Interpreting Postmortem Stimulant Data
ACMT Washington May2011
INTERPRETATION OF POSTMORTEM STIMULANT LABORATORY DETERMINATIONS Barry K Logan PhD, DABFT Director, Forensic Services NMS Labs Willow Grove PA
Routinely Detected Stimulants • Immunoassay • Amphetamine class • Cocaine (as benzoylecgonine) • Methoxy-substituted (inconsistent)
• Chromatography • All above • Cathinones • Benzylpiperazines
Stimulant Toxicity • Acute • Tachycardia • Arrhythmia • Hypertension • Aneurysm • Aortic dissection
• Impairment • Excited Delirium
• Chronic • Contraction band necrosis
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Interpreting Postmortem Stimulant Data
ACMT Washington May2011
Analytes • Cocaine • • • •
Cocaine Benzoylecgonine Ecgonine methyl ester Cocaethylene
• Methamphetamine • Methamphetamine • Amphetamine
Postmortem Redistribution
J Anal Toxicol. 2003 Nov-Dec;27(8):533-44. Mechanisms underlying postmortem redistribution of drugs: a review. Pelissier-Alicot AL, Gaulier JM, Champsaur P, Marquet P. …The underlying mechanisms are complex and of different types. Passive drug release from drug reservoirs such as the gastrointestinal tract, liver, lungs, and myocardium may occur immediately after death and, later on, cell autolysis and the putrefactive process participate in redistribution. There is evidence that basic lipophilic drugs with a large distribution volume are particularly susceptible to PMR.
Postmortem Redistribution
Sources of postmortem redistribution: Redistribution GI
from drug reservoirs:
tract
The
Lungs
Myocardium Body
Fat
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Interpreting Postmortem Stimulant Data
ACMT Washington May2011
Postmortem Redistribution
Redistribution from drug reservoirs From the Lungs to the Heart and Aorta
RV LV
RA
LHL
RHL LA RLL
AO
LLL
Pellisier-Alicot et al.
Postmortem Redistribution
From the Lungs to the Heart, and Aorta: Receive
entire blood flux from right ventricle accumulate drugs with high PKa and Vd (TCA’s, methadone, chlorpromazine). More intense than redistribution from GI tract Role of pericardial fluid Lungs
From the Lungs to the Liver Across
the diaphragm and solvents)
(Amitriptyline
Postmortem Redistribution
Redistribution from drug reservoirs RV LV
RA
LHL
RHL
From the Myocardium into the chambers of the Heart
LA RLL
AO
LLL
Pellisier-Alicot et al.
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Interpreting Postmortem Stimulant Data
ACMT Washington May2011
Postmortem Redistribution
From the Myocardium to the Heart: Some
drugs are concentrated in the myocardium (esp. High Vd, Ca++ channel blockers).
Minor mechanism for most other drugs
Increase also demonstrated in SCV blood
Comparison of L and R heart blood
Cocaine
Cocaine Metabolism
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Interpreting Postmortem Stimulant Data
1. Plasma PChE Liver benzoylesterase 2. Chemical hydrolysis Liver methylesterase 3. Liver methylesterase Ethyl alcohol
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3.5 x faster than 2 COCAINE
1.
2.
ECGONINE METHYL ESTER
3.
BENZOYLECGONINE
ECGONINE
ETHYLCOCAINE
ECGONINE ETHYL ESTER
Cocaine - PMR
Site-dependent postmortem changes in blood cocaine concentrations Hearn et al., J For Sci 1991;36(3):637-684 Seven cocaine related deaths; some time series data collected. Dramatic changes in cocaine concentrations. Magnitude and direction of changes appears to be site dependent. Generally decreases observed in subclavian vein; increases in heart, femoral vein and aorta. Potential for change greatest in heart blood.
Cocaine - PMR
Lack of predictable site-dependent differences and time-dependent changes in postmortem concentrations of cocaine, benzoylecgonine, and cocaethylene in humans. Logan et al., J For Sci 1997;20(1):30 On receipt at Medical Examiners Office specimens of left ventricular blood, femoral blood and cisternal cerebrospinal fluid were collected. At the time of autopsy, specimens of left ventricular blood, femoral blood and cisternal cerebrospinal fluid were collected, together with iIiac blood.
