op poisoning 18-aug-09 upload

8/8/2019 OP Poisoning 18-Aug-09 Upload

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Organophosphorus Insecticides andNerve Gas Agents Poisoning

Dr Bhavan


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Introduction

Organophosphorus (OP) compounds - pesticides,herbicides, and chemical warfare agents i.e., nervegases.

OP pesticide intoxications are estimated at 3 millionper year worldwide with approximately 300 000deaths.

Most of the OP pesticide poisoning and subsequentdeaths occur in developing countries following a

deliberate self ingestion.

The fatality rate following deliberate ingestion of OPpesticides in developing countries in Asia is approx20% and may reach upto 70%.


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C ompounds

OP compounds were first developed by Schradershortly before and during the Second World War.

These compounds are normally esters, thiol esters, oracid anhydride derivatives of phosphorus containingacids.

Of the more than 100 OP pesticides used worldwide,the majority are either dimethyl phosphoryl or diethylphosphoryl compounds


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Others:

Acephate D imethoate E thion F entrothionMoncrotofos

PhenthoatePhoratePhosphamidonProfenofos


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N erve gas compounds are highly potent synthetic

toxic agents.

G agents like Tabun, sarin, and soman are absorbedby inhalation or percutaneously; they are volatile anddisappear rapidly after use.

V agents are contact poisons unless aerosolised, andcontaminate ground for weeks or months.

They are related to OP pesticides but have muchhigher acute toxicity, particularly percutaneously. Thetoxicology and management of nerve agent andpesticide poisoning are similar


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Me chanism of Toxicity

OPs inactivate acetylcholinesterase (ACh E ) byphosphorylation leading to the accumulation of acetylcholine (ACh) at cholinergic synapses

And subsequent over-activation of cholinergicreceptors at the N MJ and in the autonomic and C N S.

The rate and degree of ACh E inhibition differs

according to the structure of the OP compounds andthe nature of their metabolite.


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I n general, pure thion compounds are not significantinhibitors in their original form and need metabolicactivation (oxidation) in vivo to oxon form.

E .g., parathion has to be metabolized to paraxon in

the body so as to actively inhibit AChE

.

Carbamates differ in mechanism, that the sameenzyme is reversibly inhibited and are sometimesuseful as medicines (neostigmine, pyridostigmine) as

well as insecticides (carbaryl)


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Diagrammatic representation of the possible reactivation & ageing reactions of AChE after inhibition by OP compounds


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After the initial inhibition and formation of ACh E OPcomplex two further reactions are possible:(1) Spontaneous reactivation of the enzyme

- this may occur at a slow pace, much slower than the enzymeinhibition and requiring hours to days to occur.

- the rate solely depends on the type of OP compound,

- spontaneous reactivation t 1/2 of 0.7 hrs for dimethyl and 31 hrsfor diethyl compounds.

- the spontaneous reactivation can be hastened by reagents like

oximes. These agents thereby act as an antidote in OP poisoning


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(2) Ageing

- with time, the enzyme-OP complex loses one alkyl group makingit no longer responsive to reactivating agents.

- ageing depends on - pH, temp, and type of OP compound;

- dimethyl OPs have ageing t of 3.7 hours whereas it is 33hours for diethyl OPs.

- hence, oximes are hypothetically useful before 12 hours indimethyl OPs poisoning.

- However, in diethyl OP intoxication they may be useful for manydays.

- N erve agents (especially soman) undergo ageing within minutes


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Cl inical Manifestations

The onset, severity and duration of poisoning dependon the route of exposure and agent involved.

Sequential triphasic illness follows OP intoxication :

Acute Cholinergic CrisisI ntermediate Syndrome ( I MS)Organophosphate- I nduced D elayed Polyneuropathy

(OP I D N ).


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A cut e C holin e rgic C risis

Accumulation of acetylcholine (ACh) causing excessivestimulation of cholinergic receptors at various organs.

Ach is the principle neurotransmitter in varioussynapses: parasympathetic system, autonomic

ganglia, N MJ and central nervous system.

These acute manifestations can be broadly dividedinto muscarinic, nicotinic, and central nervous system(C N S) effects.

Practical significance of this classification is thatatropine only blocks muscarinic effects whereasoximes reverse both the nicotinic and muscariniceffects


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S ummary of clinical f e atur e s and antidot e s in A cut e C holin e rgic C risis


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SLU D GESalivation

LacrimationUrine incontinenceD iarrhoea,Gastrointestinal

crampsE mesis)

D UMBE LSD iarrhoea

UrinationMiosisBronchospasm,Bronchorrhea

E mesisLacrimationSalivation

Various mnemonics have been used to describe themuscarinic signs of OP poisoning:


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Heart rate and blood pressure can be potentiallymisleading findings as increase or decrease can occurin both vital signs.

