Snake Bite Envenomation

Created on Mon, 12/07/2015 - 13:30
Last updated on Thu, 12/07/2017 - 03:20

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Incidentally, envenoming is the process of being injected with toxic snake-juice. Envenomation  is systemic poisoning which arises as a consequence of this venom transaction. The terms are not interchangeable. 

Snake bite envenomation seems to be receiving an increased amount of attention in the recent CICM Fellowship exam papers. It has occurred three times since 2012:

Only in 2017 was the snake species specified (it was a brown snake, the species which accounts for the majority of lethal or lifethreatening snakebite events in Australia). Otherwise, the college were most interested in the clinical features (not specific to any particular reptile genus), the stereotypical laboratory findings , and the basic management rituals. Additionally, the 2015 question also asked about the specifics of using polyvalent antivenoms, the risks of administering them, and the way in which you might monitor for response to treatment. Chris Nickson's LITFL page on snake bites is also an excellent resource of rapidly available material. Specifically, he points to a marvellous MJA article which is the single most important reference for this chapter  (Isbister et al, 2013). This article by itself is probably enough to pass the abovementioned questions. For a resource specific to brown snake bites, Allen et al published an excellent paper in 2012.  If one were for some reason in need of greater detail, one could do no better than the three-volume "Venomous Animals and Their Venoms" by  Bücherl Buckley and Deulofeu (2013). Within Volume 1 ("Venomous Vertebrates") the discussion of snake venoms takes approximately three hundred pages.

Pharmacology of snake venom

  • Not a standard pharmacological solution, but rather a random suspension of lipids, proteins, enzymes and random reptile fluids. It is in essence a highly refined form of saliva, secreted from modified salivary glands. Even within the same species, there is significant regional variation in composition.

Clinical features and laboratory abnormalities resulting from snake venom toxicity

Local effects

  • Local pain, swelling and bruising (eg. brown snake bites)
  • Maybe myonecrosis (from black and tiger snakes)
  • Fang marks
  • Draining lymph nodes may be enlarged and painful

Systemic effects

  • Raised aPTT (with black snake bite) without significant bleeding
  • Nausea
  • Vomiting
  • Abdominal pain
  • Diaphoresis
  • Diarrhoea
  • Headache
  • Renal impairment

Major toxin syndromes

  • Venom-induced consumption coagulopathy (VICC)
    • Usually present on presentation
    • INR is usually so high that the lab refuses to report the actual figure (i.e. the PT is infintely prolonged). In "incomplete" VICC,  the INR is over 3.0.
    • aPTT is prolonged - at least over 100
    • Fibrinogen is low
    • Quantitative D-dimer is usually extremely high
    • Associated with a thrombotic microangiopathy: thrombocytopenia, microangiopathic haemolytic anaemia and acute renal failure (platelet count should be below 100)
  • Neurotoxicity syndrome
    • Evolves over hours
    • Descending flaccid paralysis
    • Classically, eyes are the first to go (ptosis, diplopia and blurred vision)
    • Bulbar involvement follows
    • Respiratory muscle paralysis and limb paralysis are the end stage
  • Myotoxicity syndrome
    • Evolves over hours
    • CK is normal on admission, but rises in the first 48 hours
    • Rhabodmyolysis is the major feature

Investigations:

  • CK (rhabdmyolysis)
  • Coags (DIC, or "venom-induced consumption coagulpathy) - INR >3.0, APTT > 100
  • FBC (DIC, looking for thrombocytopenia and red cell fragmentation)
  • Fibrinogen (DIC)
  • EUC (renal failure)
  • LFTs (hepatic injury)
  • Snake Venom Detection Kit

Management of snake bite envenomation

Decontamination

  • Pressure bandage to reduce systemic absorption
  • Immobilisation of the affected limb
  • Weirdly, ingestion of snake venom is actually quite safe, as the fragile enzymes which do all the damage are rapidly inactivated by stomach acid and duodenal proteases. One could quite literally drink a cup of it and remain well.

Enhanced elimination

  • There is nothing on offer here. The venom components are unlikely to be removed by dialysis or haemoperfusion.

