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

1. Tox Asian Style
Andrew Dawson
South Asian Clinical Toxicology Research Collaboration

4. Lessons in Organophosphate
Poisoning

5. 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

6. 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.

7. •
No reports of nosocomial poisoning

8. Nosocomial Poisoning: Perception can be
as important as the reality

9. Review of OP Mechanism

10. Variation of organophosphate toxicity
✍ Dawson et al. PLoS Med 2010, Oct 26;7(10):e1000357

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

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

13. 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

14. 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

15. mov

16. avi

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

18. Nicotinic, Muscurinic & Central Syndrome

19. Acronyms
DUMBELS
Diarrhoea,Urination, Miosis, Bradycardia,
Bronchorrhoea, Bronchospasm,Emesis,
Lacrimation, Salivation
SLUDGE (BBB)
Salivation, Lacrimation, Urination,
Defecation, Gastrointestinal Distress and
Emesis (Bradycardia, Bronchorrhoea,
Bronchospasm)

20. 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

21. mov

22. avi

23. 1 Hz
E
I
L
3 Hz
10 Hz
15 Hz
20Hz
30 Hz

24. mov

25. avi

26. Mechanism

27. 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.

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

29. 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

30. 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

31. How to
atropinise quickly?
The doubling protocol

32. 2
4
8
16
4
Lungs Clearing
Cumulative Dose
Lungs Crackles and Wheeze
Minutes

33. 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)

34. •
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

35. 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)

36. 0.90
0.80

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

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

39. •
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.

40. 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

41. 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

42. 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

43. •
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

44. 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.

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

46. A. Effect of
pesticide on NMJ
function

47. B. Protecting NMJ
with rocuronium

48. C. Effect of
withdrawing
rocuronium

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

50. ? 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.

51. 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

52. Conclusion
•
•
Minimal panic & good supportive care
Rapid atropinisation
–
•
Oximes
–
•
Adjunctive sedation
Diethyl with evidence of response
Adjunct treatment require more
investigation
–
–
Neuromuscular antagonists
Magnesium

53. Open source
Curriculum
www.wikitox.org