over-the-counter
medications and herbal and non-traditional medications, is mandatory. Establishing a temporal
relationship between the institution of a medication and symptoms of nausea and vomiting is
highly suggestive. Alternatively, changes in dosing or the addition of a drug to an already
lengthy list of medications suggests a drug-related effect. A large number of drugs have nausea
and vomiting listed as a potential side effect; indeed, almost any drug can potentially cause
these symptoms. However, there are certain drugs for which nausea and vomiting is seen in a
significant minority of patients. These agents are listed in (Table 5) and are described below.

Narcotic analgesics such as morphine, which dramatically decrease gut motility, can lead to
constipation and GI tract obstruction. The incidence of narcotic-induced emesis was as high as
40% in one study (32). Prescription and over the counter non-steroidal anti-inflammatory drugs
(NSAIDs) have nausea (and less commonly vomiting) as a side effect. Nausea is also seen in
up to 40% of patients taking the non-narcotic analgesic tramadol. Theophylline and digoxin can
cause nausea and vomiting, especially when plasma drug levels are elevated. Nausea and
occasionally vomiting has been noted with the selective serotonin reuptake inhibitors.
Chloroquine causes nausea and vomiting as a side effect both at prescribed doses and in
overdose situations.

Antibiotics and anti-parasitic agents can cause nausea and vomiting. The most common
adverse effect of metronidazole is nausea, seen in 12% of patients. Trimethoprim-
sulfamethoxazole is associated with nausea and vomiting. Erythromycin can cause nausea and
vomiting; the mechanism may be related to its role as an agonist for the pro-motility hormone
motilin. Anti-helminthics such as albendazole and thiabendazole have been associated with
nausea and vomiting. The amebicide iodoquinol has nausea and vomiting as a side effect.

Other drugs which commonly cause nausea and vomiting include estrogens, levodopa,
bromocriptine and potassium and iron salts. For the latter two types of agents, gastric irritation
may be the mechanism. Timolol eye drops can cause severe nausea and vomiting (115).
2.3.2.1.2 Drugs associated with nausea and vomiting in overdose situations

Some drugs may cause nausea and vomiting when excessive doses are ingested, or when
serum levels increase due to renal or hepatic insufficiency. Several prescription drug overdoses
presenting with nausea and vomiting have been reported, including isoniazid (33), misoprostol
(34), colchicine (35) and metronidazole. Cinchonism secondary to quinine toxicity classically
presents with nausea, vomiting, and tinnitus. Prolongation of the Q-T interval is often noted (36).
Specific overdose situations which are known to present with nausea and/or vomiting are listed
in(Table 6) (37). This list is not comprehensive; communication with a Regional Poison Control
Center for up-to-date management recommendations should be considered.

2.3.2.2 Chemotherapeutic agents

These drugs are notorious for their emetogenic properties. In the context of chemotherapy
regimens, anti-emetic therapy is often prescribed. While this situation is unlikely to be
encountered in the primary care setting, it is important to keep this possibility in mind. In
particular, anticipatory nausea and vomiting may develop in a patient who has undergone prior
chemotherapy. In a study of 16 adult cancer patients with chemotherapy-induced anticipatory
nausea and vomiting, hypnosis was shown to be highly effective (130). In all patients studied,
anticipatory nausea and vomiting disappeared.

The severity of chemotherapy-induced emesis depends on the particular drug used (cisplatin is
associated with the highest incidence), the dose of the drug and the method of administration
(38). Vomiting may be delayed 2 to 5 days after cisplatin administration and may be difficult to
control. Nausea and vomiting may also be encountered in the setting of fractionated
radiotherapy for malignancy (39). An overview of the treatment of patients with chemotherapy-
induced nausea and vomiting is found in the section on drug therapy.
2.3.2.3 Alcohol (Ethanol)

Excessive alcohol intake may cause severe nausea and vomiting. Mallory-Weiss tears are
directly caused by vomiting or retching and can be encountered in the patient who has been
drinking alcohol. Acute pancreatitis may be present and leads to nausea, vomiting and
abdominal pain. Intracranial hemorrhage secondary to head trauma from a fall in an inebriated
patient can cloud the clinical presentation, as increased intracranial pressure can itself be a
cause of nausea and vomiting. Alcoholic hepatitis can also present with nausea and vomiting.
Nausea and vomiting in the patient with a history of alcohol use therefore requires vigilance for
these associated conditions. A history obtained from family members or witnesses, a careful
abdominal exam, head/eyes/ears/nose/throat exam and neurological exam, measurement of
blood alcohol levels, hematocrit, coagulation profile, transaminases (AST/ALT) and serum
amylase and lipase should be obtained in a patient suspected of heavy alcohol use who
presents with severe nausea and vomiting. Ancillary diagnostic tests such as chest and
abdominal X-rays and a head CT scan may be necessary to rule out the wide variety of
associated conditions that can lead to nausea and vomiting in the patient who presents after
heavy alcohol consumption (Table 7).

2.3.2.4 Environmental toxins and exposures

Exposure to certain environmental toxins can lead to nausea and vomiting as prominent
symptoms. Carbon monoxide intoxication presents in a non-specific manner. Headache,
dizziness, fatigue and nausea and vomiting are common (40). In addition, disturbed judgment
and diminished visual acuity may be seen. Blood carboxyhemoglobin levels of 40-60% are
associated with tachypnea, tachycardia, ataxia, syncope and seizures. The EKG may show ST
segment changes, conduction blocks and atrial or ventricular arrhythmias. Cherry-red coloration
of the lips or skin is rare.

Treatment consists of supportive care and 100% oxygen. Carboxyhemoglobin levels should be
measured every two to four hours, and oxygen continued until blood levels are less than 10%.
Hyperbaric oxygen (3 atm) is recommended for patients who present with neurologic signs or
symptoms, EKG changes consistent with ischemia, shock, severe metabolic acidosis and
pulmonary edema.

Acute arsenic poisoning can present with nausea and vomiting (41). Acute fluoride
poisoning from a public water system produced a clinical syndrome characterized by nausea,
vomiting, diarrhea, abdominal pain and paresthesias (42). Pesticide exposure can present with
anxiety, vertigo, nausea, vomiting, tearing and weakness (43). Elemental mercury vapor toxicity
presented with nausea, headache, lumbar pain and shortness of breath at rest (44). In each of
these examples, nausea and vomiting were present in the majority of cases but the presenting
symptom complexes were non-specific.

Food poisoning due to pre-formed bacterially-derived toxins can present with nausea and
vomiting in association with abdominal pain and diarrhea. Staphylococcal food poisoning
typically presents with nausea, vomiting, cramping abdominal pain and diarrhea between two
and four hours after ingestion of food contaminated by the enterotoxin produced
by Staphylococcus aureus . Often, a cluster of cases is identified. Treatment is symptomatic.
The illness is short, rarely lasting more than 24 hours.

