Andrew Dawson: Tox Asian Style

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Dawson draws on his experience in areas of high prevalence organophosphate poisoning to optimise management of sick patients.

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Andrew Dawson: Tox Asian Style

  1. 1. Tox Asian Style Andrew Dawson South Asian Clinical Toxicology Research Collaboration
  2. 2. Lessons in Organophosphate Poisoning
  3. 3. Messages • • • • • • Nosocomial risk of poisoning is extremely low OPs are different…significant clinical variation • thiones or oxones • solvents and excipients Admission GCS is important Aggressive Atropinisation Oximes uncertain Neuromuscular junction protection
  4. 4. Rural Developing World • Self–poisoning predominates • 15-30% mortality • (0.3% for all poisoning in the west) • 300,000 OP deaths /year Eddleston M et al. Management of acute organophosphorus pesticide poisoning. Lancet. Feb 16 2008;371(9612):597-607.
  5. 5. • No reports of nosocomial poisoning
  6. 6. Nosocomial Poisoning: Perception can be as important as the reality
  7. 7. Review of OP Mechanism
  8. 8. Variation of organophosphate toxicity ✍ Dawson et al. PLoS Med 2010, Oct 26;7(10):e1000357
  9. 9. Time to Death • • Cardiac Shock (Dimethoate) • ✍ Early & late respiratory failure Iatrogenic Eddleston M et al. Lancet. 2005 Oct 22-28;366(9495):1452-9
  10. 10. Time to Death • • Cardiac Shock (Dimethoate) • ✍ Early & late respiratory failure Iatrogenic Eddleston M et al. Lancet. 2005 Oct 22-28;366(9495):1452-9
  11. 11. ACh ACh AC h Presynaptic ACh Postsynaptic Spontaneous Reactivation OP + KSR KB AChE OP-AChE KOR Induced POX Reactivation PON & Other Enzymes Oxime Kag e Aged OP-AChE
  12. 12. t½ 33 hrs Diethyl t½ 3.7 hrs Dimethyl Rate of “Ageing” dimethoate fenthion chlorpyrifos 0 10 20 30 40 Case fatality ratio (95% CI) Eddleston M et al Differences between organophosphorus insecticides in human selfpoisoning: a prospective cohort study. Lancet. 2005
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  15. 15. Clinical Syndromes • Acute Cholinergic: – Central Muscarinic – Peripheral Muscarinic Intermediate Syndrome • • • • Respiratory failure Peripheral Nicotinic Delayed peripheral neuropathy Neurocognitive dysfunction
  16. 16. Nicotinic, Muscurinic & Central Syndrome
  17. 17. Acronyms DUMBELS Diarrhoea,Urination, Miosis, Bradycardia, Bronchorrhoea, Bronchospasm,Emesis, Lacrimation, Salivation SLUDGE (BBB) Salivation, Lacrimation, Urination, Defecation, Gastrointestinal Distress and Emesis (Bradycardia, Bronchorrhoea, Bronchospasm)
  18. 18. Nicotinic Effects • Stimulation of sympathetic nervous system – – – • Muscle Weakness – – – • Mydriasis, hypertension, tachycardia re-entrant dysrhythmias cardiorespiratory arrest Fasiculations (large muscles and tounge) clonus Tremor Respiratory diff culty (> 24 hours) i – – respiratory muscle weakness diaphragmatic weakness
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  21. 21. 1 Hz E I L 3 Hz 10 Hz 15 Hz 20Hz 30 Hz
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  24. 24. Mechanism
  25. 25. Mechanism • Correlation with pesticide levels & AUC of AChE inhibition • 23rd July Dimethoate model; – – No structural degeneration of either nerve terminal or intramuscular motor axons 35% reduction in Ach receptors • Signif cant at diaphragm where respiration is typically i driven by bursts of 4-5 impulses at about 50 Hz.
  26. 26. Predictors of Mortality Coma is bad Type of pesticide is important 3 clinical syndromes worse than 2
  27. 27. ROC plot for all OPs comparing the predictive value of GCS, pulse, blood pressure, pupil size and intubation. Davies J et al. QJM 2008;101:371-379 © 2008 The Authors
  28. 28. ROC plot comparing the ability of GCS to predict outcome for different OPs. Davies J et al. QJM 2008;101:371-379 © 2008 The Authors
  29. 29. How to atropinise quickly? The doubling protocol
  30. 30. 2 4 8 16 4 Lungs Clearing Cumulative Dose Lungs Crackles and Wheeze Minutes
  31. 31. 2 4 8 16 4 End points Lungs Clearing Lungs Crackles and Wheeze Clear Chest Cumulative Dose sBP > 80mmHg HR > 80/min Dry Axillae Minutes (Pupils no longer pinpoint)
