ORGANOPHOSPHOROUS POISONING

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PRESENTOR Dr. S.PRIYA MODERATOR Lt.Col A.K. GHOSH (Classified specialist Medicine & Cardiology)

INTRODUCTION
Acute organic insecticide poisoning is a major health problem all over the world, particularly in the developing countries, where organophosphates (OPs) are the most common suicidal poisons with high morbidity and mortality

The OP compounds are popular insecticides because of their effectiveness and nonpersistence in the environment owing to their unstable chemical nature. They do not persist in the body or environment as do organochlorides and have become the insecticide group of choice replacing DDT, an organochloride compound

PHARMACOLOGY

CLASSIFICATION
1. Agricultural insecticides (high toxicity) Paration phorate mevinphos disulfoton. 2. Animal insecticides (intermediate toxicity) chlorpyrifos. 3. Household use or use in golf courses (low toxicity) malathion dichlorvos.

PHARMACOKINETICS
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Skin Oral mucosa Conjunctival mucosa G.I.T Respiratory routes Organophosphate compounds block ACETYLCHOLINEACETICACID & CHOLINE Increased acetylcholine at synapses Most common cause of toxic effect of o.p.poisoning

PATHOPHYSIOLOGY    OPs bind to the active serine residue of acetyl cholinesterase irreversibly Convert the enzyme into an inactive protein complex Result in accumulation of acetyl choline at the receptors .

Etiology of OP Poisoning      Suicidal Accidental poisoning Occupational exposure such as farming Large proportion(68%) suicidal attempts Young patients <30 yrs with male preponderance .

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CLINICAL FEATURES  Cardiovascular: Bradycardia. miosis. diarrhea. increased lacrimation. bronchospasm. Respiratory Rhinorrhea. Ocular: Blurred vision. abdominal pain. nausea and vomiting. Gastrointestinal: Increased salivation. cough. hypotension. bronchorrhea.   . fecal incontinence.

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paralysis .)  Nicotinic Effects Cardiovascular: Tachycardia.. fasciculations. hypotension.CLINICAL FEATURES(CONTD. cramps. Musculoskeletal: Weakness.

tremors. respiratory depression. coma. absent reflexes. insomnia. restlessness.Central Receptor Stimulation  Anxiety. and circulatory collapse come under this . ataxia. convulsions. Cheyne Stokes breathing. dysarthria. hyperreflexia.

nervous system. cardiovascular system. as well as metabolic effects such as hypo.Multisystem Manifestations  The end-result may be involving the gastrointestinal tract. skeletal muscles. .or hyperglycemia. respiratory system.

Neurological Manifestations THREE  TYPE  TYPE  TYPE types of paralyses recognized I II III .

cramps.muscle fasciculations. twitching. and weakness Respond to atropine .Type-I Paralysis or Acute Paralysis       Initial cholinergic crisis Persistent depolarization at NMJ Blockade of acetylcholinesterase Develops within 24-48 h. FEATURES.

Type I (Contd…)    Muscle paralysis Upper motor neuron lesion Muscle paralysis .respiratory muscles-->respiratory failure requiring ventilation Acute respiratory failure in 33% of patients who presented with OP poisoning  .

Type-II Paralysis or Intermediate Syndrome       Wadia as Type-II paralysis Senanayake as intermediate syndrome 24-96 h after the poisoning Majority of patients. respiratory insufficiency Cranial nerve palsies Proximal muscle weakness .

)        Relative sparing of the distal muscle groups Incidence varies ..TYPE II(CONTD.8% and 49% Earliest manifestations Weakness of neck flexion Inability to lift the head from the pillow Test to assess if patient is likely to develop respiratory muscle weakness Cranial nerves involved are those supplying the extraocular muscles .

)     VII and X are less frequent. Syndrome persists for approx 4-18 days Most patients survive this with ventilatory support unless infections complicate the course There is a myopathy evidenced by significant elevation of muscle enzymes .TYPE II(CONTD..

chronic exposure One being pure motor polyneuropathy Other having a mild sensory component with a more prominent motor component. .TYPE III PARALYSIS     OP-induced delayed polyneuropathy (OPIDP) is a sensory-motor distal axonopathy Occurs after the ingestion of large doses .

resting tremor. lethargy Extrapyramidal manifestations Developing for 4-40 days following poisoning and lasting for approx 1-4 weeks. including dystonias. confusion. cog-wheel rigidity .Other Neurologic Manifestations    Impaired memory. irritability.

