Australian elapid snake envenomation in cats: Clinical priorities and approach

Abstract

Practical relevance:

No fewer than 140 species of terrestrial snakes reside in Australia, 92 of which possess venom glands. With the exception of the brown tree snake, the venom-producing snakes belong to the family Elapidae. The venom of a number of elapid species is more toxic than that of the Indian cobra and eastern diamondback rattle snake, which has earned Australia its reputation for being home to the world’s most venomous snakes.

Clinical challenges:

The diagnosis of elapid snake envenomation is not always easy. Identification of Australian snakes is not straightforward and there are no pathognomonic clinical signs. In cats, diagnosis of envenomation is confounded by the fact that, in most cases, there is a delay in seeking veterinary attention, probably because snake encounters are not usually witnessed by owners, and also because of the tendency of cats to hide and seek seclusion when unwell. Although the administration of antivenom is associated with improved outcomes, the snake venom detection kit and antivenom are expensive and so their use may be precluded if there are financial constraints.

Evidence base:

In providing comprehensive guidance on the diagnosis and treatment of Australian elapid snake envenomation in cats, the authors of this review draw on the published veterinary, medical and toxicology literature, as well as their professional experience as specialists in medicine, and emergency medicine and critical care.

Overview of elapid snakes in Australia

Australia is home to a large number of terrestrial snakes. Of the 140 species recognised, 92 possess venom glands.¹ With the exception of the brown tree snake, the venom-producing snakes belong to the family Elapidae. Elapid snakes possess two hollow, fixed, front fangs that are responsible for the delivery of venom. The mechanism of the bite is described by four phases: (i) the strike, (ii) opening of the mouth, (iii) closure of the mouth and (iv) injection of venom and retraction of the fangs.² The amount of venom injected depends on factors such as the species of snake, geographical location, sex, body size, season (early vs late) and biting behaviour (defensive or hunting).^3–8

Australia’s reputation for being home to the most venomous snakes is largely based on the late 1970s murine LD50 study of Broad et al.⁹ When injected subcutaneously into mice, the venom of 11 elapid species is more toxic than that of the Indian cobra (Naja naja) and the venom of 20 elapid species is more toxic than that of the eastern diamondback rattle snake (Crotalus adamanteus). The toxicity of Australian elapid venom, however, varies depending on the species envenomated.^10,11 Although the significance of mortality from elapid envenomation cannot be disputed, the relative susceptibility of cats to individual species is not well documented. As well as species susceptibility, the behaviour of the snake and the individual cat involved plays a role in determining the toxicity observed in the field.

The Australian elapids of clinical importance are grouped into five major categories: brown snakes (Pseudonaja species), tiger snakes (Notechis species), black snakes (Pseudechis species), death adders (Acanthophis species) and taipans (Oxyuranus species) (see box on page 1132).¹² Geographical distribution of the elapid species varies between the Australian states and territories, each being home to between three and 50 species.

Figure 1

With respect to Australian elapidenvenomated cats, brown snakes (a), tiger snakes (b) and black snakes (c) are among the most common offenders.

Despite the publication of identification keys, photographic guides and descriptions in the form of textbooks and websites, identification is not always straightforward, even with good herpetological knowledge.¹ Australians are reported to have problems identifying snakes correctly.^13,14 This may be due to use of common names that are inappropriately or regionally applied; colouration or other features that are similar between species or vary within a species; and changes in nomenclature that have not been updated in textbooks.

Venom components and activity

Snake venom comprises a highly complex mixture of a large number of proteins and peptides that may have enzymatic or non-enzymatic activity. There may be more than 100 individual protein and peptide components present in the venom of a given snake species, although the function of some of the minor components has yet to be elucidated. The individual components of elapid venom have a diverse array of activity in prey and non-prey species. Typically, the venom acts to immobilise the prey and start the process of digestion.

The most well studied components of elapid venom include prothrombin-activating enzymes, phospholipase A₂ and peptidic neurotoxins (which usually affect acetylcholine [ACh] release from motor nerve terminals).¹⁵ In some species of elapid, the disorienting and paralysing effects of the phospholipases and neurotoxins are supported by disruption of coagulation, with haemorrhage being a common feature of envenomation.

Enzymes acting on the coagulation pathway

Venom components that act on the coagulation pathway may be characterised as having either procoagulant or anticoagulant activity.¹⁵ Procoagulant venoms may be classified according to the site of their activity and include factor X activators, prothrombin activators (with or without the requirement for factor V) and thrombin-like enzymes (fibrinogenases).^16,17 The initial effect of these agents is procoagulant and this may subsequently result in consumption of fibrinogen and may be accompanied by depletion of clotting factors V and VIII. Venom-induced consumption coagulopathy (VICC) is recognised in man and may be either complete or partial. Near or total depletion of fibrinogen, and factors V and VIII, with an increased international normalised ratio and prolongation of the activated partial thromboplastin time (aPTT), characterises complete VICC, whereas partial VICC is characterised by limited depletion of fibrinogen and factor V but almost complete consumption of factor VIII. Interestingly, the amount of prothrombin present post-envenomation does not decrease below 60% of normal, and elimination or inactivation of the venom is hypothesised to account for the partial and transient reduction in prothrombin activity. Fibrinogen recovery is associated with resumption of normal clotting.^18,19

