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Nausea and Vomiting
Mark Feldman, MD
2013
Seinfeld’s description of vomiting.
Jerry: I haven’t vomited in 13 years.
Elaine: Get out!
Jerry: Not since June 29, 1980.
Elaine: You remember the date?
Jerry: Yes, because my previous vomit
was also June 29th…1972. That’s
why during the ’80 vomit I was
yelling to George: “Can you believe
it? I’m vomiting on June 29th
again.”
Elaine: Boy, you know when Joel told
me he hadn’t thrown up in 8 years,
I was wondering if he was normal.
Jerry: Your boyfriend is a normal guy.
The Masseuse. Season 5.
Case 1
• A 77 year old man was admitted to the teaching service
after he vomited 30 times over the past 2 days. He had
severe nausea that preceded vomiting. There was no
abdominal pain.
• He had a history of systolic heart failure (idiopathic dilated
cardiomyopathy) and sinus node dysfunction and had both
a pacemaker and an ICD. Medications included atenolol,
lisinopril spironolactone, and digoxin.
• Examination was unremarkable except for mild volume
depletion. ECG showed a paced rhythm at 68/min. Serum
creatinine was 1.0 mg/dL and serum K was 4.5 mM.
Case 1, continued
• Labs:
– Serum digoxin level: 5.64 ng/ml (critical, > 2 ng/ml)
• Diagnosis:
– Digitalis toxicity
Terminology
• Nausea: a very unpleasant sensation
that one may soon vomit (from naus,
Latin, ship);
• Vomiting: involuntary contractions of
the abdominal, thoracic and GI
(smooth) muscles leading to forceful
expulsion of stomach contents from
the mouth
• Retching: muscular activity of the
abdomen and thorax, often voluntary,
leading to forced inspiration against a
closed mouth and glottis without oral
discharge of gastric contents (“dry
heaves”)
• Regurgitation: effortless return of
esophageal or gastric contents into
the mouth unassociated with nausea
or involuntary muscle contractions.
• Rumination: food that is regurgitated
in the postprandial period, re-chewed
and then re-swallowed
Postulated mediators of nausea and vomiting
• Acetylcholine
• Biogenic Amines
–
–
–
–
Serotonin (5-HT)*
Dopamine*
Histamine
Norepinephrine
• Peptides
– Substance P/ Neurokinin-1*
– Opiate peptides (e.g., enkephalins)
Common etiologies of nausea and vomiting
• Pregnancy
• Medications
– Rx and OTC, including herbals
• GI/Pancreatic/Hepatic/ Biliary/Peritoneal disease
– toxins, infections, obstruction, inflammation, motility disorders, neoplasms
• Non-GI Infections
– brain, kidney, lung, ear, blood-stream, etc.
• Myocardial ischemia or infarction
Nausea and vomiting in STEMI
STEMI location
Nausea
Vomiting*†
Inferior (n = 108)
75 (69%)
36 (33%)
Anterior (N=72)
41 (57%)
P=0.11
19 (26%)
P=0.41
* All patients who reported vomiting also reported preceding nausea.
† Retching (dry heaves) was included with vomiting.
E Fuller, R Alemu, J Harper, and M Feldman. The Amer J Cardiol. 104: 1638-1640, 2009
Common etiologies of nausea/vomiting, cont’d
• CNS causes (non-infectious)
– migraine, neoplasm, bleed, high altitude cerebral edema/acute mountain suckness
• Vestibular disorders
– Motion sickness, labyrinthitis
• Metabolic/endocrine
– DKA, uremia, adrenal insufficiency, hyper- or hypothyroidism, hypo- or
hyperparathyroidism
• Alcohol/drug intoxication
• Radiation exposure
• Psychogenic, including eating disorders (AN, bulimia)
Nausea/vomiting on presentation to the
teaching service at THD (75 cases)
GI DISEASES (n= 30 ) (40%)
Gastric/Duodenal (6): PUD (2), FD, DG, GOO, food poisoning
Intestinal (8): SBO/LBO(3), pseudo-obstruction, gastroenteritis (2),
diverticulitis (2)
Pancreatic (6)
Biliary (5): cholecystitis (3), cholangitis (2)
Hepatic (5): hepatitis (3), liver masses, ischemia vs. hepatitis
Nausea/vomiting on presentation to
the teaching service at THD (75 cases)
OTHER DISEASES (n=45) (60%)
Metabolic (11)
DKA(5), hyponatremia (3),
hyperglycemia, hypoglycemia, hypercalcemia
Toxin/Medication (5)
alcohol, CO, ethylene glycol,
digoxin, lithium
Infection (5)
Urinary tract (2), malaria,
pneumonia, diabetic foot ulcer
with osteomyelitis
CNS disease 13
CVA/TIA (4), meningitis (4), seizure
(2), primary tumor, brain
metastases, toxoplasmosis
Renal causes 6
renal failure (5), renal infarct
Cardiac 4 *
MI (2), ACS, atrial fib/RVR
Eating Disorder 1
* May occur without chest pain; don’t forget to include ECG in eval.
