S29 Nerve agents Nerve Agents Ruei-Fang Wang, MD; Tzong-Luen Wang, MD, PhD Abstract Nerve agents are one of the most lethal chemical materials. They may be used as weapons of mass destruction in terrorist attacks or in the battlefield. Successful management is composed of many close organized steps. Early detection, field triage, decontamination, primary survey, resuscitation, and early antidote use are imperative in the acute stage of poisoning. Basic pharmacological therapy includes antidote (atropine and pralidoxime) and anticonvulsant therapy. We review the basic physi- cal properties, the pathophysiology, and the acute management of nerve agents poisoning. (Ann Disaster Med. 2005;4 Suppl 1:S29-S34) Key words: Nerve Agent; Poisoning; Resuscitation; Chemical Warfare Introduction son gas” is a historic misnomer for nerve agents. For developing best pesticides, nerve agents At standard pressure and temperature, they are were synthesized by German scientists in the liquids, with melting points range from -42°C 1930s. These agents are relatives of organo- (soman) to -39°C (VX).1 They can be volatile phosphate insecticides and are very toxic. In- spontaneously at room temperature. Thus one ternationally they have North Atlantic Treaty need not really contact the nerve agents to be Organization (NATO) codes and common affected by their vapors. chemical names. Abbreviations are used include All the nerve agents have vapor densities GA (tabun), GB (sarin), GD (soman), GF greater than 1, that means their vapors are (cyclosarin) and VX. The G agents are named heavier than air and tend to sink lower to the for Germany, and the VX was first synthesized ground. Besides, the rates of vaporization and in the British. the volatility determine the hazardous effects of these agents. Sarin is the most volatile agent, Pathophysiology and the VX, oily by contrast, is the least volatile The classic nerve agents are esters of phosphoric agent of all. Therefore, though sarin poses acid, namely organophosphates. Recalling phos- greater vapor hazard, VX tends to persist in gene and chloride, the first chemical agents in the environment longer. World War I, are gases at standard tempera- Nerve agents can induce life-threatening ture and pressure. The term “nerve gas” or “poi- cholinergic crisis by acting as cholinesterase From Department of Emergency Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan Address for reprints: Dr. Tzong-Luen Wang, Department of Emergency Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, No 95, Wen Chang Road, Taipei, Taiwan Received: Aug 29 2005. Revised: Sep 6 2005. Accepted: Sep12 2005. TEL: 886-2-28389425 FAX: 886-2-28353547 E-mail: [email protected] Ann Disaster Med Vol 4 Suppl 1 2005 Nerve agents S30 inhibitors, as do the organophosphates. Nerve penetrate into the circulating blood and cause agent forms a covalent binding with the acetyl- systemic effect. The gastrointestinal effects of cholinesterase (AChE), which has only one ac- nerve agents include increased bowel tive site, causing irreversible inhibition of this movement, nausea, vomiting, diarrhea, and ab- enzyme. The accumulating neurotransmitter ace- dominal cramping pain. tylcholine (ACh) in the synaptic cleft, which The cardiac effects vary since sympathetic and cannot be hydrolyzed by AChE, will in turn ac- parasympathetic inputs to the heart are some- tivate the postsynaptic cholinergic receptors. what different in each individual. Besides, nerve This can happen in the peripheral and central agents can activate both muscarinic and nico- nervous systems, at both muscarinic and nico- tinic receptors in the cardiovascular systems. tinic receptors. In our human body, our eryth- As a result, the blood pressure and heart rate rocyte cholinesterase activity correlates better are relatively unpredictable in exposed patients. with that in the nervous system than plasma In the peripheral neuromuscular systems, cholinesterase, which we often called pseudo- cholinergic nicotinic activation causes fascicu- cholinesterase or butyrylcholinesterase.2-4 lations and then twitching. This can be differen- However, the presenting symptoms are not tiated from seizure by electroencephalogram. correlate with the erythrocyte cholinesterase When adenosine triphosphate (ATP) is depleted inhibition very well. late in the course, flaccid paralysis follows. Re- member in botulinium intoxication, flaccid pa- Clinical Manifestation ralysis occurs earlier in the course due to pr- The routes of exposure determine somewhat esynaptic inhibition of ACh release by the toxin. the order and onset timing of the presenting The neuromuscular effects of nerve agents can symptoms. In terrorist or battlefield scenarios, compromise respiratory function if the respira- most victims are affected via vapor route. The tory muscles are involved. pupillary muscles are the most accessible cho- Human brain has a number of pathways linergic synapses. Thus miosis may be the first contain acetylcholine, including neurons in the symptom