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

Antivenom dosage for Australian elapid envenoming should be decided by clinical evaluation of individual patients

Snakebite is arguably the most important type of envenoming, both worldwide and in Australia, but evidence‐based management remains unclear and controversial. This is particularly evident in Australia, where it has been advocated that antivenom dosing should be limited to a single vial,1 an opinion that is commonly questioned among physicians treating snakebites. Conducting standardised clinical research on envenoming is challenging, particularly in countries like Australia, where numbers of envenomed people are relatively low and scattered geographically. Globally, snakebite particularly affects the rural poor in developing nations, where surveillance, let alone model clinical research, is problematical. Antivenom remains the cornerstone of management for snakebite, supplemented by other tools such as intensive care medicine, mechanical ventilation and haemodialysis. Antivenom use worldwide is complicated by variability in quality, availability and dosing.

Determining a reasonable dose

What is a reasonable dose for Australian snake antivenoms? Does one minimal dose suffice for every situation and for bites for all species? Perhaps we should first ask why we use antivenoms. Surely we aim to reduce both morbidity and mortality, and it is arguably the latter that is most important in determining dose, even though the vast majority of snakebite patients in Australia will survive. However, there is no clearly established therapeutic window in which the dosage is well defined, thereby ensuring that most patients will be effectively treated (clear benefit) with reduced likelihood for adverse reactions and side effects (minimised risk). Snakebite fatalities in Australia result from a catastrophic pre‐hospital event, often a cardiac arrest, or as a consequence of systemic pathophysiological effects manifest at initially sub‐lethal levels at or after initial hospital presentation.1,2,3 In the former situation, antivenom is unlikely to be available and dosing is therefore less relevant. However, in the latter setting, antivenom is often a core treatment, but the severity of an evolving envenoming may not be easily determined, either by clinical examination or laboratory testing. For example, defibrination coagulopathy often occurs rapidly and may not be caused by vast amounts of circulating venom. Once the patient is defibrinated, coagulation testing cannot determine the ultimate clinical severity of the envenoming. Early assessment of severity of neurotoxicity and myotoxicity may also not be reliably predictive relative to the precise time when antivenom should be optimally administered.

A study describing 11 years (2005–2015) of snakebite data1 concluded that one vial of antivenom was sufficient to effectively treat envenoming by all taxa of Australian elapids. These antivenom dosage recommendations were based on enzyme‐linked immunosorbent assay (ELISA) of serially tested clinical samples (eg, blood from envenomed patients) or samples from rodents injected with venom, presumably in order to quantify circulating venom and venom bound with antibody.4,5 It is arguable that this method inaccurately determines a true neutralising dose in humans, because:

• the enzyme–immunoglobulin conjugate detection of venom is limited by the antibody population linked in the conjugate, and venom components have varying antigenicity; this may generate incomparable ratios of conjugate antibody, meaning that some medically important toxins may not be accurately or proportionally detected;
• ELISA provides no information about the in vivo neutralisation of medically important toxins because it only detects what is present in the tested sample that can bind to the antibodies present in the immunoconjugate, and thus only offers a static window viewing a small part of the dynamic and animated landscape (eg, the multiple targeted physiological functions and organ systems) of the envenomed patient; and
• there are very few data on the pharmacokinetics of tissue‐bound toxins and their extent of susceptibility to antivenom action, and the clinical importance of potentially sequestered venom components.

These factors, along with other characteristics of ELISA,6 mean that caution is necessary when evaluating antivenom dosing recommendations that are significantly based on this type of in vitro assay. Longitudinal studies of snakebite envenoming, such as that by Johnston and colleagues,1 provide important information, but recommendations for management require a comprehensive evidence base derived from the combined evaluation of the best external clinical evidence, individual clinical experience and expertise, and patient values and expectations.7,8

