a) M291 Skin Decontaminating Kit (for military and civil defense use manufactured by Rohm and Haas).
b) Diluted hypochlorite (household bleach 1:10 in water) followed by a thorough water rinse.
c) 0.5% Hypochlorite solution (prepared by adding one 6 ounce bottle of calcium hypochlorite granules to 5 gallons of water).

a) Pupils will be very pinpoint following vapor exposure. Following cutaneous or ingestion exposures, pupils may be normal or slightly to moderately reduced in size (Grob, 1956).
b) Exposure to sarin vapor at a concentration of 0.09 mg/m(3) caused depressed cholinesterase levels and intense miosis in 2 workers (Rengstorff, 1985). Miosis has been recorded at doses as low as 0.06 mg/m(3). Pupillary reflexes were abolished for 11 days and normal pupillary dilatation required 30 to 45 days to return (Reutter, 1999).

a) Bradycardia and hypotension may occur following moderate to severe poisonings (Ganendran, 1974). Hypotension (systolic blood pressure less than 90 mmHg) occurred in 20% of patients in one study (Bardin et al, 1987). Following severe exposures, depression of the circulatory center may occur, resulting in peripheral vascular collapse and circulatory failure (Grob, 1956). Hypovolemic shock developed in a 28-year-old man exposed to VX (Morimoto et al, 1999).

a) Bradycardia may occur following moderate to severe poisonings. A heart rate of 50 beats/minute was reported in conjunction with severe hypothermia in a VX poisoned man (Morimoto et al, 1999). A heart rate of less than 60 beats/minute occurred in 21% of patients in one study (Bardin et al, 1987). Bradycardia is a muscarinic effect of nerve agent exposure ((Garigan, 1996)).

a) Tachycardia is a common clinical finding. Tachycardia is a result of nerve agent effects on nicotinic receptors with autonomic ganglia causing increased heart rate ((Garigan, 1996); Nozaki et al, 1993). Tachycardia was common in patients with severe sarin exposures following a terrorist attack in Tokyo (Nozaki et al, 1993).

a) Cardiac dysrhythmias and conduction defects have been reported in patients with severe organophosphate poisoning (Wren et al, 1981; Kiss & Fazekas, 1982; Chhabra & Sepaha, 1970).
b) ECG abnormalities may include sinus bradycardia, A-V dissociation, idioventricular rhythms, multiform premature ventricular extrasystoles, polymorphic ventricular tachycardia, prolongation of the PR, QRS, and QT intervals, and "Torsade de Pointes" polymorphous ventricular dysrhythmias (Brill et al, 1984; Ludomirsky et al, 1982).
c) CASE REPORT: A 33-year-old man, exposed to small quantities of soman, developed atrial fibrillation during the recovery phase (Sidell & Groff, 1974).

a) Hypertension can occur as a nicotinic effect of organophosphate poisoning (Lund & Monteagudo, 1986; (Garigan, 1996)). Hypertension was a common finding in patients following severe sarin exposure (Nozaki et al, 1993).

a) CASE REPORT: Within several minutes of a sarin gas exposure, a 35-year-old man was reported to have initial ECG reading of marked ST-segment elevation, consistent with severe anteroseptal myocardial ischemia. Severe hypokinesis of the anteroseptal left ventricular wall was seen on the ECG. Following treatment, these findings returned to normal (Kato et al, 2000). This case suggests that sarin can trigger coronary vasoconstriction. Sidell (1974) described a similar case in a 52-year-old man who developed marked ST elevation and T-wave inversion. He subsequently died from a myocardial infarction 12 months later (Sidell, 1974).

a) Acute respiratory insufficiency, due to any combination of depression of the respiratory center, respiratory paralysis, bronchospasm or increased bronchial secretions, is the main cause of death in many acute organophosphate poisonings (Lerman & Gutman, 1988; Anon, 1984; (Garigan, 1996); Nozaki et al, 1993). Children can rapidly develop respiratory muscle weakness, and be at risk for hypoxia and respiratory depression (Abraham & Weinbroum, 2003). A nicotinic effect on skeletal muscles includes muscle fasciculations, weakness, and paralysis ((Garigan, 1996)). Death due to nerve agents is a result of paralysis of the diaphragm, depression of the CNS respiratory center and airway obstruction by bronchial and salivary secretions ((Garigan, 1996); Berkenstadt et al, 1991; Grob, 1956). Two patients died following sarin gas exposure due to cardiopulmonary/respiratory arrest (Ohbu et al, 1997).

a) Muscarinic effects of nerve agent exposure include bronchial smooth muscle contraction resulting in bronchospasm or wheezing. Simultaneously, bronchial hypersecretion occurs as a result of muscarinic effects on gland secretions ((Garigan, 1996)).

a) Acute lung injury is a manifestation of severe organophosphate poisoning (Chhabra & Sepaha, 1970). Severe pulmonary edema and general edema of the soft tissue developed in a 28-year-old man following a VX injection to the neck (Morimoto et al, 1999).