Phospholipases

The class I phospholipase A₂ enzymes of elapid snakes have both non-lethal enzymatic activity and potent toxic activity. The enzymatic and toxic or pharmacological active sites are located separately within the enzyme. Protein:protein interaction accounts for the specificity of enzyme activity, with the phospholipase A₂ enzymes binding to N-type proteins of neuronal cells and M-type proteins of muscle.^15,20

The phospholipases may be broadly characterised as haemotoxic, myotoxic, neurotoxic, non-toxic enzymatic (non-lethal) and non-toxic non-enzymatic. Inflammation, oedema and bactericidal effects may also be present (see box below).^15,20

Neurotoxins

The first neurotoxins to be separated by gel electrophoresis, bungarotoxins, were from the venom of the elapid Bungarus multicinctus (many-banded krait). The site of biological activity varies between the fractions isolated. The alpha (α)-neurotoxins are three-finger toxins that bind to nicotinic ACh receptors and these have been used extensively in a purified form for nicotinic receptor research.²¹ Postsynaptic binding of α-neurotoxins to ACh receptors contributes to the flaccid paralysis associated with some elapid envenomation. The beta (β)-neurotoxins have phospholipase A₂ activity and cause pre-synaptic depletion of synaptic vesicles after initially increasing miniature end-plate potentials. Hence a two-step mechanism of action of β-neurotoxin is responsible for irreversible pre-synaptic blockade.²⁰ In addition, the nerve terminal may undergo degeneration.

The major presynaptic neurotoxins of the Australian elapid species include notexin (Notechis scutatus), textilotoxin (Pseudonaja textilis), taipoxin (Oxyuranus scutellatus) and paradoxin (Oxyuranus microlepidotus).¹² Phospholipase A₂ enzymes may alternatively or additionally bind to the sarcolemma, causing ion gradient loss, calcium influx and muscle degeneration. This accounts for the myotoxicity associated with some elapid envenomations.

Lesser known proteins

In addition to the abundant, clinically important components of elapid venom, there are a large number of lesser known proteins that have a role in the immobilisation of prey species. These include proteinase inhibitors, c-type lectins and related proteins, growth factors, bradykinin-potentiating factors, natriuretic peptides, cysteine-rich secretory proteins, waprins, vespryns, L-amino acid oxidases, hyaluronidases and phosphodiesterases.

Study of the pharmacological effects of toxin components has resulted in important discoveries in physiology and therapeutics. For example, the discovery of bradykinin-potentiating peptides (from the pit viper Bothrops jararaca) provided insight for the development of angiotensin-converting enzyme inhibitors.²² Venom isolated from Dendroaspis angusticeps (green mamba, found in eastern Africa) contains a peptide structurally similar to natriuretic peptides and induces extreme vasodilation. The sudden decrease in blood pressure is likely to contribute to incapacitation of prey species. Dendrotoxin has also been isolated from the venom of the green mamba and it causes increased and sustained release of ACh at the motor end-plate by reversible blockage of voltage-gated potassium channels. Dendrotoxin has been used as an experimental tool to investigate the role of ion channels in specific neurons and synapses.²³ Cyclic nucleotide-gated channels play a key role in visual and olfactory sensory transduction, and isolation of pseudechetoxin from the venom of Pseudechis australis (Australian elapid king brown snake) facilitated investigation into the role of such nucleotide-gated channels. Sensory blockade may contribute to incapacitation of the target prey.

Clinical signs of envenomation in cats

The predominant activity of venom – neurotoxicity, myotoxicity or coagulopathy – will depend on the species of snake, season, diet and geographical location.^11,24–27

Early landmark studies

The observation that the clinical effects of many snake venoms vary in different species of animal was already established by the time that Kellaway²⁸ proposed the likely lethal dose of tiger snake (N scutatus) venom in cats (0.1 mg/kg). The apparent resistance to the coagulopathy induced by the black snake (Pseudechis porphyriacus) venom in cats compared with dogs had been reported as early as 1893.²⁹

These early experimental studies also documented the course of events following envenomation in cats. Vomiting occurred a short time (mins) after the subcutaneous injection of cats with tiger snake (N scutatus) venom.²⁸ Vomiting is a less commonly observed clinical sign in documented cases and this may be due to the cats being unobserved when they are envenomated.^30–34 When a lethal dose of tiger snake (N scutatus) venom is injected subcutaneously, respiratory distress is followed by weakness and paralysis, resulting in recumbency. Mydriasis is present simultaneously. Circulatory collapse and respiratory failure can result in the death of envenomated cats.²⁸ The presence of hypothermia, flaccid paralysis and dyspnoea has been associated with a poorer prognosis.^31,32 Similar clinical signs (generalised weakness, hindlimb paresis and mydriasis) are reported following injection of sublethal doses of N scutatus venom, although anorexia and muscle tremor on exertion are also present. Anorexia may be the most persistent of the clinical signs.²⁸

Common clinical signs

There is considerable overlap in the constellation of clinical signs associated with envenomation of cats by different elapid species (Table 1), and the snake responsible for envenomation may not be available for identification. Common clinical signs documented in individual case reports and case series include flaccid paralysis, weakness, mydriasis, decreased pupillary light reflex, tachypnoea and dyspnoea.^{30–34,37,38}

