Andrew Dawson: Tox Asian Style

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

http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000104

Figure 4. Timing of deaths in the two study arms.



Figure 6. Forest plots of mortality for pralidoxime versus placebo for a priori defi ned study groups.



• 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

Open source Curriculum

www.wikitox.org

Health & Medicine

Andrew Dawson: Tox Asian Style