a) A nicotinic effect on automatic ganglia is tachypnea ((Garigan, 1996)). A respiratory rate greater than 30 per minute was reported in 39% of patients in one study (Bardin et al, 1987). Following severe exposures, the patient may become comatose, with decreased reflexes and development of Cheyne-Stokes respiration (Grob, 1956).

a) Soman and sarin release toxic and irritating fumes of fluorides and oxides of phosphorus when heated to decomposition (EPA, 1985; Sax & Lewis, 1989). Exposure to such fumes would be predicted to result in respiratory tract irritation with possible chemical pneumonitis or acute lung injury.
b) Tabun releases toxic and irritating fumes of oxides of nitrogen, oxides of phosphorus, and cyanide when heated to decomposition. Inhalation exposure to these fumes would be predicted to result in respiratory tract irritation with possible chemical pneumonitis or acute lung injury (Sax & Lewis, 1989).
c) VX releases toxic and irritating fumes of oxides of nitrogen and sulfur when heated to decomposition. Inhalation exposure to such fumes would be predicted to result in respiratory tract irritation with chemical pneumonitis, bronchospasm, or acute lung injury (Sax & Lewis, 1989).

a) Soman was shown to cause respiratory arrest in the cat primarily by a central nervous system-mediated mechanism, rather than by direct action on the diaphragm muscle (Rickett et al, 1986).

a) Seizures may be an early symptom after a significant exposure to military nerve agents (Joy, 1982; Capacio & Shih, 1991; (Garigan, 1996); Sidell et al, 1998; Testylier et al, 1999; Pfaff, 1998). Children may be more susceptible to seizures than adults (Zwiener & Ginsburg, 1988). This effect is likely related to the development of hypoxia in children due to the rapid onset of respiratory muscle weakness (Abraham & Weinbroum, 2003). Soman is particularly active in inducing seizures (McLeod et al, 1984; Testylier et al, 1999).
b) EEG changes similar to patterns present on interictal EEG's of temporal lobe epileptics have been described in cases of mild organophosphate poisoning (Brown, 1971).
c) CASE REPORT: For approximately 7 minutes following exposure to sarin gas in a Tokyo subway, a 35-year-old man had tonic-clonic generalized seizures and periods of dyspnea requiring artificial respiration. Treatment with atropine and pralidoxime iodide were given. The patient recovered (Kato et al, 2000).

a) Initial central nervous system effects are commonly followed by headache, ataxia, drowsiness, difficulty in concentrating, mental confusion, and slurred speech (Grob & Garlick, 1950; Ohbu et al, 1997).

a) So-called Type II neurological effects involve paralysis appearing from 12 to 72 hours after exposure; this paralysis is unresponsive to atropine and may be due to excess acetylcholine at nicotinic receptors (Wadia et al, 1987). Flaccid paralysis was common in patients following a severe sarin exposure (Nozaki et al, 1993).
b) Paralytic signs include inability to lift the neck or sit up, ophthalmoparesis, slow eye movement, facial weakness, difficulty swallowing, limb weakness (primarily proximal), areflexia, respiratory paralysis and death (Wadia et al, 1987). Persistent paralysis due to peripheral neuritis has not been reported following nerve agent exposure, although it has been reported following some organophosphate pesticide poisonings (Grob, 1956).
c) Type II paralysis occurred in 49% of patients with organophosphate poisoning. In Type II paralysis, nerve conduction velocities and distal latencies are normal, but the amplitude of the compound action potential is reduced (Wadia et al, 1987).
d) Paralysis of the diaphragm may occurred in some cases resulting in respiratory depression and death (Rivett & Potgieter, 1987).
e) The intermediate syndrome seen in some patients with severe organophosphate poisoning (proximal muscle weakness, cranial nerve weakness, areflexia, pyramidal tract signs developing 12 to 84 hours after exposure and after recovery from the severe cholinergic manifestations of poisoning) has not been reported in animal models or in the few human cases of nerve agent poisoning (Sidell & Hurst, 2000).

a) In severe poisoning, coma supervenes, rarely followed by generalized seizures (Grob & Garlick, 1950; Morimoto et al, 1999). Deep tendon reflexes are weak or absent. Loss of consciousness following severe vapor inhalations is common (Pfaff, 1998; Okudera et al, 1997; Nozaki et al, 1993). Following a VX injection, a 28-year-old man developed deep coma. Muscle fasciculations were also present, but the patient did not develop seizures (Morimoto et al, 1999).

a) Delayed neurotoxicity appears to be a rare complication of organophosphate pesticide exposure (Wadia et al, 1987), but has not been reported in humans following nerve agent exposure. Due to the mechanism of action, a delayed neuropathy may be anticipated in some cases. Although most symptoms develop rapidly, subjective improvement may be observed followed by the delayed development of peripheral neuropathy. Victims of nerve agent exposure have described a type of symmetric sensorimotor neuropathy occurring 7 to 14 days postexposure; however, a causal link between nerve agents and long-term sequelae has not been established (Pfaff, 1998). It has been predicted that if the nerve agents caused a delayed neuropathy, it would only occur at doses exceeding the LD50 value (Young et al, 1999).

