1. Post Operative Nausea & Vomiting
Nicole Weiss MD
September 22, 2010

2. Objectives Importance PONV Risk Factors
Review of anti-emetics and strategies aimed at reducing PONV
Risk based treatment
Rescue Therapy
Tulane University Pharmacy

3. The Patient
41 y/o female with a h/o of PONV scheduled for an outpatient laparoscopic cholecystectomy
Motion sickness
Non-smoker

4. PONV: Importance? High Level of patient concern (second to pain)
-willingness to pay $56-$100
Major cause of unanticipated hospital admissions
Rare complications: pulmonary aspiration, incisional disruption

5. Physiology Vomiting Center Chemoreceptor trigger zone
Located in the Medulla
Tickling the back of the Throat
Gastric Distension
Vestibular Stimulation (Etoh)
Cerebral Cortex
Chemoreceptor trigger zone
Outside of the BBB communicates with the vomiting center
Blood Borne Drugs or Hormones
Neurotransmitters involved:
Dopamine, 5-HT, Substance P, Ach

6. Apfel. Miller's Anesthesia.

7. Strategies for Minimizing PONV
Identify high risk patients
-25-30% incidence of PONV
-0.18% intractable PONV
Avoid emetogenic stimuli
Multimodal antiemetic therapy

8. Risk Factors Patient, Procedure, Anesthesia
History of previous PONV
History of motion sickness
History of migraines
Female gender post puberty
Childhood after infancy and young adulthood
Nonsmoker
The type of surgery: laparoscopic, middle ear, ophthalmologic, craniotomy
Increasing duration of surgery
Dehydration
Pain
Use of volatile anesthetics, opioids, nitrous oxide or neostigmine
Pt risk factors
Surgery risk factors
“Up to 70% incidence of PONV in “high risk” patients (Kim)

9. Apfel’s Simplified Risk (Adults)
1,2,3 or 4 risk factors-->10, 20,60,80%
Female
H/o of PONV or motion sickness
Non smoking
Postoperative IV opiods
Apfel, et al. NEJM

10. Drugs associated with PONV
Nitrous oxide
Volatile agents
Etomidate
Neostigmine (high doses)
Excessive opiods

11. Comparison of Agents
Apfel, et al

12. Protective Anesthesia
Hydration
Regional Anesthesia
TIVA
Utilizing propofol as effective as ondansetron
Dose response relationship for propofol
Oxygen
Acupuncture

13. Antiemetics Antagonists of 5-HT3 Antagonists of D2 Antagonists of H1
Antagonists of M Receptors
Antagonists of Neurokinin-1
Corticosteroids

14. Dopaminergic Agents Haloperidol Droperidol
Similar efficacy to ondansetron
Not approved for IV use secondary to cardiac arrhythmias
Droperidol
Effective
Short half life-3 hours
Increased sedation
FDA black label

15. Charbit B, et al. Anesthesiology. 2005.
Clinically Relevant?
Study comparing ondansetron and droperidol QT prolongation
Charbit B, et al. Anesthesiology

16. Dopamine Antagonists Metoclopramide Prokinetic effects
Studies show 10mg dose no more effective than a placebo
Higher doses (50mg) may be effective
Dyskinetic and extrapyramidal side effects

17. Other Drugs NOT Included in this Talk
Metoclopramide
Ranitidine
Sodium citrate
Omeprazole
GERD and aspiration precautions are different from PONV

18. 5HT-3 Antagonists Ondansetron, granisetron & dolasetron
Work at the chemoreceptor trigger zone & at vagal afferents in the GI tract
Anti-vomiting better than anti-nausea
All three equal in efficacy, few side effects
Four hour half-life, but genetic of polymorphisms of p450 can lead to ultra short metabolism
Palonosetron (Aloxi)
RCT demonstrated efficacy
Approved for PONV in 2008
Duration of up to 72 hours

19. Anticholinergics
Scopolamine patch showed to be equally effective to ondansetron
Side effects include:
Dry mouth
Visual disturbances
Dizziness
Agitation

20. Corticosteroids Dexamethasone Meta-analysis shows 8-10mg effective
No reports of dexamethasone-related side effects in small doses
Slow onset of action, better efficacy if given in the beginning of a case

21. Antihistamines Dimenhydrinate (Dramamine) & Diphenhydramine
Anticholinergic Properties
Side effects:
Sedation
Dry Mouth
Blurred vision
Urinary Retention
Prolonged recovery from anesthesia
Vascular necrosis (promethazine)

22. Neurokinin-1 Antagonists (Substance P Receptors)
Work on the final common pathway from the emetic center
Aprepitant (Emend)
Recent studies indicate more effective than ondansetron in preventing emesis, similar efficacy in preventing nausea
Patent expiration
Casopitant & Rolapitant

23. Combinations versus single drugs
Multiple RCT compare a combination of antiemetics versus a single agent
Improved outcomes with combinations of anti-emetics (except for studies with metoclopramide)

