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Chemical terrorism and nerve agents
CHEMICAL TERRORISM
Chemical terrorism and nerve agents
Nomenclature Two classes of nerve agent are recognized: G and V. Tabun (NATO designation GA), sarin (GB) and soman (GD) were synthesized in Germany in 1936, 1938 and 1944, respectively. GE and GF were synthesized subsequently. The V agents were introduced later and are exemplified by VX, synthesized in the 1950s. The G agents are both dermal and respiratory hazards, whereas the V agents, unless aerosolized, are contact poisons.
Allister Vale Timothy C Marrs Paul Rice
Mechanisms of toxicity
Abstract Sarin and VX were released on civilians in Japan on 11 occasions in the period 1994 to 1995. Clinicians must be prepared, therefore, to treat casualties from nerve agent exposure. This requires an understanding of the mechanisms of nerve agent toxicity and the factors that influence their clinical impact. Clinicians need to be able to make a rapid and accurate diagnosis and use atropine, an oxime and diazepam optimally.
Nerve agents are chemically related to organophosphorus insecticides and have a similar mechanism of toxicity, but their mammalian acute toxicity is considerably greater, particularly via the dermal route. Nerve agents phosphonylate the serine hydroxyl group at the active site of the enzyme acetylcholinesterase (AChE).1 This results in accumulation of acetylcholine (ACh), which in turn leads to enhancement and prolongation of cholinergic effects and depolarization blockade. The rate of spontaneous reactivation of AChE is variable, which partly accounts for the differences in acute toxicity between the nerve agents. With soman in particular, an additional reaction occurs termed ‘aging’. This involves monodealkylation of the dialkylphosphonyl enzyme, which is then resistant to spontaneous hydrolysis and reactivation by oximes (e.g. pralidoxime). Monodealkylation occurs to some extent with all dialkylphosphonylated AChE complexes, but is generally of clinical importance only in relation to the treatment of soman poisoning, in which it is a serious problem. The approximate aging half-lives of human AChE inhibited by soman, sarin and tabun are 1.3 minutes, 3 hours and 13 hours, respectively. With soman, therefore, aging is so fast that no clinically relevant spontaneous reactivation of AChE is possible before it has occurred, and recovery of function depends on resynthesis of the enzyme. As a consequence, it is important that an oxime is administered as soon as possible after exposure to soman, to enable some reactivation of AChE before all the enzyme becomes ‘aged’. Aging occurs more slowly and reactivation relatively rapidly with nerve agents other than soman, but early oxime administration is still clinically important in patients poisoned with these agents. Reactivation of tabuninhibited acetylcholinesterase is slow or non-existent; this is due not to aging but to its unique chemical structure.
Keywords atropine; diazepam; nerve agents; oximes; sarin; soman; tabun; VX
Chemical terrorism The acquisition of chemical weapons by some twenty countries, as well as by terrorists, has increased the likelihood of their use worldwide. In World War I, chlorine, cyanide, phosgene and sulphur mustard were used. Although available, nerve agents were not used in World War II, but were employed by Iraq against that country’s own Kurdish population, and there have been allegations that nerve agents were employed during the Iran-Iraq War. Sarin and VX were released on the civilian population in Japan on 11 occasions in 1994e5. As these releases in Japan indicate, there are important differences between on-target military attacks against relatively well-protected armed forces and nerve agent attacks initiated by terrorists against a civilian population. In contrast to military personnel, civilians are unlikely to be pre-treated with pyridostigmine or protected by personal protective equipment (PPE).
Physicochemical properties Allister Vale MD FRCP FRCPE FRCPG FFOM FAACT FBTS is Director of the National Poisons Information Service (Birmingham Unit) and the West Midlands Poisons Unit at City Hospital, Birmingham, UK. Competing interests: none declared.
These are shown in Table 1.
