Prevention and Treatment of Postoperative Nausea and Vomiting

Phillip E. Scuderi, M.D.Department of AnesthesiologyWake Forest University School of MedicineWinston-Salem, NC 27157-1009

Critical Evaluation of Data

Quality of individual clinical trials Evaluation of data in aggregate Estimation of treatment consequences

Evidence Based MedicineRating Scale

Level of evidence based on study design

I. Large randomized, controlled trial (n>100 per group)

II. Systematic review

III. Small randomized, controlled trial (n<100 per group)

IV. Nonrandomized controlled trial or case report

V. Expert opinion

Strength of Recommendation based on expert opinion

A. Good evidence to support the recommendation

B. Fair evidence to support the recommendation

C. Insufficient evidence to recommend for or against

Measures of Treatment Consequences

Relative Risk Reduction The reduction of adverse events achieved by a treatment,

expressed as a proportion of the control rate

Odds Ratio The traditional expression of the relative likelihood of an

outcome expressed as P/(1 - P) where P = probability

Absolute Risk Reduction The difference in event rates between the control and

treatment groups

Numbers Needed to be Treated (NNT) The number of patients who must be treated in order to

prevent one adverse event. It is mathematically equivalent to the reciprocal of the absolute risk reduction.

Laupacis et al. NEJM 1988;318:1728-1733

Measures of Treatment Consequences

Numbers Needed to be Treated

Relative Risk Reduction

0.5 - 0.300.50

= 0.40

Odds Ratio

[0.30 / (1 - 0.30)]

[0.50 / (1 - 0.50)] = 0.43

Absolute Risk Reduction

0.5 - 0.3 = 0.20 1 0.5 - 0.3

= 5

Placebo = 0.50Treatment = 0.30

Rates of Adverse Events

Laupacis et al. NEJM 1988;318:1728-1733

Chemoreceptor Receptor Zone

Pharmacologic Group Dopamine (D2) Muscarinic Cholinergic Histamine Serotonin

Anticholinergics Scopolamine + ++++ + –

Antihistamines Cyclizine Dimenhydrinate Diphenhydramine Hydroxyzine Medizine Promethazine

+++++++

++++++++++++++

++++++++++++++++++++++++

––––––

Antiserotonins Dolasetron Granisetron Ondansetron Ramosetron

––––

––––

––––

++++++++++++++++

Benzamides Domperidone Metoclopramide

+++++++

––

––

+++

Butyrophenones Droperidol Haloperidol

++++++++

––

++

+–

Phenothiazines Chlorpromazine Fluphenazine Perphenazine Prochlorperazine

++++++++++++++++

++

+++++

++++++++++

–+++

Steroids Betamethasone Dexamethasone

––

––

––

––

Currently Available Medications

5HT3 (serotonin) antagonists - ondansetron Butyrophenones - droperidol Benzamides - metoclopramide Antihistamines - promethazine, dimenhydrinate Steroids - dexamethasone Phenothiazines- promethazine, prochlorperazine Anticholinergics – scopolamine

Evidence Rating for Antiemetics

Strength of Evidence Treatment Consequences*

Prevention Treatment Prevention Treatment

Ondansetron 4 mg I-A I-A 5.5 – 6.5 3.2 – 3.9

*NNT

Prevention of PONV:Ondansetron Versus Placebo

62

76 77

46

0

20

40

60

80

100

Placebo 1 mg 4 mg 8 mg

Ondansetron Dose

% o

f P

atie

nts

wit

h N

o E

mes

is

McKenzie et al. Anesthesiology 1993;78:21-28

All patients, 0 - 24 hrs

*

† †

* p = 0.010† p < 0.001

Ondansetron Dose Response:Prevention

Dose of Ondansetron

Early Efficacy (0 - 6 hrs)

Late Efficacy (0 - 48 hrs)

1 mg 9.0 15

4 mg 5.5 6.5

8 mg 6.5 5.0

Only 4 mg and 8 mg were significantly different than placebo No further improvement with doses >8 mg

