A. Etiology [1,2]

1. Types of Disease
   1. Normal gastric emptying
   2. Abnormal gastric emptying - mechanical or functional
   3. Emetogenic center in poorly defined area in lateral reticular formation of medulla
   4. Area Postrema is believed to be most critical for regulating emetogenic response
   5. This area receives inputs from variety of sources
2. Inputs to Emetogenic Center
   1. Chemoreceptor trigger zone (Area Postrema) - outside blood-brain barrier
   2. Vestibular apparatus - labyrinthine inputs into vomiting center via cranial nerve VIII
   3. Cerebellum
   4. Peripheral Pathways - mechanoreceptors + chemoreceptors in GI tract, through vagus and splanchnic nerves, sympathetic ganglia, glossopharyngeal nerves, solitary tract nucleus
   5. Higher cortical center - believed due to input from 5 senses, anxiety, meningeal irritation
3. Receptors Implicated in Nausea and Vomiting
   1. Serotonin
   2. Dopamine
   3. Acetylcholine (muscarinic)
   4. Histamine
   5. Antagonists at these receptors are mainstay of therapy and prevention
   6. Substance P (binding to neurokinin 1 receptor) and Endorphins also implicated
4. Etiologies divided by normal or abnormal gastric emptying
5. Normal Gastric Emptying
   1. Food Poisoning (toxins) - staphylococci, B. cereus, clostridia, salmonella
   2. Gastroenteritis - viral, bacterial, protozoal
   3. Acid overproduction - Caffeine, NSAIDS, Gastrinoma, Zollinger-Ellisson Syndrome
   4. Esophageal motility abnormalities - diverticuli, achalasia, scleroderma
   5. Vascular (Migraine)
   6. CNS - increased intracranial pressure due to infection, trauma, or mass
   7. Psychological - anorexia, bulimia, some anxiety disorders
6. Abnormal Gastric Emptying
   1. Pancreatitis
   2. Pregnancy (Morning Sickness)
   3. Ruptured Ectopic Pregnancy
   4. Diabetes: diabetic gastropathy, diabetic ketoacidosis
   5. Emetogenic Drugs: chemotherapies, codeine, other opiates, erythromycin (high doses)
   6. Serious Infections: sepsis, pyelonephritis, peritonitis, severe ulcerative colitis
   7. Scleroderma
   8. Neuropathies
   9. Postoperative (PONV)
7. This outline will focus on functional and neurological causes of nausea
8. Obstructive causes of nausea or vomiting will generally require surgical correction

B. Treatment of Nausea and Vomiting [2,13]

1. Overview of Agents [13]
   1. Serotonin Receptor 3 (5-HT3) Antagonists - usually first line for severe nausea / emesis
   2. Combination with glucocorticoids (dexamethasone, high dose) for severe nausea / emesis
   3. Dopamine D2 antagonists usually first line for mild-moderate nausea
   4. Phenothiazines and Butyrphenones - now second line for most chemotherapy
   5. NK1 antagonist - most effective when combined with 5-HT3 antagonists
   6. Anticholinergic Agents - less effective than others for chemotherapy
   7. Tetrahydrocannabinol - active agent in marijuana; effective third line agent
2. 5-HT3 Antagonists [10]
   1. Extremely effective for moderate and highly emetogenic chemotherapy
   2. Very effective for post-operative nausea and vomiting (PONV)
   3. For emesis due to moderately emetogenic chemotherapy, palanosetron is likely most effective 5-HT3 antagonist
   4. Dexamethasone (Decadron®) definitely promotes efficacy of these agents primarily in chemotherapy setting [5]
   5. For highly emetogenic chemotherapy, 5-HT3 antagonist + aprepitant (NK1 blocker) + dexamethasone should be used [10]
   6. Also effective for post-chemotherapy residual and postoperative nausea and vomiting
   7. Effective for gastroenteritis associated nausea and vomiting [6]
   8. Main side effect is headache (~15%)
3. Specific 5-HT3 Antagonists [10]
   1. Ondansetron (Zofran®): 24-32mg bolus IV, or in 8-12mg divided doses, or continuous infusion, or oral 24mg po 30 minutes before chemotherapy, or 8mg bid
   2. Ondansetron oral disintegrating tablets also reduce emesis and improve oral rehydration in children 6 months - 10 years old treated for gastroenteritis [6]
   3. Granisetron (Kytril®): 3mg iv or 10µg/kg iv q24 hours (hrs), or 1mg bid po or 2mg qd po [4]
   4. Dolasetron (Anzemet®): 100mg iv or 1.8mg/kg once; oral 100mg once [5]
   5. Palanosetron (Aloxi®): 0.25mg IV x 1 dose only; very long half-life, covers up to 40 hrs [10]
   6. Mirtazapine (Remeron®): 15-45mg po qhs [2]
   7. Tropisetron (Vavoban®) under development
4. Phenothiazines
   1. May be used initially (but most physicians use serotonin antagonists)
   2. Mainly block dopamine receptors (D2, D3, some D4)
   3. Metoclopramide (Reglan®): 50-20mg (up to 50mg) po, sc or IV prior to each meal and qhs
   4. Prochlorperazine (Compazine®): 5-10mg po or IV, 25mg rectally, all q6 hours
   5. Perphenazine (Trilafon®)
   6. Thiethylperazine (Torecan®)
   7. Promethazine (Phenergan®): 12.5 or 25mg IV or po or 25mg rectally, all q6 hours
   8. Trimethobenzamide (Tigan®): oral, suppositories, injectable
   9. Chlorpromazine (Thorazine®): 10-25mg po or 25-50mg IM or IV all q4 hour, or 50-100mg rectally q6 hours
   10. Prochlorperazine was superior to promethazine in uncomplicated nausea and vomiting [7]
5. Butyrphenones
   1. Droperidol (Inapsine®): highly effective mainly in anesthesia induced nausea, slight increased risk of prolonged QTc interval [8]
   2. Haloperidol (Haldol®): 0.5-4.0mg po or SC or IV q6 hours
   3. Droperidone (Motilium®)
6. NK1 Antagonists [3,9]
   1. Aprepitant (Emend®) approved for CINV with highly emetogenic chemotherapy
   2. Blocks neurokinin 1 (substance P) receptors and inhibits emetogenic response
   3. When combined with standard 5-HT3 antagonist+dexamethasone, substantially reduces acute and delayed emetic responses
   4. Dose 125mg po day 1, 80mg po qd days 2 and 3
7. Glucocorticoids
   1. High dose glucocorticoid therapy is quite effective for nausea and vomiting treatment
   2. Typically dexamethasone 4-8mg iv pre-therapy, then 4mg q6-8 hrs x 24 hours given
   3. For moderately emetogenic regimens, may be as effective as ondansetron
   4. Combinations with serotonin blockers are highly synergistic in chemotherapy N/V
8. Dronabinol (tetrahydrocannabinol, THC; Marinol®)
   1. Derived from marijuana
   2. Excellent anti-nausea agent but usually used third line
   3. Strong appetite stimulant as well
   4. Dose 5mg/m2 bid-tid prn orally, initiate 1-2 hours prior to chemotherapy
   5. Tachycardia, hypotension, dysphoria, depression, memory problems, drowsiness, fatigue
   6. Moderately high abuse risk, Schedule CIII
   7. Generally limit use to patients who have failed conventional antiemetic therapies
9. Nabilone (Cesamet®) [12]
   1. Oral active, synthetic cannabinoid
   2. Similar effects to marijuana
   3. High abuse potential, schedule CII
   4. Indicated for treatment of N/V associated with chemotherapy
   5. Dose 1-2mg po bid, maximum 6mg/day in 3 divided doses
   6. First dose is given 1-3 hours (and/or night) before chemotherapy
   7. Continue 2-3 doses/day during chemotherapy
   8. Drowsiness, vertigo, dry mouth, euphoria/dysphoria, ataxia, headache
   9. Tachycardia, hypotension, concentration difficulties, sleep disturbances
   10. Generally limit use to patients who have failed conventional antiemetic therapies
10. Anticholinergic Agents [2]
    1. Diphenhydramine (Benadryl®): 25-50mg po or IV or SC q6 hours (also antihistamine)
    2. Scopolamine (Transderm Scop®): 1.5mg transdermal patch q3 days
    3. Hyoscamine (Levsin®): 0.125-0.25mg wublingual or PO or 0.25-0.5mg SC or IV, all q4 hours