Table 1

Clinical signs and laboratory changes associated with envenomation in cats

	Tiger snake	Brown snake	Black snake*
Flaccid paralysis	√	√
Weakness	√	√	√
Anisocoria	√
Mydriasis	√	√
Bite-site swelling			√
Pigmenturia	√	√*	√
Elevated CK	√		√
Prolonged clotting times	√ (vicc)	√ (vicc)	√ (VICC or anticoagulant)
Haemolysis	√ (mild, transient)	√*	√ (marked)
Anaemia			√

Clinical signs for tiger snake and brown snake envenomation are based on the published literature, unless otherwise indicated

There are no published reports of black snake envenomation in cats. Likely clinical signs are based on unpublished reports and extrapolation from other species

†

R Malik, 2017, personal communication

‡

According to brown snake venom ELISA

CK = creatine kinase; VICC = venom-induced consumption coagulopathy

Further difficulty arises in the eastern states of Australia given the potential for cats with tick paralysis to present with clinical signs that can be difficult to distinguish from those associated with elapid snake envenomation. Both result in lower motor neuron signs; however, paresis and paralysis is generally slower in onset in cases of tick paralysis, taking 2 or more days to result in recumbency. Tick paralysis is also not associated with coagulopathy, haemolysis, pigmenturia or marked elevations in CK.

Interestingly, transient signs have been reported in cats injected with a lethal dose of tiger snake (N scutatus) venom and this may account for cats being able to return to their home environment some hours after envenomation.³⁹ Indeed, cats may be presented as late as 3 days after envenomation, and the average duration of time between bite and presentation is longer in cats compared with dogs.^31,32,40

Clinical pathology findings

Abnormal clinical pathology findings may include haemoglobinuria, haematuria, myoglobinuria and increased serum CK activity.^31–34 Many in-house routine biochemistry panels do not incorporate CK activity and this analyte should be included in the diagnostic testing in a weak cat when there is a suspicion of snake envenomation. Clotting times may be normal or prolonged, although clinical coagulopathies have not been reported.^33,34,40 Peak plasma concentrations of venom are obtained 1–5 h after subcutaneous injection of tiger snake (N scutatus) or brown snake (P textilis) venom.³⁹ In contrast, venom may be detected in urine as soon as 1 h post-injection and persist for as long as 44 h.³⁹

Necropsy findings

Necropsy findings are similar in all cats fatally envenomated by elapid snakes. There may be haemorrhage and oedema at the bite site, acute hyaline degeneration of skeletal and myocardial muscles, pulmonary congestion, small intestinal congestion and haemorrhage, acute renal tubular necrosis and irregularly shaped glomeruli with an expanded Bowman’s space containing proteinaceous material.^28,31,32,38 Evidence of procoagulant effects was reported in the epicardium and myocardium of one cat.³⁸ Immunohistochemistry in the same cat demonstrated positive staining for N scutatus venom within the myocardium, skeletal muscle and throughout the lung.³⁸

Diagnosis of snake bite

Diagnosis of elapid snake envenomation is not always easy (see box on page 1136) and requires the use of a combination of history, clinical signs, local knowledge and laboratory tests.

Laboratory tests

Laboratory tests are used to confirm the diagnosis of suspected envenomation, particularly when clinical signs are vague or equivocal. It is recommended that human patients with suspected envenomation are observed in hospital and undergo serial laboratory tests for up to 24 h.⁴⁴ Abnormalities in neurological examination or blood tests are reportedly detected in nearly all cases of severe envenomation within 12 h.⁴⁴ No similar guidelines on when envenomation can be ruled out have been published for animals.

Laboratory tests to rule in or out snake envenomation in animals generally include clotting times, serum creatine kinase (CK) activity and ideally a snake venom detection kit (SVDK).

Clotting times

VICC is caused by the procoagulant toxins present in many types of elapid venom, and the anticoagulant toxins in black snake venom. Thus, prolonged clotting times are a common feature of elapid snake envenomation, but have different pathophysiology.

A review of the clinical features of tiger and brown snake envenomation found that only 36% of cats had prolonged clotting times compared with 69% of dogs.³⁴ An earlier study showed a minimal effect on coagulation times, and no increase in fibrin degradation products in seven cats with snake bite.⁴⁰

Figure 2

Tiger snake (note the brown appearance of this individual!) brought home by the cat of one of the authors (LA)

There are several reasons why cats may not have prolonged clotting times when tested. Firstly, cats have an intrinsically higher resistance to the neurotoxic effects of tiger snake venom (reported lethal dose is 0.1 mg/kg in cats vs 0.03 mg/kg in dogs), and there may be a similar influence in terms of the venom’s effects on coagulation.^28,41 The smaller body size of most cats compared with dogs, however, would presumably nullify this effect in most instances. Interestingly, the effects of tiger snake venom on dog and cat coagulation appear to be similar in in vitro studies.⁴⁰

Secondly, a likely delay in presentation after envenomation may mean that sufficient time has elapsed for clotting factors to be resynthesised, thereby normalising coagulation times.

A third potential explanation is that cats, being generally more agile than dogs, may receive a lower dose of venom when bitten. Cats may also be more likely to withdraw once bitten, rather than continue to fight with the snake, decreasing the risk of multiple bites.

