Organophosporus Poisoning and its management

8/7/2019 Organophosporus Poisoning and its management

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ORGANOPHOSPHORUS POISONING

Dr Syed Hussain Azhar Rizvi



OP compounds: What do we know?

Organophosphorus pesticide self-poisoning is

an important clinical problem in rural regions

of the developing world

A killer Poison - it kills an estimated 200 000

people every year

These are class Ia Toxic compounds ,

according to WHO ( i.e. Highly Hazardous)



WHO Toxicity Classifcation



Major Issue in Medical ICU, CHK

Major Issue in Medical ICU, CHK is

NOT occupational exposure,

But

Self Poisoning or

Suicidal Poisoning



Self Inflicted Violence

Self inflicted violence accounts for around

half of the 1.6 million violent deaths that

occur every year worldwide.

About 63% of global deaths from self harmoccur in the Asia Pacific region.



Comparison Of Methods Used For

Fatal Self Harm



Pathophysiology of Toxicity

The Toxicokineticsand Toxicodynamics

of

Organophos

phonates

the Pharmacokineticsand

Pharmacodynamics

of Oxime



Pathophysiology of OP

Compounds Organophosphorus pesticides inhibit esterase

enzymes, especially acetylcholinesterase in

synapses and on red-cell membranes, andbutyrylcholinesterase in plasma

But, there are multiple factors influencing theeffects of OP on the body and measurement

of assays for diagnosis







Simplified Acute OP Toxicity

Inactivation of acetylcholinesterase enzymeOrganophosphate



Generally Accepted Mechanism

Of OP Toxicity (TD):Interaction And Subsequent

Inhibition Of Tissue AChe It is accepted that blood and tissue

cholinesterases inhibition representsOP

exposure marker and initiating mechanisms

for toxicodynamic effects, characteristic forcholinergic crisis



OP Toxicity and Cholinesterase

1. The symptomatology appears at more than50% inhibition of RBC AChE

2. Blood ChE RBC AChE and BuChE(apparently with no cholinergic physiologicalsignificance) are a redundant system

3. Erythrocyte AChE inhibition is more closelycorrelated withOP toxic symptomatologyand represents a biomarker for exposure






... Contd

6. Toxic syndrome: resultant of cholinergic effects(cholinergic crisis) sequentially associated withnon-cholinergic effects and neurotoxicity

(excitotoxicity)

7. The treatment targeting exclusively thecholinergic segment (cholinergic crisis) leads topartial results only(Completion of treatment with anticonvulsants(such as diazepam) improves the antidotalresults)




... Contd

8. Antidotism improvement by admitting the

following premises:

-OP complex mechanism of action: cholinergic,non-cholinergic, excitotoxicity, etc.

- evaluation of OP TKTD correlations and theirtoxic consequences.

- evaluation of antidote PKPD correlations asmajor determinants of their antidotal effects(anticholinergic, ChE reactivation, GABA agonism,glutamatergic excitotoxicity antagonism, etc.).



Thus, 3 Groups of Effects

after OP Poisoning

1. Muscarinic

2. Nicotinic

3. Excitotoxic



Clinical Syndrome

Acute Cholinergic:

Central

PeripheralMuscarinic Peripheral Nicotinic

Intermediate Syndrome

OPIDN: Delayed peripheral neuropathy

Neurocognitive dysfunction

Clinical Syndrome

Respiratory

failure

Respiratory

failure



Muscarinicsymptomatology(Postsynaptic

Muscarinic Rexcessivestimulation)

Nicotinicsymptomatology(Postsynaptic Nicotinic

Rexcessive stimulation)

Central nervoussymptoms( Excitotoxic)

MyosisBradicardiaHypotensionBronchorrhoea

SalivationEmesis

Diarrhoea, abdominalpainUrinary frequency

Cardiac rhythmdisturbance

Muscular fasciculationMuscular weakness

Muscular paralysisRespiratory insufficiency

(ventilatory component)Pallor

PerspirationMydriasys*Tachycardia*

Hypertension**(Transient symptomsusuallymasked by muscarinicSymtomatology)

-anxiety, agitation, tremor;-consciousness alteration;-hallucinations;-seizures;

-respiratory centre inhibition respiratory insufficiency

(synergistic withskeletal muscle paralysis)-hypothermia

-intermediate syndrome type II paralysis appears few days later



OP Mechanisms Of Action

It is generally accepted that irreversible AChE

inhibition, whatever the location, represents

theOP characteristic mechanism. Red blood cells AChE and plasma BChE

inhibition has practically no direct functional

consequence in the cholinergic system, being

first used asOP exposure biomarker



Importance of RBC AChe

Redundancy

The most important clinical implication of

RBC Ache Redundancy is the high thresholdof clinical symtomatology afterOP exposurei.e. symptoms occur when 50% or even higher

levels of cholinesterases are inhibited



AChE inhibition by OP

biomarker of organismexposure, followed by

complex disturbances



OP Poisoning is Not just

Cholinergic Crisis Primary mechanism of OP toxic effects: cholinergic crisis

The cholinergic crisis initiates a complex pathological process andconsequences: Non-cholinergic mechanism other targets

- Ischaemia hypoxia stress

- Acidosis

- Shock state

- Energetic metabolism perturbation and ATP depletion

- ATP depletion

- Excitotoxicity Neurotoxicity

- Convulsions, induced by synergistic sequential events:

- Cholinergic crisis

- Hypoxia, anoxia

- GABA inhibition

- Glutamatergic mechanism (excitotoxic effects)



OP Targets Than AChe, Correlated With The

Toxic EffectsTargets Functional consequences

M cholinergic receptor Activation, neurotoxicityN cholinergic receptor Partial agonist

M2 andM3 receptors at GABAneurons level

M3 receptors facilitate GABA transmission

NeuronalM and N receptors Direct effects M1 and 2 receptors facilitate GABA

transmissionNicotinic cholinergic receptors Blocking effects

DFP irreversibly blockedNMDA receptors

M receptors decreased in cortex and hippocampus

Energetic metabolism Acidosis, oxidative metabolism blocked, ATP

decreasedGlutamate excessive release Glutamate e.c. increased, excitotoxicity, neuronal

lesions

Serotonin receptors andtransport blocked

Neurotoxicity

GABA-ergic system Inhibitory effects



The Unequal Efficacy Of

Oximes Oximes are reactivators of peripheral, but not cerebral

AChE

Distribution predominantly plasmatic

No reactivator is active against all major AChE inhibitors

Very low lipophilicity, therefore, very low penetrability

Oximes BBB penetration represents 410% of its plasma

concentration and is selective

2-PAM T1 2 in humans = 12 hrs , therefore, given as acontinuous infusion



Diagnosis of OP Poisoning

Diagnosis is made on the basis of:

Clinical suspicion

The characteristic clinical signs Smell of pesticides or solvents

Reduced butyrylcholinesterase oracetylcholinesterase activity in the blood.



Cholinesterase assays

Red cell acetylcholinesterase assays

Plasma butyrylcholinesterase assays



(A) dimethoate

and

(B) fenthion

poisoning

Use of butyrylcholinesterase recovery as a marker of organophosphorus pesticide elimination



Red cell acetylcholinesterase assays

These assays measure acetylcholinesterase expressedon the surface of red cells

Red-cell acetylcholinesterase inhibition is a good marker

of such inhibition in synapses and of poisoning severity

This enzyme is measured in whole blood in which

butyrylcholinesterase activity has been blocked by aninhibitor

Acetylcholinesterase is present at very low levels inhuman plasma and serum



Red cell acetylcholinesterase assays. . . contd

Once red-cell acetylcholinesterase has aged, it onlyrecovers via erythropoeisis

Regeneration at less than 1% per day is therefore muchslower than butyrylcholinesterase regeneration

The rate of spontaneous neuronal acetylcholinesterase

recovery is unclear, and thus red-cellacetylcholinesterase could be a less useful marker of

synaptic acetylcholinesterase activity as recovery occurs



Red cell acetylcholinesterase assays. . . contd

Reactions between acetylcholinesterase,organophosphorus and oximes will continue if a bloodsample is left at room temperature after sampling

The measured acetylcholinesterase activity will then notrepresent the exact activity in the blood at the time of sampling; leaving samples for different times will give

variation in assays

Blood samples must be diluted and cooled immediatelyafter sampling, to stop the reactions.