Vibrio parahemolyticus poisoning is associated with the consumption of raw or improperly

refrigerated seafood. The incubation period is between 12 and 24 hours, and patients present
with explosive watery diarrhea, nausea, vomiting and abdominal cramps. Treatment is
supportive, although in protracted cases, antibiotic therapy with tetracycline or ampicillin may be
used. Other bacterial causes of food poisoning such as Clostridium perfringens type A
and Bacillus cereus cause nausea and vomiting as predominant symptoms in a minority of
patients.

Toxin exposure can occur by consumption of seafood or exposure to marine toxins. Scombroid
poisoning by the consumption of spoiled fish of the dark meat varieties can present with skin
rash, diarrhea, palpitations, headache, nausea, abdominal cramps, paresthesias, an unusual
taste sensation and breathing difficulties. Patients respond to anti-histamines as the toxin is
histamine (45,46). Cigatuera poisoning, seen predominantly in tropical areas, presents with
nausea, abdominal pain, vomiting and diarrhea. Peripheral neuropathic symptoms are also
characteristic, including paresthesias, dental discomfort and confusion of peripheral hot and
cold sensation. Treatment is symptomatic.

Although not toxins, certain foods can cause hypersensitivity reactions which present with
nausea, vomiting, abdominal pain and diarrhea (47).

Certain envenomations can present as nausea and vomiting. Spider bites, particularly by the
female black widow spider or brown recluse spider, can present with nausea and vomiting.
Likewise, scorpion stings and snake bites can present with nausea and vomiting. In all of these
cases, pain, erythema and swelling at the site of the bite is usually evident. Unusual examples
of envenomations which present with nausea and vomiting are those due to the bite of the Gila
monster (48) and the sting of the Portuguese man-of-war (49).

Certain environmental exposures can lead to nausea and vomiting. Heat exhaustion occurs in
an unacclimatized person who exercises on a hot day. It results from loss of salt and water, with
the patient complaining of headache, nausea, vomiting, dizziness, weakness, irritability, cramps
or diaphoresis. Therapy consists of rest in a cool environment, and volume repletion with salt-
containing solutions. If vomiting is present, IV normal saline may be necessary.

High altitude illness can occur in people unacclimatized to altitude who ascend to more than
2000 meters in less than 1-2 days. Acute mountain sickness presents with headache, nausea,
vomiting, anorexia, dyspnea, lethargy, sleep disturbance, vertigo, palpitations and difficulty
concentrating. Treatment consists of liberal fluids, mild analgesics for headache,
prochlorperazine for nausea, and for severe symptoms, oxygen at 2-3 liters /minute and descent
of 1000-1500 meters.
2.3.3 Late pregnancy

If the patient is pregnant, nausea and vomiting of pregnancy, especially early in gestation, is
common and is a self-limited and benign condition. In the third trimester of a normal pregnancy,
the incidence of nausea and vomiting decreases (50). If nausea and vomiting in the pregnant
woman does not fit this typical pattern, then the following conditions should be considered. If
symptoms are severe, or begin in the second or third trimester, then other more serious
conditions need to be considered. For each of the conditions described below, management
along with an obstetrician should be considered (Table 8).

2.3.3.1 Hyperemesis gravidarum

If vomiting is protracted such that fluid and electrolyte disturbances or nutritional deficiency
develops, then the condition is termed hyperemesis gravidarum. Onset of symptoms is often
soon after the first missed menstrual period. Classically the vomiting disappears during the third
month, and rarely persists into the fourth month. Patients with hyperemesis gravidarum do not
have an increased incidence of toxemia of pregnancy or spontaneous abortion, and their babies
are not underweight or otherwise affected. In one study, however, intrauterine growth
retardation in patients with hyperemesis gravidarum was reported (51). Women with twins or
with molar pregnancy (hydatidiform mole) have an increased incidence of hyperemesis
gravidarum. These women have elevated concentrations of human chorionic gonadotropin
(HCG). Abnormalities of thyroid function tests are also common. The metabolic consequences
of hyperemesis gravidarum can be severe due to dehydration and muscle wasting, with
mortality increased in untreated patients. Gastric emptying is not delayed in patients with
hyperemesis gravidarum, suggesting that the disorder is not due to an upper GI tract motility
disturbance (122).

Treatment

Treatment is directed at fluid and electrolyte replacement and supportive psychotherapy (11).
Parenteral nutritional therapy may be necessary. Standard anti-emetics are generally not
effective. Successful management with intravenous hydrocortisone, followed by oral
prednisolone has been described in a series of seven patients (52). The combination of
intravenous droperidol and diphenhydramine was shown to improve symptoms (53).

A placebo-controlled, randomized single-blind study of manual acupressure for the treatment of

hypermesis gravidarum performed in 33 women showed that nausea and vomiting was reduced
in the acupressure group compared to the placebo group (121).
2.3.3.2 Acute fatty liver of pregnancy

This is a serious condition of unknown etiology, occurring in 1:13,000 deliveries. Symptoms of

nausea, vomiting, headache and malaise begin in the third trimester, usually around week 35.
Features of pre-eclampsia (hypertension, edema, proteinuria) may be present. The disease
often progresses to hepatic failure complicated by disseminated intravascular coagulation. If
nausea and vomiting begin in the latter part of pregnancy, serum aminotransferase activity
(AST/ALT) should be measured. Elevated aminotransferases in the 200-500 range is an
indication for liver biopsy. The characteristic finding on biopsy is microvesicular fat. Maternal
morbidity is high, and the condition should be suspected in patients with symptoms of pre-
eclampsia with hypoglycemia, low fibrinogen and prolonged prothrombin time (54).

Treatment

Once this diagnosis is established, early delivery is indicated to prevent maternal and fetal
death (55). Management by an obstetrician, and referral to a center specializing in high-risk
obstetrics should be considered.

2.3.3.3 HELLP Syndrome

A syndrome of hemolysis, elevated liver enzymes and low platelet count can complicate pre-
eclamptic/eclamptic patients. Patients typically present in the third trimester with epigastric or
right upper quadrant pain and nausea and vomiting. They may present with no signs of pre-
eclampsia (hypertension, proteinuria, or edema), and therefore a non-obstetric diagnosis may
be entertained (56).

Treatment

Management in conjunction with an obstetrician is recommended, and referral to a center

specializing in high-risk obstetrics should be considered.

2.3.4 CNS symptoms

Headache, projectile vomiting often in the morning without antecedent nausea, a history of
migraine, transient ischemic attacks, vertigo, photophobia or neck stiffness are elements of the
history which should direct the clinician to a CNS explanation for nausea and vomiting.

