org a no phosphate poisoning wiki

8/8/2019 Org a No Phosphate Poisoning Wiki

1/31

South Asian Clinical Toxicology Research Collaboration

OrganophosphateOrganophosphate PesticidePesticide

PoisoningPoisoning

OrganophosphateOrganophosphate PesticidePesticide

PoisoningPoisoning

Bishan RajapakseMBChB Otago

Emergency Medicine Advanced Trainee, MPhil Student (ANU),


Sri Lanka

Bishan RajapakseMBChB Otago

Emergency Medicine Advanced Trainee, MPhil Student (ANU),


Sri Lanka


2/31


The Case.The Case. Picture yourself in Anuradhapura hospital Sri

Lanka ED/ Medical SHO

Ward 6 , teaming with patients.

Charge Sister tells you there is a sick patient 36yo F

Taken 100mls of Dimethoate after a domestic

argument Theres nowhere to run, or hide. So you see

the patient what do you do?


3/31


Organophosphate PesticideOrganophosphate Pesticide

PoisoningPoisoning


4/31


Organophosphate Poisoning in Sri LankaOrganophosphate Poisoning in Sri Lanka

Organophosphate

pesticide (OP)

poisoning kills

300,000 worldwide

In Sri Lanka these are

mostly impulsive

deliberate self-

poisoning in young

people


5/31


Organophosphate Poisoning in Sri LankaOrganophosphate Poisoning in Sri Lanka

Case Fatality rates(CFR)

10-20% for most

50-70% for some OPs

In west CFR 0.3% from all poisons

Multifactorial

Toxicity of OPs

Patient transport Lack of resources

Training

Although less common OP

Poisoning is still a problemin West

Occupational exposure

Threat of Chemical warfare


6/31


Poisoning at Anuradhapura Hospital inPoisoning at Anuradhapura Hospital in

20052005

Poison Admissions Death Case FatalityAcid 2 0 0%

Carbamate 105 3 3%

Hydrocarbon 62 0 0%

Medicine 254 3 1%

Oleander 380 8 2%

OP 408 44 11%

Other Pest. 311 12 4%

Paraquat 59 21 35.50%

Unknown 128 7 5.50%

Un.pesticide 127 13 10%

TOTAL 1836 111 6%


7/31


Mechanism of OPsMechanism of OPs


8/31


Simplified Acute OP ToxicitySimplified Acute OP Toxicity Inactivation of acetylcholinesterase enzyme

Organophosphate


9/31


10/31


Cholinomimetic Pharmacokinetics Pharmacodynamics

Simple Alcohols

Eg edrophonium

Polar, not fat soluble Electrostatically bind to active

site of AChE

(short lived 2-10mins)

Carbamates Tertiary well absorbed, fat solubleEg physostigmine

Quaternary- polar, negligible CNS

distribution

2 step hydrolysis of to form

Carbamoylated enzyme-

inhibitor complex (30mins to 6

hours)

- Reversible inhibitors

Organophosphates Variable over50,000 varietiesMost fat soluble- thus well absorbed

and dangerous to humans

(Echothiopate is one of the water

soluble varieties)Thiophosphates -

need conversion to Oxon form to workMalathion are metabolised to inactive

forms in birds and mammals but not

fish

Binding and hydrolysis to form

Phosphorylated enzyme-

inhibitor complex

Covalent phosphorus-enzyme

hydrolyses slowly (hundreds of

hours sometimes)-Irreversible inhibitors

--May undergo Aging (different

rates for different OPs) with no

oxime regeneration thereafter


11/31


+ Death

Clinical Syndrome

Acute Cholinergic:

Central

Peripheral Muscarinic

Peripheral Nicotinic

Intermediate Syndrome

OPIDN: Delayed peripheral neuropathy Neurocognitive dysfunction

Clinical SyndromeClinical Syndrome

RespiratoryfailureRespiratoryfailure


12/31


Cholinergic EffectsCholinergic Effects

D iarrhoea

U rination

M iosis B radycardia, Bronchorrhoea, Bronchospasm

E mesis

L acrimation

S alivation


13/31


Nicotinic EffectsNicotinic Effects Respiratory difficulty

respiratory arrest diaphragmatic weakness

Muscle Weakness

fasiculations

clonus

tremor

Stimulation of sympathetic nervous system

Mydriasis, hypertension, tachycardia

re-entrant dysrhythmias

cardiorespiratory arrest


14/31


CNS effectsCNS effects Malaise

Memory loss

Confusion

Disorientation

Delirium

Seizures

Respiratory centre depression or dysfunction

Coma


15/31


Intermediate SyndromeIntermediate Syndrome Delayed Respiratory Failure

Proximal muscle weakness and cranial nerve lesions

Typically 1-4 days after cholinergic crisis has resolved

Prolonged Effects on Nicotinic receptors

Primary motor end plate degeneration

Clinical importance

Delayed respiratory failure leads to death if not aware

of it or prepared for it

Wadia et. al 1974 :Type II Paralysis, Senanayake and

Karalliedde 1987


16/31


Chronic EffectsChronic Effects Organophosphate induced delayed

neuropathy (OPIDN)