Toxicity of nerve agents
Timothy C Marrs OBE DSc FRCP FRCPath FBTS FSB MRSC Consulting Clinical Toxicologist at the National Poisons Information Service (Birmingham Unit) at City Hospital, Birmingham, UK. Competing interests: none declared.
The LCt50 (concentration in the air which kills half of the test animals) by inhalation (30-minute exposure) in the mouse is 15 mg.m 3, 5 mg.m 3 and 1 mg.m 3 for tabun, sarin and soman, respectively. By the subcutaneous route, the LD50 (dose required to kill half of the test animals) in the rabbit is 375 mg/kg, 30 mg/ kg, 20 mg/kg and 14 mg/kg for tabun, sarin, soman and VX, respectively.
Paul Rice BM FRCPath FRCP FSB is Chief Scientist for Biomedical Sciences at Dstl Porton Down, Salisbury, UK. Competing interests: none declared.
MEDICINE 40:2
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Ó 2011 Published by Elsevier Ltd.
CHEMICAL TERRORISM
a result of nerve agent poisoning. Only the number of casualties may prompt consideration of the diagnosis.
Physicochemical properties Physical state Is the nerve agent a volatile or non-volatile liquid? Sarin (volatility 22,000 mg.m 3 at 25 C) is much more volatile than tabun (610 mg.m 3 at 25 C), whereas VX is non-volatile (10.5 mg.m 3 at 25 C) Vapour pressure This is a measure of how quickly nerve agents evaporate and is increased by rises in ambient temperature. For example, the vapour pressure of sarin is 0.52 mmHg at 0 C and 2.9 mmHg at 25 C, whereas that of tabun is 0.004 mmHg at 0 C and 0.07 mmHg at 25 C Vapour density Nerve agents with a high vapour density compared to air (e.g. VX e 9.2) remain at ground level and tend to accumulate in low-lying areas Solubility in water The solubility of tabun is 9.8 g/100 g; that of soman is 2.1 g/100 g Odour Tabun is said to have an almond/fruity odour; the other agents are odourless when pure Stability Stability is the ability of nerve agents to survive dissemination and transport to sites of deployment Persistence Non-persistent agents (e.g. sarin) disperse rapidly after release and are immediate, short-duration hazards. They may be rendered persistent using a ‘thickening agent’ (e.g. polyethylmethacrylate). In contrast, persistent agents (e.g. VX) continue to be a contact hazard and may vaporize over time to produce an inhalation hazard.
Features Sidell2,3 has reviewed the features and management of nerve agent poisoning. Systemic nerve agent poisoning may follow inhalation, ingestion or dermal exposure, though the onset of systemic toxicity is slower by the latter route. Miosis, which may be painful and last for several days, occurs rapidly following ocular exposure to a nerve agent and appears to be a very sensitive index of exposure.4 Ciliary muscle spasm may impair accommodation and conjunctival injection and eye pain may occur. Contact with liquid nerve agent may produce localized sweating and fasciculation, which may spread to involve whole muscle groups. Chest tightness, increased salivation, rhinorrhoea and bronchorrhoea occur within seconds/minutes of inhalation of a nerve agent. In contrast, ingestion of food or water contaminated with nerve agent may cause abdominal pain, nausea, vomiting, diarrhoea and involuntary defecation, though the onset of symptoms may be delayed. Miosis may also occur as a systemic feature, though more usually it follows direct exposure. Abdominal pain, nausea and vomiting, involuntary micturition and defecation, muscle weakness and fasciculation, tremor, restlessness, ataxia and convulsions may follow dermal exposure, inhalation or ingestion of a nerve agent. Bradycardia, tachycardia and hypertension may occur, dependent on whether muscarinic or nicotinic effects predominate. If exposure is substantial, death may occur from respiratory failure within minutes, whereas mild or moderately exposed individuals usually recover completely, though electroencephalogram (EEG) abnormalities have been reported in those severely exposed to sarin in Japan.5,6