Approach to the patient with nausea/vomiting
• Detailed history, including menstrual and medications
– Recall that vomiting in the community is rare in adults, but is
common in hospitalized patients (  a serious sign)
• Complete head-to-toe physical exam
– Papilledema to diabetic foot ulcer
• Selected laboratory tests seeking causes of and
consequences of nausea and vomiting
• Selected imaging studies of brain and abdomen as directed
by history and physical
Nausea/Vomiting: Key Historical Questions
•
•
•
•
How long? Cyclic?
Relationship to meals?
Does vomited fluid contain blood, bile, old food,?
Associated symptoms?
– pain in chest or abdomen, fever, myalgia, diarrhea,
vertigo, dizziness, headache, focal neurological
symptoms, jaundice, weight loss
• Diabetes?
• When was last menstrual period?
Nausea/Vomiting: Key Physical Findings
•
•
•
•
•
•
•
Vital signs
Tilt test (BP and pulse)
Exam throat and ears carefully
Cardiopulmonary exam
Abdominal exam
Rectal exam ± pelvic exam
Neurological exam including funduscopic
exam (papilledema)
Laboratory studies: guided by H&P
•
•
•
•
•
•
•
Electrolytes, glucose, BUN, creatinine
Calcium, albumin, total serum proteins
CBC
Liver chemistry tests
Pregnancy test
Urinalysis (infection, ketones, bilirubin, casts)
Serum lipase or amylase
Imaging studies: guided by H&P
• Plain abdominal films
• Abdominal sonogram (or CT), if pain is key feature
• Head CT or brain MRI, if severe headache, papilledema,
marked hypertension, altered mental status, or focal
neurological findings
• EGD or upper GI series to distinguish gastric outlet
obstruction or high duodenal obstruction from
gastroparesis
• Radio-opaque marker emptying studies or radionuclide
scintigraphy, especially if diabetic
Some common syndromes
• Pregnancy
• Medication induced vomiting
• Psychogenic vomiting
– Eating disorders
– Surrepticious vomiting
• Gastroparesis
• Chemotherapy-induced (CINV)
Vomiting and pregnancy
• Pregnancy-related
–
–
–
–
Nausea of early pregnancy (‘morning’ sickness)
Hyperemesis gravidarum
Acute fatty liver of pregnancy
Hemolysis Elevated Liver tests Low Platelet (HELLP)
syndrome
• Unrelated to pregnancy
– Gastroenteritis
– Viral hepatitis
– etc.
Case 2
• A 29 year old complained of severe, recurrent
vomiting, worse in the morning but sometimes in
the later part of the day. She is in her 13th week
of her first pregnancy, and has not yet gained
weight. Her past medical history is negative
except for obsessive-compulsive disorder.
• What is the most likely diagnosis?
• What tests would you order?
Case 2, continued
• The patient was clinically diagnosed with
hyperemesis gravidarum.
• Tests: TSH, undetectable; free T4 and serum T3,
were markedly elevated.
• Her symptoms resolved in a few weeks, without
recurrence.
Goodwin et al. Transient hyperthyroidism and hyperemesis gravidarum.
