The PONV Problem

John B Leslie, MD MBA

The PONV Problem:Frequent – Predictable – Evaluable –Expensive – Dissatisfying – Avoidable

John B. Leslie, MD, MBAProfessor

Department of AnesthesiologyMayo Clinic College of Medicine

Rochester, MinnesotaConsultant in Anesthesiology

Mayo Clinic Arizona, Scottsdale, AZProfessor of Clinical Anesthesia

University of Arizona, Tucson, AZ

Leslie.John@Mayo.EDUPONVPDNVOIE

MINV

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PONV “Terminology”• Air the diced carrots• Barf - Boot - Blow - Brack• Bark at the moon• Blow foam, chunks, or bile• Bring it up for a vote• Burpin’ solid• Call Uncle Earl or Ralph• Call Europe• Call on great white telephone• Call up the beasties• Chumming• Chunder and Chunks• Clean house• Core dump• Drive the porcelain bus• Drive the Buick• Emit with a food fountain• Empty your bucket

• Fertilize the carpet• Growl at the ground• Hurl - Hack - Heave - Huey• Liquid laugh or yawn• Lunch re-run• Laugh at the carpet• Make an inventory• Make a pavement pizza• Private exorcism (AKA LB)• Produce the liquid laugh• Puke - Spew - Retch - Urp• Park the tiger• Protein spill• Shout at your shoes• Sick-up and spew• Technicolor yawn• Toss your cookies• Vomit or Un-eat

Have we solved the PONV “little big problem” ?

3 decades of clinical trialsRisk Stratification

Multiple combination therapiesGuidelines & Updated Guidelines

“Breakthrough medications”“Break-the-Bank Expenses”

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Gan TJ, et al Guidelines for the Management of PONV; Anesth Anal, Vol 105, December, 2007. Kovac. Drugs. 2000;59:213-243; Natof et al. In: Wetchler, ed. Anesthesia for Ambulatory Surgery. 2nd ed. 1991:437-474; Carroll et al. Anesth Analg. 1995;80:903-909; Gan et al. Anesth Analg. 2002;94:1199-2000; Gan. JAMA. 2002;287:1233-1236; Leslie and Bash. Poster presented at: NYSSA 57th Postgraduate Assembly; December 13, 2003; New York, NY; Gan et al. Anesth Analg. 2003;97:62-71; Chung et al. Eur J Anaesthesiol. 1999;16:669-677; Hirayama et al. Yakugaku Zasshi. 2001;121:179-185.

Incidence of PONV/PDNV/OIE

• Overall range: 25% to 30%• High-risk patients: 70% to 80%• Outpatient range: 20% to 80%, depending on the patient

population• 35% to 67% of patients may experience PDNV• PONV may persist for 5 days after surgery• Opioid-induced emesis (OIE): 10% to 60%• No 1 or No 2 adverse outcome following routine

outpatient surgery!

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Many Patients Experience PONV Beyond the PACU

• Overall: 41% had PONV and … of patients who experienced PONV, nearly 80% initially did so in the PACU and/or within 48 hours after discharge.

36%

78%

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Initial PONVin the PACU

(21/58)

Initial PONV in the PACU and/or Within 48 Hours After PACU Discharge

(45/58)

Study Design: Data from a study examining patients’ experiences with PONV following discharge from outpatient surgery centers. Incidence of PONV was measured in the recovery room, by telephone the day after discharge, and by a questionnaire that patients were instructed to complete 5 days after discharge. A total of 143 outpatients (aged ≥18 years) who received general anesthesia and underwent 1 of 4 selected surgeries (laparoscopy, dilation and curettage, arthroscopy, or hernia repair) provided complete data. Some patients who initially experienced PONV within 48 hours after PACU discharge continued to experience PONV for up to 5 days after PACU discharge.

Carroll NV et al. Anesth Analg. 1995;80:903–909.

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The PONV Problem

John B Leslie, MD MBA

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PONV Remains a Problem Despite Current Therapies

Overall Up to 30% for all surgeries and patient populations.1–3

OutpatientAbout 40% of patients with PONV treated at outpatient surgery centers.4

Breakthrough

More than 30% of patients with PONV were receiving prophylactic antiemetics.3

— No significant differences among ondansetron, dexamethasone, and droperidol

1. Kovac AL. Drugs. 2000;59:213–243.2. Habib AS, Gan TJ. Can J Anesth. 2004;51:326–341.3. Apfel CC et al. N Engl J Med. 2004;350:2441–2451.4. Carroll NV et al. Anesth Analg. 1995;80:903–909.

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The Real Value of Guidelines?