Management
Table 1
The general principles of management have been reviewed,7 and include maintaining vital body functions, undertaking adequate clinical monitoring, minimizing further absorption of the nerve agent and using atropine, oxime and diazepam optimally. Patients who are moderately or severely poisoned, as shown, for example, by drowsiness, coma, hypotension, severe bronchorrhoea and marked muscle fasciculation, require treatment in a critical care unit as soon as possible as further deterioration may occur and mechanical ventilation may be required. Bronchorrhoea requires prompt relief with intravenous atropine and supplemental oxygen should be given to maintain PaO2 > 10 kPa (75 mmHg). If these measures fail, the patient should be intubated and mechanical ventilation (with positive end-expiratory pressure) should be instituted. In severely poisoned patients who are hypotensive, it may be necessary not only to expand plasma volume but also to use an inotrope such as dobutamine 2.5e10 micrograms/kg/min or adrenaline (epinephrine) 0.5e2.0 micrograms/kg/min. Careful attention must be given to fluid and electrolyte balance and adjustments to infusion fluids made as necessary. Heart rate, blood pressure, ECG and arterial blood gases should be monitored routinely. Cardiac arrhythmias should be treated conventionally and hypoxia must be considered as a possible aetiology. The management of convulsions and muscle fasciculation with diazepam is discussed below.
Routes of delivery The major routes of delivery of nerve agents would be in air (indoor and outdoor), water (hence the solubility of the nerve agent is important) and food.
Meteorological factors Meteorological factors are important for air delivery, because the wind may disperse volatile agents, and a higher ambient temperature increases the volatility and reduces persistence. Some agents may freeze on clothing and then vaporize if carried indoors. Rain tends to dilute toxicity and may promote hydrolysis of the nerve agent.
Making the diagnosis The diagnosis of nerve agent poisoning is based on the patient’s history, clinical presentation and laboratory tests. In a patient with a positive history, characteristic symptoms and depressed erythrocyte AChE activity, the diagnosis is not difficult to make. Unfortunately, the history may be unobtainable and the clinical features may not be recognized as such by those clinicians who have no personal experience of diagnosing cholinergic crisis as
MEDICINE 40:2
78
Ó 2011 Published by Elsevier Ltd.
CHEMICAL TERRORISM
Minimizing absorption of the nerve agent
exposure treatment against dermal exposure to VX up to 2 h post-exposure has been demonstrated, though the best survival outcomes were seen when the huBuChE was administered before the onset of observable signs of systemic poisoning.10,11
In principle, after resuscitation and stabilization of the casualty, if exposure was dermal, thorough skin decontamination should be carried out by removing all contaminated clothing and washing affected skin thoroughly with soap and cold water, including exposed areas (e.g. hands, arms, face, neck and hair). This should be done without care-givers themselves being contaminated and casualties becoming hypothermic. However, given the circumstances of likely exposure and the number of casualties, decontamination may be difficult to achieve in practice. The removal and appropriate storage of contaminated clothing may be all that can be done. It is essential that decontamination does not lead to delays in the administration of antidotes to those who are severely poisoned. If exposure is by inhalation, skin decontamination is unnecessary.