Moreover, direct clinical concerns about the single vial recommendation emphasise the need in some patients for significantly larger doses of antivenom.9,10,11 In Australia, snakebite victims manifest severe envenoming in perhaps 15% of cases.12 Mirtschin and colleagues13 presented evidence of Australian elapid venom yields, of which the maximums were many times the average used to calculate venom‐neutralising units per vial of antivenom. Inadequately treating patients with particularly high venom loads exposes them to unnecessary risk and decreases the likelihood of a positive outcome. For example, for an envenomed patient with pre‐existing medical comorbidities or older people or young children who are envenomed by a large amount of injected venom, the single vial recommendation may be a “precariously narrow therapeutic strategy”.8 The severity of envenoming is also unpredictable because of the marked variability of injected venom volume and individual venom sample properties that can be influenced by geographic origin, ontogeny, as well as individual genetic factors. Medically important venom components may proportionally vary, and some venom components may act synergistically, or/and antagonistically.2 For example, some insular tiger snake (Notechis scutatus) populations (eg, on Chappell Island and Kangaroo Island) and some mainland specimens can produce venom volumes far greater than average reported yields. This was recognised by the antivenom manufacturer that recommended initial multiple vial antivenom doses for serious envenoming by snakes from insular populations.2,9,14 Even some envenoming by Australian elapid species (eg, red‐bellied black snake [Pseudechis porphyriacus]) that most authorities accept can be treated with a single vial of antivenom may sometimes require greater amounts of antivenom in order to effectively treat the seriously envenomed patient.15

Recent coronial findings

Two recent coronial investigations of fatal tiger snake (N. scutatus) envenoming highlight these concerns.16,17 These cases involved a 70‐year‐old woman who received multiple bites and a 27‐year‐old man who received a prolonged bite from a large (1.5 m) tiger snake that had to be forcibly removed. The first patient was severely envenomed and developed defibrinating coagulopathy and neurotoxicity. Pressure bandage immobilisation was applied 1 hour after the bite; about 2–3 hours post‐bite she received two vials of tiger snake antivenom but further deteriorated and was given an additional vial 6.5 hours later. Unfortunately, she died in the early evening, less than 24 hours after being bitten. An autopsy revealed massive bleeding; an early antemortem blood sample detected a tiger snake venom level of 697 ng/mL.16

The second patient was also severely envenomed, and pressure bandage immobilisation was applied within minutes after the bite. Following Poisons Information Centre advice, he was provided with one vial of tiger snake antivenom about 1 hour after the bite. He developed severe defibrinating coagulopathy, myotoxicity and neurotoxicity, was transferred to a tertiary hospital and suffered an acute kidney injury. Later that evening, a determination was made that “there was unlikely to be any benefit from further antivenom administration”, but a vial of brown snake antivenom was provided early the next morning. The patient died shortly thereafter.17 One of the physicians who cared for him queried whether the single dose recommendation was a failed strategy given the tragic outcome.17 The coroner's conclusions included reiteration of a consulted clinical toxinologist's comments that “in treating an envenomed patient we need to successfully treat the ‘outlier’ case, not the ‘median’ case”, and the coroner stated that “in light of [the patient's] death, the current recommendation to administer one ampoule of antivenom needs refinement”.17 The assessment of the first case by clinical toxinologists found that two vials as an initial dose was definitely justified.16 It is arguable whether additional antivenom would have had therapeutic benefit for this patient, but providing it earlier is highly desirable because this could conceivably neutralise sequestered venom as it is absorbed from the bite site and may therefore bind circulating venom toxins as they enter the vascular system.2,5,11 However, a single vial of antivenom would clearly be insufficient for patients with envenoming similar to these examples.

Conclusion

Fully addressing the biomedical and clinical concerns about the single vial assertion is beyond the scope of this article, but the Australian medical community should be aware that there is no consensus agreement that one vial of any Australian snake antivenom is all that is ever required for significant Australian elapid envenoming. Unlike many pharmaceuticals, there is no evidence that higher doses of antivenom are likely to result in dose‐related mortality. 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. Each envenomed patient should be individually assessed and provided with adequate antivenom in response to the envenoming severity and their individual clinical needs.