Post Operative Post Operative Nausea & VomitingNausea & Vomiting

Nicole Weiss MDNicole Weiss MDSeptember 22, 2010September 22, 2010

ObjectivesObjectives

Importance PONVImportance PONV Risk FactorsRisk Factors Review of anti-emetics and Review of anti-emetics and

strategies aimed at reducing PONVstrategies aimed at reducing PONV Risk based treatmentRisk based treatment Rescue TherapyRescue Therapy Tulane University PharmacyTulane University Pharmacy

The PatientThe Patient41 y/o female with a h/o of 41 y/o female with a h/o of PONV scheduled for an PONV scheduled for an outpatient laparoscopic outpatient laparoscopic cholecystectomycholecystectomy

Motion sicknessMotion sicknessNon-smokerNon-smoker

PONV: Importance?PONV: Importance?

1. High Level of patient concern (second to pain)-willingness to pay $56-$100

2. Major cause of unanticipated hospital admissions3. Rare complications: pulmonary aspiration, incisional

disruption

PhysiologyPhysiology Vomiting CenterVomiting Center

– Located in the MedullaLocated in the Medulla Tickling the back of the ThroatTickling the back of the Throat Gastric DistensionGastric Distension Vestibular Stimulation (Etoh)Vestibular Stimulation (Etoh) Cerebral CortexCerebral Cortex

Chemoreceptor trigger zoneChemoreceptor trigger zone– Outside of the BBB communicates with the Outside of the BBB communicates with the

vomiting centervomiting center– Blood Borne Drugs or HormonesBlood Borne Drugs or Hormones

Neurotransmitters involved: Neurotransmitters involved: – Dopamine, 5-HT, Substance P, AchDopamine, 5-HT, Substance P, Ach

Apfel. Miller's Anesthesia.Apfel. Miller's Anesthesia.

Strategies for Strategies for Minimizing PONVMinimizing PONV

1.1. Identify high risk patientsIdentify high risk patients-25-30% incidence of PONV-25-30% incidence of PONV-0.18% intractable PONV-0.18% intractable PONV

2.2. Avoid emetogenic stimuliAvoid emetogenic stimuli

3.3. Multimodal antiemetic therapyMultimodal antiemetic therapy

Risk FactorsRisk FactorsPatient, Procedure, AnesthesiaPatient, Procedure, Anesthesia

History of previous PONVHistory of previous PONV History of motion sickness History of motion sickness History of migrainesHistory of migraines Female gender post pubertyFemale gender post puberty Childhood after infancy and young adulthoodChildhood after infancy and young adulthood NonsmokerNonsmoker The type of surgery: laparoscopic, middle ear, ophthalmologic, The type of surgery: laparoscopic, middle ear, ophthalmologic,

craniotomycraniotomy Increasing duration of surgeryIncreasing duration of surgery DehydrationDehydration PainPain Use of volatile anesthetics, opioids, nitrous oxide or neostigmineUse of volatile anesthetics, opioids, nitrous oxide or neostigmine

“Up to 70% incidence of PONV in “high risk” patients (Kim)

Apfel’s Simplified Risk Apfel’s Simplified Risk (Adults)(Adults)

1,2,3 or 4 risk factors-->10, 20,60,80% 1,2,3 or 4 risk factors-->10, 20,60,80%

1.1. FemaleFemale

2.2. H/o of PONV or motion sicknessH/o of PONV or motion sickness

3.3. Non smokingNon smoking

4.4. Postoperative IV opiodsPostoperative IV opiods

Apfel, et al. NEJM. 2004.Apfel, et al. NEJM. 2004.

Drugs associated with PONVDrugs associated with PONV

Nitrous oxideNitrous oxide Volatile agentsVolatile agents EtomidateEtomidate Neostigmine (high doses)Neostigmine (high doses) Excessive opiodsExcessive opiods

Comparison of AgentsComparison of Agents

Apfel, et al. 2002.Apfel, et al. 2002.

Protective AnesthesiaProtective Anesthesia

HydrationHydration Regional AnesthesiaRegional Anesthesia TIVATIVA

– Utilizing propofol as effective as Utilizing propofol as effective as ondansetronondansetron

– Dose response relationship for propofolDose response relationship for propofol OxygenOxygen AcupunctureAcupuncture

Antiemetics

1.1. Antagonists of 5-HT3Antagonists of 5-HT3

2.2. Antagonists of D2Antagonists of D2

3.3. Antagonists of H1Antagonists of H1

4.4. Antagonists of M ReceptorsAntagonists of M Receptors

5.5. Antagonists of Neurokinin-1Antagonists of Neurokinin-1

6.6. CorticosteroidsCorticosteroids

Dopaminergic AgentsDopaminergic Agents HaloperidolHaloperidol

– Similar efficacy to ondansetronSimilar efficacy to ondansetron– Not approved for IV use secondary to Not approved for IV use secondary to

cardiac arrhythmiascardiac arrhythmias DroperidolDroperidol

– EffectiveEffective– Short half life-3 hoursShort half life-3 hours– Increased sedationIncreased sedation– FDA black labelFDA black label

Clinically Clinically

RelevantRelevant??