Creatine kinase

CK elevation in humans can be a reflection of injury to the brain, cardiac myocytes or skeletal muscle cells. In veterinary medicine, different subtypes of CK are not routinely assayed. Elevated CK activity is generally regarded as a reflection of skeletal muscle injury. However, many unwell cats without musculoskeletal or cardiac disease will have somewhat elevated CK activity.⁴⁵

The venom of several species of elapid snakes, most notably tiger and black snakes, contains phospholipase A₂ myotoxins. In human patients, myotoxicity is defined as local or generalised myalgia with an increased CK activity, usually over 1000 IU/l.⁴⁶ In cats, the CK level is often normal at admission, increasing over 24–48 h to 100,000 IU/l or higher. The authors regard a six-figure CK result in the absence of obvious trauma or severe hypokalaemia as virtually diagnostic for tiger snake envenomation.

Snake venom detection test

The Commonwealth Serum Laboratories’ SVDK (Figure 3) is used for in vitro detection of snake venom using urine, serum, plasma, blood or a bite-site swab as the diagnostic spec-imen.⁴⁷ Urine and bite-site swabs are the most reliable samples in humans. In cats, urine is the sample most often tested. Due to the very small size of elapid snake fangs and the lack of local reaction to the bite, bite sites are seldom found on cats unless they are bitten in a sparsely haired region (Figure 4).¹ The SVDK product leaflet states that the use of whole blood may result in erroneous reactions and an invalid assay. Free haemoglobin and, in humans, rheumatoid factor in whole blood can cause nonspecific binding, which increases the likelihood of an incorrect result, despite additional washing, which is recommended if blood is used.^47,48

Figure 3

Snake venom detection kit. (a) Each box contains three individual test kits. (b) Kit contents showing detailed instruction sheet, test kit (white T-shaped holder with a negative control, positive control and six test wells), and three sample diluent bottles – one for each test performed (yellow lid), chromogen solution (blue lid) and peroxide solution (grey lid)

Figure 4

Snake bite wound visible on the face of a dog, where the hair is shorter

The purpose of the SVDK is to help clinicians select the appropriate antivenom with which to treat a clinically significant envenomation. While it can be a valuable tool in reaching a diagnosis, especially in an animal with nonspecific clinical signs, the SVDK cannot be used as the sole test to rule in or out envenomation or to determine the need for antivenom. The results of the SVDK (Figures 5 and 6) must be interpreted in the light of the clinical signs and laboratory data, and knowledge of local snake geographical distribution.

Figure 5

Positive tiger snake result obtained with a snake venom detection kit

Figure 6

Negative result obtained with a snake venom detection kit

The SVDK can detect venom concentrations as low as 0.01 ng/ml, which is far below the concentration required to cause clinical signs.

In one study, the incidence of false-positive results in 25 cats and 50 dogs presented for conditions unrelated to snake envenomation was zero.⁴⁹ While this is a relatively small sample size, the study supports a specificity of 100% when using urine as a test sample.

False-positive results Positive SVDK results have been documented in human patients without clinical or laboratory signs of envenomation. Possible explanations for this include false-positive test results, subclinical envenomation, or cross-reaction with the venom (or saliva) of mildly or non-venomous snake species.⁵⁰ A positive SVDK result without clinical signs supportive of envenomation is not regarded as an indication for administration of antivenom in human medicine.

False-negative results A negative SVDK result does not mean that clinically significant envenomation has not occurred.

A negative result in a cat with clinical signs consistent with envenomation (eg, see case notes on page 1132) may be due to testing prior to venom absorption, delayed presentation or, counterintuitively, extremely high levels of venom in the sample being tested. The SVDK detects free, unbound venom. If a urine sample is collected prior to mobilisation of venom from the bite site and excretion into the urine, a negative result will be obtained, but the cat may still have clinically significant envenomation.

One small experimental study examined the timing of peak plasma and urine venom levels in cats injected with tiger or brown snake venom at doses ranging from subclinical to lethal.³⁹ This study found that, at sublethal doses, the amount of venom in the urine did not reach the sensitivity of the SVDK reliably until 8 h post-injection. A possible confounding factor in this study is that some cats were noted to be markedly hypotensive and so venom mobilisation from the subcutaneous injection site is likely to have been significantly slower than in a conscious and moving cat.

By 48–72 h after envenomation, all venom will have either been bound to target tissues or excreted in urine. The cat will still have clinical signs attributable to the envenomation, which may include a myopathy or neuromuscular dysfunction, but antivenom will not aid treatment. In the above-mentioned experimental study the serum venom level was below the level of detection in all envenomated cats still alive after 24 h.³⁹ At this time, the SVDK will return negative results, as there is no free venom in the urine.

A further, though rare, possible explanation for a negative SVDK result in an animal that has been envenomated is the ‘hook effect’.⁵¹ At extremely high venom concentrations, the antibodies in the test well are saturated by the test sample and the labelled conjugate cannot bind. It is then washed out during the test and no colour change is observed, resulting in a negative test result.

Antivenom treatment

Antivenoms (Figure 7) are preparations of antibodies produced from the serum of donor animals, usually horses or alpacas, injected with repeated, progressively increasing doses of snake venom. Antivenom does not, with the exception of some of the pre-synaptic neurotoxins, reverse the clinical effects of venom. It acts to prevent unbound circulating venom binding to target proteins and worsening any clinical effect.

