Postoperative Nausea and Vomiting Prophylaxis with Antipsychotic Agents

Should we or should we not?

Natalie Clavel

October 8, 2008

OverviewPathophysiology of nausea / vomiting

PONV Overview

PONV prophylaxis guidelines (2007)

Droperidol

What happened to it?

Evidence for and against its use for PONV prophylaxis

Ondansetron

Evidence for and against its use for PONV prophylaxis

Haloperidol

Evidence for and against its use for PONV prophylaxis

Pathophysiology ofNausea and Vomiting

Why should we care? Approximately 75 million surgeries performed (in

patient and ambulatory) annually in the USA If untreated, PONV occurs in 20-30% of the

general surgical population and in 70-80% of high-risk surgical patients

Vomiting increases the risk of : aspiration, suture dehiscence, esophageal rupture, subcutaneous emphysema, and pneumothorax

Annual cost of PONV in the United States is thought to be $ 200 million

PONV in ambulatory patients accounts for 0.1-0.2% of unanticipated hospital admissions

Approx 35% of patients will not experience PONV before discharge form PACU and may onset within the first 24-48 hrs postoperatively

SAMBA Guidelines for Management of PONV

Anesth Analg 2007 ; 105 : 1615-28

PONV Prophylaxis : Cost Effectiveness

Anesthesiology 2000 ; 92 : 958-67

• Each episode of emesis is thought to delay discharge from PACU by 20 min

• Costs associated with PONV in patients not receiving prophylaxis were 100x more than the cost of prophylaxis with a generic agent.

• Costs of treating vomiting were shown to be 3x that of treating nausea

Droperidol • A Butyrophenone & derivative of haldoperidol

• Antiemetic , sedative, antipuritic, pain adjunct• Acts at dopamine > NorAd + 5HT• Anti-emetic effects thought to be due to a triggered

imbalance in dopamine in the chemoreceptor trigger zone

• Biotranformation occurs in the liver. T1/2 = 103-134 minutes

• CNS – NMS, movement disorder, extrapyrimidal signs, drowsiness

• CVS – prolongation of QT interval (delays repolarization by inhibiting cardiac K+ channels). Vasodilation via A-adrenergic blockade

Droperidol : Is it Effective ?IMPACT TRIALCompared effectiveness of droperidol (1.25mg IV) ,

dexamethasone (4mg IV) , and ondansetron (4mg IV)

All reduced the incidence of PONV by 26%

Multimodal prophylaxis resulted in additive reduction in the incidence of PONV

0 agent = 52% risk of PONV

1 agent = 37% risk of PONV

2 agent = 28% risk of PONV

3 agent = 22% risk of PONV

N EGNL J MED 2004; 350: 2441-51

NNT to prevent an episode of PONV compared to placebo is 5 (0-24hrs)

Side effects are dose dependant. Below 2.5 mg extra-pyramidal signs and sedation were extremely rare. Incidentally found to decrease the incidence of headache

Can J Anaesth 2000; 47 : 537-51

NNT to prevent an episode of NV associated with morphine PCA is 3

Anesth Analg 1999; 88: 1354-61

Effective against established PONV in PACU.

Anesth 2005; 102:1094-100

What Happened to Droperidol?1991 : FDA approval of Ondansetron 2001 : FDA Issues Black Box Warning against use of

Droperidol (30% of market shares)2001 : Production shortage of prochlorperazine.

Consequential increase in use of 5HT agents for PONV prophylaxis

2002 : 10-fold decrease in sales of droperidol in USA2004 : Droperidol no longer manufactured in Europe2005 : SAMBA survey (25% resp rate) Droperidol use

for prophylaxis decreased from 47% to 5%. 92% of respondents felt black box warning unjustified

Dec 24, 2006 : Ondansetron patent expired (GSK)2007 : Ondansetron leading first-line agent of choice

in PONV prophylaxis (>30% of market share)Presently : Waiting for FDA internal review of

droperidol and possible withdrawal or modification of black box warning

Black box warning is the most serious warning that the FDA can require on a drug’s labeling

There is significant medical liability associated with use of a medication with a black box warning

Droperidol: The Black Box WarningEstimated >11 million ampules of droperidol sold in

USA in 2001

Nov 1,1997 – Jan 2, 2001 : 273 adverse events reported to the FDA regarding droperidol

74/273 = cardiac event / torsades17/273 = prolonged QT interval

In patients that received 0.625-1.25mg droperidol IV :10 experienced adverse cardiac events (1 torsades)

J Clin Anesth 2008: 20: 35-39

Anesth Analg 2003; 96: 1377-9

Anesth Analg 2003; 96: 1377-9

Does droperidol cause arrhythmias ?RCT , 1028 pts received droperidol 0.625 or 1.25 mg

IV. No reports of cardiovascular events or sudden deaths

Anesth Analg 1998; 86: 731-8Meta-Analysis of 76 trials involving 5351 pts receiving

0.625-5mg IV did not report an increased risk of arrhythmias or sudden death

Can J Anaesth 2000; 47: 537-51Retrospective study of 16790 pts who were exposed

to droperidol. No torsades/ arrythmias noted. 1 episode of arrhythmia documented to have occurred 2 hrs post administration of 0.625mg droperidol. Pt had baseline QT prolongation (chronic cyclobenzaprine tx) w concurrent fluoxetine tx (P450 inhib)

Anesth 2007;107:531-6

Does droperidol cause QT prolongation ?

