pesticide poisoning in the 21 st century toxic issues in the ed 2012
TRANSCRIPT
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Pesticide Poisoning in the 21st century
Toxic Issues in the ED2012
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Objectives
• Variability in organophosphates
• Clinical relevance
• Implication for treatment
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Take Home Messages
• The patient is poisoned…not the staff
• Atropine is good
• Oximes are uncertain
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Perth case
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A 30 yo male ingests 250 mls of chlorpyrifos in the northern
suburbs
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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
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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
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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
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Hanoi: Dr Pham Due
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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
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Targeting Treatment for Organophosphate Poisoning
Andrew Dawson
South Asian Clinical Toxicology Research Collaboration
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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
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Chemical Variation
• Chemical– Thione or Oxone– Dimethyl or Diethyl
• The solvent
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Thione Prodrugs & Oxones
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Dimethyl
P
O
X
O CH3
O CH3
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Diethyl
P
O
X
O CH2 CH3
O CH2 CH3
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The Mechanism
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Acetylcholinesterase
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Cholinergic Muscarinic EffectsDUMBELS
• D iarrhoea• U rination• M iosis• B radycardia, Bronchorrhoea, Bronchospasm• E mesis• L acrimation• S alivation
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Nicotinic, Muscurinic & Central Syndrome
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Normal Nerve Function
ACh
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Normal Nerve Function
ACh
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Normal Nerve Function
ACh
AChE
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How OP Work: Reversible & Aged Binding
AChE
ACh OP
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Clinical
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Clinical Syndromes• Acute Cholinergic:
– Central Muscarinic– Peripheral Muscarinic
• Intermediate Syndrome Peripheral Nicotinic
• Delayed peripheral neuropathy• Neurocognitive dysfunction
Respiratory failure
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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
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Respiratory Failure
78 symptomatic patients 12 respiratory failure
< 24 hours7
All Normal RNS
3 Subsequently forme fruste IMS >24
hours
>24 hours5
All severe decrement
• Normal RNS in early respiratory failure suggests a muscarinic syndrome. – Supports early rapid atropinisation to be the initial priority
Pradeepa Jayawardane
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Intermediate SyndromeWadia et. al 1974 :Type II Paralysis, Senanayake and Karalliedde 1987, Jayawardane 2008
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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
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Pradeepa Jayawardane
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1 Hz 3 Hz 10 Hz 15 Hz 20Hz 30 Hz
E
I
L
“Intermediate Syndrome” • a spectrum disorder 50% of patients• Pre & postsynaptic failure
Patient ID: N100234
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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
• Significant at diaphragm where respiration is typically driven by bursts of 4-5 impulses at about 50 Hz.
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Cases for discussion
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• 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.
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• 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.
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• 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?
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Are the patients the same?
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Relative Toxicity of Organophosphates
✍ Dawson et al. PLoS Med 2010, Oct 26;7(10):e1000357
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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
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Chlorpyrifos poisoning
0 24 48 72 96ti -5,0
100
200
300
400
500
600
700AChE in vivo
AChE in vitro
Time [h]
mU
/µm
ol H
b
0 24 48 72 96ti -5,0#
500
1000
1500
2000
2500
3000
BChE
Time [h]
mU
/ml P
lasm
a
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Dimethoate poisoning
0 24 48 72 96ti -2,2
100
200
300
400
500AChE in vivo
AChE in vitro
Time [h]
mU
/µm
ol H
b
0 24 48 72 96ti -2,2
500
1000
1500
2000
2500
3000
BChE
Time [h]m
U/m
l Pla
sma
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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
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.
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SpontaneousReactivation
KSR
Oxime
KOR
InducedReactivation
OP-AChEKB
POX
PON&
OtherEnzymes
AgedOP-AChE
Kage
ACh
OP + AChE
ACh
ACh
AC
h
Pre
syna
ptic
Pos
tsyn
aptic
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Cyclohexanone EC40 vs EC35
Eddleston et al Toxicology 2012, Apr;294(2-3):94-103.
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Predictors of Mortality
Coma is badType of pesticide is important
3 clinical syndromes worse than 2
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Clinical Signs and Mortality
ROC plot GCS, Pulse, BP andPupil size
0.000.250.500.751.000.00
0.25
0.50
0.75
1.00
GCSPulseBPsysPupils
Sensitivity
Sp
ecif
icit
y
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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
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Glasgow Coma Score & Mortality• Normal GCS 5%• GCS <14 30%• GCS <10 60%
OP Type & Mortality Chlorpyrifos 7% Fenthion 14% Dimethoate 21%
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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
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Treatment Priorities• ABC first
– Ventilate: Benzodiazepines ? Competitive neuromuscular blockers
• Atropinisation
• Consider decontamination
• ? Oximes
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How quickly should we atropinise?
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• 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
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Doubling atropine against response
Cum
ulat
ive
atro
pine
mgs
Minutes
2 4 8 16 8
Lungs Clearing Lungs Crackles and Wheeze
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End points of atropinisation
Lung Secretions
Hypotension
Bradycardia
Sweating
(Miosis)
Clear Chest
sBP > 80mmHg
HR > 80/min
Dry Axillae
(Pupils no longer pinpoint)
ATROPINE
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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)
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0.90
0.80
Incremental bolusBolus injection
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Use of Oxime reactivators
• Oximes reverse the inhibition of AChE– Mucarinic– Nicotinic
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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
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Pralidoxime plama conc.
Reproduced from - Eyer P, Buckley NA “Pralidoxime for organophosphate poisoning”.Comment in the Lancet 2006: 368:2110-2111
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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
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• 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.
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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
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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.1000104http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000104
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• 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
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Key Tests
• ECG– QT prolongation is reported– Myocarditis
• Chest X-ray—aspiration and other respiratory complications are very common.
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? Blood• Plasma butyrylcholinesterase
– highly sensitive – may be useful when the diagnosis is in – does not correlate with severity of poisoning.
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? 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.
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Are old drugs the new hope?
>>200 ‘proof of concept’ publications 1962-2004
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Alternate Sites for Antidotes• Protect AChE• Supply AChE
• FFP
• Reduce ACh • Clonidine• Magnesium
• Protect ACh Receptor• Reduce OP Load
• FFP or Albumin• OP hydrolases
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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.
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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.
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Magnesium sulfate in acute human OP poisoning Pajoumand A et al Hum Exp Toxicol. 2004 23(12):565-9
• 16 gram continuous infusion MgSO4 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
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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)
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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.
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Using nAChRs antagonists to prevent OP-induced NMJ failure
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Conclusion
• Rapid atropinisation– Adjunctive sedation
• Oximes– Diethyl OPs with evidence of response– Explore other dose protocols
• Adjunct treatment require more investigation– Neuromuscular antagonists– Magnesium