The Treatment of Postoperative Nausea and Vomiting

1. The Treatment of Postoperative Nausea and Vomiting C. M. Prada, MD August 4th 2005

2. Nausea • by Jean-Paul Sartre

4. Muscular contractions associated with nausea and vomiting

5. Chemoreceptor Trigger Center(CTZ) • “Antiemetics” , J Scholz, MD, PhD, M Steinfath, MD, PhD, PT Tonner, MD, Phd p777 – 791; in Anesthetic Pharmacology, AS Evers and M Maze, 2004

6. Anatomy and physiology of the vomiting centre and the chemoreceptor trigger zone World Federation of Societies of AnaesthesiologistsWWW implementation by the NDA Web Team, Oxford Issue 17 (2003) Article 2: Page 1 of 1

7. 5HT-Receptor and PONV Pathophysiology • “Antiemetics” , J Scholz, MD, PhD, M Steinfath, MD, PhD, PT Tonner, MD, Phd p777 – 791; in Anesthetic Pharmacology, AS Evers and M Maze, 2004

8. Chemoreceptor Trigger Zone and Emetic Center Antagonist 5-HT3 RAs Droperidol Promethazine Atropine NK-1 RA Agonist Dopamine (D2) 5-HT3 Muscarinic Histamine Substance P Receptor Site • Nitrogen mustard • Cisplatin • Digoxin glycoside • Opioid, analgesics • Vestibular portion • of 8th nerve • N2O • GI tract distension • Higher centers (vision, taste) • Pharynx Chemoreceptor Trigger Zone (CTZ) Area Postrema Mediastinum Parvicellular Reticular Formation Emetic Center ? Vagus Post Operative Nausea & Vomiting: The Role of Antiemetics - Cedric Dupont-Eisner M.D. Watcha MF, White PF. Anesthesiology. 1992;77:162–184.

9. Schematic representation of the factors influencing nausea and vomiting

10. www.marinol.com/images/graphic-cancer.gif

12. A final pathway for nausea http://www.mywhatever.com/cifwriter/library/70/4938.html

13. PONV Impact • Incidence of PONV: varies with age, surgical procedure, anesthetic technique • Emesis frequently occurs after D/C from PACU = incidence lower in PACU than over 24 – 48 h • Delayed emesis: timing of oral intake or waning effects of perioperative antiemetics • Vomiting - unpleasant and medical risks: aspiration of gastric content; jeopardizes abdominal or inguinal closures; increased IV pressure: increase morbidity after ocular, tympanic, intracranial procedures; elevate HR and BP: risk for MI and dysrhythmias; gagging and retching: parasympathetic response: bradycardia and hypotension.

14. Demographic Factors for PONV • Study of 17,638 ambulatory patients: increased risk in younger pts.: PONVdecreasing13% per decade of age. (“Anesthesiology” – 1999;91:109, Sinclair DR, Chung F, Mezei G) • Women: 3 times higher incidence than men • Increased with GA and duration of GA • ENT and dental had higher incidence (14.3%), followed by orthopedic shoulder and plastic • Hx. of preop. emesis or motion sickness • GA near menses (increase E2) • High: procedures of extraocular muscles or middle ear, peritoneal or intestinal irritation, testicular traction • Smokers: lower risk

15. Contributing Factors • Risk of PONV: increased by starvation, gastricirritation, effects of anesthetics on chemotactic centers, autonomic imbalance, postoperative pain • Swallowed blood or tissue, gas in the stomach • General Anesthesia more than regional, although vomiting frequently when parenteralnarcotics.

16. Major causes of nausea and vomiting

17. Major Risk Factors for PONV in Adults • Patient-specific Risk Factors - Age (adult) - Non-smoking status - History of PONV / motion sickness - Predisposing gastric disorders - Low threshold for nausea - Preoperative anxiety - Obesity (disputed in recent studies) - Gastric distension (disputed in recent studies) • Anesthetic Risk Factors - Pre-anestheticmedications (opioids, atropine) - Volatile anesthetics - Nitrous Oxide - Intraoperative or postoperative use of opioids - Duration of anesthesia (> 120 min) • Surgical Risk Factors - Duration of surgery (each 30 min increases PONV risk by 60%) - Type of surgery (craniotomy; ear, nose, throat procedures; major breast procedures; strabismus surgery; laparoscopy; laparotomy). - Intubation (disputed in recent studies) - Early oral intake Am J Health Syst Pharm 1999;56:729-764

