Transcript Carbamazepine Forensic

In Excess – Death and Toxicology
The interface between clinical toxicology, forensic sciences and the law
Dr Ian Whyte, FRACP
Hunter Area Toxicology Service
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Clinical Toxicology

Medical specialty concerned with the
effects of drugs and toxins (poisons)
on humans
–
–
–
–
paediatricians
accident and emergency specialists
occupational physicians
clinical pharmacologists
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Paracelsus (1493–1541)


All substances are poisons; there is
none which is not a poison. The right
dose differentiates a poison and a
remedy
Justice is like poison; whether it kills
or heals depends on the dosage

Stephen J. Nardi, US criminal defence lawyer
– http://www.nocolpa.com/quotes.html
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
MLE (32 years old)



Alcoholic father killed his mother
(MVA) when he was 3
State ward in multiple institutions with
repeated physical and sexual abuse
Cerebral aneurysm rupture in 1988
– on carbamazepine (Tegretol) for seizures

Alcoholic for 15 years – 18–36 cans of
beer a day
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
On arrival at hospital

19/7/94 1440 hours
–
–
–
–
–
Arrived by ambulance
Found unconscious in police cell
No response to Naloxone
? Stroke, ? Drug overdose
Unconscious
Coma level 2
 Glasgow coma scale 3/15

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Glasgow coma scale


Developed in Scotland to help predict
long term outcome of head injury
Assesses
– eye response (Nil, 1 – Spontaneous, 4)
– motor response (Nil, 1 – Obeys, 6)
– voice response (Nil, 1 – Oriented, 5)


Maximum 15/15
Minimum 3/15
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Coma level


Designed to assess current conscious
level
Assesses
– response to external stimuli
voice
 touch
 pain

– blood pressure (BP)
– breathing
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Coma level
Grade
Description
Alert
Normal
Drowsy
Responds without specific stimulation
Stuporous Responds to voice or touch in
meaningful fashion
Coma 1
Responds only to pain
Coma 2
No response to pain
Coma 3
Coma 2 + abnormal BP or breathing
Coma 4
Coma 2 + inadequate BP or breathing
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Progress 19/7/94

1800 hours
– Carbamazepine concentration 335
μmol/L


therapeutic range 20–50 μmol/L
2100 hours
– Police phone call concerning a note found
in the patient’s wallet
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Note (detail)
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Progress 19/7/94

2210 hours
– gastroscopy performed because of
delayed absorption


small amounts of dispersible white powder
throughout stomach
2230 hours
– stomach washed out and activated
charcoal given regularly to bind the
carbamazepine
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Progress 20/7/94


Stable during day
1700 hours
– rapid irregular heart rhythm disturbance
with partial response to usual treatment
– given more potent drugs to slow heart

1815 hours
– slow rhythm disturbance and low blood
pressure
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Progress 20/7/94

cont
1845 hours
– drugs to increase blood pressure to
counteract drugs to slow heart rate
– blood pressure and pulse now “stable”

2300 hours
– blood pressure began to fall slowly in
spite of drug treatment and without
rhythm problems
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Progress 21/7/94

0100 hours
–
–
–
–
–

began having multiple epileptic seizures
seizures stopped
blood pressure fell very low
heart stopped
unable to be restarted
0130 hours
– deceased
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Carbamazepine
400
Concentration
(µmol/L)
350
300
250
200
150
100
50
0
0
10
20
30
40
Hours from overdose
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
50
60
Evidence based toxicology



If this single case was our only
experience of carbamazepine
poisoning then incorrect conclusions
would be inevitable
Timely, accurate collection of data on
multiple cases is essential
The Hunter Area Toxicology Service
has been collecting such data on all
admissions for poisoning since 1987
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
HATS database



Database written in 1986 and began
collecting data on 13/1/1987
Since then there have been 6125
admissions
Of these, 5181 admissions were for
deliberate self harm (drug overdose)
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
HATS database