C. Postoperative Nausea and Vomiting (PONV) [1,11]

1. Incidence is ~30% overall
2. Rates up to 70% in high risk populations including pediatric cases
3. Factors Contributing to Postoperative Emesis
   1. Patient - underlying conditions
   2. Surgical Procedure: increased risk craniotomy, ear, nose, throat, major breast, strabismus, laparotomy, laparoscopy, plastic surgery
   3. Anesthesia - primarily volatile anesthetics such as isoflurane, desflurane, sevoflurane
   4. Intravenous anesthetic propofol reduced risk of PONV versus volatile anesthetics
4. Increased Risk Factors
   1. Female Patient
   2. History of motion sickness or PONV
   3. Nonsmoking status
   4. Use of postoperative opiods - remifentanil similar risk as fentanyl
   5. Incidence of PONV with 0,1,2,3 or 4 of these risk factors was: 10%, 21%, 39%, 61%, 79%
   6. Pain, anxiety, dehydration may also increase risk
   7. Nitrous oxide 12% increased risk versus nitrogen
5. Prophylaxis
   1. Agents blocking single receptor reduce PONV incidence ~30%
   2. Combination antiemetics may be most effective
   3. Use one agent for patients with 20-40% risk
   4. Use serotonin antagonist + one other agent for 40-60% risk
   5. For very high risk, combination agents with total IV anesthesia with propofol
6. Specific Agents [11]
   1. 5-HT3 antagonist such as ondansetron 4mg IV
   2. Droperidol - 1.25mg IV effective but some increased risk of QTc interval prolongation [8]
   3. Dexamethasone - 4mg IV very effective
   4. Scopalamine - rarely used
   5. Propofol IV anesthetic reduced risk of PONV versus volatile (inhaled) anesthetic
   6. Avoid using nitrous oxide in high risk patients

References

1. Gan TJ. 2002. JAMA. 287(10):1233
2. Wood GJ, Shega JW, Lynch B, Von Roenn JH. 2007. JAMA. 298(10):1196
3. Navari RM, Reinhardt RR, Gralla RJ, et al. 1999. NEJM. 340(3):190
4. Granisetron. 1994. Med Let. 36(926):61
5. Dolasetron. 1998. Med Let. 40(1026):53
6. Freedman SB, Adler M, Seshadri R, et al. 2006. NEJM. 354(16):1698
7. Ernst AA, Weiss SJ, Park S, et al. 2000. Ann Emerg Med. 36:89
8. Arrhythmias from Droperidol ? 2002. Med Let. 44(1132):53
9. Aprepitant (Emend®). 2003. Med Let. 45(1162):62
10. Palanosetron. 2004. Med Let. 46(1179):27
11. Apfel CC, Korttila K, Abdalla M, et al. 2004. NEJM. 350(24):2441
12. Nailone. 2006. Med Let. 48(1249):103
13. Hesketh PJ. 2008. 358(23):2482