From the Department of Emergency Medicine (Seow VK, Wang TL), Shin-Kong Wu Ho-Su Memorial Hospital, Taiwan

Correspondence to Dr. Tzong-Luen Wang, Department of Emergency Medicine, 95 Wen Chang Road, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan . E-mail M002183@ms.skh.org.tw

 

Organophosphates (OP) are used widely in agriculture, horticulture, and veterinary medicine. These insecticides also are used domestically and in public hygiene to control vectors of disease. Some OP compounds (e.g., malathion) are used to treat human infestation with scabies, head lice, and crab lice. Examples of OPs include insecticides (malathion, parathion, diazinon, fenthion, chlorpyrifos), nerve gases (soman, sarin, tabun, VX), ophthalmic agents (echothiophate, isoflurophate), and antihelmintics (trichlorfon).¹ The primary action of OP insecticides on insects, and the source of their potential toxicity to humans, is a consequence of their ability to inhibit the enzyme acetylcholinesterase (AChE).^2,3 The result is an acetylcholine (ACh) excess syndrome.

 

Top Abstract Introduction Pathophysiology of Toxic Effects The Route of OP Poisoning Clinical Presentation Intermediate Syndrome OPIDP Diagnosis Management Conclusion References

Pathophysiology of Toxic Effects (CNS). The primary mechanism of action of OP is inhibition of acetylcholinesterase (AChE). Acetylcholinesterase (true or red blood cell acetylcholinesterase) is a neurotransmitter found primarily in erythrocyte membranes, nervous tissue, and skeletal muscle.Plasma cholinesterase(pseudocholinesterase, butyrylcholinesterase) is found in the serum, liver, pancreas, heart, and brain. Its normal physiologic action is to break down acetylcholine (ACh). OP inactivates AChE by phosphorylating the serine hydroxyl group located at the active site of ACh. Inhibition of cholinesterase leads to acetylcholine accumulation at nerve synapses and neuromuscular junctions, resulting in overstimulation of acetylcholine receptors, including muscarinic and nicotinic receptors. This initial overstimulation is followed by paralysis of cholinergic synaptic transmission in the CNS, in autonomic ganglia, at parasympathetic and sympathetic ganglionic nicotinic sites, postganglionic cholinergic sympathetic and parasympathetic muscarinic sites and skeletal muscle nicotinic sites.^4,5
Once an OP binds to AChE, the enzymes can undergo 3 processes, including (1) endogenous hydrolysis of the phosphorylated enzyme by esterases or paraoxonases, (2) reactivation by nucleophile such as pralidoxime (2-PAM), and (3) biological changes that render the phosphorylated enzyme inactive (aged).⁷ Aging is a term describing the permanent, irreversible binding of the organophosphorous compound to the cholinesterase. The time to aging is slightly variable with different agents. It can take minutes to a day or more. Once aging occurs, the enzymatic activity of cholinesterase is permanently destroyed, and new enzyme must be resynthesized over a period of weeks before clinical symptoms resolve and normal enzymatic function returns. Therapeutic agents must be given before aging occurs to be effective.

Toxicity may occur after inhalation, after ingestion, or through skin contamination. Although dermal absorption of OP compounds tends to be slow, severe poisoning still may ensue if exposure is prolonged. Skin contact and subsequent absorption is the major route of exposure occupationally. Inhalation of OP insecticides, particularly during the manufacture of formulations (e.g., because of inefficient operating ventilation equipment) or during spraying or mixing, is a recognized occupational hazard. Ingestion is uncommon in the workplace but can occur accidentally in workers with poor personal hygiene, such as those who do no remove contaminated clothing or fail to wash their hands. This exposure is likely to lead to only mild features, whereas the deliberate ingestion of an OP insecticide is likely to result in more severe features of intoxication. Massive OP intoxication can occur during suicidal and accidental events such as terrorist action in Tokyo subway in 1995.