Headache may be due to migraine, increased intracranial pressure or cerebral vascular

hemorrhage. The clinical diagnosis of migraine is based on headache characteristics and
associated symptoms, particularly nausea and vomiting. The treatment of migraine has been
recently reviewed (57). Treatment strategies include 5-hydroxytryptamine agonists, ergotamine
tartrate, sumatriptan, dihydroergotamine, NSAIDs and opiates. Sumatriptan, a selective
serotonin receptor agonist, is particularly effective and well-tolerated (58) (59). Treatment with
oral sumatriptan has been studied in a randomized double-blind placebo-controlled study,
and found to be effective (60).

Headache in the presence of fever and neck stiffness suggests meningitis (61). Nausea and
vomiting may be a feature of meningitis. Cerebral cysticercosis can present with positional
headache and nausea and vomiting (62)(116).

Primary intraventricular hemorrhage presented with nausea and vomiting in 71% of cases in a
review of 14 cases. Headache and mental status changes were noted in an equal number of
cases (63). Referral to a neurologist or neurosurgeon may be necessary.

Vertebrobasilar vascular insufficiency is a common cause of vertigo in the elderly. Vertigo is

abrupt in onset, lasts several minutes and is often associated with nausea and vomiting.
Associated symptoms due to ischemia in the territory of the posterior circulation include visual
hallucinations, drop attacks, diplopia, headache and visual field defects. CT scans are usually
normal, as symptoms are transient. Angiography may be helpful, but carries a risk of arterial
spasm and stroke. Referral to a neurologist should be considered.

Vertigo with nausea and vomiting may also accompany infarction of the lateral brain stem or
cerebellum or both. Key findings are an acute onset of symptoms, clear cerebellar signs such as
extremity and gait ataxia and gaze-evoked nystagmus. These patients must be carefully
observed for the development of progressive brain stem dysfunction due to edema at the site of
infarction. Consultation with a neurologist should be obtained.

Cerebellopontine-angle tumors, such as acoustic neuroma, meningioma and epidermal cysts

grow slowly, so that acute vertigo with associated nausea and vomiting are rarely presenting
symptoms. Occasionally, acute onset of vertigo may be present. Unilateral, progressive hearing
loss is present, identified by an abnormal brain-stem auditory evoked response. Evaluation by
magnetic resonance imaging (MRI) is the most sensitive study. Every patient with vertigo and a
unilateral hearing loss or tinnitus must be assumed to have a retrocochlear lesion until
radiographically proven otherwise (18). Treatment is surgical removal, so that referral to an
otolaryngologist or neurosurgeon is indicated.

2.3.5 Infections as a Cause of Nausea and Vomiting

Infections may present with nausea and vomiting, especially if viral in origin. Nausea and
vomiting accompanied by diarrhea and fever suggests viral gastroenteritis. Often, this is self-
limited, and patients recover with supportive care. Occasionally, volume depletion is severe, and
may require volume replacement. Blood in the stool and fever warrants further investigation and
may indicate inflammatory bowel disease or bacterial enteritis or colitis.

Certain other infections of the upper GI tract of non-viral etiology, although rare, should be
considered. Esophageal infections are more commonly seen in immunocompromised patients,
and can present with nausea and vomiting alone, although most patients will develop
esophageal symptoms such as dysphagia and odynophagia. For immunocompromised patients,
the most common pathogens are Candida, CMV and HSV (64).

Gastric syphilis has become an uncommon disease, with only 24 cases reported in the literature
in the past 2 decades. The most common symptoms in a review of 7 cases were abdominal
pain, nausea, and vomiting, with signs of syphilis present in 5 patients. The diagnosis was
established by identification of spirochetes on mucosal biopsy in 6 patients. The diagnosis
should be considered in patients at risk for sexually transmitted disease who complain of
nausea, vomiting and abdominal pain and in whom unusual gastric lesions or ulcers are
refractory to therapy (65).

Unusual infections such as Rocky Mountain Spotted Fever can present with nausea and
vomiting, along with fever, headache, myalgia and anorexia. These symptoms can be difficult to
distinguish from self-limited viral infection. A rash may appear later in the course, but is not
pathognomonic (66).

Hepatic abscess presented with nausea and vomiting in 40% of cases in a review of 35
patients. Twenty-nine patients had bacterial abscesses, and 6 had amebic abscesses. Fever
was present in 95% and right upper quadrant pain in 63% of patients (67).

2.3.6 Systemic disease as a cause of nausea and vomiting

Acute nausea and vomiting may be the manifestation of a definable disease process. While
diseases such as diabetes mellitus, endometriosis and renal insufficiency are chronic in nature,
acute exacerbations may lead to presentations that include nausea and vomiting.

Endocrine emergencies can present with nausea and vomiting. Diabetic ketoacidosis can
present with vomiting, along with polyuria, polydypsia, abdominal pain and changes in mental
status. Ninety percent of patients are known diabetics. The smell of acetone on the patient's
breath, and the deep-breathing pattern of Kussmaul's respiration aid in the diagnosis (68).
Likewise, severe vomiting and abdominal pain are central clinical features of alcoholic
ketoacidosis. As in diabetic ketoacidosis, severe dehydration can lead to Kussmaul's
respiration and mental status changes (69).

Acute adrenal insufficiency usually presents with nausea, vomiting, severe hypotension and
dehydration (70). Nausea and vomiting are common in the uremic patient (71).

Intestinal endometriosis can present with abdominal pain and nausea and vomiting. In a review
of 26 cases, abdominal pain was the main presenting feature in 20, with associated nausea and
vomiting in 12. Establishing the diagnosis preoperatively was difficult in patients without a
known history (72).

2.3.7 Immunosuppression

The immunosuppressed patient can be considered in a separate category because such

patients deserve a thorough diagnostic workup even if signs and symptoms initially point to a
benign self-limited condition as the cause.

The classic situation is the patient with AIDS, although immunosuppression due to drugs and
severe illness need to be considered. While the cause of nausea and vomiting may be similar to
those seen in immunocompetent patients, several other etiologies need to be considered.
Chiefly, opportunistic infections of the upper GI tract, such as Candida esophagitis, CMV or
HSV infection (73) may be present. While nausea and vomiting are rarely the sole symptoms
seen in these situations, other more typical symptoms such as odynophagia or dysphagia,
hematemesis and weight loss may be accompanied by nausea and vomiting. For these
patients, referral to a gastroenterologist for endoscopy to establish the diagnosis should be
considered, especially if an empiric trial of therapy (e.g. fluconazole for presumptive Candida
esophagitis) is unsuccessful.

2.3.8 Unusual causes and consequences

There can be unusual causes or consequences of nausea and vomiting. This question should
be asked by the examiner if the patient does not fit a typical profile in terms of symptoms, or if
an unusual complaint arises as a consequence of vomiting.

There are several consequences of nausea and vomiting which are rare but should be
considered. Visual floaters may be due to vitreous hemorrhage and retinal vein rupture caused
by emesis (74). Stress fracture of the hyoid bone caused by induced vomiting has been
described (75). Tooth surface enamel loss may occur with repeated emesis (76). Benign
retropneumoperitoneum can be induced by vomiting (77).