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PONV vs PDNV: Under-Recognized Problem

C Apfel, S Shi, A Kovac, A Shilling, J Leslie, B Philip, on behalf of the PDNV Study Group: IARS Annual Mtg. 2009

Prospective Study of 2170 Outpatients in 12 USA Centers

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PONV vs PDNV: Under-Recognized Problem

C Apfel, S Shi, A Kovac, A Shilling, J Leslie, B Philip, on behalf of the PDNV Study Group: IARS Annual Mtg. 2009

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PONV vs PDNV: Under-Recognized Problem

C Apfel, S Shi, A Kovac, A Shilling, J Leslie, B Philip, on behalf of the PDNV Study Group: IARS Annual Mtg. 2009

Conclusion: The results of this 12-center multicenter cohort study showed a substantial incidence of PDNV in the US.…Clinical trials that address this patient population with a longacting antiemetic strategy are needed

What does failure to prevent PONV actually cost?

Patient Risk

Patient discomfort

Patient dissatisfaction

Economic burden

The PONV Problem

John B Leslie, MD MBA

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Potential Consequences of PONV

• Medical Consequences PONV— Can cause electrolyte abnormalities and dehydration1

— Can cause tension on suture lines1,2

— Venous hypertension2

— Can cause hematomas (increased bleeding) beneath surgical flaps,1 vascular anastomosis, aneurysm clipping, etc

— Can place the patient at risk for pulmonary aspiration of vomit if airway reflexes are depressed from lingering effects of anesthetic and analgesic drugs1,2 (esp increased risk with jaw wired closed)

• Practical Consequences of PONV— Delayed Discharge after out-patient surgery2

— Unanticipated hospital admission1

1. Golembiewski J, et al Am J Health-Sys Pharm; Vol 62 Jun, 2005 2. Watcha MF, White PF. Anesthesiology. 1992;77:162–184.

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PONV: #1 Patient Problem

Recall without pain5Residual weakness6Shivering7Sore throat8Somnolence9

Incisional pain3Gagging on endotracheal tube2

Nausea4

Vomiting1Postoperative OutcomesRank

Postoperative Outcomes Least Preferred by Patients

Adapted from Macario A et al. Anesth Analg. 1999;89:652–658. © 1999. With permission from Lippincott Williams & Wilkins.

Data from a survey of adult patients (N=101) conducted at Stanford University Medical Center. Patients were eligible if they were scheduled to undergo surgery at the center. Patients were asked to rank-order 10 possible postoperative outcomes from most to least desirable. F-test <0.01.

Emesis is the postoperative outcome least preferred by patients

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$18.05 $17.86$16.96

$13.82$11.82

$7.99 $7.60

$3.04

$-

$5

$10

$15

$20

Vomiting Gagging on ETTube

Pain Recall w/outPain

Nausea ResidualWeakness

Shivering Sore Throat

Ranking and Relative Values ($100) of Patient Outcomes*

“… avoiding Post-Operative Nausea and Vomiting seems to be a high priority for most Patients”1

Macario, A, et al Which Clinical Anesthesia Outcomes; Anesth Anal, 1999; 89;652-8

What do Surgical Patients Most Want to Avoid?

*Patients were asked to distribute $100 among 10 outcomes, with proportionally more money being allocated to the more undesirable outcomes (eg, patients assigned $18.05 of $100 to avoid vomiting).

n=62

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Cost Components in PONV Episodes

PACU nurses78%

MD/CRNA5%

Personnel83%

*Per item of basin, gloves, paper, linen, and gown

Antiemetic cost3%

Materials*0.2%

PACU delay4%

Hospital admission

10%

Cost Components for an Episode of Emesis(% total median management cost per patient)

Hill RP et al. Anesthesiology. 2000;92:958-967.

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PONV Incurs Higher Cost$

• In a study conducted in 2000, PONV was associated with increased cost*— A single episode of emesis costs an average of $305— A single episode of nausea costs an average of $82

• PONV is a major factor limiting early discharge of ambulatory surgical patients (1st or 2nd all major studies)

• PONV is a leading cause of unanticipated hospital admissions (24% primary reason)

• Preventing PONV can be cost-effective

Hill RP et al. Anesthesiology. 2000;92:958-967Lau H & Brooks DC. Arch Surg (2001) 136:1150-53.

* PACU personnel costs are biggest component:NOT PHARMACEUTICALS

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The PONV Problem

John B Leslie, MD MBA

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Why do patients develop PONV?

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1180 patients50% pediatric

Apfel BJA 2002;88:659

“Volatile anaesthetics may be the main cause of early but not delayed postoperative vomiting: a randomized

controlled trial of [5x] factorial design.”

