The organophosphate nerve agents tabun (GA), sarin (GB), soman (GD), and cyclosarin (GF) are among the most toxic chemical warfare agents known.[1, 2] Together they comprise the G-series nerve agents, thus named because German scientists first synthesized them, beginning with GA in 1936. The only other known nerve agent, O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate (VX), is discussed in a separate Medscape article (see CBRNE - Nerve Agents, V-series - Ve, Vg, Vm, Vx).
G-series nerve agents share a number of common physical and chemical properties. At room temperature, the G-series nerve agents are volatile liquids, making them a serious risk for exposure from dermal contact with liquid nerve agent or inhalation of nerve agent vapor. GB is the most volatile of these agents and evaporates at the same rate as water; GD is the next most volatile. Dispersal devices or an explosive blast also can aerosolize nerve agents. Nerve agent vapors are denser than air, making them particularly hazardous for persons in low areas or underground shelters. GB and GD are colorless, while GA ranges from colorless to brown. GB is odorless, while GA has a slightly fruity odor and GD has a slight camphor-like odor.
Nerve agent exposure may occur as a result of any of the following[3] :
Because nerve agents are soluble in fat and water, they are absorbed readily through the eyes, respiratory tract, and skin. Vapor agents penetrate the eyes first, producing localized effects, then pass into the respiratory tract, with more generalized effects when the exposure is greater. Liquid agents penetrate the skin at the point of contact, producing localized effects followed by deeper penetration and generalized effects if the dose is large enough. Vapors are not absorbed through the skin except at very high concentrations. Ocular effects may result from both direct contact and systemic absorption.
Accordingly, the lethality of these agents varies with the route of exposure. The lethal concentration time product in 50% of the exposed population is ranges from 10 mg·min/m3 to 400 mg·min/m3 for GA. For dermal exposures, 1 to 10 mL of GA, GB, or GD can be fatal.[4]
Nerve agents act by first binding and then irreversibly inactivating acetylcholinesterase (AChE), producing a toxic accumulation of acetylcholine (ACh) at muscarinic, nicotinic, and CNS synapses.[5] Excessive ACh at these cholinergic receptors may account for the spectrum of clinical effects observed in nerve agent exposure.
At muscarinic receptors, nerve agents cause miosis, glandular hypersecretion (salivary, bronchial, lacrimal), bronchoconstriction, vomiting, diarrhea, urinary and fecal incontinence, and bradycardia. At nicotinic receptors in skin, nerve agents cause sweating, and on skeletal muscle, they cause initial defasciculation followed by weakness and flaccid paralysis. At CNS cholinergic receptors, nerve agents produce irritability, giddiness, fatigue, lethargy, amnesia, ataxia, seizures, coma, and respiratory depression.[6, 7]
Nerve agents also cause tachycardia and hypertension via stimulation of the adrenal medulla. They also appear to bind nicotinic, cardiac muscarinic, and glutamate N -methyl-d-aspartate (NMDA) receptors directly, suggesting that they may have additional mechanisms of action yet to be defined. Nerve agents also antagonize gamma-aminobutyric acid (GABA) neurotransmission, which in part may mediate seizures and CNS neuropathology.
Clinical effects of nerve agents depend on the route and amount of exposure. The effect of inhalational exposure to nerve agent vapor in turn depends on the vapor concentration and the time of exposure. Exposure to low concentrations of nerve agent vapor produces immediate ocular symptoms, rhinorrhea, and in some patients, dyspnea. These ocular effects are secondary to the localized absorption of GB vapor across the outermost layers of the eye, causing lacrimal gland stimulation (tearing), pupillary sphincter contraction (miosis), and ciliary body spasm (ocular pain).[8] As the exposure increases, dyspnea and gastrointestinal symptoms ensue.
