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1.2 Four problems have been addressed to date. This summary provides short accounts of the Group's findings.

(i) Use of oximes in nerve agent poisoning

1.3 Nerve agents are organophosphorus compounds, which act by inhibiting the enzyme acetylcholinesterase. This results in the accumulation of acetylcholine at synapses, parasympathetic effector sites and neuromuscular junctions. The enzyme can, in some situations, be reactivated by the use of pyridinium oximes. These mono or bispyridinium compounds bind to the nerve agent-enzyme complex and cause the latter to be hydrolyzed. The effectiveness of oximes is dependent upon the exact nerve agent compound that has been bound to the enzyme, for example, the oxime pralidoxime mesilate is effective in sarin (GB) and VX poisoning but less so in tabun (GA ) or cyclosarin (GF) poisoning. Furthermore, a secondary irreversible reaction described as aging of the nerve agent-enzyme complex, renders the complex refractory to oxime reactivation. Aging occurs very rapidly in the case of GD (soman) but more slowly with other nerve agents.

1.4 A number of oximes are available. The pralidoxime salts (including the chloride, methanesulfonate known as the mesilate, and the methyl sulphate) are perhaps the best known. Obidoxime (Toxogonin) is used in some countries but the H (Hagedorn) oximes are not yet in general use.

1.5 It is probable that the claim that asoxime chloride (HI-6) can reactivate soman-inhibited enzyme only applies to unaged enzyme and there is no unequivocal evidence of reactivation of aged soman-inhibited acetylcholinesterase by any oxime in any species in vivo. However, other pharmacological effects of HI-6, may be important after aging of the agent-enzyme complex is established. Therefore, HI-6 may still have some advantage in soman poisoning. It is recommended that a supply of HI-6 should be procured for this purpose.

1.6 With the possible exception of the treatment of soman and cyclosarin, when HI-6 might be preferred, a review of available experimental evidence suggests that there are no clinically important differences between pralidoxime, obidoxime and HI-6 in the treatment of nerve agent poisoning, if studies employing pre-treatment with pyridostigmine and/or prophylactic administration of oxime are excluded. In practice it is unlikely that the identity of the nerve agent to which people are exposed will be known. It is recommended, therefore, that all nerve agent casualties should receive pralidoxime mesilate initially, and preferably prior to admission to hospital.

1.7 In the case of cyclosarin and soman poisoning, consideration should be given to the hospital use of HI-6, once supplies become available. It is recommended that HI-6 be obtained now for this purpose.

1.8 Whilst we recognise that it will be difficult to initiate treatment soon after poisoning in the setting of a terrorist incident, we believe that the acquisition and use of autoinjection devices, such as the ComboPen, would help. For the hospital setting we recommend that pralidoxime mesilate remains the oxime of choice in the UK, though we accept that HI-6 may be a better choice in cases of soman and cyclosarin poisoning. Thus we recommend that a supply of HI-6 be procured now for this purpose. Further research into the mode of action of H oximes and into alternative approaches to the treatment of nerve agent casualties is needed: research recommendations are provided in Chapter 7.

1.9 In the medium term, it is recommended that HI-6 should eventually replace pralidoxime mesilate for the treatment of nerve agent poisoning, at least in a civilian context.

1.10 Although we have been asked to focus on oximes we feel it important to stress the importance of atropine and, if necessary, assisted ventilation with supplementary oxygen and airway management in the early management of nerve agent casualties.

(ii) Use of antidotes in treatment of poisoning by hydrogen cyanide

1.11 Hydrogen cyanide, like all cyanide compounds, acts by binding to cytochrome enzymes and blocking the electron transport chain in mitochondria. Inhalation of hydrogen cyanide produces more rapid effects than ingestion of cyanide salts, such as potassium cyanide, and for treatment to be effective it must be given very rapidly following poisoning. In cases of ingestion of cyanide salts or of extensive skin contamination an interval between exposure and the onset of very severe effects may occur. Delayed therapy in such cases can be effective; this is unlikely to be the case in patients exposed to hydrogen cyanide.