750 combinations:Gender, Surgery, Opioids, Maintenance, PONV Prophylaxis

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PONV Risk Prediction Tool?JBL

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PONV Risk Factors

1. Watcha MF, White PF. Anesthesiology. 1992;77:162-184. 2. Kovac AL. Drugs. 2000;59:213-243. 3. Apfel CC, et al. Acta Anaesthesiol Scand. 1998;42:495-501. 4. Apfel CC, et al. Anesthesiology. 1999;91:693-700. 5. Koivuranta M, et al. Anaesthesia. 1997;52:443-449. 6.Apfel CC, Roewer N. Int Anesthesiol Clin. 2003;41:13-32. 7. Apfel CC. Anesthesiology News Special Edition. 2006:71-76.

• Patient related1-7

—Female gender—History of PONV and/or motion sickness—Nonsmokers—Younger age—Anxiety—Underlying disease (e.g., GI obstruction,

neuromuscular disorders, gastric hypomotility)

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PONV Risk Factors (cont)

1. Watcha MF, White PF. Anesthesiology. 1992;77:162-184. 2. Kovac AL. Drugs. 2000;59:213-243. 3. Apfel CC, et al. Br J Anaesth. 2002;88:659-668. 4. Cohen MM, et al. Anesth Analg. 1994;78:7-16. 5. Koivuranta M, et al. Anaesthesia. 1997;52:443-449. 6. Apfel CC, et al. Anaesthesia. 2004;59:1078-1082. 7. Roberts GW, et al. Anesth Analg. 2005;101:1343-1348. 8. Apfel CC, et al. Anesthesiology. 1999;91:693-700.

• Surgery related1-5

—Duration of surgery—Operative procedure (e.g., gynecologic,

laparoscopic, eye, plastic, abdominal)

• Anesthesia related1-3,6-8

—Volatile anesthetics—General anesthesia—Duration of anesthesia—Postoperative opioids—Muscle relaxant antagonists (e.g., neostigmine)

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The PONV Problem

John B Leslie, MD MBA

JBL

PONV Risk Factors (cont)

1. Kovac AL. Drugs. 2000;59:213-243. 2. Apfel CC, et al. Anesthesiology. 1999;91:693-700. 3. Apfel CC. Anesthesiology News Special Edition. 2006:71-76.

• Most predictive1-3

—Female gender—Nonsmokers—History of PONV/motion sickness—Postoperative opioid analgesics

• Multiple (≥3) risk factors2

—60%–80% of patients may experience PONV

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Apfel Koivuranta

Palazzo Sinclair

Comparison of predictive models for PONV

Apfel et al. Br J Anaesth 2002;88:234-40

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1137 ENT patients split into an evaluation set (533) and a validation set (584)

“A risk score to predict the probability of postoperative vomiting in adults.”

• POV Risk (probability) = 11 + e-z

• Where: Z = (no=0, yes=1)+ 1.28*(female gender)- 0.029*(age)- 0.74*(smoking)+ 0.63*(history motion sickness or PONV)+ 0.26*(duration)- 0.92

Apfel et al. Acta Anaesthesiol Scand 1998;42:495-501

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SAMBA Algorithm Factors for PONV

Gan et al. Anesth Analg. 2007;105:1615-28.

Adult Risk Factors Children Risk Factors

Patient Related EnvironmentalSurgery > 30 min

History of PONV or Motion Sickness

Postop Opioids Age > 3 years

Female Gender Emetogenic surgery (type & duration)

Strabismus surgery

Non-Smoker History of POV or relative with PONV

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Simplified Risk Score to Predict PONV in Adults1

1. Gan TJ, et al Guidelines for the Management of PONV; Anesth Anal, Vol 105, December, 2007

Risk Factors Points

Female Gender 1

Non-Smoker 1

History of PONV** 1

Postoperative Opioids 1

Sum = 0, 1, 2, 3, 4

When either 1, 2, 3 or 4 of the independent PONV predictors are present, the corresponding risk for PONV increases

For example (YELLOW BOX), if a patient is a “female” “non-smoker”she has 2 risk factors and there is a 40% chance of her experiencing PONV

1020

40

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80

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0 RiskFactor

1 RiskFactor

2 RiskFactors

3 RiskFactors

4 RiskFactors** or motion sickness?

Percent Risk for PONV

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Where are we in the development and implementation of “best practices” PONV guidelines?