Study comparing Study comparing ondansetron and ondansetron and droperidol QT droperidol QT prolongationprolongation

Charbit B, et al. Anesthesiology. Charbit B, et al. Anesthesiology. 2005.2005.

Dopamine AntagonistsDopamine Antagonists

MetoclopramideMetoclopramide– Prokinetic effectsProkinetic effects– Studies show 10mg dose no Studies show 10mg dose no

more effective than a placebomore effective than a placebo– Higher doses (50mg) may be Higher doses (50mg) may be

effectiveeffective– Dyskinetic and extrapyramidal side Dyskinetic and extrapyramidal side

effectseffects

Other Drugs NOT Included Other Drugs NOT Included in this Talkin this Talk Metoclopramide Metoclopramide RanitidineRanitidine Sodium citrateSodium citrate OmeprazoleOmeprazole

GERD and aspiration precautions GERD and aspiration precautions are different from PONVare different from PONV

5HT-3 Antagonists5HT-3 Antagonists Ondansetron, granisetron & dolasetronOndansetron, granisetron & dolasetron Work at the chemoreceptor trigger zone & at Work at the chemoreceptor trigger zone & at

vagal afferents in the GI tractvagal afferents in the GI tract Anti-vomiting better than anti-nauseaAnti-vomiting better than anti-nausea All three equal in efficacy, few side effectsAll three equal in efficacy, few side effects Four hour half-life, but genetic of polymorphisms Four hour half-life, but genetic of polymorphisms

of p450 can lead to ultra short metabolismof p450 can lead to ultra short metabolism Palonosetron (Aloxi)Palonosetron (Aloxi)

– RCT demonstrated efficacy RCT demonstrated efficacy – Approved for PONV in 2008Approved for PONV in 2008– Duration of up to 72 hoursDuration of up to 72 hours

AnticholinergicsAnticholinergics

Scopolamine patch showed to be Scopolamine patch showed to be equally effective to ondansetronequally effective to ondansetron

Side effects include: Side effects include: – Dry mouthDry mouth– Visual disturbancesVisual disturbances– DizzinessDizziness– AgitationAgitation

CorticosteroidsCorticosteroids DexamethasoneDexamethasone Meta-analysis shows 8-10mg effectiveMeta-analysis shows 8-10mg effective No reports of dexamethasone-related No reports of dexamethasone-related

side effects in small dosesside effects in small doses Slow onset of action, better efficacy if Slow onset of action, better efficacy if

given in the beginning of a casegiven in the beginning of a case

AntihistaminesAntihistamines Dimenhydrinate (Dramamine) & Dimenhydrinate (Dramamine) &

DiphenhydramineDiphenhydramine Anticholinergic PropertiesAnticholinergic Properties Side effects:Side effects:

– SedationSedation– Dry MouthDry Mouth– Blurred visionBlurred vision– Urinary RetentionUrinary Retention– Prolonged recovery from anesthesiaProlonged recovery from anesthesia– Vascular necrosis (promethazine)Vascular necrosis (promethazine)

Neurokinin-1 Antagonists Neurokinin-1 Antagonists (Substance P Receptors)(Substance P Receptors)

Work on the final common pathway Work on the final common pathway from the emetic centerfrom the emetic center

Aprepitant (Emend)Aprepitant (Emend)– Recent studies indicate more effective Recent studies indicate more effective

than ondansetron in preventing emesis, than ondansetron in preventing emesis, similar efficacy in preventing nauseasimilar efficacy in preventing nausea

– Patent expiration 2011-2015Patent expiration 2011-2015 Casopitant & RolapitantCasopitant & Rolapitant

Combinations versus single Combinations versus single drugsdrugs

Multiple RCT compare a combination Multiple RCT compare a combination of antiemetics versus a single agentof antiemetics versus a single agent

Improved outcomes with Improved outcomes with combinations of anti-emetics (except combinations of anti-emetics (except for studies with metoclopramide)for studies with metoclopramide)

IMPACT IMPACT International Multicenter Protocol to International Multicenter Protocol to

Assess Antiemetic Combinations, 2004Assess Antiemetic Combinations, 2004 Large multicenter RCTLarge multicenter RCT 5,199 high risk patients5,199 high risk patients Six Variables: 2x2x2x2x2x2 (64 groups)Six Variables: 2x2x2x2x2x2 (64 groups)

