organophosphorous poisoning

Organophosphorus (OP) insecticides/nerve agents
OP compounds are widely used as pesticides, especially in developing countries. The case fatality rate following deliberate ingestion of OP pesticides in developing countries in Asia is 5-20%.
Organophosphorus compounds
Nerve agents
• G agents: sarin, tabun, soman
• V agents: VX, VE
Insecticides
Dimethyl compounds
Diethyl compounds
Nerve agents developed for chemical warfare are derived from OP insecticides but are much more toxic. G agents are volatile, are absorbed by inhalation or via the skin, and dissipate rapidly after use. V agents are contact poisons unless aerosolised, and contaminate ground for weeks or months.
The toxicology and management of nerve agent and pesticide poisoning are similar.
Mechanism of toxicity
OP compounds phosphonylate the active site of acetylcholinesterase (AChE), inactivating the enzyme and leading to the accumulation of acetylcholine (ACh) in cholinergic synapses. Spontaneous hydrolysis of the OP-enzyme complex allows reactivation of the enzyme. However, loss of a chemical group from the OP-enzyme complex prevents further enzyme reactivation, a process termed ageing . After ageing has taken place, new enzyme needs to be synthesised before function can be restored.
Clinical features and management
OP poisoning causes an acute cholinergic phase, which may occasionally be followed by the intermediate syndrome or organophosphate-induced delayed polyneuropathy (OPIDN).

Acute cholinergic syndrome
The acute cholinergic syndrome usually starts within a few minutes of exposure. Nicotinic or muscarinic features may be present.
Cholinergic features in poisoning
Cholinergic muscarinic
Bronchorrhoea, bronchoconstriction, Bradycardia, hypotension, Confusion, Fever, Diplopia, mydriasis, Ileus, palpable bladder, Dry mouth, Flushing, hot, dry skin, Seizures
Cholinergic nicotinic
Reduced ventilation, Tachycardia, hypertension, Fasciculation, paralysis, Lacrimation, miosis, Vomiting, profuse diarrhea, Salivation, Sweating, Seizures
Vomiting and profuse diarrhoea are typical following oral ingestion. Bronchoconstriction, bronchorrhoea and salivation may cause severe respiratory compromise. Miosis is characteristic and the presence of muscle fasciculations strongly suggests the diagnosis, although this feature is often absent, even in serious poisoning. Subsequently, the patient may develop generalised flaccid paralysis which can affect respiratory and ocular muscles and result in respiratory failure. Ataxia, coma and convulsions may occur. In severe poisoning, cardiac repolarisation abnormalities and torsades de pointes may occur. Other early complications of OP poisoning include extrapyramidal features, pancreatitis, hepatic dysfunction and pyrexia.

