Nerve agents are the deadliest of the chemical weapons. Next to botulinum toxin, they are the most lethal compounds known. Terrorists have great interest in these agents and have manufactured and used these toxins. Nerve agents cause a recognizable cholinergic syndrome that can be treated with readily available pharmacologic agents. Children are particularly vulnerable to the effects of these agents, and rapid treatment can prevent death and significant morbidity.
Excellent reviews of nerve agent poisoning are available.1 However, with few exceptions, the goal of research on nerve agent poisoning has been to develop effective casualty care for adult soldiers in a battlefield environment. In turn, current domestic plans for civil defense have often adopted a paradigm where one-size fits all. This article outlines the aspects of casualty care for nerve agent poisoning that differ for children.
Nerve agents have been deployed against civilians both in military operations and in terrorist attacks. Tabun was first synthesized in Germany before World War II. Although Germany stockpiled these weapons, they were never used in combat. Nerve agents were first used by Iraq in their war against Iran (1980-1988). At the end of this war, Iraq attacked Kurdish civilians with nerve agents in northern Iraq in a yearlong chemical offensive. The most infamous of these attacks was at the town of Halabja in March 1987.
More recently, the cult Aum Shrinrikyo independently synthesized the nerve agent sarin and launched two attacks on Japanese civilians. Few children were involved in these attacks, and none were severely poisoned. These attacks, however, were very instructive regarding the ways in which a chemical attack on civilians might evolve. Current terrorist groups appear to have a strong interest in nerve agents, but there is no evidence that proves they possess nerve agents.
Nerve agents are organophosphorus compounds that are akin chemically to organophosphate pesticides. Organophosphorus compounds are ubiquitous in industry and agriculture, and they are frequent causes of accidental poisoning.
Nerve agents are typically colorless liquids at room temperature. Some volatilize easily, creating a toxic vapor that can disperse with distant effects. In the Tokyo subway, for instance, the vast majority of victims were poisoned by sarin vapors circulating in the enclosed subway cars and tunnels. Other agents (eg, VX) are viscous liquids that persist on surfaces and in the environment. They do not vaporize readily, but physical contact with a miniscule amount of VX liquid can be fatal.
Pediatric Nerve Agents:Triage and Dosing
Pediatric Nerve Agents:Triage and Dosing
A lethal dose of liquid VX for 50% of adults (LD50) is approximately 10 mg. Accounting for body mass differences, the lethal dose in a child is a fraction of that amount. There is evidence, however, that younger individuals may have a unique susceptibility to organophosphorus compounds. One study of organophosphorus pesticides in immature rats found that on an equivalent mg/kg basis, lethal doses in infant rats were only 10% of those for adult rats. Juveniles tended to succumb to 33% of the dose lethal to adults.2
Organophosphorus compounds inhibit esterase enzymes, including acetylcholinesterase. Acetylcholinesterase mediates the cleavage of acetylcholine in the synaptic space. When it cannot be deactivated, acetylcholine accumulates in the clefts of the neuromuscular junction, at glandular receptors, and in the central nervous system, leading to overstimulation of the postsynaptic tissue. This causes the immediate pathology recognized as a cholinergic crisis. The maximal effects of exposure to nerve agents are typically seen in seconds to minutes after exposure; only one other chemical weapon (cyanide) presents as quickly.
The actual symptoms of nerve agent exposure vary, however, with dose and route of exposure. Victims who have inhaled nerve agent vapor present differently from those who contact liquid with their skin or mucus membranes. A mild inhaled exposure may only cause miosis, rhinorrhea, and dyspnea. A mild or moderate ingested dose may begin with nausea, vomiting, diarrhea, and weakness.
Cutaneous exposures to liquid nerve agent, in contrast, may not necessarily evolve rapidly. After skin exposure to liquid nerve agent and consequent slow absorption, it may take 18 to 24 hours for symptoms to evolve. Therefore, health care professionals should not underestimate an exposure when patients are evaluated only hours after the event. Mild or early cutaneous exposure may result in localized fasciculation and sweating, while a significant liquid exposure to skin may cause severe or rapidly evolving cholinergic signs and symptoms.
