Nerve Agents

Etiology

The etiology of nerve agent toxicity is primarily environmental exposure. Patients can be exposed to nerve agents through agriculture and bioterrorism. Organophosphates and carbamates found in many insecticides commonly cause toxicity in agricultural and industrial workers. Synthetic nerve agents like soman, tabun, sarin, and VX have been used in bioterrorism in the past and present.

• Soman: A volatile liquid nerve agent; originally developed in Germany during World War II, but never used in warfare
• Tabun: An organophosphorus compound, first synthesized in Germany; during the Nuremberg trials, a military officer admitted to conspiring to assassinate Adolf Hitler in his bunker with tabun.
• Sarin: Highly volatile; death from respiratory paralysis can occur in as little as 1 to 10 minutes. Sarin was used in the 1995 Tokyo subway attack, killing 12 people.[1] 
• VX: A synthetic, nonvolatile liquid nerve agent; used in the assassination of North Korea's Kim Jong Un's half-brother, Kim Jong Nam, in February 2017

Epidemiology

Organophosphate and carbamate toxicity affects over 10,000 people in the United States annually and over 3,000,000 worldwide. Up to 300,000 deaths per year are attributable to insecticides, herbicides, rodenticides, and chemical warfare agents like soman, sarin, tabun, and VX.[2] Clinical situations in which nerve agent toxicities are seen include agricultural accidents, bioterrorism, and industry.

Pathophysiology

Nerve agents like organophosphates are primarily absorbed in the body through the lungs, skin, and gastrointestinal tract. Nerve agents bind and phosphorylate acetylcholinesterase (AChE), leading to the inactivation of the enzyme and excess amounts of acetylcholine (ACh) in the neuromuscular junction. Excessive ACh leads to constant depolarization of the postsynaptic neurons, which causes the symptoms of cholinergic and muscarinic toxicity. Until the new AChE is synthesized or an oxime like pralidoxime is used to displace the organophosphate from AChE, ACh persists in the neuromuscular junction, constantly binding the muscarinic and nicotinic receptors, leading to the signs and symptoms of cholinergic excess. Following the initial phosphorylation, a conformational change, known as "aging," may occur where an alkoxy group leaves the phosphorylated enzyme. The aging process is clinically important for quick recognition of symptoms and treatment with oximes. Once AChE has aged, it cannot be reactivated by oximes. Aging is variable between nerve agents. The nerve agent soman ages quickly at 5 to 8 minutes compared to the long aging process of VX, which takes 24 hours.[3]

History and Physical

Nerve agent toxicity causes excessive cholinergic stimulation, which leads to the classic DUMBELS symptomatology: defecation, urination, muscle weakness, miosis, bradycardia, bronchospasm, bronchorrhea, emesis, lacrimation, and salivation. ACH binding at nicotinic receptors results in muscle fasciculations, cramps, weakness, paralysis, and areflexia. ACh can also stimulate the brain, where it can induce seizures and coma. Nerve agent toxicity affects all organ systems, leading to a multitude of signs and symptoms often clouding the clinical picture, and patients often present in extremis quickly after exposure.

Evaluation

Diagnosis is primarily clinical, as specific assays and reference laboratory testing take time and often do not have the sensitivity and specificity necessary for an accurate assessment. Cholinesterase levels can help establish a diagnosis and accurately predict prognosis. Assays of red blood cell (RBC)-AChE can give more information about the degree of toxicity and if subsequent dosing of oximes may be required. Follow-up measurements of RBC-AChE can demonstrate the reactivation of the enzyme over time and the effectiveness of treatment.[1][4] Routine laboratory analysis is often low-yield but can help cinch alternative diagnoses and guide care. If clinically suspected, a trial of atropine 1 mg in adults (0.01 mg/kg in children) can be used to assess for clinical improvement.[5][6][7]

Treatment / Management

Treatment is primarily supportive. Airway control, respiratory support, cardiac monitoring, decontamination, and administration of antidotes are the cornerstones of management in treating acute nerve agent exposures. All healthcare personnel need to don personal protective equipment as dermal exposure is a significant route of toxicity. Atropine is a competitive antagonist of ACH at the neuromuscular junction and is the primary antidote in nerve agent poisoning. The dose is 1 to 3 mg intravenously every 5 minutes until tracheobronchial secretions attenuate. Oximes like pralidoxime displace organophosphates from acetylcholinesterase and help reactivate the enzyme. This is recommended early in the treatment of nerve gas toxicities to prevent the aging process. The recommended dosage is 30 mg/kg intravenous (IV) bolus followed by an infusion of 8 mg/kg per hour and continued for 24 to 48 hours. Death from nerve agents primarily occurs from respiratory failure secondary to paralysis, and thus, supportive care with definitive airway control and mechanical ventilation when necessary is key. Patients and their respiratory status should be continually monitored from a cardiac standpoint. Excessive ACH stimulation can cause bradycardia, and corrected QT interval (QTc) prolongation can lead to ventricular tachycardia. Ventricular tachycardia should be treated with cardioversion when necessary. If the patient is hemodynamically stable, antidysrhythmics like amiodarone can be used. If QTc interval prolongation is seen, IV magnesium should be administered.[8][9](A1)

Patients with excessive secretions may require intubation. In the case of intubation, succinylcholine should not be used. AChE metabolizes succinylcholine, and its inhibition will lead to an extended duration of drug action. Rocuronium or other nondepolarizing paralytics are preferred for rapid sequence intubation. Seizures are also commonly seen with nerve agent poisoning. The first-line treatment for seizures in organophosphate poisoning is benzodiazepines. Ativan 2 mg push is a good first-line choice. Antiepileptics like levetiracetam and fosphenytoin are generally less effective but can be used when benzodiazepines are not abating seizures.

Differential Diagnosis

The differential diagnosis of nerve agent toxicity is broad. Without a history of known exposure to an agent, diagnosis tends to be difficult. Other considerations would include physostigmine, edrophonium, or other acetylcholinesterase inhibitor overdose. Additional toxidromes/ingestions must also be considered. Infectious sources could present with signs and symptoms similar to cholinergic toxicity. An astute clinician must rule out other causes by getting appropriate phlebotomy and imaging studies when indicated.

Prognosis

The prognosis depends on the specific nerve agent exposure, amount, route, and duration of contact with the agent. A Glasgow coma score (GCS) of less than 13 portends a poor prognosis. The poisoning severity scale was originally used to determine prognosis. Still, other scoring systems like Acute Physiology and Chronic Health Evaluation II (APACHE-II), Simplified Acute Physiology Score II (SAPS-II), and the Mortality Prediction Model II (MPM-II) outperformed it in predicting death in multiple studies.[8]

Complications

Inadequate dosing of oximes can lead to the development of intermediate syndrome in patients poisoned with organophosphates. The intermediate syndrome occurs 24 to 96 hours after exposure and is characterized by hyporeflexia, respiratory depression, proximal muscle weakness, and cranial nerve abnormalities. Patients may also experience problems up to one to three weeks after exposure. Organophosphorous agent-induced delayed neuropathy (OPIDN) affects mainly distal muscle groups and is characterized by painful stocking-glove paraesthesia and lower extremity weakness. OPIDN is independent of the initial cholinergic toxicity. Neurology consultation and follow-up are recommended if clinicians suspect OPID.[8]