1. Unexplained Sudden Death in Drug Abusers Blake Hutchinson, MS-4 Faculty Representative Gregory Davis, MD Department of Pathology

2. Key Points Cocaine causes deleterious effects on the heart Clinical toxicity from cocaine use does not correlate with blood or urine levels Even in the absence of acute cocaine intoxication, abusers are at higher risk for sudden death

3. Cocaine Cardiovascular Toxicity Coronary Artery Disease Coronary artery spasm 10% decrease in vessel caliber Preexisting coronary disease Accelerated atherosclerosis Supported by lab studies

4. Cocaine Cardiovascular Toxicity Coronary Artery Disease Coronary artery dissection Left anterior descending Hematoma compresses true lumen Intimal proliferation Resembles chronic rejection Entire length of vessel; angiography

5. Cocaine Cardiovascular Toxicity Myocardial Hypertrophy Clinical and autopsy studies ECG Heart weights Mechanism Cocaine induced hypertension Direct oxidant effect Direct oxidant effect

6. Cocaine Cardiovascular Toxicity Myocardial Hypertrophy Angiogenesis lags hypertrophy Underperfusion and ischemia Ischemia disrupts repolarization Reentry arrhythmias

7. Cocaine Cardiovascular Toxicity Catecholamine Toxicity Norepinephrine “myocarditis” Microfocal fibrosis Contraction band necrosis Result Favors reentry arrhythmias

9. Cocaine Cardiovascular Toxicity Microvascular disease Microangiopathy Cocaine induced apoptosis Thickening of small intramyocardial arteries Treatment implications Therapeutic anti-apoptotic drugs

10. Cocaine Cardiovascular Toxicity QT abnormalites QT interval dispersion QT in max lead – QT in min lead Increased dispersion increases chance of SCD Increased QTd in cocaine users occurs in absence of hypertrophy

11. Cocaine Cardiovascular Toxicity QT abnormalities Torsade de pointes Cocaine modulates ion channels Cocaine induced LQTS increases TdP risk Greater risk in partially expressed congenital LQTS and drug induced LQTS

12. Cocaine Clinical Toxicity Dose- response relationship Hypothesis: The severity of symptoms in patients presenting to an ED do not correlate with either blood cocaine or metabolite concentrations Blood cocaine and metabolite concentrations, and outcome of patients presenting to an ED. Blaho, et al. Am J Emerg Med 2000.

13. Cocaine Clinical Toxicity Dose- response relationship Methods Stimulant Intoxication Scale HR, BP, Orientation, MS, Temp Cocaine equivalents Sum of cocaine and metabolite concentration (mM)

14. Cocaine Clinical Toxicity Dose- response relationship Stimulant Intoxication Scale Admitted7.9 +/- 3.5 Discharged5.3 +/- 2.2 Significant difference (P = 0.008)

15. Cocaine Clinical Toxicity Dose- response relationship Blood cocaine levels Admitted0.33 +/- 0.64 Discharged0.29 +/- 0.50 No significant difference

16. Cocaine Clinical Toxicity Dose- response relationship Stimulant Intoxication Scale Survivor5.7+/- 2.5 Decedent12

17. Cocaine Clinical Toxicity Dose- response relationship Blood cocaine concentration Survivor0.27 +/- 0.51 Decedent0.20 +/- 0.25 No significant difference

18. Cocaine Clinical Toxicity Dose- response relationship Summary Neither cocaine nor metabolite concentrations were different among patients who were admitted vs discharged or who lived vs died No statistical correlation was noted between cocaine and metabolite blood concentration and SIS (r = 0.120)

19. Myocardial Ischemia In absence of Cocaine Hypothesis: Cocaine abusers have increased prevalence of myocardial ischemia even in the absence of cocaine on urine drug screen Myocardial Ischemia during Cocaine Withdrawal. Nademanee, et al. Annals of Internal Medicine. 1989.

20. Myocardial Ischemia In absence of Cocaine Methods Patient population Male chronic cocaine abusers No history of heart disease Study Protocol Urine drug screen, Holter monitor, Treadmill

21. Myocardial Ischemia In absence of Cocaine Cocaine Abusers Normal Volunteers Total ST Changes 819 No ST changes 134154 Total2142

22. Myocardial Ischemia In absence of Cocaine Cocaine abusers were at higher risk for ST changes than healthy volunteers (P = 0.0004, RR = 16) despite the absence of cocaine from the body and negative treadmill tests Mechanism for these changes remains unknown but coronary vasospasm is suspected

23. Unexplained Sudden Death Absence of established pathology Hypothesis: Deaths where neither toxicological or anatomical cause is found at autopsy share a common history of drug abuse Unexplained Sudden Death and the Likelihood of Drug Abuse. Gruszecki et al. J Forensic Sci 2005.

24. Unexplained Sudden Death Absence of established pathology Methods Retrospective case-control study Control group killed in MVC Study group undetermined death Matched for age and date of death Social trends Toxicological methods

25. Unexplained Sudden Death Absence of established pathology Methods All patients were evaluated for compelling evidence of drug abuse Decedents lacked sufficient disease to explain death, including autopsy and toxicological findings

26. Unexplained Sudden Death Absence of established pathology History of drug abuse Study group17 Control group1

27. Unexplained Sudden Death Absence of established pathology Evidence of drug abuse Study group21 Control group5 Significant difference (P = 0.0017)

28. Unexplained Sudden Death Absence of established pathology Decedents in study group were 4.2 times (95% CI 1.6 – 11.1) more likely to have evidence of drug abuse than the control group A history of drug abuse was also present in a statistically disproportionate number of study group cases

29. Conclusions Evidence indicates that blood and urine concentrations of cocaine and cocaine metabolites do not correlate with severity of clinical symptoms or clinical outcomes Evidence indicates that blood and urine concentrations of cocaine and cocaine metabolites do not correlate with severity of clinical symptoms or clinical outcomes Evidence indicates that, in cases of unexplained sudden death, cocaine use plays a major role despite the lack of acute intoxication with cocaine Evidence indicates that, in cases of unexplained sudden death, cocaine use plays a major role despite the lack of acute intoxication with cocaine

30. Conclusions Evidence suggests that cocaine use induces chronic biochemical and physiologic changes that persist beyond the presence of cocaine in the blood Evidence suggests that cocaine use induces chronic biochemical and physiologic changes that persist beyond the presence of cocaine in the blood Evidence suggests that these changes increase the likelihood of sudden death; further research will better characterize these changes Evidence suggests that these changes increase the likelihood of sudden death; further research will better characterize these changes

31. References 1. Gruszecki A, McGwin G, Robinson C, Davis G. Unexplained Sudden Death and the Likelihood of Drug Abuse 2.Karch, SB: Cocaine cardiovascular toxicity. The Southern Medical Journal 2005; 98; 794-799 3. Nademanee K, Gorelick DA, Josephson MA, Ryan MA, Wilkins JN, Robertson HA, Mody FV, Intarachot V. Myocardial ischemia during cocaine withdrawal. Ann Intern Med 1989;111:876–80. 4. Blaho K, Logan B, Winbery S, Park L, Schwilke E. Blood cocaine and metabolite concentrations, clinical findings, and outcome of patients presenting to an ED. Am J Emerg Med 2000;18:593–8. 5. Stephens B, Jentzen J, Karch S, Mash D, Wetli C. Criteria for the Interpretation of Cocaine Levels in Human Biological Samples and Their Relation to the Cause of Death. Am J Forensic Med Pathol 2004;25:1-10