1. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital In Excess – Death and Toxicology The interface between clinical toxicology, forensic sciences and the law Dr Ian Whyte, FRACP Hunter Area Toxicology Service

2. 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

3. 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 l Stephen J. Nardi, US criminal defence lawyer –http://www.nocolpa.com/quotes.html

4. 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

5. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital On arrival at hospital  19/7/941440 hours –Arrived by ambulance –Found unconscious in police cell –No response to Naloxone –? Stroke, ? Drug overdose –Unconscious l Coma level 2 l Glasgow coma scale 3/15

6. 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

7. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Coma level  Designed to assess current conscious level  Assesses –response to external stimuli l voice l touch l pain –blood pressure (BP) –breathing

8. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Coma level

9. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Progress 19/7/94  1800 hours –Carbamazepine concentration 335 μmol/L l therapeutic range 20–50 μmol/L  2100 hours –Police phone call concerning a note found in the patient’s wallet

10. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Note (detail)

11. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Progress 19/7/94  2210 hours –gastroscopy performed because of delayed absorption l small amounts of dispersible white powder throughout stomach  2230 hours –stomach washed out and activated charcoal given regularly to bind the carbamazepine

12. 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

13. 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

14. 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

15. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Carbamazepine

16. 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

17. 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)

18. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

19. 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

20. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Time from overdose to admission

21. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Coma level (less than 6 hours)

22. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Coma level (6 hrs or more)

23. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Toxicoepidemiology  Changes in drug regulation –Nembudeine removed –Chloral hydrate withdrawn  Relative toxicity –Differences in toxicity between l antidepressant drugs l sedative drugs l antihistamines

24. 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)

25. 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

26. 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 PARACETAMOL Livertoxiccompound Non–toxiccompounds Non–toxiccompounds 85–95% 5–15% SH Paracetamol

27. 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

28. 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

29. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Paracetamol deaths  Paracetamol is frequently combined with other pain relieving agents –codeine –dextropropoxyphene l is rapidly converted to a compound toxic to the heart l is the most likely cause of the early deaths  Paracetamol likely to have caused 150 deaths

30. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital The future  National data collection and linkage –health services l toxicologists l accident and emergency departments –coroners l NCIS –forensic pathologists l MEMO project –http://www.ctlu.se/CTLU_MEMO.html

31. 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

32. 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)

33. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Carbamazepine (PJS)

34. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital 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

35. 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

36. 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