Treatment of casualties outside hospital Healthcare workers should don adequate self-protection before decontaminating casualties, because secondary contamination has been reported. If available, pressure-demand, self-contained breathing apparatus should be used in contaminated areas. Casualties should be moved to hospital as soon as possible. Casualties should receive antidotal treatment as soon as possible after exposure. This is of particular importance in poisoning with soman, because of the very rapid aging of the soman-enzyme complex. In casualties who develop rhinorrhoea and bronchorrhoea, atropine and whatever oxime is available should be administered as a matter of urgency. This can be achieved most conveniently by the use of an autoinjector.1 A
Atropine and oximes Atropine competes with ACh and other muscarinic agonists for a common binding site on the muscarinic receptor, thus effectively antagonizing the actions of ACh at muscarinic receptor sites. If rhinorrhoea or bronchorrhoea develops, atropine (2 mg in an adult; 20 micrograms/kg in a child) should be administered intravenously immediately and the dose repeated (with doubling of the dose in severe cases) at least every 2-5 minutes until secretions are minimal and the patient is atropinized (dry skin and sinus tachycardia). In severe cases, very large doses of atropine may be required. Although HI-6 is probably the best antidote overall,8 it is not yet generally available. However, with the possible exception of the treatment of cyclosarin and soman poisoning, when HI-6 is preferred, a review of the available experimental evidence suggests that there are no clinically important differences between pralidoxime, obidoxime and HI-6 in the treatment of poisoning due to other nerve agents.1 An oxime, such as pralidoxime chloride, should be administered parenterally in a dose of 30 mg/kg every 4 hours to patients with systemic features who require atropine. Alternatively, an infusion of pralidoxime chloride (8e10 mg/kg/hour) may be given, the infusion rate depending on the severity. The duration of oxime treatment depends on the presence of features, the clinical response and the red blood cell (RBC) AChE activity. It is recommended that an oxime should be administered for as long as atropine is indicated. In most individuals, this will be less than 48 hours.
REFERENCES 1 Marrs TC, Rice P, Vale JA. The role of oximes in the treatment of nerve agent poisoning in civilian casualties. Toxicol Rev 2006; 25: 297e323. 2 Medical aspects of chemical and biological warfare. In: Sidell FR, Takafuji ET, Franz DR, eds. Medical aspects of chemical and biological warfare. Washington DC: Office of the Surgeon General at TMM Publications, 1997. 3 Sidell FR. Clinical considerations in nerve agent intoxication. In: Somani SM, ed. Chemical warfare agents. San Diego: Academic Press, 1992; 155e194. 4 Nozaki H, Hori S, Shinozawa Y, et al. Relationship between pupil size and acetylcholinesterase activity in patients exposed to sarin vapor. Intensive Care Med 1997; 23: 1005e7. 5 Murata K, Araki S, Yokoyama K, et al. Asymptomatic sequelae to acute sarin poisoning in the central and autonomic nervous system 6 months after the Tokyo subway attack. J Neurol 1997; 244: 601e6. 6 Sekijima Y, Morita H, Yanagisawa N. Follow-up of sarin poisoning in Matsumoto. Ann Intern Med 1997; 127: 1042. 7 Vale JA, Rice P, Marrs TC. Managing civilian casualties affected by nerve agents. In: Marrs TC, Maynard RL, Sidell FR, eds. Chemical warfare agents: toxicology and treatment. 2 edn. Chichester: John Wiley & Sons, 2007; 249e260. 8 Lundy PM, Hamilton MG, Sawyer TW, Mikler J. Comparative protective effects of HI-6 and MMB-4 against organophosphorous nerve agent poisoning. Toxicology 2011; 285: 90e6. 9 Marrs TC. The role of diazepam in the treatment of nerve agent poisoning in a civilian population. Toxicol Rev 2004; 23: 145e57. 10 Mumford H, Price E, Lenz DE, Cerasoli DM. Post-exposure therapy with human butyrylcholinesterase following percutaneous VX challenge in guinea pigs. Clin Toxicol 2011; 49: 287e97. 11 Lenz DE, Clarkson ED, Schulz SM, Cerasoli DM. Butyrylcholinesterase as a therapeutic drug for protection against percutaneous VX. Chem Biol Interact 2010; 187: 249e52.
Diazepam Intravenous diazepam 10e20 mg (1e5 mg in children) is useful in controlling apprehension, agitation, fasciculation and convulsions.9 The dose may be repeated as required. In some experimental studies, addition of diazepam to an atropine and oxime regimen further increased survival.
Human butyrylcholinesterase The successful experimental use of a protein bioscavenger, human plasma-derived butyrylcholinesterase (huBuChE), as a post-
MEDICINE 40:2
79
Ó 2011 Published by Elsevier Ltd.