a) Acute or chronic exposure to organophosphates may impair concentration and induce confusion and drowsiness. Impaired memory is a major CNS effect of organophosphate exposure and may occur in the absence of other overt clinical signs (Levin & Rodnitzky, 1976).

a) Persons with other signs of organophosphate poisoning have shown reduced cognitive efficiency and slowness of thought related to the degree of cholinesterase inhibition (Levin & Rodnitzky, 1976).
b) Intravenous VX doses of 1.5 to 1.7 mcg/kg caused performance and cognitive decrements in normal human volunteers (Sidell et al, 1973).

a) Slowed speech, problems in finding words, slurring, intermittent pauses, and perseveration have been seen in persons who have other clinical signs of organophosphate poisoning (Levin & Rodnitzky, 1976).

a) Depression, correlated with the severity of cholinesterase inhibition, has occurred in cases of acute organophosphate poisoning, including exposure to sarin and soman (Sidell & Groff, 1974); this finding is consistent with the theory of affective disorders being the result of cholinergic predominance in the central nervous system (Levin & Rodnitzky, 1976).

a) Sarin exposure has resulted in persistent changes in the electroencephalogram (EEG) in both primates and humans (Burchfiel et al, 1976; Duffy et al, 1979).

a) SEQUELAE: A study compared neurobehavioral tests of 23 man subjects 7 years after exposure to sarin with a referent group of 13 subjects. Exposed subjects performed less well in the finger tapping test of both the dominant and nondominant hands, compared with the referent group; the difference was statistically significant in the finger tapping of the dominant hand. Median numbers of backward and forward digit span and correct answer of Benton visual memory retention test were 1 unit lower in the exposed subjects, compared with the referent group (Miyaki et al, 2005).

a) Soman produced severe delayed neuropathy at a dose of 1.5 mg/kg in the atropinized hen assay (Willems et al, 1984). In animals nerve agents cause peripheral neuropathy at doses far exceeding the LD50 (Sidell & Hurst, 2000).

a) Koplovitz et al (1992a) reported histologic lesions following lethal cyclohexyl sarin dosing in rhesus monkeys. In the CNS the primary lesions were neuronal degeneration/necrosis and spinal cord hemorrhage (Koplovitz et al, 1992a). In another study, Kadar et al (1992) used rats to study soman-induced brain lesions and found a degenerative process with lethal and sublethal doses which might be due to a secondary effect unrelated to soman's clinical toxicity but leading to long-term brain injuries. Sarin- and soman-induced brain lesions have been described in rodent studies (McLeod, 1985).

a) Nausea, vomiting, diarrhea, abdominal cramps and hypersalivation are common muscarinic signs of organophosphate poisoning, particularly when absorbed through the skin or ingested or injected ((Garigan, 1996); Pfaff, 1998; Morimoto et al, 1999). Vomiting and diarrhea occurred in 38% and 21% of patients, respectively, in one study (Bardin et al, 1987). In the pediatric population, the muscarinic effects related to the gastrointestinal system (i.e., diarrhea and increased salivation) may occur less frequently than in adults (Abraham & Weinbroum, 2003).
b) Intravenous VX doses of 1.5 to 1.7 micrograms/kg caused mild gastrointestinal signs and symptoms in normal human volunteers (Sidell et al, 1973).

a) Fecal incontinence is a muscarinic effect and may occur following exposure to nerve agents ((Garigan, 1996); Hayes, 1965; Pfaff, 1998).

a) Involuntary urination occurs in severe exposures as a result of muscarinic effects. Urinary frequency may be evident (Done, 1979; (Garigan, 1996)).

a) Metabolic acidosis has occurred in several cases of severe organophosphate pesticide poisoning and has been reported following nerve agent exposures (Hui, 1983; Meller et al, 1981; Moore & James, 1981; Morimoto et al, 1999).

a) The hallmark of organophosphate poisoning is the inhibition of plasma pseudocholinesterase or erythrocyte acetylcholinesterase, or both (Namba, 1972).
b) Soman inhibited erythrocyte acetylcholinesterase to a greater extent than plasma pseudocholinesterase in rabbits (Hu et al, 1988). The cholinesterase inhibited by soman ages especially rapidly. The in vivo half-lives for aging were 8.6 minutes in rats, 7.5 minutes in guinea pig and 0.99 minute in marmoset. The rapid aging of soman-poisoned enzyme means that reactivation by oxime treatment is less likely to be effective than with many other organophosphates (Talbot et al, 1988).

a) Soman produced modest reductions in the red blood cell count and hematocrit in rabbits. This was thought not to be significant enough to interfere with simultaneous treatment of trauma (24).

a) Profuse sweating may occur as one of the muscarinic signs of nerve agent poisoning (Ganendran, 1974; (Garigan, 1996)). Intense perspiration was noted following VX poisoning in a 28-year-old man (Morimoto et al, 1999). Pallor is sometimes noted (Done, 1979).