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Interpreting Postmortem Stimulant Data
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Cocaine - PMR
Logan et al., J For Sci 1997;20(1):30
Cocaine - PMR
Logan et al., J For Sci 1997;20(1):30
Cocaine - PMR
Logan et al., J For Sci 1997;20(1):30
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Interpreting Postmortem Stimulant Data
ACMT Washington May2011
Cocaine - PMR
Logan et al., J For Sci 1997;20(1):30
Cocaine - PMR
Competing processes of release and hydrolysis result in the potential for significant but unpredictable changes in cocaine, benzoylecgonine and cocaethylene concentrations. Complete loss of all markers for cocaine use, over times up to 222 hours, appear unlikely based on this study. The application of strict ranges for therapeutic, toxic and fatal ranges for cocaine related deaths is not appropriate. Pathologists and toxicologists need to be wary of overinterpreting quantitative postmortem concentrations of cocaine and it’s metabolites. Logan et al., J For Sci 1997;20(1):30
Cocaine - Toxicity Interpreting blood cocaine concentrations Therapeutic
Toxic
Fatal
Winek
0.05 – 0.31
0.90
1.00 – 20.00
Baselt
0.01 – 0.93
0.00 – 5.20
0.00 – 26.00
Stead & Moffat Garriott
0.12 – 0.30
0.25 – 5.00
>0.90
0.90
0.00 – 7.6
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Interpreting Postmortem Stimulant Data
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Cocaine – Clinical Toxicity Blood cocaine and metabolite concentrations, clinical findings, and outcome of patients presenting to an ED. Logan et al., J For Sci 1997;20(1):30 Concentrations (mg/L) Cocaine
0.00 – 1.72
Benzoylecgonine
0.09 – 5.86
Ecgonine Methyl Ester
0.00 – 1.31
Ecgonine
0.08 – 1.67
Norcocaine
0.00 – 0.29
Cocaethylene
0.00 – 0.10
Cocaine – Clinical Toxicity Concentrations (mg/L) Living Subjects Drivers arrested for DUI ER Patients Deceased Subjects
Homicide Victims Suspected drug overdose
0.00 – 2.31 (median 0.09) 0.00 – 1.74 (median 0.09) 0.00 – 1.20 (median 0.17) 0.00 – 84 (median 0.30)
Excited Delirium
Syndrome associated with hyperthermia, delirium, agitation, cardiorespiratory arrest, and sudden death
DAT upregulation not observed in these subjects Results in excessive DA in synapse
Downregulation of DA-2 receptors in hypothalamus
Individuals with high BMI (kg/m2) are at greatest risk as heat is generated through skeletal muscle activity Upregulation of kappa-2 opiate receptors observed in amygdala with excited delirium but not in other users
amygdala thought to mediate emotional and autonomic behavior
kappa-2 responsible for psychosis in PCP intoxication
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Interpreting Postmortem Stimulant Data
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Cocaine and Driving The Role of Cocaine in Fatal Crashes: First Results of the Quebec Drug Study. Dussault, Brault, et al., Annu Proc Assoc Adv Automot Med. 45:125-37 (2001) 265 fatally injured drivers, case controlled Cocaine in 7.9% of fatally injured drivers. Cocaine in 1.1% of 5,931 controls* *49.6% provided a urine sample.