Figure 7

Stocks of commonly used snake antivenom

Historically, it was believed that coagulopathy indicated that antivenom was required. The previous recommendations were to continue giving antivenom until clotting times normalised, resulting in human and animal patients receiving up to 10 vials or more of antivenom.⁵² More recent research in human patients has shown that one vial of antivenom (the amount originally recommended by the manufacturers) is sufficient to treat envenomation by the most commonly encountered Australian snakes in almost all cases.⁵³

Types of antivenom

As there are multiple toxins contained in snake venom, the antivenom is a polyclonal antibody mixture. If the donor animal is immunised with venom from a single species of snake, the antivenom is referred to as ‘monovalent’. If the donor animal is exposed to the venom of more than one species of snake, or if monovalent antivenoms are mixed, the antivenom produced is referred to as ‘polyvalent’. There are five monovalent elapid snake antivenoms available in Australia: used for tiger, brown, black, death adder and taipan snake venoms.

Antivenom selection

In regions where there is only one species of venomous snake – for example, Tasmania has only tiger snakes – antivenom selection is straightforward. In areas where there are multiple species of venomous snake, often with similar clinical signs of envenomation, antivenom selection can be more difficult. Ideally, monovalent antivenom is given to reduce the potential for an immunological reaction; however, there is the risk of administering the wrong antivenom if snake identification is incorrect.

In the absence of definitive snake identification, the appropriate antivenom may be chosen with the aid of an SVDK. The test takes 30 mins to run and, for reasons discussed earlier, may not always yield a positive result. The SVDK is also expensive, at a wholesale cost of around A$450 for a pack of three tests at the time of writing, and has a shelf-life of 12 months. Many veterinary practices that see only the occasional snake envenomation case do not stock the kit.

In areas where there are two or more venomous snakes, most practices will stock at least some polyvalent antivenom. At the clinic of one of the authors (LA) in Victoria, tiger or brown snakes are responsible for most snake bite cases, with a rare case of red-bellied black snake (Pseudechis porphyriacus) envenomation also seen (tiger snake antivenom is effective for this envenomation). The clinic stocks polyvalent tiger–brown antivenom, which enables treatment of all cases of envenomation prior to definitive diagnosis if necessary.

An additional reason to use tiger–brown polyvalent antivenom in preference to monovalent brown snake antivenom in areas where both snakes occur is the cross-reactivity between tiger snake venom and brown snake venom. In a study of tiger snake envenomation, 10% of people diagnosed using a serum venomspecific enzyme immunoassay had initially tested positive to brown snake using the SVDK.⁵⁴

Indications

Tiger and brown snake venoms contain a procoagulant protein and envenomation can result in VICC. In vitro studies have shown that antivenom can prevent the procoagulant effect of these venoms. However, for coagulation times to return to normal after a VICC, consumed factors must be resynthesised.⁵² In clinical cases, it takes 12–18 h after antivenom administration for coagulation times to return to normal. Antivenom is, therefore, not effective in resolving a VICC, and mildly prolonged coagulation times alone after tiger or brown snake envenomation are not necessarily indications for antivenom administration in human medicine.⁵² In dogs, and probably also in cats, brown and tiger snake envenomation is associated with a severe junctionopathy. Tiger snake envenomation may also result in a severe myopathy (see page 1142). For this reason, coagulopathy in a cat due to VICC is still regarded as supportive evidence for clinical envenomation by a tiger or brown snake, and antivenom is indicated.³⁴

Black snake envenomation causes an anticoagulant coagulopathy in humans and dogs, and is likely also to have this effect in cats. Antivenom will neutralise the venom and rapidly resolve the coagulopathy in black snake envenomation.⁵⁵ A clinically significant coagulopathy is, therefore, an indication for antivenom in black snake envenomation.

Administration

The administration protocol for antivenom is outlined in the ‘summary of initial treatment’ box on pages 1144–1145.

Hypersensitivity and anaphylaxis

Antivenom is a foreign protein (raised in horses or camelids) and, as such, has the potential to elicit a hypersensitivity reaction in the recipient animal.

In vitro studies have shown that adrenaline administered prior to antigen challenge will attenuate an anaphylactic reaction; however, adrenaline is not recommended as a routine prophylactic in animals or people receiving antivenom.⁵⁶ Administration of adrenaline is commonly associated with adverse effects such as tachycardia and hypertension. In coagulopathic animals, hypertension may increase the risk of intracranial haemorrhage. Subcutaneous adrenaline has also been associated with long-term or permanent haircoat changes and skin sloughing at the site of the injection, possibly due to the profound vasoconstriction that occurs.

Premedication with corticosteroids or antihistamines has not been shown to decrease the incidence of hypersensitivity reactions. Premedication with adrenaline, antihistamines and corticosteroids is no longer recommended for human patients in Australia.⁴⁶

Treatment of mild hypersensitivity reactions involves stopping the infusion of antivenom and restarting at a slower rate (perhaps 25% of the initial rate) 20–30 mins later once clinical signs have resolved. The recommended treatment for severe allergic reactions and anaphylaxis is outlined in the box above. It is interesting to note that despite the well-accepted recommendation that adrenaline is the first-line treatment for anaphylaxis, the only evidence to support its use comes from a canine ragweed anaphylactic shock model.⁵⁸ In this study, adrenaline hastened resolution of hypotension only when given as a constant rate infusion (CRI); intramuscular (IM) or intravenous (IV) adrenaline was not effective in hastening resolution of hypotension.