a) Muscle weakness, fatigability and fasciculations occur commonly as a nicotinic effect. Fasciculations were present in 23/61 patients (54%) with organophosphate intoxication in one study (Bardin et al, 1987). Muscle weakness progressing to paralysis may occur ((Garigan, 1996)). Muscle fasciculations may be severe ((Garigan, 1996); Nozaki et al, 1993). Muscle weakness and fasciculation were common effects reported in 106 patients following moderate sarin poisoning (Ohbu et al, 1997). However, studies in children indicate that muscle fasciculation only occurs in about 20% of children following organophosphate poisoning (Abraham & Weinbroum, 2003).
b) PEDIATRIC EXPOSURE: Based on a review of the literature, children exposed to nerve agents may respond differently than adults. In a series of organophosphate exposures, children developed significant weakness and hypotonia in 70% to 100% of moderate to severe exposures. These symptoms in the absence of glandular secretion or miosis are not typical of an adult nerve agent exposure (Rotenberg & Newmark, 2003). In another review, severe hypotonia and CNS depression were found to be the primary clinical features of nerve agent poisoning (Abraham & Weinbroum, 2003).

a) Muscle paralysis occasionally supervenes (Done, 1979; (Garigan, 1996)).

a) In animal studies, soman appears to be stored in some body "depot"; animals which survived initial treatment often succumbed several days later (Wolthuis et al, 1986).

a) Koplovitz et al (1992a) reported histologic lesions following lethal cyclohexyl sarin dosing in rhesus monkeys. Skeletal muscle degeneration, occasionally progressing to necrosis and mineralization, was one of the primary non-neural lesions reported (Koplovitz et al, 1992a).

a) Dermal sensitization has occurred with some organophosphates following skin exposure (Milby et al, 1964). In general, organophosphates can react with proteins and are potential haptens for allergic reactions.
b) Some organophosphates can cause dermal sensitization, but the majority have not been adequately evaluated for this activity (Coye, 1984).

a) Soman has shown immunosuppressive effects in mice (Clement, 1985).

a) Plasma ChE appears to be a more sensitive index of exposure, and erythrocyte AChE activity may be better correlated with clinical effects (Muller & Hundt, 1980). Usually this biochemical manifestation of toxicity appears at lower dosage levels than amounts producing signs or symptoms.

a) Obtain and ECG and institute continuous cardiac monitoring in symptomatic patients to monitor for dysrhythmias and ischemia.

a) INDICATION: Atropine-containing autoinjectors are used for the initial treatment of poisoning by organophosphate nerve agents and organophosphate or carbamate insecticides (Prod Info DuoDote(R) intramuscular injection solution, 2011; Prod Info ATROPEN(R) IM injection, 2005). Pralidoxime use following carbamate exposure may not be indicated.
b) NOTE: The safety and efficacy of MARK I kit (Note: the MARK I autoinjector kit was last produced by Meridian Medical Technologies, Columbia, MD in 2008. This product may still be available in some locations.), ATNAA, or DuoDote(R) has not been established in children. All of these autoinjectors contain benzyl alcohol as a preservative (Prod Info DuoDote(R) intramuscular injection solution, 2011; Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002). Since the AtroPen(R) comes in different strengths, certain dose units have been approved for use in children (Prod Info ATROPEN(R) IM injection, 2005).
c) The AtroPen(R) autoinjector (atropine sulfate; Meridian Medical Technologies, Inc, Columbia, MD) delivers a dose of atropine in a self-contained unit. There are 4 AtroPen(R) strengths: AtroPen(R) 0.25 mg in 0.3 mL of solution (dispenses 0.21 mg of atropine base; equivalent to 0.25 mg of atropine sulfate), AtroPen(R) 0.5 mg in 0.7 mL of solution (dispenses 0.42 mg of atropine base; equivalent to 0.5 mg of atropine sulfate), Atropen(R) 1 mg in 0.7 mL of solution (dispenses 0.84 mg of atropine base; equivalent to 1 mg of atropine sulfate), and AtroPen(R) 2 mg in 0.7 mL of solution (dispenses 1.67 mg of atropine base; equivalent to 2 mg of atropine sulfate) (Prod Info ATROPEN(R) IM injection, 2005).
d) ATNAA (Antidote Treatment Nerve Agent Autoinjector, Meridian Medical Technologies, Columbia, Maryland) is currently used by the US military and provides atropine injection and pralidoxime chloride injection in a single needle. Each self-contained unit dispenses 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL via intramuscular injection (Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002).
e) MARK I: This device (Meridian Medical Technologies, Columbia, Maryland) was used by the US military. (Note: the MARK I autoinjector kit was last produced by Meridian Medical Technologies, Columbia, MD in 2008. This product may still be available in some locations.) Each kit contains two autoinjectors: an atropine and a pralidoxime autoinjector. The atropine autoinjector delivers 2.1 mg of atropine in 0.7 mL via intramuscular injection. The pralidoxime autoinjector delivers 600 mg pralidoxime chloride in 2 mL via intramuscular injection (Prod Info DUODOTE(TM) IM injection, 2006).
f) DuoDote(R) is a dual chambered device (Meridian Medical Technologies, Columbia, Maryland) that delivers 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL sequentially using a single needle for use in a civilian or community setting. It should be administered by Emergency Medical Services personnel who have been trained to recognize and treat nerve agent or insecticide intoxication (Prod Info DuoDote(R) intramuscular injection solution, 2011).
g) DuoDote(R): DOSE: ADULT: Two or more mild symptoms, initial dose, 1 injector (atropine 2.1 mg/pralidoxime chloride 600 mg) IM into the mid-lateral thigh, wait 10 to 15 minutes for effect; subsequent doses, if at any time severe symptoms develop, administer 2 additional injectors in rapid succession IM into the mid-lateral thigh and immediately seek definitive medical care; MAX 3 doses unless definitive medical care is available (Prod Info DuoDote(R) intramuscular injection solution, 2011).
h) Therapeutic plasma concentrations of pralidoxime exceeding 4 mcg/mL were achieved within 4 to 8 minutes after injection (Sidell & Groff, 1974).
i) DIAZEPAM Autoinjector (Meridian Medical Technologies): Contains 10 mg of diazepam in 2 mL for intramuscular injection for seizure control (Prod Info diazepam autoinjector IM injection solution, 2005).
j) These devices are designed for initial field treatment. Although autoinjector doses may be adequate for nerve agent exposures, ORGANOPHOSPHATE exposures may require additional atropine or pralidoxime doses in the hospital setting that exceed those in the available autoinjectors.
k) For medical questions concerning Meridian products, you can call 1-800-438-1985. For general product information, call 1-800-638-8093.

