Tox Asian Style

South Asian Clinical Toxicology Research Collaboration

Andrew Dawson

Lessons in Organophosphate Poisoning

Messages• Nosocomial risk of poisoning is extremely low

• OPs are different…significant clinical variation• thiones or oxones• solvents and excipients

• Admission GCS is important

• Aggressive Atropinisation• Oximes uncertain• Neuromuscular junction protection

Rural Developing World

•Self–poisoning predominates

•15-30% mortality

• (0.3% for all poisoning in the west)

•300,000 OP deaths /year

Eddleston M et al. Management of acute organophosphorus pesticide poisoning. Lancet. Feb 16 2008;371(9612):597-607.

• No reports of nosocomial poisoning

Nosocomial Poisoning: Perception can be as important as the reality

Review of OP Mechanism

Variation of organophosphate toxicity

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

Time to Death

• Early & late respiratory failure

• Cardiac Shock (Dimethoate)

• Iatrogenic

✍ Eddleston M et al. Lancet. 2005 Oct 22-28;366(9495):1452-9

Time to Death

• Early & late respiratory failure

• Cardiac Shock (Dimethoate)

• Iatrogenic

✍ Eddleston M et al. Lancet. 2005 Oct 22-28;366(9495):1452-9

SpontaneousReactivation

KSR

Oxime

KOR

InducedReactivation

OP-AChEKB

POX

PON&OtherEnzymes

AgedOP-AChE

Kage

ACh

OP + AChE

ACh

ACh AC

h

Presynaptic Postsynaptic

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

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Clinical Syndromes

• Acute Cholinergic: –Central Muscarinic–Peripheral Muscarinic

• Intermediate Syndrome• Peripheral Nicotinic

• Delayed peripheral neuropathy• Neurocognitive dysfunction

Respiratory failure

Nicotinic, Muscurinic & Central Syndrome

Acronyms

DUMBELSDiarrhoea,Urination, Miosis, Bradycardia, Bronchorrhoea, Bronchospasm,Emesis, Lacrimation, Salivation

SLUDGE (BBB)Salivation, Lacrimation, Urination, Defecation, Gastrointestinal Distress and Emesis (Bradycardia, Bronchorrhoea, Bronchospasm)

Nicotinic Effects• Stimulation of sympathetic nervous system

– Mydriasis, hypertension, tachycardia– re-entrant dysrhythmias– cardiorespiratory arrest

• Muscle Weakness– Fasiculations (large muscles and tounge)– clonus– Tremor

• Respiratory diffi culty (> 24 hours)– respiratory muscle weakness– diaphragmatic weakness

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1 Hz 3 Hz 10 Hz 15 Hz 20Hz 30 Hz

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I

L

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Mechanism

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

• Signifi cant at diaphragm where respiration is typically driven by bursts of 4-5 impulses at about 50 Hz.

Predictors of Mortality

Coma is badType of pesticide is important

3 clinical syndromes worse than 2

ROC plot for all OPs comparing the predictive value of GCS, pulse, blood pressure, pupil size and intubation.

Davies J et al. QJM 2008;101:371-379

© 2008 The Authors

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

How to atropinise quickly?

The doubling protocol

Cu

mu

lati

ve

Do

se

Minutes

2 4 8 16 4

Lungs Crackles and Wheeze

Lungs Clearing

Cu

mu

lati

ve

Do

se

Minutes

2 4 8 16 4

Lungs Crackles and Wheeze

Lungs Clearing End points

Clear Chest

sBP > 80mmHg

HR > 80/min

Dry Axillae

(Pupils no longer pinpoint)

• 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 effi cacy or toxicity

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

Use of Oxime reactivators

• Oximes reverse the inhibition of AChE– Mucarinic– Nicotinic

Pralidoxime plama conc.

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

• 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 3. Pharmacodynamics of oxime administration.

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

Diethyl DimethylOximePlacebo

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 defi ned 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 signifi cant 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

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

A. Effect of pesticide on NMJ function

B. Protecting NMJ with rocuronium

C. Effect of withdrawing rocuronium

Key Tests

• ECG– QT prolongation is reported– Myocarditis

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

? Blood• Red cell acetylcholinesterase

– more closely refl ects 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.

Messages• Nosocomial risk is extremely low

• OPs are different…significant clinical variation• thiones or oxones• solvents and excipients

• Admission GCS is important

• Aggressive Atropinisation• Oximes uncertain• Neuromuscular junction protection

Conclusion

• Minimal panic & good supportive care• Rapid atropinisation

– Adjunctive sedation• Oximes

– Diethyl with evidence of response• Adjunct treatment require more

investigation– Neuromuscular antagonists– Magnesium

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