For obvious personal reasons in addition to academic curiousity (as well as the public benefit) I have several projects going on that investigate how regional variations in venom composition, even between populations of the same species, affect the relative neutralisation ability of antivenom. In one of our studies, we found profound variations in the venoms of Acanthophis species (death adders) and and the efficacy of the antivenoms.
Australia is the only country in the world that has snake venom detection kits. A swab from the bite site, blood, or urine allows the doctor to select the type of snake antivenom which may have to be used. Only one in ten cases of snake bite need antivenom because often the snake injects very little venom.
Antivenoms therefore should not be given unless there is evidence of significant poisoning. For example, in snake bite, signs of systemic poisoning such as nausea, vomiting, ptosis, etc., or positive laboratory findings such as coagulation defect. Fang marks alone are not an indication of antivenom. Likewise, after a Red-back spider bite, if the only problem is moderate local pain, then antivenom is not indicated at that stage.
Australian antivenoms are established as the safest in the world. Provided they are administered with appropriate premedication, there is no reason for them to be withheld, even if the patient has a past history of reaction to equine proteins. Such patients, eg. snake handlers who have suffered reactions in the past, have had minimal or no problems with repeat antivenom therapy after appropriate premedication.
Most antivenoms are given by the intravenous route. Skin testing with antivenom for allergy to antivenom is unreliable and waste of time. It may also delay urgent therapy.
It is wise to give premedication before most antivenoms. Patients should recieve 0.25 mg of adrenaline by the subcutaneous route (0.005 - 0.07 mg/kg for a child). The adrenaline should never be given intravenously especially in a normotensive patient. An antihistamine may also be given parenterally, bearing in mind it may have sedatory effects and may also cause hypotension. If the patient has a known history of reacting to antivenoms, then steroids should be administered. Antivenoms which are to be given intravenously are preferably diluted 1 in 10.
Note: The antivenom requirements of patients will vary considerably. Some patients with minimal envenomation will require no antivenom, whereas others may require multiple doses of antivenom.
Serum Sickness: Both the incidence and severity of delayed serum sickness may be markedly reduced by the administration of prednisolone, 50 mg (adult dose) for five days after the administration of antivenom.
Quantitity
How much snake antivenom should be held by hospitals?
The following is a suggested guide as to the quantity of antivenoms to be held.
Metropolitan and Regional Centres
1. Adequate antivenom to cover two serious cases of envenomations by the major snakes found in that State, ie. four ampoules of each monovalent antivenom
2. Except in southern Victoria and Tasmania, four ampoules of polyvalent antivenom should be held for the treatment of cases in which the snake has not been positively identified. In Victoria polyvalent antivenom is not required and a combination of tiger snake antivenom and brown snake antivenom can be employed when the identity of the snake has not been determined. In Tasmania, only tiger snake antivenom is required.
Small Centres and One Doctor Hospitals, etc. As a general rule, sufficient antivenom should be held to treat one serious case of snakebite. The decision is up to the local practitioner as to whether two ampoules of polyvalent should be held or two ampoules each of the appropriate monvalent antivenom. If a small centre treats a significant number of snake bites per year, the quantity of antivenoms should be increased. Alternately, if snake bite is rare in the area and a larger hospital can be reached within 30 minutes, then it is probably inappropriate to stock polyvalent antivenoms.
Note: The shelf life of antivenom is three years when stored protected from light at 2 degrees C to 8 degrees C. Antivenom should never be frozen!
Australian antivenoms and species covered
At present, one polyvalent and six monovalent Australian snake antivenoms are currently commercially available. These are all products of CSL Ltd made by immunising horses with increasing doses of specific snake venoms. The ability of the elicited antibody response to neutralise native snake venom is then regularly monitored. At appropriate intervals the horses are bled, the serum harvested, IgG purification followed by digestion into F(ab')2 fragments. As such they are among the best quality snake antivenoms in the world. Yet these relatively expensive pharmaceuticals do have some risk of evoking an adverse reaction such as anaphylaxis and serum sickness, are derived from animal products with a theoretical risk of transmitting infectious disease (although no cases have been recorded) and are not equally good at neutralising neurotoxic and procoagulant snake venom toxins.
Antivenoms - future prospects
The ideal antivenom will be cheap, have a long shelf life under variable storage conditions, will have a broad specificity, be orally active, very low to zero allergenicity, rapidly penetrate tissue compartments, have a high affinity for the clinically relevant toxins and will be synthetically derived to avoid the potential risks of human and animal products. As yet no available antivenom fits all these criteria!
Still some progress has been achieved. Sheep and rabbit immunoglobulins appear to be far less allergenic than equine IgG though the basis of these differences in immunoreactivity remain to be investigated. Rabbits may prove too labour intensive for large scale antivenom production and as yet only CSL Ltd's Sydney funnel web spider antivenom is made from rabbit IgG. Ovine IgG Fab fragment snake antivenoms produced by Therapeutic Antibodies Incorporated are also under investigation for use in Australia. It remains contentious whether Fab or F(ab')2 type antivenoms are most technically desirable.
Avian yolk immunoglobulin (IgY) based antivenoms had been suggested a decade ago as less expensive, safer and more robust than other animal antivenoms. An Australian collaboration claims great success in trialing its IgY antivenom for veterinary use. The safety and efficacy of this remains to be determined.
Recent success at engineering dust
mite allergens to disrupt undesirable IgE epitopes while retaining T cell epitopes suggests that anaphylactic and anaphylactoid reactions to animal immunoglobulins might be circumvented in the future. However, remarkably little is known of the immunogenicity of snake venom toxins. Improved understanding of antigen presenting cell function may assist in targeting the important venom antigens to optimal immunological pathways for the highest quality of antibody response. It may also assist the development of desensitising therapy for herpetologists, many of whom suffer from potentially lethal allergy to snakes and their venom.
Human antibody based antivenoms would seem ideal to reduce adverse reactions and the theoretical risk of animal diseases. However it should be noted that current human Ig preparations can occasionally cause significant adverse reactions. Further research is required. A collaboration between Cambridge Antibody Technologies UK, The Institute Pasteur in Paris and the Institute Butantan in Brazil has demonstrated neutralising anti-viper antibodies using phage display technology. Unfortunately this technology is, for now, impractically expensive. However, reports that human proteins can now be made in quantity in vitro using human cells suggest that an affordable, high affinity, human IgG snake antivenom may eventually be feasible.
Clinical problems have largely driven Australian venom research to date. Much remains to be done in this area. This includes improving paraspecific protection by different antivenoms, investigating the cause of sudden death due to the eastern Brown snake, snake venom vaccines for veterinary use, analysing the immunomodulatory actions of venoms, improving immunoassays of venom components and in vitro methods of antivenom potency testing.
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