a) Spilled liquid may first be adsorbed with soil, sweeping compound, sawdust, or dry sand and then both the adsorbed material and the floor decontaminated with one of the above solutions (EPA, 1975a).

a) Treatment is symptomatic and supportive, including treatment with atropine and oximes (eg, pralidoxime in the US and obidoxime and HI-6 internationally). Treatment is the same regardless of the route of exposure. Monitor the patient for respiratory distress (from bronchospasm, increased bronchial secretion, or muscle weakness). Administer IV fluids and electrolytes as needed to replace fluid losses. Administer atropine for muscarinic manifestations (eg, salivation, diarrhea, bronchospasm, bronchorrhea, bradycardia) and pralidoxime for nicotinic manifestations (eg, weakness, fasciculations). If atropine is unavailable or if central anticholinergic toxicity is present, glycopyrrolate is a reasonable alternative. Supplemental therapy with oxygen and beta-2 adrenergic agonist aerosols (eg, albuterol) may be helpful.

a) Treatment is symptomatic and supportive, including treatment with atropine and oximes (eg, pralidoxime in the US and obidoxime and HI-6 internationally). Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation, and replace fluids and electrolytes as required. Treatment is the same regardless of the route of exposure. Monitor the patient for respiratory distress (from bronchospasm, increased bronchial secretion, or muscle weakness). Administer atropine for muscarinic manifestations (eg, salivation, diarrhea, bronchospasm, bronchorrhea, bradycardia) and pralidoxime for nicotinic manifestations (eg, weakness, fasciculations). If atropine is unavailable or if central anticholinergic toxicity is present, glycopyrrolate is a reasonable alternative. Supplemental therapy with oxygen and beta-2 adrenergic agonist aerosols (eg, albuterol) may be helpful. If induction of paralysis with muscle relaxing agents is required for intubation, succinylcholine should be avoided because of potential for prolonged duration of paralysis. In contrast, nondepolarizing neuromuscular blockers such as pancuronium may protect the neuromuscular junction from injury. If seizure develops, administer a benzodiazepine IV. Consider phenobarbital or propofol if seizures recur. Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

a) Monitor vital signs.
b) Obtain an ECG and institute continuous cardiac monitoring.
c) Monitor pulse oximetry and/or arterial blood gases in symptomatic patients.
d) Plasma cholinesterase (butyrylcholinesterase) and red blood cell cholinesterase activities may be useful to confirm exposure and monitor response to therapy but are rarely available in a timely fashion. While there may be poor correlation between cholinesterase values and clinical effects, especially in milder poisonings, acute depression in excess of 50% of baseline activity is generally associated with severe symptoms.
e) If an acute nerve agent exposure is suspected, initiation of treatment is not dependent on laboratory confirmation.

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

a) ATROPINE USE FOR SEIZURES
b) BENZODIAZEPINES WITH ANTICHOLINERGIC DRUGS
c) DIAZEPAM
d) DIAZEPAM, PROCYCLIDINE, AND PENTOBARBITAL
e) FOSPHENYTOIN

a) Nerve agent-poisoned patients are generally tolerant to the toxic effects of atropine (eg, dry mouth, rapid pulse, dilated pupils). If these findings occur following a diagnostic atropine dose, the patient is probably not seriously poisoned.