Numbers Needed to be Treated

Tramer et al. Anesthesiology 1997;87:1277-1289

Evidence Rating for Antiemetics

Strength of Evidence Treatment Consequences*

Prevention Treatment Prevention Treatment

Ondansetron 4 mg I-A I-A 5.5 – 6.5 3.2 – 3.9

Ondansetron 1 mg - I-A - 3.8 – 4.8

*NNT

Treatment of PONV:Ondansetron Versus Placebo

32

20

57

40

60

45 44

57

0

20

40

60

80

100

0 - 2 hr 2 - 24 hr

% w

ith

Com

plet

e R

espo

nse

Placebo 1 mg 4 mg 8 mg

Scuderi et al. Anesthesiology 1993;78:2-5Hantler et al. Anesthesiology 1992;77:A16

** *

* **

* p < 0.001

Ondansetron Dose Response:Treatment

Dose of Ondansetron

Early Efficacy (0 - 6 hrs)

Late Efficacy (0 - 24 hrs)

1 mg 3.8 4.8

4 mg 3.2 3.9

8 mg 3.1 4.1

All three doses significantly different than placebo No significant difference in antiemetic efficacy

between the three doses of ondansetron

Numbers Needed to be Treated

Tramer et al. BMJ 1997;314:1088-1092

Evidence Rating for Antiemetics

Strength of Evidence Treatment Consequences*

Prevention Treatment Prevention Treatment

Ondansetron 4 mg I-A I-A 5.5 – 6.5 3.2 – 3.9

Ondansetron 1 mg - I-A - 3.8 – 4.8

Dolasetron 12.5 mg I-A I-A 4.0 – 5.0 3.6 – 4.2

*NNT

Prevention of PONV:Dolasetron Versus Placebo

31 28 33

50 465252

39

5543

56 57

0

20

40

60

80

100

All Patients Previous PONV No PONV

Com

ple

te R

esp

onse

%

Placebo 12.5 mg 25 mg 50 mg

*p < 0.0003 compared to placeboGraczyk et al. Anesth Analg 1997;84:325-330

***

****

* *

Treatment of PONV:Dolasetron Versus Placebo

27

11

55

35

50

28

51

2929

48

0

20

40

60

80

100

0 - 2 hrs 0 - 24 hrs

Com

ple

te R

esp

onse

%

Placebo 12.5 mg 25 mg 50 mg 100 mg

*p < 0.001 compared to placeboKovac et al. Anesth Analg 1997;85:546-552

****

** * *

Evidence Rating for Antiemetics

Strength of Evidence Treatment Consequences*

Prevention Treatment Prevention Treatment

Ondansetron 4 mg I-A I-A 5.5 – 6.5 3.2 – 3.9

Ondansetron 1 mg - I-A - 3.8 – 4.8

Dolasetron 12.5 mg I-A I-A 4.0 – 5.0 3.6 – 4.2

Granisetron 1mg I-A I-A 3.1 – 4.2 3.1 – 3.8

*NNT

Prevention of PONV:Granisetron Versus Placebo

49.658.3

78.4 76.6

33.844.7

63.4 61.7

0102030405060708090

100

Placebo 0.1 mg 1.0 mg 3.0mg

% P

atie

nts

0-6 hr 0-24 hr

Wilson et al. BJA 1996;76:515-518

* *

*p < 0.001 compared to placebo

No Vomiting

Prevention of PONV:Granisetron Versus Placebo

34.6 38.6

63.457

21.828

5042.2

0102030405060708090

100

Placebo 0.1 mg 1.0 mg 3.0mg

% P

atie

nts

0-6 hr 0-24 hr

Wilson et al. BJA 1996;76:515-518

* *

*p < 0.001 compared to placebo

No Nausea

Prevention of PONV:Granisetron Versus Placebo

31.637.1

63.454.7

1826.5

49.342.2

0102030405060708090

100

Placebo 0.1 mg 1.0 mg 3.0mg

% P

atie

nts

0-6 hr 0-24 hr

Wilson et al. BJA 1996;76:515-518

* *

*p < 0.001 compared to placebo

Total Control

Treatment of PONV:Granisetron Versus Placebo

26.3

53.157.9 60

19.6

38.345.9 48.8

0102030405060708090

100

Placebo 0.1 mg 1.0 mg 3.0mg

% P

atie

nts

0-6 hr 0-24 hr

Taylor et al. JCA. 1997:9;658-663

* * *

*p < 0.001 compared to placebo

No Vomiting