Of the 5181 admissions for deliberate
self harm, 117 were for overdose of
carbamazepine
Of these, 2 (1.7%) died
Overall 32 of 5181 (0.6%) died
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Time from overdose to
admission
25%
Patients
20%
15%
10%
5%
0%
0
<1
1–2
2–3
3–4
4–5
5–6
6–12
12–24 24–48 48–72
Time periods in hours
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
> 72
Coma level (less than 6 hours)
50%
45%
40%
Patients
35%
30%
25%
20%
15%
10%
5%
0%
Alert
Drowsy
Stuporous
Coma 1
Coma 2
Coma level
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Coma 3
Coma 4
Coma level (6 hrs or more)
50%
45%
40%
Patients
35%
30%
25%
20%
15%
10%
5%
0%
Alert
Drowsy
Stuporous
Coma 1
Coma 2
Coma level
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Coma 3
Coma 4
Toxicoepidemiology

Changes in drug regulation
– Nembudeine removed
– Chloral hydrate withdrawn

Relative toxicity
– Differences in toxicity between
antidepressant drugs
 sedative drugs
 antihistamines

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Repackaging



In 1993 the company changed from
supplying carbamazepine in bottles of
100 tablets to blister packing
The median overdose before the
change was 21 tablets (3–180)
The median overdose after the change
was 12 tablets (1–200)
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Teaching toxicology


To assign cause of death when drugs
or toxins are involved requires an
understanding of toxicology
Lack of understanding will lead to
errors
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Paracetamol
PARACETAMOL
5–15%
Liver
toxic
compound
SH
85–95%



Non–toxic
compounds
Very safe in standard doses
In overdose, more toxic
compounds are produced than
can be handled
Signs of liver damage appear at
24 hours and peak at 2–3 days
Non–toxic
compounds
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Paracetamol deaths

National Coronial data collection in
the United Kingdom
– Coroners’ returns to the Registrar General
– Office of Population Censuses and
Surveys

In 1990, 547 deaths were reported
where paracetamol was mentioned
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Paracetamol deaths




Of the 547, 331 were found dead or
were dead on arrival at hospital
These deaths are very unlikely to be
due to paracetamol
A further 66 died in hospital but did
not have any evidence of liver injury at
autopsy
These deaths were not paracetamol
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Paracetamol deaths

Paracetamol is frequently combined
with other pain relieving agents
– codeine
– dextropropoxyphene
is rapidly converted to a compound toxic to
the heart
 is the most likely cause of the early deaths


Paracetamol likely to have caused 150
deaths
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
The future

National data collection and linkage
– health services
toxicologists
 accident and emergency departments

– coroners

NCIS
– forensic pathologists

MEMO project
– http://www.ctlu.se/CTLU_MEMO.html
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
The future




Better communication between
services
Education in basic principles of
toxicology for coroners and those
assisting
More rigorous research in toxicology
Less reliance on reports of rare, if
interesting, cases
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Admission





Had an epileptic seizure
CAT scan of head excluded a stroke
Admitted to the Intensive Care Unit
Intubated and ventilated
Thought to be a sedative drug
overdose
– Carbamazepine (Tegretol)
– Diazepam (Valium)
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Carbamazepine (PJS)
Concentration (µmol/L)
300
250
200
150
100
50
0
0
10
20
30
40
Hours from overdose
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
50
60
HATS database






Database began 13/1/1987
We have had 6125 admissions
Of these, 5181 were for deliberate self
harm (drug overdose)
Of these, 117 were for overdose of
carbamazepine
Of these, 2 (1.7%) died
Overall 32 of 5181 (0.6%) died
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Paracelsus

All things are poisons, and nothing is
without toxicity. Only the dose permits
anything not to be poisonous. For
example, every food and every drink is
a poison if consumed in more than the
usual amount: which proves the point.
I admit that a poison is a poison; but
that is no reason for condemning it
outright
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Paracelsus Healthcare

Paracelsus Healthcare Corp. will pay
$3 million to settle allegations that the
hospital chain ran a revolving door
drug rehabilitation clinic where some
patients never saw a physician, said
the U.S. Justice Department
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital