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, 3 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 do 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 do 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 5 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 1 g IV or 2 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 2 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 1 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 2 to 3 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