Treatment of PONV:Granisetron Versus Placebo

16.6

39.8 40.6 42.4

12.8

26.6 30.136.8

0102030405060708090

100

Placebo 0.1 mg 1.0 mg 3.0mg

% P

atie

nts

0-6 hr 0-24 hr

Taylor et al. JCA. 1997:9;658-663

* * *

*p < 0.005 compared to placebo

No Nausea

Evidence Rating for Antiemetics

Strength of Evidence Treatment Consequences*

Prevention Treatment Prevention Treatment

Ondansetron 4 mg I-A I-A 5.5 – 6.5 3.2 – 3.9

Ondansetron 1 mg - I-A - 3.8 – 4.8

Dolasetron 12.5 mg I-A I-A 4.0 – 5.0 3.6 – 4.2

Granisetron 1 mg I-A I-A 3.1 – 4.2 3.1 – 3.8

Droperidol I-A - 4.3 – 5.0 ?

*NNT

Prevention of PONV:Ondansetron Versus Droperidol

4636

63

48

6956 53

62

0

20

40

60

80

100

0 - 2 hr 0 - 24 hr

% o

f P

atie

nts

Placebo Droperidol 0.625 mg Droperidol 1.25 mg Ondansetron 4 mg

Fortney et al. Anesth Analg 1998;86:731-738

Complete Response

*** *

**

†

* p < 0 .05 compared to placebo† p < 0.05 compared to ondansetron 4 mg‡ p ,<0.05 compared to droperidol 0.625 mg

‡

I-A

Prevention of PONV:Ondansetron Versus Droperidol

2329

4329

0

20

40

60

80

100

0 - 24 hr

% o

f Pa

tient

s

Placebo Droperidol 0.625 mg Droperidol 1.25 mg Ondansetron 4 mg

Fortney et al. Anesth Analg 1998;86:731-738

No Nausea

†

* p < 0 .05 compared to placebo† p < 0.05 compared to droperidol 0.625 mg and ondansetron 4 mg

I-A

Droperidol FDA Box Warning

Droperidol Adverse Events Reports

273 “reports” from 1997-2001 127 serious adverse events 89 total deaths Droperidol 1.25 mg or less

10 cases 5 VT/VF 2 deaths

Habib et al. Anesth Analg 2003;96:1377-1379

Droperidol and QTc Prolongation

Effect of Low-dose Droperidol on the QT Interval during and after General AnesthesiaWhite et al. Anesthesiology 2005; 102:1101-1105

Prolongation of QTc Interval after Postoperative Nausea and Vomiting Treatment by Droperidol or OndansetronCharbit et al. Anesthesiology 2005; 102:1094-1100

You (Still) Can’t Disprove the Existence of DragonsScuderi. Anesthesiology 2005; 102:1081-1082

Droperidol:The FDA Box Warning

Droperidol has been used for over 40 years Why a problem now? No evidence of adverse events in published trials No published case reports An association does not prove cause and effect If prolonged QTc is an issue then 5HT3 antagonists

should also carry the same warning At least 3 cases of VT associated with 5HT3

administration No “denominator” provided (or available)

BOGUS!

Droperidol FDA Box Warning

Evidence Rating for Antiemetics

Strength of Evidence Treatment Consequences*

Prevention Treatment Prevention Treatment

Ondansetron 4 mg I-A I-A 5.5 – 6.5 3.2 – 3.9

Ondansetron 1 mg - I-A - 3.8 – 4.8

Dolasetron 12.5 mg I-A I-A 4.0 – 5.0 3.6 – 4.2

Granisetron 1 mg I-A I-A 3.1 – 4.2 3.1 – 3.8

Droperidol I-A - 4.3 – 5.0 ?

Dexamethasone II-A - 4.3 – 7.1 -

*NNT

Prevention of PONV:Dexamethasone

“In conclusion, in the surgical setting, a single prophylactic dose of dexamethasone is antiemetic compared with placebo without evidence of clinically relevant toxicity in otherwise healthy patients. Late efficacy (i.e., Up to 24 hours) seems to be most pronounced.”

