Describe organophosphate poisoning with its mechanism, clinical features and management.

Sources and Mechanism

• Organophosphate poisoning is the single commonest cause of fatal poisoning in India, and one of the leading methods of suicide worldwide. The compounds are freely available in every agricultural household
• Compounds — malathion, parathion, monocrotophos, dichlorvos, chlorpyrifos, fenthion and diazinon; and the nerve agents sarin, tabun, soman and VX, which are organophosphates of extreme potency. carbamates — carbaryl, propoxur, aldicarb — act by the same mechanism but differ critically in reversibility
• Mechanism — inhibition of acetylcholinesterase by phosphorylation of the enzyme, so that acetylcholine accumulates at muscarinic, nicotinic and central receptors. The result is a cholinergic crisis affecting every system innervated by acetylcholine
• "ageing" is the concept that governs treatment. The enzyme-organophosphate bond undergoes a further chemical change over hours which makes the inhibition irreversible, and after which the enzyme can no longer be reactivated by an oxime. This is why pralidoxime must be given early to be of any use
• Carbamates do not age — the inhibition is reversible and hydrolyses spontaneously within 24 to 48 hours. They are therefore generally less lethal, they do not require pralidoxime, and pralidoxime may be harmful in carbaryl poisoning
• Absorption is by ingestion, inhalation and through intact skin, the last being of great importance for agricultural workers and for the staff treating them

• Death is from the airway, and the three killer Bs are the reason.
• Bronchorrhoea floods the lungs with secretion, bronchospasm closes them, and bradycardia fails the circulation — compounded by paralysis of the respiratory muscles and central depression. Everything else in the syndrome is secondary.
• Atropine is titrated to a dry chest, not to the pupils, because it is the secretions that kill.

The Three Neurological Syndromes

Diagnosis and Treatment

• Cholinesterase estimation — plasma (pseudo) cholinesterase is more readily measured and falls first, so it is the more sensitive test, but it is affected by liver disease and by genetic variation; red cell (true) acetylcholinesterase correlates better with the severity and with recovery, and is the more specific. A fall to below about 50% of normal indicates significant poisoning
• Decontamination — remove all clothing and wash the skin and hair thoroughly with soap and water. protect the staff with gloves and aprons; secondary poisoning of doctors and nurses from contaminated clothing and vomit is documented. Gastric lavage has a limited role and carries an aspiration risk because of the kerosene solvent
• Atropine is the mainstay, and the doses required are very much larger than in any other setting — often tens to hundreds of milligrams. Give 2 to 5 mg intravenously and double the dose every 5 minutes until atropinised, then maintain by infusion. The endpoint is a clear chest on auscultation and dry axillae, with a heart rate above about 80 and a systolic pressure above about 80 — not the pupils, which respond late and may be affected by local contamination of the eye
• Pralidoxime (2-PAM) — reactivates the enzyme by removing the phosphate group, but only before ageing has occurred, so it must be given as early as possible. It acts chiefly on the nicotinic features — the fasciculation and muscle weakness — which atropine does not touch. Not required in carbamate poisoning
• Supportive care — oxygen and early intubation and ventilation, which is what saves lives; diazepam for convulsions and agitation; and careful fluid management
• Avoid — morphine, succinylcholine, aminophylline and phenothiazines, all of which are contraindicated

Organophosphate Compared with Carbamate

Applied Aspects

• Titrate atropine to a dry chest, not to the pupils; under-atropinisation from watching the pupils is the commonest treatment error and the patient drowns in secretions
• Give pralidoxime early or not at all; once the enzyme has aged it cannot be reactivated, and a late dose achieves nothing
• Do not discharge on apparent recovery; the intermediate syndrome appears at 24 to 96 hours, does not respond to atropine, and needs ventilation. Observe every patient for at least four days
• Protect yourself and the staff; the compound is absorbed through intact skin, and secondary poisoning from clothing and vomit has affected treating teams
• Remember the kerosene solvent; it causes an aspiration pneumonitis of its own and makes aggressive lavage dangerous
• Distinguish carbamate from organophosphate; the carbamate patient recovers spontaneously in 24 to 48 hours, needs no pralidoxime, and may be harmed by it
• Warn about OPIDN at discharge; a foot drop appearing three weeks later is otherwise attributed to something else entirely and the connection is missed
• Carbamates do not age and need no pralidoxime, and the inhibition hydrolyses spontaneously within one to two days
• Fasciculation is the most useful nicotinic sign, best seen in the eyelids, face and calves, and it responds to pralidoxime rather than atropine
• Plasma cholinesterase is more sensitive and red cell more specific, and a fall below half of normal indicates significant poisoning
• OPIDN is caused by neuropathy target esterase, not by cholinesterase, so it is unrelated to the severity of the acute phase
• Triorthocresyl phosphate caused the ginger jake paralysis, and Indian outbreaks have followed adulteration of cooking oil
• Avoid morphine, succinylcholine and aminophylline, all of which are contraindicated in organophosphate poisoning
• Nerve agents are organophosphates of extreme potency, and the same principles of atropine and oxime apply to them
• Absorption through intact skin is efficient, which is why decontamination and staff protection come before anything else
• The three killer Bs are what kill — bronchorrhoea, bronchospasm and bradycardia — and atropine is titrated against them
• Intubate early rather than late; respiratory failure is the mode of death and ventilation is what changes the outcome
• The intermediate syndrome needs ventilation, not atropine, and appears after the patient has apparently recovered
• Kerosene is the solvent in most formulations, adding an aspiration pneumonitis and making aggressive lavage dangerous
• Observe every patient for at least four days; discharge on apparent recovery is how the intermediate syndrome kills
• Warn about foot drop at three weeks; OPIDN is otherwise attributed to something else entirely and the link is missed