andrew dawson: tox asian style
DESCRIPTION
Dawson draws on his experience in areas of high prevalence organophosphate poisoning to optimise management of sick patients.TRANSCRIPT
Tox Asian Style
South Asian Clinical Toxicology Research Collaboration
Andrew Dawson
Lessons in Organophosphate Poisoning
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
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.
• No reports of nosocomial poisoning
Nosocomial Poisoning: Perception can be as important as the reality
Review of OP Mechanism
Variation of organophosphate toxicity
✍ Dawson et al. PLoS Med 2010, Oct 26;7(10):e1000357
Time to Death
• Early & late respiratory failure
• Cardiac Shock (Dimethoate)
• Iatrogenic
✍ Eddleston M et al. Lancet. 2005 Oct 22-28;366(9495):1452-9
Time to Death
• Early & late respiratory failure
• Cardiac Shock (Dimethoate)
• Iatrogenic
✍ Eddleston M et al. Lancet. 2005 Oct 22-28;366(9495):1452-9
SpontaneousReactivation
KSR
Oxime
KOR
InducedReactivation
OP-AChEKB
POX
PON&OtherEnzymes
AgedOP-AChE
Kage
ACh
OP + AChE
ACh
ACh AC
h
Presynaptic Postsynaptic
0 10 20 30 40
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
Die
thyl
Dim
eth
yl
Rate of “Ageing”
t ½ 3.7 hrs
t ½ 33 hrs
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Clinical Syndromes
• Acute Cholinergic: –Central Muscarinic–Peripheral Muscarinic
• Intermediate Syndrome• Peripheral Nicotinic
• Delayed peripheral neuropathy• Neurocognitive dysfunction
Respiratory failure
Nicotinic, Muscurinic & Central Syndrome
Acronyms
DUMBELSDiarrhoea,Urination, Miosis, Bradycardia, Bronchorrhoea, Bronchospasm,Emesis, Lacrimation, Salivation
SLUDGE (BBB)Salivation, Lacrimation, Urination, Defecation, Gastrointestinal Distress and Emesis (Bradycardia, Bronchorrhoea, Bronchospasm)
Nicotinic Effects• Stimulation of sympathetic nervous system
– Mydriasis, hypertension, tachycardia– re-entrant dysrhythmias– cardiorespiratory arrest
• Muscle Weakness– Fasiculations (large muscles and tounge)– clonus– Tremor
• Respiratory diffi culty (> 24 hours)– respiratory muscle weakness– diaphragmatic weakness
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1 Hz 3 Hz 10 Hz 15 Hz 20Hz 30 Hz
E
I
L
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Mechanism
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
• Signifi cant at diaphragm where respiration is typically driven by bursts of 4-5 impulses at about 50 Hz.
Predictors of Mortality
Coma is badType of pesticide is important
3 clinical syndromes worse than 2
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
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
How to atropinise quickly?
The doubling protocol
Cu
mu
lati
ve
Do
se
Minutes
2 4 8 16 4
Lungs Crackles and Wheeze
Lungs Clearing
Cu
mu
lati
ve
Do
se
Minutes
2 4 8 16 4
Lungs Crackles and Wheeze
Lungs Clearing End points
Clear Chest
sBP > 80mmHg
HR > 80/min
Dry Axillae
(Pupils no longer pinpoint)
• 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 effi cacy or toxicity
Conventional Bolus Protocol
N= 81
Titrated Doubling Protocol
N= 75
Odds Ratio
Mortality 18 (22.5%) 6 (8%) 0.31 (CI 0.11, 0.80)
Time to atropinisation 152 min(95% CI 130-173)
24 min(95% CI 20-28)
Atropine toxicity 23 (28.4%) (9) 12% 0.35 (CI 0.15, 0.80)
Atropine Dose 109 mg (104-114) 136 mg (129-144)
Ventilation 20 (24.7%) 6 (8%) 0.27 (CI 0.10, 0.70)
0.90
0.80
Use of Oxime reactivators
• Oximes reverse the inhibition of AChE– Mucarinic– Nicotinic
Pralidoxime plama conc.
Reproduced from - Eyer P, Buckley NA “Pralidoxime for organophosphate poisoning”.Comment in the Lancet 2006: 368:2110-2111
• 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.
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.1000104http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000104
Diethyl DimethylOximePlacebo
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.1000104http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000104
Figure 6. Forest plots of mortality for pralidoxime versus placebo for a priori defi ned 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.1000104http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000104
• No signifi cant 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
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.
Using nAChRs antagonists to prevent OP-induced NMJ failure
A. Effect of pesticide on NMJ function
B. Protecting NMJ with rocuronium
C. Effect of withdrawing rocuronium
Key Tests
• ECG– QT prolongation is reported– Myocarditis
• Chest X-ray—aspiration and other respiratory complications are very common.
? Blood• Red cell acetylcholinesterase
– more closely refl ects 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.
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
Conclusion
• Minimal panic & good supportive care• Rapid atropinisation
– Adjunctive sedation• Oximes
– Diethyl with evidence of response• Adjunct treatment require more
investigation– Neuromuscular antagonists– Magnesium
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