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OPC Poisoning- Role of oximes , Controversies and newer compounds explored

OPC Poisoning- Role of oximes , Controversies and newer compounds explored. Dr Binila Chacko MBBS, MD Gen Med, DNB, FCICM, DM Crit Care Professor Medical ICU Christian Medical College, Vellore 632004. Introduction. Major problem developing countries. Epidemic proportions in India

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OPC Poisoning- Role of oximes , Controversies and newer compounds explored

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  1. OPC Poisoning- Role of oximes, Controversies and newer compounds explored Dr Binila Chacko MBBS, MD Gen Med, DNB, FCICM, DM Crit Care Professor Medical ICU Christian Medical College, Vellore 632004

  2. Introduction Major problem developing countries • Epidemic proportions in India • 60% of deliberate self harm (unpublished data-Vellore)

  3. Mortality and morbidity • Unpublished Vellore data • 92.13% required intubation and ventilation • Mean duration of ventilation 7.75 (6.07)days • Mortality 8.4% • West India data • 34.21% ventilated • 10.5% mortality • Data from other places • Sri Lanka 15.8%-24.8% • Pakistan 17.39% • Mega dose intoxications • Use of class I compounds • Delay in presentation to hospital • Concentrated formulations

  4. Oximes N-acetyl cysteine Magnesium Glycopyrrolate DECREASE ABSORPTION Atropine OXIDATIVE STRESS Bronchorrhea Decremental muscle response MODULATE EFFECTS Adenosine Clonidine Magnesium Diazepam Atropine Atropine Respiratory depression, Seizures Arrhythmias, long QTc CIRCULATING ORGANOPHOSPHATE OP- AChE Complexes ABSORTION OF TOXIN THROUGH SKIN AND GUT NEUTRALIZE TOXIN Albumin (FFP) BuChE (FFP) ENHANCE ELIMINATION Hydrolases BIO-REMEDIATION Alkalinisation Hemoperfusion

  5. Managing the OP poisoned patient • Reducing toxin load • Neutralizing toxin • Counteracting effects • Enhancing elimination

  6. Neutralize toxin - oximes • Are oximes beneficial in human OP poisoning? • Subject of much debate & literature • Reasons for failure

  7. What are they? • Nucleophilic agents • Reactivate bound acetyl cholinesterase • Common – pralidoxime and obidoxime

  8. Oximes - animals • Early animal experiments • Oximes administered either before the poison or just after the poison • Regeneration of cholinesterase • Animals survived Peter JV, Cherian AM. Organic insecticides. Anaesth Intensive Care 2000; 28: 11-21

  9. Oximes - humans • Initial reports retrospective • Prospective non-randomized trials • Randomized controlled trials • Systematic reviews and meta-analysis

  10. Oximes – controlled trials

  11. So how do we look at all this evidence?

  12. Mortality Ventilation Meta-analytic evidence Peter JV, Moran JL, Graham P. Advances in the management of organophosphate poisoning. Expert Opin. Pharmacother. 2007; 8: 1-13 Oxime vs. Control arm trials only Need for ICU

  13. Oxime therapy – Pawar trial High dose oximes – 50 gm in 48 hours Pawar KS, Bhoite RR, Pillay PP et all. Continuous pralidoxime infusion versus repeated bolus injections to treat organophosphorus poisoning: a randomised controlled trial. Lancet 2006; 368: 2136-41

  14. Oxime therapy – Pawar trial Pawar KS, Bhoite RR, Pillay PP et all. Continuous pralidoxime infusion versus repeated bolus injections to treat organophosphorus poisoning: a randomised controlled trial. Lancet 2006; 368: 2136-41

  15. Oxime therapy • Largest trial - 235 patients, PAM=121, Saline=114 • 2 gm loading dose over 20 min • Then 0.5 g/hr for maximum 7 days • Till atropine not required for 12-24 h or death Eddleston M, Eyer P, Worek F et al. Pralidoxime in acute organophosphorus insecticide poisoning – A randomised controlled trial. PLoS Med 6(6): e1000104. doi:10.1371/journal.pmed.1000104

  16. Oxime therapy Eddleston M, Eyer P, Worek F et al. Pralidoxime in acute organophosphorus insecticide poisoning – A randomised controlled trial. PLoS Med 6(6): e1000104. doi:10.1371/journal.pmed.1000104

  17. Summary of oxime trials • Meta-analysis - null effect or potential harm • The largest oxime study trend to harm • Pune study - reduction in mortality with high dose • Moderate poisoning (severe to GH) • Patients presented very early (< 2.5 hours) • Used fairly high doses (50 gm)

  18. Why is there no benefit?

  19. Reasons for oxime failure • Study design • Timing • Dose of oximes • Type of compounds • Toxicity of antidotes

  20. Study design • Some retrospective and prospective studies • Only 7 RCTs (4 placebo controlled and 3 trials of different doses) • Some methodological flaws in design • More RCTs - stratified?