1.12 A number of approaches to the treatment of cyanide poisoning have been developed. Each depends, at least initially, upon the binding of cyanide ions to produce a non-toxic complex. Binding can be achieved with cobalt ions or by reaction with iron in methaemoglobin to produce cyanmethaemoglobin. Dicobalt edetate (a chelate of cobalt ions) contains some free cobalt ions and it is probable that both dicobalt edetate and the free cobalt ions bind cyanide, but free cobalt is itself toxic and, in the absence of cyanide, may produce significant adverse effects. Intravenous glucose is given to oppose these effects. In the case of proven cyanide poisoning the administration of glucose, in addition to dicobalt edetate has been found to be unnecessary, but glucose is generally given as a precautionary measure.

1.13 It is stressed that therapy must be given as rapidly as possible after poisoning and it is accepted that this may be difficult in cases of exposure to hydrogen cyanide poisoning resulting from terrorist activity. It is, in our view, unlikely that those most in need of therapy could be treated sufficiently quickly to save their lives and that the great majority of those surviving the initial exposure and reaching the point at which therapy could be given, will not benefit from such treatment. Despite this conclusion we appreciate that a minority of patients reaching clinical care may still benefit from therapy.

1.14 The Department of Health has stockpiled dicobalt edetate and we support this approach. In our view, dicobalt edetate, given intravenously, is likely to lead to more rapid binding of cyanide ions than the main alternative: the production of methaemoglobin by sodium nitrite. We have examined the case for use of hydroxocobalamin and find it less well supported in cases of exposure of hydrogen cyanide than that of dicobalt edetate.

1.15 We have also considered the need to provide assisted respiration and oxygen to casualties suffering from exposure to cyanide. There is some experimental evidence derived from studies in animals to support the use of oxygen. We therefore recommend that assisted ventilation and oxygen should be provided as soon after exposure to cyanide as possible.

1.16 Amyl nitrite provides the only form of treatment for cyanide poisoning that need not be given intravenously. However, we think that the generation of useful amounts of methaemoglobin by any possible means of providing amyl nitrite is unlikely and we do not recommend that this approach be pursued.

(iii) Treatment of patients exposed to lung damaging compounds

1.17 A large number of chemicals can, if inhaled, damage the lung. These include the early chemical warfare agents chlorine and phosgene, and a number of comparatively common industrial chemicals. Exposure to such compounds produces inflammation of the conducting airways and of the delicate tissues of the gas exchange zone of the lung. This causes bronchoconstriction and pulmonary oedema. No specific antidotes are known. However, bronchodilator substances, as used in the management of asthma, can be useful in reversing bronchoconstriction. The use of corticosteroids, in the management of chemically induced pneumonitis and pulmonary oedema, remains controversial and we have not been able to discover strong evidence to suggest that parenteral administration of steroids should be recommended. The use of inhaled steroids is not likely to be associated with the side effects that may accompany the parenteral use of high dose steroids and may be useful in treating bronchial reactions.

1.18 As in cases of nerve agent or cyanide exposure, early access to assisted ventilation and oxygen may be needed.

(iv) Acute management of mustard gas-induced eye injuries

1.19 Sulphur mustard is an oily liquid that gives off a vapour which on contact with the skin produces blisters: the liquid and the vapour are described as vesicants. Both liquid and vapour can produce severe damage to the eyes though this tends to be limited to the anterior part of the eye: conjunctiva, cornea and, sometimes, the iris, the deeper parts of the eye seldom being affected. Rapid removal of any liquid contamination of the eye by irrigation with copious amounts of water is essential: any delay will significantly reduce the effectiveness of irrigation as mustard binds rapidly to protein thus becoming impossible to remove. Exposure to vapour produces a delayed but severe inflammatory reaction and all treatment is essentially palliative. Eye injuries caused by mustard gas should be managed by ophthalmologists: a range of therapeutic substances may be used and details are provided in this report though the evidence base for their efficacy is scant. It is important to recall that there is no specific antidote for mustard gas and no known way of reversing the effects of mustard gas on tissues.

1.20 A short note outlining the general principles of management of casualties contaminated by chemical compounds has been provided as Annex 1. This note sets out a modification of the standard ABC approach.

1.21 Research recommendations are made in Chapter 7.