We routinely dilute by a factor of 20 at the bedside bymixing 200 L of blood freshly drawn into an EDTA tubewith 4 mL of cold saline (at 4C) and then place thesample in a freezer at 20C within 5 min



Therapeutic Monitoring by

Acetylcholinesterase Assays Monitoring a patients cholinesterase status

after organophosphate poisoning enables the

verification of substantial exposure toanticholinesterase agents

In future, such assays could facilitate the

decision about when to stop oxime treatment

and allow cautious weaning of a patient froma ventilator when butyrylcholinesteraseactivity is increasing



Principles Of Therapy

Resuscitation of patients and giving oxygen and fluids

A muscarinic antagonist (usually atropine)

An acetylcholinesterase reactivator (an oxime thatreactivates acetylcholinesterase by removal of thephosphate group)

Respiratory support is given as necessary

Gastric decontamination should be considered only after

the patient has been fully resuscitated and stabilised.



Initial Resuscitation

Check airway, breathing, and circulation.

Place patient in the left lateral position, preferably with

head lower than the feet, to reduce risk of aspiration of stomach contents.

Provide high flow oxygen, if available.

Intubate the patient if their airway or breathing is

compromised

Set up an infusion of 0.9% normal saline; aim to keep thesystolic blood pressure above 80 mm Hg and urineoutput above 0.5 mL/kg/h



Initial Resuscitation

... Contd

Continuous cardiac monitoring and pulseoximetry should be established; an ECG shouldbe performed

Remove all clothing and gently cleanse patientssuspected of organophosphate exposure with

soap and water because organophosphates arehydrolyzed readily in aqueous solutions with ahigh pH. Consider clothing as hazardous wasteand discard accordingly.



Muscarinic Antagonist

Atropine Give 13 mg of atropine as a bolus, depending on

severity

Record pulse rate, blood pressure, pupil size, presence of sweat, and auscultatory findings at time of first atropinedose

5 min after giving atropine, check pulse, blood pressure,pupil size, sweat, and chest sounds

If no improvement has taken place, give double the

original dose of atropine




Atropine ... Contd

Continue to review every 5 min; give doubling

doses of atropine if response is still absent

Once parameters have begun to improve, ceasedose doubling. Similar or smaller doses can be

used




Atropine ... Contd

Give atropine boluses until the heart rate is more than 80beats per minute, the systolic blood pressure is morethan 80 mm Hg, and the chest is clear (appreciating that

atropine will not clear focal areas of aspiration)

Sweating stops in most cases

Tachycardia is not a contraindication to atropine since itcan be caused by many factors




Atropine ... Contd

The pupils will commonly dilate; however, this

sign is not a useful endpoint for initial atropinetreatment because a delay exists beforemaximum effect.

However, very dilated pupils are an indicator of atropine toxicity



Scheme Of Atropinization

(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 ± ClinicalToxicology 2004;6:865-875.

0 5 10 1 5

0

10

20

30

40

min af ter f irst atropine

dose

2 4 8 16 Atropine requirement

Poor air entry into lungs caus ed 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



Monitoring of Atropine

Infusion Once the patient is stable, start an infusion of atropine

giving every hour about 1020% of the total dose neededto stabilize the patient

If too little is given, cholinergic features will re-emergeafter some time

If too much is given, patients will become agitated and

pyrexial, and develop absent bowel sounds and urinary

retention If this happens, stop the infusion and wait 3060 min for

these features to settle before starting again at a lowerinfusion rate



Atropine ... Summary

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



Acetylcholinesterase

Reactivator Give pralidoxime chloride 2 g intravenously over

2030 min into a second cannula

Follow with an infusion of pralidoxime 0.51 g/hin 0.9% normal saline

Continue the oxime infusion until atropine hasnot been needed for 1224 h and the patient hasbeen extubated