Rare neurological Guillian-Barrι syndrome. sphincter involvement. degeneration of retina. and ototoxicity . defective vertical smooth pursuit movements. myopia owing to spasm. isolated bilateral recurrent laryngeal nerve paralysis. or paresis of accommodation.Other Neurologic Manifestations(contd…)   optic atrophy.

sinus bradycardia (28%). extra systoles . Other manifestations noncardiogenic pulmonary edema (43%). Inverted T-waves (17%). Rhythm abnormalities such as sinus tachycardia (35%). Prolonged PR interval (9%). . ventricular tachycardia . Elevated ST segment (24%). and hypotension (17%). hypertension (22%). atrial fibrillation.Cadiovascular Manifestations       Prolonged Q-T corrected (QTc) interval (67%).

. and development of ventricular fibrillation. including atrioventricular block.CARDIAC TOXICITY    Phase 1: A brief period of increased sympathetic tone Phase 2: Prolonged periodof increased parasympathetic activity. ventricular tachycardia. Phase 3: QT prolongation followed by torsade de points .

hypoxemia. overactivity of cholinergic or nicotinic receptors. acidosis. electrolyte abnormalities .)   Recent study QTc prolongation at admission respiratory failure and higher mortality Mech of toxicitydirect toxic effect on the myocardium..CARDIAC TOXICITY (contd.

bronchospasm and laryngeal spasm result in airway obstruction.mechanical ventilation .Respiratory Manifestations     Muscarinic effects of bronchorrhea. The nicotinic effects ->weakness and paralysis of respiratory and oropharyngeal muscles Central depression ->respiratory arrest Intermediate syndrome develop respiratory failure.

Gastrointestinal Manifestations   GI manifestations are the first to appear They respond well to atropine therapy .

Grading the Severity of OP Poisoning   These do not always correlate with outcomes Patients who recover 24 h later develop intermediate syndrome .

pseudocholinesterase levels do not .Diagnosis    History and a combination of clinical features True and pseudocholinesterase levels can be estimated. The levels are markedly reduced in OP poisoning. Although true cholinesterase levels correlate with severity at presentation.

5-fold reduction of mortality. .Management    Decontamination of the skin is very important. The patient should be stripped and washed with soap and water Forced emesis if the patient is fully awake or through a gastric lavage 0.5-1 g/kg activated charcoal every 4 h  Serotonin adipinate that enhances the propulsive function of git resulted in shortening of the toxicogenic phase and a 3.

(d) tidal volume or vital capacity (e) Single breath count.g. and (f) arterial blood gas estimation or pulse oximetry. (c) respiratory rate.. Respiratory infections should be anticipated and treated appropriately . diplopia). (b) neck muscle weakness.Airway and Respiration    Adequate oxygenation should be ensured (a) Symptoms of ocular muscle involvement (e.

 . Some of these may revert with atropine.Cardiac Monitoring    Hemodynamic and electrocardiographic monitoring Hypoxemia and electrolyte abnormalities contribute to cardiac complications. Ventricular tachycardia with a prolonged QTc is best treated with electrical pacing SVT can be treated with IV bolus of shortacting β-blockers.

No longer necessary to achieve total atropinization i. and absent bowel sounds.Specific Therapy    Anticholinergic Agents Atropine can be started initially as a 2-mg intraventricular (IV) bolus Then at doses of 2-5 mg IV bolus every 5-15 min until atropinization is achieved. .e full mydriasis. heart rate more than 150/min.

Pupils' midsize. .   At approx 100/min. maintains adequately atropinization without risks of hyperexcitability. hyperpyrexia and cardiac complications that are seen with total atropinization. restlessness. Bowel sounds just present.

. The dose of atropine required is maximal on day 1 and tends to decrease over the next few days.

Oximes    Reactivate the phosphorylated acetylcholinesterase by binding to the organophosphorus molecule. Reactivation has been shown to be complete when oximes are given 1 hr after exposure  . Report by de Silva et al found that P2AM did not maker any difference to the outcomes.

controlled studies with similar protocols using 12 g of P2AM infusion over 3 days. The first was 12 g infusion over 4 days vs 1 g at admission Second was 12 g infusion over 4 days vs placebo .OXIMES (Contd…)    Two major randomized.