Chemical terrorism and nerve agents
Nomenclature Two classes of nerve agent are recognized: G and V. Tabun (NATO designation GA), sarin (GB) and soman (GD) were synthesized in Germany in 1936, 1938 and 1944, respectively. GE and GF were synthesized subsequently. The V agents were introduced later and are exemplified by VX, synthesized in the 1950s. The G agents are both dermal and respiratory hazards, whereas the V agents, unless aerosolized, are contact poisons.
Allister Vale Timothy C Marrs Paul Rice
Mechanisms of toxicity
Abstract Sarin and VX were released on civilians in Japan on 11 occasions in the period 1994 to 1995. Clinicians must be prepared, therefore, to treat casualties from nerve agent exposure. This requires an understanding of the mechanisms of nerve agent toxicity and the factors that influence their clinical impact. Clinicians need to be able to make a rapid and accurate diagnosis and use atropine, an oxime and diazepam optimally.
Nerve agents are chemically related to organophosphorus insecticides and have a similar mechanism of toxicity, but their mammalian acute toxicity is considerably greater, particularly via the dermal route. Nerve agents phosphonylate the serine hydroxyl group at the active site of the enzyme acetylcholinesterase (AChE).1 This results in accumulation of acetylcholine (ACh), which in turn leads to enhancement and prolongation of cholinergic effects and depolarization blockade. The rate of spontaneous reactivation of AChE is variable, which partly accounts for the differences in acute toxicity between the nerve agents. With soman in particular, an additional reaction occurs termed ‘aging’. This involves monodealkylation of the dialkylphosphonyl enzyme, which is then resistant to spontaneous hydrolysis and reactivation by oximes (e.g. pralidoxime). Monodealkylation occurs to some extent with all dialkylphosphonylated AChE complexes, but is generally of clinical importance only in relation to the treatment of soman poisoning, in which it is a serious problem. The approximate aging half-lives of human AChE inhibited by soman, sarin and tabun are 1.3 minutes, 3 hours and 13 hours, respectively. With soman, therefore, aging is so fast that no clinically relevant spontaneous reactivation of AChE is possible before it has occurred, and recovery of function depends on resynthesis of the enzyme. As a consequence, it is important that an oxime is administered as soon as possible after exposure to soman, to enable some reactivation of AChE before all the enzyme becomes ‘aged’. Aging occurs more slowly and reactivation relatively rapidly with nerve agents other than soman, but early oxime administration is still clinically important in patients poisoned with these agents. Reactivation of tabuninhibited acetylcholinesterase is slow or non-existent; this is due not to aging but to its unique chemical structure.
Keywords atropine; diazepam; nerve agents; oximes; sarin; soman; tabun; VX
Chemical terrorism The acquisition of chemical weapons by some twenty countries, as well as by terrorists, has increased the likelihood of their use worldwide. In World War I, chlorine, cyanide, phosgene and sulphur mustard were used. Although available, nerve agents were not used in World War II, but were employed by Iraq against that country’s own Kurdish population, and there have been allegations that nerve agents were employed during the Iran-Iraq War. Sarin and VX were released on the civilian population in Japan on 11 occasions in 1994e5. As these releases in Japan indicate, there are important differences between on-target military attacks against relatively well-protected armed forces and nerve agent attacks initiated by terrorists against a civilian population. In contrast to military personnel, civilians are unlikely to be pre-treated with pyridostigmine or protected by personal protective equipment (PPE).
Physicochemical properties Allister Vale MD FRCP FRCPE FRCPG FFOM FAACT FBTS is Director of the National Poisons Information Service (Birmingham Unit) and the West Midlands Poisons Unit at City Hospital, Birmingham, UK. Competing interests: none declared.
These are shown in Table 1.
Toxicity of nerve agents
Timothy C Marrs OBE DSc FRCP FRCPath FBTS FSB MRSC Consulting Clinical Toxicologist at the National Poisons Information Service (Birmingham Unit) at City Hospital, Birmingham, UK. Competing interests: none declared.
