dr bishan rajapakse - south asian clinical toxicology research collaboration organophosphate...

Dr Bishan Rajapakse - South Asian Clinical Toxicology Research Collaboration

OrganophosphateOrganophosphate PesticidePesticide

PoisoningPoisoning

Bishan RajapakseMBChB Otago

Emergency Medicine Advanced Trainee Registrar, MPhil Student (ANU),

South Asian Clinical Toxicology Research Collaboration (SACTRC)


OP Poisoning - OverviewOP Poisoning - Overview

• Epidemiology

• Mechanism

• Clinical features

• Management

• Current developments in Oxime therapy


CASE

36 yo femaleIngestion of Dimethoate

(Severely Toxic OP)

Village

• Drunk 100mls after dispute

• Found by family vomiting

• Taken to nearest peripheral hospital (1 doctor, 2 nurses)

• Sent by Ambulance (no paramedics) to nearest General hospital

0930 hrs

1000 hrs

0900 hrs(village)

1115 hrs


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ManagementManagement

• Initial Management?– ABC’s– Atropine

• Ongoing Assessment & Management– Oximes (Pralidoxime, Obidoxime) -yes/no?– Dose? Duration?– Acetylcholinesterase assays?


Organophosphorus (OP) Pesticide Organophosphorus (OP) Pesticide PoisoningPoisoning


Organophosphate Poisoning in Sri LankaOrganophosphate Poisoning in Sri Lanka

• Organophosphorus poisoning– High acuity and fatality– 12,000 admissions– 800 deaths – Mostly self-ingestion in

Young adults

• South Asian Clinical Toxicology Research Colaboration (SACTRC)

• 5 Hospitals


Organophosphate Poisoning in Sri LankaOrganophosphate Poisoning in Sri Lanka

• Case Fatality rates (CFR)– 10-30% for most OP’s

• In west CFR– 0.3% from all poisons

• Multifactorial– Toxicity of OP’s– Patient transport– Lack of resources– Training

• Although less common OP Poisoning is still a problem in West– Occupational exposure– Threat of Chemical warfare


Mechanism of OP Mechanism of OP toxicitytoxicity


Inhibition of AcetycholinesteraseInhibition of Acetycholinesterase


Nicotinic, Muscurinic & Central Nicotinic, Muscurinic & Central SyndromeSyndrome


Simplified Acute OP ToxicitySimplified Acute OP ToxicityOP’s are CholinomimeticsOP’s are Cholinomimetics

Organophosphate


+ Death

• Acute Cholinergic Syndrome: – Central– Peripheral Muscarinic– Peripheral Nicotinic

• Intermediate Syndrome• OPIDN: Delayed peripheral neuropathy• Neurocognitive dysfunction

Clinical FeaturesClinical Features

Respiratory failure}}


Cholinergic Effects – “DUMBELS”Cholinergic Effects – “DUMBELS”

• D iarrhoea

• U rination

• M iosis

• B radycardia, Bronchorrhoea, Bronchospasm

• E mesis

• L acrimation

• S alivation


Nicotinic EffectsNicotinic Effects

• Muscle Weakness• Respiratory difficulty

– diaphragmatic weakness – respiratory arrest

• Stimulation of sympathetic nervous system


CNS effectsCNS effects

• Serious Effects– Coma– Respiratory centre depression – Seizures

• Other effects– Confusion– Memory loss– Disorientation– Delirium


Case 2Case 2

• 24 yo female ingested 50 mls of Chlorpyrifos after an argument with her husband

• Forced emesis at the local hospital

• Arrived at the district hospital 4 hours later


• A- Airway threatened, secretions present

• B - RR 20, O2 sats 79-90% on oxygen – Widespread creps and poor air entry

• C- P80 BP 100/70

• D- Pupils 2mm – GCS 10/15 (M5 V2 E3)

• about V on the A V P U scale


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FasiculationsFasiculations

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Intermediate SyndromeIntermediate Syndrome

• Delayed Respiratory Failure– Proximal muscle weakness and CN 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”


