1. Pesticide Poisoning in the 21 st century Toxic Issues in the ED 2012

2. Objectives Variability in organophosphates Clinical relevance Implication for treatment

3. Take Home Messages The patient is poisoned…not the staff Atropine is good Oximes are uncertain

4. Perth case

5. A 30 yo male ingests 250 mls of chlorpyrifos in the northern suburbs

6. As a result A HAZMAT is declared, street evacuated Symptomatic patient stripped and decontaminated in street Driven on back of truck to city Major teaching hospital is blocked off

7. Perth case ED staff are prevented from assessing patient Patient is denied access to ED Eventually toxicology service convinces FESA to release patient Patient has stormy course in ICU but survives

8. Management of an OP patient in Asia Common in Asia – 300 000 – 400 000 deaths in Asia and Western Pacific per year Managed in general wards No reports of nosocomial poisoning

9. Hanoi: Dr Pham Due

10. Management of an OP patient in Australia Rare poisoning 1 – 2 deaths in Australia per year Much anxiety about nosocomial poisoning ED’s evacuated, patients refused admission to ED’s, ICU’s, transport platforms

12. Targeting Treatment for Organophosphate Poisoning Andrew Dawson South Asian Clinical Toxicology Research Collaboration

13. Epidemiology Prevalent in developing world – 300,000 deaths /year – Self–poisoning predominates 15-30% mortality – (0.3% for all poisoning in the west) Agrochemicals = Weapons of mass destruction Eddleston M et al. Management of acute organophosphorus pesticide poisoning. Lancet. Feb 16 2008;371(9612):597-607. X

14. Chemical Variation Chemical – Thione or Oxone – Dimethyl or Diethyl The solvent

15. Thione ? Prodrug Oxone

16. Thione Prodrugs & Oxones

17. Hydrolysis of DETP and DEP to dialkyl phosphates

18. Dimethyl

19. Diethyl

20. The Mechanism

21. Acetylcholinesterase

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

23. Nicotinic, Muscurinic & Central Syndrome

24. Normal Nerve Function ACh

25. ACh

26. ACh AChE

27. How OP Work: Reversible & Aged Binding AChE ACh OP

28. Clinical

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

30. Central Mediated Respiratory Depression Dickson EW, Bird SB, Gaspari RJ, Boyer EW, Ferris CF. Diazepam inhibits organophosphate-induced central respiratory depression. Acad Emerg Med 2003, Dec;10(12):1303-6

32. Respiratory Failure 78 symptomatic patients 12 respiratory failure < 24 hours 7 All Normal RNS 3 Subsequently forme fruste IMS >24 hours >24 hours 5 All severe decrement Normal RNS in early respiratory failure suggests a muscarinic syndrome. – Supports early rapid atropinisation to be the initial priority Pradeepa Jayawardane

33. Intermediate Syndrome Intermediate Syndrome Wadia et. al 1974 :Type II Paralysis, Senanayake and Karalliedde 1987, Jayawardane 2008

34. Intermediate Syndrome A cause of delayed Respiratory Failure – Proximal muscle weakness and cranial nerve lesions – Typically 1-4 days after cholinergic crisis has resolved – Weakness <3/5 is predictive Prolonged effects on Nicotinic receptors – Pre synaptic post synaptic failure Clinical importance – Delayed respiratory failure leads to death if not aware of it or prepared for it

35. Pradeepa Jayawardane

36. 1 Hz3 Hz10 Hz15 Hz20Hz30 Hz E I L “Intermediate Syndrome” a spectrum disorder 50% of patients Pre & postsynaptic failure Patient ID: N100234

37. Mechanism Correlation with pesticide levels & AUC of AChE inhibition 23 rd July Dimethoate model; – No structural degeneration of either nerve terminal or intramuscular motor axons – 35% reduction in ACh receptors Significant at diaphragm where respiration is typically driven by bursts of 4-5 impulses at about 50 Hz.