Significant vapor or liquid exposure ultimately shares a common clinical picture. Cardiopulmonary failure, apnea, loss of consciousness, seizures (convulsive or nonconvulsive), generalized muscle dysfunction (twitching, weakness or paralysis), and loss of bowel or bladder control may occur. These patients require immediate antidotal treatment and intensive supportive care.
Dimming of vision is not a widely discussed symptom of nerve agent exposure; however, it was widely noted in the survivors of the sarin attacks in Japan. One victim stated, "My eyes stopped working. Suddenly, it was as if night had fallen."3 This effect may be due to central nervous system toxicity. No other chemical weapon causes this phenomenon.
Respiratory failure is the primary cause of death in victims exposed to nerve agents, which poison the respiratory system at many levels. Central apnea, flaccid neuromuscular paralysis, bronchoconstriction, and profound glandular secretions may be noted.
Children and infants are vulnerable to the pathophysiological derangements of nerve agents. The nerve agent toxidrome can be recognized by its cholinergic features, but certain manifestations of nerve agents may differ between adults and children. Miosis, for instance, frequently is cited as a hallmark sign of organophosphorus intoxication in adults. Children, however, may not necessarily manifest miosis. In a recent series of severe anticholinesterase pesticide ingestion in South African children aged 5 months to 14 years, miosis was noted in only 57%. 4
Additionally, children are less likely to manifest autonomic signs of excessive glandular secretions. In the pediatric organophosphorous poisoning literature, children often presented with isolated central nervous system effects (stupor, coma) in the absence of peripheral muscarinic effects.5 Only 8% to 22% of childhood oral organophosphorus pesticide poisonings presented with frank seizures.2·6 Significant weakness and hypotonia ocurred in 70% to 100% of pediatric victims with moderate to severe exposures.
Nerve agents are far more epileptogenic than their organophosphorus relatives. They overwhelm the inhibitory systems with a flood of glutamate, an excitatory neurotransmitter. Thus, nerve agentinduced seizures can progress within minutes to status epilepticus.
Because children are more dependent on inhibitory neurotransmitter systems to modulate excitation than are adults, the potentially heightened vulnerability of children to the convulsive effect of nerve agents is of grave concern. Even in the usual clinical settings, children are more likely than adults to seize and to experience status epilepticus. Children also may be less resistant to the toxicity of these agents because the blood-brain barrier and intrinsic detoxifying enzymes (eg, paraoxonase) are less protective than at an older age.
Even in the event of a chemical weapon attack, the pediatrician should keep in mind a differential diagnosis. Of the chemical weapons, cyanide is the only other agent that can induce rapidly evolving pulmonary and nervous system dysfunction. Like nerve agents, cyanide poisoning has an effective antidotal regimen that improves outcome. Other environmental and occupational toxins (eg, hydrogen sulfide, carbon monoxide) may induce similar clinical presentations.
Nerve agent poisoning may not occur alone. Victims should be evaluated for traumatic injury, blast injury, and psychiatric decompensation.
Serum acetylcholinesterase levels are not helpful for diagnosing a nerve agent exposure acutely. The processing time for the test is likely to be too long to be practically helpful. Additionally, because of variation of population norms, the results of single tests can be misleading. Levels may be helpful for confirming exposure, in tracking recovery, or for epidemiologic purposes.
APPROACH TO CARE: THE BASICS
Although this article outlines the approach to a nerve agent casualty in distinct sections, a real-world scenario is likely to blur mese steps. For instance, severely affected patients may need treatment before, during, and after decontamination.
Evacuation is the single most important step in limiting mass exposure to toxic nerve agent vapors. Evacuation may seem to be a self-evident strategy following a chemical exposure, but at the moment (as in Tokyo), it did not occur to all victims and responders. Not only does such a maneuver arrest exposure, but some mildly affected individuals may also improve. With evacuation, collecting the victims in one area assists with triage and treatment.
Triage is the process of quickly assessing victims in order to allocate care to those most in need. One schema for triage of nerve agent victims is offered in Table 1. Based on signs and symptoms, victims can be categorized into delayed or immediate categories. The health care professional should be hesitant to apply the category "expectant" to children for nerve agent poisoning alone. As noted after the Tokyo sarin attacks, even full-blown cardiopulmonary arrest in adults has been reversed with aggressive antidotal therapy.
Decontamination is an important consideration following exposure to a nerve agent. Secondary exposures of medical personnel were frequent following the attacks in Japan. Furthermore, once contaminated victims are allowed into a medical facility, the entire facility and its previous patients are considered contaminated. It is of great importance to patients, staff, and institutions to have a decontamination plan that is realistic and rehearsed.
Because decontamination is an arduous undertaking, the process should be approached rationally. An accompanying article in this issue on the decontamination of children (page 260) details the methods and materials for this process. The type of decontamination, if any, depends on the type of exposure. A vapor exposure, for instance, does not require decontamination beyond a change of clothes and perhaps a shower.
For liquid contact, gross decontamination should be rapidly initiated, as this is the single greatest contributor to limiting morbidity. Readily available materials such as dirt, paper towels, or powders can be used to remove any chemical agent quickly, and washing skin with soap and copious water is optimal.
Treatment of pediatric nerve agent victims focuses on three areas: intensive respiratory support, antidotal therapy, and care of complications.
Apnea following nerve agent exposure is multifactorial. Through its interaction with acetylcholine receptors, a nerve agent directly induces central apnea as well as muscular weakness. At the same time, nerve agents induce severe bronchospasm and profound secretions; airway resistance pressures of 50 to 70 cm of H2O may be noted.7 In addition to mechanical ventilation, the use of bronchodilators or even ipratropium may be beneficial.
Nerve agents may induce vomiting, and the risk of aspiration is higher in children with impaired sensoria. Following the sarin attacks in Tokyo, only 0.6% of the 640 victims at one hospital required mechanical ventilation.8 Except for one fatality, all were extubated in 2 days. However, numerous factors limited the effects of this attack, including the fact that the sarin used in the attack was only a 30% dilution and not all of the available agent was actually released.
Mouth-to-mouth resuscitation carries a risk of secondary contamination as 10% of inhaled nerve agent is expired. To prevent secondary contamination of the ventilatory apparatus, a filter should be used between the patient's tracheal tube and the ventilator tubing. An adapted bag-valve-mask with an in-line filter for care of chemical casualties is available commercially.
Several agents should be used with caution in patients with nerve agent poisoning. Ketamine can enhance the production of secretions and induce central apnea in nonatropinized nerve agent victims. Esterase enzymes metabolize remifentanyl, and following nerve agent exposure, this analgesic's pharamacokinetics may become unpredictable. Finally, succinylcholine is rapidly hydrolyzed by butyrylcholinesterase, an enzyme also inhibited by nerve agents.
Antidotal therapy for nerve agent should be tailored to patients' clinical picture, preexisting conditions, and the environment of the encounter. For instance, children in the field should be treated differently than in an intensive care unit. Guidelines for treatment and dosing are listed in Table 1 .
In an environment with ample supplies, it is both medically prudent and compassionate to treat moderately affected and even mildly affected individuals. Especially among children, a victim who initially appears to be only moderately poisoned can decompensate quickly. Instituting early therapy arrests progression of the toxidrome.
Furthermore, in a mass casualty situation, it may not be possible to return to a given victim while treating other victims or during decontamination. Finally, because animal models show even subconvulsive doses of nerve agents can cause neurological damage, antidotal treatment should be initiated early and aggressively. Neuroprotection should be sought through the prevention of seizures and supportive care.
