Organophosphate Pesticide Poisoning

1. OrganophosphatePesticidePoisoning Bishan Rajapakse MBChB Otago Emergency Medicine Advanced Trainee, MPhil Student (ANU), South Asian Clinical Toxicology Research Collaboration Sri Lanka

2. The Case…. • Picture yourself in Anuradhapura hospital Sri Lanka – ED/ Medical SHO • Ward 6 , teaming with patients…. • Charge Sister tells you there is a sick patient • 36yo F • Taken 100mls of Dimethoate after a domestic argument • There’s nowhere to run, or hide…. So you see the patient – what do you do?

3. Organophosphate Pesticide Poisoning

4. Organophosphate Poisoning in Sri Lanka • Organophosphate pesticide (OP) poisoning kills 300,000 worldwide • In Sri Lanka these are mostly impulsive deliberate self-poisoning in young people

5. Organophosphate Poisoning in Sri Lanka • Case Fatality rates (CFR) • 10-20% for most • 50-70% for some OP’s • In west CFR • 0.3% from all poisons • Multifactorial • Toxicity of OP’s • Patient transport • Lack of resources • Training • Although less common OP Poisoning is still a problem in West • Occupational exposure • Threat of Chemical warfare

6. Poisoning at Anuradhapura Hospital in 2005

7. Mechanism of OP’s

8. Simplified Acute OP Toxicity • Inactivation of acetylcholinesterase enzyme Organophosphate

9. Pharmacology of Cholinomimetics according to Katzung • Structure • Simple Alcohols eg edrophonium • Carbamates Eg Neostigmine and Physostigmine (tertiary) • Organophosphates eg Parathion

11. } Respiratory failure + Death Clinical Syndrome • Clinical Syndrome • Acute Cholinergic: • Central • Peripheral Muscarinic • Peripheral Nicotinic • Intermediate Syndrome • OPIDN: Delayed peripheral neuropathy • Neurocognitive dysfunction

12. Cholinergic Effects • D iarrhoea • U rination • M iosis • B radycardia, Bronchorrhoea, Bronchospasm • E mesis • L acrimation • S alivation

13. Nicotinic Effects • Respiratory difficulty • respiratory arrest • diaphragmatic weakness • Muscle Weakness • fasiculations • clonus • tremor • Stimulation of sympathetic nervous system • Mydriasis, hypertension, tachycardia • re-entrant dysrhythmias • cardiorespiratory arrest

14. CNS effects • Malaise • Memory loss • Confusion • Disorientation • Delirium • Seizures • Respiratory centre depression or dysfunction • Coma

15. Intermediate Syndrome • Delayed Respiratory Failure • Proximal muscle weakness and cranial nerve lesions • Typically 1-4 days after cholinergic crisis has resolved • Prolonged Effects on Nicotinic receptors • Primary motor end plate degeneration • Clinical importance • Delayed respiratory failure leads to death if not aware of it or prepared for it • Wadia et. al 1974 :Type II Paralysis, Senanayake and Karalliedde 1987

16. Chronic Effects • Organophosphate induced delayed neuropathy (OPIDN) • 1-3weeks • Peripheral neuropathy • Axonopathy due to Neuropathy Target Esterases (NTE) • Chronic organophosphate induced neuropsychiatric disorder (COPIND)

17. Management The priorities in management are to: Resuscitation Atropinisation of symptomatic patients Decontamination Other Treatments - Oximes

18. ? Dose • ? Duration • ? Effectiveness Antidotes • Atropine • Oximes • Expensive • Does treatment affect outcome • Intermediate Syndrome? • OPIDN?

19. Does the patient need atropine? • How much and for how long

20. A t r o p i n i z a t i o n A t r o p i n e r e q u i r e m e n t 2 4 1 6 8 C l e a r l u n g s P o o r a i r e n t r y i n t o l u n g s c a u s e d b y b r o n c h o s p a s m a n d b r o n c h o r r h o e a 4 0 D r y a x i l l a e E x c e s s i v e s w e a t i n g 3 0 S y s t o l . B P > ( H y p o t e n s i o n ) 8 0 m m H g 2 0 H e a r t r a t e > ( B r a d y c a r d i a ) 8 0 / m i n N o m i o s i s 1 0 ( M i o s i s ) 0 0 5 1 0 1 5 m i n a f t e r f i r s t a t r o p i n e d o s e 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.

21. Atropine • Loading • Doubling dose regime e.g. 2 4 8 16 mgs every 5 minutes • Maintenance • Continuous infusion < 3mg/hr • 10-20% of loading dose/hour • Endpoints • Clear chest on auscultation with no wheeze • Heart rate >80 beats/min • Withdrawal • Atropine toxicity • Clinical Improvement

22. What if you give too much Atropine ? • Anticholinergic Syndrome: • Hot as hell • Blind as a bat • Red as a beet • Dry as a bone • Mad as a hatter • A sensitive indicator for ingestion, but poor predictor for toxicity. • Full syndrome is rare

23. Gastrointestinal Decontamination ?

24. Our Decision should depend on a risk/benefit analysis • Nothing • Emesis • Gastric Lavage • Activated Charcoal • Whole bowel irrigation

25. Risk of Intervention • Aspiration • Impaired GCS + Unprotected Airway • Emesis, Lavage, Charcoal (worse with cathartics) • Trauma • Oesphageal Injury • Emesis, Lavage, Charcoal • Electrolyte Abnormalities • Forced Emesis, Cathartics • Cardiac Arrest • Toxin induced bradycardia + Vagal Tone • Induced emesis, Lavage • Cost

26. Summary of Experimental Evidence • Ideal settings • Little benefit in outcomes after 1 hour • Activated Charcoal is equivalent or better than emesis or lavage • Position statement: single-dose activated charcoal. J Toxicol Clin Toxicol 1997;35:721-41. • Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999;37:731-51.

27. Oximes • Ineffective in some situations • Ageing • Variation between organophosphates • Effective protocols not established • Variation in use • Zero – 24 grams a day • Expensive • USA $30-600 / gram • India $6- 9 / gram • Sri Lanka 55 cents / gram • Unlikely to address Non-ACh effects

28. Alternate sites for antidotes • Protect AChE • Supply AChE • Reduce ACh • Protect ACh Receptor • Reduce OP Load • Multiple Mechanisms

29. Other Treatments under investigation • Magnesium • Reduces acetylcholine release • Blockage pre-synaptic calcium channels • Limited human studies • Clonidine • Decrease the presynaptic synthesis and release of acetylcholine. • Central nervous system > peripheral cholinergic synapses • Diazepam • Diazepam reduces respiratory failure (rats) and cognitive deficit (primates) • Postulate “uncoordinated stimulation of the respiratory centres decreases phrenic nerve output”.

30. The Case…. • Picture yourself in Anuradhapura hospital Sri Lanka – ED/ Medical SHO • Ward 6 , teaming with patients…. • Charge Sister tells you there is a sick patient • 36yo F • Taken 100mls of Dimethoate after a domestic argument • There’s nowhere to run, or hide…. So you see the patient – what do you do?

31. Summary • OP’s are Indirect Cholinomimetic • Block AChE, prolonged duration of ACh in synapse • Effects • Muscarinic, Nicotinic, CNS • Respiratory failure and Death result from this • Treatment • ABC’s, Atropine, Decontaminate, Oximes • Important also in West