in these patients. Nozaki et al reported neostriatum, the medial septal nucleus, and the that pupil size less than 3mm is a sensitive and reticular formation. Nerve agents can cause great simple method for sarin exposure detection.5 hazard here. Loss of consciousness, multi-fo- In the sarin subway attack in Japan, the patients cal seizures and apnea due to central respira- complained of dim and blurred vision. They tory center suppression will occur. described that everything seemed dark at that Nerve agents can be absorbed through the time.6 Rhinorrhea and salivation can be the next skin. Volatility determines the topical dose the presenting symptoms in the vapor exposure. nerve agents need to produce toxicity. Less This can also be a systemic effect. The severity volatile nerve agents need fewer dose and time is dose-related.4,7 With the vapor inhalation, to be absorbed. VX is the least volatile agent nerve agents induce bronchorrhea and and it can be absorbed into the skin well after a bronchoconstriction of the respiratory tract. small contact time.8 The dermal LD50 of liquid When the nerve agents enter the body, they VX is 6 mg for a 70-kg adult, and that of liquid Ann Disaster Med Vol 4 Suppl 1 2005 S31 Nerve agents sarin is much larger, about 1960mg. (LD50: the patients. This delayed neurobehavioral syn- dose needed to kill 50% of the patients drome in some patients, if not at all, may be exposed).3, 4, 7, 9 Relative large proportion of sarin posttraumatic stress disorder.11,12 In others, it and tabun evaporate before they can be may due to hypoxic encephalopathy.13,14 The absorbed, since they are more volatile nerve pathophysiology is still unclear now. agents. In Marrs et al’s study, the symptoms can onset 18 hours after dermal exposure to Treatment liquid nerve agent.8 Delayed presentation may The patients’ clinical condition and the exposed be due to continuous penetration of the already pathway should be kept in mild in the manage- absorbed nerve agent into the blood circulation, ment of nerve agent hazard. though the skin has been decontaminated.8,10 In general, the more delayed onset of the Decontamination symptoms, the less severe the effects will be. Decontamination should be considered in the With a drop of nerve agent, it may cause local- management of nerve agent victims. Simply by ized sweating, localized fasciculation, however, taking off the clothes or the garments and brief these may be subtle if the patients are not aware decontamination can remove most of the toxins. of them. Then the nerve agents enter the blood- Nerve agents can be absorbed through the skin. stream through the well vascularized subcuta- Therefore, unrecognized contamination or in- neous tissue or muscles. Miosis will occur much adequate decontamination may cause second- later in the course by this route of exposure, ary injury to the healthcare workers. because the nerve agents have to cross many The nerve agents can be inactivated by barriers and diffuse into the aqueous humor to alkaline solutions. The US Army recommend reach the receptors of the papillary muscles. 0.5% sodium hydrochloride ( household bleach: Commonly, the cholinergic effects of liquid nerve water= 1:9) can be used. Detergent and water agent exposure take more time to reach peak are used in the most situations, however. than vapor exposure. Thus, much longer time for treatment and close monitoring is needed if Atropine liquid exposure cannot be excluded. Atropine is highly selective for muscarinic Nerve agent intoxication-related death receptors, but it can not distinguish between the usually is respiratory failure. This can result from M1, M2, and M3 subgroups of muscarinic bronchospasm, bronchorrhea, respiratory receptors. Its potency at nicotinic receptors is muscle paralysis, and central inhibition of the much lower than that at muscarinic receptors. respiratory center. Atropine causes reversible blockade of the ac- Delayed neurobehavioral syndrome are tions of acetylcholine. This can be overcome noted in some patients survived the nerve agent by a larger amount of AChs by competition with attack. Some patients have difficult in atropine at the binding site of muscarinic concentrating, sleeping, or working. Mood receptors. disturbance, headache, and personality change Initially, administer 2 mg for adults and 0. have been reported in the Japan subway attack 02mg/kg for children intravenously is Ann Disaster Med Vol 4 Suppl 1 2005 Nerve agents S32 considered. Intramuscular (IM) route via an IM versing the central effects of nerve agents. autoinjector can be used in the filed treatment. 2-PAM-Cl is administered by intravenous In a severely nerve-agent-poisoned adult, treat- infusion, 1- to 2-g given over 15-30minutes, ment begins with three IM autoinjectors or 6mg for a 70-kg adult. A maximum single dosage of of atropine, then to retreat every 5 to 10 min- 2000mg or 30mg/kg per hour is currently ac- utes if needed.15 Nerve agent–induced broncho- cepted in United States.19,20 Higher doses (e.