Transcript COMPARISON OF PROPOFOL VERSUS METHOHEXITAL AS …

Indriani Wang, Pharm.D.-PGY1
University of Southern California (USC)
USC University Hospital, Los Angeles, CA
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Contemporary guidelines for ECT specify a seizure duration of at least 25
seconds1,2 and an average of 9-12 total administrations2 to ensure adequate
treatment of depression
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However, many anesthesia agents used in ECT have anticonvulsant properties
and suppress the generation of seizure
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Moreover, individual seizure threshold varies which makes it more difficult for
some patients to experience seizures of adequate duration. The following
factors can increase seizure threshold3:
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Age
Skull bone thickness
Bilateral stimulation
Repeated ECT
Drugs (benzodiazepines, barbiturates)
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1. Fredman CP, et al. ECT Handbook 1995
2. American Psychiatric Association Task Force on ECT.
Washington DC: APA 2001
3. Wagner KJ et al. CNS Drugs 2005;19(9):745-758
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Methohexital has been the standard anesthesia used for ECT but
may not always be available from various suppliers
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Propofol is more readily available and already used for other
multiple indications within the hospital (e.g. used for sedation in ICU
settings)
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However, propofol has been shown in studies to produce seizures
of shorter duration in comparison to methohexital1,2,3,4
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1.
2.
3.
4.
The duration of seizures, as measured clinically, was reduced with propofol (17.9
+ 2.5s) in comparison with methohexital (30.9s +2.8s) (p<0.001) in fifteen
patients studied during the course of six ECT administrations1
Its place as an anesthesia agent in ECT is still yet to be determined
Rampton AJ et al. Anesthesiology 1989; 70:412-417
Malsch E et al. Convulsive Therapy 1994; 10(3):212-219
Fredman B et al. Anesth Analog 1994;79:75-79
Simpson KH et al. Br J Anaesth 1987;59:1323-1324
General Question: Will propofol pose greater barriers in achieving a
seizure of adequate duration (> 25 seconds)?
Question 1: Will maximum machine
settings be reached faster with
propofol?
(ECT devices are regulated by the FDA
and are limited to 576 mC)
Question 2: Will the use of
propofol require more seizure
augmenting interventions during
ECT compared to methohexital?
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Retrospective chart review of all depressed patients (n=84) meeting DSMIV criteria for recurrent unipolar or bipolar depression from March 1999 to
September 2008 treated with ECT (776 total treatments)
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Patients received at least six consecutive bilateral ECT via empirical
stimulus titration method
Inclusion
Exclusion
All charts meeting DSM-IV criteria for
recurrent unipolar or bipolar depression
Charts of patients with other diagnosis (e.g.
schizophrenia, bipolar mania)
Patients receiving at least six
consecutive bilateral ECT
Patients who received less than six
treatments
Question 1:
Will maximum machine settings be
reached faster with propofol?
(ECT devices are regulated by the FDA and
are limited to 576 mC)
Question 2:
Will the use of propofol require
more seizure augmenting
interventions during ECT compared
to methohexital?
1. Number of patients who reached
maximum machine settings during
the first six treatments
1. Number of patients who require
caffeine (seizure augmenting
agent)
2. Cumulative total ECT charge (in
mC) exposure across all
treatments (measured as Area
Under the Curve- AUC)
2. Number of patients who require
anesthesia dose lowering due to
short or missed seizure
3. Number of patients who require
ECT re-stimulation due to short or
missed seizure
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Baseline characteristics:
 Independent samples two-tailed t-tests
 Chi-square
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Question #1:
 Patients who reached maximum machine settings during the first
six treatments (Chi-Square)
 Cumulative total ECT charge measured across treatments
(Wilcoxon-Mann-Whitney test)
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Question #2 (Chi-Square):
 Patients who used seizure lowering agent (caffeine)
 Patients who needed re-stimulation with higher ECT stimulus
charge
 Patients who needed their anesthesia dose lowered
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Statistical significance defined at p<0.05
Propofol
Methohexital
P-value
40
44
---
17 (42.5%)
23(52.27%)
0.3704
