Biomedical subjects
Publications and source records attributed to S K Sutherland.
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A young pregnant woman, near term, died shortly after being bitten by an immature brown snake (genus Pseudonaja). Analysis of the bitten area suggested that the degree of envenomation was mild, and could not satisfactorily explain her rapid demise. It was concluded that the supine hypotensive syndrome of pregnancy was a contributing factor in her death.
An antivenom to the Sydney Funnel-web Spider, Atrax robustus, developed in rabbits, passed exhaustive quality control studies and was subsequently tested in monkeys. It was shown to reverse the syndrome that follows envenomation in both a conscious unmonitored monkey and in two anaesthetised, monitored monkeys. This paper reports the results of these experiments. An autonomic crisis appears to be the major cause of mortality and morbidity in human victims and monkeys; this aspect of the syndrome is rapidly attenuated by the antivenom. We observed no ill-effects of antivenom.
This paper describes the successful use of funnel-web antivenom in two severe cases of envenomation from bites by a male funnel-web spider, Atrax robustus. Rapid resolution of the syndrome occurred in both cases. Although the first patient, a 49-year-old man, may have slowly recovered without antivenom, it is unlikely that the other patient, a three-year-old boy, would have survived without antivenom therapy. In both cases the duration of hospitalisation was dramatically reduced.
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Rhesus monkeys were kept in a restraining apparatus and while conscious injected with the venoms of a range of Australian snakes. Although the action of restraining itself caused an elevation of the animals' plasma creatine kinase (C.K.), the rise was up to 5 times greater in envenomed monkeys. The venoms of the Tiger snake, Mulga, Beaked Sea snake, Rough-Scaled, Copperhead and Red-Bellied snakes were all powerfully myolytic, and those of the Taipan and Small-Eyed snake less so. No myolytic activity was found in the venoms of the Common Brown snake and Death Adder, and the results with Dugite, Gwardar and Small-Scaled snake venom were equivocal. Significant coagulation disturbances were produced by all venoms studied except those of the Small-Eyed and Rough-Scaled snakes. When first aid measures were used, the coagulation disturbances which developed after the release of the injected venom were significantly less than when no first aid was used. This finding, which was observed with all snake venoms studied, suggests that the procoagulant factor may be subject to some inactivation whilst immobilized at the injection site.
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Monkeys were injected subcutaneously with 6 mg of Crotalus adamanteus venom and a solid phase radioimmunoassay was used to measure levels of venom in plasma and urine. When no attempt was made to retard venom movement from the site of injection, plasma levels as high as 1,300 ng/ml occurred within 15 min of injection and progressive swelling developed in the injected limb. When first aid was employed (firm pressure to the injection site and immobilization of limb with a splint), plasma levels remained very low until cessation of first aid. No swelling of the injected limb occurred while the first aid measures were in position, and animals which received first aid an antivenom fared much better than did those which received antivenom alone. The best result was obtained when antivenom was infused prior to removal of the pressure bandages and splint. This first aid procedure is effective in delaying venom movement, and its simplicity and safety suggest it should be considered for use in cases of human envenoming by C. adamanteus.
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The effects of the venom of the male Sydney funnel-web spider were studied in closely monitored monkeys, and a number of new features were observed. Excessive catecholamine release was demonstrated and linked to the development of hypertension, arrhythmias, pulmonary oedema, hyperthermia, and metabolic acidosis. Acute intracranial hypertension was found, and may partly explain the central neurological manifestations. It is believed that a neurogenic basis for pulmonary oedema may sometimes exist. Survival after massive envenomation was achieved with the use of aggressive pharmacological denervation of the motor and autonomic nervous systems.
Venom of the male Sydney funnel-web spider was injected subcutaneously into the limbs of monkeys (Macaca fascicularis), and the central movement of venom was delayed by first-aid treatment. This treatment consisted of the application of firm pressure over the site of injection and immobilization of the limb. It was found that quantities of venom as high as 2 mg were inactivated when the first-aid procedures were maintained for 24 hours. Over a six-hour period, 0.5 mg of venom could be inactivated. Since the amount of venom injected by the spider into a human victim is unlikely to exceed 0.2 mg, these findings have immediate application both to the first aid and to actual medical management of human victims.
A purified rabbit IgG (antivenom) has been isolated from rabbits immunized with male Atrax robustus venom. This preparation has been shown to neutralize in vitro, male venom in a ratio of 97 microgram of IgG to 1 microgram of male venom. The venoms of a number of other members of the Atrax genus are also neutralized in vitro by this antivenom. Of particular importance is the fact that the venom of the extremely dangerous female A. formidabilis is neutralized. A serum harvest of 55 mL from an immunized rabbit yielded a total of 1.1869 g of immune IgG using the Protein A-Sepharose procedure. This quantity is sufficient antivenom to neutralize in vitro the average yield of 67 spiders. These findings suggest the preparation of an antivenom for human use is now feasible. The antivenom was shown to effectively neutralize venom in monkeys either when it was premixed with the venom before injection or when it was injected separately 10 minutes after injection of venom. This is the first time in-vitro and in-vivo neutralization of this venom has been demonstrated in the monkey. In other studies, a range of non-immunized animal sera was shown to have no inherent ability to neutralize male A. robustus venom in vitro.
Trypsin has been claimed a new and effective treatment for venomous snake bite. We found that significant inactivation of snake venom lethal potency occurred in vitro when trypsin was incubated with venom and subsequently injected into mice. Premixing of tiger snake venom (TSV) and trypsin just before injection did not significantly increase the survival rate of mice over that of controls injected with TSV alone. Trypsin injected 10 to 30 minutes after TSV injection did not increase the survival rate of mice compared with controls. Specific antivenom was effective as an antidote when there was a 10 minute delay after venom injection. There was varying susceptibility of different venoms to trypsin inactivation in vivo.
The treatment of snakebite could be simplified if the identity of the offending snake was more frequently known. A positive identification, which allows the use of a specific monovalent antivenom, probably occurs in less than 20% of cases. Recently published methods of venom detection (RIA and ELISA) take at least three hours to complete. We have developed a sandwich enzyme immunoassay (EIA) which is capable of detecting 0.5 ng of crude snake venom in about 90 minutes or 2 ng of crude venom in about 30 minutes. This substantial reduction in incubation times, while still retaining the sensitivity required, was due to the use of protein A purified rabbit IgG antivenom from hyperimmune serum and the enzyme horseradish peroxidase (HRPO). A rapid identification of the offending snake by this method may reduce the use of large-volume polyvent antivenoms, thus avoiding the clinical and economic disadvantages of such preparations. Other advantages would be an increased understanding of the clinical syndrome produced by the individual species of snake, and accumulation of data about the incidence of envenoming attributed to specific snakes.
The advantages of the pressure/immobilization technique as the first-aid measure for envenomation are discussed. The use of arterial tourniquets is no longer recommended in the management of any type of envenomation in Australia.
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