Likewise, unusual causes of nausea and vomiting have been described. Systemic
mastocytosis can present with nausea due to mast cell infiltration of the gastric mucosa (78).
Visually induced paroxysmal nausea and vomiting can be the presenting manifestation
of multiple sclerosis (79). Acquired or hereditary angioedema can present with
gastrointestinal complaints including episodic nausea (80). Gastric outlet obstruction may occur
due to a giant duodenal gallstone. This condition is called Bouveret's syndrome, and often
indicates the presence of a cholecystoduodenal fistula (81). Emesis of gallstones has been
described, indicative of a fistula between the gallbladder and the stomach or duodenum (82).
3.0 Chronic nausea and vomiting

Chronic nausea and vomiting is defined as the presence of symptoms for over a week. The
patient may describe intermittent symptoms lasting months or years. A number of different
conditions may be responsible for such symptoms, and a thorough history and physical exam
are invaluable in pointing to the correct diagnosis.

3.1 The cause is known from prior workup

In certain situations of chronic or recurrent nausea and vomiting, the cause has been
established on previous diagnostic workup. In these situations, treatment may be instituted
without extensive diagnostic workup, although the physician must keep an open mind regarding
alternative etiologies. If the patient does not respond to specific therapy, further diagnostic
studies should be initiated.

3.2 The cause is not known

If no prior diagnosis or underlying etiology is evident, the patient with chronic or recurrent
nausea and vomiting requires a diagnostic work-up. Conditions such as the post-gastrectomy
state, diabetes mellitus leading to gastroparesis and prior abdominal surgery can predispose to
recurrent nausea and vomiting. Knowledge of the underlying condition aids the physician in
fashioning a diagnostic and treatment plan. In this situation, a full diagnostic workup may not
have been performed in the past despite the chronicity of symptoms. If such is the case, the
history, physical examination, screening laboratory tests and abdominal X-rays (supine and
upright) are the first steps in the diagnostic workup. Diagnostic tests useful in the evaluation of
the patient with chronic nausea and vomiting are outlined in (Table 9). Some of the causes of
chronic nausea and vomiting are rare, and referral for specialized diagnostic testing may be
necessary. Certain conditions prompt referral to a gastroenterologist
(Table 12).
3.2.1 The gastrointestinal tract is involved

Chronic nausea, accompanied in a subset of patients by vomiting, can be due to a variety of

gastrointestinal causes. Achalasia, esophageal masses, peptic ulcer disease, gastroparesis,
occult gastrointestinal cancer, intestinal pseudo-obstruction and gastroesophageal reflux
disease are examples of gastrointestinal diseases that can present with nausea with or without
vomiting.

3.2.1.1 GI tract obstruction

GI tract obstruction needs to be ruled out early in the diagnostic workup, and this can be
accomplished initially by supine and upright abdominal X-rays, followed by contrast studies if
indicated. GI tract obstruction can lead to acute nausea and vomiting. If abdominal pain
precedes nausea and vomiting, obstruction of the GI tract should be strongly
considered. Gastric outlet obstructioncan be caused by peptic ulcer disease, particularly in
the pyloric channel or duodenal bulb. Tumor and bezoar formation are less common reasons
for gastric outlet obstruction. Other causes of GI tract obstruction such as small bowel
obstruction and stricture formation (e.g. with Crohns disease) need to be considered.

A history of prior gastric resection is associated with nausea and vomiting, often presenting
many years following the surgery date. Vomiting of bile may be noted. Vagotomy with partial
gastrectomy with Billroth I or II anatomy can predispose to obstruction. Roux-en-Y
gastrojejunostomies can lead to altered gastric emptying rates, manifesting as nausea and
vomiting. The Roux stasis syndrome, characterized by abdominal discomfort, nausea, vomiting
or bezoar formation was noted in 6% of 20 patients following Roux-en-Y gastrojejunostomy
(83). A prior fundoplication can lead to distal esophageal obstruction leading to vomiting with
associated dysphagia. Nausea has been described following laparoscopic fundoplication (84).
In each of these situations, contrast studies help in defining the altered anatomy, and
endoscopic examination allows mucosal lesions to be identified and appropriately treated.
Referral to a gastroenterologist, and in some cases to a surgeon, is necessary in many of these
patients.
Other causes of nausea and vomiting involving the GI tract include esophageal lesions such as
achalasia or esophageal masses that may cause obstruction to the passage of food.
Regurgitation of undigested food, rather than true vomiting, may be the presenting complaint.
Dysphagia, with or without odynophagia, is usually part of the patient's complaints. Referral to a
gastroenterologist for endoscopy, biopsy and management is indicated for these disorders.

3.2.1.2 Other GI causes

Certain situations where GI causes of nausea and vomiting are present without evidence of
mechanical obstruction also need to be considered.

Chronic intractable nausea can be the primary symptom of gastroesophageal reflux disease.
In a study of 10 outpatients with this symptom, acid reflux was the cause of intractable nausea
in all patients. In this group of three men and seven women, the average duration of nausea
was 2 years, with a range of 3 months to 6 years. None had responded to empiric therapies for
nausea. Either upper endoscopy or 24 hour esophageal pH studies showed gastroesophageal
acid reflux in all patients. Esophagitis was documented on upper endoscopy in 5 patients; and in
the 6 patients who had esophageal pH testing, abnormally increased acid reflux was
documented. Treatment included omeprazole, ranitidine or cisapride; one patient who did not
respond to high dose H2 blocker or proton pump inhibitor therapy underwent Nissen
fundoplication. Treatment of gastroesophageal reflux led to symptom resolution in all patients
(85). With a mean follow-up of 6 months, all patients reported no recurrence of nausea.

Chronic peptic inflammation due to peptic ulcer, gastritis or Zollinger-Ellison syndrome can
present with nausea and vomiting. Helicobacter pylori infection leads to chronic gastritis and has
been associated with gastric and duodenal ulcers. Nausea and vomiting can be associated
symptoms of ulcer disease. Patients with recurrent vomiting and suspected peptic ulcer disease
should undergo endoscopy to evaluate this possibility. The diagnosis of H pylori infection can be
established via several methods. H pylori serology provides evidence of exposure to the
organism. Breath testing and a stool antigen test are available to non-invasively determine
whether active infection is present. Endoscopy with biopsy of the antrum to demonstrate the
organism is the gold standard, and should be considered in cases where peptic ulcer disease is
a diagnostic consideration. A rapid urease enzyme test may be used concurrently with biopsy.
Once the presence of the organism has been established, and the symptoms and clinical
picture are deemed suitable for treatment, several drug combinations are available.

Eosinophilic gastroenteritis is characterized by peripheral eosinophilia, eosinophilic infiltration

of the GI tract and symptoms referable to the GI tract including abdominal pain, nausea,
vomiting, diarrhea, anemia and protein-losing enteropathy. Peripheral eosinophilia is not an
invariable finding. In a review of 8 patients, the diagnosis was established by endoscopic
mucosal biopsy in 5 and by laparotomy with full-thickness biopsy in the remainder. Patients
were treated with prednisone with response in all patients (86, 87).