The LCt50 (concentration in the air which kills half of the test animals) by inhalation (30-minute exposure) in the mouse is 15 mg.m 3, 5 mg.m 3 and 1 mg.m 3 for tabun, sarin and soman, respectively. By the subcutaneous route, the LD50 (dose required to kill half of the test animals) in the rabbit is 375 mg/kg, 30 mg/ kg, 20 mg/kg and 14 mg/kg for tabun, sarin, soman and VX, respectively.
Paul Rice BM FRCPath FRCP FSB is Chief Scientist for Biomedical Sciences at Dstl Porton Down, Salisbury, UK. Competing interests: none declared.
MEDICINE 40:2
77
Ó 2011 Published by Elsevier Ltd.
CHEMICAL TERRORISM
a result of nerve agent poisoning. Only the number of casualties may prompt consideration of the diagnosis.
Physicochemical properties Physical state Is the nerve agent a volatile or non-volatile liquid? Sarin (volatility 22,000 mg.m 3 at 25 C) is much more volatile than tabun (610 mg.m 3 at 25 C), whereas VX is non-volatile (10.5 mg.m 3 at 25 C) Vapour pressure This is a measure of how quickly nerve agents evaporate and is increased by rises in ambient temperature. For example, the vapour pressure of sarin is 0.52 mmHg at 0 C and 2.9 mmHg at 25 C, whereas that of tabun is 0.004 mmHg at 0 C and 0.07 mmHg at 25 C Vapour density Nerve agents with a high vapour density compared to air (e.g. VX e 9.2) remain at ground level and tend to accumulate in low-lying areas Solubility in water The solubility of tabun is 9.8 g/100 g; that of soman is 2.1 g/100 g Odour Tabun is said to have an almond/fruity odour; the other agents are odourless when pure Stability Stability is the ability of nerve agents to survive dissemination and transport to sites of deployment Persistence Non-persistent agents (e.g. sarin) disperse rapidly after release and are immediate, short-duration hazards. They may be rendered persistent using a ‘thickening agent’ (e.g. polyethylmethacrylate). In contrast, persistent agents (e.g. VX) continue to be a contact hazard and may vaporize over time to produce an inhalation hazard.
Features Sidell2,3 has reviewed the features and management of nerve agent poisoning. Systemic nerve agent poisoning may follow inhalation, ingestion or dermal exposure, though the onset of systemic toxicity is slower by the latter route. Miosis, which may be painful and last for several days, occurs rapidly following ocular exposure to a nerve agent and appears to be a very sensitive index of exposure.4 Ciliary muscle spasm may impair accommodation and conjunctival injection and eye pain may occur. Contact with liquid nerve agent may produce localized sweating and fasciculation, which may spread to involve whole muscle groups. Chest tightness, increased salivation, rhinorrhoea and bronchorrhoea occur within seconds/minutes of inhalation of a nerve agent. In contrast, ingestion of food or water contaminated with nerve agent may cause abdominal pain, nausea, vomiting, diarrhoea and involuntary defecation, though the onset of symptoms may be delayed. Miosis may also occur as a systemic feature, though more usually it follows direct exposure. Abdominal pain, nausea and vomiting, involuntary micturition and defecation, muscle weakness and fasciculation, tremor, restlessness, ataxia and convulsions may follow dermal exposure, inhalation or ingestion of a nerve agent. Bradycardia, tachycardia and hypertension may occur, dependent on whether muscarinic or nicotinic effects predominate. If exposure is substantial, death may occur from respiratory failure within minutes, whereas mild or moderately exposed individuals usually recover completely, though electroencephalogram (EEG) abnormalities have been reported in those severely exposed to sarin in Japan.5,6
