Nerve agents represent a significant contributor to morbidity and mortality in toxicology and emergency medicine. Patients affected by nerve agents present primarily with symptoms of cholinergic excess namely increased secretions, respiratory distress, and paralysis. Diagnosis is clinical, and management is aggressive supportive care with the timely use of antidotes atropine and pralidoxime. Physicians must be familiar with nerve agents to diagnose and treat patients afflicted with this deadly toxidrome properly.
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 is a volatile liquid nerve agent originally developed by the Germans in World War II but was never used in warfare. VX is a synthetic nonvolatile liquid nerve agent and was most famously used recently in the assassination of Kim Jong Un's half-brother Kim Jong Nam in February of 2017. The Germans also synthesized tabun in World War II, and during the Nuremberg trials post-war, a military officer admitted to conspiring to assassinate Adolf Hitler in his bunker with Tabun. Sarin is highly volatile, and 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.
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. Clinical situations in which nerve agent toxicities are seen include agricultural accidents, bioterrorism, and industry.
Nerve agents like organophosphates are primarily absorbed in the body through the lungs, skin, and gastrointestinal tract. Nerve agents bind and phosphorylate acetylcholinesterase (AChE) which leads to 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 will persist 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 when it comes to the quick recognition of symptoms and treatment with oximes. Once AChE has aged, it cannot be reactivated by the use of oximes. Aging is variable between nerve agents. The nerve agent soman ages quickly at 5 to 8 minutes compared to the longer aging process of VX which takes 24 hours.
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.
Diagnosis is primarily clinical as specific assays and reference laboratory testing take time and often do not have the sensitivity and specificity necessary for accurate assessment. Cholinesterase levels can help establish a diagnosis and be an accurate predictor of prognosis. Assays of 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 effectiveness of treatment. 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.
Treatment is primarily supportive. Airway control, respiratory support, cardiac monitoring, decontamination, and administration of antidotes are the cornerstones of management in the treatment of acute nerve agent exposures. It is essential for all healthcare personnel 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 (IV) 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 IV bolus followed by infusion 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. Along with their respiratory status, patient's should be continually monitored from a cardiac standpoint. Excessive ACH stimulation can cause bradycardia and QTc prolongation leading 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.
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 action of the drug. Rocuronium or other nondepolarizing paralytics are preferred for rapid sequence intubation. Seizures are also commonly seen with nerve agent poisoning. 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.
The differential diagnosis of nerve agent toxicity is broad. Without the 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 be considered as well. 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 depends on the specific nerve agent exposure, amount, route, and duration of contact with the agent. Glasgow coma score (GCS) less than 13 portends a poor prognosis. The poisoning severity scale was originally used to determine prognosis but 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.
Inadequate dosing of oximes can lead to the development of intermediate syndrome in patients poisoned with organophosphates. 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 a painful stocking-glove paraesthesia and lower extremity weakness. OPIDN is independent of the initial cholinergic toxicity. Neurology consultation and follow up is recommended if clinicians are suspecting OPIDN.
The symptoms of nerve agent toxicity are sometimes very subtle. Therefore, health care providers must be on the lookout for key findings especially if the clinical situation is agriculture or terrorism. Nerve agent toxicity is a clinical diagnosis often presenting with excessive secretions, respiratory distress, and paralysis. Staff should first protect themselves by dressing in the proper personal protective equipment if nerve agent exposure is suspected. All patients with suspected nerve agent toxicity should receive atropine and pralidoxime in a timely fashion along with aggressive supportive care. Patient’s respiratory status should be closely monitored as patients may need airway protection. Cardiac status should also be monitored as ventricular tachycardia brought on by QTc prolongation can sometimes occur. Patients may also experience excessive central nervous system (CNS) stimulation which can cause seizures. In summary, nerve agent toxicity is a potentially deadly exposure that must be promptly diagnosed and managed in patients afflicted with this syndrome.
Nerve agent toxicity is best managed by an interprofessional team that includes nurses and respiratory therapists. Because these agents can be inhaled and absorbed via the skin, minimum interaction with the patient is the key. In addition, healthcare workers should wear personal protective equipment to prevent self-poisoning.
The outcomes for patients poisoned with nerve agents is guarded and depends on the dose and time to treatment.
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