South Asian Clinical Toxicology Research Collaboration Organophosphate Toxicity Lessons from Anuradhapura Andrew Dawson Program Director Sri Lanka

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 )


Organophosphate PoisoningOrganophosphate Poisoning

Asia 300,000 deaths /year Sri Lanka

– 17000 admissions– 35% ICU– 10% Die (20% of symptomatic)


Past Pivotal Points : Past Pivotal Points : Pesticide RestrictionPesticide Restriction

Personal Communication Gunnell D, Fernando R, Heganawathna N et al


Clinical ChallengesClinical Challenges


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


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


Lesson 1Lesson 1

Influence of Initial CareInfluence of Initial Care


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


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


Lesson 2Lesson 2

Variability of ToxicityVariability of Toxicity


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)


Lesson 3Lesson 3

Predictors of MortalityPredictors of Mortality


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


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%


Review of OP MechanismReview of OP Mechanism


Normal Nerve FunctionNormal Nerve Function

AChACh



AChACh



AChACh

AChEAChE


How OP Work: How OP Work: Reversible & Aged BindingReversible & Aged Binding

AChEAChE

AChACh OPOP


Nicotinic, Muscurinic & Central Nicotinic, Muscurinic & Central SyndromeSyndrome


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


Lesson 4Lesson 4

Use of AtropineUse of Atropine


How Atropine WorksHow Atropine Works

AChEAChE

AChACh OPOP

AtropineAtropine


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


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


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


Clinical ChallengesClinical Challenges


Lesson 5Lesson 5

Reasons for VariationReasons for Variation


Most common organophosphorus Most common organophosphorus pesticidespesticides


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


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


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%


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


OPs are differentOPs are different

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


Alternate Sites for AntidotesAlternate Sites for Antidotes• Protect AChE

• Supply AChE

• Reduce ACh

• Protect ACh Receptor

• Reduce OP Load


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


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


ConclusionConclusion OP Poisoning remains a complex problem

There are many reasons contributing to death

Multiple Points of Intervention (Medical, Regulatory & Social) requires Research

Documents

South Asian Clinical Toxicology Research Collaboration Organophosphate Toxicity Lessons from Anuradhapura Andrew Dawson Program Director Sri Lanka