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Oximes, atropine and diazepam in organophosphate and carbamate poisoning

Oximes, atropine and diazepam in organophosphate and carbamate poisoning. Dr Martin Wilks, Syngenta Crop Protection AG, Basel, Switzerland. Modes of action of the top-selling insecticides/acaricides and their world market share (Nauen, 2002). The scale of the problem.

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Oximes, atropine and diazepam in organophosphate and carbamate poisoning

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  1. Oximes, atropine and diazepam in organophosphate and carbamate poisoning Dr Martin Wilks, Syngenta Crop Protection AG, Basel, Switzerland

  2. Modes of action of the top-selling insecticides/acaricides and their world market share (Nauen, 2002)

  3. The scale of the problem Asia: est. 300,000 deaths /year from pesticide poisoning Est. 200,000 involve ingestion of OPs (and carbamates) (Eddleston and Phillips, 2004, BMJ 328: 32 – 44) Sri Lanka 17000 admissions 35% ICU 10% Die (20% of symptomatic)

  4. Outline • Review the Mechanism • Does the type of compound matter? • Aspects of treatment • Do they need Atropine? • Do they need Decontamination? • Do they need Oximes? • Magnesium, Diazepam, Bicarbonate • Lessons learned

  5. Organophosphate Carbamate O(S) II P - O - X O II R1 - NH - C - O - R2 R1 R2 R1,2 = alkyl or aryl groups X = wide range of branched or substituted groups R1 = methyl, aromatic or benzimidazol group R2 = aromatic or aliphatic group

  6. Acetylcholinesterase and OP Organophosphate

  7. Nicotinic, muscarinic and central syndrome

  8. Clinical Syndromes Acute Cholinergic: Central Peripheral Muscarinic Peripheral Nicotinic Intermediate Syndrome Delayed peripheral neuropathy Neurocognitive dysfunction Respiratory failure

  9. Acute Cholinergic Syndrome

  10. Moat common OP pesticides used in self-poisoning in Sri Lanka Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Oct 22-28;366(9495):1452-9

  11. ChlorpyrifosDimethoateFenthion Number of cases 440 266 100 WHO Toxicity II II II Formulation 40% EC 40% EC 50% EC Chemistry Diethyl Dimethyl Dimethyl Rat oral LD50 (mg/kg) WHO  135 150 Not Given OSHA 97 250 215-245 Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Oct 22-28;366(9495):1452-9

  12. X symptomatic X X X Relative human toxicity of pesticides in self-poisoning Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Oct 22-28;366(9495):1452-9

  13. Time to Death • Early & late respiratory failure • Hypotensive Shock (Dimethoate) • Iatrogenic

  14. Chlorpyrifos poisoning

  15. Fenthion poisoning

  16. Dimethoate poisoning

  17. Complicates Assessment of the Evidence OPs are different • Differing Toxicity • Different Kinetics • Different Clinical Syndromes • Different Response to Antidotes • ? Need Different Treatment Responses

  18. Sequence of Medical Management • Basic Supportive Care • Does the patient need Atropine ? • Poor air entry into the lungs due to bronchorrhoea and bronchospasm • Bradycardia • Excessive sweating • Small pupils • Hypotension. • Decontamination ? • Oximes? • Adjunctive Treatment ?

  19. Mechanism Blocks the muscarinic effects due to excess acetylcholine Competitive inhibitor Control of symptoms determines the dose by titration Endpoint Which cholinergic effect should be the endpoint? Pupil size? Secretions? Heart rate? Blood Pressure? Measurement of peripheral vascular resistance? Atropine – mechanism and endpoints

  20. Atropine Dose in Organophosphates • Sri Lankan ventilated OP patients who survived require • Mean initial dose of 23.4 mgs. • Maximum initial dose of 75 mg • 38 texts with 31 different recommendations Eddleston M et al .Speed of initial atropinisation in significant organophosphorus pesticide poisoning. J Tox Clin Tox 2004;42(6):865-75

  21. Range of times it would take to give adequate doses of atropine (23mg and 75 mg) following the expert advice from each text

  22. 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)

  23. 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

  24. Decontamination • Don’t confuse creating mess with efficacy • Decisions based on risk/benefit analysis

  25. Gastric emptying – what happens if you stop?

  26. The results of observational data on gastric emptying (GE) in pesticide self-poisoning

  27. Eddleston M, et al (2008) Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial. Lancet 371: 579 - 587 • 4632 patients recruited • Overall death rate around 7%, pesticide death rate around 13% • No significant difference between no AC, SDAC and MDAC • Mortality did not differ between groups. Odds ratios: • SDAC vs no AC 1.05 (95% CI: 0.79, 1.40) • MDAC vs no AC 0.93 (95% CI: 0.69, 1.25) • MDAC vs SDAC 0.89 (95% CI 0.66, 1.19) • No difference in rates of ventilation for OP and Carb poisoned patients

