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Organophosphate poisoning
The patient presented with seizures, altered sensorium, and respiratory failure. Low serum cholinesterase levels and response to atropine treatment suggested organophosphate poisoning. He was treated with atropine, pralidoxime, antibiotics, and supportive care and showed gradual improvement over 5 days, though fluctuating sensorium was seen initially.
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Organophosphate poisoning
- 1. ORGANOPHOSPHORUS COMPOUNDS DR.VIVEK PAUL BENJAMIN,M.D(GEN.MEDICINE)
- 2. ORGANOPHOSPHATES (ORGANOPHOSPHORUS COMPOUNDS) • Callingthese compounds “organophosphates” is not correct, and they should be referred to as “organophosphorus compounds”.
- 3. HISTORY • Organophosphorus (OP)compounds are organic derivatives of phosphorus that have largely been used as pesticides and nerve agents. • Early pioneers in the field include Jean Louis Lassaigne (early 19th century) and Philippe de Clermont • Tetraethylpyrophosphate was synthesized in 1854 as the first OP cholinesterase inhibitor. Philippe de Clermont
- 4. • In 1932,German chemist Willy Lange and his graduate student, Gerde von Krueger, first described the cholinergic nervous system effects of organophosphates, noting a choking sensation and a dimming of vision after exposure on themselves, which they attributed to the esters themselves
- 5. This discovery laterinspired German chemist Gerhard Schrader at company IG Farben in the 1930s to experiment with these compounds as insecticides. Their potential use as chemical warfare agents soon became apparent, and the Nazi government put Schrader in charge of developing organophosphate (in the broader sense of the word) nerve gases
- 6. • Schrader's laboratorydiscovered the G series of weapons, which included Sarin, Tabun, and Soman. The Nazis produced large quantities of these compounds, though did not use them during World War II • Sarin is a colorless, odorless, tasteless, human- made chemical warfare agent. It was originally developed in Germany in the 1930's as a pesticide. Sarin is a nerve agent-it disrupts the functioning of the nervous system. Nerve agents are the most toxic and rapidly acting of all known chemical warfare agents. Sarin is highly toxic in both its liquid and vapor states.
- 7. Historic Use • Iraqused sarin in the 1980-1988 war with Iran. The Japanese religious sect, Aum Shinriko, released sarin in Matsumoto in 1994 and the Tokyo subway in 1995. In May 2004, the presence of sarin was detected in the debris of a bomb that exploded in Iraq.
- 8. • Organophosphorus (OP)compounds are widely used as pesticides, especially in developing countries. • Case fatality following deliberate ingestion is high (5–20%). • Nerve agents, developed for chemical warfare, are derived from OP insecticides and are much more toxic. • They are commonly classified as G (originally synthesised in Germany) or V (‘venomous’) agents. • The ‘G’ agents, such as tabun, sarin and soman, are volatile, absorbed by inhalation or via the skin, and dissipate rapidly after use. • ‘V’ agents, such as VX, are contact poisons unless aerosolised, and contaminate ground for weeks or months.
- 9.
- 14. Organophosphates MOA: 1.Organophosphates arepowerful inhibitors of acetylcholinesterase.{acetylycholine = acetic acid and choline}. 2.Although organophosphates differ structurally from acetylcholine, they can bind to the acetylcholinesterase molecule at the active site a nd phosphorylate. 3.Once the acetylcholinesterase is phosphorylated, over the next 24 to 48 hours an alkyl group is eventually lost from the conjugate, further exacerbating the situation. As this occurs, the enzyme can no longer spontaneously hydrolyse and becomes permanently inactivated.
- 15. TOXICOKINETICS • Organophosphates canbe absorbed by any route including transdermal, transconjunctival, inhalational, across the GI and GU mucosa, and through direct injection. • Manifestations usually begin within a few minutes to few hours, but may be delayed upto 12 hours or more in the case of certain compounds (e.g. fenthion, parathion).
- 16. TOXIDROME From time ofingestion, 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
- 17. CLINICAL FEATURES What arethe types of paralysis that OPpoisoning cancause? Type I – acute cholinergic crisis Type II – intermediate syndrome Type III – organophosphate induced delayed polyneuropathy (OPIDP)
- 18. TYPE 1 (ACUTECHOLINERGIC CRISIS) Defecation, diaphoresis Gastric Emesis / B B ronchorrhea ronchospasm Bradycardia* • Seen in initial stages and due to persistent depolarisation SLUDGE/BBB DUMBELS Salivation Defecation, diaphoresis Lacrimation Urination Urination Miosis* Bronchorrhea/Bronchospasm/Bradycardia* Emesis Lacrimation Salivation * Sometimes mydriasis and tachycardia observed as sympathetic ganglia also contain nicotinic receptors CNS Nicotinic effects – fasciculations, muscle weakness, paralysis effects – central respiratory depression, lethargy, seizures, coma
- 19. CNS Effects—Restlessness, headache,tremor, drowsiness, delirium, slurred speech, ataxia, and convulsions. Coma supervenes in the later stages.