Chronic EffectsChronic Effects

• Organophosphate induced delayed neuropathy (OPIDN)

• 1-3weeks• Peripheral neuropathy• Axonopathy due to Neuropathy Target Esterases

(NTE)

• Chronic organophosphate induced neuropsychiatric disorder (COPIND)


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Difference in OPs - ToxicityDifference in OPs - Toxicity

• 3 most common OP’s ingested in NCP– Chlorpyrifos (Diethly OP)– Dimethoate & Fenthion (Dimethly OP)

• Higher case fatality and intubation rates – in Dimethoate (CFR 23%, Intu 35%) and

Fenthion (CFR 16%, Intu 31%) – compared with Chlorpyrifos (CFR 8%, Intu

15%)


Clinical Variation Risk:Relative human toxicity of pesticides in self-poisoning

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

X symptomatic

X

X

X

Die

thyl

Dim

eth

yl


• AChE inhibition responded poorly to oxime therapy in the 2 Dimethyl OP’s

• Short half life of Ageing – (Dimethly vs Diethyl)

Difference in OPs - ToxicityDifference in OPs - Toxicity


Different rates of OP - AChE inhibition, Different rates of OP - AChE inhibition, reactivation and ageingreactivation and ageing

• t 1/2 inhibition– Milliseconds for both

diMethyl and diEthyl OPs

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

• t1/2 Spontaneous reactivation – 0.7 hr for diMethyl– 31 hrs for diEthyl

• t1/2 of Ageing – 3.7 hrs for diMethyl– 33 hrs for diEthyl


Time to DeathTime to Death

Chlorpyrifos Dimethoate Fenthion

0

25

50

75

100

200

300

400

500

Time (hrs) between OP ingestion and death



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 PChE (mU/ml) 33.5 1129 0.0

Median AChE (mU/mol Hb) 63.5 69.0 64.2

MedianAged AChE 19.4% 71.9% 70.3%



Effectiveness of 1 gram pralidoxime treatmentEffectiveness of 1 gram pralidoxime treatment

0 24 48 72 96ti -5,0

100

200

300

400

500

600

700AChE in vivo

AChE in vitro

Time [h]

mU/µmol Hb

0 24 48 72 96ti -2,2

100

200

300

400

500AChE in vivo

AChE in vitro

Time [h]

mU/µmol Hb

Chlorpyrifos Dimethoate


Dimethyl OPs - specific featuresDimethyl OPs - specific features

• Oximes less effective

• Dimethoate patients died sooner– Hypotensive shock

• Fenthion patients had higher incidence of delayed respiratory failure– Initially few symptoms– Later required intubation



?



The priorities in management are :

• Resuscitation!– A,B,C,D,E

• Atropinisation of symptomatic patients

• Decontamination• Other Treatments - Oximes


Resuscitation of OP poisoned Resuscitation of OP poisoned patientspatients

• ABCDE – Careful attention to

management of “airway + breathing”

• ATROPINE is part of A, B, and C and – administer simultaneously to resuscitation

• GI Decontamination is NOT a life saving procedure!– Should not be performed before resuscitation


Respiratory Failure in OP patientsRespiratory Failure in OP patients

• Review of 376 OP poisoned patients in NCP1

– 90pts (24%) required intubation• 52 (58%) intubated within 2 hours• 46 (51%) died

– 29 (32%) Well on admission but required intubation >24hrs

1Eddleston M, Mohamed F, Davies JO, Eyer P, Worek F, Sheriff MH et al. Respiratory failure in acute organophosphorus pesticide self-poisoning. QJM. 2006;99(8):513-22.


When OP Patients were intubated When OP Patients were intubated in NCPin NCP

Eddleston et al. Respiratory failure in acute organophosphorus pesticide self-poisoning. QJM. 2006;99(8):513-22.