Rapid Onset, Dose dependent increase in QT interval with 0.1-0.25 mg/kg

Max prolongation occurred within 60s of administration and decreased over the following 10 min (no arrhythmias)

Anesth Analg 1994; 79: 983-6

Can we blame the droperidol ?

RCT using low dose droperidol (0.625 and 1.25mg IV) in 120 ASA I-III, healthy

0.625 mg increased QT by 15 +/- 40 msec1.25 mg increased QT by 22+/-41 msecQT Interval returned to baseline 2 hrs post-

opNo arrhythmias documentedPlacebo increased QTc by 12 +/-35 msecGA alone assoc with 14-16 msec

prolongation of QTc postoperatively (not explained by droperidol)

Anesth 2005; 102:1101-5

Routinely Used Drugs that prolong QT Interval in Anesthesia

Thiopental Succinylcholine

Isoflurane Neostigmine

Sevoflurane Atropine

Desflurane Glycopyrrolate

Anesth Analg 2008; 106: 1414-17

Drugs that prolong QT Interval

Antibiotics

Clarithromycin, erythromycin, gatifloxacin, levofloxacin, moxifloxacin

Antiarrythmics

Amiodarone, Procainamide

Antidepressants

Fluoxetine, Paroxetine, Sertraline

Antipsychotics

Chlorpromazine, Droperidol, Haloperidol, Seroquel, Risperidone

Other

Indapamide, Nicardipine, Octreotide, Sumitriptan

Conclusion• Droperidol has a long-established safety

record when used in antiemetic dosages• No evidence suggesting an increased risk

of arrhythmia when using dosages <1.25mg

• QTc is prolonged in a dose-dependent fashion after administration of droperidol. Prolongation is modest and transient.

• A product warning would likely have been sufficient. A black box warning is excessive for use of droperidol at <1.25mg dosages and is not evidence based.

2003 Consensus Guidelines for the Management of PONV Anesth Analg 2003; 97: 62-71

Ondansetron : Better Safety Profile?

“setrons” share with droperidol the ability to block the HERG cardiac potassium channel

Anesth 2007; 106: 967-76

RCT (16 healthy pts) showed 1mg droperidol and 4mg ondansetron increased QTc by 25+/-8ms and 17+/-10ms respectively. Together QTc increased by 28+/-10ms.

Anesth 2008; 109: 206-212

Droperidol 0.75mg vs. ondansetron 4mg for established PONV in PACU. QTc was prolonged in 21% pts before anti-emetic administration. Max prolongation occurred 2-3 min after administration and returned to below baseline 90 min after administration. SVT in 1 pt receiving ondansetron

Anesth 2005; 102:1094-100

Ondansetron : Better efficacy ?

Meta-analysis confirmed that 1.25mg droperidol was found to possess greater antinausea efficacy that ondansetron(4mg). There was no increase in sedation or other side effects.

Can J Anaesth 2000; 47: 537-51

Droperidol and ondansetron have been shown to be similarly effective against established PONV

Anesth 2005; 102:1094-100

What about Haloperidol ?• A Butyrophenone• Obtained FDA approval in 1967 for use as an antipsychotic/

neuroleptic/ tranquilizer• Metabolized in liver via CYP450 • Mechanism of action via D2 (low dose) 5-HT2 (high dose)• CNS – EPS, NMS, extrapyramidal, tardive dyskinesia• CVS – QT interval prolongation

Established use in treatment of chemotx / XRTx / and opioid-related N/V (1.5-3mg po)

Palliat Med 2004; 18: 195-201

Systematic review (1962-1988) suggested that haloperidol at 1-2 mg might be effective against PONVNNT to prevent an episode of PONV compared to placebo determined to be 4-6

Anesth 2004; 101:1454-63

Haloperidol as a safer alternative to Droperidol?

Haloperidol 1mg and droperidol 0.625mg were better than placebo for PONV prophylaxis. Both equally effective. No difference in QTc prologation.

Acta Anaesthesiol Scand 2007; Epub

Haloperidol (1mg) was as effective as ondansetron (4mg). No difference in QTc prolongation

Anesth Analges 2006; 106 : 1407-9

.

Haloperidol was not more effective in reducing incidence of late onset PONV than droperidol (T1/2 18 hr vs. 2hr)

No increase in sedation, extrapyrimidal symptoms, of clinically significant prolongation of QTc was observed at anti-emetic dosages

Anesth Analg 2008; 106: 1402-6

Future ConcernsIn September 2007, the FDA issued an alert regarding

the updated labeling for haloperidol.

Warning states:

Risk of QT prolongation / torsades

Haldol not approved for IV use

EKG monitoring required if given IV

Administration

Dosage , Timing, Safety/ Side effect profile of repeated dosages of long acting drug

Trials

Unlikely to have large clinical trials conducted on a generic drug

ConclusionsAvailable evidence suggests that small-dose

haloperidol appears to be safe and effective when given as a single dose (1-2mg) for PONV prophylaxis.

Large studies are required to provide additional safety and efficacy information.

In the absence of this safety data, droperidol is a better choice for PONV prophylaxis

Given the FDA Black Box warning for droperidol, the anesthesia community has “reinvented the wheel”

Thank You

Antiemetic and Timing of Administration

Anesth Analg 2007 ; 105 : 1615-28