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The PONV Problem

John B Leslie, MD MBA

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PONV Patient-At-Risk “Game Plan”JBL

Strategies to Reduce Baseline PONV Risk

• Avoidance of general anesthesia by the use of regional anesthesia (RCT)

• Use of propofol for induction and maintenance of anesthesia (RCT/SR)

• Avoidance of nitrous oxide (RCT/SR)• Avoidance of volatile anesthetics (RCT)• Minimization of intraoperative and postoperative

opioids (RCT/SR)• Minimization of neostigmine (SR)• Adequate hydration (RCT)

Gan et al. Anesth Analg. 2007;105:1615-28.

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Guidelines for Antiemetic Prophylaxis for PONV

ASA=American Society of Anesthesiologists; ASPAN=American Society of PeriAnesthesia Nurses; SAMBA=Society for Ambulatory Anesthesia.1. ASA Task Force on Postanesthetic Care. Anesthesiology. 2002;96:742-752. 2. ASPAN PONV/PDNV Strategic Work Team. J Perianesth Nurs. 2006;21:230-250. 3. Gan TJ, et al. Anesth Analg. 2007;105:1615-1628.

ASA 20021 ASPAN 20062 SAMBA 20073

• Prophylaxis with:—5-HT3 RA—Droperidol—Dexamethasone—Metoclopramide—5-HT3 RA +

dexamethsone • If required, rescue with 5-HT3 RA

• Prophylaxis with 1 or more: —5-HT3 RA—Droperidol —Dexamethasone —H1 receptor blocker—Transdermal scopolamine patch

• Give adequate IV hydration• Use total IV anesthesia• If patient fails in PACU, then administer another category of agent

• If required, rescue with promethazine, prochlorperazine, or metoclopramide

• Assess patient risk• Reduce baseline risk factors• Prophylaxis with 1-2 interventions for patients at moderate risk:

—5-HT3 RA—Droperidol, haloperidol—Dexamethasone—H1 receptor blocker—Transdermal scopolamine

patch—Promethazine,

prochlorperazine, perphenazine—Ephedrine

• High-risk multimodal approach

• If patient fails, then administer another category of agent

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PONV AntiemeticsReceptor Site Affinity

1. Watcha MF, White PF. Anesthesiology. 1992;77:162-184. 2. Scuderi PE. Int Anesthesiol Clin. 2003;41:41-66. 3. Prommer E. J Pain Palliat Care Pharmacother. 2005;19:31-39.

Drug FDAApproved

Receptor Site Affinity

Serotonin Dopamine Histamine Muscarinic Neurokinin

Prochlorperazine + + + + + + + + +

Haloperidol + + + + +

Droperidol + + + + + +

Metoclopramide + + + + + +

Scopolamine + + + + + +

Dimenhydrinate + + + + + + +

Hydroxyzine + + + + + + +

Promethazine + + + + + + + +

Aprepitant + + + +

Dolasetrron + + + +

Granisetron + + + +

Ondansetron + + + +

Palonosetron + + + +

Dexamethasone Antagonism of prostaglandins and release of endorphins

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Anesthesiologists & Nurse Anesthetists

Gan TJ, et al Guidelines for the Management of PONV; Anesth Analgesia, Vol 105, December, 2007

The Consensus Guidelines for the management of PONV was written by a multi-disciplinary panel that included such clinicians as …

Surgeons

Peri-Anesthesia Nurse

Pharmacist

PONV Treatment TeamJBL

SAMBA Treatment Algorithm Options for PONV

Gan et al. Anesth Analg. 2007;105:1615-28.

The PONV Problem

John B Leslie, MD MBA

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SAMBA Treatment Algorithm Options for PONV

Gan et al. Anesth Analg. 2007;105:1615-28.

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SAMBA Treatment Algorithm Options for PONV

Gan et al. Anesth Analg. 2007;105:1615-28.

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Selecting “Best Shot” PONV/PDNV Drugs?JBL

Increasing the Number of Antiemetics Reduces the Incidence of PONV (n=5161 patients at high risk for PONV)

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37

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50

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No Antiemetic 1 Antiemetic 2 Antiemetics 3 Antiemetics

% In

cide

nce

of P

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V

0 Antiemetics 1 Antiemetic

IV Ondansetron IV Dexamethasone

IV Droperidol

2 Antiemetics

IV Ond + IV Dex IV Ond + IV DroIV Dro + IV Dex

3 Antiemetics

52% chance of PONV

37% chance of PONV

28% chance of PONV22% chance of PONV

Adapted from Apfel et al. N Engl J Med. 2004;350:2241-2251.

95% Confidence Interval

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Adapted from Apfel et al. N Engl J Med. 2004;350:2241-2251.

