Beruflich Dokumente
Kultur Dokumente
DR A J JEFFERY
MBChB MD FRCPath (Forensic) MFFLM
Areas to Cover
Why take toxicology
What samples
How to take them
What does the toxicologist do with the samples?
How to interpret the results general considerations
Alcohol
Drugs of abuse
Toxicology in other causes of death
Other specimens
Case examples
WHY TAKE
TOXICOLOGY
?
Eg epilepsy / antidepressants
WHAT SAMPLES
ARE
APPROPRIATE
?
Samples
Blood
Blood
Urine
Urine
(plain) (peripheral)
(preserved) (peripheral)
(plain)
(preserved)
Fluoride inhibits further alcohol production but wont undo the damage
already done.
Vitreous
Stomach Contents
Tissues
Liver
(mid R lobe)
Skeletal muscle
(eg psoas) (if embalmed buttock)
OBTAINING
THE
BLOOD SAMPLE
below
Routine = clean catch
Ideal = dont milk the leg
Routine = required to gain sufficient sample
Problem:
MINIMAL FEMORAL BLOOD
OBTAINING
THE
URINE SAMPLE
Urine Sampling
Needle and syringe
or
Open dome of bladder and aspirate with syringe
alone
Presence of a catheter may be important
Vitreous
WHAT DO THE
TOXICOLOGISTS
DO WITH THE SAMPLE
?
Analysis
Screening (GC / Immunoassay)
Confirmation (GCMS)
Quantification
HOW TO
INTERPRET
THE RESULTS
General Considerations
Accuracy of reference ranges
Re-distribution site matters!
Individual variation (e.g. renal disease)
Decomposition
Tolerance
ranges
General Considerations
Re-distribution site matters!
Individual variation (renal disease)
Decomposition
Tolerance
Redistribution
Discovered with digoxin
Most drugs that undergo
redistribution do so
because of their relative
lipid solubility.
Due to
GI tract to adjacent
structures
Through conduits lymph
Diffusion from bladder
Natural Disease
Depends or route of administration
Absorption
Elimination / Clearance
Renal impairment
Liver impairment
Decomposition
Significant redistribution
Some drug levels increase
Others degrade
If there is a degree of decomposition make sure you
Tolerance
Increasing doses required over time to achieve same
effects.
What is lethal to a nave user may have no effect at all
in a chronic user.
Alcohol
Alcohol
Acute alcohol toxicity
Ketoacidosis
Alcohol in combination with
other drugs
Death respiratory
30 50 = deterioration in
generally considered
insignificant.
driving
50 100 = inhibitions /
laughter
100 150 = slurring,
insteadiness, poss nausea
150 200 = obvious
drunkenness, nausea staggering
200 300 = stupor, vomiting,
coma
300 + = stupor, coma,
aspiration &
e.g.
What is ketoacidosis?
Can you explain why this happens?
Ketoacidosis
Brain can utilise ketone bodies when glucose is unavailable fasting /
starvation
Ketone bodies, formed by the breakdown of fatty acids and the de-amination of
amino acids.
Ketoacidosis is an extreme and uncontrolled form of ketosis, which is a normal
Metabolic acidosis
Malnutrition
Binge drinking superimposed on chronic alcohol abuse
Ketoacidosis
Ketones:
<0.5 mg/100ml
<0.5 mmol/L
1.26 47.2 mmol/L (assoc with fatalities)
Causes
Alcoholic ketoacidosis
Diabetic ketoacidosis
Alcoholic vs Diabetic
How might you differentiate?
Urine glucose
HbA1c
4 - 6.1%
Calculations
AVOID !
