Prevention and Treatment of Postoperative Nausea and Vomiting

1
Prevention and Treatment of Postoperative Nausea
and Vomiting

• Phillip E. Scuderi, M.D.
• Department of Anesthesiology
• Wake Forest University School of Medicine
• Winston-Salem, NC 27157-1009

2
Critical Evaluation of Data

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

3
Evidence Based MedicineRating Scale

• Level of evidence based on study design
• I. Large randomized, controlled trial (ngt100
  per group)
• II. Systematic review
• III. Small randomized, controlled trial (nlt100
  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

4
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 19883181728-1733
5
Measures of Treatment Consequences
Laupacis et al. NEJM 19883181728-1733
6
Chemoreceptor Receptor Zone
7
(No Transcript)
8
Currently Available Medications

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

9
Evidence Rating for Antiemetics
NNT
10
Prevention of PONVOndansetron Versus Placebo
All patients, 0 - 24 hrs



p 0.010 p lt 0.001
McKenzie et al. Anesthesiology 19937821-28
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Ondansetron Dose ResponsePrevention
Numbers Needed to be Treated

• Only 4 mg and 8 mg were significantly different
  than placebo
• No further improvement with doses gt8 mg

Tramer et al. Anesthesiology 1997871277-1289
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Evidence Rating for Antiemetics
NNT
13
Treatment of PONVOndansetron Versus Placebo






p lt 0.001
Scuderi et al. Anesthesiology 1993782-5 Hantler
et al. Anesthesiology 199277A16
14
Ondansetron Dose ResponseTreatment
Numbers Needed to be Treated

• All three doses significantly different than
  placebo
• No significant difference in antiemetic efficacy
  between the three doses of ondansetron

Tramer et al. BMJ 19973141088-1092
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Evidence Rating for Antiemetics
NNT
16
Prevention of PONVDolasetron Versus Placebo









p lt 0.0003 compared to placebo
Graczyk et al. Anesth Analg 199784325-330
17
Treatment of PONVDolasetron Versus Placebo








p lt 0.001 compared to placebo
Kovac et al. Anesth Analg 199785546-552
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Evidence Rating for Antiemetics
NNT
19
Prevention of PONVGranisetron Versus Placebo
No Vomiting


p lt 0.001 compared to placebo
Wilson et al. BJA 199676515-518
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Prevention of PONVGranisetron Versus Placebo
No Nausea


p lt 0.001 compared to placebo
Wilson et al. BJA 199676515-518
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Prevention of PONVGranisetron Versus Placebo
Total Control


p lt 0.001 compared to placebo
Wilson et al. BJA 199676515-518
22
Treatment of PONVGranisetron Versus Placebo
No Vomiting



p lt 0.001 compared to placebo
Taylor et al. JCA. 19979658-663
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Treatment of PONVGranisetron Versus Placebo
No Nausea



p lt 0.005 compared to placebo
Taylor et al. JCA. 19979658-663
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Evidence Rating for Antiemetics
NNT
25
Prevention of PONVOndansetron Versus Droperidol
Complete Response
I-A








p lt 0 .05 compared to placebo p lt 0.05
compared to ondansetron 4 mg p ,lt0.05 compared
to droperidol 0.625 mg
Fortney et al. Anesth Analg 199886731-738
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Prevention of PONVOndansetron Versus Droperidol
No Nausea
p lt 0 .05 compared to placebo p lt 0.05
compared to droperidol 0.625 mg and
ondansetron 4 mg
I-A
?

?
?
Fortney et al. Anesth Analg 199886731-738
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Droperidol FDA Box Warning

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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 2003961377-1379
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Droperidol and QTc Prolongation

• Effect of Low-dose Droperidol on the QT Interval
  during and after General Anesthesia
• White et al. Anesthesiology 2005 1021101-1105
• Prolongation of QTc Interval after Postoperative
  Nausea and Vomiting Treatment by Droperidol or
  Ondansetron
• Charbit et al. Anesthesiology 2005 1021094-1100
• You (Still) Cant Disprove the Existence of
  Dragons
• Scuderi. Anesthesiology 2005 1021081-1082

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DroperidolThe 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)

31
Droperidol FDA Box Warning

• BOGUS!

