Pesticide Poisoning in the 21st century

Toxic Issues in the ED2012

Objectives

• Variability in organophosphates

• Clinical relevance

• Implication for treatment

Take Home Messages

• The patient is poisoned…not the staff

• Atropine is good

• Oximes are uncertain

Perth case

A 30 yo male ingests 250 mls of chlorpyrifos in the northern

suburbs

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

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

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

Hanoi: Dr Pham Due

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

Targeting Treatment for Organophosphate Poisoning

Andrew Dawson

South Asian Clinical Toxicology Research Collaboration

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

Chemical Variation

• Chemical– Thione or Oxone– Dimethyl or Diethyl

• The solvent

Thione Prodrugs & Oxones

Dimethyl

P

O

X

O CH3

O CH3

Diethyl

P

O

X

O CH2 CH3

O CH2 CH3

The Mechanism

Acetylcholinesterase

Cholinergic Muscarinic EffectsDUMBELS

• D iarrhoea• U rination• M iosis• B radycardia, Bronchorrhoea, Bronchospasm• E mesis• L acrimation• S alivation

Nicotinic, Muscurinic & Central Syndrome

Normal Nerve Function

ACh

Normal Nerve Function

ACh

Normal Nerve Function

ACh

AChE

How OP Work: Reversible & Aged Binding

AChE

ACh OP

Clinical

Clinical Syndromes• Acute Cholinergic:

– Central Muscarinic– Peripheral Muscarinic

• Intermediate Syndrome Peripheral Nicotinic

• Delayed peripheral neuropathy• Neurocognitive dysfunction

Respiratory failure

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

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

Intermediate SyndromeWadia et. al 1974 :Type II Paralysis, Senanayake and Karalliedde 1987, Jayawardane 2008

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

Pradeepa Jayawardane

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

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.

Cases for discussion

• 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.

• 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.

• 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?

Are the patients the same?

Relative Toxicity of Organophosphates

✍ Dawson et al. PLoS Med 2010, Oct 26;7(10):e1000357

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

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

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

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.

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

Cyclohexanone EC40 vs EC35

Eddleston et al Toxicology 2012, Apr;294(2-3):94-103.

Predictors of Mortality

Coma is badType of pesticide is important

3 clinical syndromes worse than 2

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

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

Glasgow Coma Score & Mortality• Normal GCS 5%• GCS <14 30%• GCS <10 60%

OP Type & Mortality Chlorpyrifos 7% Fenthion 14% Dimethoate 21%

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

Treatment Priorities• ABC first

– Ventilate: Benzodiazepines ? Competitive neuromuscular blockers

• Atropinisation

• Consider decontamination

• ? Oximes

How quickly should we atropinise?

• 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

Doubling atropine against response

Cum

ulat

ive

atro

pine

mgs

Minutes

2 4 8 16 8

Lungs Clearing Lungs Crackles and Wheeze

End points of atropinisation

Lung Secretions

Hypotension

Bradycardia

Sweating

(Miosis)

Clear Chest

sBP > 80mmHg

HR > 80/min

Dry Axillae

(Pupils no longer pinpoint)

ATROPINE

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

Incremental bolusBolus injection

Use of Oxime reactivators

• Oximes reverse the inhibition of AChE– Mucarinic– Nicotinic

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

Pralidoxime plama conc.

Reproduced from - Eyer P, Buckley NA “Pralidoxime for organophosphate poisoning”.Comment in the Lancet 2006: 368:2110-2111

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

• 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 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 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

• 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

Key Tests

• ECG– QT prolongation is reported– Myocarditis

• Chest X-ray—aspiration and other respiratory complications are very common.

? Blood• Plasma butyrylcholinesterase

– highly sensitive – may be useful when the diagnosis is in – does not correlate with severity of poisoning.

? 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.

Are old drugs the new hope?

>>200 ‘proof of concept’ publications 1962-2004

Alternate Sites for Antidotes• Protect AChE• Supply AChE

• FFP

• Reduce ACh • Clonidine• Magnesium

• Protect ACh Receptor• Reduce OP Load

• FFP or Albumin• OP hydrolases

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.

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.

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

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)

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

Conclusion

• Rapid atropinisation– Adjunctive sedation

• Oximes– Diethyl OPs with evidence of response– Explore other dose protocols

• Adjunct treatment require more investigation– Neuromuscular antagonists– Magnesium