Management
Table 1
The general principles of management have been reviewed,7 and include maintaining vital body functions, undertaking adequate clinical monitoring, minimizing further absorption of the nerve agent and using atropine, oxime and diazepam optimally. Patients who are moderately or severely poisoned, as shown, for example, by drowsiness, coma, hypotension, severe bronchorrhoea and marked muscle fasciculation, require treatment in a critical care unit as soon as possible as further deterioration may occur and mechanical ventilation may be required. Bronchorrhoea requires prompt relief with intravenous atropine and supplemental oxygen should be given to maintain PaO2 > 10 kPa (75 mmHg). If these measures fail, the patient should be intubated and mechanical ventilation (with positive end-expiratory pressure) should be instituted. In severely poisoned patients who are hypotensive, it may be necessary not only to expand plasma volume but also to use an inotrope such as dobutamine 2.5e10 micrograms/kg/min or adrenaline (epinephrine) 0.5e2.0 micrograms/kg/min. Careful attention must be given to fluid and electrolyte balance and adjustments to infusion fluids made as necessary. Heart rate, blood pressure, ECG and arterial blood gases should be monitored routinely. Cardiac arrhythmias should be treated conventionally and hypoxia must be considered as a possible aetiology. The management of convulsions and muscle fasciculation with diazepam is discussed below.
Routes of delivery The major routes of delivery of nerve agents would be in air (indoor and outdoor), water (hence the solubility of the nerve agent is important) and food.
Meteorological factors Meteorological factors are important for air delivery, because the wind may disperse volatile agents, and a higher ambient temperature increases the volatility and reduces persistence. Some agents may freeze on clothing and then vaporize if carried indoors. Rain tends to dilute toxicity and may promote hydrolysis of the nerve agent.
Making the diagnosis The diagnosis of nerve agent poisoning is based on the patient’s history, clinical presentation and laboratory tests. In a patient with a positive history, characteristic symptoms and depressed erythrocyte AChE activity, the diagnosis is not difficult to make. Unfortunately, the history may be unobtainable and the clinical features may not be recognized as such by those clinicians who have no personal experience of diagnosing cholinergic crisis as
MEDICINE 40:2
78
Ó 2011 Published by Elsevier Ltd.
CHEMICAL TERRORISM
Minimizing absorption of the nerve agent
exposure treatment against dermal exposure to VX up to 2 h post-exposure has been demonstrated, though the best survival outcomes were seen when the huBuChE was administered before the onset of observable signs of systemic poisoning.10,11
In principle, after resuscitation and stabilization of the casualty, if exposure was dermal, thorough skin decontamination should be carried out by removing all contaminated clothing and washing affected skin thoroughly with soap and cold water, including exposed areas (e.g. hands, arms, face, neck and hair). This should be done without care-givers themselves being contaminated and casualties becoming hypothermic. However, given the circumstances of likely exposure and the number of casualties, decontamination may be difficult to achieve in practice. The removal and appropriate storage of contaminated clothing may be all that can be done. It is essential that decontamination does not lead to delays in the administration of antidotes to those who are severely poisoned. If exposure is by inhalation, skin decontamination is unnecessary.