Supportive care

No studies have evaluated the efficacy of supportive care measures in envenomated patients. Animals that have been bitten by a snake often have severe multisystem abnormalities requiring attention, in addition to the need for venom neutralisation. Cardiovascular support with IV fluids, respiratory support with supplemental oxygen or mechanical ventilation, nutritional support, analgesia and nursing care in recumbent animals may all be necessary.

Animals with elapid snake envenomation can deteriorate extremely rapidly. An ambulatory patient can progress to respiratory arrest within minutes. Cats presented with suspected envenomation must be triaged immediately, and then kept under constant observation until clinically significant envenomation has been ruled out.

Assessment of patient ‘ABCs’

The cat is assessed along the lines of all critically ill patients, with a check of the ‘ABCs’ followed by a more thorough primary survey involving all body systems.

Airway

Pharyngeal and laryngeal muscles are affected by neurotoxins. The effect of the toxins at the neuromuscular junction results in decreased or absent gag responses and swallowing reflexes, leaving the animal unable to protect its airway. Respiratory and gastrointestinal secretions can accumulate in the oropharynx causing airway obstruction.

Positioning the animal in a head-elevated position can assist, as can regular cleaning or suctioning of the mouth if the cat tolerates this intervention. In some instances, an endotracheal tube or tracheostomy may be needed to maintain a patent airway.

Venom, antivenom or other medications can induce nausea and vomiting, and animals with decreased gag reflexes due to pharyngeal weakness are at increased risk of aspiration pneumonitis and airway obstruction from regurgitation and/or vomitus. Recumbent animals and those that appear nauseous (eg, cats with increased salivation) may benefit from the use of prokinetic and antiemetic medications.

Breathing

The basic functions of breathing (or, more correctly, ventilation) are two-fold: obtaining oxygen and eliminating carbon dioxide (C0₂).

All of the major elapid snake groups have neurotoxins in their venom, although generalised skeletal muscle paralysis occurs most commonly after tiger and brown snake envenomation. Neurotoxins cause progressive paralysis of skeletal muscles, including the intercostal muscles and the diaphragm, leading to weakness and hypoventilation (ie, insufficient movement of gas into and out of the alveoli to allow adequate gas exchange).

Hypoventilation in animals breathing room air leads to hypoxaemia, which initially will improve with oxygen supplementation. Hypoventilation also reduces the elimination of C0₂, causing respiratory acidosis. Supplementing with oxygen does nothing to hasten the elimination of C0₂ or treat the resulting respiratory acidosis. Blood gas analysis or end-tidal C0₂ determinations will reveal elevations in both venous and arterial C0₂ levels: if C0₂ levels are elevated, the animal is hypoventilating.

Table 2

Indications for ventilation

Hypoxaemia despite supplemental oxygen	SPO₂ <93% Moderate: PaO₂ <80 mmHg Severe: PaO₂ <60 mmHg
Hypercapnoea	PaCO₂ >55 mmHg PvCO₂ >60 mmHg ETCO₂ >50 mmHg
Unsustainable effort of breathing	Cat not resting or grooming (subjective assessment); open-mouth breathing; sustained increase in respiratory rate; marked abdominal effort and/or excursions

PaO₂ = partial pressure of oxygen in arterial blood; PaCO₂ = partial pressure of carbon dioxide in arterial blood; PvCO₂ = partial pressure of carbon dioxide in venous blood; ETCO₂ = end-tidal carbon dioxide concentration; SPO₂ = oxygen saturation

Decreased oxygen and increased C0₂ levels stimulate the respiratory centres of the brain and normally a cat will initially increase its respiratory rate and/or effort in an attempt to normalise blood gas values. Due to these compensatory responses, these cats may exhibit only mild changes in their blood gas values and an oxygen saturation (SP0₂) >93% (using pulse oximetry), and they can therefore be assessed to be ventilating adequately. However, the extra work involved in maintaining these normal blood gas levels is not sustainable: these animals will eventually develop respiratory fatigue and suffer respiratory arrest. In almost all cases, animals that arrest due to prolonged respiratory effort are unable to be resuscitated. Immediate intubation and ventilation will fail to stop the progression to irreversible cardiac arrest.

As paralysis progresses, supplemental oxygen will no longer be sufficient to maintain adequate blood oxygen concentrations and respiratory acidosis will worsen. Respiratory muscle paralysis may mask physical signs of dyspnoea and, unless active monitoring of ventilation is performed, a severely affected cat may be mistaken for a sleeping one.

Pulse oximetry is the most readily available method of objectively and non-invasively measuring oxygenation. Pulse oximetry readings are generally fairly accurate (± 5%) between saturations of 70% and 100%. Any cat with a pulse oximetry reading <93% requires supplemental oxygen.

Arterial blood gas analysis is the gold standard method for assessing and monitoring respiratory function; however, the only peripheral artery that can reliably be sampled in cats is the femoral artery. To restrain a cat for arterial sampling, and then to ensure haemostasis afterwards, is often very stressful and will cause a dyspnoeic animal to deteriorate, possibly to the point of an arrest. Arterial blood sampling is, in the authors’ opinion, not a procedure that ought to be attempted in unstable cats. Arterial sampling is also contraindicated in coagulopathic animals. Venous blood gases are suitable to assess C0₂ concentrations and thus the adequacy of ventilation.