1-3weeks

Peripheral neuropathy Axonopathy due to Neuropathy Target Esterases

(NTE)

Chronic organophosphate inducedneuropsychiatric disorder (COPIND)


17/31


ManagementManagementThe priorities in management are to:

Resuscitation

Atropinisation of symptomatic patients

Decontamination

Other Treatments - Oximes


18/31


AntidotesAntidotes

Atropine

Oximes

Expensive Does treatment affect outcome

Intermediate Syndrome?

OPIDN?

? Dose

? Duration

?

Effectiveness


19/31


Does the patient needDoes the patient needatropine?atropine?

How much and for how long


20/31


Scheme of atropinizationScheme 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 Toxicology2004;6:865-875.

0 5 10 15

0

10

20

30

40

min after first atropine

dose

2 4 8 16 Atropine requirement

Poor air entry into lungs caused by

bronchospasm and bronchorrhoea

Excessive sweating

(Hypotension)

(Bradycardia)

(Miosis)

Atropinization

Clear lungs

Dry axillae

Systol. BP >

80 mm Hg

Heart rate >

80/min

No miosis


21/31


AtropineAtropine Loading

Doubling dose regime e.g. 2 4 8 16 mgs every 5minutes

Maintenance

Continuous infusion < 3mg/hr

10-20% of loading dose/hour

Endpoints

Clear chest on auscultation with no wheeze

Heart rate >80 beats/min

Withdrawal

Atropine toxicity

Clinical Improvement


22/31


What if you give too much Atropine ?What if you give too much Atropine ?

Anticholinergic Syndrome: Hot as hell

Blind as a bat

Red as a beet

Dry as a bone

Mad as a hatter

A sensitive indicator for ingestion, but

poor predictor for toxicity.

Full syndrome is rare


23/31


Gastrointestinal DecontaminationGastrointestinal Decontamination


24/31


Our Decision should dependOur Decision should depend

on a risk/benefit analysison a risk/benefit analysisNothing

Emesis Gastric Lavage

Activated Charcoal

Whole bowel irrigation


25/31


Risk of InterventionRisk of Intervention Aspiration

Impaired GCS + Unprotected Airway Emesis, Lavage, Charcoal (worse with cathartics)

Trauma

Oesphageal Injury Emesis, Lavage, Charcoal

Electrolyte Abnormalities Forced Emesis, Cathartics

Cardiac Arrest Toxin induced bradycardia + Vagal Tone

Induced emesis, Lavage

Cost


26/31


Summary of Experimental EvidenceSummary of Experimental Evidence

Ideal settings

Little benefit in outcomes after 1 hour

Activated Charcoal is equivalent or betterthan emesis or lavage

Position statement: single-dose activated charcoal. JToxicol Clin Toxicol1997;35:721-41.

Position statement and practice guidelines on the use of multi-doseactivated charcoal in the treatment of acute poisoning. JToxicol ClinToxicol1999;37:731-51.


27/31


OximesOximes

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


28/31


Alternate sites for antidotesAlternate sites for antidotes

Protect AChE

Supply AChE

Reduce ACh

Protect ACh

Receptor

Reduce OP Load

Multiple

Mechanisms


29/31


Other Treatments underOther Treatments under

investigationinvestigation Magnesium Reduces acetylcholine release

Blockage pre-synaptic calcium channels

Limited human studies

Clonidine Decrease the presynaptic synthesis and release of acetylcholine.

Central nervous system > peripheral cholinergic synapses

Diazepam

Diazepam reduces respiratory failure (rats) and cognitivedeficit (primates)

Postulate uncoordinated stimulation of the respiratory centres

decreases phrenic nerve output.


30/31


The Case.The Case. Picture yourself in Anuradhapura hospital Sri

Lanka ED/ Medical SHO

Ward 6 , teaming with patients.

Charge Sister tells you there is a sick patient 36yo F

Taken 100mls of Dimethoate after a domestic

argument

Theres nowhere to run, or hide. So you see

the patient what do you do?


31/31


SummarySummary OPs are Indirect Cholinomimetic

Block AChE, prolonged duration of ACh in

synapse

Effects Muscarinic, Nicotinic, CNS

Respiratory failure and Death result from this

Treatment ABCs, Atropine, Decontaminate, Oximes

Important also in West

org a no phosphate poisoning wiki

Documents