in excess – death and toxicology the interface between clinical toxicology, forensic sciences and...

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 ToxicologyClinical Toxicology

Medical specialty concerned with the effects of drugs and toxins (poisons) on humans– paediatricians – accident and emergency specialists– occupational physicians– clinical pharmacologists


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


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


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


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


Coma levelComa level Designed to assess current conscious

level Assesses

– response to external stimuli voice touch pain

– blood pressure (BP)– breathing


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


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


Note Note (detail)(detail)



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



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


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



0100 hours– began having multiple epileptic seizures– seizures stopped– blood pressure fell very low– heart stopped– unable to be restarted

0130 hours– deceased


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)


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


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)



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


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


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


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


ToxicoepidemiologyToxicoepidemiology

Changes in drug regulation– Nembudeine removed– Chloral hydrate withdrawn

Relative toxicity– Differences in toxicity between

antidepressant drugs sedative drugs antihistamines


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)


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


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


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



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



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


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


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


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)


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)



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


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


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

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