Transcript Cocaine & Beta-Blockers - Division of Emergency Medicine

Cocaine & Beta-Blockers
Liza Halcomb, MD
Journal Club 1/17/2008
Cocaine Chest Pain
• Common presentation.
• Human cardiac catheterization studies have
shown cocaine to be a powerful coronary
vasoconstrictor.
• In the case described, there was concern
about ongoing tachycardia and hypertension
in face of myocardial ischemia.
Cocaine
• Causes HTN and tachycardia by inhibiting the
reuptake of NE and DA.
• Sympathetic activation – Running away from a
dinosaur:
– Dilated Pupils – alpha receptors activated
– Tachycardia – beta receptors activated
– Hypertension – alpha receptors activated
– Diaphoresis – sympathetic cholinergic
Cocaine
• Lange et al. showed that cocaine induced
coronary artery vasospasm in the cath lab.1
• Also has type Ia sodium channel blocking
effects, can lead to arrhythmias.
• Accelerates CAD by increasing platelet
aggregation and plaque formation.
• What about MI?
Cocaine and MI
• Hollander et al. showed that patients with
cocaine related CP had a low incidence of MI.2
– 5%
• On follow up of 203 patients over 408 days
after visit for cocaine related CP, only 2 nonfatal MIs were reported in patients who
continued to use cocaine.3
Cocaine Chest Pain
Unlikely to have significant mortality
or morbidity.
Cocaine + UDS
• Urine remains + for 3
days after use.
• Tests for
benzylecognine, a
metabolite.
• Exceedingly
uncommon to have a
false + result.
Beta- Blockers
• Used in ED to treat tachycardia associated
with possible ACS.
• Do not acutely lower BP.
• Block both Beta 1 and Beta 2 receptors.
– In asthmatics can cause bronchospasm
– In pheochromcytoma can cause unopposed alpha
Beta Blockers & AMI
• Post-MI beta blocker vs. placebo to prevent six-month total
mortality for different risk groups:
• Low risk (no PVC’s and no clinical CHF)
NNT = 242
• Medium risk (1-10 PVC’s and no CHF)
NNT = 217
• High risk (1-10 PVC’s and CHF)
NNT = 44
• Very High risk (> 10 PVC’s and CHF)
NNT = 30
• For NNH, using the high-risk subset from the COMMIT trial
– OR = 1.42 and Control Event Rate = 15.7%
– NNH = 19
Beta Blockers
WHAT IS UNOPPOSED ALPHA
ACTIVATION?
WHY DON’T PEOPLE WHO TAKE BETABLOCKERS GET ORTHOSTATIC
HYPOTENSION?
Beta Blockers
• Beta 2 receptors are located on the
vasculature to the skeletal muscle.
• No orthostatic hypotension because these
vessels constrict when beta-blockers are
administered.
• In the presence of alpha activation, betablockade can exacerbate HTN.
Beta Blockers and AMI
• Proven mortality benefit in the setting of MI
• Adopted into quality of care guidelines
• However, little data on administration in the
1st 12-24 hours of symptoms.
• COMMIT trial suggests that early
administration decreases arrhythmias,
however benefit offset by increase in
cardiogenic shock.4
Cocaine and Beta Blockers
• Propanolol was routinely used in treatment of
cocaine intoxication in the 1970s
• Catravas conducted a lethality study in dogs –
all cocaine intoxicated dogs that got
propanolol died.5
– All animals that got diazepam survived.
• Led to removal of beta-blockers as 1st line
treatment for cocaine intoxication.
Now we’re back to square 1
Article #1
• Retrospective review of 348 admissions to
telemetry and ICU with + UDS for cocaine.6
• 60 people got beta-blockers.
• Multivariate analysis showed decrease risk of
MI in patients who got beta-blockers (1.7% vs.
4.5%)
Article #1
• Lots of fancy stats!
• Parsimonious multivariate generalized
estimating equations.
• Covariates considered for inclusion were those
with a P< 0.25 on bivariate analysis.
• Propensity scores to address non-randomized
administration of beta-blockers.
Remember with statistics…..
Article #1 Problems
• < 50% of patients presented with CP
(165/348).
• ~ 30% of the patients who presented with CP
had an MI. (51/165)
– “Beta-blocker use was of borderline significance in
reducing the risk of a myocardial infarction (OR
0.05; 95% CI 0.00-2.08)”
• + UDS cutoff level may remain + for up to 2
weeks in chronic users.