1 (2.5%)
1 (2.27%)
1.0000
Mean Age ±SD, years
53.2 + 15
54.9 + 15.3
0.7258
Average Weight, lbs
(mean±SD)
175.9 + 44.3
171.4 + 46.9
0.5971
32 (80%)
8 (20%)
39 (88.6%)
5 (11.4%)
0.3683
Number of patients
(N=84)
Male Gender
Number (%)
African American Race
Number (%)
Primary Diagnosis
Number (%)
MDD
Bipolar Depressed
Number of patients who
reached maximum settings
during first 6 treatments
Number (%)
Propofol (N=40)
Methohexital (N=44)
P-value
21 (52.5%)
10 (22.7%)
0.0047
Total Charge (mC)
N=40, 44
Total Treatments
*Not significant at P<.05
Propofol (N=40)
Methohexital (N=44)
P-value
Number of treatments
(Range)
9.5 + 2.3
(6-13)
9.0 + 2.7
(6-16)
0.2303
Range of total charge in
millicoulombs (mC)
112-576
64-576
---
Patients who needed to
use caffeine
14 (35%)
2 (4.5%)
0.0005
26 (65%)
24 (54.6%)
0.3296
34 (85%)
16 (36%)
<0.0001
Number (%)
Patients re-stimulated at
higher stimulus charge
Number (%)
Patients who needed
lowering of anesthesia
Dose- Number (%)
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This study supports current literature stating
propofol use in ECT results in shorter seizure
duration as demonstrated by:
 Significantly higher administration of seizure
augmenting interventions among patients using
propofol versus methohexital
 Greater number of patients who reached maximum
machine settings during the first six treatments in the
propofol group
 Higher total stimulus charge is cumulatively needed
for seizure induction with propofol
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Data supports propofol having anticonvulsant effects which
have clinical implications for ECT clinicians who are aiming
for at least 25 seconds of seizure duration
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However, some proponents for propofol use in ECT argue:
 Seizure quality measures (Postictal Suppression Index and Mean
Integrated Amplitude) may be superior with propofol and efficacy of
ECT is proven equal between the two anesthetic agents despite
lower seizure duration with propofol 1
 Side effects profile of propofol is better in comparison to methohexital
(better hemodynamic stability, less nausea, and earlier return of
cognitive function after ECT) 2
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Potential future studies: prospective clinical outcome study
to compare efficacy and side effect profile of each drug
1. Geretsegger C et al. J of ECT 2007; 23(4):239-243
2. Fredman B et al. Anesth Analog 1994;79:75-79
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Not a prospective, randomized, controlled study
 However, selection bias was minimized as
demonstrated by similar patient demographics
 ECT administered by the same anesthesiologist and
psychiatrist for a large majority of treatments
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Did not assess clinical outcomes
 Efficacy of ECT using propofol versus methohexital as
anesthesia
 Side effect profile of propofol versus methohexital
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Erin D. Knox, Pharm.D
Mimi Lou, MS
Kathleen A. Johnson, Pharm.D, M.P.H,Ph.D.
Tien Ng, Pharm.D, BCPS
Julie Dopheide, Pharm.D, BCPP
Carlos Figueroa, MD
Anoush Afrasiabi, MD
Chris Linton, RN
Augmentation Strategies
Problem(s)
Addition of caffeine or theophylline
-have not been demonstrated to
directly improve treatment outcome
-cannot use in certain population of
patients (e.g. hypertensive)
Re-stimulation at higher stimulus
intensity of ECT
-higher stimulus charge may be
associated with greater side effects
-May reach maximum settings
sooner
Lowering the dose of anesthetic
agent
-often accompanied by restimulation
PROPOFOL
METHOHEXITAL
Class
Anesthesia
Oxybarbiturate
Onset
Few seconds
Few minutes
T1/2
1-8 minutes (shortest half-life
among all hypnotic agents)
5-9 minutes
Place in
Therapy
Have been demonstrated to
show improved hemodynamic
stability, earlier return of
cognitive function after ECT, less
nausea & vomiting (1)
Considered gold standard of preECT anesthetic agent for over 40
years by the American
Psychiatric Association (APA)
Agent
Dose
Succinylcholine
~1 mg/kg
Propofol or
Methohexital
Range: 1-2 mg/kg
Range: 0.75-1 mg/kg
As Needed Medications:
Benzodiazepines
Diazepam 5-10 mg
Lorazepam 2mg
Midazolam 1-5 mg
Lidocaine
0.5- 1 mg/kg
Anti-nausea agents
Metoclopramide 10 mg
Ondansetron
Blood pressure medication
Hydralazine
Caffeine
200-600 mg
Propofol
20 mL- $1.64
100 mL- $7.74
Methohexital
50mL (500mg)- $35.60
20mL (2.5 gm)- $150.47
Propofol
Methohexital
P-value
Use at least one
time bzd (total:
59)
31 (77.5%)
28(63.6%)
Use of high ,
medium, and low
dose bzd
Med &High 1 (3.2%)
Med & High 15 (53.6%) <0.0001
Low only 30 (96.7%) Low only 13 (46.43%)
Low dose benzodiazepines: midazolam 1-4mg , lorazepam 1-2mg
Medium dose: midazolam 5mg, diazepam 5mg
High dose: diazepam 10mg
0.1651