1.1. OndansetronOndansetron

2.2. DexamethasoneDexamethasone

3.3. DroperidolDroperidol

4.4. Air (versus NO)Air (versus NO)

5.5. Propofol (versus inhaled agents),Propofol (versus inhaled agents),

6.6. Remifentanil (versus fentanyl)Remifentanil (versus fentanyl) Primary Outcome- PONV in 1Primary Outcome- PONV in 1stst 24 hours 24 hours Relative risk of combined antiemetics equal to Relative risk of combined antiemetics equal to

multiplying the relative risk of each single agent multiplying the relative risk of each single agent together together Apfel, C, et al. IMPACT. Anaesthetist. 2005.Apfel, C, et al. IMPACT. Anaesthetist. 2005.

Algorithms for the prevention Algorithms for the prevention of PONVof PONV

Risk adapted algorithms can reduce Risk adapted algorithms can reduce PONV in select patient populationsPONV in select patient populations

None have proved to be universally None have proved to be universally applicableapplicable

Guidelines for Antiemetic Guidelines for Antiemetic TherapyTherapy

Patient Factors•Female

•H/o of PONV or motion sickness

•Non-smoker•Use of opiods

2-4 Factors1. Droperidol +5HT-3 Antag2. Decadron+5HT-3 Antag.3. Droperidol+Decadron

1-2 Factors1.5HT-3 Antag.2.Decadron3.Scopolamine4.Droperidol

>4 Factors

Combination of antiemetics +TIVA with propofol

Surgical Factors•Laparoscopy•Laparotomy•Craniotomy•Strabismus

• ENT

Evidence Based AnesthesiaEvidence Based Anesthesia

Rescue TherapyRescue Therapy Lack of dataLack of data Mechanical Factors:Mechanical Factors:

– Secretions, gastric distension, opiatesSecretions, gastric distension, opiates Choose a different drug class in the first six hoursChoose a different drug class in the first six hours 5HT-3 Antagonists5HT-3 Antagonists

– Non-sedatingNon-sedating– Better anti-vomiting than anti nauseaBetter anti-vomiting than anti nausea– Not dose responsiveNot dose responsive– Not indicated if failed ondansetron prophylaxisNot indicated if failed ondansetron prophylaxis

DroperiolDroperiol DexamethasoneDexamethasone

Tulane Pharmacy CostsTulane Pharmacy Costs

Wholesale PriceWholesale Price Markup 5x wholesale priceMarkup 5x wholesale price Submitted to Insurance CompanySubmitted to Insurance Company Government Reimbursement for Government Reimbursement for

Operative Antiemetic DrugsOperative Antiemetic Drugs Facility Surgery FeeFacility Surgery Fee

Ondansetron $0.78 per doseOndansetron $0.78 per dose Droperidol $4.08Droperidol $4.08 Dimenhydrinate$0.04Dimenhydrinate$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

Courtesy of Bob Self, Tulane Pharmacy Director

What does this mean?What does this mean? High risk patients ALWAYS warrant High risk patients ALWAYS warrant

aggressive prophylaxisaggressive prophylaxis OndansetronOndansetron

– 50 patients a day, 260 days a year…costs 50 patients a day, 260 days a year…costs Tulane: $57,000 per yearTulane: $57,000 per year

– Puts patients at risk for side effectsPuts patients at risk for side effects Only 0.18% patients experience severe Only 0.18% patients experience severe

PONV requiring hospitalization…almost PONV requiring hospitalization…almost all can be identified by risk factorsall can be identified by risk factors

ReferencesReferences Costanzo, Linda. Physiology. 4th Ed. Lippincott Williams & Wilkins: Philadelphia, 2007. Gan TJ. Risk factors for postoperative nausea and vomiting. Anesth Analog 2006;102:1884-98. 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. 269-275. Kranke P. Algorithms for the prevention of postoperative nausea and vomiting: an efficacy and

efficiency simulation. European Journal of Anaesthesiology 2007, 24,10:856-867. Kim, Eun Jin. Combination of Antiemetics for the Prevention of Postoperative Nausea and

Vomiting in High Risk Patients. J Korean Med Sci 2007; 22:878-82. Apfel, CC. A Factorial Trial Six Interventions for the prevention of postoperative nausea and

vomiting. Anaesthesist. 54 (3). Mar 2005. 201-9. 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: 659-668, 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. 2004; 350, 2441-2451.

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

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Charbit B, et al.. AnesthesioDroperidol and ondansetron-induced QT interval prologation: a clinical drug interaction studylogy. Aug 2008; 109 (2): 206-12.