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South Asian Clinical Toxicology Research Collaboration
Organophosphate Toxicity Organophosphate Toxicity Lessons from AnuradhapuraLessons 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 )
South Asian Clinical Toxicology Research Collaboration
Organophosphate PoisoningOrganophosphate Poisoning
Asia 300,000 deaths /year Sri Lanka
– 17000 admissions– 35% ICU– 10% Die (20% of symptomatic)
South Asian Clinical Toxicology Research Collaboration
Past Pivotal Points : Past Pivotal Points : Pesticide RestrictionPesticide Restriction
Personal Communication Gunnell D, Fernando R, Heganawathna N et al
South Asian Clinical Toxicology Research Collaboration
Clinical ChallengesClinical Challenges
South Asian Clinical Toxicology Research Collaboration
Expensive: Expensive: Costs Anuradhapura General HospitalCosts Anuradhapura General Hospital
Types of Poisons and Different Cost Categories
0 2000 4000 6000
All
Pesticides
Seeds
Medicine
Ty
pe
of
Po
iso
n
Average cost (Rs.)
Drugs Other treatments Tests
Nurses Doctors Psychiatrist
Attendants Capital Cost Recurrent Cost
Steel et al APAMT August 2006, Colombo. www.asiatox.org
South Asian Clinical Toxicology Research Collaboration
OP Case Fatality RatesOP Case Fatality Rates
0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
14.00%
16.00%
2004 2005 2006
Anu All OP
Polo All OP
South Asian Clinical Toxicology Research Collaboration
Lesson 1Lesson 1
Influence of Initial CareInfluence of Initial Care
South Asian Clinical Toxicology Research Collaboration
Gastric emptying – Gastric emptying – what happens if you stop?what happens if you stop?
Case fatalityAnuradhapura Hospital
1998-2002
1998
1999
2000
2001
2002
0
10
20
30
Cas
e fa
tali
ty
South Asian Clinical Toxicology Research Collaboration
The results of observational data on gastric The results of observational data on gastric emptying (GE) in pesticide self-poisoningemptying (GE) in pesticide self-poisoning
Case fatalityAnuradhapura Hospital
in and not in RCT
GCS <14 GCS <100
25
50
75No GE (in trial)
GE (NIT)
Cas
e fa
tali
ty
South Asian Clinical Toxicology Research Collaboration
Lesson 2Lesson 2
Variability of ToxicityVariability of Toxicity
South Asian Clinical Toxicology Research Collaboration
Predictors of DeathCase Fatality Rates of pesticides in self-poisoning
0 10 20 30 40 50 60 70
carbofuranfenobucarbcarbosulfan
malathion
phenthoatediazinon
chlorpyrifosfenthion
profenofosquinalphosdimethoate
etofenprox
imidaclopridchlorfluazuron
bispyribacglyphosate
MCPApropanilparaquat
Case fatality ratio (95% CI)
South Asian Clinical Toxicology Research Collaboration
Lesson 3Lesson 3
Predictors of MortalityPredictors of Mortality
South Asian Clinical Toxicology Research Collaboration
Clinical Signs and MortalityClinical Signs and MortalityROC plot GCS, Pulse, BP and
Pupil size
0.000.250.500.751.000.00
0.25
0.50
0.75
1.00
GCSPulseBPsysPupils
Sensitivity
Sp
ecif
icit
y
South Asian Clinical Toxicology Research Collaboration
Glasgow Coma Score & MortalityGlasgow Coma Score & Mortality Normal GCS 5% GCS <14 30% GCS <10 60%
OP Type & MortalityOP Type & Mortality Chlorpyrifos 7% Fenthion 14% Dimethoate 21%
South Asian Clinical Toxicology Research Collaboration
Review of OP MechanismReview of OP Mechanism
South Asian Clinical Toxicology Research Collaboration
Normal Nerve FunctionNormal Nerve Function
AChACh
South Asian Clinical Toxicology Research Collaboration
Normal Nerve FunctionNormal Nerve Function
AChACh
South Asian Clinical Toxicology Research Collaboration
Normal Nerve FunctionNormal Nerve Function
AChACh
AChEAChE
South Asian Clinical Toxicology Research Collaboration
How OP Work: How OP Work: Reversible & Aged BindingReversible & Aged Binding
AChEAChE
AChACh OPOP
South Asian Clinical Toxicology Research Collaboration
Nicotinic, Muscurinic & Central Nicotinic, Muscurinic & Central SyndromeSyndrome
South Asian Clinical Toxicology Research Collaboration
Muscarinic– Diarrhoea– Urination– Miosis– Bronchospasm– Emesis– Lacrimation– Salivation
CNS– CNS depression, coma– Respiratory Centre Dysfunction– Seizures
Nicotinic– Paralysis– Sweating– Mydriasis– Hypertension – Tachycardia
Cardiovascular– Arrhythmias– Hypertension– Tachycardia– Tissue ischaemia
South Asian Clinical Toxicology Research Collaboration
Lesson 4Lesson 4
Use of AtropineUse of Atropine
South Asian Clinical Toxicology Research Collaboration
How Atropine WorksHow Atropine Works
AChEAChE
AChACh OPOP
AtropineAtropine
South Asian Clinical Toxicology Research Collaboration
Range of Range of times it times it
would take would take to give to give
adequate adequate doses of doses of atropine atropine
(23mg and (23mg and 75 mg) 75 mg)
following the following the expert expert
advice from advice from each texteach text
South Asian Clinical Toxicology Research Collaboration
Scheme of atropinization Scheme of atropinization (endpoints to be reached)(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 2004;6:865-875.
