11.terrorismo
Post on 12-May-2017
216 Views
Preview:
TRANSCRIPT
CHEMICAL TERRORISM
Chemical terrorism and nerveagentsAllister Vale
Timothy C Marrs
Paul Rice
AbstractSarin 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 accu-
rate diagnosis and use atropine, an oxime and diazepam optimally.
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).
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.
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.
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
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.
Mechanisms of toxicity
Nerve agents are chemically related to organophosphorus insecti-
cides and have a similar mechanism of toxicity, but their mamma-
lian 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 dialkyl-
phosphonyl enzyme, which is then resistant to spontaneous
hydrolysis and reactivation by oximes (e.g. pralidoxime). Mono-
dealkylation occurs to some extent with all dialkylphosphony-
lated 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 reac-
tivation relatively rapidly with nerve agents other than soman,
but early oxime administration is still clinically important in
patients poisoned with these agents. Reactivation of tabun-
inhibited acetylcholinesterase is slow or non-existent; this is
due not to aging but to its unique chemical structure.
Physicochemical properties
These are shown in Table 1.
Toxicity of nerve agents
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.
� 2011 Published by Elsevier Ltd.
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.
Table 1
CHEMICAL TERRORISM
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
a result of nerve agent poisoning. Only the number of casualties
may prompt consideration of the diagnosis.
Features
Sidell2,3 has reviewed the features andmanagement of nerve agent
poisoning. Systemic nerve agent poisoningmay 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 expo-
sure.4 Ciliary muscle spasm may impair accommodation and
conjunctival injection and eye painmay occur. Contact with liquid
nerve agent may produce localized sweating and fasciculation,
which may spread to involve whole muscle groups. Chest tight-
ness, 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 involun-
tary 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 weak-
ness and fasciculation, tremor, restlessness, ataxia and convul-
sions 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 electro-
encephalogram (EEG) abnormalities have been reported in those
severely exposed to sarin in Japan.5,6
Management
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 bron-
chorrhoea 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 intu-
bated 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 moni-
tored routinely. Cardiac arrhythmias should be treated conven-
tionally and hypoxia must be considered as a possible aetiology.
The management of convulsions and muscle fasciculation
with diazepam is discussed below.
� 2011 Published by Elsevier Ltd.
CHEMICAL TERRORISM
Minimizing absorption of the nerve agent
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 prac-
tice. The removal and appropriate storage of contaminated
clothing may be all that can be done. It is essential that decon-
tamination 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.
Atropine and oximes
Atropine competes with ACh and other muscarinic agonists for
a common binding site on the muscarinic receptor, thus effec-
tively 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 featureswho require atropine.Alternatively, an infusionof
pralidoxime chloride (8e10 mg/kg/hour) may be given, the infu-
sion rate depending on the severity. The duration of oxime treat-
ment 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.
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
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
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
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.
� 2011 Published by Elsevier Ltd.
top related