25 December 2003
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Abstracts of the European Association of Poisons Centres and Clinical
Toxicologists XXII International Congress*
06/18/2002
Vale JA
National Poisons Information Service (Birmingham Centre) and West Midlands Poisons Unit, City Hospital, Birmingham, United Kingdom
Introduction:
The organophosphorus nerve agents are related chemically to organophosphorus insecticides and have a similar mechanism of toxicity, but a much higher mammalian acute toxicity, particularly via the dermal route. For example, in an in vitro study, sarin had 1000 fold more inhibitory effect on acetylcholinesterase (AChE) than parathion. Two classes of nerve agents are recognized, G agents (G allegedly stands for Germany where the early agents were first synthesized) and V agents (V allegedly stands for venomous). 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), though VE, VG and VM have also been produced. 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 of use of nerve agents during the Iran–Iraq War. The nerve agent, sarin was also employed in two terrorist attacks in Japan in 1994 and 1995.
Factors influencing the choice of nerve agent employed: The following factors are not only potentially relevant to those intending to release a nerve agent deliberately, but an understanding of these factors is also of importance to clinical toxicologists to optimize the clinical and public health responses to a deliberate release.
Physicochemical properties:
(i) Physical state. Is the nerve agent a volatile or non-volatile liquid? Sarin (22,000 mg/m3 at 25°C) is much more volatile than tabun (610 mg/m3 at 25°C); VX is non-volatile (10.5 mg/m3 25°C);(ii) Vapor pressure. This is a measure of how quickly a nerve agent will evaporate and is increased by a rise in ambient temperature. For example, the vapor pressure for 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;
(iii)Vapor density. Nerve agents with a high vapor density compared to air, such as VX (9.2), stay at ground level and tend to accumulate in low lying areas;
(iv) Odor. Tabun is said to have an almond/fruity odor, while the other agents are odorless if pure;
(v) Solubility in water;
(vi) Stability. This refers to the ability of a nerve agent to survive dissemination and transport to the site of deploy;
(vii) Persistence. Non-persistent agents disperse rapidly after release and present an immediate short duration hazard but may be made persistent by a “thickening agent” such as polyethylmethacrylate. In contrast, persistent agents such as VX continue to be a contact hazard and may vaporize over a period to produce an inhalation hazard.
Intent: If the intent is to cause permanent injury to a substantial number of those exposed rather than to cause mass panic, a relatively more toxic nerve agent may be chosen by the terrorists.
Toxicity of nerve agents: The LCt50 (the exposure (Ct) necessary to cause death in 50% of the population) for VX vapor is 10mg/min/m3, whereas the LCt50 for sarin vapor is 100mg/min/m3 and tabun vapor is 400mg/min/m3 (these data refer to humans at rest). The percutaneous LD50 for sarin is 1700 mg and for VX is 6–10 mg.
Ease of synthesis: Many of the precursors to produce nerve agents are available readily and common chemical processes can be adapted easily for their production. It has been calculated that it would cost only some $200,000 to produce 1000 kg of sarin. However, tabun is technically easier to synthesize in bulk than sarin or soman.
Intended route of delivery: The major routes of delivery of nerve agents are air (both indoor and outdoor), water (hence the solubility of the nerve agent is important) and food.
Meteorological factors: Meteorological factors are important in the case of air delivery as the wind may disperse volatile agents and a higher ambient temperature increases volatility and decreases persistence. Moreover, 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. Temperature inversions may increase persistency.
“Effectiveness”: “Effectiveness” is the capacity of an agent to produce the maximum number of casualties with the least amount of material. The duration of “effectiveness” is dependent on physicochemical characteristics, the amount delivered, the mode of delivery and environmental conditions.
Mechanisms of toxicity: Nerve agents phosphorylate a serine hydroxyl group in the active site of the enzyme, acetylcholinesterase, which results in accumulation of acetylcholine and which in turn causes enhancement and prolongation of cholinergic effects and depolarization blockade. Reactivation of acetylcholinesterase occurs by dephosphorylation, and the rates of phosphorylation and dephosphorylation are very variable, which partly accounts for differences in acute toxicity between the nerve agents. With soman in particular, an additional reaction occurs known as “aging.” This consists of monodealkylation of the dialkylphosphonyl enzyme, creating a much more stable monoalkylphosphonyl enzyme, with the result that reactivation of inhibited acetylcholinesterase does not occur to any clinically significant extent. The human in vivo “aging” half-life for soman is 2–6 min, for sarin (human in vitro data) 3 hr and tabun (human in vitro data) 14 hr. In the case of soman, therefore, recovery of function depends on resynthesis of acetylcholinesterase. As a result, it is important that an oxime is administered as soon after soman exposure as possible so that some reactivation of acetylcholinesterase occurs before all the enzyme becomes “aged.” Even though “aging” occurs more slowly and reactivation occurs relatively rapidly in the case of other nerve agents, such as tabun and sarin, early oxime administration is still clinically important.