Am J Obstet Gynecol 167: 648, 1992 and J. Clin Endocrin Metab 75: 1333, 1992
Medication causes of nausea/vomiting
• Chemotherapy agents*
• Analgesics
– e.g. opiates*, NSAIDs
• Antibiotics
– e.g., erythromycin
• Cardiac
– e.g., digoxin, quinidine
• Oral contraceptives,
estrogen, progesterone
• Metformin
• Parkinsonian drugs
– e.g., bromcryptine, L-DOPA
• Anticonvulsants
– e.g., phenytoin, carbamazepine
• Theophylline
• Anesthetics
• HAART
* Preventive measures are often warranted due to high incidence
Inter-subject variability of nausea and vomiting
• In one study, 18 volunteers received an identical sq dose of
apomorphine (0.03 mg/kg, or around 1.5-3 mg)
– Apomorphine is an opiate/dopamine agonist that, like digoxin,
acts on the chemoreceptor trigger zone (CTZ)
• Responses reported and observed:
– 16 volunteers reported nausea within 6 ± 2 minutes
– 14 of the 16 developed vomiting within 8 ± 2 minutes, while the
other 2 never vomited
– 2 had no nausea or vomiting
Behavior Research & Therapy 21:669-73,1983
Psychogenic vomiting
•
•
•
•
Usually female and often young
May deny or minimize nausea
Rarely occurs in public or in front of others
Co-existent eating disorder, laxative abuse,
diuretic abuse common
• Psychological disturbances common
• Complications of vomiting may be present
Surreptitious vomiting
• Unexplained weight loss
• Co-existent eating disorder or other
psychological/psychiatric condition
• Co-existent laxative and/or diuretic abuse
• Electrolyte and/or acid-base disturbances
consistent with vomiting, including hypokalemic
nephropathy
• Emetic complications (with denial of vomiting)
Gastroparesis
Delayed gastric emptying not due to
obstruction, with or without symptoms of
delayed gastric emptying such as bloating,
nausea, vomiting, pain, early satiety:
Idiopathic
Diabetic
Post-surgical
Misc. causes*
30-40%
25-30%
10-15%
10-25%
* Includes malignancy-associated gastroparesis
CINV
Chemotherapy-Induced Nausea/ Vomiting
• Three types of CINV
– Acute CINV( 24 hours, but usually 1-2 hours post chemo)
– Delayed CINV(> 24 hours), an area of renewed attention
– Anticipatory CINV (immediately before next chemo cycle)
• Risk factors for CINV:
–
–
–
–
Dose of chemotherapeutic agent (e.g., cisplatin)
Female gender
Younger age (< 65)
Low alcohol intake (< 5 drinks per week)
• Incidence varies widely with the regimen/drugs used
Therapeutic index of anti-emetic drug classes
(Hekseth, UpToDate)
• High therapeutic index
• 5-HT3 RAs (e.g., palonosetron)
• Corticosteroids (e.g., dexamethasone)
• Neurokinin-1 antagonists (e.g., aprepitant)
• Low therapeutic index
• Metoclopramide (Reglan, others)
• Prochlorperazine
• Nabilone (Cesamet) and dronabinol (Marinol)
Palonosetron (Aloxi, others)
• 2nd generation 5-HT3 RA
• T ½ ~ 40 hours
• Superior to 1st generation 5-HT3 RAs in preventing
both acute CINV and delayed CINV
• Usually combined with a high dose corticosteroid
ADDITIVE EFFECT OF A GLUCOCORTICOID
Aprepitant (Emend) in prevention of CINV
• Neurokinin -1 receptor antagonist
• Blocks the emetic effect of Substance P, which acts
on the Substance P/Neurokinin-1 Receptor
• Used alone, aprepitant (40 mg po) prevents PONV
• Used in combination with a 5-HT3 RA and
dexamethasone, aprepitant prevents CINV better
than a 5-HT3 RA plus dexamethasone alone
PONV, postoperative nausea/vomiting; CINV, chemotherapy-induced nausea/vomiting
Impact of Oral Aprepitant (Aprep) on CINV
with a Highly Emetic Regimen
Day 1
Day
Control
Control
Aprep
Ond
32iv
32iv
Dex
20po
12po
Apr
125po
8
2
Aprep
8
80po
Day
Control
8
3
Aprep
8
Day
Control
8
4
Aprep
8
80po
1° endpoint: no vomiting or use of rescue Rx
– 1° endpoint reached in 48% with Control and 68 % with Aprepitant (P < 0.001)
– ARR= 20%
– NNT=5
IV Formulation
• Fosaprepitant dimeglumine
Prodrug
• Hepatic metabolism
CYP34A
• Aprepitant
Drug
Fosaprepitant (Emend)
• 115 mg IV  125 mg po aprepitant.
– Equal efficacy
– Headache main side effect
• Can be given IV on day 1, 2, 3, 4 instead of p.o. aprepitant, especially
in patients with oral mucositis, dysphagia, or intestinal problems
• As it inhibits CYP3A4 (and mildly induces CYP2C9), it may:
–
–
–
–
Prolong QTc
Increase levels of CyA/tacrolimus/sirolimus and of midazolam/alpazolam
Lower warfarin, phenytoin
Double AUC for dexamethasone; thus, lower the dexa dose by 50%
• Aprepitant levels are lowered by strong CYP3A4 inducers such as
rifampicin and raised by strong inhibitors such as ketoconazole.
Complications of Vomiting*
• Nutritional
– adults: weight loss; kids: failure to gain/grow
• Cutaneous (petechia, purpura)
• Oropharyngeal (dental erosion, sore throat)
• Esophageal: esophagitis/hematoma
• GE junctional: M-W tears; rupture (Boorhaave’s)
• Metabolic: electrolyte, acid-base, water
• Renal: pre-renal azotemia; ATN; hypokalemic nephropathy
• Spread of infection to close contacts and caregivers
– H. pylori; GI viruses; ?others
* Can be clues to a diagnosis of surrepticious vomiting
Mallory-Weiss tear with oozing
Tear begins at GE junction (large arrow) and extends into stomach (hiatal hernia pouch; small arrow).