Estimated Incidence of PONV as a function of Baseline RiskAssumption: Each Intervention Reduces risk by 26%1

0

10

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60

70

80

Baseline Riskwith No

Intervention

One Intervention

TwoInterventions

ThreeInterventions

FourInterventions

Perc

enat

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n=5161 patients at risk for PONV

26% reduction in relative risk of PONV for each additional antiemetic used

The baseline risk levels 0f 10%, 20%, 40%, 60% and 80% reflect the presence of 0,1,2,3 and 4 risk factors respectively, according to a simplified score

80% baseline risk 4 Risk Factors

60% baseline risk 3 Risk Factors

40% baseline risk 2 Risk Factors

20% baseline risk 1 Risk Factor

10% baseline risk 0 Risk Factors

JBLDespite multiple combinations with current drugs, we fail…yes, we fail!

Number of interventionsBaseline risk

(no intervention)1 2 3 4

10% 7% 5% 4% 3%

20% 15% 11% 8% 6%

40% 29% 22% 16% 12%

60% 44% 33% 24% 18%

80% 59% 44% 32% 24%

Estimated PONV incidence as a function of baseline risk, assuming each intervention reduces relative risk by 26%

Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004;350:2441-51.

The PONV Problem

John B Leslie, MD MBA

JBL

Selecting the Ideal Antiemetic? Pathway?The Numbers are In. We Are Failing ;-(

JBLCurrent & Future Antiemetic Therapy for PONV Prophylaxis in Adults

• Serotonin (5-HT3) antagonists— Ondansetron (Zofran®)— Dolasetron (Anzemet®)— Granisetron (Kytril®)— Tropisetron (Navoban®)*— Palonosetron (Aloxi®)

• Dexamethasone (Decadron®)*• Droperidol (Inapsine®)†

— Haloperidol (Haldol®)*• Scopolamine (Transderm Scop®)• Promethazine (Phenergan®)• Prochlorperazine (Compazine®)• Ephedrine*

• Diphenhydramine (Benadryl®)• Nonpharmacologic

techniques*— Acupuncture* (Acupressure)*— Hypnosis*— Aromatherapy*— Music therapy*

• Dimenhydrinate (Dramamine®)• Neurokinin-1 Antagonists

— Aprepitant (Emend®)— Casopitant (Rezonic)* 5-20-09

• Cannabinoid— Nabilone (Cesamet®)*— Dronabinol (Marinol®)*

*Currently not FDA-approved for PONV in the United States; †Note package insert black box warning.Modified from Gan et al. Anesth Analg. 2003;97:62-71.

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PONV Summary and Conclusions

• PONV: Ranked as most undesirable consequence of surgery 1— 30% overall incidence 2— PONV incidence increases with each additional risk factor, thus

underscoring need for assessment and preventative intervention 3

• Risk assessment helps identify patients who would benefit from prophylactic antiemetics

• Effective PONV prevention strategy incorporates risk assessment that reflects its multifactorial etiology 2

• Global risk assessment includes evaluation of: 2

— Patient-related characteristics— Surgery-related characteristics— Anesthesia-related characteristics

1. Macario A., et al. Anesth Analg 1999;89:652-658. 2. Kovac. Drugs. 2000;59:213-243. 3. Apfel CC et al. Anesthesiology 1999;91:693-700

JBLPONV Summary and Conclusions(cont)

• Understanding of emetic pathways continues to evolve— Peripheral versus central emetogenic triggers 1,2

— Peripheral versus central neurotransmitter/receptor pathways 3.4

• Involvement of different emetic neurotransmitter pathways may impact treatment strategies— Source of emetic stimuli impacts effectiveness of

pharmacologic antiemetic intervention 5

— Multiple receptor approach probably logical and effective• Ideal combination unproven: Consider 5-HT3 + steroid +

droperidol/haloperidol + SCOP + “special needs” + techniques— New pharmacology 5HT3 antagonist palonosetron— First substance P/NK1 antagonist now available for prevention

of troublesome PONV and PDNV: Aprepitant 40 mg

1. Kovac. Drugs. 2000;59:213-243. 2. Nelson TP. J PeriAnesthesia Nursing 2002;17:178-189. 3. Saito R., et al. J Pharmacol Sci 2003;91:87-94. 4. Hornby PJ. Amer J Med 2001;111:106S-112S. 5. Diemunsch P., Grelot L. Drugs 2000;60:533-546

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SCOAP PONV Challenge

Risk stratification can and should be done.Prevention measures should be implemented.Outcome benefits should be producible and

measurable.Benefits should include patient satisfaction and

reduced costs.The PONV initiative should be widely applicable.

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Questions?