Management
In the event of external contamination, further exposure should be prevented, contaminated clothing and contact lenses removed, the skin washed with soap and water, and the eyes irrigated. The airway should be cleared of excessive secretions and high-flow oxygen administered. Intravenous access should be obtained. Gastric lavage or activated charcoal may be considered within 1 hour of ingestion. Convulsions should be treated. The ECG, oxygen saturation, blood gases, temperature, urea and electrolytes, amylase and glucose should be monitored closely.
Early use of sufficient doses of atropine is potentially life-saving in patients with severe toxicity. Atropine reverses ACh-induced bronchospasm, bronchorrhoea, bradycardia and hypotension. When the diagnosis is uncertain, a marked increase in heart rate associated with skin flushing after a 1 mg intravenous dose makes OP poisoning unlikely. In OP poisoning, atropine should be administered in doses of 0.6-2 mg i.v., repeated every 10-25 mins until secretions are controlled, the skin is dry and there is a sinus tachycardia. Large doses may be needed but excessive doses may cause anticholinergic effects.
In patients requiring atropine, an oxime such as pralidoxime chloride (or obidoxime), if available, should also be administered, as this may reverse or prevent muscle weakness, convulsions or coma, especially if administered rapidly after exposure. The dose for an adult is 2 g i.v. over 4 mins, repeated 4-6-hourly. Oximes work by reactivating AChE that has not undergone ageing . Oximes may provoke hypotension, especially if administered rapidly.
Ventilatory support should be instituted before the patient develops respiratory failure. Benzodiazepines may be used to reduce agitation and fasciculations, treat convulsions and sedate patients during mechanical ventilation.
Exposure is confirmed by measurement of plasma (butyrylcholinesterase) or red blood cell cholinesterase activity. These correlate poorly with the severity of clinical features, although values are usually less than 10% in severe poisoning, 20-50% in moderate poisoning and > 50% in subclinical poisoning.
The acute cholinergic phase usually lasts 48-72 hours, with most patients requiring intensive cardiorespiratory support and monitoring.
The intermediate syndrome
About 20% of patients with OP poisoning develop weakness rapidly spreading from the ocular muscles to those of the head and neck, proximal limbs and the muscles of respiration, resulting in ventilatory failure. This intermediate syndrome (IMS) generally develops quite rapidly between 1 and 4 days after exposure, often after resolution of the acute cholinergic syndrome, and may last 2-3 weeks. There is no specific treatment but supportive care, including maintenance of airway and ventilation, is important.
Organophosphate-induced delayed polyneuropathy (OPIDN)
This is a rare complication that usually occurs 2-3 weeks after acute exposure. It is a mixed sensory/motor polyneuropathy, especially affecting long myelinated neurons, and appears to result from inhibition of enzymes other than AChE. Early clinical features are muscle cramps followed by numbness and paraesthesiae, proceeding to flaccid paralysis of the lower and subsequently the upper limbs. Paralysis of the lower limbs is associated with foot drop and a high-stepping gait, progressing to paraplegia. Paralysis of the arms leads to wrist drop. Sensory loss may also be present but is variable. Initially, tendon reflexes are reduced or lost, but later mild spasticity may develop.
There is no specific therapy for OPIDN. Regular physiotherapy may limit deformity caused by muscle-wasting. Recovery is often incomplete and may be limited to the hands and feet, although substantial functional recovery after 1-2 years may occur, especially in younger patients.
Carbamate insecticides
Carbamate insecticides (e.g. aldicarb, carbofuran, methomyl) inhibit a number of tissue esterases, including AChE. The mechanism of action, clinical features and management are similar to those of OP compounds. However, clinical features tend to be less severe and of shorter duration, because the carbamate/AChE complex dissociates quickly, with a half-life of 30-40 minutes, and does not undergo ageing. Also, carbamates penetrate the CNS poorly. Pancreatitis has been reported as a sequel, and deaths have occurred.
Atropine may be given intravenously in frequent small doses (0.6-2.0 mg i.v. for an adult) until signs of atropinisation develop. Diazepam may be used to relieve anxiety. The use of oximes is unnecessary.
Methanol and ethylene glycol
Ethylene glycol (1,2-ethanediol) is found in antifreeze, brake fluids and, in lower concentrations, windscreen washes. Methanol is present in some antifreeze products and commercially available industrial solvents, and in low concentrations in some screen washes and methylated spirits. Both are rapidly absorbed after ingestion. Although methanol and ethylene glycol are not of high intrinsic toxicity, they are converted via alcohol dehydrogenase to toxic metabolites that are largely responsible for their clinical effects.
Management
Urea, electrolytes, chloride, bicarbonate, glucose, calcium, magnesium, albumin and plasma osmolarity and arterial blood gases should be measured in all patients with suspected methanol or ethylene glycol toxicity. The osmolal and anion gaps should be calculated. The diagnosis can be confirmed by measurement of ethylene glycol or methanol concentrations, but these assays are not widely available.
An antidote, either ethanol or fomepizole, should be administered to all patients with suspected significant exposure while awaiting the results of laboratory investigations. These block alcohol dehydrogenase and delay the formation of toxic metabolites until the parent drug is eliminated either naturally or by dialysis. The antidote should be continued until ethylene glycol or methanol concentrations are undetectable. Metabolic acidosis should be corrected with sodium bicarbonate (e.g. 250 mL of 1.26% solution, repeated as necessary). Convulsions should be treated with an intravenous benzodiazepine. In ethylene glycol poisoning, hypocalcaemia should only be corrected if there are severe ECG features or seizures occur, since this may increase calcium oxalate crystal formation.
Haemodialysis or haemodiafiltration should be used in severe poisoning, especially if renal failure is present or there is visual loss in the context of methanol poisoning. It should be continued until acute toxic features are no longer present and ethylene glycol or methanol concentrations are no longer detectable.
Substances taken less commonly in overdose
Anticonvulsants
Carbamazepine, phenytoin
Cerebellar signs, Convulsions, Cardiac arrhythmias, Coma
Treatment
Multiple-dose activated charcoal (carbamazepine)
Sodium valproate
Coma, Metabolic acidosis
Treatment
Haemodialysis for severe poisoning
Isoniazid
Peripheral neuropathy, Convulsions
Treatment
Activated charcoal
I.v. pyridoxine
Theophylline
Cardiac arrhythmias, Convulsions, Coma
Treatment
Multiple-dose activated charcoal
Corrosives and bleach
Injuries to stomach (esp. acids) and oesophagus (esp. alkali)
GI perforation and late strictures, Aspiration pneumonitis
Treatment
(1) Gastric lavage and neutralising chemicals are contraindicated
(2) Chest X-ray to exclude perforation, (3) Consider early endoscopy or Gastrografin studies to assess extent of damage and need for surgery
Lead, e.g. chronic occupational exposure, leaded paint, water contaminated by lead pipes, use of kohl cosmetics
Abdominal pain, Microcytic anaemia with basophilic stippling, Headache and encephalopathy, Motor neuropathy, Nephrotoxicity, Hypertension, Hypocalcaemia
Treatment
(1) Prevent further exposure, (2) Measure blood lead concentration, (3) full blood count and blood film, urea and electrolytes, liver function tests and calcium, (4) Abdominal X-ray in children to detect pica, (5) Bone X-ray for lead lines , (6) Chelation therapy with dimercaprol, DMSA, DMPS or sodium calcium edetate for severe poisoning (esp. in children)
Petroleum distillates, white spirit, kerosene
Vomiting, Aspiration pneumonitis
Treatment
(1) Gastric lavage contraindicated, (2) Activated charcoal ineffective, (3)Oxygen and nebulised bronchodilators, (4) Chest X-ray to assess pulmonary effects
Anticoagulant rodenticides (e.g. brodifacoum, bromodialone) and warfarin
Abnormal bleeding (prolonged)
Treatment
(1)Monitor INR/prothrombin time, (2) Vitamin K1 by slow i.v. injection if coagulopathy, (3) Fresh frozen plasma or specific clotting factors for bleeding