Henzi I, Walder B, and Tramer, MR. Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg 2000;90:186-194

Eberhart LH. Morin AM. Georgieff M. Dexamethasone for prophylaxis of postoperative nausea and vomiting. A meta-analysis of randomized controlled studies. Anaesthesist. 2000 ;49:713-20

Evidence Rating for Antiemetics

Strength of Evidence Treatment Consequences*

Prevention Treatment Prevention Treatment

Ondansetron 4 mg I-A I-A 5.5 – 6.5 3.2 – 3.9

Ondansetron 1 mg - I-A - 3.8 – 4.8

Dolasetron 12.5 mg I-A I-A 4.0 – 5.0 3.6 – 4.2

Granisetron 1 mg I-A I-A 3.1 – 4.2 3.1 – 3.8

Droperidol I-A - 4.3 – 5.0 ?

Dexamethasone II-A - 4.3 – 7.1 -

Dimenhydrinate II-A V-B 4.8 – 8.0 ?

*NNT

Prevention of PONV:Dimenhydrinate

Early (0-6 h) Overall (0-48 h)

Outcome Trials NNT Trials NNT

PONV 8 8.3 16 5.0

Vomiting 6 7.7 14 4.8

Nausea 2 8.3 7 5.9

Kranke, et al. Acta Anaesth Scand 2002;46:238-244

Evidence Rating for Antiemetics

Strength of Evidence Treatment Consequences*

Prevention Treatment Prevention Treatment

Ondansetron 4 mg I-A I-A 5.5 – 6.5 3.2 – 3.9

Ondansetron 1 mg - I-A - 3.8 – 4.8

Dolasetron 12.5 mg I-A I-A 4.0 – 5.0 3.6 – 4.2

Granisetron 1 mg I-A I-A 3.1 – 4.2 3.1 – 3.8

Droperidol I-A - 4.3 – 5.0 ?

Dexamethasone II-A - 4.3 – 7.1 -

Dimenhydrinate II-A V-B 4.8 – 8.0 ?

*NNT

Evidence Rating for Antiemetics

Strength of Evidence Treatment Consequences*

Prevention Treatment Prevention Treatment

Ondansetron 4 mg I-A I-A 5.5 – 6.5 3.2 – 3.9

Ondansetron 1 mg - I-A - 3.8 – 4.8

Dolasetron 12.5 mg I-A I-A 4.0 – 5.0 3.6 – 4.2

Granisetron 1 mg I-A I-A 3.1 – 4.2 3.1 – 3.8

Droperidol I-A - 4.3 – 5.0 ?

Dexamethasone II-A - 4.3 – 7.1 -

Dimenhydrinate II-A - 4.8 – 8.0 ?

Metoclopramide - IV-B - ?

*NNT

Prevention of PONV:Metoclopramide

“In summary, metoclopramide, although used as an antiemetic for almost 40 years in the prevention of PONV, has no clinically relevant antiemetic effect . . . it is very likely that the doses used in daily clinical practice are too low.”

Henzi I, Walder B, and Tramer, MR. Metoclopramide in the prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized, placebo-controlled studies. BJA 1999;83:761-771

Evidence Rating for Antiemetics

Strength of Evidence Treatment Consequences*

Prevention Treatment Prevention Treatment

Ondansetron 4 mg I-A I-A 5.5 – 6.5 3.2 – 3.9

Ondansetron 1 mg - I-A - 3.8 – 4.8

Dolasetron 12.5 mg I-A I-A 4.0 – 5.0 3.6 – 4.2

Granisetron 1 mg I-A I-A 3.1 – 4.2 3.1 – 3.8

Droperidol I-A - 4.3 – 5.0 ?

Dexamethasone II-A - 4.3 – 7.1 -

Dimenhydrinate II-A - 4.8 – 8.0 ?

Metoclopramide - V-B - ?

Scopolamine patch II-B - 5.0 – 7.0 ?

