Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
In Excess – Death and Toxicology In Excess – Death and Toxicology
The interface between clinical toxicology, forensic sciences and the lawThe interface between clinical toxicology, forensic sciences and the law
Dr Ian Whyte, FRACPHunter Area Toxicology Service
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Clinical ToxicologyClinical 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 Paracelsus (1493–1541)(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 MLE (32 years old)(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 hospitalOn 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 scaleGlasgow 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 levelComa 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 levelComa levelGrade Description
Alert Normal
Drowsy Responds without specific stimulation
Stuporous Responds to voice or touch inmeaningful 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 Progress 19/7/9419/7/94
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 Note (detail)(detail)
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Progress Progress 19/7/9419/7/94
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 Progress 20/7/9420/7/94
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 Progress 20/7/94 20/7/94 contcont
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 Progress 21/7/9421/7/94
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
CarbamazepineCarbamazepine
0
50
100
150
200
250
300
350
400
0 10 20 30 40 50 60
Hours from overdose
Con
cent
ratio
n (µ
mol
/L)
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Evidence based toxicologyEvidence 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 databaseHATS 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
HATS databaseHATS 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 Time from overdose to admissionadmission
0%
5%
10%
15%
20%
25%
0 <1 1–2 2–3 3–4 4–5 5–6 6–12 12–24 24–48 48–72 > 72
Time periods in hours
Patie
nts
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Coma level Coma level (less than 6 hours)(less than 6 hours)
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Alert Drowsy Stuporous Coma 1 Coma 2 Coma 3 Coma 4
Coma level
Patie
nts
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Coma level Coma level (6 hrs or more)(6 hrs or more)
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Alert Drowsy Stuporous Coma 1 Coma 2 Coma 3 Coma 4
Coma level
Patie
nts
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
ToxicoepidemiologyToxicoepidemiology
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
RepackagingRepackaging
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 toxicologyTeaching 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
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
PARACETAMOLPARACETAMOL
Liver Liver toxic toxic
compoundcompound
Non–toxic Non–toxic compoundscompounds
Non–toxicNon–toxiccompoundscompounds85–95%85–95%
5–15%5–15%
SHSH
ParacetamolParacetamol
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Paracetamol deathsParacetamol 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 deathsParacetamol 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 deathsParacetamol 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 futureThe 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 futureThe 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
AdmissionAdmission
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)Carbamazepine (PJS)
0
50
100
150
200
250
300
0 10 20 30 40 50 60
Hours from overdose
Con
cent
ratio
n (µ
mol
/L)
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
HATS databaseHATS 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
ParacelsusParacelsus
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 HealthcareParacelsus 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