Infiltrative lesions of the stomach (linitis plastica) can present with early satiety and nausea
and vomiting. Pancreatic cancer can lead to gastroparesis and nausea and vomiting.

Nausea and vomiting may be caused by disorders of gastric motility without obstruction or
evidence of inflammation. Gastroparesis is the most common of these motility disorders. In
most cases, the diagnosis is made clinically, in the absence of mechanical lesions causing
obstruction of the GI tract. Scintigraphic gastric emptying studies are the gold standard (88, 89).
In difficult to treat cases, the patient may be referred to a gastroenterologist at a tertiary care
center. Esoteric tests such as antroduodenal motility tests and electrogastrography may be
used to document slowed gastric muscular activity. Treatment of gastroparesis includes dietary
measures, such as maintaining adequate hydration, eating small frequent meals, and avoiding
fatty foods and indigestible solids. Pharmacologic therapy includes antiemetics as well as
prokinetic agents. Prokinetic agents such as metoclopramide and cisapride have been used to
treat this disorder (90). Domperidone has also been shown to enhance gastric emptying.
Erythromycin in low, prokinetic doses (250 mg PO TID 30 minutes before meals) may also be
tried. Usually prokinetic agents are given 15 to 30 minutes prior to meals to enhance the effect
on gastric emptying at mealtime. A bedtime dose may help in emptying the stomach of
indigestible solids and thereby prevent bezoar formation.

3.2.2 The nervous system is involved

Nervous system causes of chronic nausea and vomiting include organic brain disease, often
manifesting with focal neurologic signs; autonomic nervous system diseases; and degenerative
neuromuscular diseases of the gut.
3.2.2.1 Focal neurologic signs are present

Central nervous system (CNS) causes of vomiting may be due to stimulation of the emetic
center in the medulla oblongata. It may be seen in patients with brain lesions, increased
intracranial pressure, hydrocephalus, vestibular disorders and posterior cranial fossa lesions.
Metabolic-induced and drug-induced vomiting are partially mediated by the CNS through
stimulation of the chemoreceptor trigger zone in the floor of the fourth ventricle (area postrema).

A thorough neurologic exam is critical to rule out CNS lesions, and includes testing of cranial
nerves, vestibular function and pupillary function. The presence of peripheral neuropathy and
extrapyramidal signs should be ascertained. Imaging studies of the head (CT or MRI) are
important diagnostic studies to rule out CNS lesions. For vertiginous symptoms, referral to an
otolaryngologist and consideration for electronystagmography is appropriate.

Treatment will depend on the diagnosis. Conditions such as increased intracranial pressure,
intracranial bleed and intracranial or posterior fossa tumor indicate the need for referral to a
neurologist or neurosurgeon.

3.2.2.2 The autonomic nervous system is involved

Disorders of autonomic supply may alter gut motility and result in vomiting. Autonomic system
degenerations such as idiopathic orthostatic hypotension, as well as diseases causing
autonomic neuropathy such as diabetes mellitus, may produce motility disturbances in the gut.
Signs of autonomic neuropathy such as orthostatic hypotension, absence of sweating and
absence of pulse and blood pressure responses to Valsalva maneuver should be sought.
Chronic nausea and vomiting is encountered in the diabetic patient.

3.2.2.3 Degenerative neuromuscular diseases of the gut

Motility disturbances in the GI tract can lead to acute presentations mimicking that of GI tract
obstruction. Most of the neuromuscular disorders are uncommon. Neuromuscular diseases of
the GI tract such as intestinal pseudo-obstruction and hollow visceral neuropathy or myopathy
may alter the muscle of the intestinal wall or the nerves of the myenteric plexus or both.

Patients can present with chronic unexplained abdominal pain, abdominal distention and
bloating, early satiety, nausea, vomiting and alterations in bowel habits (91) (92). Both purely
myogenic (familial visceral myopathy, somatovisceral myopathy, scleroderma) and purely
neurogenic motility disorders (von Recklinghausens disease or Chagas disease) exist. Mixed
conditions also exist. For example, in amyloidosis the lesion may be an infiltration of muscle and
nerve. Nausea and vomiting are frequent but not invariable features of gut motility disorders.
The area of the gut involved is important in determining the predominant clinical presentation:
whereas gastroduodenal motility disorders often cause nausea and vomiting, the predominantly
intestinal motility disorders (chronic intestinal pseudo-obstruction syndrome) may present as
abdominal distension, pain and disturbances of bowel movement often without recurrent
vomiting. Intestinal pseudo-obstruction caused by paraneoplastic syndromes can also present
with nausea and vomiting.
For the diagnosis of neuromuscular causes of nausea and vomiting, referral for specialized
testing may be necessary, especially in those patients with longstanding symptoms who remain
undiagnosed and who do not respond to therapeutic trials. Mechanical causes of GI tract
obstruction should be ruled out with contrast studies or endoscopy. While radionuclide studies
may document delayed gastric emptying, the precise etiology for such an abnormality in the
non-diabetic patient will not be known. Esophageal, antro-duodenal or anorectal manometry
may be useful to document altered GI tract motility; however, the precise etiology behind such
abnormalities will not be known. In these situations, referral for specialized studies is
appropriate. Tests such as small bowel manometry and electrogastrography may prove useful.
In a small number of cases, laparotomy with full thickness small bowel biopsy may be
necessary in order to arrive at a diagnosis.

3.2.3 Endocrine or metabolic cause

Endocrine and metabolic causes can lead to chronic nausea and vomiting. The classic
situations are the patient with diabetes mellitus, the patient with adrenal insufficiency and the
patient with hypercalcemia.

3.2.3.1 Diabetes mellitus

Nausea and vomiting, often accompanied by weight loss and early satiety, are common
gastrointestinal symptoms in patients with diabetes. Episodes of nausea and vomiting may last
days to months or occur in cycles (89). About half of patients with insulin or non-insulin-
dependent diabetes have delayed gastric emptying (diabetic gastroparesis). Some complain of
epigastric pain, nausea, vomiting or postprandial fullness. Bezoars may form in the stomach,
leading to gastric outlet obstruction exacerbating the underlying gastroparesis. Diabetic
gastroparesis may contribute to inadequate glycemic control and impaired absorption of orally
administered drugs. Although less common, gastric emptying rates may be accelerated in
diabetics as well (93).