Fenthion

<2hours

All OP’s

2-24hours

>24hours


Atropine administration in OP Atropine administration in OP poisoningpoisoning

• Indications

• How fast to give

• For how long

• Toxicity of Atropine


Indications for AtropineSpeed of Indications for AtropineSpeed of intial Atropinisationintial Atropinisation

Indications Atropinisation – Endpoint

Poor air entry in lungs caused bronchospasm and bronchorrhoea

Hypotension

Bradycardia

Excessive sweating

(Miosis)

Chest Clear

Systolic BP >80mmHg

Heart rate >80/min

Dry Axillae

Pupils no longer pinpoint

Atropine


Speed of intial AtropinisationSpeed of intial Atropinisation

• Study looked at severely poisoned OP patients in Sri Lanka– 22 patients, all required intubation, but survived to

discharge– Mean dose of atropine required 23.4mg (range 1-

75mg)Eddleston et al. Speed of initial atropinisation in significant organophosphorus pesticide poisoning--a

systematic comparison of recommended regimens. J.Toxicol.Clin.Toxicol. 2004;42(6):865-75.

• Text book recommendations for atropinisation varied markedly– Average patient 23.4mg – (8 to 1380 mins)– Severely ill patient 75mg – (25 to 4440 mins)


Suggested Atropine RegimenSuggested Atropine Regimen• Loading

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

• Maintenance– Continuous infusion < 3mg/hr– 10-20% of loading dose/hour

• Endpoints– Clear chest on auscultation with no

wheeze– Heart rate >80 beats/min


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

CVS - Severe Tachycardia (eg HR >120)

Risk of ischaemia in elderly patients

CNS - Confusion, Agitation

Hyperthemia


Gastrointestinal Gastrointestinal DecontaminationDecontamination

?


Risks

•Aspiration

•Trauma

•Electrolyte Imbalances

•Cardiac Arrest

•Cost

Benefits

•Removal of poison load

•Prevention of ongoing poison absorption

•More beneficial in Toxic OP’s

Gastrointestinal Gastrointestinal DecontaminationDecontamination


Gastrointestinal Gastrointestinal Decontamination Options:Decontamination Options:

• Nothing

• Emesis

• Gastric Lavage

• Activated Charcoal


Risk of InterventionRisk of Intervention

• Aspiration

• Trauma– Oesphageal Injury– Nasopharyngeal injury

1. Eddleston M, Haggalla S, Reginald K, Sudarshan K, Senthilkumaran M, Karalliedde L, et al. The hazards of gastric lavage for intentional self-poisoning in a resource poor location. Clin Toxicol (Phila) 2007;45(2):136-43.


Risk of InterventionRisk of Intervention

• Electrolyte Abnormalities• Cardiac Arrest

– Increased Vagal Tone especially with toxin induced bradycardia

• Induced emesis, Lavage

• Cost


Summary of Experimental EvidenceSummary of Experimental Evidence

• GI decontamination should be done in ideal settings– Means to protect airway– Expertise to carry out procedure safely

• Little benefit in outcomes after 1 hour

• Position statement: single-dose activated charcoal. J Toxicol Clin Toxicol 1997;35:721-41.

• Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999;37:731-51.


Decontamination for OPsDecontamination for OPs

• Within 1 hour– Gastric lavage if no contraindications

• Able to protect airway• GCS >12

– Followed by single dose AC

• 1-2 hours – debatable– In some centres the above treatment is acceptable

• > 2 hours ingestion– No place for Gastric Lavage or AC


OximesOximes?


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


Oxime treatment?Oxime treatment?


Oxime Dose and AdministrationOxime Dose and Administration

• Most common Oxime dose in Asia is 1g every 4-6hrs (ie 4-6g/day) – is this the best??