24. Apfel, C, et al. IMPACT. Anaesthetist. 2005.
IMPACT International Multicenter Protocol to Assess Antiemetic Combinations, 2004
Large multicenter RCT
5,199 high risk patients
Six Variables: 2x2x2x2x2x2 (64 groups)
Ondansetron
Dexamethasone
Droperidol
Air (versus NO)
Propofol (versus inhaled agents),
Remifentanil (versus fentanyl)
Primary Outcome- PONV in 1st 24 hours
Relative risk of combined antiemetics equal to multiplying the relative risk of each single agent together
Apfel, C, et al. IMPACT. Anaesthetist

25. Algorithms for the prevention of PONV
Risk adapted algorithms can reduce PONV in select patient populations
None have proved to be universally applicable

26. Guidelines for Antiemetic Therapy
Patient Factors
Female
H/o of PONV or motion sickness
Non-smoker
Use of opiods
Surgical Factors
Laparoscopy
Laparotomy
Craniotomy
Strabismus
ENT
2-4 Factors
1. Droperidol +5HT-3 Antag
2. Decadron+5HT-3 Antag.
3. Droperidol+Decadron
>4 Factors
Combination of antiemetics +
TIVA with propofol
1-2 Factors
5HT-3 Antag.
Decadron
Scopolamine
Droperidol
Evidence Based Anesthesia

27. Rescue Therapy Lack of data Mechanical Factors:
Secretions, gastric distension, opiates
Choose a different drug class in the first six hours
5HT-3 Antagonists
Non-sedating
Better anti-vomiting than anti nausea
Not dose responsive
Not indicated if failed ondansetron prophylaxis
Droperiol
Dexamethasone

28. Tulane Pharmacy Costs Wholesale Price Markup 5x wholesale price
Submitted to Insurance Company
Government Reimbursement for Operative Antiemetic Drugs
Facility Surgery Fee

29. Ondansetron $0.78 per dose Droperidol $4.08 Dimenhydrinate$0.04 DRUG
WHOLE SALE
INSTITUTION COST
Ondansetron
$0.78
$3.90
Droperidol
$4.08
$20.40
Dimenhydrinate
$0.04
$1.00
Scopolamine
$11.90
$47.26
Dexamethasone
$3.12
$15.60
Promethazine
$0.54
$2.70
Prochlorperazine
$3.60
$18.00
Ondansetron $0.78 per dose
Droperidol $4.08
Dimenhydrinate$0.04
Courtesy of Bob Self, Tulane Pharmacy Director

30. What does this mean?
High risk patients ALWAYS warrant aggressive prophylaxis
Ondansetron
50 patients a day, 260 days a year…costs Tulane: $57,000 per year
Puts patients at risk for side effects
Only 0.18% patients experience severe PONV requiring hospitalization…almost all can be identified by risk factors
Not cost effective
One institution…imagine healthcare costs across the US if every physician or crna chooses to use ondnasetron

31. References
Costanzo, Linda. Physiology. 4th Ed. Lippincott Williams & Wilkins: Philadelphia, 2007.
Gan TJ. Risk factors for postoperative nausea and vomiting. Anesth Analog 2006;102:
Gan, T.J. Effective Management of PONV and Pain in Ambulatory Settings.
Glidden, Randall. NMS Clinical Manuals. Lippincott Williams & Wilkins: Philadelphia, 2003.
Habib, Ashraf. What Is the Best Strategy to Prevent Postoperative Nausea and Vomiting? Evidence-Based Practice of Anesthesiology. 2nd edition. Sunders Elsevier
Kranke P. Algorithms for the prevention of postoperative nausea and vomiting: an efficacy and efficiency simulation. European Journal of Anaesthesiology 2007, 24,10:
Kim, Eun Jin. Combination of Antiemetics for the Prevention of Postoperative Nausea and Vomiting in High Risk Patients. J Korean Med Sci 2007; 22:
Apfel, CC. A Factorial Trial Six Interventions for the prevention of postoperative nausea and vomiting. Anaesthesist. 54 (3). Mar
Apfel CC., Kranke P, Katz MH, et al: Volatile Anesthetics may be the main cause of early, but not delayed postoperative vomiting: A randomized controlled trial of factorial design. Br J of Anesthesia. 88: , 2002.
Apfel, CC, Korttila K, Abdallah M, et al.: A factorial Trial of Six interventions for postoperative nausea and vomiting. New England Journal of Medicine ; 350,
Miller, R, et al. Miller’s Anesthesia. 7th ed. Churchill Livingstone: 2009.
Kovac A. A randomized, double-blind controlled trial of three different doses of palonosetron versus placebo in preventing postoperative nausea and vomiting over a 72-hour period. Anesthesiology Analogue. 107 (2):
Charbit B, et al.. AnesthesioDroperidol and ondansetron-induced QT interval prologation: a clinical drug interaction studylogy. Aug 2008; 109 (2):