3.2.3.2 Adrenal insufficiency

Adrenal insufficiency presents with nonspecific symptoms such as weakness, fatigue, nausea,
vomiting, anorexia and weight loss. It should be suspected if the patient has hyperpigmentation,
hyponatremia and/or hyperkalemia; a history of autoimmune disease such as hypothyroidism or
diabetes; or recent use of corticosteroids (70). Gastric stasis has been demonstrated in a
patient with primary adrenal insufficiency (94), and therefore this diagnosis should be
considered in patients presenting with chronic nausea and vomiting. The short cosyntropin
(Cortrosyn) stimulation test (250 ug IV or IM, with measurement of plasma cortisol 30 minutes
later) is diagnostic, with a normal response being stimulated plasma cortisol greater than 20
ug/dl. With the diagnosis of adrenal failure, therapy with hydrocortisone 100 mg IV q 8h should
be given, along with normal saline with 5% dextrose until hypotension is treated. Maintenance
therapy with prednisone is required.

3.2.3.3 Hypercalcemia

Hypercalcemic states can alter gut motility and present with nausea and vomiting. GI symptoms
of severe hypercalcemia (serum calcium > 12 mg/dl) includes nausea and vomiting, as well as
anorexia, constipation and abdominal pain. Neurologic symptoms include such as weakness,
fatigue, confusion, stupor and coma; renal effects such as polyuria and nephrolithiasis may be
seen. Dehydration resulting from nausea and vomiting and anorexia can lead to even more
severe hypercalcemia (95). Serum ionized calcium is a better indicator of true hypercalcemia,
as total serum calcium levels are linked to serum albumin levels. Primary hyperparathyroidism
and malignancy are the two most common causes of hypercalcemia. Treatment of the
underlying cause, as well as treatment of the hypercalcemia with extracellular volume
restoration, saline diuresis and treatment with bisphosphonates should be instituted when
appropriate.

3.2.4 Psychogenic causes

Repetitive vomiting may be a conscious and voluntary act as in patients with bulimia who vomit
in part to control their weight. In rumination, the patient increases intraabdominal pressure,
regurgitates food into the mouth and swallows it again. At a more subconscious level, vomiting
may occur in otherwise healthy persons as part of a strong emotional reaction, and in patients
as an expression of an underlying psychopathologic condition or as a conversion reaction.

In the diagnostic workup of psychogenic vomiting, a thorough history including a family and
social history are important. Volume depletion and signs of nutritional deficiencies should be
sought on physical examination. A complete neurologic exam should be performed. Depression,
weight loss and altered perception of body image suggest anorexia nervosa. Excessive
concern with body weight, loss of dental enamel, parotid hypertrophy, electrolyte disturbances
and chronic diarrhea indicate bulimia (96). Almost 50% of bulimics report nausea and other
gastrointestinal symptoms (97). Formal psychiatric testing including inpatient evaluation and
assessments such as the Minnesota Multiphasic Personality Inventory should be considered.
These types of tests may be helpful if an abnormality in the hypochondriasis, depression or
hysteria scales is found. Referral to a psychiatrist should be considered.

Often, psychogenic causes of nausea and vomiting are diagnoses of exclusion. Recently,
however, hypomotility in the gastric antrum, abnormal gastric electrical activity and delayed
gastric emptying have been reported in patients thought to have psychogenic nausea and
vomiting. Psychologic stress may in fact lead to vomiting in otherwise normal people (98). In
patients with functional nausea and vomiting, tricyclic antidepressants at low doses may be of
benefit. In a retrospective analysis of 37 such patients treated with amitriptyline, desipramine,
nortriptyline doxepin or imipramine, symptomatic response was documented in 84% of the
patients. Dose at response averaged 50 mg/day, and the outcome was not related to the
tricyclic antidepressant used (117).

Panic disorder has been associated with nausea (99). Patients with borderline personality
disorder can present with episodic vomiting (100). Social phobia may manifest as nausea and
fear of eating in public (101).

The cyclic vomiting syndrome is characterized by recurrent, self-limited episodes of nausea

and vomiting separated by symptom-free intervals. In a report of 71 cases, the length and
symptomatology of episodes were stereotyped and characteristic for each patient (102). There
was a coincident relationship with migraine and irritable bowel syndrome. Patients could identify
conditions that precipitated episodes, commonly heightened emotional states and infections
(103). While all patients in the series were children, a case in a 65-year old diabetic woman with
a 10 year history of recurrent nausea and vomiting was reported (104). Episodes of vomiting
were always characterized by elevations in serum ACTH, serum cortisol and urinary cortisol.
However, suppression of these elevations with dexamethasone did not alleviate the clinical
symptoms. Intramuscular ketorolac produced prompt and sustained relief.

A review of 17 adult patients with cyclic vomiting syndrome who had been treated with tricyclic
antidepressants was published (118). Symptoms began at age 35 (range 14-73 years). The
average duration of each episode was 6 days (range 1-21 days). The symptom-free interval
averaged 3.1 months (range 0.5 to 6 months). Fewer than a third of the patients reported a
prodrome or triggering events. Tricyclic antidepressant therapy led to complete remission of
symptoms in 17.6% of patients, and partial response in 58.5% of patients.

3.2.5 No cause found despite thorough investigation

Finally, there may be patients in whom no etiology can be determined despite extensive
diagnostic testing. In this group of patients, a gastric emptying study should be performed (105).
If the emptying study is abnormal, a trial of a prokinetic agent such as metoclopramide may be
useful. In cases of intractable gastroparesis, placement of gastrostomy tubes and jejunostomy
tubes for decompression and feeding respectively may be effective (106). Prior to the institution
of these measures, the patient should be considered for referral to a tertiary care center for
further testing, including electrogastrography and small bowel motility studies.

If the gastric emptying study is normal, then consideration can be given to laparotomy with full
thickness biopsy of the small intestine to rule out a neuropathic or myopathic disorder. Such an
invasive approach should be considered in the rare patient in whom vomiting is severe and has
led to nutritional compromise or to severe disruption of quality of life.

4.0 Drug Therapy for Nausea and Vomiting

4.1 Classes of Drugs

The following is a brief summary of the drugs used to treat nausea and vomiting, including
indications, contraindications and potential adverse reactions. For most of these agents, safety
for use in pregnancy has not been established. Whenever possible, the potential benefits must
be weighed against potential adverse effects. This is not a comprehensive list of potential uses
and adverse effects. For detailed information regarding these drugs, the package insert should
be consulted prior to prescribing. A summary of anti-emetic agents is provided in (Table 11).

4.1.1 Phenothiazines

Prochlorperazine and chlorpromazine are the phenothiazines used most frequently for nausea
and vomiting of various causes. They act at the CTZ to block dopamine receptors.
Prochlorperazine has good absorption after parenteral and oral administration, with a serum
half-life of 7 hours. Side effects include hypotension, autonomic responses, hypersensitivity
reactions (e.g. cholestatic jaundice) and hormonal dysfunction. Antidopaminergic effects include
dystonia, dyskinesia and tardive dyskinesia.