Reactions Of Acetylcholinesterase After

Inhibition With Organophosphorus

Inhibited acetylcholinesterase reactivates spontaneouslybut slowly

Oximes speed up this reactivation

Unfortunately, if the organophosphorus is present in highconcentrations, newly reactivated acetylcholinesterasewill be rapidly reinhibited

Whether reactivation or inhibition predominatesdepends on the type of organophosphorus and relativeconcentrations and affinities of organophosphorus andoxime



Concept of Aging of AChe

Inhibited acetylcholinesterase can also become aged, byloss of one of the two alkyl groups attached to the boundphosphate

Aged acetylcholinesterase cannot be reactivated byoximes

The half-life of ageing varies according to the inhibiting

pesticide: if dimethyl, the half-life is around 3 h; if diethyl,the half-life is around 33 h

Thus ageing has important clinical consequences



Evidence of Benefit of

Pralidoxime A randomised controlled trial* in Baramati, India studied

the effect of very-high-dose pralidoxime iodide (2 gloading dose, then 1 g either every hour or every 4 h for48 h, then 1 g every 4 h until recovery) in 200 patients

with moderate organophosphorus poisoning (excludingseverely ill patients)

The high-dose regimen was associated with reducedcase fatality (1% vs 8%; odds ratio [OR] 0·12, 95% CI

0·0030·90), fewer cases of pneumonia (8

% vs 35%; 0·16,0·060·39), and reduced time on mechanical ventilation(median 5 days vs 10 days).

*Continuous pralidoxime inf usion versus repeated bolus injection to treatorganophosphorus pesticide poisoning: a randomised controlled trial.

Lancet 2006; 368: 213641.



Is There Convincing Evidence

Of Benefit Of Pralidoxime?

We look at the 2011 Cohrane Review. . .



The Cochrane Database of Systematic

Reviews 2011Conclusion

Seven pralidoxime RCTs were found

Three RCTs including 366 patients studied pralidoxime vsplacebo and four RCTs including 479 patients comparedtwo or more different doses. These trials found quitedisparate results with treatment effects ranging from

benefit to harm. However, many studies did not take intoaccount several issues important for outcomes..

Buckley NA, Eddleston M, Li Y, Bevan M, Robertson J.Oximes for acuteorganophosphate pesticide poisoning. Cochrane Database of Systematic

Reviews 2011, Issue 2



The Cochrane Database of Systematic

Reviews 2011 In particular, baseline characteristics were not balanced,oxime doses varied widely, there were substantial delaysto treatment, and the type of organophosphate was nottaken into account

Only one RCT compared the World Health Organization(WHO) recommended doses with placebo. This trial

showed no clinical benefits and a trend towards harm in

all sub-groups, despite clear evidence that these dosesreactivated acetylcholinesterase in the blood





The Cochrane Database of

Systematic Reviews 2011

Summary:

No evidence that oximes are a usef ultreatment for organophosphate pesticide

poisoning

Current evidence is insufficient to indicate

whether oximes are harmf ul or beneficial





Special Situations In Giving

Pralidoxime Pregnancy Category: C

A:Generally acceptable. Controlled studies in pregnant

women show no evidence of fetal risk. B:May be acceptable. Either animal studies show no risk

but human studies not available or animal studies showedminor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animalstudies show risk and human studies not available orneither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no saferdrug available. Positive evidence of human fetal risk.



Indications for Respiratory

Support Intubate and ventilate patients if:

Tidal volume is below 5 mL/kg, or Vital capacity is below 15 mL/kg, or

If they have apnoeic spells, or

PaO2 is less than 8 kPa (60 mm Hg) on FiO2 of more than 60%



Intermediate 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



Chronic Effects

Organophosphate induced delayed

neuropathy (OPIDN)

� 1-3weeks

� Peripheral neuropathy

� Axonopathy due to Neuropathy Target Esterases

(NTE)

Chronic organophosphate induced

neuropsychiatric disorder (COPIND)



How To Monitor For Onset Of

Intermediate Syndrome Assess flexor neck strength regularly in consciouspatients by asking them to lift their head off the bed andhold it in that position while pressure is applied to theirforehead.