a) MILD TO MODERATE EFFECTS
b) SEVERE EFFECTS

a) AUTOINJECTORS

a) Many parenteral atropine preparations contain benzyl alcohol or chlorobutanol as preservatives. High-dose therapy with these preparations may result in BENZYL ALCOHOL or CHLOROBUTANOL TOXICITY.
b) Preservative-free atropine preparations are available, and should be used if large doses are required.
c) The half-life of atropine is significantly longer in children under 2 years of age and in adults over 60 years of age (Kanto & Klotz, 1988); rate of administration in these patients should be adjusted to compensate for this phenomenon.
d) Effects of overdosing with atropine include fever, warm dry skin, inspiratory stridor, irritability, and dilated and unresponsive pupils, as seen in accidental poisonings in children (Meerstadt, 1982). Up to 580 mg atropine has been given to a child as an accidental overdose, with complete recovery following observation and diazepam (Arthurs & Davies, 1980).

a) Atropinization must be maintained until all of the absorbed nerve agent has been metabolized. Typically, this may require administration of 2 to 20 milligrams of atropine over a few hours.

a) PRALIDOXIME/INDICATIONS
b) PRALIDOXIME/CONTROVERSY

a) MILD TO MODERATE EFFECTS
b) SEVERE EFFECTS

a) PRALIDOXIME/ADMINISTRATION

a) SUMMARY
b) MINIMAL TOXICITY
c) NEUROMUSCULAR BLOCKADE
d) VISUAL DISTURBANCES
e) ASYSTOLE
f) WEAKNESS
g) ATROPINE SIDE EFFECTS
h) CARDIOVASCULAR

a) HALF-LIFE: Pralidoxime is relatively short-acting with an estimated half-life of 75 minutes (Prod Info PROTOPAM(R) CHLORIDE injection, 2006). One report found that the effective half-life of pralidoxime chloride was longer in poisoned individuals than in healthy volunteers. This was attributed to a reduced renal blood flow in the poisoned patients (Jovanovic, 1989).

a) AUTOINJECTORS

a) Glycopyrrolate, a quaternary ammonium compound, has been used in the treatment of organophosphate poisoning because of its better control of secretions, less tachycardia, and fewer CNS effects.

a) At the time of this review, obidoxime chloride is not available in the United States.

a) Obidoxime dichloride, Toxogonin(R), may be a less toxic and more efficacious alternative to pralidoxime in poisonings from organophosphates containing a dimethoxy or diethoxy moiety.
b) Clinical experience with this compound is limited (Kassa, 2002; Willems, 1981; De Kort et al, 1988; Barckow et al, 1969).
c) It is apparently favored over pralidoxime in clinical practice in Belgium, Israel, The Netherlands, Scandinavia, and Germany and is the only oxime available in Portugal. It is currently not available in the US, but may be available through Merck in some countries.

a) INITIAL: Obidoxime may be given as an intravenous bolus of 250 milligrams and may be repeated once or twice at 2 hour intervals (Prod Info TOXOGONIN(R) IV injection, 2007). It is more effective if given early, and the manufacturer recommends that it not be administered more than after 6 hours following organophosphate intoxication (Prod Info TOXOGONIN(R) IV injection, 2007), however in clinical practice it is often used in patients presenting more than 6 hours after poisoning (Thiermann et al, 1997).
b) ALTERNATIVE DOSING: For the treatment of organophosphorous pesticide poisoning, administer 250 milligrams of obidoxime as an intravenous or intramuscular bolus, followed by a continuous intravenous infusion of 750 milligrams/day (Antonijevic & Stojiljkovic, 2007; Thiermann et al, 1997).
c) CONTINUOUS INFUSION: To achieve a 4 microgram/milliliter threshold plasma level of obidoxime for the treatment of nerve agent intoxication, the following loading and maintenance doses are suggested: LOADING DOSE: 0.8 milligram/kilogram. INFUSION RATE: 0.5 milligram/kilogram/hour (Kassa, 2002).

a) Children may be given single doses of 4 to 8 milligrams/kilogram, followed by an intravenous infusion of 0.45 milligrams/kilogram/hour (Prod Info TOXOGONIN(R) IV injection, 2007; Antonijevic & Stojiljkovic, 2007; Thiermann et al, 1997) not to exceed 250 milligrams, usual adult dose, in older children (Prod Info Toxogonin(R), obidoxime chloride, 1989).

a) More severely poisoned patients generally require a longer duration of infusion (Thiermann et al, 1997). If cholinergic signs or symptoms worsen or if cholinesterase concentrations decline after obidoxime is discontinued, therapy should be reinstituted.

a) Mild, transient liver dysfunction has been noted with obidoxime use (Finkelstein et al, 1989).

