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 the chemoreceptor 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 alkalosis results 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 anticoagulated (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 selflimited 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 placebocontrolled 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 horizontalrotatory
Never purely vertical
Any direction
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
Labyrinth or vestibular
Brainstem or
location of
problem
nerve
cerebellum
Induced Nystagmus
Feature
Peripheral (BPV)
Central
Time to onset after
quick position change
(latency)
3-20 seconds
Immediate
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 and vertigo. 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), or antihistamines (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. Antihistamines 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 costeffective 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 5HT3 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 selflimited 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 bezoar is 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. Complete small 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 narcoticinduced 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. MalloryWeiss 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 saltcontaining 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 placebocontrolled 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 deepbreathing 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 pseudoobstruction 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
obstruction can 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 druginduced 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 nondiabetic 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 121 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. Antroduodenal motility and coordination is enhanced specifically by its peripheral antidopaminergic 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 noncontrolled 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).