Clinical features:
Ocular exposure: Miosis, which may be painful and last for several days, occurs rapidly following exposure to nerve agent vapor and appears to be a very sensitive index of exposure.1 Ciliary muscle spasm may impair accommodation and conjunctival injection and eye pain may occur.Dermal exposure: Contact with liquid nerve agent may produce localized sweating and fasciculation, which may spread to involve whole muscle groups. Systemic features may develop, though the onset is slower than following vapor inhalation.
Inhalation: Chest tightness, rhinorrhea and increased salivation may occur within minutes. Systemic features may then develop.
Ingestion: Ingestion of contaminated food or water may cause abdominal pain, nausea, vomiting, diarrhea and involuntary defecation. Systemic features may then develop.
Systemic features: 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 hypotension may occur dependent on whether muscarinic or nicotinic effects predominate. If exposure is substantial, death may occur from respiratory failure within minutes.
Chronic sequelae: Mild or moderately exposed individuals usually recover completely, though EEG abnormalities have been reported in severely exposed patients.2,3
Management: Adequate self protection should be donned by healthcare workers before decontaminating casualties, as secondary contamination from casualties exposed to sarin vapor has been reported.4,5 If available, pressure demand, self-contained breathing apparatus should be used in contaminated areas. Casualties should be moved to hospital as soon as possible.
Ocular exposure: The victim should remove contact lenses if present and they are easily removable. The eyes should be irrigated immediately with lukewarm water or sodium chloride 0.9% solution. Local anesthetic should be applied if ocular pain is present.
Dermal exposure: Contaminated clothing should be removed, if possible by the victim, to reduce further nerve agent absorption.
Inhalation: The priority is to remove the casualty from further exposure. Establish and maintain a clear airway and give supplemental oxygen as required. In symptomatic patients, intravenous access should be established and blood should be taken for measurement of erythrocyte cholinesterase activity to confirm the diagnosis. If the characteristic features of nerve agent poisoning are present, however, antidotal treatment should not be delayed until the result is available.
Atropine: If bronchorrhea develops, atropine (2 mg in an adult; 20 microgram/kg in a child) should be administered intravenously every 5–10 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.
Oximes: In a clinically relevant time, it is unlikely that it will be known with certainty which nerve agent has been released. Hence, the oxime most readily available should be administered in the appropriate therapeutic dose. Experimental studies in guinea pigs and monkeys have shown that pralidoxime+atropine and obidoxime+atropine were less effective in soman poisoning than HI-6+atropine, though pralidoxime+atropine was more effective than obidoxime+atropine.6 Studies have shown invariably that higher oxime doses, together with atropine, have increased survival further, irrespective of the nerve agent.6 HI-6 was also more effective in GF poisoning than obidoxime+atropine.7 Overall, however, pralidoxime is the oxime of first choice for civilian use in many countries as it is the most widely available, it is cheaper to synthesize than HI-6 and produces fewer adverse effects than obidoxime in equimolar concentrations. If pralidoxime is available (either as the mesylate, chloride or methylsulfate salt) it should be administered to moderately or severely poisoned patients in a dose of 30 mg/kg body weight (2 g in an adult) intravenously over four minutes to reactivate phosphorylated enzyme. Early administration is a priority. In severe cases, pralidoxime mesylate or chloride 30 mg/kg body weight will be required intravenously every four to six hours, depending on the clinical features and erythrocyte cholinesterase activity. Alternatively, an infusion of pralidoxime mesylate or chloride 8–10 mg/kg/hr may be administered.