a) Two Hagedorn oximes, HI-6 and HLo 7 have shown some efficacy against nerve agents. These agents have the ability to reactivate the inhibited acetylcholinesterase (AChE) (Worek et al, 2005).
b) HI-6 is an oxime that was developed to treat organophosphate poisoning, and appears to be effective against the diethoxy group of organophosphates, which age more slowly than the dimethoxy portion (Kusic et al, 1991). It has been used increasingly in autoinjectors because it has been found to be a more effective reactivator of acetylcholinesterase inhibited by nerve agents compared with pralidoxime and obidoxime (Roberts & Aaron, 2007)
c) HI-6 provides good response to sarin, soman and VX exposures. It provides poor to no response following tabun exposures (Hoffman, 1999). HI-6 is 3 to 5 times more effective than 2 PAM Cl ((Garigan, 1996)).
d) HI-6 dimethanesulfonate (HI-6 DMS) has a better solubility and bioavailability than HI-6 chloride which makes it a better choice as an antidote against nerve agents in autoinjectors. Atropine, HI-6, and diazepam can be used in three chambered autoinjector at the same time (Bajgar, 2010).
e) HI-6 should be given as a continuous IV infusion with a loading dose of 1.6 mg/kg and an infusion rate of 0.8 mg/kg/hour (EMA, 2000). HI-6 has been administered as a single intramuscular injection of 500 mg, administered 4 times daily for a maximum of 7 days, in conjunction with atropine and diazepam therapy, for organophosphate pesticide poisoning (Kusic et al, 1991a).
f) ANIMAL STUDIES

a) PROPHYLACTIC ANTIDOTE: This drug may be used for PRETREATMENT for organophosphate nerve agent exposure in the military field. It is an inhibitor of acetylcholinesterase (at 25%) and protects the enzyme against inhibitory effects of nerve agents. Its effectiveness in humans has NOT been demonstrated, but it has been shown to increase the LD50 in monkeys. It is NOT effective for sarin or VX exposures. Pyridostigmine is useful for soman exposures when antidotes are administered after exposure. Recommended dose is 30 mg 3 times daily for a maximum of 7 days prior to an expected nerve agent attack. There is NO CNS penetration of pyridostigmine ((Garigan, 1996)). Pretreatment with physostigmine has been successful for sarin exposures in mice (Tuovinen et al, 1999).
b) PHYSOSTIGMINE will cross the blood brain barrier. Philippens et al (2000) reported that marmosets given physostigmine prior to exposure to twice the LD50 of soman survived with negligible post-intoxication incapacitation. As physostigmine has a short plasma half-life, a method of subchronic administration (e.g., transdermal patch) needs to be devised (Philippens et al, 2000).

a) This oxime is given intravenously as a dose of 125 to 250 mg (Vojvodic, 1988).

a) Acetylcholinesterase from fetal calf serum completely protected rhesus monkeys from the fatal effects of sarin, as long as the added enzyme was present in stoichiometric excess. Co-addition of bis-quaternary oximes, such as HI-6, amplified the efficiency of the added enzyme by providing continuous detoxification of the enzyme (Caranto et al, 1994). Wolfe et al (1992) reported similar success with acetylcholinesterase used in soman poisoned monkeys (Wolfe et al, 1992).
b) Organophosphorus hydrolyzing enzyme organophosphorus acid anhydrolase (OPAA) produced a 2- to 3-fold enhanced protection when supplemented with atropine or pralidoxime (Petrikovics et al, 2000).

a) In an experimental study using Han-Wistar male rats, organophosphate-induced convulsions and severe neurotoxic damage were prevented by giving a combination of N(6)-cyclopentyl adenosine (CPA), diazepam and pralidoxime-2-chloride (2PAM) with atropine (Tuovinen, 2004).
b) In another rat study the known cardiodepressant effects of CPA (an A1 receptor agonist) were analyzed. It has been noted that the use of CPA (doses of 0.5 and 2 mg/kg) following sarin toxicity results in almost immediate attenuation of cholinergic symptoms and increased survival, but lasting bradycardia and hypotension are also characteristic of therapy. The study was conducted to evaluate the use of a peripheral adenosine A1 receptor antagonist (8-p-sulphophenyltheophylline {8-PST}) to counter the cardiodepressant effects of CPA. It was noted, however, that the therapeutic efficacy of CPA against sarin poisoning was almost completely negated by pretreatment with an adenosine A1 receptor antagonist. The authors concluded that peripheral adenosine A1 receptors play a major role in the therapeutic efficacy of CPA in the case of sarin poisoning (Joosen et al, 2004).

a) The effects of a ketamine/atropine combination were studied in soman-poisoned male guinea pigs to determine the effectiveness in stopping soman-induced seizures. The animals received pyridostigmine 26 mcg/kg intramuscularly 30 minutes before receiving soman 62 mcg/kg intramuscularly followed by atropine methyl nitrate 4 mg/kg 1 minute later. After the onset of seizures, ketamine was then administered intramuscularly at different times with doses starting at 30 minutes after poisoning. Sub-anesthetic doses of ketamine 10 mg/kg prevented death and stopped seizures only when administered 30 minutes after poisoning. A delay in treatment of up to 2 hours required an increase in the ketamine dose up to 60 mg/kg 3 times. Ketamine was effective in highly reducing seizure-related brain damage, stopping seizures, and allowing survival. There was a progressive loss of efficacy when treatment was delayed more than 1 hour after poisoning (Dorandeu et al, 2005).