Figure 1 . A Mark 1 kit contains both an atropine (2 mg/0.7 cc) as well as a pralidoxime chloride (600 mg/2cc) autoinjector; these autoinjectors also are distributed as individual units (photograph courtesy of Meridian).
Figure 2. Contains diazepam (10 mg/2 cc) (photograph courtesy of Meridian).
Anticholinergics: atropine. Acetylcholine muscarinic receptor antagonists are the mainstay of antidotal therapy for nerve agent. The preferred agent in the United States is atropine. It should be emphasized that atropine does not restore function at the neuromuscular junction's nicotinic receptors. Therefore, with atropine alone, significant weakness and respiratory failure may persist.
Atropine and other antidotes can be delivered with 2 mg (0.7 cc) autoinjector devices. The practitioner should be aware of this product, as municipalities are purchasing this device to be used in an attack. A recently approved device combines atropine (2 mg) and pralidoxime chloride (600 mg) (Figure 1). Autoinjectors with lower doses that might be more suitable for small children are manufactured in the United States but have not yet received approval from the Food and Drug Administration (FDA) for use.
Autoinjectors deliver antidote at a rate superior to standard intramuscular administration. When activated, autoinjectors disperse medication as they pass through tissue in an all or nothing event. Intramuscularly injected fluids, in contrast, tend to coalesce in a more slowly absorbed depot. Since time is critical for reversing a cholinergic crisis, autoinjectors are preferred in the absence of intravenous access.
No studies have been performed in animal models to confirm an optimal dose for children exposed to nerve agent. However, guidance can be gleaned from experience with therapeutic atropine use in children as well as from an important clinical series of Israeli children injected with atropine during the Gulf War in 1990.9 During the Gulf War, atropine autoinjectors were distributed to all Israeli citizens in the event of a nerve agent attack. A 1992 study examined the medical records of 240 children who presented to Israeli emergency departments after receiving accidental injections. The doses ranged between 0.01 and 0.17 mg/kg. The main untoward effects were dilated pupils, tachycardia, dry mucous membranes, flushed skin, temperature higher than 37.8°, and neurological abnormalities. Doses up to 0.045 mg/kg did not produce signs of atropinization. There were no fatalities or life-threatening dysrhythmias. Only 5 of the 240 children were admitted for 24 hours of observation becuase of excessive sinus tachycardia and agitation.9
Pediatricians should treat victims aggressively with substantial amounts of atropine, because high doses are often required to treat organophosphorous poisoning. A dose of 0.05 mg/kg is suggested for the initial treatment of a pediatric nerve agent victim. This dose can be repeated every 3 to 5 minutes if the patient continues to have high airway resistance or copious secretions. In the war between Iran and Iraq, soldiers required 20 to 200 mg of atropine. Iranian physicians who treated exposed children advocated similar dosing.10
With respect to an end point for atropinization, some sources recommend looking for excessive tachycardia or the resolution of increased secretions. In children, atropine should be repeated until airway resistance improves and copious airway secretions resolve. Tachycardia should be an end point if cardiac output becomes impaired.
Although atropine is considered the agent of choice, other anticholinergic agents can be used if resources become depleted. The efficacy of scopolamine is similar to that of atropine, but it can impair the sensorium for hours. GIycopyrrolate may be helpful for controlling peripheral cholinergic symptoms in mildly affected victims. Veterinary atropine also can be considered in an emergency. This is important because atropine stocks could be depleted in a mass casualty.
Oxirnes: pralidoxime chloride. In the United States, the preferred agent is pralidoxime chloride. Oximes restore Cholinesterase function by dislodging the nerve agent from its bond with the enzyme. Improvement in function is noted primarily at nicotinic receptors and consequently reverses muscular dysfunction but not seizures or glandular secretions.