Dose dependent effects :

Muscarinic < N icotinic < C N S

Tachycardia/Hypertension s/o severe poisoning

Patients can also develop pancreatitis, hypo orhyperglycaemia and acute renal failure during thisphase


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D epending on the severity of the exposure, the

spectrum of the clinical presentation variesMild

Small or pinpointpupilsPainful, blurredvision

Runny nose andeyesE xcess salivaE yes look "glassy"Headache, N auseaMild muscleweakness

Localized muscletwitching

ModeratePinpoint pupils,conjunctivalinjectionD izziness,

disorientationCoughing,wheezing, sneezingD rooling,bronchorrhoea,bronchospasm

Breathing difficultyMarked muscletwitching, tremorsMuscle weakness,fatigue

SeverePinpoint pupilsConfusionAgitationConvulsions

Copious secretionsCardiacarrhythmias,CollapseRespiratorydepression,

Respiratory arrestComaD eath


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Prognosis in acute poisoning may dependdose and toxicity of the ingested OP (e.g., neurotoxicitypotential, half life, rate of ageing, pro-poison or poison),andwhether dimethyl or diethyl compound.

The time of death after exposure may range from


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Int e rm e diat e syndrom e

The intermediate syndrome is a distinct clinical entitythat occurs 24 to 96 hours after the ingestion of anOP compound;

Approximately 10-40% of patients treated for acutepoisoning develop this illness.

The onset of the I MS is often rapid, with progressionof muscle weakness from the

ocular muscles to the neck (the patient cannot raise their

head from the pillow)proximal limbs,to the respiratory muscles (intercostals and diaphragm)over the course of 24 hours.


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I ncreasing respiratory difficulty causes anxiety,sweating and use of accessory muscles of respiration.

I f endotracheal intubation and ventilation are notinstituted early, cyanosis, coma and death follow

rapidly. Paralysis may continue for 2-18 days.

Proposed mechanisms includepersistent inhibition of ACh E leading to functionalparalysis of neuromuscular transmission,

muscle necrosis, andoxidative free radical damage to the receptors


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O rganophosphat e- induc e d d e lay e d

polyne

uropathy (OP

IDN)This occurs about 1-3 weeks after acute exposure andan uncertain period following chronic exposure, due todegeneration of long myelinated nerve fibres.

Mechanism is inhibition of neuropathy target esterase( N TE ) enzyme in nervous tissues by certain OPcompounds (chloropyriphos)

A distinct acute or intermediate phase may not alwaysprecede its development


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Sympto ms

Cramping muscle pains in the legs numbness andparaesthesiae in the distal upper and lower limbs.

Acute weakness of the lower limbs follows andspreads to the hands, causing a shuffling gait, andfootand wrist-drop.

Muscle wasting and deformity, such as clawing of the

hands, follow.Sensory loss is variable and is often mild andinconspicuous.


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Signs

Physical examination reveals symmetrical flaccidweakness of the distal muscles, especially in the legs.

Tendon reflexes are reduced or lost, absent anklereflexes being a constant feature.

Later, mild pyramidal tract signs (spasticity,hypertonicity, hyper-reflexia and clonus) may

develop.


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F igure showing effects of OP poisoning


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Diagnosis

D iagnosis of OP poisoning depends on the H/oexposure to OP compounds, characteristicmanifestations of toxicity and improvements of thesigns and symptoms after administration of atropine.

This may be aided by insisting that the pts party tosearch for a possible poison container in the vicinity of the pt.

Garlic-like smell is an added clinical sign especially if the patient has ingested sulphur containing OPcompound.


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C holines terase ( C hE) es tima tions (plasma bu tyr ylcholines terase and red cell A C hE) are the onl y usefulbiochemical tool for confirming exposure to OP s, bu t are apoor guide to managemen t and prognosis.

C linical severi ty graded on the basis of thepseudocholines terase level

mild 20-50% enz yme ac tivity,modera te 10-20% enz yme ac tivity

severe


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BuChE activityE asily assayedResponse to antidotal

therapy lessD oes not correlatewell with neuronaleffectsLevels altered in

malnutrition, chronicillness, cirrhosis,infections

R BC AChE activityMore difficult to assayI ncreased activity

after pralidoximetherapyCorrelates well withpredictable neuronaleffects and severity as

wellLevels altered inhemoglobinopathies,thalassemia

On the other hand, true or erythrocyte cholinesterase correlates wellwith clinical severity but is not available in most centres, especially indeveloping countries


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Analytical identification of OP compound in gastricaspirate or in the body fluids gives the clue that pthas been exposed to OP compound.

However in doubtful cases and especially if laboratory

facilities are not available, 1mg atropine can be givenintravenously.