Exposure to high concentrations of nerve agent vapor causes immediate loss of consciousness, followed shortly by convulsions, flaccid paralysis, and respiratory failure. These generalized effects are caused by the rapid absorption of nerve agent vapor across the respiratory tract, producing maximal inhibition of AChE within seconds to minutes of exposure. Nerve agent vapor is expected to have had its full effect by the time victims present to the emergency care system.[6]
The effect of dermal exposure to liquid nerve agent depends on the anatomic site exposed, ambient temperature, and dose of nerve agent. Percutaneous absorption of nerve agent typically results in localized sweating caused by direct nicotinic effect on the skin, followed by muscular fasciculations and weakness as the agent penetrates deeper and a nicotinic effect is exerted on underlying muscle. In moderate dermal exposures, vomiting and/or diarrhea occur. Vomiting and/or diarrhea soon after exposure are ominous signs. With further absorption, full-blown systemic or remote effects occur.
Because percutaneous absorption takes time, the onset of symptoms in dermal exposures usually is delayed. Even with thorough decontamination, symptoms may not occur until several hours have elapsed if some agent was absorbed prior to decontamination. A small droplet of GB liquid on the skin may not produce any clinical effects for as long as 18 hours postexposure. A large droplet of GB liquid rapidly causes loss of consciousness, seizures, paralysis, and apnea but only after a brief asymptomatic period typically lasting 10-30 minutes.
Miosis cannot be used as a marker for the severity of nerve agent exposure, because it depends on the route and time course of exposure. In inhalational exposures, miosis occurs early and frequently. In such exposures, normal pupil size is predictive of nontoxicity.[9] However, in dermal exposures at sites distinct from the eye, miosis occurs later in the progression of toxicity and depends on whether significant systemic absorption has occurred.
Nerve agents cause death via respiratory failure, which in turn is caused by increased airway resistance (bronchorrhea, bronchoconstriction), respiratory muscle paralysis, and most importantly, loss of central respiratory drive.[10]
Two chemical properties of nerve agents also provide the rationale for effective measures against them. First, nerve agents are hydrolyzed readily by alkaline solutions, which explains why soap and water or hypochlorite solutions are effective skin decontaminants. Second, the bond between the nerve agent and AChE takes time to chemically mature and become a stable covalent bond. During the period immediately after nerve agent binding to enzyme, the bond is vulnerable to disruption by agents called oximes. This aging phenomenon forms the pharmacologic basis for the effective use of the antidote, pralidoxime, during this early window of opportunity before the bond becomes permanent.
Nerve agent exposure is extremely rare in the United States. Despite international attempts to control the proliferation of chemical weapons, nerve agents reportedly still are stockpiled by the militaries of several countries.
Sarin gas has been documented as the chemical wapon used in the attacks by the Syrian goverment on Eastern Ghouta and Aleppo in 2013, and Khan Sheikhoun in 2017,[11] resulting in over 1500 fatalities.[12]
In 1994, the Japanese terrorist cult, Aum Shinrikyo, synthesized and then deployed GB against civilians at Matsumoto, Japan, killing 8 people.[13] The following year, the same terrorist group released GB again in the infamous Tokyo Subway sarin attack, killing 13 and sending 5500 persons to local hospitals.[14]
Indirect evidence exists that the Iraqi military used GB against Kurdish villagers in 1988 as well as during the Iraq-Iran War.[15] In 2004, Iraqi insurgents exploded a device improvised from an artillery shell that contained degraded sarin. The attack failed to inflict casualties, but two U.S. service members were treated for minor symptoms usually associated with the agent.[16]
Incapacitating effects and fatal effects can occur within 1 to 10 minutes for GA, GB, and GD.[4] CNS effects such as fatigue, irritability, nervousness and impairment of memory may persist for as long as 6 weeks after recovery from acute effects.[17]
Few data are available describing long-term effects of nerve agent exposure. Structural brain damage in animals has been attributed to nerve agent–induced seizures. A consensus panel of experts concluded that structural brain damage does not occur until seizures have lasted longer than 45 minutes.[18]
A study by Chao et al examined long-term effects of sarin exposure on brain function in 40 soldiers with suspected exposure.[19] No long-term cognitive effects were noted.
Miosis-related visual problems in dim light and mental lapses have been reported as long as 6-8 months after nerve agent exposure.
In long-term studies of victims of the Tokyo subway GB attack, postural imbalance has been reported 8 months after exposure to GB.[20] Fatigue, asthenia, nausea, shoulder stiffness, and blurred vision have been reported 3 years after exposure to GB.[21]
Counsel patients who are discharged home with miosis to avoid driving at night. For patient education information, see the First Aid and Injuries Center, as well as Chemical Warfare and Personal Protective Equipment. For more information, see the Disaster Preparedness and Aftermath Resource Center.
Symptoms of nerve agent toxicity vary with the type of cholinergic receptor affected (muscarinic, nicotinic, or CNS) and include the following[6] :
Signs of nerve agent toxicity also vary with the type of cholinergic receptor affected, and include the following:
Although no laboratory test exists to directly measure nerve agent levels in serum or urine, the acute effects of nerve agents can be estimated by measuring the percent reduction in the activity of red blood cell (RBC) cholinesterase.
Respiratory impairment in nerve agent intoxication produces expected derangement in arterial blood gas values, including a reduction in partial pressure of arterial oxygen (PaO2).
Hypokalemia has been reported in GB intoxication, although the mechanism is unclear.
Chest x-ray may be helpful in treating patients with significant pulmonary symptoms.
A number of electrocardiographic changes have been reported in nerve agent intoxication, including bradycardia and varying degrees of atrioventricular block (first through third degree) from the direct muscarinic effect on the heart and tachycardia and ventricular dysrhythmias from hypoxia. Nerve agent toxicity has been associated with PR interval prolongation, QT prolongation, and torsade de pointes.
Bedside electroencephalographic monitoring is recommended for patients paralyzed from nerve agent exposure, because paralysis from nicotinic effects of these agents may mask seizures from CNS effects.
RBC cholinesterase and plasma cholinesterase (pseudocholinesterase) appear to have a physiologic role as buffers for the tissue acetylcholinesterases found in the nervous system. These two enzymes are clinically important, because their activities can be assayed directly in blood, whereas the tissue cholinesterases cannot. Activity of RBC cholinesterase is considered a more sensitive indicator of nerve agent toxicity than that of plasma cholinesterase.
Despite the clinical use of RBC cholinesterase, keep certain limitations in mind when using the activity of RBC cholinesterase to interpret nerve agent effects. Activity of RBC cholinesterase is subject to some individual variation. Without establishing the baseline value of RBC cholinesterase in individuals, measuring the percent reduction in enzyme activity is difficult.
Poor correlation exists between clinical effects of nerve agents and the percent reduction of RBC cholinesterase activity at low-dose exposures. Accordingly, RBC cholinesterase activity always must be correlated with the patient's clinical status and never should determine patient disposition alone.
A good guideline is that severe clinical effects tend to correlate with a 20-25% reduction in RBC cholinesterase activity. A rising RBC cholinesterase level indicates that no further nerve agent absorption is occurring and that the enzyme is regenerating. RBC cholinesterase is replaced fully every 120 days at the natural regeneration rate of RBCs (approximately 1%/d). Draw blood for RBC cholinesterase activity level prior to administering oxime antidotes.
Atropine and pralidoxime chloride (2-PAM Cl) are antidotes for nerve agent toxicity; however, pralidoxime must be administered within minutes to a few hours following exposure (depending on the specific agent) to be effective. Treatment consists of supportive measures and repeated administration of antidotes.[4]
Toxic effects of GB usually peak within minutes to hours and resolve within 24 hours. Thus, patients who inhale nerve agent vapor suffer peak toxic effects before arriving in the ED. Patients who present to the ED with only ocular findings following vapor exposure can be discharged home safely. Refer patients discharged home with miosis or other eye complaints to an ophthalmologist.