  28. Therapy with Oximes: Basics O E H C R O O E 3 - X + P O H C P O + EOH P O 3 R O H C 3 R O X H + X + Inhibition H O H O H O N R 2 2 H O O E R O + + R H + + P O H C P O P O + EOH + H C 3 EOH H C 3 3 O R O O N R Reactivation Aging Spontaneous reactivation Worek et al. Biochem Pharmacol. 2004

  29. AChE-Status in a Patient with Parathion Poisoning obidoxime 200 inhibitory activity 150 poison 100 50 0 0 25 50 75 100 hours Patient: A 45-year old, male Emergency situation: Unconscious, severe signs and symptoms of cholinergic crisis. 1.5 mg of atropine, intubation and initiation of artificial ventilation. Clinical course: 2 bolus doses of obidoxime together with an atropine infusion at the local hospital. Transfer to the ICU of Technical University, Munich. The patient recovered uneventfully. Eyer et al. Toxicol Rev. 2003

  30. Oximes • Effective protocols not established • Variation in use • Zero – 24 grams a day • Intermittent bolus vs continuous infusion • Ineffective against some OPs • Issues of availability/affordability • Pralidoxime • USA $600 / gram • India $9 / gram • Sri Lanka 55 cents / gram

  31. ... but do they work? • Buckley et al (2005) Cochrane Database Syst Rev, CD005085 • Two published RCTs, one abstract RCT • Insufficient evidence whether oximes are harmful or beneficial • Peter et al (2006) Crit Care Med 34: 502 – 510 • Two published RCTs, 5 controlled trials • Oximes either ineffective or harmful • Rahimi et al (2006) Human Exp Toxicol 25: 157 – 162 • Six clinical trials • Oximes are not effective and can be dangerous

  32. Protect AChE Cholinesterase inhibitors Supply AChE Sacrifice Synthetic and Natural (FFP) Reduce ACh Release Magnesium, Clonidine Protect Receptor Neuromuscular Blockers Reduce OP Load Increase Hydrolase capacity Multiple Mechanisms Altering Ph New antidotes, new therapies?

  33. Magnesium • Reduces acetylcholine release • Blocks pre-synaptic calcium channels • Central and Peripheral Nervous System • Decrease toxicity in animal models Pajoumand A et al (2004) Hum Exp Toxicol 23(12):565-9 • 16 gram continuous infusion MgSO4 for 24 hours • Normal care (oximes and atropine) in both groups • 0/11 patients died with magnesium • 5/34 control patients • Methodological issues • pseudorandomisation

  34. Diazepam • Routinely used in OP poisoning for treatment of agitated delirium and seizures • Diazepam reduces respiratory failure (rats) and cognitive deficit (primates) • Postulate “uncoordinated stimulation of the respiratory centres decreases phrenic nerve output” • Role for peripheral benzodiazepine receptor?

  35. Diazepam • Synergistic response with anticholinergics • Dickson EW et al Diazepam inhibits organophosphate-induced central respiratory depression. Acad.Emerg.Med. 2003;10(12):1303-

  36. Organophosphates and pH • Organophosphate Hydrolase is pH sensitive. • Binding of pralidoxime is pH sensitive. • Acetylcholinesterase • Aging of OP-AChe complex and reactivation.

  37. Comparative efficacy of i.v. pralidoxime vs. NaHCO3 in rats lethally poisoned with OP insecticide (A Wong, Brazil) • 5 Groups of 10 rats • DDVP only (no treatment) 0/10 • Atropine (17 mg/kg) alone 3/10 • Atropine + pralidoxime (1 g/kg) 4/10 • Atropine + NaHCO3 (3 meq/kg) 9/10 • Atropine + NaCl 0.9% (1.9 ml/kg) 5/10

  38. p<0.001 D~B and D~C p<0.01 D~E 8000 7012.12 7000 6000 5000 4000 2611.17 3000 2000 462.17 309.43 1000 0 0 D.D.V.P. Atropine Atrop. + Atrop. + Atrop. + Oxime Bicarb. NaCl Comparative efficacy of i.v. pralidoxime vs. NaHCO3 in rats lethally poisoned with OP insecticide (A Wong, Brazil) N = 10 rats in each group

  39. Balali­Mood M. Effect of High Doses of Sodium Bicarbonate in Acute Organophosphorous Pesticide Poisoning. Clinical Toxicology, 43:571­574, 2005 • RCT N=30 • NaHCO3 pH 7.45-7.55 • 5 mEq/Kg over 60 minutes • 5-6 mEq/Kg over 24 hours • Length of hospital stay • Controls 5.59 ± 1.97 • Treatment 4.33 ± 1.99

  40. Some lessons from clinical research Influence of Initial Care on Mortality Risk of decontamination Predictors of Mortality Pesticide type & Clinical Status Use Atropine Aggressively but Titrate The doubling protocol Reasons for Oxime Failure Chemical and Kinetic Implications for where, how and what treatment is delivered More Large-Scale Randomised Controlled Trials Are Needed, and They Will Be Coming from Sri Lanka

  41. Special thanks to Andrew Dawson Michael Eddleston Horst Thiermann for helpful discussion, permission to use their slides, and many shared drinks

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