Organophosphate Toxicity Lessons from Anuradhapura

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Organophosphate Toxicity Lessons from
Anuradhapura

• Andrew Dawson
• Program Director
• Sri Lanka

www.asiatox.org
Wellcome Trust Australian National Health and
Medical Research Council International
Collaborative Capacity Building Research Grant
(GR071669MA )
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Organophosphate Poisoning

• Asia 300,000 deaths /year
• Sri Lanka
• 17000 admissions
• 35 ICU
• 10 Die (20 of symptomatic)

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Past Pivotal Points Pesticide Restriction
Personal Communication Gunnell D, Fernando R,
Heganawathna N et al
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Clinical Challenges
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Expensive Costs Anuradhapura General Hospital
Steel et al APAMT August 2006, Colombo.
www.asiatox.org
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OP Case Fatality Rates
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Lesson 1Influence of Initial Care
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Gastric emptying what happens if you stop?
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The results of observational data on gastric
emptying (GE) in pesticide self-poisoning
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Lesson 2Variability of Toxicity
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Predictors of Death Case Fatality Rates of
pesticides in self-poisoning
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Lesson 3Predictors of Mortality
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Clinical Signs and Mortality
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Glasgow Coma Score Mortality

• Normal GCS 5
• GCS lt14 30
• GCS lt10 60

OP Type Mortality

• Chlorpyrifos 7
• Fenthion 14
• Dimethoate 21

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Review of OP Mechanism
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Normal Nerve Function
ACh
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Normal Nerve Function
ACh
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Normal Nerve Function
AChE
ACh
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How OP Work Reversible Aged Binding
AChE
OP
ACh
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Nicotinic, Muscurinic Central Syndrome
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• Nicotinic
• Paralysis
• Sweating
• Mydriasis
• Hypertension
• Tachycardia
• Cardiovascular
• Arrhythmias
• Hypertension
• Tachycardia
• Tissue ischaemia

• Muscarinic
• Diarrhoea
• Urination
• Miosis
• Bronchospasm
• Emesis
• Lacrimation
• Salivation
• CNS
• CNS depression, coma
• Respiratory Centre Dysfunction
• Seizures

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Lesson 4Use of Atropine
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How Atropine Works
AChE
Atropine
OP
ACh
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Range of times it would take to give adequate
doses of atropine (23mg and 75 mg) following the
expert advice from each text
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Scheme of atropinization (endpoints to be
reached)

• Eddleston M, Buckley NA, Mohamed F, Senarathna
  L, Hittarage A, Dissanayake W, Azhar S, Sheriff
  MHR, Dawson AH. Speed of initial atropinisation
  in significant organophosphorus pesticide
  poisoning - a comparison of recommended regimens.
  Journal of Toxicology Clinical Toxicology
  20046865-875.

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Results
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Clinical Challenges
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Lesson 5Reasons for Variation
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Most common organophosphorus pesticides
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Clinical Variation Risk Relative human toxicity
of pesticides in self-poisoning

• Eddleston M, Eyer P, Worek F, Mohamed F, et al
  Differences between organophosphorus insecticides
  in human self-poisoning a prospective cohort
  study. Lancet. 2005 Oct 22-28366(9495)1452-9

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Time to Death
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Chlorpyrifos Chlorpyrifos Dimethoate Fenthion
Median (IQR) Hours to Adm 4 (2 to 5) 4 (2 to 5) 3 (2 to 5) 4 (2 to 7)
Admission values Admission values Admission values
Mean OP (uM) Mean OP (uM) 1.28 355.5 4.86
Median BuChE (mU/ml) Median BuChE (mU/ml) 33.5 1129 0.0
Median AChE (mU/?mol Hb) Median AChE (mU/?mol Hb) 63.5 69.0 64.2
Median aged AChE Median aged AChE 19.4 71.9 70.3
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Effectiveness of 1 gram pralidoxime treatment
Chlorpyrifos
Dimethoate
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OPs are different

• Differing Toxicity Kinetics
• Different Clinical Syndromes
• Different Response to Antidotes
• ? Need Different Treatment Responses

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Alternate Sites for Antidotes

• Protect AChE
• Supply AChE
• Reduce ACh
• Protect ACh Receptor
• Reduce OP Load

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Magnesium

• Reduces acetylcholine release
• Blockage pre-synaptic calcium channels
• Central and Peripheral Nervous System
• Decrease toxicity in animal models
• Limited human studies
• Singh G. Electroencephalogr.Clin.Neurophysiol.
  1998107(2)140-8.
• Magnesium sulfate in acute human OP poisoning
  Pajoumand A et al Hum Exp Toxicol. 2004
  23(12)565-9

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Lessons from Anuradhapura

• Influence of Initial Care on Mortality
• Risk of decontamination
• Variability of Toxicity
• Applied to regulatory decisions, pesticide
  withdrawal
• Predictors of Mortality
• Pesticide type Clinical Status
• Use of Atropine
• The doubling protocol
• Reasons for Variation
• Chemical and KineticOxime Failure
• Implications for where, how and what treatment is
  delivered

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Conclusion

• OP Poisoning remains a complex problem
• There are many reasons contributing to death
• Multiple Points of Intervention (Medical,
  Regulatory Social) requires Research