4.1.1.1 Prochlorperazine (Compazine)

Indications are moderate to severe nausea and vomiting. Contraindications include concomitant
use of CNS depressants including alcohol. Extrapyramidal side effects including tardive
dyskinesia are related to duration and total cumulative dose of neuroleptics. Neuroleptic
malignant syndrome (hyperpyrexia, muscle rigidity, altered mental status, autonomic instability
including tachycardia, labile blood pressure and cardiac arrhythmias) can occur. Safety for use
in pregnancy has not been unequivocally established, although based on limited information,
the drug appears relatively safe.

A randomized, double-blind comparison of treatment of uncomplicated nausea and vomiting due

to viral gastroenteritis with prochlorperazine (Compazine) or promethazine (Phernergan) was
published. The results showed that prochlorperazine was significantly better in terms of
symptom relief compared to promethazine (119). Time to complete symptom relief was
significantly shorter with prochlorperazine than with promethazine. Prochlorperazine also
caused significantly fewer complaints of drowsiness.

4.1.1.2 Promethazine (Phenergan)

This is a phenothiazine derivative which also has anti-H1 histamine receptor effects. Indications
are the prevention and control of nausea and vomiting associated with anesthesia and surgery,
and active and prophylactic treatment of motion sickness. Side effects include drowsiness, and
seizure threshold may be lowered. Use with alcohol and other CNS depressants effects should
be avoided.
4.1.1.3. Chlorpromazine (Thorazine)

Indications are nausea and vomiting. As for other phenothiazines, side effects include
extrapyramidal reactions and the neuroleptic malignant syndrome. Safety is not established in
pregnancy.

4.1.1.4. Thiethylperazine maleate (Torecan)

Indications are nausea and vomiting. Contraindications are CNS depression and comatose
states. IV administration is contraindicated due to hypotension. Extrapyramidal side effects can
be seen.

4.1.1.5 Perphenazine (Trilafon)

Indications are severe nausea and vomiting. Contraindications are obtunded patients, those
receiving large doses of CNS depressants, and when blood dyscrasias, bone marrow
suppression or liver damage is present. Tardive dyskinesia and neuroleptic malignant syndrome
may occur.

4.1.2 Antihistamines

These agents work predominantly at the level of the vestibular afferents and within the brain
stem. Their use in antiemesis is limited mainly to motion sickness and postoperative emesis.
The drugs most commonly used are cyclizine, diphenhydramine and promethazine.

4.1.2.1 Meclizine (Antivert ) (Bonine ).

Indications are nausea, vomiting and dizziness associated with motion sickness. It may also be
used to treat vertigo associated with diseases affecting the vestibular system. The major side
effect is drowsiness. Use with alcohol is to be avoided. Due to its potential anticholinergic
actions, it should be used with caution in asthma, glaucoma and prostate gland enlargement.
Meclizine appears to be relatively safe for use in pregnancy.

4.1.2.2 Diphenhydramine (Benadryl ).

Indication is primarily for treatment of motion sickness. Side effects include sedation. It should
be used with caution with narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal
obstruction and symptomatic prostatic hypertrophy. Additive effects with alcohol and other CNS
depressants occurs.

4.1.3 Prokinetic agents

These agents influence GI motility through one or more of the following pathways: 1. Directly or
indirectly promoting cholinergic tone; 2. Antagonizing inhibitory neurotransmitters (e.g.
serotonin, dopamine); or 3. Mimicking noncholinergic nonadrenergic compounds that increase
motility (e.g. motilin). Prokinetic agents have been used in the treatment of gastroparesis.
Metoclopramide, domperidone and cisapride are effective both in eliminating the symptoms of
gastroparesis and in enhancing the rate of gastric emptying (107).

4.1.3.1 Cholinergic agents

Direct cholinergic agents include bethanechol, which is the most commonly prescribed agonist,
and acts by enhancing the amplitude of contractions throughout the GI tract, including the lower
esophageal sphincter. These agents also stimulate the secretion of saliva and gastric acid. Side
effects develop due to enhanced parasympathetic tone, including abdominal cramps, diarrhea,
salivation, flushing, bradycardia and blurred vision.

4.1.3.2 Substituted Benzamides

This class of drugs promotes GI tract motility and increases antroduodenal coordination by
indirectly stimulating cholinergic nerves. They cause the release of acetylcholine from enteric
neurons. Side effects include a usually transient increase in stool frequency. Drugs that belong
to this class include metoclopramide, cisapride and trimethobenzamide. As metoclopramide
exhibits significant anti-dopaminergic effects, it is discussed in the following section.

Cisapride (Propulsid) was used as a prokinetic for conditions in which delayed gastric
emptying may be etiologic. Antro-duodenal motility is enhanced by this agent. In contrast to
metoclopramide, cisapride exhibits no anti-dopaminergic activity. It is also used for
gastroesophageal reflux disease. Cardiac arrhythmias such as ventricular tachycardia,
ventricular fibrillation, torsade de pointes and QT prolongation may occur when cisapride is
used concurrently with ketoconazole, itraconazole, miconazole, fluconazole, erythromycin,
troleandomycin and clarithromycin. Due to these adverse effects, cisapride was withdrawn from
the market, and is only available from the manufacturer under a compassionate use protocol.

Trimethobenzamide (Tigan) is used to treat nausea and vomiting. Its side effects include
drowsiness. Safety in pregnancy is not established, although based on limited information, the
drug appears to be relatively safe.

4.1.3.3 Dopamine receptor antagonists

Metoclopramide is the prototype drug of this class, and has both peripheral and central
dopamine receptor antagonist effects. Peripherally, it enhances release of acetylcholine from
intrinsic cholinergic neurons. It is an effective antiemetic in patients receiving chemotherapy.
Side effects limit the use of metoclopramide, with an incidence between 10-20%. The most
common are due to CNS effects, ranging from mild anxiety, restlessness, depression,
nervousness and insomnia, to marked anxiety, confusion, disorientation and hallucinations.
Fatigue and extrapyramidal side effects such as tremor, akathisia, tardive dyskinesia and
dystonic reactions that mimic Parkinson's disease are due to its central antidopaminergic
properties. Gynecomastia due to enhanced prolactin release has been described (107). Based
on limited information, metoclopramide appears to be relatively safe for use in pregnancy.

Domperidone (Motilium) is a benzimidazole derivative with anti-dopamine effects in the upper

GI tract. A distinguishing feature compared to other substituted benzimidazole agents is the lack
of cholinergic activity. Antro-duodenal motility and coordination is enhanced specifically by its
peripheral anti-dopaminergic effects. Because domperidone does not cross the blood-brain
barrier, no significant central nervous system anti-dopaminergic effects are seen. Central
nervous system side effects as seen with metoclopramide are rare. Female patients may
develop galactorrhea due to increased prolactin levels.

Domperidone was effective in improving delayed gastric emptying in 17 patients with

documented gastroparesis. Furthermore, quality of life was enhanced in more than 80% of
these patients. Symptoms such as nausea and vomiting, abdominal pain and bloating were
improved significantly in this group of patients (109).