38. Cases for discussion

39. A 56-year-old man presents 2 hours after drinking an unknown amount of chlorpyrifos concentrate. Prior to this he had been drinking alcohol. you are in a hospital that has had its pathology service restricted..’There are no fancy tests here, doctor.’ was the prerecorded message you receive when you ring the lab On arrival, his Glasgow Coma Score is 9. He smells of cheap liquor, pesticide and the vomit that covers his chest. His pulse is 130, BP 130/80. There is scattered wheeze throughout his chest. His mouth contains some vomit, which has not made it to his chest. He is moving his limbs and his reflexes are present but depressed. You do not see any muscle fasciculations.

40. A 56-year-old man presents 2 hours after drinking an unknown amount of fenthion concentrate. Prior to this he had been drinking alcohol. You are in a hospital that has the leading (recently privatised) pathology service in your area. The pathology car park is congested with late model Mercedes On arrival his Glasgow Coma Score is 9. He smells of cheap liquor, pesticide and the vomit that covers his chest. His pulse is 130, BP 130/80. There is scattered wheeze throughout his chest. His mouth contains some vomit, which has not made it to his chest. He is moving his limbs and his reflexes are present but depressed. You do not see any fasciculations.

41. Are these patients the same? What is the risks.? What would help you define the risk? What is your initial treatment? – What would you do? – What drugs would you use, – how would you estimate dose? – How would you decide when to stop administering antidotes?

42. Are the patients the same?

43. Relative Toxicity of Organophosphates ✍ Dawson et al. PLoS Med 2010, Oct 26;7(10):e1000357

44. Time to Death  Early & late respiratory failure  Cardiac Shock ? Vasodilation ? Cardiac (Dimethoate) ✍ Eddleston M et al. Lancet. 2005 Oct 22-28;366(9495):1452-9

45. Chlorpyrifos poisoning

46. Dimethoate poisoning

47. 010203040 chlorpyrifos fenthion dimethoate Case fatality ratio (95% CI) Eddleston M et al Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet. 2005 Di ethyl Di methyl Rate of “Ageing” t ½ 3.7 hrs t ½ 33 hrs Variation in toxicity of OP agents Eddleston M, Szinicz L, Eyer P, Buckley N. Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials. Qjm. May 2002;95(5):275-283.

48. Spontaneous Reactivation K SR Oxime K OR Induced Reactivation OP-AChE KBKB POX PON & Other Enzymes Aged OP-AChE K age ACh OP + AChE ACh Presynaptic Postsynaptic

49. Cyclohexanone EC40 vs EC35 Eddleston et al Toxicology 2012, Apr;294(2-3):94-103.

50. Predictors of Mortality Coma is bad Type of pesticide is important 3 clinical syndromes worse than 2

51. Clinical Signs and Mortality

52. 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

53. Glasgow Coma Score & Mortality Normal GCS 5% GCS <1430% GCS <1060% OP Type & Mortality  Chlorpyrifos 7%  Fenthion14%  Dimethoate21%

54. Time to Death  Early & late respiratory failure  Cardiac Shock ? Vasodilation ? Cardiac (Dimethoate) ✍ Eddleston M et al. Lancet. 2005 Oct 22-28;366(9495):1452-9

55. Treatment Priorities ABC first – Ventilate: Benzodiazepines ? Competitive neuromuscular blockers Atropinisation Consider decontamination ? Oximes

56. How quickly should we atropinise?

58. 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 efficacy or toxicity

59. Doubling atropine against response Cumulative atropine mgs Minutes 248168 Lungs ClearingLungs Crackles and Wheeze

60. End points of atropinisation Lung Secretions Hypotension Bradycardia Sweating (Miosis) Clear Chest sBP > 80mmHg HR > 80/min Dry Axillae (Pupils no longer pinpoint) ATROPINEATROPINE