.OXIMES(Contd. Ventilatory requirement and incidence of intermediate syndrome was higher in the treatment group These studies concluded that P2AM has no role in the routine management of patients with OP poisoning .)    A higher mortality was observed in the P2AM group in both the studies.

Vol39.Randomized control trials (Indian Journal of Pharmacology. Placebo group was given saline infusion. .6-> placebo arm 5-> treatment group. 5-> the placebo group 5-> treatment group. No2. While 12 g PAM infusion/day was used for severe cases for three days 4 g/day was used for moderate cases also for 3 days. In the severe group. Mar-Apr07) TRIAL 1      moderately severe group.

Conclusion  Treatment with PAM did not make any difference in OP poisoning The more useful treatment options are anticholinergic drugs like atropine and supportive ventilation.  .

Trial 2  The study was on the effect of oximes on nerve agents and pesticide poisoning .

. 50% (6/12) in the group treated with obidoxime and atropine There was no mortality in the group treated with 2-PAM (eight patients). Mortality was 9% (4/43) in the group treated with atropine.Conclusion     Respiratory complications were more common in the group treated with obidoxime or 2-PAM.

. . This RCT reported an increased mortality rate (22% vs 14%.Trial 2    A 1 g bolus of pralidoxime (termed 'low dose') was compared with 12 g given as a reducing infusion over 4 days without a loading dose (termed 'high dose').

Conclusion   The authors argued that 'high-dose' pralidoxime was therefore 'associated with a worse outcome' and should have 'no role in op poisoning management Increased requirement for ventilation among patients who received the infusion as compared to those who received the bolus dose. .

e. 12 g by continuous infusion without loading dose) with the placebo saline infusion 'high-dose' regimen was associated with a significantly higher risk of death .Trial 3   It compared 'high-dose' pralidoxime (i..

Nonrandomized Clinical Trials Trial 1     One group (group I) received atropine alone Other group (group II) received atropine &PAM PAM neither improved the atropine profile in group II patients as compared to group I nor did it significantly change the ventilatory profile in the two groups. Mortality was negligible in both the groups .

Patients in the control group were also given a median of 4 g PAM intravenously during the first 24 h of treatment.Trial 2     Atropine was given intravenously to all patients in amounts sufficient to maintain the pulse rate > 120/minute and to keep the pupil fully dilated. . Thereafter PAM was given intravenously at a 1 g daily dose for up to five days. patient with intermediate syndrome and median hospital stay (days) or the patient needing intensive care treatment or ventilation. There were no significant differences between the study and control groups with regard to any of the outcomes such as median atropine requirement in first 24 hours.

Discussion    There was no statistically significant association of oxime therapy with mortality ventilator requirements or the incidence of intermediary syndrome Increased need for intensive care therapy Oximes in OP poisoning was associated with either a null effect or possible harm  concluded that use of oximes in OP poisoning was associated with either a null effect or possible harm .

Discussion (contd…)     Studies have given following results De Silva et al:.No benefit from pralidoxime was found Johnson and Vale:-(a) failure of treatment is usually a function of inadequate dosing (b) Emphasized that dosage should be maintained continuously until clear. clinical improvement is achieved . irreversible.

)  Current WHO guidelines :-Recommend giving a 30 mg/kg loading dose of pralidoxime over 1020 minutes followed by a continuous infusion of 8-10 mg/kg/h until clinical recovery or seven days have elapsed.. . whichever is later .Discussion(contd.

These concentrations should be maintained as long as circulating poison is expected to be present.8 mg/L pralidoxime chloride) should be attained . which may require oxime therapy for up to 10 days .22(3):165-90    These studies impressively demonstrated that any generalisation regarding an effective oxime concentration is inappropriate pralidoxime plasma concentrations of around 80 mumol/L (13. 2003.Toxicol Rev.

5 g/h appears appropriate to maintain the target concentrtion of about 13 mg/L (70 kg person). For pralidoxime chloride. a 1 g bolus over 30 minutes followed by an infusion of 0. . The most appropriate consists of a bolus short infusion followed by a maintenance dosage.

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