a) The effects of pretreatment with donepezil and scopolamine on anticholinesterase toxicity were studied in rats. Pretreatment (approximately 30 minutes prior to exposure) with donepezil or donepezil and scopolamine significantly reduced the hypothermic, hypokinetic, diarrhea-inducing effects, and behavioral inhibiting effects of diisopropyl fluorophosphate (DFP) (an organophosphorus cholinesterase inhibitor) 4 hours after administration. The authors suggested that based on this preliminary study, donepezil may be as effective as physostigmine with fewer side effects. However, further study is recommended (Janowsky et al, 2004).

a) Galantamine is a reversible and centrally-acting AChE inhibitor. In one animal study, galantamine with atropine combination administered to guinea pigs before or soon after an exposure to soman, sarin, and paraoxon (an active metabolite of parathion). reduced toxicity and lethality of these nerve agents. Overall, galantamine was more effective than pyridostigmine, and was less toxic than huperzine (Albuquerque et al, 2006).

a) In one animal study, rats and guinea pigs were treated with various doses of procyclidine (PC: 0 to 6 mg/kg) and a fixed dose of physostigmine (PhS: 0.1 mg/kg) subQ 30 minutes before exposing the animals to soman. The prophylactic use of PhS in combination with PC exerted great synergistic protective effects against soman poisoning in a dose-dependent manner, resulting in 1.92 to 5.07 folds of protection ratio in rats and 3 to 4.7 folds in guinea pigs. In contrast, low effect (1.65 fold) was observed with the traditional antidotes atropine (17.4 mg/kg) plus 2-pralidoxime (30 mg/kg) treated immediately after soman poisoning, compared with a marked protection (5.5-fold) with atropine (17.4 mg/kg) plus HI-6 (125 mg/kg) in unpretreated rats. In addition, the prophylactic combination of PC and PhS further enhanced the efficacy of standard antidotes (atropine plus 2-pralidoxime to 6.13 to 12.27 folds and that of atropine plus HI-6 to 12 or 21.5 folds with 1 or 3 mg/kg of PC, respectively. Rats pretreated with HI-6 (125 mg/kg) experienced severe epileptiform seizures resulting in brain injuries after receiving a high-dose (100 mcg/kg; 1.3 x LD50) of soman; however, pretreatment with PhS (0.1 mg/kg) and PC (1 mg/kg) completely prevented such seizures and excitotoxic brain injuries in rats (Kim et al, 2002).

a) Monkeys were treated with intramuscular pyridostigmine 0.2 mg/kg and 1 hour later were injected with intramuscular soman 30 mcg/kg. The first group was treated with intramuscular atropine 0.5 mg/kg and pralidoxime 30 mg/kg given together and intramuscular diazepam 0.2 mg/kg. The other group was treated with atropine at the same dose, HI-six 50 mg/kg, and avizafone 0.35 mg/kg. All monkeys had severe signs of toxicity; duration of coma and respiratory problems were less with atropine/HI-6/avizafone therapy (Marrs, 2004).

a) Monkeys were treated with intramuscular pyridostigmine 0.2 mg/kg and 1 hour later were injected with intramuscular soman 30 mcg/kg. The first group was treated with intramuscular atropine 0.5 mg/kg, pralidoxime 30 mg/kg, and intramuscular diazepam 0.2 mg/kg. The other group was treated with intramuscular atropine 0.5 mg/kg, pralidoxime 30 mg/kg, and avizafone 0.35 mg/kg. Animals had seizures after both treatments. At 3 weeks post-exposure, autopsy findings showed evidence of neuropathological changes in the animals treated with avizafone, but not those treated with diazepam (Marrs, 2004).

a) ANIMAL DATA

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

a) The kit has been tested for safety and efficacy against mustard vesicant agents and organophosphate nerve agents. This kit is a replacement for the M258-A1 kit and offers several advantages over the older kit. It is safe to use on the skin, even in the absence of suspected exposure, and can therefore be used in training as well as actual field conditions (Product Info, 1991).
b) In March 2000, the US Army Medical Research and Material Command received FDA approval for a new product called Skin Exposure Reduction Paste Against Chemical Warfare Agents.

a) Control of anticholinergic signs and symptoms, and levels of plasma pseudocholinesterase and erythrocyte acetylcholinesterase are more meaningful parameters than actual blood concentrations of nerve agents.

a) 17 mg/kg (LOLI, 2000)

a) 28 mg/kg ((RTECS, 2000))

a) 5 mg/m(3)/30 min ((RTECS, 2000))

a) 1080 mcg/kg ((RTECS, 2000))

a) 550 mcg/kg ((RTECS, 2000))

a) 90mcg/m(3) ((RTECS, 2000))

a) 89 mcg/kg ((RTECS, 2000))

a) 7800 mcg/kg ((RTECS, 2000))

a) 62 mcg/kg ((RTECS, 2000))

a) 1 mg/kg ((RTECS, 2000))

a) 3700 mcg/kg ((RTECS, 2000))

a) 18 mg/kg ((RTECS, 2000))

a) 162 mcg/kg ((RTECS, 2000))

a) 50 mcg/kg ((RTECS, 2000))

a) 12 mcg/kg ((RTECS, 2000))