Onset of signs and symptoms in patients with dermal exposure to liquid GB may be delayed for as long as 18 hours. Observe these patients in the ED or hospital for at least 18 hours. As discussed in Workup, RBC or plasma cholinesterase activity alone should never determine disposition and must always be correlated with the patient's clinical status.
A variety of neurobehavioral symptoms may persist in patients exposed to nerve agents. Such patients may benefit from neurologic consultation.
A key consideration in prehospital care is protection of emergency medical service personnel from exposure to the nerve agent until victims are decontaminated thoroughly or the need for decontamination is excluded. This involves personal protective equipment.[22]
First Responders should use a NIOSH-certified Chemical, Biological, Radiological, Nuclear (CBRN) Self Contained Breathing Apparatus (SCBA) with a Level A protective suit when entering an area with an unknown contaminant or when entering an area where the concentration of the contaminant is unknown. Level A protection should be used until monitoring results confirm the contaminant and the concentration of the contaminant.[17]
Goals of decontamination are to prevent further absorption of nerve agents by victims and to prevent the spread of nerve agents to others. If possible, decontamination should take place at the site of exposure.
Decontamination of liquid nerve agent exposure consists of removing all clothing, copiously irrigating with water to physically remove the nerve agent, and then washing the skin with an alkaline solution of soap and water or 0.5% hypochlorite solution (made by diluting household bleach 1:10) to chemically neutralize the nerve agent. Avoid hot water, strong detergents, and vigorous scrubbing, since they tend to enhance nerve agent absorption.
Skin exposure to liquid nerve agents will not necessarily result in systemic exposure if the site of exposure is decontaminated promptly. Before administering nerve agent antidotes, observe the site of exposure for localized sweating and muscular twitching. If these physical findings appear, administer antidotes; otherwise careful observation is all that is needed.
Exposure to nerve agent vapor does not require decontamination.
Often the first physical finding of minimal symptomatic exposure to nerve agent vapor is markedly constricted pupils (miosis). When exposed to liquid nerve agent, immediately flush the eyes with water for about 5 to 10 minutes by tilting the head to the side, pulling the eyelids apart with fingers, and pouring water slowly into the eyes. When exposed to nerve agent vapor, there is no need to flush the eyes. Do not cover eyes with bandages.[17]
In cases of moderate to severe exposure, antidotes alone will not provide effective treatment, and ventilatory support is essential. Evaluate respiratory function and pulse. Ensure that the patient/victim has an unobstructed airway. Assist with ventilation as required. Ventilatory distress is a physical finding of systemic exposure and marked resistance to ventilation is expected due to bronchial constriction and spasm. Resistance lessens after administration of atropine. Do not provide mouth-to-mouth resuscitation; contact with vapor or liquid agent may occur. If shortness of breath occurs, or breathing is difficult (dyspnea), administer oxygen. Suction secretions from the nose, mouth, and respiratory tract.[4]
Use of nerve agent treatment autoinjectors by prehospital personnel should be guided by local policy.[22] Administration of antidotes is a critical step in managing a patient. However, do not administer antidotes preventatively; there is no benefit to doing so. Diazepam (or other benzodiazepines) should be administered when there is evidence of seizures, usually seen in cases of moderate to severe exposure to a nerve agent.
Changes in the eye can lead to nausea and vomiting without necessarily being a sign of systemic exposure. However, if eye pain, nausea, or vomiting are seen in combination with any other physical findings of nerve agent poisoning, administer antidotes atropine and 2-PAM Cl as directed.
Emergency department (ED) personnel should wear personal protective equipment similar to that worn by prehospital care personnel until adequate decontamination of victims is assured or the need for decontamination is eliminated.[22]
Goals of decontamination are to prevent further absorption of nerve agent by victims and to prevent the introduction of nerve agent into the clean ED environment.
Liquid nerve agent exposure requires formal decontamination, as outlined in Prehospital Care, before victims enter the ED. No decontamination is necessary in vapor exposure.