Circulation

No cardiac toxins have been identified in elapid venom. The neurotoxins and myotoxins affect striated skeletal muscles and, although generalised acute skeletal and myocardial hyaline degeneration has been described at necropsy examination in a small number of cases, cardiac changes do not appear to significantly affect myocardial function.

A syndrome of sudden collapse with possible cardiac arrest occurs in up to one-third of people with brown snake envenomation, and occasionally in those with tiger snake envenomation.^46,62 The collapse is likely to be due to vasodilation-induced hypotension after the release of endogenous mediators, rather than a primary cardiac event, although it is also possible that there may be a direct effect of phospholipase A₂ in venom that causes vascular smooth muscle relaxation.⁶³

A syndrome of collapse and apparent recovery is seen in dogs with massive tiger snake envenomation. These animals progress to paralysis and VICC within 30 mins, and death rapidly ensues in the absence of aggressive treatment including antivenom. This syndrome has not been reported in cats but is likely to occur. It is probable that affected cats are simply found dead.

Recumbency – nursing care

Animals may be recumbent due to myopathy or failure of neuromuscular transmission. Appropriate nursing care, including use of soft, padded, moisture-wicking bedding and frequent position changes, is required for animals that are recumbent. Due to their small size, cats on appropriate bedding are unlikely to suffer from pressure ulcers.

Myopathy – respiratory support and analgesia

Rhabdomyolysis occurs as a result of direct muscle cell injury by phospholipase A₂ and possibly other muscle toxins in tiger, taipan and black snake venom. It causes pain, which can be severe, as well as muscle weakness. Significant myolysis releases muscle cell components including myoglobin, CK and potassium into the circulation. Free myoglobin is normally bound to haptoglobin and α₂-globulin. Once the binding capacity of these molecules has been exceeded (at levels greater than 0.05–0.15 mg/l in humans) excess myoglobin is filtered by the kidneys and brown discolouration of the urine (myoglobinuria) develops.⁶⁴

Tiger snake envenomation can result in a profound myopathy (Figure 8); CK levels of 220,000 IU/l have been reported in a dog,⁶⁵ and 805,100 IU/l in a cat.³⁸ Red-bellied black snake envenomation appears to cause a mild to moderate myopathy in dogs, with CK levels of 5040 IU/l and 3621 IU/l documented in two case reports.^42,43 In the one report of coastal taipan envenomation in a dog, the peak CK level was 6360 IU/l.⁶⁶

Figure 8

(a,b) Hospitalised cat recovering from a tiger snake bite. This was the second in the cat’s second summer living in a new suburb of Melbourne built on reclaimed swamp land, the favoured habitat of the tiger snake. The cat has recovering myopathy, hence being slouched in the food bowl

Animals with myopathy should have their serum potassium concentrations monitored. Cats with serum potassium concentration >7.0 mmol/l are at risk of fatal cardiac arrhythmia.

Local reactions causing regional swelling are reported in people after black and tiger snake envenomation,⁴⁶ and in dogs after black snake envenomation.⁶⁷ It is possible that snake bite-site reactions also occur with tiger snake bites but are not recognised because of the haircoat, or because pain is mistakenly attributed to systemic myopathy.

Muscle weakness in severe rhabdomyolysis may manifest as recumbency and inability to ventilate adequately. Despite not having neuromuscular effects, these animals can require respiratory support, including mechanical ventilation (see box on page 1141).

Analgesia is indicated in animals with myopathy. Because rhabdomyolysis is a risk factor for acute kidney injury (AKI), opioids are the safest option; non-steroidal antiinflammatory drugs (NSAIDs) cannot be recommended in this setting. In cases of severe pain, adjunctive analgesics such as ketamine, lignocaine and α₂-adrenoreceptor agonists may be indicated.

Prevention of renal injury

No nephrotoxin has been identified in elapid snake venom. Despite this, AKI or renal failure is a documented complication of envenomation in both humans and animals,^43,46,68 and there are understood to be two mechanisms by which this occurs (see box). In human medicine, the risk of AKI is regarded as low, unless the CK activity exceeds 15,000–20,000 IU/l; however, in dehydrated or acidaemic patients AKI can occur with levels as low as 5000 IU/l.⁶⁹

Ensuring renal perfusion through the use of IV fluids is the mainstay for preventing AKI secondary to myoglobinuria (see box). Moderate volume expansion, if tolerated by the patient, induces diuresis to aid clearance of myoglobin from the renal tubules. Isotonic crystalloids at rates of up to 5 ml/kg/h are used. Close attention is required to ensure that the cat does not suffer fluid overload.

Other therapies recommended to prevent heme protein-induced renal tubular injury include the use of mannitol for its volume expanding and potential free-radical scavenging properties and chelation. In animal models, chelation with deferoxamine was protective.⁶⁴ Although of theoretical benefit, no clinical data on the use of deferoxamine in myoglobinuria exists for humans or cats.

Myoglobin is more toxic to renal tubular cells if the urine pH is less than 6.5.⁶⁹ Clinical studies have not, however, shown any difference in renal outcomes for people treated with or without bicarbonate. As there is no convincing evidence to support bicarbonate use, and because it can complicate the monitoring of both acid–base balance and serum sodium levels, it is not recommended.