Article #1
Look at the mortality table and tell
me which of those patients should
get beta-blockers
Article #2
• Prospective study in 15 patients undergoing
cardiac catheteriztation.7
• All got low dose of intranasal cocaine (1/2 of
that used for intranasal anesthesia for ENT)
• 6 got saline.
• 9 got labetalol.
• Conclusion: Labetalol reduces MAP, but not
coronary vasoconstriction.
Article #2
• Look at Table #1
• Trend to increased vasoconstriction although
this is not statistically significant.
• Conclusion: Not much of a benefit if coronary
artery diameter does decrease in size.
Article #3
• Prospective study of 7 patients all under 50
years of age.8
• All had recent cocaine use or + UDS.
• Got 0.5 mg/kg esmolol followed by infusion of
0.05 mg/kg/min
• Outcome: 3 patients had “good” outcome, 3
patients “failed”, 1 patient “equivocal”.
• Conclusion: Cannot recommend routine use of
esmolol.
Beta blockers in Cocaine users
200
150
100
50
BP
Be
fo
re
BP
Af
te
r
0
Article #4
• Randomized double-blind placebo controlled
prospective study of 30 patients.9
• 15 got intranasal saline, 15 got intranasal
cocaine.
• 5/15 in saline group got propanolol
• 15/15 in cocaine group got propanolol
Article #4
• Cocaine decreased coronary-sinus blood flow
from 139 to 120 ml per minute.
• Propranolol further decreased coronary-sinus
blood flow to 100 ml per minute.
• Coronary vascular resistance rose from a baseline value of 0.87 mm Hg /ml/min to 1.05 mm
Hg/ml/min after cocaine and 1.20 mm
Hg/ml/min after propranolol.
Article #4
With propranolol one subject had
complete coronary-artery occlusion,
symptoms of myocardial ischemia, and
electrocardiographic changes.
Evidence Based Medicine + Toxicology
• Very difficult, unable to conduct randomized
controlled trial where half the study group is
poisoned and half not.
• How to decide what is best?
– Physiologic principles
– Pharmacologic principles
– Animal studies
– Case reports
– Human studies
Cocaine and Beta Blockers
• Physiologic principles suggest that it is
contraindicated.
• Pharmacologic principles suggest that it is
contraindicated.
• Animal studies suggest that it is contraindicated.
• Case reports suggest that it is contraindicated.
• Randomized trials in humans suggest that it is
contraindicated.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
Lange RA, Cigarroa RG, Yancy CW Jr, et al. Cocaine-induced coronary-artery vasoconstriction. N Engl J
Med 1989;321:1557-1562.
Hollander JE, Hoffman RS, Gennis P, et al. Prospective multicenter evaluation of cocaine associated
chest pain (COCHPA) study group. Acad Emerg Med. 1994;1:330-339.
Hollander JE, Hoffman RS, Gennis P, et al. Cocaine associated chest pain: one year follow up. Acad
Emerg Med 1995;2:179-84.
Chen ZM, Pan HC, Chen YP, et al. COMMIT (ClOpidogrel and metoprolol in myocardial infarction trial)
collaborative group. Early intravenous then oral metoprolol in45,852 patients with acute myocardial
infarction: randomised placebo-controlled trial. Lancet. 2005;366;1622-1632.
Catravas JD, Waters IW. Acute cocaine intoxication in the conscious dog: studies on the mechanism of
lethality. J Pharmacol Exp Ther. 1981;217:350-356.
Dattilo PB, Hailpern SM, Fearon K, etal. B-blockers are associated with reduced risk of myocardial
infarction after cocaine use. Ann Emerg Med. 2007, IN press.
Boehrer JD et al. Influence of Labetolol on Cocaine-Induced Coronary Vasoconstriction in Humans. Am
J Med 1993;94:608-610
Sand IC, Brody SL, Wrenn KD, Slovis CM. Experience with esmolol for the treatment of cocaineassociated cardiovascular complications. Am J Emerg Med 1991;9:161-163.
Lange RA, Cigarroa RG, Flores ED, et al. Potentiation of cocaine-induced coronary vasoconstriction by
beta-adrenergic blockade. Ann Intern Med 1990;112:897-903.