Over time, nerve agents become bound permanently to the enzymes and resistant to oximes in a process called aging. The time for this process to occur is unique to each nerve agent. Soman ages in minutes, while other agents may take hours. Although oximes are less effective after the nerve agentcholinesterase bond has aged, there may be some residual function that can be restored.
The half-life of pralidoxime chloride in one series of children was noted to be approximately 3.5 ± 0.8 hours; previous studies in adults indicate a half-life of approximately 90 minutes." Therefore, dosing in children may not need to be repeated as frequently as in adults.
Common untoward effects of oximes include dizziness, transient diplopia, and blurred vision. Hypertension is the most serious untoward effect at higher doses, and in children, blood pressure should be monitored during treatment. Because this medication is excreted almost entirely unchanged by the kidneys, caution is advised when treating individuals with renal insufficiency. Laryngospasm and rigidity can result from rapid intravenous administration.
Benzodiazepines. Nerve agentinduced seizures are refractory to most common anticonvulsants used in clinical practice except for the benzodiazepines.1
A benzodiazepine should be considered for treatment of not only frank seizures but also diffuse muscular twitching and rapid progression of symptoms. Rapid progression indicates both a substantial exposure to nerve agent and a high likelihood of progression to seizures. At any age, subtle muscle twitching can represent the final manifestations of seizures in muscle depleted of substrate.
In the pediatric population, seizures can be subtle, focal, or only manifest with autonomic variability. The Department of Defense has deployed diazepam because it is the best agent for the treatment of seizures that also has FDA approval. An autoinjector containing 10 mg (2 ce) of diazepam is available commercially (Figure 2). Other benzodiazepines are as effective as diazepam in arresting nerve agent-induced seizures.
Physiological Manifestations of Poisoning With Organophosphorus Compounds Including Nerve Agents
Diazepam has significant limitations as an intramuscular anticonvulsant. Absorption of diazepam is erratic after intramuscular injection. Diazepam has a long half-life and a high rate of untoward effects when administered for status epilepticus.12 Midazolam, in contrast, avoids these problems. Midazolam is water-soluble and can be administered by oral, intravenous, intramuscular, intranasal, and sublingual routes.
In patients who remain flaccid or have prolonged impaired consciousness, electroencephalography may help rule out nonconvulsive status epilepticus. Neuroimaging should be considered if trauma is suspected. In an intensive care setting with respiratory support, phénobarbital at high doses (40 mg/kg) can be instituted for seizures refractory to benzodiazepines.
In patients exposed to nerve agents, time is critical, and the choice of benzodiazepine (midazolam, diazepam, or lorazepam) is less important than the promptness of treatment. Arresting seizures within the first 15 minutes after exposure is easier than treating refractory status epilepticus.
Table 2 lists physiological derangements and complications that have been noted after organophosphorus compound poisonings in adults. In children, special attention should be paid to core body temperature as nerve agent exposure and decontamination may cause hypothermia. Atropine treatment can arrest sweating, in turn contributing to hyperthermia. Either extremes of temperature can worsen neurological outcomes in children.
Ophthalmic care should be instituted to treat miosis and eye pain. Patients should be reminded that even after treatment, miosis will resolve over weeks.
Prolonged unconsciousness can be caused by many factors following nerve agent exposure. Particularly in children, an electroencephalogram should be performed to ensure patients do not have nonconvulsive status epilepticus. At the same time, other sources of secondary injury should be considered.
A survey of victims 3 weeks after the sarin attack in Tokyo revealed more than 40% still complained of cough, dyspnea. rhinorrhea, dark vision, and headache.13 Survivors of even mild and moderate nerve agent exposure often report residual neuropsychiatrie symptoms such as memory deficits, visual deficits, depressed mood, insomnia, anxiety, headaches, and impaired concentration.