Blood products

The rationale for using blood products in cats is to provide red blood cells when clinically significant anaemia is present and to provide fresh clotting products in coagulopathy. There are currently no feline blood banks in Australia and, in most instances, fresh whole blood is the only blood product available.

The venom of red-bellied black snakes contains haemolysins and can cause marked haemolysis and subsequent anaemia in dogs.^42,43,67 A review of envenomation of human patients by these snakes did not report haemolysis or anaemia as clinically significant effects;⁵⁵ whether cats would have clinically significant haemolysis and anaemia is unknown.

In patients with a procoagulant venom coagulopathy, antivenom is indicated and will result in normalisation of coagulation times. In patients with clinically significant VICC after venom neutralisation, additional coagulation factors may need to be provided by way of blood transfusion to hasten normalisation of coagulation times.⁷⁰ Blood products must only be given once venom neutralisation is complete (ie, after antivenom has been given).

Nutritional support

Nutrition is an important part of the care of any hospitalised cat. Ideally, nutritional support is provided within a week to an animal eating less than 75% of its resting energy requirements, and within 3 days to an animal that is anorexic. All treatments, however, must be assessed in the light of the potential for adverse effects – and nutrition is no exception. Cats without a gag or swallow reflex are at increased risk of aspiration if they are given early enteral nutrition, especially if they are also recumbent. For this reason, it may be prudent to delay nutrition for 24–48 h in cases that are clinically improving, rather than risk aspiration. Parenteral nutrition may be required in cases of prolonged anorexia in cats with decreased gag reflexes.

Antibiotics

Infection secondary to elapid snake envenomation is very rare and the use of prophylactic antibiotics is not indicated. A bite-site reaction may occur after black snake envenomation but this is a chemical cellulitis in most instances. Should an infection develop, culture and susceptibility testing is indicated prior to starting any antibiotic treatment.

Table 3

Clinical assessment of the ‘ABCs’

	A: Airway	B: Breathing		C: Circulation
		Oxygenation	Ventilation
Specific attention to:	Pharyngeal obstruction by secretions or vomitus Pharyngeal dysfunction secondary to paralysis	Pulse oximetry, arterial blood gases	Arterial or venous blood gases, end-tidal CO₂*	Perfusion parameters⁺ Blood pressure
Possible intervention(s):	Suction Anaesthesia and intubation	If SPO₂ or SaO₂ <93%: give supplemental oxygen	If PvCO₂ >60 mmHg or ETCO₂ >50 mmHg: ventilation is indicated	IV fluids Warming

Most capnographs require a patient to be intubated

†

Mucous membrane colour, capillary refill time, heart rate, pulse character

SPO₂ = oxygen saturation; SaO₂ = haemoglobin saturation; PvCO₂ = partial pressure of carbon dioxide in venous blood; ETCO₂ = end-tidal carbon dioxide concentration; IV = intravenous

Outcomes

If there are no financial constraints, and access to 24 h care is available, the prognosis for cats with snake envenomation is good. Poor prognostic indicators in envenomated cats are similar to those noted in all critically ill cats: hypothermia, flaccid paralysis and dyspnoea.^31,32

observational studies show that administration of antivenom is associated with improved outcomes. one study reported a 91% survival rate in cats treated with antivenom, compared with 66% in cats not given antivenom.⁷¹ it is unclear from this study what, if any, other treatment was given to cats that did not receive antivenom. A 1984 survey found that 90% of cats treated with antivenom survived compared with 70% of cats not receiving antivenom.³² other studies have reported 66%³³ and 89%³¹ survival when antivenom treatment was used.

A 2014 study found that 84% of 45 cats treated for tiger or brown snake envenomation survived, and survival improved to 97% of 39 cats once those euthanased for financial reasons were removed from analysis.³⁴ Clearly, for most veterinary patients, costs of treatment are an important factor in the care provided – animals with snake envenomation are no exception. Antivenom is expensive, retailing at A$900 or more per vial in many clinics at the time of writing. Supportive care including 24 h monitoring and ventilation may also be required, adding significantly to the costs of treatment.

Key Points

The Australian elapids of clinical importance are brown snakes, tiger snakes, black snakes, death adders and taipans. Species identification is not always straightforward.

There is considerable overlap in the constellation of clinical signs associated with envenomation of cats by different elapid species. Common clinical signs include flaccid paralysis, weakness, mydriasis, decreased pupillary light reflex, tachypnoea and dyspnoea.

Laboratory tests are used to rule in or out snake envenomation and generally include clotting times, serum CK activity and, ideally, use of an SVDK.

The purpose of the SVDK is to help clinicians select the appropriate antivenom, which acts to prevent unbound circulating venom binding to target proteins and worsening any clinical effect.

Cats presented with suspected envenomation should be assessed along the lines of all critically ill cats, with a check of the ‘ABCs’ followed by a more thorough primary survey involving all body systems.

If there are no financial constraints, and access to 24 h care is available, the prognosis for cats with snake envenomation is good.

Footnotes

Supplementary material

Video of a cat presented with brown snake envenomation displaying signs of flaccid paralysis. The cat has a very slow palpebral reflex, the inability to withdraw the tongue into the mouth and a slow, weak withdrawal in response to pinching the toes of the hind leg. Video courtesy of Simon Lewin.

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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