Clearance
Widmark equation
Decomposition
70 190 mg/100ml reported as artefact
Consider pm findings
Look for other substances produced pm
Use vitreous and urine as supportive evidence
Urine : Blood
1.23 : 1
Vitreous : Blood
1 : 0.81
Drugs of Abuse
OPIOID AGONISTS
SYMPATHOMIMETICS
Opioid agonists
Opioid agonists
Respiratory depression
miosis
Findings
History / scene / paraphernalia
External
iv sites
Foam at nose / mouth
Morphine / Heroin
Heroin / diamorphine synthetic morphine
derivative
4
9
Therapeutic
Free morphine 10 100ng/ml
:
:
1
1
Lethal_______
50 4000 ng/ml
Heroin
A contaminate of street heroin is acetylcodeine
the drug
Sleepy / snoring
May have time to metabolise drug despite irreversible
respiratory depression
Methadone
Therapeutic
75 1100 ng/ml
Toxic
Lethal
Significant overlap
Methadone
Breakdown product EDDP
This is inactive
Titration is important
and 3x in
Opioids
Tolerance = V V important consideration
Free Codeine
Therapeutic
Lethal_______
30 340ng/ml
>1600 ng/ml
Sympathomimetics
Sympathomimetics
Adrenalin
Hypertension
Tachycardia
Mydriasis
Serotonin
Excitement
Hyperthermia
Stimulants
Cocaine
Amphetamine
Ecstasy
Other methamphetamines
Associated with subarchnoid haemorrhage
Intracerebral haemorrhage
Findings
Hearts of stimulant users tend to be heavier than
controls
Fibrosis
Contraction band necrosis
Accelerated atherosclerosis
Non specific pulmonary changes
Crack cocaine smokers prominent anthracosis esp
Cocaine
Naturally occurring plant alkaloid stimulant
Snorted, smoked, cutaneous, injected
Nb always consider in sudden death in the same way
Benzoylecgonine
Methylecgonine
Cocaethylene
Inactive
As active as cocaine itself & indicative of alcohol
consumption at the same time
Cocaine Toxicity
Less than 50 ng/ml cocaine is considered not to produce
>900 ng/ml
Lethal
>1000 ng/ml
Benzoylecgonine
Cocaine
But lethal nature not dose related
Long term effects:
Cardiovascular damage
Non cardiac -
at room temperature.
Hyperthermia
Mental & physiological arousal
Excited, erratic & sometimes bizarre, violent behaviour
May have florid psychosis
May exhibit extra-ordinary strength
Amphetamine
Prevalence second only to cannabis
Synthetic stimulant
Effects similar to cocaine
Stimulate release of catecholamines, particularly
adrenaline
Tolerance & dependence develop
Absorbed by GIT, clinical effects commence within
20 minutes, last 4-6 hours.
Amphetamine
Toxic
Lethal
Different Forms
Amphetamine (Benzedrine, uppers, 'A', speed, whizz, cranks,
Amphetamine
Alcohol can potentiate effects on the heart.
Rare toxic effects:
Coma
Cerebral vasculitis
Cerebral haemorrhage
Rhabdomyolysis
D.I.C.
Renal dysfunction
Cardiac long term users
Accelerated coronary atherosclerosis
Microvascular disease
MDMA / Ecstasy
Amphetamine-like drugs
3,4-methylenedioxymethamphetamine
Gamma hydroxybutyrate
Other
Benzodiazepines
Diazepam 20 4000 ng/ml
Cannabis
Cannabinoids
THC tetrahydrocannabinol
Delta 9 THC carboxylic acid
Blood up to ~ 5 days
Urine up to ~ 12-36 days
to the top.
Tie off whole lung and place within a nylon bag.
Head space
New Drugs
Mephadrone
Cream
Toxicology
IN
OTHER
CAUSES OF DEATH
Fire deaths
Carboxyhaemoglobin
Normal <10%
Toxic 15 35%
Lethal >48%
Cyanide
Carbon Monoxide
In an individual breathing air
T = 4 hours
Breathing O2 in Hospital
T = 60 minutes
Therapeutic Drugs
Anti-depressants
Anti-convulsants
Overdose
Aspirin
Therapeutic
Toxic
20 100mg/l
>150 mg/l
Lethal
>500 mg/l
330mg/L
T up to 36 hours in massive OD
Findings
Pm
Paracetamol
Therapeutic
Toxic
10 20 mg/l
>150 mg/l
Lethal
>160 mg/l
Immunology - Anaphylaxis
Secure ante-mortem samples
Needs to be peripheral as mast cell rich organs can
confirmatory evidence.
Normal Levels:
IgE
MCT
0 122 kU/L
2-14 mg/L
Biochemistry - Diabetes
Vitreous is best for biochem as most blood is already haemolysed
Glucose drops significantly after death
Bacterial metabolism
Drops even in vitreous
So low glucose hypoglycaemia
It is not possible to diagnose hypoglycaemia accurately at pm.
