INTERPRETATION OF POST- MORTEM STIMULANT LABORATORY DETERMINATIONS. Routinely Detected Stimulants. Stimulant Toxicity

Interpreting Postmortem Stimulant Data ACMT Washington May2011 INTERPRETATION OF POSTMORTEM STIMULANT LABORATORY DETERMINATIONS Barry K Logan PhD, D...
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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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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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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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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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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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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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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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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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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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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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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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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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