Previously reported terrorist episodes have demonstrated that victims who physically can flee the scene frequently bypass emergency medical services (EMS) and go directly to the nearest ED.
The rapidity with which nerve agents act necessitates rapid medical response.
Moderately symptomatic patients require supplemental oxygen, pulse oximetry, cardiac monitoring, and early IV access.
Early endotracheal intubation and ventilatory support is paramount in treating patients with manifestations of severe toxicity.
Suction is an important adjunct to airway management, since airway secretions may be profuse in these patients.
Rapid sequence intubation may be required for airway treatment of patients with respiratory failure caused by nerve agent exposure. If rapid sequence intubation is used, avoid succinylcholine, since it is metabolized by plasma cholinesterase, leading to markedly prolonged paralysis.
Because atropine administered to hypoxic patients is associated with an increased risk of ventricular fibrillation, administer it after initial oxygenation and ventilation if possible.
Severely poisoned patients in respiratory arrest may need ventilatory assistance for several hours despite aggressive antidotal therapy. Patients in critical condition caused by complications of nerve agent poisoning, such as hypoxic brain injury, may require prolonged intensive care.
Antidotes for nerve agent toxicity are atropine and pralidoxime.There is also generally no benefit in giving more than three injections of 2-PAM Cl. Atropine should be administered every 5 to 10 minutes until secretions begin to dry up. If the military Mark I kits containing autoinjectors are available, they provide the best way to administer the antidotes to healthy adults.[4] Seizures may require benzodiazepines. See Medication.
Consultation with a toxicologist via a regional poison control center may be helpful.
Reversal of nerve agent toxicity depends on the prompt parenteral administration of the two antidotes, atropine and pralidoxime.
Although intravenous administration of these antidotes is preferred, this may not be practical in combat situations or civilian mass casualty incidents. The US military Mark 1 kit contains 2 IM autoinjectors, one with atropine 2 mg and the other with pralidoxime 600 mg, to be administered simultaneously in the event of nerve gas exposure. The recommended number of Mark 1 kits to be administered varies from 1-3 and depends on the route of exposure, severity of clinical effects, and elapsed time after exposure.
Deployed US military personnel typically carry three Mark 1 kits per person. The Antidote Treatment-Nerve Agent Auto-Injector (ATNAA) contains 2.1 mg of atropine and 600 mg of pralidoxime chloride in a single injector. A pediatric dosage atropine autoinjector (AtroPen) is commercially available. This product contains atropine and does not include pralidoxime. A Pediatric Expert Advisory Panel recommends the use of the Mark 1 kit in children 3 years and older.[23]
While seizures complicating nerve agent exposure often respond to IV atropine and pralidoxime, they also may require IV benzodiazepines titrated to effect. The convulsant antidote for nerve agent (CANA) autoinjector consists of diazepam and is recommended after three Mark 1 kits have been administered. Midazolam has been considered as a replacement to diazepam. Midazolam is twice as potent and acts more rapidly than diazepam in nonhuman primates with nerve agent–induced seizures.[24]
Another common complication of vapor nerve agent exposure is ocular pain, which may be treated effectively with a mild, mydriatic-cycloplegic ophthalmic solution (eg, 0.5% tropicamide). Atropine or homatropine ophthalmic solution also can be used to treat ocular pain, but these agents tend to exacerbate visual impairment.