In children, there are additional concerns. Organophosphorus pesticides at low (subconvulsive) doses have been linked to developmental neurotoxicity by a mechanism independent of acetylcholinesterase inhibition.14 In children, numerous lines of evidence show prolonged seizures can permanently alter brain development in a way that may impair learning, increase seizure susceptibility, and increase risk of subsequent neuronal injury.15 No studies have been performed to analyze the long-term effects in children exposed to nerve agent.
Nerve agents are the most lethal of the chemical weapons and cause significant long-term morbidity for survivors. If used again in a terrorist attack, it is likely there will be pediatric victims.
Nerve agents cause a characteristic syndrome that can be treated successfully. To prevent morbidity and mortality, decontamination, supportive care, and antidotal administration must be initiated quickly. Antidotal treatment consists of an anticholinergic, an oxime, and a benzodiazepine. Pediatricians should not feel bound to doctrine developed for soldiers, as the choice of agent depends on the clinical situation. Antidotes are inexpensive and typically available even in small hospitals.
If prepared, pediatricians can prevent deaths and neurological impairment in children. In anticipation of a terrorist event, pediatricians should query local institutions about their readiness to support the care of children.
1. Sidell FR. Nerve agents. In: Sidell F. Tkafuji E, Franz D, eds. Textbook of Military Medicine: Medical Aspects of Chemical and Biological Warfare. Washington, DC: Office of the Surgeon General at TMM Productions; 1997:129-180.
2. Zheng Q, Olivier K, Won YK. Pope CN. Comparative cholinergic neurotoxicity of oral chlorpyrifos exposures in preweanling and adult rats. Toxicol Sci. 2000;55:124-132.
3. Murakami H. Underground: The Tokyo Gas Attack and the Japanese Psyche. New York, NY: Vintage International; 2001.
4. Verhulst L, Waggie Z, Hatherill M, Reynolds L, Argent A. Presentation and outcome of severe anticholinesterase insecticide poisoning. Arch Dis Child. 2002;86:352-355.
5. Lifshitz M, Shahak E, Sofer S. Carbamate and organophosphate poisoning in young children. Pediatr Emerg Care. 1999;15:102-103.
6. Zwiener RJ, Ginsburg CM. Organophosphate and carbamate poisoning in infants and children. Pediatrics. 1988;81:121-126.
7. Sidell F. Clinical considerations in nerve agent intoxication. In: Somani SM. ed. Chemical Warfare Agents. Burlington, VT: Academic Press; 1992:165.
8. Okumura T, Takasu N, Ishimatsu S, et al. Report on 640 victims of the Tokyo subway sarin attack. Ann Emerg Med. 1996;28: 129-135.
9. Amitai Y, Almog S, Singer R, Hammer R, Bentur Y, Danon YL. Atropine poisoning in children during die Persian Gulf crisis. A national survey in Israel. JAMA. 1992;268:630-632.
10. Foroutan SA. Medical notes concerning chemical warfare V [original in Farsi]. Kowsar Medical Journal. 1997;2.
11. Sidell FR, Groff WA. Intramuscular and intravenous administration of small doses of 2pyridinium aldoxime methochloride to man. J Pharm Sci. 1 97 1 ;60: 1 224- 1 228.
12. De Negri M, Baglietto MG. Treatment of status epilepticus in children. Paediatr Drugs. 2001;3:411-420.
13. Karalliedde L. Wheeler H. Maclehose R. Murray V. Possible immediate and long-term health effects following exposure to chemical warfare agents. Public Health. 2000; 114; 238-248.
14. Slotkin TA. Developmental cholinotoxicants: nicotine and chlorpyrifos. Environ Health Perspect. 1999;107(suppl l):71-80.
15. Holmes G, Ben- Ari Y. The neurobiology and consequences of epilepsy in the developing brain. Pediatr Res. 2001;49:320-325.
Pediatric Nerve Agents:Triage and Dosing
Pediatric Nerve Agents:Triage and Dosing
Physiological Manifestations of Poisoning With Organophosphorus Compounds Including Nerve Agents