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ORGANOPHOSPHORUS POISONING
Dr Syed Hussain Azhar Rizvi
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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)
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WHO Toxicity Classifcation
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Major Issue in Medical ICU, CHK
Major Issue in Medical ICU, CHK is
NOT occupational exposure,
But
Self Poisoning or
Suicidal Poisoning
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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.
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Comparison Of Methods Used For
Fatal Self Harm
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Pathophysiology of Toxicity
The Toxicokineticsand Toxicodynamics
of
Organophos
phonates
the Pharmacokineticsand
Pharmacodynamics
of Oxime
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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
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Simplified Acute OP Toxicity
Inactivation of acetylcholinesterase enzymeOrganophosphate
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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
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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
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OP Toxicity and Cholinesterase
... 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)
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OP Toxicity and Cholinesterase
... 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.).
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Thus, 3 Groups of Effects
after OP Poisoning
1. Muscarinic
2. Nicotinic
3. Excitotoxic
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Clinical Syndrome
Acute Cholinergic:
Central
PeripheralMuscarinic Peripheral Nicotinic
Intermediate Syndrome
OPIDN: Delayed peripheral neuropathy
Neurocognitive dysfunction
Clinical Syndrome
Respiratory
failure
Respiratory
failure
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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
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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
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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
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AChE inhibition by OP
biomarker of organismexposure, followed by
complex disturbances
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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)
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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
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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
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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.
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Cholinesterase assays
Red cell acetylcholinesterase assays
Plasma butyrylcholinesterase assays
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(A) dimethoate
and
(B) fenthion
poisoning
Use of butyrylcholinesterase recovery as a marker of organophosphorus pesticide elimination
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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
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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
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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
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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
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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.
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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
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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.
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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
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Muscarinic Antagonist
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
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Muscarinic Antagonist
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
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Muscarinic Antagonist
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
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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
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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
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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
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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
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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
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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
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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.
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Is There Convincing Evidence
Of Benefit Of Pralidoxime?
We look at the 2011 Cohrane Review. . .
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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
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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
Buckley NA, Eddleston M, Li Y, Bevan M, Robertson J.Oximes for acuteorganophosphate pesticide poisoning. Cochrane Database of Systematic
Reviews 2011, Issue 2
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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
Buckley NA, Eddleston M, Li Y, Bevan M, Robertson J.Oximes for acuteorganophosphate pesticide poisoning. Cochrane Database of Systematic
Reviews 2011, Issue 2
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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.
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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%
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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
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Chronic 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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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
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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.
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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
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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
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The Duration of IMS
Complete recovery develops 518 days later
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Comparison of RNS Changes with Neck Power
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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
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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
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Supportive Measures
Benzodiazepines
Gastrointestinal decontamination
Other therapies
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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
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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
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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).
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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)
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Interventions To Reduce /
Prevent OP Self-Poisoning LoveMarriages Law
Rights to Affairs Law
Parents Restraints Law/ Child protection
Learn to Live with cockroaches
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Thank You