1. South Asian Clinical Toxicology Research Collaboration Organophosphate Toxicity Lessons from Anuradhapura Andrew Dawson Program Director Sri Lanka www.asiatox.org Wellcome Trust & Australian National Health and Medical Research Council International Collaborative Capacity Building Research Grant (GR071669MA )

2. South Asian Clinical Toxicology Research Collaboration Organophosphate Poisoning  Asia 300,000 deaths /year  Sri Lanka –17000 admissions –35% ICU –10% Die (20% of symptomatic)

3. South Asian Clinical Toxicology Research Collaboration Past Pivotal Points : Pesticide Restriction Personal Communication Gunnell D, Fernando R, Heganawathna N et al

4. South Asian Clinical Toxicology Research Collaboration Clinical Challenges

5. South Asian Clinical Toxicology Research Collaboration Expensive: Costs Anuradhapura General Hospital Steel et al APAMT August 2006, Colombo. www.asiatox.org

6. South Asian Clinical Toxicology Research Collaboration OP Case Fatality Rates

7. South Asian Clinical Toxicology Research Collaboration Lesson 1 Influence of Initial Care

8. South Asian Clinical Toxicology Research Collaboration Gastric emptying – what happens if you stop?

9. South Asian Clinical Toxicology Research Collaboration The results of observational data on gastric emptying (GE) in pesticide self-poisoning

10. South Asian Clinical Toxicology Research Collaboration Lesson 2 Variability of Toxicity

11. South Asian Clinical Toxicology Research Collaboration Predictors of Death Case Fatality Rates of pesticides in self-poisoning

12. South Asian Clinical Toxicology Research Collaboration Lesson 3 Predictors of Mortality

13. South Asian Clinical Toxicology Research Collaboration Clinical Signs and Mortality

14. South Asian Clinical Toxicology Research Collaboration Glasgow Coma Score & Mortality  Normal GCS 5%  GCS <1430%  GCS <1060% OP Type & Mortality  Chlorpyrifos 7%  Fenthion14%  Dimethoate21%

15. South Asian Clinical Toxicology Research Collaboration Review of OP Mechanism

16. South Asian Clinical Toxicology Research Collaboration Normal Nerve Function ACh

17. South Asian Clinical Toxicology Research Collaboration Normal Nerve Function ACh

18. South Asian Clinical Toxicology Research Collaboration Normal Nerve Function ACh AChE

19. South Asian Clinical Toxicology Research Collaboration How OP Work: Reversible & Aged Binding AChE ACh OP

20. South Asian Clinical Toxicology Research Collaboration Nicotinic, Muscurinic & Central Syndrome

21. South Asian Clinical Toxicology Research Collaboration  Muscarinic –Diarrhoea –Urination –Miosis –Bronchospasm –Emesis –Lacrimation –Salivation  CNS –CNS depression, coma –Respiratory Centre Dysfunction –Seizures  Nicotinic –Paralysis –Sweating –Mydriasis –Hypertension –Tachycardia  Cardiovascular –Arrhythmias –Hypertension –Tachycardia –Tissue ischaemia

22. South Asian Clinical Toxicology Research Collaboration Lesson 4 Use of Atropine

23. South Asian Clinical Toxicology Research Collaboration How Atropine Works AChE ACh OP Atropine

24. South Asian Clinical Toxicology Research Collaboration Range of times it would take to give adequate doses of atropine (23mg and 75 mg) following the expert advice from each text

25. South Asian Clinical Toxicology Research Collaboration Scheme of atropinization (endpoints to be reached)  Eddleston M, Buckley NA, Mohamed F, Senarathna L, Hittarage A, Dissanayake W, Azhar S, Sheriff MHR, Dawson AH. Speed of initial atropinisation in significant organophosphorus pesticide poisoning - a comparison of recommended regimens. Journal of Toxicology – Clinical Toxicology 2004;6:865-875. 051015 0 10 20 30 40 min after first atropine dose 24 8 16 Atropine requirement Poor air entry into lungs caused by bronchospasm and bronchorrhoea Excessive sweating (Hypotension) (Bradycardia) (Miosis) Atropinization Clear lungs Dry axillae Systol. BP > 80 mm Hg Heart rate > 80/min No miosis

26. South Asian Clinical Toxicology Research Collaboration Results

27. Clinical Challenges

28. South Asian Clinical Toxicology Research Collaboration Lesson 5 Reasons for Variation

29. South Asian Clinical Toxicology Research Collaboration Most common organophosphorus pesticides

30. South Asian Clinical Toxicology Research Collaboration Clinical Variation Risk: Relative human toxicity of pesticides in self-poisoning Eddleston M, Eyer P, Worek F, Mohamed F, et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Oct 22-28;366(9495):1452-9 X symptomatic X X X

31. South Asian Clinical Toxicology Research Collaboration Time to Death

32. South Asian Clinical Toxicology Research Collaboration ChlorpyrifosDimethoate Fenthion Median (IQR) Hours to Adm 4 (2 to 5) 3 (2 to 5) 4 (2 to 7) Admission values Mean [OP] (uM) 1.28 355.5 4.86 Median BuChE (mU/ml) 33.511290.0 Median AChE (mU/  mol Hb) 63.569.064.2 Median aged AChE 19.4%71.9%70.3%

33. South Asian Clinical Toxicology Research Collaboration Effectiveness of 1 gram pralidoxime treatment Chlorpyrifos Dimethoate

34. South Asian Clinical Toxicology Research Collaboration OPs are different  Differing Toxicity & Kinetics  Different Clinical Syndromes  Different Response to Antidotes  ? Need Different Treatment Responses

35. South Asian Clinical Toxicology Research Collaboration Alternate Sites for Antidotes Protect AChE Supply AChE Reduce ACh Protect ACh Receptor Reduce OP Load

36. South Asian Clinical Toxicology Research Collaboration Magnesium  Reduces acetylcholine release –Blockage pre-synaptic calcium channels –Central and Peripheral Nervous System  Decrease toxicity in animal models  Limited human studies Singh G. Electroencephalogr.Clin.Neurophysiol. 1998;107(2):140-8. Magnesium sulfate in acute human OP poisoning Pajoumand A et al Hum Exp Toxicol. 2004 23(12):565-9

37. South Asian Clinical Toxicology Research Collaboration Lessons from Anuradhapura  Influence of Initial Care on Mortality –Risk of decontamination  Variability of Toxicity –Applied to regulatory decisions, pesticide withdrawal  Predictors of Mortality –Pesticide type & Clinical Status  Use of Atropine: –The doubling protocol  Reasons for Variation –Chemical and Kinetic:Oxime Failure –Implications for where, how and what treatment is delivered

38. South Asian Clinical Toxicology Research Collaboration Conclusion  OP Poisoning remains a complex problem  There are many reasons contributing to death  Multiple Points of Intervention (Medical, Regulatory & Social) requires Research