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

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

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

South Asian Clinical Toxicology Research Collaboration Clinical Challenges

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

South Asian Clinical Toxicology Research Collaboration OP Case Fatality Rates

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

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

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

South Asian Clinical Toxicology Research Collaboration Lesson 2 Variability of Toxicity

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

South Asian Clinical Toxicology Research Collaboration Lesson 3 Predictors of Mortality

South Asian Clinical Toxicology Research Collaboration Clinical Signs and Mortality

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

South Asian Clinical Toxicology Research Collaboration Review of OP Mechanism

South Asian Clinical Toxicology Research Collaboration Normal Nerve Function ACh

South Asian Clinical Toxicology Research Collaboration Normal Nerve Function ACh

South Asian Clinical Toxicology Research Collaboration Normal Nerve Function ACh AChE

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

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

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

South Asian Clinical Toxicology Research Collaboration Lesson 4 Use of Atropine

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

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

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: min after first atropine dose 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

South Asian Clinical Toxicology Research Collaboration Results

Clinical Challenges

South Asian Clinical Toxicology Research Collaboration Lesson 5 Reasons for Variation

South Asian Clinical Toxicology Research Collaboration Most common organophosphorus pesticides

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 Oct 22-28;366(9495): X symptomatic X X X

South Asian Clinical Toxicology Research Collaboration Time to Death

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) Median BuChE (mU/ml) Median AChE (mU/  mol Hb) Median aged AChE 19.4%71.9%70.3%

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

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

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

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): Magnesium sulfate in acute human OP poisoning Pajoumand A et al Hum Exp Toxicol (12):565-9

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

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