18. Specific factors increasing risk of nausea and vomiting - PONV • adults have more PONV than children • women • obesity • delayed gastric emptying disorders (GERD, GI obstruction, & neuromuscular disorders) • history of motion sickness (which can cause movement-induced PONV when patient is moved or turned) and/or history of PONV • history of smoking decreases risk • anxious person • emotogenic factors of anaesthetic • etomidate(Amidate),ketamine, and gaseous general anaesthesia, including nitrous oxide have higher risk • atropine decreases risk because it is a vagolytic • propofol (Diprivan) also decreases risk, probably because has slightly anti-serotonergic properties; but, is indicated only as a sedative-hypnotic; it has anti-emetic properties, but is not currently indicated solely for that use • longer procedures with general anaesthesia Garrett, K., Tsuruta, K., Walker, S., Jackson, S., & Sweat, M. (2003) http://www.eddyelmer.com/tools/aemetic.htm

19. Risk Score for Predicting PONV Apfel CC et al – “A simplified risk score for predicting postoperative nausea and vomiting” – Anesth; 91:693-700, 1999.

21. Anesthetic Agents • Exclusion of Nitrous Oxide reduces the incidence of PONV • PONV not different among potent inhalation anesthetics: except sevoflurane (marginally higher incidence) • Barbiturate induction less offensive than ketamine or etomidate; propofol induction lowest incidence • Narcotic analgesics: increase PONV • Ketorolac with small doses of narcotics: reduce severity of PONV • Neostigmine, physostigmine: increase the incidence of PONV

22. PONV Prevention and Treatment • Adequate postop. analgesia • Limit postoperative vestibular stimulation (minimize brisk head movement) • Avoid gastric distension (OG tube?) • Adequate hydration (Anesth Analg 1995;80:682; Yogendran S, Kumar B, Cheng D), but initiation of postop drinking is frequently a triggering event • Sometimes D/C children or high-risk patients before they take oral fluids • Nausea and Vomiting: also signs of serious underlying physiologic abnormalities – evaluate hypotension, increased ICP, hypoxemia, hypoglycemia, gastric bleeding.

23. Strategies to Reduce Baseline Risk • Use Regional Anesthesia • Use of Propofol for induction and maintenance • Use of intraoperative supplemental oxygen • Hydration • Avoid Nitrous Oxide and Volatile Anesthetics • Minimize intraoperative and postoperative opioids • Minimize the use of Neostigmine Anesth Analg 2004; 99;77-81.

24. “Management of PONV’ – Habib et al / CAN J ANESTH; 2004; 51:4; pp 326 - 341

25. Effect of intraoperative intravenous crystalloid infusion on PONV • IV administration of CSL 30 ml/kg to healthy women undergoing day-case gynecological laparoscopy reduced the incidence of vomiting, nausea and anti-emetic use when compared with CSL 10 ml/kg. Br J Anaesth. 2004 Sep;93(3):381-5. Epub 2004 Jun 25

26. Phenothiazines Chlorpromazine, prochlorperazine, promethazine Butyrophenones Droperidol (haloperidol) Benzamides Metoclopramide Anticholinergics Scopolamine Antihistamines Dimenhydrinate, hydroxyzine, cyclizine 5-HT3 antagonists Dolasetron, granisetron, ondansetron Others Dexamethasone Dronabinol (9THC) Antiemetics—Members by Class • Upcoming class for PONV already approved for CINV • NK1-receptor antagonists Post Operative Nausea & Vomiting: The Role of Antiemetics - Cedric Dupont-Eisner M.D.

27. “Antiemetics” , J Scholz, MD, PhD, M Steinfath, MD, PhD, PT Tonner, MD, Phd p777 – 791; in Anesthetic Pharmacology, AS Evers and M Maze, 2004

28. Main classes of anti-emetic drugs Source: British National Formulary, March 2002

30. Agonists and Antagonists Associated with Nausea and Vomiting

31. Clinical Aspects in Selecting Antiemetics for Prevention of PONV

33. “Management of PONV’ – Habib et al / CAN J ANESTH; 2004; 51:4; pp 326 - 341

34. Antiemetic treatment for PONV Patients with No Prophylaxis or Failed Prophylaxis Agent from a different class. When PONV occurs <6h after surgery: use agent from different class or Propofol 20 mg in PACU (adults). When PONV occurs >6h after surgery: repeat 5-HT3-receptor antagonist and droperidol (except dexamethasone or scopolamine) Use agents from a different class. Anesth Analg 2003;97:62-71

35. Standard Dosages of Antiemetics for the Prophylaxis of PONV in Adults Am J Health Syst Pharm 1999;56:729-764

36. Standard Dosages of Antiemetics for the Treatment of PONV in AdultsAm J Health Syst Pharm 1999;56:729-764

37. Standard Dosages of Antiemetics for the Management of POV in Pediatric Patients Am J Health Syst Pharm 1999;56:729-764