- 21. TYPE 1 (ACUTECHOLINERGIC CRISIS) • Cardiac • Cardiac arrhythmias – heart block, QTc prolongation • Myocardial ischemia – elevated troponin and changes on ECG • Respiratory • Respiratory failure – combination of CNSresp. centre depression, neuromuscular weakness, excessive respiratory secretions and bronchoconstriction
- 22. TYPE 2 (INTERMEDIATESYNDROME) • 24-48 hours after poisoning, often when acute cholinergic syndrome signs decreased/gone (take care!) • 10-40% of patients • Exact pathology not clear • No clear association between particular OPpesticide 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 • 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
- 23. TYPE 3 (ORGANOPHOSPHATE INDUCEDDELAYED POLYNEUROPATHY–OPIDP)• 2-3 weeks after poisoning • Distal degeneration of axons of both peripheral andCNS (The mechanism appears to involve phosphorylation of esterases in peripheral nervous tissue and results in a “dying back” pattern of axonal degeneration) • 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 independent of severity of acute cholinergic toxicity • Recovery 6-12 months – spastic ataxia may be permanent outcome of OPIDP
- 24. DELAYED ORGANOPHOSPHATE ENCEPHALOPATHY (DOPE)• “CNSintermediate” • 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) • CTbrain and CSFanalysisnormal • Persistently low pseudo-cholinesterase levels and increasing atropine requirements during coma • Prognosis excellent with adequate supportive care
- 25. 2. Chronic Poisoning: a.Polyneuropathy: paraesthesias, muscle cramps, weakness, gait disorders. b. CNS Effects : drowsiness, confusion, irritability, anxiety. c. Sheep Farmer’s Disease : psychiatric manifestations encountered in sheep farmers involved in long-term sheep-dip operations. d. “chronic organophosphate- induced neuropsychiatric disorder; (COPND)
- 27. 1. Depression ofcholinesterase activity: Serum cholinesterase level (reference range- 5000 – 9000 units). 2. P-Nitrophenol Test: P-nitrophenol is a metabolite of some organophosphates (e.g. parathion, ethion), and is excreted in the urine. Steam distill 10 ml of urine and collect the distillate. Add sodium hydroxide (2 pellets) and heat on a water bath for 10 minutes. Production of yellow colour indicates the presence of p- nitrophenol. The test can also be done on vomitus or stomach contents.
- 28. 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.
- 29. GOALS OF TREATMENT Reduceabsorption of toxin Enhance elimination Neutralize toxin
- 30. REDUCE ABSORPTION • Removalfrom skin, eyes and hair • Emesis induction • Gastric Lavage • Activated charcoal and cathartics • Whole bowel irrigation • Endoscopic or surgical removal of ingested chemical
- 31. ATROPINIZATION Adequacy of atropinization Mandatorytargets: • SBP > 90 mmHg • Hr > 110/min • Clear lung fields Other targets: • Pupils mid position • Bowel sounds just present
- 32. TARGETS ON SUBSEQUENTDAYS • Day 2: HR> 100/min • Day 3: HR> 90/min • Subsequent days:At least 80/min
- 33. ATROPINIZATION DOSE • Blocksthe muscarinic manifestations of organophosphates. However, since atropine affects only the postsynaptic muscarinic receptors, it has no effect on muscle weakness or paralysis Two approaches: 1.Bolus Dose Adminstration: 2-5 mg Atropine every 10-15 min • followed by maintainance using reduced doses 2.Incremental dose administration with rapid escalation: • 1.8–3 mg Atropine by iv infusion repeat every 5 min interval doubling the dose each • time 10 - 20%of atropine required for atropininzation every hour by ivinfusion
- 34. ATROPINE 2 –3 MG BY IV BOLUS Double the dose every 5 min until atropinization occurs 10-20% of atropine required for atropinisation ashourly infusion
- 35. BOLUS DOSE VSINCREMENTAL DOSE • Incremental dose clearly better in relation to the outcomesof death and intermediate syndrome. • Superior to Bolus Dose Regime • Recommended as standard of care Studies by Abedin and Blain PG
- 36. ROLE OF PRALIDOXIME •Mode of action: It is usually given along with atropine. Pralidoxime competes for the phosphate moiety of the organophosphorus compound and releases it from the acetylcholinesterase enzyme, thereby liberating the latter and reactivating it. • Pralidoxime, Obidoxime, Trimedoxime • WHO recommendation - (30 mg/kg pralidoxime chloride bolus followed by 8 mg/kg/hour infusion)
- 37. ACTIVATED CHARCOAL • Nohigh quality RCTs to support the benefit of activated charcoal use in acute organophosphate poisoning. • Also there is no evidence of harm.
