Transcript Antipsychotics for PONV Prophylaxis

Postoperative Nausea
and Vomiting
Prophylaxis with
Antipsychotic Agents
Should we or should we not?
Natalie Clavel
October 8, 2008
Overview
Pathophysiology 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 of
Nausea 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 0.10.2% 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
• 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
Anesthesiology 2000 ; 92 : 958-67
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 TRIAL
Compared 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 extrapyramidal 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 USA
2004 : Droperidol no longer manufactured in Europe
2005 : 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 Warning
Estimated >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 / torsades
17/273 = 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: 731-8
Meta-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: 537-51
Retrospective 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 msec
1.25 mg increased QT by 22+/-41 msec
QT Interval returned to baseline 2 hrs postop
No arrhythmias documented
Placebo increased QTc by 12 +/-35 msec
GA 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
Isoflurane
Sevoflurane
Desflurane
Succinylcholine
Neostigmine
Atropine
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 opioidrelated N/V (1.5-3mg po)
Palliat Med 2004; 18: 195-201
Systematic review (1962-1988) suggested that haloperidol at 12 mg might be effective against PONV
NNT 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 antiemetic dosages
Anesth Analg 2008; 106: 1402-6
Future Concerns
In 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
Conclusions
Available evidence suggests that small-dose
haloperidol appears to be safe and
effective when given as a single dose (12mg) 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