0 5 10 150
10
20
30
40
min after first atropinedose
2 4 8 16 Atropine requirement
Poor air entry into lungs caused bybronchospasm and bronchorrhoea
Excessive sweating
(Hypotension)
(Bradycardia)
(Miosis)
Atropinization
Clear lungs
Dry axillae
Systol. BP >80 mm HgHeart rate >80/minNo miosis
South Asian Clinical Toxicology Research Collaboration
ResultsResults
0
10
20
30
40
50
60
Fixed Dose Titrated Dose
Auditory
Visual
Either
Restrained
Delirium by CAM
Delirium by DSM-IV
Mean Hospital Stay
South Asian Clinical Toxicology Research Collaboration
Clinical ChallengesClinical Challenges
South Asian Clinical Toxicology Research Collaboration
Lesson 5Lesson 5
Reasons for VariationReasons for Variation
South Asian Clinical Toxicology Research Collaboration
Most common organophosphorus Most common organophosphorus pesticidespesticides
South Asian Clinical Toxicology Research Collaboration
0 10 20 30 40
chlorpyrifos
fenthion
dimethoate
Case fatality ratio (95% CI)
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 22-28;366(9495):1452-9
X symptomatic
X
X
X
South Asian Clinical Toxicology Research Collaboration
Time to DeathTime to Death
Chlorpyrifos Dimethoate Fenthion
0
25
50
75
100
200
300
400
500
Tim
e (
hrs
) b
etw
ee
n
OP
in
ge
sti
on
an
d d
ea
th
South Asian Clinical Toxicology Research Collaboration
Chlorpyrifos Dimethoate Fenthion
Median (IQR) Hours to Adm 4
(2 to 5)
3
(2 to 5)
4
(2 to 7)
Admission values
Mean [OP]
(uM)1.28 355.5 4.86
Median BuChE (mU/ml) 33.5 1129 0.0
Median AChE (mU/mol Hb) 63.5 69.0 64.2
Median aged AChE 19.4% 71.9% 70.3%
South Asian Clinical Toxicology Research Collaboration
Effectiveness of 1 gram pralidoxime Effectiveness of 1 gram pralidoxime treatmenttreatment
0 24 48 72 96ti -5,0
100
200
300
400
500
600
700AChE in vivo
AChE in vitro
Time [h]
mU
/µm
ol
Hb
0 24 48 72 96ti -2,2
100
200
300
400
500AChE in vivo
AChE in vitro
Time [h]
mU
/µm
ol
Hb
Chlorpyrifos Dimethoate
South Asian Clinical Toxicology Research Collaboration
OPs are differentOPs are different
Differing Toxicity & Kinetics Different Clinical Syndromes Different Response to Antidotes ? Need Different Treatment Responses
South Asian Clinical Toxicology Research Collaboration
Alternate Sites for AntidotesAlternate Sites for Antidotes• Protect AChE
• Supply AChE
• Reduce ACh
• Protect ACh Receptor
• Reduce OP Load
South Asian Clinical Toxicology Research Collaboration
MagnesiumMagnesium
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. 1998;107(2):140-8.
• Magnesium sulfate in acute human OP poisoning Pajoumand A et al Hum Exp Toxicol. 2004 23(12):565-9
South Asian Clinical Toxicology Research Collaboration
Lessons from Anuradhapura 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 Kinetic:Oxime Failure
– Implications for where, how and what treatment is delivered
South Asian Clinical Toxicology Research Collaboration
ConclusionConclusion OP Poisoning remains a complex problem
There are many reasons contributing to death
Multiple Points of Intervention (Medical, Regulatory & Social) requires Research