Any sign of weakness is a sign that the patient is at risk of

developing peripheral respiratory failure (IntermediateSyndrome).

Tidal volume should be checked every 4 h in such

patients. Values less than 5 mL/kg suggest a need forintubation and ventilation



Intermediate Syndrome (IMS)

A Disorder Of Neuromuscular Junctions

Acute organophosphate insecticide poisoningcan manifest 3 different phases of toxic

effects, namely: Acute cholinergic crisis

Intermediate syndrome (IMS), and

Delayed neuropathy

Intermediate syndrome (IMS) is a major causeof death from respiratory failure followingacute organophosphate poisoning.



Intermediate syndrome (IMS)

... Contd Proposed mechanisms of IMS include:

Different susceptibility of various cholinergicreceptors

Muscle necrosis

Prolonged acetylcholinesterase inhibition

Inadequate oxime therapy

Downregulation or desensitization of postsynapticacetylcholine receptors, failure of postsynapticacetylcholine release, and oxidative stress-relatedmyopathy



The clinical manifestations

of IMS Typically occur within 24 to 96 hours

Affecting conscious patients withoutcholinergic signs

Involve the muscles of respiration, proximallimb muscles, neck flexors, and muscles

innervated by motor cranial nerves



The Duration of IMS

Complete recovery develops 518 days later









Comparison of RNS Changes with Neck Power



Proposed Treatments for IMS

other than Supportive i.e.

Mechanical Ventilation

1. Therapy with obidoxime, a more potent

oxime compared to pralidoxime,significantly decreased the incidence of

respiratory failure, the length of

hospitalization, and mortality

2. Whole blood transfusion of 400800mL/dayfor up to 5 days

3. FFPs



Organophosphate - Induced Delayed

Neurotoxicity (OPIDN)

Occurs 23 weeks after acute exposure to certainorganophosphate insecticides

The clinical features are predominantly motorneuropathy and primarily manifest as numbness andweakness of the lower extremities, followed by

progressive ascending weakness of limb muscles.

The disease entity is believed to be due to the inhibition

of a poorly characterized esterase called theNeuropathy Target Esterase



Supportive Measures

Benzodiazepines

Gastrointestinal decontamination

Other therapies



Benzodiazepines

Treat agitation by reviewing the dose of atropine being given and provide adequatesedation with benzodiazepines

Physical restraint of agitated patients inwarm conditions risks severe hyperthermia,which is exacerbated greatly by atropine

because it inhibits normal thermoregulatoryresponses, including sweating

Adequate sedation is therefore important



Gastrointestinal

Decontamination No evidence shows any form of gastric

decontamination to benefit patients poisonedwith organophosphorus

Lavage should be considered only if the patientarrives within 1 hour of ingesting poison

Gastric decontamination should only be doneafter the patient has been stabilised and treatedwith oxygen, atropine, and an oxime



Role of Magnesium Sulphate

in OP Poisoning Magnesium sulphate blocks ligand-gated calcium

channels, resulting in reduced acetylcholine release frompre-synaptic terminals, thus improving function at

neuromuscular junctions, and reduced CNSoverstimulation mediated via NMDA receptor activation

A trial in people poisoned with organophosphorus

pesticides recorded reduced mortality with magnesiumsulphate (0/11 [0%] vs 5/34 [14·7%]; p<0·01).



Role Of Other Substances is

Controversial In OP Poisoning

Clonidine

Sodium Bicarbonate

FFPs (A small controlled study (12 patients given fresh frozen

plasma with 21 control patients) recorded benefit, but this trial was

not randomised and allocation decisions were unclear)

Recombinant Bacterial Phosphotriesterases (break

down organophosphorus pesticides enzymatically)



Interventions To Reduce /

Prevent OP Self-Poisoning LoveMarriages Law

Rights to Affairs Law

Parents Restraints Law/ Child protection

Learn to Live with cockroaches



Thank You

Documents

Organophosporus Poisoning and its management