Pathophysiology and clinical presentation

Toxicity from organophosphate compounds can occur via almost any route of exposure, including dermal, ocular, inhalation, ingestion, or injection. The onset, severity, and duration of effects depend on the potency of the agent; the route, concentration, and duration of exposure; and the use of antidotal therapy. Patients with vapor exposure experience a rapid onset of effects, whereas dermal exposure will often have a delayed onset of toxicity.

Organophosphates bind to the enzyme responsible for acetylcholine hydrolysis, acetylcholinesterase, resulting in an elevated synaptic concentration of acetylcholine at both nicotinic and muscarinic receptors. Initially the binding is reversible; water may enter the enzyme active site and hydrolyze the organophosphate moiety off. However, after a time, depending upon the organophosphate, the moiety bound to the enzyme undergoes a chemical change and is no longer able to undergo hydrolysis. This is called aging and results in permanent inhibition of the acetylcholinesterase enzyme. The carbamate pesticides are very similar clinically and pharmacologically to the organophosphosphate compounds, the main difference being that they will not age and pralidoxime is not necessary for therapy.

Acetylcholinesterase inhibition results in prolongation and potentiation of acetylcholine action at cholinergic synapses. In the central nervous system, this causes confusion, agitation, and seizures. In the autonomic nervous system, increased cholinergic transmission results in diaphoresis, bradycardia (tachycardia is seen for other reasons), miosis (not always present), lacrimation, salivation, vomiting, defecation, and urination due to overstimulation of muscarinic receptors. The latter constellation of symptoms is represented by the cholinergic toxidrome mnemonic DUMBBELS (diarrhea, urination, miosis, bronchorrhea/bronchospasm/bradycardia, emesis, lacrimation, and salivation). Increased cholinergic activity at neuromuscular junctions results in muscle fasciculations and motor weakness.

Late effects of organophosphate poisoning include “intermediate syndrome,” a return of weakness and neuromuscular symptoms 1–4 days after initial clinical improvement. Patients may require additional supportive therapy or reintubation. Late neurological sequelae include peripheral neuropathies, persistent miosis, and neuropsychiatric sequelae (nightmares, headache, anxiety); this effect is likely to compound the psychological effect of a nerve agent attack.

Decontamination and personal protective equipment

The risk of provider poisoning by an organophosphate depends upon the class of the agent. With the highly lethal war nerve agents (GA, GB, VX, etc.), most are volatile (except VX) and very small doses will potentially be lethal. For protection, a level A fully encapsulated garment is required. Personnel responding to war nerve agent attacks are at significant risk of becoming secondarily exposed and suffering from adverse effects from insufficiently decontaminated victims. In the Tokyo sarin attack, first responders and nurses suffered adverse effects from the vapors of insufficiently decontaminated patients in poorly ventilated areas, but injuries were mild with improvement once they ventilated the vehicles during transport [2].

Exposures to organophosphate pesticides are more common and less lethal to humans. These agents have much lower volatility than the war agents; the smell reported is partially due to the solvent hydrocarbon. Unless the patient is completely drenched in concentrated organophosphate pesticide, standard universal precautions with double nitrile gloves should be sufficient to prevent any significant exposure. The vomitus from patients ingesting concentrated organophosphate pesticide should be handled with caution. Although there is a report about secondary ED staff contamination by “pesticide vapors,” there are uncertainties about the exact etiology of this event [3].

Decontamination includes removal of all clothing and jewelry, physical removal of visible residue, and irrigation with water or soap and water; for the organophosphate pesticides, significant scrubbing with soap and water will be required. Items of leather and cloth are difficult to clean and should not be returned to the patient. There is no consensus regarding gastric decontamination of pesticide organophosphates. In many cases, the patient will already have vomited and so the utility of lavage is questionable. Activated charcoal could be of benefit, but this should only be considered when the airway is secure (i.e. intubation) to prevent possible aspiration.

Detection and diagnosis

First responders should be vigilant for potential organophosphate exposures in instances in which there are multiple casualties presenting with similar symptoms. In the 1995 sarin attacks in Tokyo, the most common physical sign was miosis, with presenting symptoms ranging from eye pain, headache, and bronchorrhea to apnea and death [1]. The miosis was a very useful sign to separate those suffering from toxicity from those who were “worried well.” Note that miosis is not useful in organophosphate toxicity with other routes of exposure (such as ingestion). Rapid development of the cholinergic toxidrome in a number of casualties should prompt immediate consideration of an organophosphate. Activity of red blood cell cholinesterase and plasma cholinesterase may assist diagnosis in hospital.

Treatment and disposition

After decontamination, supportive care includes airway maintenance and support of ventilation, as respiratory failure is the primary reason for death with organophosphates. Aggressive suctioning may be required because of copious airway secretions and vomiting; aspiration is not uncommon with organophosphate pesticide ingestion. If intubation is required, succinylcholine should be avoided because it may lead to prolonged neuromuscular blockade due to the organophosphate inhibition of butyrylcholinesterase. The mainstay of treatment in nerve agent and organophosphate poisoning consists of antidotal therapy with atropine, pralidoxime, and diazepam.

Atropine competitively antagonizes excess acetylcholine effects at central and peripheral muscarinic receptors but has no effect at nicotinic receptors. Atropine can effectively reverse bronchorrhea, bradycardia, and gastrointestinal symptoms and treat seizures, but has no effect on nicotinic symptoms such as fasciculations, weakness, or paralysis [4]. Side-effects may include delirium, tachycardia, and agitation. The initial dose of atropine is 2 mg in adults (0.05 mg/kg in children, minimum 0.1 mg) administered intravenously or intramuscularly. Although it can be administered via the endotracheal route, this has disadvantages because of the excessive secretions and ventilation difficulties. The dose is titrated to effect and may be repeated every 1–5 minutes; although tachycardia may develop, atropine is given until the patient is well ventilated as demonstrated by reduced secretions and resolution of bronchoconstriction and/or is no longer bradycardic. Atropine will also potentially decrease vomiting, diarrhea, and bradydysrhythmia. The required dose of atropine can be very large for oral pesticide poisoning, with some patients requiring hundreds of milligrams of atropine; much less is required to treat war nerve agent poisoning. Unless symptoms resolve with a single dose of atropine, patients who require administration of atropine following organophosphate exposure should also receive pralidoxime.

Pralidoxime chloride is an oxime that reactivates acetylcholinesterase by reacting with the phosphorus moiety, resulting in an oxime-phosphate compound that leaves the regenerated enzyme. Oxime therapy must be administered before the aging of that bond is complete, a process that can begin within minutes of exposure and depends upon the organophosphate. The initial dose is 1–2 g for adults (25–50 mg/kg for children), and repeated dosing may be required; continuous infusions of 8–10 mg/kg/hour have been recommended. Slow administration over 15–30 minutes has been advocated to minimize side-effects which include hypertension, headache, blurred vision, weakness, epigastric discomfort, nausea, and vomiting. Rapid administration can result in laryngospasm, muscle rigidity, and transient impairment of respiration.

Benzodiazepines are used for the treatment and prevention of seizures. Diazepam 5–10 mg intravenously may be used, but repeated dosing may potentiate organophosphate-induced respiratory depression.

All three of these agents are available as autoinjectors; the commercially available MARK I autoinjector contains both 2 mg of atropine and 600 mg of pralidoxime and requires two injections. A new autoinjector, the Antidote Treatment Nerve Agent Auto-Injector (ATNAA or DuoDote®), allows for both atropine (2.1 mg) and pralidoxime (600 mg) to be injected simultaneously; one disadvantage to this device is the inability to give more atropine without also giving more pralidoxime [5].