38. Phenothiazines • Chlorpromazine, Prochlorperazine, Promethazine • Antipsychotic agents • Blocks D2 receptors in CTZ and CNS • SIDE EFFECTS: EPS, sedation, dizziness, blurred vision, skin reactions, orthostatic hypotension chlorpromazine Post Operative Nausea & Vomiting: The Role of Antiemetics - Cedric Dupont-Eisner M.D. • Prochlorperazine-heterocyclic side chain

39. Butyrophenones • Droperidol • α blocker, D2 receptor antagonist (binds to D2 receptor) • Acts at both CTZ and area postrema • 1.25 mg droperidol given at the beginning of surgery is as effective as 4 mg dexamethasone or 4 mg ondansetron ( Apfel et al. New Engl J Med 2004 ). • SIDE EFFECTS: EPS, sedation, QTc prolongation with torsade de pointes (there is little evidence that antiemetic doses trigger this condition - Gan et al. Anesthesiology 2002). - high doses: hypotension (a blockade) - low-dose droperidol may cause dysphoria (Melnick et al. Anesth Analg 1989, Lim et al. Anaesth Intensive Care 1999) EPS = extrapyramidal symptoms Post Operative Nausea & Vomiting: The Role of Antiemetics - Cedric Dupont-Eisner M.D.

40. Anesthesiology, Vol.102, Number 6, June 2005

41. Benzamide • Metoclopramide • Specific dopamine D2 antagonist •  LES tone which enhances gastric motility • Short (1 to 2 hours) duration of action. • SIDE EFFECTS: EPS, restlessness, drowsiness, fatigue, agranulocytosis, methemoglobinemia, hypotension and bradycardia (or tachycardia) • Cisapride (removed from use – cardiac side effects) EPS = extrapyramidal symptoms Post Operative Nausea & Vomiting: The Role of Antiemetics - Cedric Dupont-Eisner M.D.

42. Anticholinergics • Scopolamine • Inhibit cholinergic and muscarinic CNS receptors. • Crosses the blood-brain barrier. • More effective against motion-induced emesis than against motion-induced nausea. • SIDE EFFECTS: sedation, CNS excitation, dry mouth, urinary retention, blurred vision, confusion, disorientation, hallucinations Night Shade = Atropa belladonna Post Operative Nausea & Vomiting: The Role of Antiemetics - Cedric Dupont-Eisner M.D.

43. Antihistamines • Dimenhydrinate, Hydroxyzine, Cyclizine • Block acetylcholine in the vestibular apparatus and histamine H1 receptors in the nucleus of the solitary tract. • SIDE EFFECTS: blurred vision, urinary retention, dry mouth, and sedation Cyclizine has similar efficacy to ondansetron; side effects: sedation and dry mouth (anticholinergic). Br J Anaesth 2000; 85(5):678-682/ Ahmed AB, Hobbs GJ, Curran JP: “Randomized, placebo-controlled trial of combination antiemetic prophylaxis for day-case gynaecological laparoscopic surgery”. Post Operative Nausea & Vomiting: The Role of Antiemetics - Cedric Dupont-Eisner M.D.

44. 5-HT3 Antagonists • (Ondansetron (Zofran®), Granisetron (Kytril®), Tropisetron (Navoban®), and Dolasetron (Anzemet®) • - No difference in efficacy • No sedation, extrapyramidal reactions, adverse effects on vital signs or laboratory tests, or drug interactions with other anesthetic medications. • Because repeating ondansetron is of limited effectiveness (Kovac et al. J Clin Anesth 1999) - reasonable to use ondansetron predominantly as a rescue treatment ( White PF, New Engl J Med 2004) • SIDE EFFECTS: Headache, dizziness, flushing, elevated liver enzymes,constipation Post Operative Nausea & Vomiting: The Role of Antiemetics - Cedric Dupont-Eisner M.D. Management of PONV’ – Habib et al / CAN J ANESTH; 2004; 51:4; pp 326 - 341

45. Ondansetron Pharmacokinetics

46. www.anzemet.com/images/chart_c_pharmacology.jpg

47. “Management of PONV’ – Habib et al / CAN J ANESTH; 2004; 51:4; pp 326 - 341

48. Dexamethasone Synthetic steroid Hypotheses • inhibition of prostaglandin syn. •  tryptophan • release of endorphins • change in CSF opening pressure • + psychological effects of steroids ACUTE SIDE EFFECTS: flushing and perineal itching. - Wang et al. Anesth Analg 2000 and the IMPACT data (unpublished observation) - dexamethasone has a delayed onset of antiemetic actions which might need a few hours to work. Post Operative Nausea & Vomiting: The Role of Antiemetics - Cedric Dupont-Eisner M.D.

49. Dexamethasone (contin.) “Management of PONV’ – Habib et al / CAN J ANESTH; 2004; 51:4; pp 326 - 341

50. “Management of PONV’ – Habib et al / CAN J ANESTH; 2004; 51:4; pp 326 - 341