• 1990’s Randomised trials compared12g infusion over 3-4 days, with 1g bolus and placeabo

• They concluded no benefit from pralidoxime, and increased mortality– No loading dose used – inadequate levels

Johnson et al “Evaluation of two treatment regimens of pralidoxime (1gm single bolus dose vs 12gm infusion) in management of OP Poisoning. J Assoc Physicians Indi. 1996; 44 529

Cherian et al “Effectiveness of oximes (PAM- Pralidoxime) in the treatment of organophosphorus poisoning (OPP) a randomised, double blind placaebo controlled clinical trial. J Assoc Physicians India. 1997; 45 22-24


Early RCTs - Low dose Pam, NO Bolus Loading dose

(0.16g/hr infusion without bolus in 50kg person)

Suggested therapeutic plasma level of Oxime

0 4 8 12 16 20 24 28

0

20

40

60

80

100

Hrs

Plasma PAM mg/L


More Recent Oxime Dose and More Recent Oxime Dose and Administration studiesAdministration studies

Pawar et al Lancet 2006Pawar et al Lancet 2006

• OP Poisoned patients treated in India 200 OP patients given 2g bolus and then, randomised either

– 1g “bolus” every 4 hours for 48hours (Control)

– 1g “continuous infusion” every hour for 48hours (Study)

Pawar et al. “Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial.” Lancet 2006: 368:2136-41


Results Results Pawar et al Lancet 2006Pawar et al Lancet 2006

Study group (High dose PAM infusion) :-• Required less atropine in 1st 24hours

– 6mg vs 30mg (median dose)

• Lower intubation Rates– 64% in Study Patients vs 88% in Controls

• Shorter duration of ventilatory support– 5 days vs 10 days

• Lower mortality (1% vs 8%)• Lower incidence of pneumonia


Pralidoxime plama conc.Pralidoxime plama conc.

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


Oxime Dose and AdministrationOxime Dose and AdministrationPawar et al Lancet 2006Pawar et al Lancet 2006

– Short time to admission (median 2h)• Early PAM• Results may not be reproduceable to many other South Asian

settings– No measurement of acetylcholinesterase or neuromuscular

function to explain a causal link of findings with dose of Oxime– Specific pesticide type not recorded (eg dimethy / diethyl)– Underpowered trial size– No reproduceable algorithm for atropine dosing or pralidoxime

cessation

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


Acetylcholinesterase AssaysAcetylcholinesterase Assays• Biomarkers of Exposure to Organophosphorus

insecticide– Plasma cholinesterase(PChE)

• Sensetive but Not specific

– Red cell acetylcholinestersase (RBC-AChE)• Correlates better with AChE at synapse

• Different levels of inhibition with different OP agents– Chlorpyrifos vs Dimethoate

• Uses– Confirmation of diagnosis– Severity


Testmate ChETestmate ChE

• Designed for occupational exposure

• Quantitative test

• RBC-AChE and PChE

• Ellman method

• 4 minutes


Alternate sites for antidotesAlternate sites for antidotes

• Protect AChE

• Supply AChE

• Reduce ACh

• Protect ACh Receptor

• Reduce OP Load

• Multiple Mechanisms


Other Treatments under Other 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 cognitive deficit

(primates)• Postulate “uncoordinated stimulation of the respiratory centres

decreases phrenic nerve output”.


OP Poisoning -SummaryOP Poisoning -Summary• Epidemiology• Mechanism

– Muscarinic, Nicotinic, CNS effects– Causing “Respiratory failure” and Death

• Treatment– Resucitation is the mainstay– ABCD’s include Atropine– Decontamination may be useful in certain circumstances– Oximes may be more useful in high dose regimens if

administered early


With thanks to:

SACTRCAssociate Professor Nick BuckleyProfessor Andrew DawsonDr Mark PereraDr A Aroona Asfir

Ox-Col Study Team Dr Michael Eddleston

Consultant Physicians NCP Medical and Nursing Staff of: Dr S Jayamanne Polonnaruwa General HospitalDr Hettiarachchi Peradeniya Teaching Hospital

Consultant Physicians PeradeniyaDr I GawaramannaDr K Kularatne


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dr bishan rajapakse - south asian clinical toxicology research collaboration organophosphate...

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fasiculations slide

acrimation s alivation

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common op poisoning

acute op toxicity ops

ops toxicity

prolonged effects

dimethoate cfr