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Review of the literature

3.3 All available open literature has been reviewed and, in addition, access to relevant documentation at DSTL Porton Down has been provided.

3.4 Experimental studies on the treatment of nerve agent poisoning have to be interpreted with caution for several reasons. Antidotal studies in animals have to be designed with great care or they may demonstrate the efficacy of antidotes in circumstances that do not occur in civilian clinical practice. Thus, some studies have used prophylactic protocols, whereas the drugs concerned (atropine, oxime, diazepam) would only be given to a civilian population after exposure. The experimental use of pyridostigmine before nerve agent exposure, though rational, is not of relevance in the civilian context. Hence, these studies are difficult to interpret in relation to post-exposure treatment. Even those experimental studies in which antidotes have been administered after nerve agent dosing are not beyond reproach. In many studies antidotes were administered within a few minutes of, or even immediately after, exposure.

3.5 Specific issues considered were:

(i) The clinical relevance of the species employed in experimental studies, particularly in relation to rates of ageing of the AChE enzyme in soman poisoning;

(ii) The time relationship between exposure and treatment in experimental studies, including the impact of pre-treatment.

3.6 It has been assumed generally that monkeys would be a reasonable model for humans and it has been stated (Inns and Leadbeater, 1983; Leadbeater et al., 1985) that guinea pigs are also good models for humans. This was on the basis of similarity of protection ratios achieved for the treatment of soman-poisoned rhesus monkeys with atropine and oxime as compared with similarly poisoned and treated guinea pigs.

3.7 There are, however, significant differences between the aging rates of the nerve agent-acetylcholinesterase complex depending both on the identity of the nerve agent and the animal species concerned. Aging of complexes involving soman is always much more rapid than that of complexes involving other nerve agents. In the case of soman-bound acetylcholinesterase the mean half life (t½) (1) for aging in primates is 0.88-1.4 minutes, whilst in rodents and guinea pigs it is much longer: 7.6-8.6 minutes. The aging process is thus much slower in rodents and guinea pigs than in primates. The t½ of the soman-erythrocyte acetylcholinesterase complex in man is short (1.3 minutes) as in other primates (i.e. aging of the complex in man is rapid). This leads us to think that the guinea pig would not be a good model for man in soman poisoning. Unfortunately, the studies performed by Inns and Leadbeater (1983) were not published in full and it is impossible to say why similar protection ratios were observed in primates and guinea pigs.
(1) Aging half-life, t½: this is the time taken for 50% of the nerve agent-AchE complex to change to its aged form.

3.8 In vitro studies on human erythrocyte AChE have employed measures to prevent aging of the soman-inhibited complex. In vivo studies in rodents have employed protocols in which treatment was given before substantial ageing would have occurred. Neither approach can be used to predict successful reactivation of the aged soman-inhibited complex in humans. Hence, the results of such studies probably have little relevance to the management of human soman poisoning.

3.9 It is probable that the claim that HI-6 can reactivate soman-inhibited enzyme only applies to unaged enzyme and there is no unequivocal evidence of reactivation of aged soman-inhibited AChE by any oxime, in any species, in vivo. However, other pharmacological effects of some oximes (i.e. those not mediated by AChE reactivation), such as have been reported in the case of HI-6, may be important once aging of the agent-enzyme complex is established, and therefore HI-6 may have some advantage in soman poisoning. Although this has still to be confirmed, it is recommended, that a supply of HI-6 should be procured specifically for the treatment of soman and cyclosarin poisoning.

3.10 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 are excluded. Moreover there is much more clinical experience of pralidoxime in UK than of any other oxime.

3.11 It is recommended, therefore, that all casualties should receive pralidoxime mesilate initially, and preferably prior to admission to hospital.

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

3.13 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 the civilian context.

3.14 In experimental studies, a delay of even 12 minutes in the administration of oximes reduced the protection ratio (LD50 with treatment/LD50 without treatment) substantially. It is therefore important that oximes are administered as soon as possible after exposure, even in the case of nerve agents other than soman (Green et al. unpublished observations).

Treatment of nerve agent poisoning outside hospital

3.15 Arrangements need to be in place to ensure that civilian casualties receive antidotal treatment as soon as possible after exposure. This is of particular importance in the case of soman poisoning, as aging of the soman-enzyme complex occurs very rapidly. However, as it is very unlikely that the identity of the nerve agent will be known with certainty before the admission of casualties to hospital, therefore, HI-6 does not need to be substituted for pralidoxime mesilate prior to hospital admission.

3.16 Civilian casualties who have been exposed to nerve agents and who have developed rhinorrhea and bronchorrhea should be given atropine as a matter of urgency. These casualties should also receive pralidoxime mesilate as soon as possible. This could be done most conveniently by the administration of the contents of an autoinjection device such as the ComboPen (2), intramuscularly. Severely intoxicated casualties may require the administration of the contents of up to three ComboPens at five fifteen-minute intervals prior to admission to hospital.
(2) Autoinjection devices, such as the ComboPen, generally contain 2 mg atropine, an oxime and, in some cases, a soluble form of diazepam (Avizafone)

3.17 Children more than eight years of age who meet the criteria for treatment should be given the contents of one ComboPen, which may be repeated at 5-15 minute intervals. In the case of children less than eight years of age but more than 1 year old and who have features of systemic toxicity, atropine, 600 µg, should be administered initially, preferably intravenously. For those under 1 year of age a dose of 200 µg atropine should be used.

3.18 Pregnant women who have the features of systemic nerve agent toxicity should receive the same treatment regimen as other adults.

3.19 Casualties who do not develop the features of systemic toxicity, notably rhinorrhoea and bronchorrhea, should be triaged but not given atropine and/or pralidoxime.

Treatment of nerve agent poisoning in hospital

3.20 If rhinorrhea or bronchorrhea develops, atropine 2 mg in an adult (20 µg /kg in a child of less than 8 years of age) should be administered intravenously every 5-15 minutes until secretions are minimal and the patient is atropinized (dry skin and sinus tachycardia). In severe cases, repeated doses of atropine will be required.

3.21 Pralidoxime mesilate 30 mg/kg body weight intravenously every four to six hours should be administered to patients with systemic features of poisoning, and who require atropine, the duration of treatment depending on the clinical response, the presence of clinical features and the erythrocyte acetylcholinesterase activity. Alternatively, an infusion of pralidoxime mesilate 8-10 mg/kg/hr may be administered following an initial loading dose.

3.22 It is recommended that pralidoxime mesilate (or HI-6) should be administered for as long as atropine is indicated. For the majority of individuals this will be for less than 48 hours.

References

Green DM, Inns RH, Leadbeater L. Unpublished observations on the consequences of delaying oxime administration.

Inns RH, Leadbeater L. The efficacy of bispyridinium derivatives in the treatment of organophosphonate poisoning in the guinea-pig. J Pharm Pharmacol 1983; 35: 427-433.

Leadbeater L, Inns RH, Rylands JM. Treatment of poisoning by soman. Fundam Appl Toxicol 1985; 5: S225-S231.