- 38. GASTRIC LAVAGE Decreasesabsorption by 42% at 20 min 16% at 60 min Preferably in awake patients Choice of fluid is tap water: 5-10ml/kg No evidence that a larger tube is better No human studies showing benefit in OPP
- 39. ALKALINIZATION IN OPP UsingSodium Bicarbonate 5 mEq/kg in 60 minutes followed by 5–6 mEq/kg/day was shown to be useful. Alkalinization products are shown to be less toxic.
- 40. MAGNESIUM SULPHATE • IntravenousMgSO4 (4 g) given in the first day after admission have been shown to decrease hospitalization period and improve outcomes in patients with OPpoisoning. • Magnesium sulfate blocks calcium channels and thus reduces acetylcholine release. • Also reduces CNSoverstimulation resulting from N-methyl D-aspartate receptor (NMDAR) activation.
- 41. • A malestudent, aged 20 years, was admitted in neuro ICU with an episode of seizure and altered sensorium. He had no premorbid illness. He had travelled to Mumbai four days before admission. Relatives denied consumption of any poison and medications. At the time of hospitalization, he was restless and was in postictal state. Vital signs revealed pulse rate of 62/minute, blood pressure of 120/80 mmHg, respiratory rate of 14 per minute, afebrile, and had plenty of oral secretions. Neurological examination revealed GCS of 6/15 with reduced movements of all four limbs. Pupils were pin point bilaterally with absent Doll’s eye movement. Plantar reflex was extensor bilaterally. Deep tendon reflexes were sluggish. There were no fasciculation and no smell of OP compound. He had cellulitis of left arm.
- 42. • Examination ofchest showed bilateral crepitations. Examination of other systems was normal. Investigations at admission showed normal renal functions, liver functions, and normal serum levels of sodium, potassium, calcium, and magnesium. Blood picture showed leukocytosis. Chest X-ray showed bilateral haziness suggesting acute respiratory distress syndrome. Ultrasonography of left arm showed pus collection in the intramuscular plane. Debridement was done and 250 ml of pus was drained. At this point of time, differential diagnosis of metabolic encephalopathy, toxic encephalopathy due to sepsis, possible brain stem diseases, and OP poisoning/drug over dosage were considered. Computed tomography and magnetic resonance imaging scan of the brain, lumbar puncture and CSF analysis were done and they were normal. His EKG, cardiac enzymes, and echocardiography were normal and blood, urine, and pus cultures were sterile. Screening for benzodiazepine, antiepileptic drugs were negative. Serum cholinesterase level was 1234 units (reference range- 5000 – 9000 units).
- 43. • On day2, he developed respiratory distress with carbon dioxide retention, ABG revealed PaCO2 of 54 mmHg, and he required ventilator support. At this point of time, we had reasonably excluded metabolic and structural causes for his problem; hence, possibility of OP poisoning was considered on the basis of respiratory failure, pulmonary secretions, supported by low plasma cholinesterase level. Ryle’s tube aspiration was done at the time of hospitalization and gastric aspirate was minimal. Empirically, he was treated with atropine and pralidoxime along with broad spectrum antibiotics. Atropine was given 5 mg bolus, followed by infusion at the rate of 2 mg/h, and the dose was titrated as per his clinical response and signs of atropinisation. Response to atropine treatment was good and over five days gradual improvement in sensorium was noticed. Pralidoxime was given at a dose of 1 gm infusion, three times per day for initial two days.
- 44. • He wastreated with phenytoin sodium for seizures. Initial antibiotics were piperacillin-tazobactam and metronidazole but during the course of illness, there were worsening of chest shadows and antibiotics were changed to meropenem and linezolid. Cultures of endotracheal tube secretions were sterile. His chest X-ray and oxygenation improved. In the initial three to four days, fluctuation in the sensorium was noticed but continued to have neuroparalysis, neck muscle weakness, and his respiratory efforts were poor. His restlessness was controlled with diazepam. He continued to require ventilator support for breathing.
- 45. • We kepttalking to relatives regarding possible consumption of OP poison, but they had no clue about any such event. Plasma cholinesterase level was repeated and value had gone down to 934 units. His restlessness was better, became more alert and neuroparalysis started recovering slowly. The entire problem got sorted out on sixth day, when he communicated to us in writing that he had injected metacid (methyl parathion) to his left arm while travelling in train. He required ventilator support for 12 days and recovered completely. He revealed that he had injected poison with suicidal intention and all the legal protocols were done as per the hospital rules. Following recovery, he was evaluated by psychiatrists and revealed that injection of poison was an impulsive act due to poor social and financial support from family.