An intermediate syndrome may occur 24~96 hours after resolution of an acute organophosphate poisoning. It may manifest as paralysis and respiratory distress syndrome involves neck flexor muscles, proximal muscle groups, respiratory muscles and muscles innervated by the cranial nerves, with relative sparing of distal muscle. It may be prevented by aggressive early antidote therapy. It may resolve within 4~18 days.⁶

Organophosphate-induced delayed polyneuropathy occurs 2 weeks after exposure to large doses of certain OPs. Unlike intermediate syndrome, it may involve distal muscle with relative sparing of the neck muscles, cranial nerves, and proximal muscle groups.^12,13,14,16

The diagnosis of organophosphate poisoning is often difficult. Suspicion of OP poisoning is based on history, the presence of a suggestive toxidrome and maybe noting a characteristic hydrocarbon or garlic-like odor. It may be confirmed by demonstrating reduced levels of cholinesterase activity in plasma and erythrocytes. Unfortunately, many hospital laboratories do not have the in-house capability to determine cholinesterase levels. RBC AChE represents the AChE found in CNS gray matter, RBCs and brain. Plasma AChE is a liver acute phase protein that circulates in the blood, white matter, the pancreas and the heart. In acute exposures, the plasma cholinesterase levels fall first, with decreases in RBC cholinesterase levels lagging behind. Patients with chronic exposures may demonstrate only reduced RBC cholinesterase activity, and their plasma cholinesterase may show false-negative result, with symptomatic patients having determinations in the normal range. Plasma cholinesterase levels have little prognostic value in patients with OP poisoning. Its level does not correlate with severity.
Other laboratory findings are nondiagnostic but may be used as reference such as leukocytosis with a normal differential, anion gap acidosis, evidence of pancreatitis, hypo- or hyperglycemia and liver function abnormalities. ECG findings can be prolonged QTc interval, elevated ST segment and prolonged PR interval.⁹

Management of poisoning with OP is directed toward four goals: (1) decontamination, (2) supportive care, (3) reversal of acethylcholine excess at muscarinic sites, and (4) reversal of toxin binding at active sites on the cholinesterase molecule.^10,11
Decontamination is very important in cases of dermal exposure since its absorption is rapid. These should include: rapid identification of the offending agent and swift decontamination by well-protected emergency medical personnel. Universal precautions including eyeshields, protective clothing, and nitrile or butyl rubber gloves instead of latex must be worn to prevent secondary contamination of health care workers. In the case of ingestion, standard GI decontamination procedures are of questionable benefit because of the rapid absorption of these compounds.
Since most of the morbidity and mortality primarily results from airway and respiratory failure, airway protective and management should be put on the first priority. Supportive care should be directed to suctioning of secretions and vomitus, 100 percent oxygenation, a cardiac monitor, pulse oximeter, and when necessary, ventilatory support. A nondepolarizing agent for rapid sequence intubation should be used when neuromuscular blockade is needed. Succinylcholine is metabolized by plasma cholinesterase, and therefore, prolonged paralysis may result. Monitor neck muscle weakness and mental status regularly to assess progression or decompensation.
The mainstay of medical therapy in OP poisoning is atropine or glycopyrrolate and 2-PAM (pralidoxime). Atropine, a competitive antagonist of acetylcholine at CNS and peripheral muscarinic receptors, is used to reverse muscarinic and central effects secondary to excessive parasympathetic stimulation. Large doses of atropine may be required, and the usual regimen is 2 to 5 mg intravenously every 5 minutes until control of mucous membrane hypersecretion is attained and the airway cleared. Mydriasis and marked tachycardia are the early signs of atropinization. The end-point of atropinization is drying of respiratory secretions. Atropine should not be withheld in the face of a tachycardia that may be the result of hypoxia due to secretions, respiratory muscle paralysis, or ganglionic stimulation. Atropine does not reverse muscle weakness.¹⁸
Pralidoxime (2-PAM, Protopam) is a nucleophilic agent that reactivates the phosphorylated AChE by binding to the OP molecule. It breaks up the organophosphate-acetylcholinesterase complex and restores acetylcholinesterase activity at both muscarinic and nicotinic sites. The medication may be given in a bolus of 1 to 2 g intravenously over 30 ~ 60 minutes every 4 to 8 hours. It is commonly stated that pralidoxime is useful only within the first 24 hours after poisoning because of aging of the organophosphate-acetylcholinesterase complex. Pralidoxime is not administered to asymptomatic patients or to patients with known carbamate exposures presenting with minimal symptoms.

Organophosphate is a chemical compound that brings hazardous effects to people. Thus, prevention of getting exposure and professional management of intoxication by emergency staff should be emphasized. Due to potential prolonged effects of acetylcholinesterase inhibition, most individuals with significant exposures require hospital admission and regular follow up.

Top Abstract Introduction Pathophysiology of Toxic Effects The Route of OP Poisoning Clinical Presentation Intermediate Syndrome OPIDP Diagnosis Management Conclusion References