  21. The timing CMC study Pune study Peter JV, Moran JL, Graham P. Advances in the management of organophosphate poisoning. Expert Opin. Pharmacother. 2007; 8: 1-13

  22. The dose • Initial study by Cherian – 12 gm over 3 days – considered too little • Pawar study used 50 gm – showed benefit • Sri Lankan study – relatively high dose 12 gm/day – no benefit • 2 new studies (2015 & 2016 from India – high dose (n=100 & 150) – no benefit

  23. Type of compound • Di-methyl OP compounds • Rather resistant to oxime therapy. • Eddleston study • Reactivation happened with di-ethyl but not di-methyl • No difference in mortality • Median pseudocholinesterase levels were lower in survivors who received placebo than those who died with pralidoxime • Dimethylphosphoryl-inhibited human cholinesterases: inhibition, reactivation, and aging kinetics. Arch. Toxicol 1999; 73:7-14

  24. Toxicity of antidote • Oximes by themselves can cause muscle weakness • Rapid infusion causes dizziness, flushing, numbness • Formation of stable phosphoryl oximes (POXs) with high anticholinesterase activity • The phosphoryloxime-destroying activity of human plasma. Arch. Toxicol 2000; 74:27-32

  25. Aging of the OP-AChE complex.. Phosphoryloximes (POXs) T1/2 aging Dimethyl 3 hours and diethyl 30 hours

  26. Oximes • Oxime therapy in humans not shown to be beneficial • Several reasons why it may not work • Early presenters (<2 h) with diethyl poisoning, there may be role • Good supportive care important for good outcome

  27. Other agents

  28. Neutralize toxin - Bioscavenger • Cholinesterases to sequester OP • Purified human BChE under trials in animals • Has a long shelf life (lyophilised form) > 2 years • Single dose in mice – therapeutic concentration for at least 4 days • Potential for immunological responses limited as human in origin

  29. Neutralize toxin - Bioscavenger • Still not commercial • So alternative – FFP – rich in cholinesterases • Concentrations is > 4000 IU/L in FFP

  30. Neutralize toxin - Bioscavenger • Preliminary study of 33 OP poisoned patients • 20 received atropine and PAM and 9 in addition 2 bags of plasma daily from day 2 till they no longer needed atropine • Intermediate syndrome did not occur in plasma arm

  31. Neutralize toxin - Bioscavenger • Is cholinesterase the secret ingredient in FFP? • The amount of cholinesterase in FFP alone cannot account for the clinical improvement • Recent animal studies suggest that albumin is also a bioscavenger • Our BIOSTOP study

  32. BIOSTOP study

  33. BIOSTOP study

  34. Modulate effects • Anti-cholinergic agents • Magnesium • Clonidine • Diazepam • N-acetyl cysteine

  35. Role of nebulised beta 2 agonists • Facilitate fluid elimination from the lungs. • Up-regulation of sodium transport in the alveolar epithelium

  36. Nicotinic receptor antagonist drugs • ?role in preventing intermediate syndrome • Role of neuromuscular blocking drugs • In a porcine model of OP poisoning • Encouraging protective effects on NMJ function following early administration of rocuronium (Eddlestonet al., unpublished observations). • Might prevent subsequent nicotinic receptor overstimulation and NMJ dysfunction. • A pilot RCT of this approach is currently underway in Sri Lanka (NCT02147054).

  37. Lipid emulsions • Lipid sink for treatment of severe cardiotoxicity from local anesthetics and other including antipsychotic agents and antidepressants  • ? Role in lipid soluble OP insecticide poisoning • However, a rodent study of unformulated parathion showed little benefit • One case report suggested a benefit after parathion poisoning  • No formal Phase II/III trial done

  38. Enhancing elimination

  39. Enhance elimination

  40. So where do we go from here?

  41. OP management over the years.. • What has made the difference?

  42. Improving mortality Presently – don’t expect anyone with OP poisoning to die Peter JV, John G. Management of acute organophosphorus pesticide poisoning. Lancet 2008; 371: 2170

  43. Conclusion • Supportive care and early atropinisation • Oximes debatable • Currently no evidence of benefit • Recent interest in • Rocuronium • Beta 2 agonists • Lipid emulsions

  44. Acknowledgment • Dr JV Peter and Dr George John • Medical ICU team CMC Vellore

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