Diazepam: Intravenous diazepam (adult 10–20 mg; child 1–5 mg) is useful in controlling apprehension, agitation, fasciculation and convulsions; the dose may be repeated as required. In some experimental studies, the addition of diazepam to an atropine+oxime regimen increased survival further.6
Deliberate releases of sarin in Japan:
Matsumoto: Some 600 people were exposed to sarin released from a truck using a heater and fan in a residential area of the Japanese city of Matsumoto on June 27 1994.8 Fifty-eight residents were admitted to hospital and all recovered: seven casualties died. Eight of 95 rescuers had mild symptoms of OP poisoning. The features experienced by the casualties are summarized in Table 1. Follow up one to two years after exposure of those casualties with the most severe initial features has shown that four had developed epileptiform EEG abnormalities and one had developed a sensory neuropathy,3 though it is not known whether these features were related to sarin exposure.Tokyo: In March 1995 a terrorist attack occurred in the Tokyo subway system during rush hour. Sarin was placed in five subway cars on three separate lines in plastic bags opened so that the agent, which is liquid under temperate conditions, could evaporate. Over 5,000 “casualties” sought medical attention of whom 984 were moderately poisoned and 54 were severely poisoned; 12 died.9,10 However, a substantial number of those presenting (some 4000) had no signs of OP toxicity and 4,973 individuals were seen on day one and sent home. In the following 24?x00A0;hours many more individuals presented, though none had features of OP poisoning. The features in 111 hospitalized patients are shown in Table 1.
Lessons to be learned from these sarin releases and recommendations for further action:
Triage: Substantial numbers of casualties presented to a variety of hospitals over a short time period after both incidents which stretched the resources available significantly. Hence, every hospital should now have a major accident plan that covers chemical releases. This plan should be tested at least annually. It should include arrangements to triage substantial numbers of non-poisoned casualties as well as those who are severely poisoned and require admission.Training: It has been claimed11 that if paramedics had been allowed to maintain an airway with an endotracheal tube or to use a laryngeal mask airway without physician oversight more patients might have survived in the Tokyo incident. The implication is that all paramedics/ambulance staff should be trained to an adequate level.
Personal protective equipment (PPE): PPE was not donned in the Matsumoto incident and substantial secondary contamination occurred. Similar contamination also occurred in the Tokyo incident where PPE was either not available or not employed. PPE is now readily available and for $200–300 full protection against nerve agents can be afforded. Every hospital should now have suitable PPE available for handling those exposed to nerve agents.
Supplies of atropine and oximes: Adequate supplies of atropine and oxime need to be available in every major city or be readily transportable to cities and towns within 1–2 hours.
References:
1. 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, 1005–1007.
2. Murata, K.; Araki, S.; Yokoyama, K. et al. Asymptomatic Sequelae to Acute Sarin Poisoning in the Central and Autonomic Nervous System 6?x00A0;Months After the Tokyo Subway Attack. J. Neurol. 1997, 244, 601–606.
3. Sekijima, Y.; Morita, H.; Yanagisawa, N. Follow-Up of Sarin Poisoning in Matsumoto. Ann. Intern. Med. 1997, 127, 1042–1042.
4. Nozaki, H.; Aikawa, N. Sarin Poisoning in Tokyo Subway. Lancet 1995, 345, 1446–1447.
5. Nozaki, H.; Aikawa, N.; Shinozawa, Y. et al. Sarin Poisoning in Tokyo Subway. Lancet 1995, 345, 980–981.
6. Dawson, R.M. Review of Oximes Available for Treatment of Nerve Agent Poisoning. J. Appl. Toxicol. 1994, 14, 317–331.
7. Clement, J.G. Efficacy of Various Oximes Against GF (Cyclohexyl Methylphosphonofluoridate) Poisoning in Mice. Arch. Toxicol. 1992, 66, 143–144.
8. Okudera, H.; Morita, H.; Iwashita, T. et al. Unexpected Nerve Gas Exposure in the City of Matsumoto: Report of Rescue Activity in the First Sarin Gas Terrorism. Am. J. Emerg. Med. 1997, 15, 527–528.
9. 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.
10. Sidell, F.R. Chemical Agent Terrorism. Ann. Emerg. Med. 1996, 28, 223–224.
11. Okumura, T.; Suzuki, K.; Fukuda, A. et al. The Tokyo Subway Sarin Attack: Disaster Management. Part 1: Community Emergency Response. Acad. Emerg. Med. 1998, 5, 613–617.
12. Morita, H.; Yanagisawa, N.; Nakajima, T. et al. Sarin Poisoning in Matsumoto, Japan. Lancet 1995, 346, 290–293.
13. Ohbu, S.; Yamashina, A.; Takasu, N. et al. Sarin Poisoning on Tokyo Subway. South. Med. J. 1997, 90, 587–593.1
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