ORGANOPHOSPHORU

S
POISONING
Case Scenario..
◦ A 56 year old male brought to ER at 1:00 AM with h/o altered sensorium
with alleged h/o DSH with Dichlorvos mixed with alcohol
following which he had multiple episodes of vomiting and breathing difficulty
ORGANOPHOSPHATES
• Organic compounds containing phosphorus group

• Widely used in agricultural sector as PESTICIDES.

• Toxic and lethal effects in humans

• Leading agent for poisoning in the developing world

 1600

1400
Death Cases

1200

1000

800

AGENTS OF 600

POISONING
400

200

Dr. Bishan Rajapakse – OP Update (Port Hedland – Jan 31st ,

2012)
What are different types of
organophosphate compounds???
 CLASSIFICATION
⚫ There are more than a hundred organophosphorus
compounds in common use. These are classified according to
their toxicity and clinical use:

⚫ 1. Highly toxic organophosphates: (e.g. tetra-ethyl

pyrophosphates, parathion, phorate). These are
mainly used as agricultural insecticides.

⚫ 2. Intermediately toxic organophosphates: (e.g.

coumaphos, clorpyrifos, trichlorfon). These are used as animal
insecticides.

⚫ 3. Low toxicity: (e.g. diazinon, malathion, dichlorvos). These

are used for household application and as field sprays.
◦ Derivatives of Phosphoric/phosphinic/phosphorous acids
dichlorvos, glufosinate
◦ Derivatives of phosphine
◦ Derivatives of phosphorothioates
parathion, bromophos, diazinon
How organophosphates differ from
carbamates??? *Carbaryl, carbofuran, aldicarb
1. Chemical structure
2. MOA
3. Ageing
4. 2-PAM

The similarities
5. Symptoms after ingestion
6. Antidote as atropine
 LIST OF COMMON OP
POISONS
Dimethylated Diethylated S - ALKYL Others
Mononchrotophos Phorate (THIMATE) Propanofos 50% Acephate (ASATOP)
(TATA MONO) Parachion/diethylepar (BANJO/PARABAL) Trimethoate
Methyleparathion athion Thiamate
(METACIL) Chlorpyruphos Propophenos
Duchlorvos (DDVP) (LETHAL) Monochlorphos
Dimethoate Triazophos
(ROGORIN) Malathion

• Acetylcholinesterase ageing is much faster for dimethyl poisoning (shorter half life) than for diethyl
poisoning (longer half life), so management would have to occur sooner for dimethyl poisoning
(Eddleston et al., 2008)
Exposure
Home Exposure Occupational Exposure Other Exposure

Accidental ingestion Farms & Farm worker Dietary exposure-

Pesticide residues
on crops
Lawn and garden use Pesticide applicator Leaching from soils to
ground water

Insect control Manufacture Community exposure

Food supply Mixing and handling Airborne drift

from commercial
app

Water supply Landscapers Contaminated

drinking water
NORMAL
PHYSIOLOGY
 MOA:
• Bind to acetylcholinesterase (AChE)
rendering enzyme non-functional

• Overabundance of ACh at neuronal

synapses

• Resultant cholinergic toxicity

• Over time (dependent on OP agent),

AChE-OP compound undergoes
conformational change (‘aging’)
rendering enzyme irreversibly
resistant to reactivation by antidotal
oximes
HOW DO ORGANOPHOSPHATES
WORK??

COVALEN
T BOND

AGING
TOXIDROME
From time of ingestion, when would you expect clinical features of OP
poisoning to manifest?

• Great variability in toxicity and treatment response depending on OP agent

•Generally, oral/respiratory exposures result in clinical manifestations within 3

hours

• Dermal routes can take up to 12 hours

CLINICAL FEATURES

What are the types of paralysis that OP poisoning can cause?