A direct comparison of metoclopramide and domperidone in a randomized, double-blind study

has been reported. Ninety-five patients with nausea and vomiting due to a variety of
gastrointestinal causes were given either metoclopramide (15 mg bid) or domperidone (10 mg
or 20 mg tid). While both metoclopramide and low and high dose domperidone reduced nausea
and vomiting compared to baseline, there were no significant differences noted between the
three treatment groups (110).

4.1.3.4 Motilin agonists

Erythromycin acts as a prokinetic agent by binding to receptors for the hormone motilin, which
regulates the gastric migrating motor complex. As such, it can be used for delayed gastric
emptying. Tachyphylaxis can be a problem, making long-term use of this drug difficult.

4.1.4 Anticholinergics

The most commonly used agent is hyoscine hydrobromide (scopolamine hydrobromide). It is

one of the best agents for motion sickness, and is useful in postoperative nausea and vomiting.
In the palliative care setting, it is used for the management of intractable retching and for the
control of nausea, emesis and pain produced by intestinal obstruction.
4.1.4.1 Scopolamine (Transderm Scop)

Indications are nausea and vomiting associated with motion sickness. The patch should be
applied to the skin behind the ear. Programmed delivery of 0.5 mg of scopolamine over 3 days
is provided. It should be used with caution in elderly patients, and in patients with pyloric
obstruction or urinary bladder neck obstruction, or those with intestinal obstruction. It can be
used in pregnancy if the anticipated benefit justifies the potential risk to the fetus. Adverse
reactions include dry mouth, drowsiness, blurred vision and transient dilation of pupils.

4.1.5 5-HT3 receptor antagonists

5-HT3 receptors are located both centrally and peripherally, with high concentrations in the GI
tract. Antagonists for this receptor have been evaluated and found to be effective for a variety of
conditions, including cancer chemotherapy-induced emesis, emesis due to total body irradiation
(111), GI motility disturbances, carcinoid syndrome and nausea and vomiting related to migraine
and anxiety (3).

4.1.5.1 Ondansetron

Ondansetron is the prototype drug of this class. It is effective in the control of chemotherapy-
induced emesis. The principal site of action is in the area postrema, with some gastric prokinetic
activity. Ondansetron is not effective against motion sickness. Given orally, ondansetron can be
dosed q8-12 hours. Ondansetron is superior to high-dose metoclopramide in chemotherapy-
induced emesis. Side effects are few, and include constipation, headache and a transient rise in
transaminases.

4.1.5.2 Other 5-HT3 receptor antagonists

Additional 5-HT3 receptor antagonists which have been tested clinically are granisetron and
tropisetron. Comparative studies have shown similar efficacy for these two agents (112). Direct
costs of the drugs in this class did vary widely (129). Efficacy is more pronounced for cisplatin-
containing regimens than for less emetogenic regimens. Effectiveness is greater for acute
emesis than for delayed emesis. Nausea is more difficult to control than emesis by these
agents. Granisetron (Kytril ) is indicated for the prevention of nausea and vomiting associated
with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin.

4.1.6 Miscellaneous agents

4.1.6.1 Corticosteroids
These agents can assist in relief of cytotoxic drug-induced emesis, especially when combined
with other antiemetics. Dexamethasone alone or in combination with ondansetron were shown
to be equally efficacious in preventing delayed chemotherapy-induced nausea and vomiting in
patients at low risk for this (131). A meta-analysis of the available randomized evidence of the
effectiveness of dexamethasone in the treatment of chemotherapy-induced nausea and
vomiting was published. Thirty-two studies met the inclusion critieria. Dexamethasone was
superior to placebo or no treatment for complete protection of acute emesis (odds ratio 2.22;
95% confidence interval [Cl], 1.89 to 2.60). Also, dexamethasone was superior to placebo or no
treatment for complete protection from delayed emesis (odds ratio 2.04; 95% Cl; 1.63-2.56)
(132). In adrenal insufficiency, treatment of the underlying cortisol deficiency with corticosteroids
will ameliorate the symptoms of this disorder, including nausea and vomiting.

4.1.6.2 Megestrol Acetate

This is a progesterone used in the treatment of advanced breast cancer, which has appetite-
stimulating properties and can improve the symptoms of nausea from a variety of causes in
cancer patients.

4.1.6.3 Tetrahydrocannabinol (dronabinol) and Nabilone

The role of delta-9-tetrahydrocannabinol, the active component of marijuana, and nabilone, a

synthetic cannabinoid, is mainly in cytotoxic drug-induced emesis (113). Side effects tend to
limit their usefulness. Alterations in mood, motor coordination, cognitive function and memory
are common. Nabilone has been used successfully for the management of intractable nausea
and vomiting in terminally staged AIDS patients (114).

Dronabinol (Marinol) is an orally active cannabinoid. It is used for prophylaxis of

chemotherapy-induced emesis. Combination treatment with prochlorperazine may result in
synergistic or additive antiemetic effects and attenuate the toxicities. A potential for abuse
exists.

4.1.6.4 Benzodiazepines

The anxiolytic and amnesic properties of some benzodiazepines can be beneficial for patients
whose nausea and vomiting have a psychological component. This is particularly so for the
conditioned emesis of cytotoxic chemotherapy.

4.1.6.5 Bismuth subsalicylate (Pepto-Bismol)

Although usually used for the symptomatic control of diarrhea, associated upper GI complaints
such as nausea may be relieved.

4.1.6.6 Tricyclic Antidepressants

The tricyclic antidepressant class of drugs (amitriptyline, nortriptyline, doxepin, desipramine, and
imipramine) have been used at low doses (average does 50 mg/day for the treatment of fuctional nausea
and vomiting (117) and cyclic vomiting syndrome (118), with some efficacy.

4.1.6.7 Ginger (Zingiber officinale)

Ginger has been advocated as a treatment for nausea and vomiting. A systematic review, however, of the
evidence from six randomized clinical trials did not show a significant difference from placebo. However,
individual non-controlled studies have favored ginger over placebo for the treatment of nausea and
vomiting caused by seasickness, early pregnancy and chemotherapy (120).

4.1.6.8 Neurkinin-1 antagonists

The tachykinin substance P is localized within both the gastrointestinal vagal afferent nerve fibers and in
the neural pathways involved in the emetic response in the brainstem. Therefore, substance P is thought
to be a key mediator of nausea and vomiting, and antagonists to its receptor, nuerokinin-1 (NK-1), are
now being tested for their anti-emetic properties. Preliminary studies in humans show that NK1 receptor
antagonists are effective in controlling both chemotherapy-induced and postoperative nausea and
vomiting (133). In a randomized, double-blind comparison with ondansetron in the prevention of
postoperative nausea and vomiting, the NK1 receptor antagonist CP-122,721 200 decreased emetic
episodes more effectively than ondansetron (134).

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