*NNT

Prevention of PONV:Scopolamine

Small Studies Large Studies

Outcome Trials NNT Trials NNT

Vomiting 6 3.3 5 5.9

Nausea 2 5.3 5 5.0

PONV 8 2.9 8 6.7

Rescue 4 3.8 3 7.0

Kranke, et al. Anesth Analg 2002;95:133-143

Defined control event rate

Prevention of PONV:Scopolamine

Event NNH

Visual disturbances 5.6

Dry mouth 12.5

Dizziness 50.0

Agitation 100.1

Kranke, et al. Anesth Analg 2002;95:133-143

Adverse Events

Evidence Rating for Antiemetics

Strength of Evidence Treatment Consequences*

Prevention Treatment Prevention Treatment

Ondansetron 4 mg I-A I-A 5.5 – 6.5 3.2 – 3.9

Ondansetron 1 mg - I-A - 3.8 – 4.8

Dolasetron 12.5 mg I-A I-A 4.0 – 5.0 3.6 – 4.2

Granisetron 1 mg I-A I-A 3.1 – 4.2 3.1 – 3.8

Droperidol I-A - 4.3 – 5.0 ?

Dexamethasone II-A - 4.3 – 7.1 -

Dimenhydrinate II-A - 4.8 – 8.0 ?

Metoclopramide - IV-B - ?

Scopolamine patch II-B - 5.0 – 7.0 ?

*NNT

Ondansetron and DolasetronPerception versus Reality

Browning BA, Fort CA, Kemp KD, Shimata MF, Strube MD: Ondansetron versus dolasetron: a comparison study in the prevention of postoperative nausea and vomiting in patients undergoing gynecological procedures. AANA.J. 2004; 72: 129-32

Karamanlioglu B, Turan A, Memis D, Sut N: Comparison of oral dolasetron and ondansetron in the prophylaxis of postoperative nausea and vomiting in children. Eur.J.Anaesthesiol. 2003; 20: 831-5

Olutoye O, Jantzen EC, Alexis R, Rajchert D, Schreiner MS, Watcha MF: A comparison of the costs and efficacy of ondansetron and dolasetron in the prophylaxis of postoperative vomiting in pediatric patients undergoing ambulatory surgery. Anesth.Analg. 2003; 97: 390-6

Walker JB: Efficacy of single-dose intravenous dolasetron versus ondansetron in the prevention of postoperative nausea and vomiting. Clin.Ther. 2001; 23: 932-8

Ondansetron and DolasetronPerception versus Reality

Paech MJ, Rucklidge MW, Banks SL, Gurrin LC, Orlikowski CE, Pavy TJ: The efficacy and cost-effectiveness of prophylactic 5-hydroxytryptamine3 receptor antagonists: tropisetron, ondansetron and dolasetron. Anaesth.Intensive Care 2003; 31: 11-7

Sukhani R, Pappas AL, Lurie J, Hotaling AJ, Park A, Fluder E: Ondansetron and dolasetron provide equivalent postoperative vomiting control after ambulatory tonsillectomy in dexamethasone-pretreated children. Anesth.Analg. 2002; 95: 1230-5

Zarate E, Watcha MF, White PF, Klein KW, Sa RM, Stewart DG: A comparison of the costs and efficacy of ondansetron versus dolasetron for antiemetic prophylaxis. Anesth.Analg. 2000; 90: 1352-8

Prevention of PONV:Combination Therapy

McKenzie R, et al. Comparison of ondansetron with ondansetron plus dexamethasone in the prevention of postoperative nausea and vomiting. Anesth Analg 1994;79:961-964

Lopez-Olaondo L, et al. Combination of ondansetron and dexamethasone in the prophylaxis of postoperative nausea and vomiting. BJA 1996;76:835-840

Eberhart LH. Morin AM. Georgieff M. Dexamethasone for prophylaxis of postoperative nausea and vomiting. A meta-analysis of randomized controlled studies. Anaesthetist. 2000 ;49:713-20 (meta analysis)

Ondansetron/Dexamethasone

Prevention of PONV:Combination Therapy

Pueyo FJ, et al. Combination of ondansetron and droperidol in the prophylaxis of postoperative nausea and vomiting. Anesth Analg 1996;83:117-122

McKenzie R, et al. Droperidol/ondansetron combination controls nausea and vomiting after tubal banding. Anesth Analg 1996;83:1218-1222

Klockgether-Radke A, et al. Ondansetron, droperidol and their combination for the prevention of post-operative vomiting in children. Eur J Anesthesiology. 1997;14:362-367

Eberhart LH. Morin AM. Bothner U. Georgieff M. Droperidol and 5HT3-receptor antagonists, alone or in combination, for prophylaxis of postoperative nausea and vomiting. A meta-analysis of randomized controlled trials. Acta Anaesthesiologica scandinavica. 2000;44:1252-7

Ondansetron/Droperidol

Prevention of PONV:Combination Therapy

Which Combination?