Treatment of casualties outside hospital Healthcare workers should don adequate self-protection before decontaminating casualties, because secondary contamination has been reported. If available, pressure-demand, self-contained breathing apparatus should be used in contaminated areas. Casualties should be moved to hospital as soon as possible. Casualties should receive antidotal treatment as soon as possible after exposure. This is of particular importance in poisoning with soman, because of the very rapid aging of the soman-enzyme complex. In casualties who develop rhinorrhoea and bronchorrhoea, atropine and whatever oxime is available should be administered as a matter of urgency. This can be achieved most conveniently by the use of an autoinjector.1 A
Atropine and oximes Atropine competes with ACh and other muscarinic agonists for a common binding site on the muscarinic receptor, thus effectively antagonizing the actions of ACh at muscarinic receptor sites. If rhinorrhoea or bronchorrhoea develops, atropine (2 mg in an adult; 20 micrograms/kg in a child) should be administered intravenously immediately and the dose repeated (with doubling of the dose in severe cases) at least every 2-5 minutes until secretions are minimal and the patient is atropinized (dry skin and sinus tachycardia). In severe cases, very large doses of atropine may be required. Although HI-6 is probably the best antidote overall,8 it is not yet generally available. However, with the possible exception of the treatment of cyclosarin and soman poisoning, when HI-6 is preferred, a review of the available experimental evidence suggests that there are no clinically important differences between pralidoxime, obidoxime and HI-6 in the treatment of poisoning due to other nerve agents.1 An oxime, such as pralidoxime chloride, should be administered parenterally in a dose of 30 mg/kg every 4 hours to patients with systemic features who require atropine. Alternatively, an infusion of pralidoxime chloride (8e10 mg/kg/hour) may be given, the infusion rate depending on the severity. The duration of oxime treatment depends on the presence of features, the clinical response and the red blood cell (RBC) AChE activity. It is recommended that an oxime should be administered for as long as atropine is indicated. In most individuals, this will be less than 48 hours.
REFERENCES 1 Marrs TC, Rice P, Vale JA. The role of oximes in the treatment of nerve agent poisoning in civilian casualties. Toxicol Rev 2006; 25: 297e323. 2 Medical aspects of chemical and biological warfare. In: Sidell FR, Takafuji ET, Franz DR, eds. Medical aspects of chemical and biological warfare. Washington DC: Office of the Surgeon General at TMM Publications, 1997. 3 Sidell FR. Clinical considerations in nerve agent intoxication. In: Somani SM, ed. Chemical warfare agents. San Diego: Academic Press, 1992; 155e194. 4 Nozaki H, Hori S, Shinozawa Y, et al. Relationship between pupil size and acetylcholinesterase activity in patients exposed to sarin vapor. Intensive Care Med 1997; 23: 1005e7. 5 Murata K, Araki S, Yokoyama K, et al. Asymptomatic sequelae to acute sarin poisoning in the central and autonomic nervous system 6 months after the Tokyo subway attack. J Neurol 1997; 244: 601e6. 6 Sekijima Y, Morita H, Yanagisawa N. Follow-up of sarin poisoning in Matsumoto. Ann Intern Med 1997; 127: 1042. 7 Vale JA, Rice P, Marrs TC. Managing civilian casualties affected by nerve agents. In: Marrs TC, Maynard RL, Sidell FR, eds. Chemical warfare agents: toxicology and treatment. 2 edn. Chichester: John Wiley & Sons, 2007; 249e260. 8 Lundy PM, Hamilton MG, Sawyer TW, Mikler J. Comparative protective effects of HI-6 and MMB-4 against organophosphorous nerve agent poisoning. Toxicology 2011; 285: 90e6. 9 Marrs TC. The role of diazepam in the treatment of nerve agent poisoning in a civilian population. Toxicol Rev 2004; 23: 145e57. 10 Mumford H, Price E, Lenz DE, Cerasoli DM. Post-exposure therapy with human butyrylcholinesterase following percutaneous VX challenge in guinea pigs. Clin Toxicol 2011; 49: 287e97. 11 Lenz DE, Clarkson ED, Schulz SM, Cerasoli DM. Butyrylcholinesterase as a therapeutic drug for protection against percutaneous VX. Chem Biol Interact 2010; 187: 249e52.
Diazepam Intravenous diazepam 10e20 mg (1e5 mg in children) is useful in controlling apprehension, agitation, fasciculation and convulsions.9 The dose may be repeated as required. In some experimental studies, addition of diazepam to an atropine and oxime regimen further increased survival.
Human butyrylcholinesterase The successful experimental use of a protein bioscavenger, human plasma-derived butyrylcholinesterase (huBuChE), as a post-
MEDICINE 40:2
79
Ó 2011 Published by Elsevier Ltd.