 Type I – acute cholinergic crisis

 Type II – intermediate syndrome

 Type III – organophosphate induced delayed

polyneuropathy (OPIDP)
TYPE 1 (ACUTE CHOLINERGIC CRISIS)
◦ Seen in initial stages and due to persistent depolarization
◦ SLUDGE/BBB
Salivation + Lacrimation + Urinary incontienence + Defecation & Diaphoresis + GI
disturbances + Emesis +
Bronchorrhoea + Bronchospasm + Bradycardia * Sometimes mydriasis and tachycardia observed as sympathetic
ganglia also contain nicotinic receptors

◦ DUMBELS
Defecation & Diaphoresis + Urinary incontinence + Miosis + Bronchorrhoea,
Bronchospasm, Bradycardia + Emesis + Lacrimation + Salivation

Nicotinic effects – fasciculations, muscle weakness, paralysis effects – central respiratory depression,

lethargy, seizures, coma

TYPE 1 (ACUTE CHOLINERGIC CRISIS)
• Cardiac
Phase1(brief period of increased symp tone) phase2 (prolonged period of
parasymp activity including AV block phase3 (Q-T prolong followed by
TDP, VT, VF)
• Cardiac arrhythmias – heart block, QTc prolongation
• Myocardial ischemia – elevated troponin and changes on ECG

• Respiratory
• Respiratory failure – combination of CNS resp. centre depression,
neuromuscular weakness, excessive respiratory secretions and
bronchoconstriction
On examination
◦ He was conscious but restless
◦ Pupils pin point
◦ Excessive oral secretions with garlicky odour
◦ Tachypnoeic RR 30
◦ HR 60 bpm, Bp 150/80
◦ B/l crepitations with wheeze+
TYPE 2 (INTERMEDIATE
SYNDROME) • 24-48 hours after poisoning, often when
◦What are the characteristic clinical
findings in intermediate syndrome?
• Weakness of muscles of
respiration (diaphragm, intercostal
muscles, accessory muscles
including neck muscles)
• Weakness of proximal limb
muscles
• Others – cranial nerve
abnormalities, decreased deep
tendon reflexes
acute cholinergic syndrome signs
decreased/gone
(take care!)head lift+hold against
resistance
• 10-40% of patients
• Exact pathology not clear.
• No clear association between particular
OP pesticide and development of
syndrome
• Persists for 14-20 days
• Resolution within 2-3 weeks (with
adequate supportive care eg. ventilatory
support)
• Recovery usually without sequelae
◦ Excess Ach causing downregulation of nicotinic receptors
◦ Inadequate oxime therapy
◦ Muscle necrosis
◦ Oxidative stress related myopathy

◦ Tv<5ml/kg, VC<15ml/kg, Pao2<60 on Fio2 >60

TYPE 3 (ORGANOPHOSPHATE INDUCED
DELAYED POLYNEUROPATHY – OPIDP)
• 2-3 weeks after poisoning
• Distal degeneration of axons of both peripheral and CNS due to inhibition of Neuropathy Target
Esterase

• Clinical features
• Transient painful ‘stock & glove’ paraesthesias followed by a symmetrical motor polyneuropathy
characterised by flaccid weakness of lower extremities which ascends to involve upper extremities
• High-stepping gait associated with bilateral foot drop
• Predominantly distal but can involve proximal in severe neurotoxicity

• Risk of development is independent of severity of acute cholinergic toxicity

• Recovery 6-12 months – spastic ataxia may be permanent outcome of OPIDP
DELAYED ORGANOPHOSPHATE
ENCEPHALOPATHY (DOPE)
• “CNS intermediate”
• New syndrome recognised and described in 2008
• Clinical features
• Normal sensorium then progression to coma days after poisoning (delayed coma)
• Miosed non-reacting pupils
• Extra-pyramidal signs – dystonia, resting tremor, cog-wheel rigidity, choreo-athetosis
• Investigations
• EEG – bi hemispheric slow waves (features consistent with encephalopathy)
• CT brain and CSF analysis normal
• Persistently low pseudo-cholinesterase levels and increasing atropine requirements during coma
• Prognosis excellent with adequate supportive care
Other sequele
◦ Neuro-ophthalmic manifestationsoptic neuropathy, Retinal degeneration
◦ ARDS
◦ Pancreatitis
◦ COPIND (chronic OP induced neuropsychiatric disorder)
Dreisbach classification
to grade the severity
◦ Mild::: nausea, vomiting, diarrhoea, sweating
◦ Moderate::: lacrimation, sweating, miosis, fasciculation
◦ Severe:: incontinence,ARDS, apnoeic spells, areflexia, seizures, coma
Diagnosis
◦ History
◦ Petroleum/garlic like odor
◦ Examination findings
◦ Atropine challenge 0.01-0.02mg/kg absence of anticholinergic effects supports diagnosis
investigations
◦ 1. Toxicology
◦ 2. Butyrylcholinesterase activity in plasma (allows cautious weaning of a patient)
◦ Acetylcholinesterase in whole blood
Acute exposures are usually classified based on the degree of depression of RBC cholinesterase: mild
(20% to 50% of baseline), moderate (10% to 20% of baseline), and severe (less than 10% of baseline)
◦ 3. CXR (pulmonary oedema, aspiration)
◦ 4. ECG (cardiac arrythmias) & echo
◦ 5. ABG
◦ 6. Electrolytes
◦ 7. RFT
Current Conc
epts In Manag
ement Of
Organophosph
ate Poisoning
RESUSCITATION
• Airway – Early Intubation to secure
airway and prevent aspiration