Event

5-HT3 + drop 5-HT3 + dex

N Rate N Rate P-value OR

Early

Nausea 138 17% 260 11% 0.12 1.6

Vomiting 318 1% 419 1% 1.00 1.0

Late

Nausea 358 27% 623 21%* 0.02 1.4

Vomiting 443 9% 813 9% 1.00 0.9Ashraf et al. Anesthesiology 2001; 95:A-41

Prevention of PONV:Timing of Administration

Sun et al. The effect of timing on ondansetron administration in outpatients undergoing otolaryngologic surgery. Anesth Analg 1997;84:331-336

Chen et al. The effect of timing of dolasetron administration on its efficacy as a prophylactic antiemetic in the ambulatory setting. Anesth Analg 2001;93:906-911

Wang et al. The effect of timing of dexamethasone administration on its efficacy as a prophylactic antiemetic for postoperative nausea and vomiting. Anesth Analg 2000;91;136-139

Ondansetron

Dexamethasone

Dolasetron

Breakthrough PONV:Repeat Dosing With Ondansetron

43

323428

0

20

40

60

80

100

0 - 2 hours 0 - 24 hours

Per

cen

t C

omp

lete

Res

pon

se

Placebo Ondansetron 4 mg

Kovac et al. J. Clin Anesth 1999;11:453-459

* †

* p = 0.074

† p = 0.342

Propofol and PONV

Early Late

Nausea Vomiting Any Nausea Vomiting Any

Induction 9.3* 13.7* 20.9 50.1 14.9 NA

Maintenance 8* 9.2* 6.2* 5.8* 10.1* 10

Early Late

Nausea Vomiting Any Nausea Vomiting Any

Induction 5.0* 7.0* 14 28 10 NA

Maintenance 4.7* 4.9* 4.9* 6.1* 8.3* 7.1

All Control Event Rates

20% - 60% Control Event Rate

*Analysis by NNT

Tramer et al. BJA 1997;78:247-255

Propofol and PONV

Determination of Plasma Concentrations of Propofol Associated with 50% Reduction in Postoperative Nausea

Gan TJ, Glass PSA, Howell ST, Canada AT, et al.Anesthesiology 1997;87:779-784

CACI devise targeted plasma concentrations of 100, 200, 400, and 800 ng/ml

Median plasma concentration associated with antiemetic response - 343 ng/ml

17 mcg/kg/min propofol yields 400 - 540 ng/ml plasma concentration

Propofol “PCA”

Propofol Patient Controlled Antiemesis is a Safe and Effective Method for Treatment of Postoperative Nausea and Vomiting

Gan TJ, El-Molem H, Ray J, Glass PSA, Anesthesiology 1999; 90:1564-1570

Three medications per delivery: propofol 20mg, propofol 40 mg, or placeboLockout interval 5 min, no maximum dose limitNausea scores were 34% and 40% less than placeboPlacebo group had an 8 and 5 fold increase in risk of emesis and a 5 fold increase in incidence of rescueNo differences in sedationPatients in treatment groups were more satisfied than those in placebo group

Intravenous Fluid Therapy

0

5

10

15

20

Inci

denc

e %

30 min 60 min DIS Day 1

Time

High Infusion Low Infusion

*

Yogendran S, et al. Anesth Analg 1995;80:682-686

High Infusion = 20 ml/kg

Low Infusion = 2 ml/kg

Incidence on Postop NauseaIII-A

Intravenous Fluid Therapy

10 ml/kg

n = 71

30 ml/kg

n = 70 P value

Cumulative 48 h

vomiting 25.7 8.6 0.01

nausea, severe 27.1 5.7 0.001

nausea, total 37.1 37.1 0.86

antiemetic use 22.9 11.9 0.146

Manger et al. BJA 2004;93:381-385

All values in percent

III-A

Intravenous Fluid Therapy

Preoperative Intravenous Fluid Therapy Decreases Postoperative Nausea and Pain in High Risk PatientsMaharaj et al. Anesth Analg 2005; 100:675-682