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Evidence Rating for Antiemetics
NNT
33
Prevention of PONVDexamethasone

• 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 200090186-194
Eberhart LH. Morin AM. Georgieff M. Dexamethasone
for prophylaxis of postoperative nausea and
vomiting. A meta-analysis of randomized
controlled studies. Anaesthesist. 2000 49713-20
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Evidence Rating for Antiemetics
NNT
35
Prevention of PONVDimenhydrinate
Kranke, et al. Acta Anaesth Scand 200246238-244
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Evidence Rating for Antiemetics
NNT
37
Evidence Rating for Antiemetics
NNT
38
Prevention of PONVMetoclopramide

• 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
199983761-771
39
Evidence Rating for Antiemetics
NNT
40
Prevention of PONVScopolamine
Defined control event rate
Kranke, et al. Anesth Analg 200295133-143
41
Prevention of PONVScopolamine
Adverse Events
Kranke, et al. Anesth Analg 200295133-143
42
Evidence Rating for Antiemetics
NNT
43
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

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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-pretreat
  ed 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

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Prevention of PONVCombination Therapy
Ondansetron/Dexamethasone

• McKenzie R, et al. Comparison of ondansetron with
  ondansetron plus dexamethasone in the prevention
  of postoperative nausea and vomiting. Anesth
  Analg 199479961-964
• Lopez-Olaondo L, et al. Combination of
  ondansetron and dexamethasone in the prophylaxis
  of postoperative nausea and vomiting. BJA
  199676835-840
• Eberhart LH. Morin AM. Georgieff M. Dexamethasone
  for prophylaxis of postoperative nausea and
  vomiting. A meta-analysis of randomized
  controlled studies. Anaesthetist. 2000 49713-20
  (meta analysis)

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Prevention of PONVCombination Therapy
Ondansetron/Droperidol

• Pueyo FJ, et al. Combination of ondansetron and
  droperidol in the prophylaxis of postoperative
  nausea and vomiting. Anesth Analg 199683117-122
• McKenzie R, et al. Droperidol/ondansetron
  combination controls nausea and vomiting after
  tubal banding. Anesth Analg 1996831218-1222
• Klockgether-Radke A, et al. Ondansetron,
  droperidol and their combination for the
  prevention of post-operative vomiting in
  children. Eur J Anesthesiology. 199714362-367
• 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.
  2000441252-7

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Prevention of PONVCombination Therapy
Which Combination?
Ashraf et al. Anesthesiology 2001 95A-41
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Prevention of PONVTiming of Administration
Ondansetron

• Sun et al. The effect of timing on ondansetron
  administration in outpatients undergoing
  otolaryngologic surgery. Anesth Analg
  199784331-336
• Chen et al. The effect of timing of dolasetron
  administration on its efficacy as a prophylactic
  antiemetic in the ambulatory setting. Anesth
  Analg 200193906-911
• Wang et al. The effect of timing of dexamethasone
  administration on its efficacy as a prophylactic
  antiemetic for postoperative nausea and vomiting.
  Anesth Analg 200091136-139

Dolasetron
Dexamethasone
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Breakthrough PONVRepeat Dosing With Ondansetron
p 0.074 p 0.342


Kovac et al. J. Clin Anesth 199911453-459
50
Propofol and PONV
Analysis by NNT
Tramer et al. BJA 199778247-255
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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
199787779-784

• 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

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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 901564-1570

• Three medications per delivery propofol 20mg,
  propofol 40 mg, or placebo
• Lockout interval 5 min, no maximum dose limit
• Nausea scores were 34 and 40 less than placebo
• Placebo group had an 8 and 5 fold increase in
  risk of emesis and a 5 fold
• increase in incidence of rescue
• No differences in sedation
• Patients in treatment groups were more satisfied
  than those in placebo group

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Intravenous Fluid Therapy
III-A
Incidence on Postop Nausea

High Infusion 20 ml/kg Low Infusion 2 ml/kg
Yogendran S, et al. Anesth Analg 199580682-686
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Intravenous Fluid Therapy
III-A
All values in percent
Manger et al. BJA 200493381-385
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Intravenous Fluid Therapy
III-A