From Sleisenger & Fordtran, 9th ed., p. 304
Post-emetic purpura
(“mask phenomenon)
Cutis, 1986
Electrolyte and acid-base disorders due to vomiting
Metabolic alkalosis
retention of HCO3- + volume-contraction
Hypokalemia*
*Pearl: Patients with uremia
= Σ renal K+ loss
or Addison’s disease may
+ GI K+ loss
have normal or even high
+
+  K intake
serum K+ despite vomiting
Hypochloremia
gastric chloride losses
Hyponatremia
free water retention due to volume contraction
Principles in treatment of nausea/vomiting
1. Treat the complications, regardless of cause
e.g., replace salt, water, and potassium losses
2. Identify and treat the underlying cause, if possible
3. Provide temporary symptomatic relief of symptoms
4. Consider preventive medication when vomiting is
very likely to occur (e.g., cancer chemotherapy,
parenteral opiate administration)
Antiemetic drugs with known mechanisms
• Anti (H1)-histamine, e.g., meclizine (AntivertR)
– esp. for vestibular disorders
• Anticholinergic, e.g., scopolamine (Transderm ScopR, DonnatalR)
– esp. for vestibular and GI disorders
• Dopamine antagonist, e.g., metoclopramide (ReglanR) or
phenothiazines, e.g., prochlorperazine (CompazineR)
– esp. for GI disorders
• Selective serotonin-3 (5HT3) RAs, e.g., ondansetron (Zofran),
granisetron (Kytril), dolasetron (Anzamet), tropisetron (Navoban),
palonosetron (Aloxi, others)
– esp. to prevent/Rx chemotherapy-induced nausea/vomiting
• Neurokinin-1 RAs, e.g., aprepitant, fosaprepitant
– esp. to prevent CINV
Anti-emetic drugs with multiple
mechanisms of action
• Promethazine (PhenerganR)
– dopamine antagonist
– H1-antihistamine
– anticholinergic
– CNS sedative
– prevention of opiate-induced nausea and vomiting
• Hydroxyzine (AtaraxR, VistarilR)
– H1-antihistamine
– anticholinergic
– CNS sedative
– prevention of opiate-induced nausea and vomiting
Anti-emetic drugs with uncertain
mechanism of action
• Trimethobenzamide (TiganR)
– blocks apomorphine-induced emesis in dogs
– does not block emesis from p.o. CuSO4 in dogs
 probably acts in the chemoreceptor trigger zone
(CTZ) of the medulla oblongata
• Bismuth subsalicylate (Pepto-BismolR)
Adjunctive anti-emetic agents
• Dexamethasone
– Used in conjunction with other anti-emetics for prevention
of CINV
• Benzodiazepines
– Especially useful for anticipatory nausea/vomiting
– Alprazolam and lorazepam used, although few studies
• Dronabinol and Nabilone
– Used for prevention of cancer chemotherapy-induced
emesis refractory to other agents, but many side effects
An approach
History, physical, ±labs, ± fluid/electrolyte repletion, ± empirical anti-emetic therapy
No
Underlying disorder?
Imaging, Endoscopy
Lesion
No lesion identified
Treat it
Med./Surgical therapy
Gastric emptying study
normal
Psychiatry
Referral ?
* FDA, humanitarian device exemption
yes
abnormal (slow)
•Prokinetic drug
•Gastric electrical
stimulation @ 12 cpm ? *
Take home points
• Nausea and vomiting are features of many GI and non-GI diseases
and disorders.
• Regardless of its cause, treatment of nausea and vomiting should
initially focus on replacing volume and electrolyte deficits. Later,
nutritional deficits may be addressed.
• Regardless of its cause, vomiting can cause several life-threatening GI
and non-GI complications.
• Elucidation of the cause is often possible, and treatment of the
underlying cause will usually be successful.
• Effective symptomatic therapies for nausea and vomiting are
available when the cause is unclear or when the treatment of the
underlying cause takes time to work.
Less common causes of nausea/vomiting
• Rapid weight loss/
body casts (SMA syndrome)
• Infectious esophagitis
– esp. if immunocompromised
• Opiate withdrawal
Diagnosis in a patient with vomiting?
What is this?
Markers in stomach 24 hours after
ingestion in patient with pseudoobstruction and small cell lung cancer
Test meal: liquid, digestible solid and
indigestible solid
M-W tears: 7 o’clock and 1 o’clock
Esophageal hematoma 2° to emesis
Lumen
mass
Digestive Diseases and Sciences 26: 1019, 1981