Frequency of all, moderate, and severe nausea decreased

Overall incidence of PONV decreased

NNT to prevent an occurrence of nausea or vomiting was 3.45

III-A

NK-1 Antagonists:Prevention

Ondansetron (n=52)

CP122,721 (n=52)

Combination (n=53)

Emesis (24 hr) (%) 18 6 2*

Rescue antiemetics (%) 60 47 44

Median emesis free time 75% of pts. (min)

82 75 362*

Nausea 8 hr (%) 24 hr (%)

76 98

80 96

80 98

Satisfaction with nausea management (%)

81 75 80

Gesztesi Z, Scuderi PE, D’Angelo R, et al. Anesthesiology 2000;93:931-937

III-A

NK-1 Antagonists:Treatment

2821

5 5

77

50

31 31

0

20

40

60

80

100

2 hr 6 hr 24 hr 72 hr

Time After Treatment

% o

f Pa

tien

ts

Placebo GR205171

Complete Control of Emesis

Diemunsch et al. Anesth Analg 1998;86:S436

21 16

0 0

55

2010 10

0

20

40

60

80

100

2 hr 6 hr 24 hr 72 hr

Time After Treatment

% o

f Pa

tien

ts

Placebo GR205171

Complete Control of Nausea

III-A

Prevention of PONV:Clonidine

Effects of clonidine on postoperative nausea and vomiting in breast cancer surgery

Oddby-Muhrbeck, Eksborg, Bergendahl, Muhrbeck, et al. Anesthesiology 2002; 96:1109-1111

The efficacy of oral clonidine premedication in the prevention of postoperative vomiting in children following strabismus surgery

Handa, Fujii. Paediatr Anaesth 2001; 11:71-74

Oral clonidine premedication reduces vomiting in children after strabismus surgery. Can J Anaesth 1995; 42: 977––81

Mikawa, Nishina, Maekawa, Asano, Obara. Can J Anaesth 1995; 42: 977-981

III-A

Clonidine 1 mg IV = $55.34

Prevention of PONV:Clonidine

Effects of clonidine on postoperative nausea and vomiting in breast cancer surgery

Oddby-Muhrbeck, Eksborg, Bergendahl, Muhrbeck, et al. Anesthesiology 2002; 96:1109-1111

The efficacy of oral clonidine premedication in the prevention of postoperative vomiting in children following strabismus surgery

Handa, Fujii. Paediatr Anaesth 2001; 11:71-74

Oral clonidine premedication reduces vomiting in children after strabismus surgery. Can J Anaesth 1995; 42: 977–81

Mikawa, Nishina, Maekawa, Asano, Obara. Can J Anaesth 1995; 42: 977-981

III-A

Clonidine 1 mg IV = $55.34 Clonidine 0.3 mg PO = $0.12

Prevention of PONV:Haloperidol

Is Low-dose Haloperidol a Useful Antiemetic?Buttner et al. Anesthesiology 2004; 101:1454-1463

Haloperidol 0.5 – 4.0 mg

compared to placebo 0 – 24 hr:

relative benefit: 1.26 – 1.51

NNT: 3.20 – 5.10

P-6 Acupuncture Point Stimulation

Zarate E, Mingus M, White PF, Chiu JW, Scuderi PE, et al. The use of transcutaneous acupoint electrical stimulation for preventing nausea and vomiting after laparoscopic surgery. Anesth Analg 2001;92:629-35.

P-6 Stimulation:Control of Nausea

TAES Sham PlaceboPACU 25 17 28

45 min 36 51 32

90 min 27* 51 33

120 min 27 40 41

4 hr 26* 52 35

6 hr 22*† 47 43

9 hr 18*† 42 47

Zarate E, et al. Anesth Analg 2001;92:629-35* compared to sham

† compared to placebo

III-A

P-6 Acupuncture Point Stimulation

TEAS

n = 26

Ondansetron

n = 25

Placebo

n = 24 P value

Nausea 2 h 19 40 79 <0.0001

Emesis

2 h 12 8 25 0.22

24 h 19 32 46 0.12

Complete Response

2 h 77 64 42 0.01

24 h 73 52 38 0.006

Rescue Antiemetic 19 28 54 0.04

Gan et al. Anesth Analg 2004;99:1070-1075All values in percent

III-A

Multimodal Management of PONV:Hypothesis

Scuderi at al. Anesth Analg 2000;91:408-414

A multi-modal approach to the management of PONV can result in a zero incidence of vomiting (and perhaps nausea) in the immediate postoperative period (i.e., PACU)