A high vitreous glucose virtually rules out hypoglycaemia as one can assume it was
the same or higher in the antemortem period unless peri-mortem dextrose admin
If endogenous the body has to cleave C peptide from pro-insulin to make active insulin.
If exogenous the insulin is already cleaved and so they will have no C peptide.
Case Examples
Case 1
60 yr old male, in house fire, extensive burns, no suspicious injuries, no
soot in airways or stomach.
Ranges
Norm
Tox
Leth
CO = 40%
<10%
15-35%
>50%
<0.1mg/L
Paracetamol
6mg/l
10-20mg/l
>150mg/l
>160mg/l
Codeine
56ng/ml
30-340ng/ml
>1600ng/ml
Morphine (free)
<5ng/ml
10-100ng/ml
50-4000ng/ml
Case 2
30 year old female found on floor with green fluid trailing
Ethanol
Blood
181 mg/100mls
Urine
244 mg/100ml
Ethylglucuronide present in urine
Acetone
negative
Methanol negative
Isopropanol negative
Ranges:
Methadone
75-1100ng/ml
413 ng/ml
EDDP = 276 ng/ml
Amphetamine
471 ng/ml
Diazepam
21 ng/ml
Nordiaz = 73ng/ml
Cause of Death??
Normal
Toxic
Lethal
200-2000ng/ml
400-2000ng/ml
>500ng/ml
20-4000ng/ml
20-1800ng/ml
>1000ng/ml
>5000ng/ml
>30 000ng/ml
Case 3
Chronic alcoholic found dead at home, head injury
Ethanol
16 mg/100mls
72 mg/100mls
25 mg/100mls
145 mg/100mls
Acetone
Blood
Urine
Vitreous
Stom Cont
Blood
Urine
Vitreous
3mg/100mls
9mg/100mls
4mg/100mls
Ketone
But
Can be produced pm
Case 4
Decomposed @ home on sofa with drug paraphenalia around
LIVER
Homogenate
Ethanol
Methanol
0.88 mg/g
Not detected
Not detected
Isopropanol
Not detected
Acetone
Liver homogenate:
Morphine, cocaine metabolites, flupenthixol and metabolites, paracetamol,
chlorpromazine metabolites and cotinine detected detected
Liver Tissue Homogenate Quantitative Analysis by Gas chromatography
nothing?
COMMENTS
The external examination showed an advanced state of decomposition with no evidence of
been dead for some time. Drug levels are altered after death by diffusion of the
substances throughout the body (post-mortem redistribution) and certain substances are
produced or degraded in the post-mortem period. As such, it would be unreliable to draw
conclusions from the drug concentrations themselves. However cocaine and morphine
are not produced endogenously by the body and so their presence indicates that cocaine
and morphine (possibly heroin) were taken by the deceased. Alcohol can be produced by
the body after death but the presence of cocaethylene would suggest that alcohol and
cocaine were used concurrently.
The exact levels of the fore-mentioned drugs within the body at the time of death cannot be
determined with any accuracy. However, we feel that their presence, along with the drug
paraphernalia noted in the vicinity of the body and the absence of identifiable natural disease is
significant. Based on the above information, we are of the opinion that, on the balance of
probabilities, death was in keeping with polydrug toxicity.
The information given within this report represents our understanding of the views, opinions
and circumstances of this case based on the information that we have received to date, either in
writing (all forms) or by oral communication. We recognise that in part this may reproduce or
rely upon witness statements, oral communications or hearsay evidence of second parties and
that the information given to us by others may or may not be factually correct at the time of our
consideration.
We reserve the right to reconsider any aspect of this report should further factual information
arise that contradicts the information provided at the time of the post-mortem examination,
upon which we have based our interpretations.
Cause of Death
Ia. In keeping with polydrug toxicity
Confounding Factors
Considerations
Ask Yourself
absorption
Redistribution
Post-mortem production or
degradation
Tolerance
Limited reference range data
redistribtution / pm production
Do you know about their drug
taking / drinking habits
In Practice
Seek a drug history from coroners officer
Always give the toxicologists as much info as you
have
If you are looking for a specific substance tell them
as it might not be on their routine screen
Appropriate specimens / appropriate site
If tox is important talk to coroners officer about
accessing ante-mortem bloods.
Resources
http://www.dundee.ac.uk/forensicmedicine/
C. Baselt, Disposition of Toxic Drugs & Chemicals in
Man.