Popular combinations: Cocaine with alcohol and/or cannabis
Amphetamines
Patterns of Use
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Interpreting Postmortem Stimulant Data
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Stimulants and Impairment Type
Mean (mg/L)
Range (mg/L)
Heishman, 1998 (amphetamine)
Lab
0.043
-
Silber, 2005
Lab
0.06-0.07
-
Jones, 2005 (i) (amphetamines)
DUI
0.93
0.03 – 2.3
Jones, 2005 (ii) (amphetamines)
DUI
0.89
0.03 – 8.69
Jones, 2008 (methamphetamine)
DUI
0.34
0.01 – 3.7
Gustavsen et al, 2005
DUI
0.52
0.04 – 3.74
Senna et al, 2010
DUID
0.18
0.02 – 1.37
Logan et al, 1996
DUI
0.55
0.01 – 9.46
1159 DUI cases
DUI
0.31
0.05 – 9.46
101 DRE cases
DRE
0.36
0.05 – 2.36
Methamphetamine - PMR Site dependence of methamphetamine concentrations in blood samples collected from cadavers of people who had been methamphetamine abusers. Miyazaki T, Kojima T, Yashiki M, Wakamoto H, Iwasaki Y, Taniguchi T. Case #
Left Heart/ PV
Left Heart/ Cavity
Right heart/ IVC
Right Heart/ Cavity
Femoral
4 5
15.8
-
7.07
-
3.96
3.32
1.76
1.05
-
0.78
6
12.6
7.54
5.76
6.88
5.27
7
17.3
8.33
6.55
6.52
5.61
Miyazaki et al, 1993, Am J For Med Path 14(2), 121-4
Methamphetamine and PMR
Miyazaki, 1993; Barnhart, 1999; Moriya and Hashimoto, 2000
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Interpreting Postmortem Stimulant Data
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Methamphetamine and Death Methamphetamine Caused Death: Death resulting from or directly precipitated by the use of the drug. Methamphetamine Related Death: Death in which the drug was present in the subjects blood and played a contributary role in their death. Natural Death: Death from natural causes where the presence of the drug played no significant role. Logan BK, Fligner CL, Haddix T. Cause and manner of death in fatalities involving methamphetamine. J Forensic Sci. 1998 Jan;43(1):28-34.
Methamphetamine and Death Methamphetamine Caused and Related Deaths
Manner of Death
Drug Caused
Drug Related
Traffic
0
20 (0.05 - 2.60)
Other
22 (0.05 - 68.90)
18 (0.05 - 1.64)
Accident
Suicide
3 (0.20 - 36.70)
14 (0.10 – 6.50)
1 (0.46)
40 (0.03 - 9.30)
16 (0.10 - 24.20)
3 (0.10 - 3.40)
42
95
Homicide Undetermined Total
Logan BK et al, 1998
Methamphetamine and Death Methamphetamine Caused and Related Deaths (n=161) Manner of Death Accident
Total % 40%
Traffic
14%
Other
26%
Suicide
15%
Homicide
30%
Undetermined
14%
Total
100% Logan BK et al, 1998
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Interpreting Postmortem Stimulant Data
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Methamphetamine and Death Sex
Age
Conc. (mg/ L)
Cause of death
F
41
0.09
ASCVD
M
39
0.10
MI dt CAD & ASCVD, Alc. & Hepatitis
F
-
0.10
ASHD
M
44
0.20
ASCVD
M
63
0.32
Multiple organ failure w/lactic-acidosis dt end stage liver disease. Sudden Cardiac Arrest dt Hypertrophic Myocardiopathy
F
47
0.40
M
37
0.40
ASCVD
M
44
0.41
Malignant melanoma w/brain metastasis
M
59
0.47
MI dt thrombosis of arterial ascending aorta; severe CAD
M
-
0.60
Probable Cerebral or MI
M
40
1.6
Probable MI
Methamphetamine and Death
Deaths were attributed to methamphetamine alone with concentrations as low as 0.09mg/L in the absence of any other risk factors. (median 0.96mg/ L, n=13). In the presence of other drugs, median concentrations were lower, (0.37mg/L, n=25) In patients with cardiac risk factors, median concentrations were also lower (0.36mg/L, n=14). Logan et al, J Forens Sci, 1998;43(1):26-32
Behavioral Toxicity Aggression and violence associated with substance abuse. Miller et al. J Chem Dep Treatment 1989;3(1):1-36 Substance abuse related violent acts are a combination of the physiological effects of the drug, the underlying personality of the user, and the social setting that favors or disfavors aggression.
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Interpreting Postmortem Stimulant Data
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Behavioral Toxicity
Ellenwood. Amer J Psychiat 1971;127(9):90-95 Describes thirteen cases of murders committed by subjects using amphetamines. Murders appear related to amphetamine induced paranoid thinking/delusions, panic, emotional lability, lowered impulse control, triggered by a specific situation leading to violence “…there are many cases where murder or mayhem are avoided by the slimmest of margins”.
Behavioral Toxicity Violence and illegal drug use among adolescents: Evidence from the US National Adolescent Student Health Survey. Kingery et al.
Int J Addictions 1992;27(12):1445-1464
Notes an established association between use of PCP, ethanol, amphetamines and cocaine, and violent acts. Drug users fight more, and take more risks that predispose them to assault.
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