Multimodal Management of PONV:Algorithm for Management

I. PREOPERATIVE

A. Anxiolysis - 10-30 mcg/kg midazolam

B. Fluid - 10 ml/kg minimum

II. INDUCTION

A. PreO2

B. Droperidol 10 mcg/kg

C. Decadron 8 mg

D. Propofol - 2 mg/kg + 200 mcg/kg/min

E. Remifentanil - 1 mcg/kg + 1 mcg/kg/min

F. Intubate 90-120 seconds

G. Gastric decompression

Scuderi at al. Anesth Analg 2000;91:408-414

Multimodal Management of PONV: Algorithm for Management

III. MAINTENANCE A. Propofol

200 mcg/kg/min x 5 min, then150 mcg/kg/min x 5 min, then100 mcg/kg/min x 5 min, then75 mcg/kg/min until10 minutes prior to end of surgery, then D/C

B. Remifentanil1 mcg/kg/min until intubated, then0.5 mcg/kg/min until trocar, then0.25 mcg/ kg/min titrated to effect or BISD/C 2-3 minutes prior to end of surgery

C. Ketorolac30 mg IV after induction

D. Ondansetron1 mg at end of surgery

E. Fentanyl25 mcg IV 10 minutes prior to end of surgery

Scuderi at al. Anesth Analg 2000;91:408-414

IV. PACU

A. PONV rescue - Dramamine 25 mg

B. Pain rescue - Fentanyl 25 mcg prn

C. Fluids - 25 ml/kg total for OSC stay

Multimodal Management:Results

Group I Group II Group III P values

Multimodal Ondansetron Placebo

Patients 60 42 37

Hx Risk Factors (%) 48 64 65 0.17*†

Tx required (%) 2 24 41 <0.0001*†

Vomiting before discharge (%) 0 7 22 0.67* 0.003†

Vomiting after discharge (%) 12 21 32 0.27* 0.02†

Satisfaction with PONV (%) 100 100 92 0.05†‡

Satisfaction score <10 (%)5 6 37

1.00* 0.0013‡

Time to discharge ready (mean)128 162 192

0.0015*; 0.0001†

*Group I vs II; † Group I vs III; Group II vs III‡Scuderi at al. Anesth Analg 2000;91:408-414

III-A

Multimodal Management of PONV:Simplified Algorithm

I. INDUCTION

A. PreO2

B. Propofol 2 - 4 mg/kg

C. Opioid prn

D. NMB prn

C. Droperidol 10 mcg/kg

D. Decadron 4 - 8 mg

II. MAINTENANCE

A. Propofol 50 mcg/kg/min

B. Potent inhalation agent

C. Nitrous oxide prn

E. NMB reversal prn

III. EMERGENCE

A. Ondansetron 1 mg IV

B. Suction oropharynx

C. Extubate when awake

Multimodal Management of PONV:Simplified Algorithm

COST ($)

Case duration 1 hour 2 hours 3 hours

Droperidol (10 mcg/kg) $2.10 $2.10 $2.10

Dexamethasone (8 mg) $1.30 $1.30 $1.30

Ondansetron (1 mg) $4.00 $4.00 $4.00

Propofol (50 mcg/kg/min)

$7.50 $15.00 $22.50

Total Cost $14.90 $22.40 $29.90

Cost Analysis

PONV Risk Reduction

Intervention % Relative Risk Reduction

Ondansetron 4mg 26.0

Dexamethasone 4mg 26.4

Droperidol 1.25mg 24.5

Propofol vs volatile 18.9

Nitrogen vs Nitrous 12.1

Apfel, et al. NEJM 2004; 350:2441-2451

I-A

General Recommendations

Use generic drugs for “routine” prophylaxis Treat breakthrough symptoms with 5HT3 antagonists

Don’t repeat dose with 5HT3 antagonists for failure Treat/prevent with different classes of antiemetics For “high risk” patients use combination prophylaxis and

consider “alternative” therapy Consider propofol infusion as part of anesthetic Hydrate aggressively The best chance for “complete response” is a

multimodal approach