Nausea and Vomiting

1. Nausea and Vomiting Mark Feldman, MD 2013

2. 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.

3. 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, lisinoprilspironolactone, 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.

4. Case 1, continued • Labs: • Serum digoxin level: 5.64 ng/ml (critical, > 2 ng/ml) • Diagnosis: • Digitalis toxicity

5. 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

7. 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)

8. 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

9. Nausea and vomiting in STEMI STEMI location Inferior (n = 108)Anterior (N=72) Nausea 75 (69%) 41 (57%) P=0.11 Vomiting*† 36 (33%) 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

10. 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)

11. Nausea/vomiting on presentation to the teaching service at THD (75 cases) 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 GI DISEASES (n= 30 ) (40%)

12. Nausea/vomiting on presentation to the teaching service at THD (75 cases) OTHER DISEASES (n=45) (60%) Metabolic (11) DKA(5), hyponatremia (3), hyperglycemia, hypo- glycemia, 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.

13. 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

14. 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?

15. 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)

16. 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

17. 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

18. Some common syndromes • Pregnancy • Medication induced vomiting • Psychogenic vomiting • Eating disorders • Surrepticious vomiting • Gastroparesis • Chemotherapy-induced (CINV)

19. 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.

20. 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?

21. 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

22. 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

23. 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

24. 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

25. 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)

26. 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 30-40% Diabetic 25-30% Post-surgical 10-15% Misc. causes* 10-25% * Includes malignancy-associated gastroparesis

27. CINV

28. 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

31. 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)

32. 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

33. ADDITIVE EFFECT OF A GLUCOCORTICOID

34. 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

35. Impact of Oral Aprepitant (Aprep) on CINV with a Highly Emetic Regimen 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

36. IV Formulation

37. 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.

39. 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

40. 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

41. Post-emetic purpura(“mask phenomenon) Cutis, 1986

42. Electrolyte and acid-base disorders due to vomiting Metabolic alkalosis retention of HCO3- + volume-contraction Hypokalemia* = Σrenal K+ loss + GI K+ loss +  K+intake Hypochloremia gastric chloride losses Hyponatremia free water retention due to volume contraction *Pearl: Patients with uremia or Addison’s disease may have normal or even high serum K+ despite vomiting

43. 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)

44. 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

45. 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

46. 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)

47. 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

48. An approach History, physical, ±labs, ± fluid/electrolyte repletion, ± empirical anti-emetic therapy yes No Underlying disorder? Treat it Imaging, Endoscopy Lesion Med./Surgical therapy No lesion identified Gastric emptying study normal abnormal (slow) Psychiatry Referral ? • Prokinetic drug • Gastric electrical stimulation @ 12 cpm ? * * FDA, humanitarian device exemption

49. 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.