• Breathing – Ensure adequate

ventilation

• Circulation – Obtain large bore IV

access. Start IV fluids if victim is in
hypotension

• Decontamination – Remove any

remnants of the toxin in contact with
the patient.
 GOALS OF TREATMENT

Reduce absorption of toxin

Enhance elimination

Neutralize toxin
All personnel who are involved in the resuscitation and decontamination process should wear masks
or respirators, aprons, and nitrile or butyl rubber gloves to avoid secondary contamination.
◦ Clinical scoring systems are used in a variety of disease processes to predict mortality
◦ 1. Acute Physiology and Chronic Health Evaluation (APACHE) II
◦ 2. Peradeniya Organophosphorus Poisoning (POP) scale
◦ 3. International Program on Chemical Safety Poison Severity Score (IPCS PSS)
◦ 4. Mortality Prediction Model (MPM)
◦ 5. Poisoning Severity Score (PSS)
◦ 6. Sequential Organ Failure Assessment (SOFA)
◦ 7. Glasgow Coma Score (GCS)
◦ 8. Simplified Acute Physiology Score (SAPS) II

◦ define a patient population that will require transfer to a higher level of care in under-resourced countries
REDUCE ABSORPTION
• Removal from skin, eyes and hair

• Emesis induction

• Gastric Lavage

• Activated charcoal and cathartics (50gm in 200ml)

• Whole bowel irrigation

• Endoscopic or surgical removal of ingested chemical

◦ Decontamination can limit absorption and prevent reexposure. All of the patient’s clothing
should be removed, bagged in plastic and discarded, and the person should be thoroughly
washed with mild soap and water. Dilute hypochlorite solution (household bleach) inactivates
the organophosphorus ester and can be used to decontaminate equipment but should not be
used on skin
Airway & breathing
◦ Most patients with severe cholinergic poisoning will require airway management and
ventilatory assistance for respiratory failure.
◦ Succinylcholine should be used with caution to aid intubation because prolonged (hours to
days) paralysis may result . A reasonable alternative is to use a rapid-onset nondepolarizing
neuromuscular blocker such as rocuronium.
◦ Airway and bronchial secretions are treated with atropine. The initial adult dose of atropine is 1
to 2 mg parenterally, which is doubled every 5 minutes (pediatric dose, 0.05 mg per kg) as
needed until pulmonary secretions are controlled
◦ Rapid sequence induction and prevent aspiration
circulation
◦ Initial resuscitation with intravenous (IV) fluids is needed because of significant fluid losses.
◦ Blood pressure support may require direct-acting pressors such as norepinephrine,
phenylephrine, and epinephrine, and cardiac depression may require the use of inotropes such
as dobutamine
◦ Patients should be treated with atropine until the systolic blood pressure is greater than 80 mm
Hg and urine output exceeds 0.5 mL/kg/h in addition to biochemical signs of improved
perfusion.
◦ Electrical pacing is rarely needed to treat ventricular dysrhythmias.
◦ Potassium and magnesium should be normalized to minimize QTc prolongation.
◦ Seizures should be treated with IV atropine and a benzodiazepine (diazepam, 0.2 to 0.4 mg per
kg or an equivalent). It is reasonable to administer a benzodiazepine even if seizures are not
apparent
◦ Antimuscarinic antagonism is the mainstay of initial antidotal therapy.
◦ Atropine is a competitive antagonist of acetylcholine at the muscarinic receptors but has no
effect at the neuromuscular junction, so muscle weakness and paralysis are not affected and it
does not affect the AChE regeneration rate.
◦ primarily indicated for control of pulmonary secretions and bronchospasm.
◦ has a secondary role in helping to control seizures and CNS manifestations of poisoning
◦ Tachycardia is not a contraindication to atropine therapy and may reflect hypoxia or
sympathetic stimulation.
◦ Mydriasis is an early response but is a poor marker for adequate atropinization.
 Adequacy of atropinization
Mandatory targets:

• SBP > 80 mm Hg
• Hr > 110/min
• Clear lung fields

Other targets:

• Pupils mid position

• Bowel sounds just present
• Urine output>0.5ml/kg/hr
TARGETS ON SUBSEQUENT DAYS

• Day 2: HR > 100/min

• Day 3: HR > 90/min

• Subsequent days: At least 80/min

Atropinisation
◦ Start with 1.8 to 3 mg iv bolus
◦ After 3 to 5 mins, check for signs of atropinisation
◦ If not corrected double the dose of atropine every 5mins until signs of atropinisation is present
◦ Maintenance infusion
10-20% of the initial dose of atropine in 5D on hourly basis as continuous infn
Atropine toxicity
◦ Confusion, Delirium, Coma
◦ Urinary retention, Ileus
◦ Hyperthermia
◦ Agitation, Psychosis
◦ Flushing
◦ Tachycardia>140
◦ Fixed dilated pupil
◦ Glycopyrrolate is an antimuscarinic agent that does not penetrate the CNS and is unlikely to be
effective in treating CNS effects such as seizures or coma. It can be substituted for atropine
when isolated peripheral cholinergic toxicity is present. The recommended starting dose is
0.005 mg per kg.
◦ One study suggested that a combination of atropine and glycopyrrolate may improve outcomes
ROLE OF PRALIDOXIME
• Nucleophilic agents – reactivate bound acetylcholinesterase

• Pralidoxime, Obidoxime, Trimedoxime

• WHO recommendation - (30 mg/kg pralidoxime chloride

bolus followed by 8 mg/kg/hour infusion)
• To be continued until atropine is not needed for 12-24 hrs and
patient is extubated
• Rapid administration may lead to tachycardia,
laryngospasm, muscle spasm, and transient
neuromuscular blockade.
Oximes get attached to the free anionic site of the
enzyme ChE. The oxime end then reacts with the
phosphorus atom of OP attached at the esteratic
site of the enzyme. This oxime phosphate so
formed diffuses away leaving the enzyme
intact (Reactivated ChE).
Other modalities
◦ 1. Mag So4
Reduced Acetylch release+blocks presyn Ca channel
Also reduces CNS overstimulation resulting from N-methyl D-aspartate receptor (NMDAR) activation.
Improved hospital outcomes

◦ Clonidine not much benefit

◦ Soda bicarb
Supportive care
◦ 1. iv antibiotics
◦ 2. anti-ulcer prophylaxis
◦ 3. antipyretics like paracetamol
◦ 4. anti-anxiety agents like midazolam/lorazepam
◦ 5. antipsychotics like haloperidol
Antidote kits
◦ MARK-1 NAAK/MARK-1 KIT
A dual chamber auti-injector (Atropine+pralidoxime)
Against sarin,soman,tabun

ATNAA (Antidote Treatment Nerve Agent Auto-Injector+

◦ Toxicologic differential diagnosis for cholinergic toxicity includes poisoning with nicotine,
carbachol, methacholine, arecoline, bethanechol, pilocarpine, and Inocybe or Clitocybe
mushrooms.
◦ Nontoxicologic Diagnoses that may be mistaken for cholinergic toxicity include myasthenia
gravis, Guillain–Barré, and Eaton–Lambert syndrome.