• Preoperative Intravenous Fluid Therapy Decreases
  Postoperative Nausea and Pain in High Risk
  Patients
• Maharaj et al. Anesth Analg 2005 100675-682

• 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

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NK-1 AntagonistsPrevention
III-A
Gesztesi Z, Scuderi PE, DAngelo R, et al.
Anesthesiology 200093931-937
57
NK-1 AntagonistsTreatment
III-A
Complete Control of Emesis
Complete Control of Nausea
Diemunsch et al. Anesth Analg 199886S436
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Prevention of PONVClonidine
III-A
Effects of clonidine on postoperative nausea and
vomiting in breast cancer surgery
Oddby-Muhrbeck, Eksborg, Bergendahl, Muhrbeck, et
al. Anesthesiology 2002 961109-1111
The efficacy of oral clonidine premedication in
the prevention of postoperative vomiting in
children following strabismus surgery
Handa, Fujii. Paediatr Anaesth 2001 1171-74
Oral clonidine premedication reduces vomiting in
children after strabismus surgery. Can J Anaesth
1995 42 97781
Mikawa, Nishina, Maekawa, Asano, Obara. Can J
Anaesth 1995 42 977-981
Clonidine 1 mg IV 55.34
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Prevention of PONVClonidine
III-A
Effects of clonidine on postoperative nausea and
vomiting in breast cancer surgery
Oddby-Muhrbeck, Eksborg, Bergendahl, Muhrbeck, et
al. Anesthesiology 2002 961109-1111
The efficacy of oral clonidine premedication in
the prevention of postoperative vomiting in
children following strabismus surgery
Handa, Fujii. Paediatr Anaesth 2001 1171-74
Oral clonidine premedication reduces vomiting in
children after strabismus surgery. Can J Anaesth
1995 42 97781
Mikawa, Nishina, Maekawa, Asano, Obara. Can J
Anaesth 1995 42 977-981
Clonidine 1 mg IV 55.34
Clonidine 0.3 mg PO 0.12
60
Prevention of PONVHaloperidol

• Is Low-dose Haloperidol a Useful Antiemetic?
• Buttner et al. Anesthesiology 2004 1011454-1463

Haloperidol 0.5 4.0 mg
compared to placebo 0 24 hr relative
benefit 1.26 1.51 NNT 3.20
5.10
61
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
  200192629-35.

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P-6 StimulationControl of Nausea
III-A
compared to sham compared to placebo
Zarate E, et al. Anesth Analg 200192629-35
63
P-6 Acupuncture Point Stimulation
III-A
Gan et al. Anesth Analg 2004991070-1075
All values in percent
64
Multimodal Management of PONVHypothesis

• 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)

Scuderi at al. Anesth Analg 200091408-414
65
Multimodal Management of PONVAlgorithm 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 200091408-414
66
Multimodal Management of PONV Algorithm for
Management
IV. PACU A. PONV rescue - Dramamine 25 mg B.
Pain rescue - Fentanyl 25 mcg prn C. Fluids - 25
ml/kg total for OSC stay
III. MAINTENANCE A. Propofol 200
mcg/kg/min x 5 min, then 150 mcg/kg/min x 5 min,
then 100 mcg/kg/min x 5 min, then 75 mcg/kg/min
until 10 minutes prior to end of surgery, then
D/C B. Remifentanil 1 mcg/kg/min until
intubated, then 0.5 mcg/kg/min until trocar,
then 0.25 mcg/ kg/min titrated to effect or
BIS D/C 2-3 minutes prior to end of surgery
C. Ketorolac 30 mg IV after induction D.
Ondansetron 1 mg at end of surgery E.
Fentanyl 25 mcg IV 10 minutes prior to end of
surgery
Scuderi at al. Anesth Analg 200091408-414
67
Multimodal ManagementResults
III-A
Group I vs II Group I vs III Group II vs III
Scuderi at al. Anesth Analg 200091408-414
68
Multimodal Management of PONVSimplified
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

69
Multimodal Management of PONVSimplified
Algorithm
Cost Analysis
70
PONV Risk Reduction
I-A
Apfel, et al. NEJM 2004 3502441-2451
71
General Recommendations

• Use generic drugs for routine prophylaxis
• Treat breakthrough symptoms with 5HT3 antagonists
• Dont 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