61. Conventional Bolus Protocol N= 81 Titrated Doubling Protocol N= 75 Odds Ratio Mortality18 (22.5%)6 (8%)0.31 (CI 0.11, 0.80) Time to atropinisation152 min (95% CI 130-173) 24 min (95% CI 20-28) Atropine toxicity23 (28.4%)(9) 12%0.35 (CI 0.15, 0.80) Atropine Dose109 mg (104-114)136 mg (129-144) Ventilation20 (24.7%)6 (8%)0.27 (CI 0.10, 0.70)

62. 0.90 0.80 Incremental bolus Bolus injection

63. Use of Oxime reactivators Oximes reverse the inhibition of AChE – Mucarinic – Nicotinic

64. Nicotinic Effects Respiratory difficulty (> 24 hours) – respiratory muscle weakness – diaphragmatic weakness Muscle Weakness – Fasiculations (large muscles and tounge) – clonus – tremor Stimulation of sympathetic nervous system – Mydriasis, hypertension, tachycardia – re-entrant dysrhythmias – cardiorespiratory arrest

65. Pralidoxime plama conc. Reproduced from - Eyer P, Buckley NA “Pralidoxime for organophosphate poisoning”.Comment in the Lancet 2006: 368:2110-2111

66. 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

67. 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.

68. Figure 3. Pharmacodynamics of oxime administration. 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 Diethyl Dimethyl Oxime Placebo

69. 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

70. Figure 6. Forest plots of mortality for pralidoxime versus placebo for a priori defined study groups. 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

71. No significant difference between mortality in 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

72. Key Tests ECG – QT prolongation is reported – Myocarditis Chest X-ray—aspiration and other respiratory complications are very common.

73. ? Blood Plasma butyrylcholinesterase – highly sensitive – may be useful when the diagnosis is in – does not correlate with severity of poisoning.

74. ? Blood Red cell acetylcholinesterase – more closely reflects synaptic ACHase activity – 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.

75. Are old drugs the new hope? >>200 ‘proof of concept’ publications 1962-2004

76. Alternate Sites for Antidotes Protect AChE Supply AChE FFP Reduce ACh Clonidine Magnesium Protect ACh Receptor Reduce OP Load FFP or Albumin OP hydrolases

77. Clonidine Decrease the presynaptic synthesis and release of acetylcholine. – Central nervous system > peripheral cholinergic synapses Animal Work: Soman models – 1/7 deaths vs 14/16 in controls (Soman) – Ineffective against echothiopate ( a peripheral acting OP) Centrally Mediated – Aronstam RS, Smith MD, Buccafusco JJ. Clonidine protection from soman and echothiophate toxicity in mice. Life Sci. 1986;39(22):2097-102.

79. Magnesium Reduces acetylcholine release – Blockage pre-synaptic calcium channels – Central and Peripheral Nervous System Decreased toxicity in animal models ? Non neuromuscular effects Limited human studies – in 4 OP patients improved neuromuscular response to repetitive nerve stimulation » Singh G. Electroencephalogr.Clin.Neurophysiol. 1998;107(2):140-8.

80. Magnesium sulfate in acute human OP poisoning Pajoumand A et al Hum Exp Toxicol. 2004 23(12):565-9 16 gram continuous infusion MgSO 4 for 24 hours Normal care (oximes and atropine) in both groups – Death 0/11 patients died with magnesium 5/34 control patients – Methodological issues pseudorandomisation

81. Phase II study of Magnesium Sulfate Bolus Dose escalation study n=40 with 10 controls – Group 1: 4 gm single bolus, – Group 2: 8 gm (in two 4gm doses q4H) – Group 3: 12 gm (in three 4gm doses q4H) – Group 4: 16 gm (in four 4gm doses q4H) Risk ratio for death for patients who received any magnesium 0.25 (CI 0.10 & 0.61)

82. 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.

83. Using nAChRs antagonists to prevent OP-induced NMJ failure

86. Conclusion Rapid atropinisation – Adjunctive sedation Oximes – Diethyl OPs with evidence of response – Explore other dose protocols Adjunct treatment require more investigation – Neuromuscular antagonists – Magnesium