  32. 32. • Load quickly until atropinsed – Doubling protocol – If you are needing more than 60 mgs consider other additional diagnosis and complications • Use the loading dose to calculate the maintenance infusion – 10-20% • loading dose/hour but should be under 3 mgs/hour Review for eff cacy or toxicity i
  33. 33. Conventional Bolus Protocol N= 81 Mortality Time to atropinisation Atropine toxicity Atropine Dose Ventilation Titrated Doubling Protocol N= 75 Odds Ratio 18 (22.5%) 6 (8%) 0.31 (CI 0.11, 0.80) 152 min (95% CI 130-173) 24 min (95% CI 20-28) 23 (28.4%) (9) 12% 109 mg (104-114) 136 mg (129-144) 20 (24.7%) 6 (8%) 0.35 (CI 0.15, 0.80) 0.27 (CI 0.10, 0.70)
  34. 34. 0.90 0.80
  35. 35. Use of Oxime reactivators • Oximes reverse the inhibition of AChE – – Mucarinic Nicotinic
  36. 36. Pralidoxime plama conc. Reproduced from - Eyer P, Buckley NA “Pralidoxime for organophosphate poisoning”.Comment in the Lancet 2006: 368:2110-2111
  37. 37. • Double blind RCT, n= 235 • WHO protocol 2g bolus and 500 mg/h infusion pralidoxime – LD50 for pralidoxime 125 mg/kg Eddleston M, Eyer P, Worek F, et al. Pralidoxime in acute organophosphorus insecticide poisoning--a randomised controlled trial. PLoS Med. Jun 30 2009;6(6):e1000104.
  38. 38. Figure 3. Pharmacodynamics of oxime administration. Diethyl Dimethyl Oxime Placebo Eddleston M, Eyer P, Worek F, Juszczak E, et al. (2009) Pralidoxime in Acute Organophosphorus Insecticide Poisoning—A Randomised Controlled Trial. PLoS Med 6(6): e1000104. doi:10.1371/journal.pmed.1000104 http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000104
  39. 39. Figure 4. Timing of deaths in the two study arms. Eddleston M, Eyer P, Worek F, Juszczak E, et al. (2009) Pralidoxime in Acute Organophosphorus Insecticide Poisoning—A Randomised Controlled Trial. PLoS Med 6(6): e1000104. doi:10.1371/journal.pmed.1000104 http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000104
  40. 40. Figure 6. Forest plots of mortality for pralidoxime versus placebo for a priori def ned study groups. i Eddleston M, Eyer P, Worek F, Juszczak E, et al. (2009) Pralidoxime in Acute Organophosphorus Insecticide Poisoning—A Randomised Controlled Trial. PLoS Med 6(6): e1000104. doi:10.1371/journal.pmed.1000104 http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000104
  41. 41. • No signif cant difference between mortality in i treatment arm and control (saline) • Point estimates suggested increased mortality • Conclusions:– – Reasons for failure were not apparent Further studies of different dose regimes of oximes are required
  42. 42. Neuromuscular Antagonists • Besser R, Gutmann L. A quantitative study of the pancuronium antagonism at the motor endplate in human organophosphorus intoxication. Muscle Nerve 1995, Sep;18(9):956-60.
  43. 43. Using nAChRs antagonists to prevent OP-induced NMJ failure
  44. 44. A. Effect of pesticide on NMJ function
  45. 45. B. Protecting NMJ with rocuronium
  46. 46. C. Effect of withdrawing rocuronium
  47. 47. Key Tests • ECG – – • QT prolongation is reported Myocarditis Chest X-ray—aspiration and other respiratory complications are very common.
  48. 48. ? Blood • Red cell acetylcholinesterase – – – more closely ref ects synaptic ACHase activity l better correlation with severity Ex vivo reactions continue • • • whole blood is put into an EDTA tube, diluted 1:20 with water, put onto ice and then transported rapidly to the laboratory. Pre & post oxime treatment samples may show the extent of reactivation of acetylcholinesterase. Samples taken before and 6 hours after ceasing oximes may indicate if inhibitory activity is still present.
  49. 49. Messages • • • • • • Nosocomial risk is extremely low OPs are different…significant clinical variation • thiones or oxones • solvents and excipients Admission GCS is important Aggressive Atropinisation Oximes uncertain Neuromuscular junction protection
  50. 50. Conclusion • • Minimal panic & good supportive care Rapid atropinisation – • Oximes – • Adjunctive sedation Diethyl with evidence of response Adjunct treatment require more investigation – – Neuromuscular antagonists Magnesium
  51. 51. Open source Curriculum www.wikitox.org

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