Intranasal delivery is an emerging method for bypassing the blood brain barrier (BBB) and targeting therapeutics to the central nervous system. Oximes used to counteract the effects of nerve agents do not readily cross the BBB and are less effective counteracting the central neuropathologies caused by cholinergic over-activation. In a study of intranasal administration of oximes in an animal model of severe organophosphate poisoning the standard treatment (intramuscular pralidoxime plus atropine sulphate) was administered to all animals and then compared tobthe effectiveness of intranasal obidoxime (OBD) to saline in the control groups. Intranasally administered OBD was effective in partially reducing paraoxon-induced acetylcholinesterase inhibition in the brain and substantially reduced seizure severity and duration and prevented mortality, which was 41% in the animals given standard treatment plus intranasal saline.[25]
A number of other novel treatments currently are under investigation. Newer H-series oximes and dioximes (HI-6, HLo7) have greater ability to reactivate phosphorylated AChE. These agents demonstrate greater efficacy against all nerve agents (particularly GD) in animal studies and have direct antimuscarinic and antinicotinic actions to antagonize the effects of nerve agents.[26]
Other promising treatments currently under investigation include exogenous cholinesterase and the use of human monoclonal antibodies against nerve agents, both of which scavenge nerve agents and prevent them from binding to tissue AChE.[27, 28]
Clinical Context: Initial DOC for symptomatic victims of nerve agent exposure; acts via muscarinic receptors to reverse bronchoconstriction, bronchorrhea, abdominal pain, nausea, vomiting, and bradycardia; appears to be involved in stopping seizure activity. Because atropine does not act on nicotinic receptors, has no effect on muscle weakness or paralysis. The most important therapeutic endpoints are drying of respiratory secretions, reversal of bronchoconstriction, and reversal of bradycardia; pupillary response and tachycardia are not useful measures of adequate atropinization; >20 mg rarely is needed in first 24 h, unlike in organophosphate insecticide poisoning where up to 200 mg may be required; atropine almost never is required beyond 24 h postexposure.
Act directly on smooth muscles and secretory glands innervated by cholinergic nerves to block muscarinic effects of excess ACh.
Clinical Context: Reverses skeletal muscle weakness by reactivating AChE; acts by disrupting covalent bond between nerve agent and AChE before it becomes permanent. Bonds between different nerve agents and AChE have various aging periods. The half-time of the aging reaction for GD is approximately 2 min, for GB it is 5 h, and for GA it is 13 h. Accordingly, administer pralidoxime IV as early as possible (ideally concurrently with atropine). Excreted rapidly and almost completely unchanged by the kidneys.
Administration over 30-40 min minimizes adverse effects (eg, hypertension, headache, blurred vision, epigastric pain, nausea, vomiting).
Reactivate AChEs, which have been inactivated from phosphorylation by nerve agents (or other compounds, such as organophosphate pesticides).
Clinical Context: Indicated for treatment of seizures associated with nerve agent toxicity. Depresses all levels of CNS function by increasing activity of the inhibitory neurotransmitter GABA.
Believed to exert antiseizure effect by enhancing binding of the major CNS inhibitory neurotransmitter, GABA, to A-type GABA receptors in the CNS, reducing depolarization of neurons and preventing generation and spread of seizures.
Clinical Context: Anticholinergic compound that reverses miosis and relieves ocular pain in nerve agent toxicity. Acts by blocking cholinergic stimulation of sphincter muscle of iris and ciliary muscle. When applied as weaker preparation (0.5%), causes pupillary dilation (mydriasis); when applied as stronger preparation (1%), results in loss of accommodation (cycloplegia). Acts rapidly; effect is relatively short lasting.
Dilate iris and relax ciliary muscle, reversing ocular pain and miosis of nerve agent toxicity.
Clinical Context: Orally available cholinesterase inhibitor, which may be useful as chemoprophylactic agent when administered prior to exposure to GA, GD, and GF. This recommendation is based on animal studies; little information is available regarding the efficacy of pyridostigmine chemoprophylaxis in humans. Only effective in preventing peripheral (non-CNS) effects of nerve agents; since it exists in an ionized form (quaternary amine), does not readily pass into CNS and thus cannot prevent nerve agent–induced CNS injury; no evidence demonstrates that pretreatment before exposure to GB or VX is effective.
Temporarily bind and inhibit AChE, thus blocking subsequent binding of certain nerve agents to AChE. Although usually used to treat myasthenia gravis or reverse nondepolarizing neuromuscular blockade, also may be useful as chemoprophylactic agents when administered before exposure to certain nerve agents.