Risks and realities of single vial antivenom recommendations for envenoming by Australian elapid snakes

In reply: We note incorrect assertions in the comments by Isbister and colleagues regarding our article on single vial antivenom recommendations for elapid envenoming in Australia.1

They state that we assigned the single dose recommendation solely to the study conducted by Johnston and colleagues.2 However, we specifically indicated that this study was a summarised presentation of a longitudinal study — the Australian Snakebite Project — that “concluded that one vial of antivenom was sufficient to effectively treat envenoming by all taxa of Australian elapids”.1

Isbister and colleagues cite the Australian Snakebite Project as their sole evidence base, although evidence‐based medical practice is based on a triad of evidence, of which clinical trials or other formal clinical research represent only one‐third.3

They also object to our criticisms about applying in vitro venom measurements using enzyme‐linked immunosorbent assay (ELISA) and cited the in vitro measurement of venom–antivenom complexes to support their claim that a single vial of antivenom provides a concentration “at which every venom molecule is bound to at least one antivenom molecule”. They use the cited research2 to emphasise that: “Serial measurement of venom concentrations using enzyme immunoassays in patients with snake envenoming demonstrated complete neutralisation after any dose”. By citing studies that rely almost exclusively on venom component detection with enzyme immunoassays, this suggests that they erroneously assert that the fate of a broad array of components in a given venom can be confidently determined within the confines of static immunological sampling. Australian elapid venoms contain a diverse array of components (often numbering in the hundreds),4 and not all medically significant snake venom components generate clinically effective precipitating or neutralising antibody.5 It is therefore most unlikely that the antibodies included in the conjugate used in ELISA correspond to the plethora of medically relevant toxins. Limitations of ELISA include its unproven validity for measurement of in vivo pharmacokinetics of numerous venom components that have unknown individual and combined metabolism in vivo, as well as the venom components rendered undetectable after becoming bound in vivo. In vitro assays also are incapable of assessing other important factors that influence the severity of envenoming; for example, venom sequestration and the greater susceptibilities of envenomed patients with medical comorbidities relevant to envenoming, including cardiovascular disease, renal insufficiency or chronic kidney disease, seizure disorders and diabetes.

Isbister and colleagues also state that we “provide no citations to support [our] contentions, other than single cases and opinion”. Unfortunately, they miss the basis of our comments that advocated a patient‐centred approach contingent on factors in addition to and not excluding formally procured clinical evidence. These factors include individual patient morbidities, clinical evolution and previous observations.2,4 We also emphasised the unpredictability of delivered venom volumes and the need to effectively manage all envenomed patients, including outliers. They also comment that we “argue for just one non‐evidence‐based solution — higher doses of antivenom”, when we actually stated: “We do not suggest that multiple vial doses should routinely be used for all Australian snakebite patients requiring antivenom, but the patient‐centred factors and biomedical reasons outlined here support our contention that recommendations for a uniform single vial treatment are inappropriate”.1

They also miss our stated concerns when they comment: “A coroner's case in which a person died after three vials of antivenom is strangely cited as highlighting concerns that a single vial is insufficient”. By citing the tragic coronial examples, we emphasised that a single vial of antivenom would very likely be insufficient to treat these severely envenomed patients.

Isbister and colleagues state that national guidelines recommend provision of one vial each of brown snake and tiger snake antivenoms in “most snake envenoming cases in Australia”, and emphasise the polyvalency of Australian antivenoms. While the former minimises the antivenom volume, and the latter is to some extent true, the manufacturer still recommends provision of the correct antivenom for a given species of Australian elapid, as do we. This increases the likely therapeutic benefit and probably reduces the risks to the patient; when there is persistent doubt and the envenoming has occurred in a locale with sympatric species other than brown snakes and tiger snakes (eg, Queensland), provision of polyvalent antivenom is preferable because it contains standardised antibody titres that equal a vial of each monovalent antivenom used in Australia.4,5