The clinical presentation of severe nerve-agent poisoning overlaps with that of severe cyanide poisoning, though nerve agents may produce cholinergic effects and are more likely to produce cyanosis Hemodynamic effects may be either excitatory or inhibitory, depending on balance between sympathomimetic and muscarinic effects Nerve-agent poisonings generally require atropine to counter the cholinergic effects, as well as pralidoxime to counter the neuromuscular effects Prophylactic treatment with benzodiazepines to prevent seizures is indicated in large exposures Nerve agents (including the compounds sarin, soman, tabun, and VX) are organophosphorus esters and, like the less potent “organophosphate” (OP) insecticides, are potent and essentially irreversible inhibitors of acetylcholinesterase (see Chapter 102 Toxicologic Emergencies ) Certain oximes can dissociate bound nerve agents from acetylcholinesterase but only initially; after a variable period a portion of an alkyl group is nonenzymatically lost from the enzyme in a process called aging, and the resulting nerve agent— cholinesterase complex becomes refractory to oxime action The time required for these agents to undergo aging varies from a few minutes for soman to 48 hours for VX Nerve-agent vapors are heavier than air and would thus affect persons closer to the ground (e.g., young children) disproportionately Toxicology Nerve agent–induced inhibition of acetylcholinesterase causes the neurotransmitter acetylcholine to accumulate in cholinergic synapses and in neuromuscular and neuroglandular junctions; this excess of acetylcholine initially causes end-organ stimulation that may then lead to end-organ failure Cholinergic sites are found in the central nervous system (CNS), in the neuromuscular junctions of somatic nerves, in parasympathetic nerve endings, in some sympathetic nerve endings (e.g., sweat glands), and in both parasympathetic and sympathetic ganglia The cholinergic syndrome thus produced is classically divided into CNS effects, nicotinic effects (at neuromuscular junctions and sympathetic ganglia), and muscarinic effects (in smooth muscles and exocrine glands) CNS effects include altered mental status progressing through lethargy to coma, ataxia, convulsions, and respiratory depression (central apnea) Nicotinic effects include muscle fasciculations (including tics) and twitching, and then weakness (including ptosis) progressing to flaccid paralysis Nicotinic effects on sympathetic activity may also result in tachycardia, hypertension, and metabolic aberrations (e.g., hyperglycemia, hypokalemia, metabolic acidosis) Muscarinic toxicity is manifested by ocular findings (miosis, visual blurring, eye pain, lacrimation), respiratory distress (watery rhinorrhea, bronchospasm, increased bronchial secretions causing cough, wheezing, dyspnea), dermal involvement (flushing, sweating, cyanosis), GI signs and symptoms (salivation, nausea, vomiting, diarrhea progressing to fecal incontinence and abdominal cramps), genitourinary complaints (frequency, urgency, incontinence), and cardiovascular findings (bradycardia, hypotension, atrioventricular block) Because muscarinic effects on the heart are opposed by the cardiovascular effects of nicotinic hyperstimulation at autonomic ganglia, heart rate and blood pressure may be either elevated or depressed and are not reliable indicators of the severity of nerve-agent intoxication Clinical Presentation The clinical presentation in a given patient depends on dose and route of exposure For vapor exposures, mild toxicity would be suggested by miosis, rhinorrhea, mild dyspnea, and wheezing—all local effects caused by contact of vapor with epithelial surfaces As the dose increases and systemic distribution of the agent occurs, the victim might experience increased respiratory secretions and dyspnea, nausea, vomiting, and muscle weakness In the Tokyo experience with sarin vapor exposure, miosis (99%), dyspnea (63%), nausea (60%), and headache (74%) were particularly common among moderately symptomatic patients at hospital admission In severe cases with exposure to high vapor concentrations, paralysis, and seizures leading to death from respiratory arrest may occur within minutes and sometimes nearly instantaneously In the Tokyo incident, of 640 patients presented to one ED in cardiopulmonary arrest The asymptomatic period between exposure and the onset of signs and symptoms is termed the latent period It is important to stress two aspects of this concept with respect to nerve agents: First, the onset of clinical effects is immediate or nearly immediate after the inhalation of a substantial dose of vapor, whereas there is a delay after skin exposure This is because it takes time for nerve agent to pass through the stratum corneum (where it forms a temporary depot) and reach the dermal capillaries for introduction into the systemic circulation Second, the length of the latent period, whether for inhalation or dermal exposure, is inversely correlated with dose For example, a very small drop of VX applied to the skin may cause rapid local effects (localized sweating and then fasciculations of underlying muscle fibers) but may take up to 18 hours to cause systemic effects, whereas a fatal dose (still smaller than a pinhead) may lead to sudden collapse, convulsions, paralysis, apnea, and death after a latent period of only 10 to 30 minutes Because absorption from inhalation is fast and complete, patients who have inhaled nerve-agent vapor typically not deteriorate once they are removed from exposure However, the latency conferred by the time needed for the nerve agent to traverse the epidermis means that symptoms may arise (gradually or, with a high dose, suddenly) and progress minutes to hours after exposure and even after successful decontamination of the surface of the skin Vapor-exposed patients typically exhibit either gradual or sudden-onset local effects such as miosis, lacrimation, rhinorrhea, hypersalivation, bronchoconstriction, and bronchorrhea followed or accompanied by, if the dose or duration of exposure is high enough, systemic effects involving the GI tract, skeletal muscles, and the CNS Patients exposed via the skin may also exhibit local effects (diaphoresis and fasciculations) and then systemic effects either gradually or all at once, but after a delay With high doses, collapse, apnea, and death from bolus delivery to the circulation may be so rapid that miosis and other peripheral muscarinic effects may not have time to develop Management The diagnosis of traditional nerve-agent poisoning is primarily by clinical recognition of acute signs and symptoms and by observing the response to antidotal therapy Routine toxicologic studies not identify OP compounds or their metabolites in blood or urine, and the ability to measure acetylcholinesterase is not widely available Although presumptive antidotal therapy for symptomatic patients is indicated, treatment is not needed for exposed asymptomatic patients These patients, however, should be carefully observed if there is any possibility of concomitant exposure to liquid nerve agent As discussed previously, in this setting immediate decontamination is an urgent medical intervention, since it can decrease the internal dose of the agent The drugs of choice to treat nerve-agent toxicity are atropine for its antimuscarinic effects and pralidoxime (also called 2PAM), which serves to reactivate acetylcholinesterase Atropine treats bronchospasm and increased bronchial secretions, bradycardia, and GI effects and may lessen seizure activity However, atropine will not improve skeletal muscle paralysis Atropine is dosed initially at 0.05 mg/kg, with a minimum dose of 0.1 mg and a maximum of mg ( Table 132.4 ) It should be given in repeat doses until secretions decrease and airway resistance lessens; a typical total dose of atropine for an adult nerve-agent victim is 20 to 30 mg, as opposed to over 20,000 mg that may be needed in an adult exposed to an OP pesticide (there is at least one known case of a pediatric pesticide poisoning that required a total of 5,000 mg of atropine) In this setting, atropine is typically delivered IM via an autoinjector However, in severe cases, both atropine and pralidoxime should be administered IV once the patient has been decontaminated and delivered to the ED Animal data suggest that hypoxia should be corrected, if possible, prior to IV atropine use, to prevent arrhythmias; otherwise, IM use might be safer initially Pralidoxime cleaves OP away from the cholinesterase and regenerates the intact enzyme if aging has not yet occurred The beneficial effect is observed predominantly as improved muscle strength Pralidoxime is dosed initially at 25 mg/kg, with maximum doses of g IV or g IM ( Table 132.5 ) Pediatric experience with OP pesticide poisoning suggests that the continuous infusion of pralidoxime may be optimal However, the IM route is acceptable if IV access is not readily available In practice, atropine and pralidoxime are often given concurrently because of the availability of autoinjector kits containing separate vials of mg atropine and 600 mg 2-PAM Recently, combination autoinjectors containing 2.1 mg atropine and 600 mg pralidoxime in a single vial have also become available (Duodote) Additionally, pediatric-sized autoinjectors of pure atropine are now available in 0.25 mg, 0.5 mg, and mg doses Of note, during the Gulf War, 240 Israeli children were evaluated for accidental autoinjection of atropine None had been exposed to nerve agents and systemic anticholinergic effects occurred in many, but seizures, severe dysrhythmias, and deaths were not observed 2-PAM autoinjectors that deliver a proper dose for children are not currently available However, in dire circumstances, the adult autoinjectors with 600 mg pralidoxime might find utility in children older than ages to years or who weigh more than 13 kg (suggested guidelines and weight-based dosing for children of all sizes are detailed in Table 132.5 ) For infants, one might consider using the pediatric-sized atropine autoinjectors, along with conventionally administered IM 2-PAM This can be effected by the discharge of one or several autoinjectors’ contents into an emptied 10 cc sterile saline vial ( Fig 132.7 ) The 300 mg/mL solution may then be withdrawn through a filter needle into one or several syringes suitable for small-volume IM injections Finally, the routine administration of anticonvulsant doses of benzodiazepines is recommended in significant cases, even without observed convulsive activity Diazepam is available in autoinjectors for IM administration, but midazolam absorption from muscle is more rapid than for diazepam Because the latent periods of fourth-generation agents (FGAs) can be up to two days or longer and because it may be difficult to treat FGA-poisoned patients if one simply waits for signs and symptoms to arise, the approach to the ... that may be needed in an adult exposed to an OP pesticide (there is at least one known case of a pediatric pesticide poisoning that required a total of 5,000 mg of atropine) In this setting, atropine... Pralidoxime is dosed initially at 25 mg/kg, with maximum doses of g IV or g IM ( Table 132.5 ) Pediatric experience with OP pesticide poisoning suggests that the continuous infusion of pralidoxime... atropine and 600 mg pralidoxime in a single vial have also become available (Duodote) Additionally, pediatric- sized autoinjectors of pure atropine are now available in 0.25 mg, 0.5 mg, and mg doses