I f this does not produce marked anticholinergicmanifestations, anticholinesterase poisoning should be

strongly suspected


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Tr e atm e nt:

AcuteC

hol

inergic crisisD econtamination and Supportive therapy

Blockade of Muscarinic activity withATROP IN E

Reversal of cholinesterase inhibition withOXI ME nucleophiles

Correction of Metabolic abnormalities


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D e contamination and S upportiv e th e rapy

Protection of the health care staff

ABC(Airway, Breathing & Circulation)

Comatose or vomiting patients should be kept in lateral,

preferably head down position with neck extension to reducethe risk of aspiration.Patent airway should be secured with placement of Guedelsairway or with endotracheal intubation especially if the patientis unconscious, fitting, or vomiting.F requent suctioning is essential as excessive oropharyngeal

and respiratory secretions may occlude the airway.N eed for o2 therapy this can be assessed by frequent

assessment of arterial oxygen saturation


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D e contamination:

Skin decontamination.

The skin and clothes of these patients are frequentlycontaminated with poison and vomiting.

Hence should be removed and the skin vigorously washed withsoap and water

Gastric lavage.

Gastric lavage should be considered in patients presenting

within 1-2 hours of ingestion of poison.

Risks of gastric lavage include aspiration, hypoxia, andlaryngeal spasm, and these can be reduced with propermanagement of airway


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Activated charcoal

Activated charcoal helps to reduce the poison loadby adsorbing it;

Though its efficacy has not been conclusivelyproven in humans, single to multiple dose activatedcharcoal is routinely used in clinical practice.

AVO I D cathartics and induced emesis


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Specific antidote for muscarinic effects ; no effect onnicotinic symptoms.

I t reverses life threatening features that can result indeath central respiratory depression,bronchospasm, excessive bronchosecretion, severebradycardia, and hypotension

Current guidelines recommend the use of bolus dosesto attain target endpoints, followed by setting up aninfusion to maintain these end-points.

A tropin e


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Target end-points for Atropine therapy

Heart rate >80/ minD ilated pupilsD ry axillaeSystolic blood pressure >80 mm HgClear chest on auscultation with resolution of bronchorrhea(absence of wheeze and crepts)

Recommended dose is an initial iv bolus of 1.8-3mgwith subsequent doses do uble d every 5 minutes untilatropinization is achieved.(0.05mg/kg in children)

Maintenance dose: 20% of initial atropinizing dose perhour for first 48 hours and gradually taper over 5 -10days, continuously monitoring the adequacy of therapy.(0.02-0.08mg/kg/hr)


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Look for atropine TOX I CI TY

Agitation, confusion, hyperthermia, urinary retentionand severe tachycardia that can precipitate ischaemicevents in patients with underlying coronary arterydisease.

Close observation and dose adjustment is essential toavoid the features of both under- and over-atropinization.

Anticholinergic agent glycopyrrolate along withatropine can be used in order to limit the centralstimulation produced by atropine


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Oximes

Oximes work by reactivating acetylcholinesterase thathas been bound to the OP molecule.

Pralidoxime is the most frequently used oximeworldwide; other members include obidoxime, andexperimental H I 6 and HLO 7.

They can be highly effective in restoring skeletalmuscle strength and improving diaphragmaticweakness where atropine has virtually no effect.

The therapeutic window for oximes is limited by thetime taken for ageing of the enzyme-OP complex,because aged enzyme can no longer be reactivatedby oximes


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WHO recommends pralidoxime dose of 30 mg/kg

bolus iv followed by continuous infusion of 8mg/kg/hour

I nfusion continued until recovery :12 hrs after atropine has been stopped.

BCh E noted to increase.

D izziness, headache, blurred vision, and diplopia, arecommon side effects of oxime therapy.

Rapid administration may lead to tachycardia,laryngospasm, muscle spasm, and transientneuromuscular blockade.


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Inter mediate sy ndro me

V en tilator y suppor t should be ins tituted before a p t developsresp failure to main tain a P a O2 > 97 mmHg (>13k P a), P a C O2of 30-45 mmHg (4-6 k P a) and pH > 7.3.

Diazepam or midazolam ma y be used for seda tion duringven tilation. Weaning from respira tor y suppor t should beinitiated as earl y as possible.

P aren teral nu trition is of ten required.

Unless OPI DN develops, recover y from IMS is comple te wi thadequa te ven tilator y care


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OPIDN

There are no specific therapeutic measures.

Regular physiotherapy may reduce deformity causedby muscle-wasting.

Recovery from OP I D N is incomplete and may belimited to the hands and feet, although substantialfunctional recovery after 1-2 years may occur inyounger patients .


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Figure showing effects of OP poisoning


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30 mg / kg bolus

8 mg / kg / hr

4 mg / kg bolus

0.5 mg / kg / hr


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op poisoning 18-aug-09 upload

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