Specific antidote:

Indications for antivenom

  • Coags or CK become abnormal
  • Neurological deficit develops
  • Cardiac arrest occurs (or, even sudden collapse without arrest)

The polyvalent snake antivenom

  • It is appropriate in the following circumstances:
    • Unsure which snake species was involved
    • SVDK not available
    • monovalent antivenom not available
    • The patient is deteriorating rapidly and there is no time to wait for a VDK result
    • the patient has been bitten by multiple different species of unidentified snakes.

The monovalent snake venom

  • Snake identification becomes important for this reason.
  • The Snake Venom Detection Kit is helpful, but it gets the species wrong one bite out of ten.
  • Choice of monovalent antidote is guided by:
    • Local knowledge of herpetology
    • Observation of characteristic toxidrome
    • Identification of the snake by the victim
  • One ampoule of antivenom is all that is required.
  • Using multiple doses is pointless - it does not speed recovery. Moreover, biochemistry confirms that there does not seem to be any active venom present in the patient after the administration of a single dose of antivenom.

Pre-treatment for polyvalent antivenom

  • Yes, the polyvalent vaccine is more likely to cause anaphylaxis.
  • No, that does not mean that everybody should be pre-treated with steroids and antihistamines
  • These days, one merely remains aware of the possibility, and keeps some adrenaline handy.
  • Management of a reaction to antivenom is identical to any stereotypical ALS response to anaphylaxis.
  • The risk of anaphylaxis is approximately 3-5% in Australia.
  •  Serum sickness occurs in about a third of patients given antivenom, after about 4-14 days.
    • influenza-like symptoms
    • fever
    • myalgia
    • arthralgia
    • rash

Monitoring of treatment response

  • You never know whether the antidoe is working. There are no guidelines for this.
  • It takes tme for some of the irreversible features to resolve (eg. it takes time to synthesis the coagulation factors which have been depleted)
  • Giving more antivenom will not improve the situation.
  • The empiric dose administered should be enough.
  • Resolution of nonspecific constitutonal symptoms can be used as an informal measure of success (i.e. the patient "feels better" in some nonspecific way)

Supportive management

  • Airway control and mechanical ventilation:  the predominantly neurotoxic bite is going to need a period of SIMV
  • Circulatory support  in case of significant haemodynamic collapse (it is unlikely unless the venom was cardiothoxic)
  • Sedation and analgesia
  • Renal replacement therapy particularly in the context of rhabdomyolysis
  • FFP and correction of coagulopathy is controversial, as it may be just as easy to wait for a resolution of the toxidrome.

Features and management specific to brown snake bites

This section addresses the needs of the time-poor exam candidate preparing to answer a detailed herpeto-toxicology question about brown snake bite,  such as Question 1 from the second paper of 2017.  The college wanted to simulate some sort of real life scenario; they asked the candidates to outline the advice they would offer to a junior colleague at a remote location who is trying to keep the victim alive until arrival of the retrieval team. Specific comments from the college included criticism of respondents who asked for TEG and intubation, ignoring the possibility that the tiny tural hospital has neither equipment nor expertise.

The venom itself is a mixture of presynaptic and postsynaptic neurotoxins and procoagulants. There is nothing myotoxic or nephrotoxic in the venom. This makes sense, as the brown snake evolved to poison small mammals which it would then eat immediately. There was no evolutionary pressure on this species to create something that kills kidneys over a period of days. Acute kidney injury is seen anyway because of thrombotic microangiopathy, which is a side-effect of the procoagulant venom.

Brown snake venom produces the following stereotypical effects:

  • Venom-induced consumpation coagulopathy (VICC): all of the clotting factors are depleted, fibrinogen drops to 0 and INR increases dramatically. Apparently this takes about 24 hours to resolve near-completely. Giving clotting factors may shorten this time- Brown et al (2009) observed that people were generally giving 4 units of FFP and 8 units of cryoprecipitate.
  • Haemorrhage from trivial injuries: for example, Allen et al (2012) found that 32% of the victims end up having haemorrhage from cannula sites.
  • Myotoxicity: this is usually a feature of envenoming by the king brown snake, Pseudechis australis  (Ponraj et al, 1996). Normal brown snake bites should not cause rhabdomyolysis or myoglobinuria; whereas the king brown snake venom can cause local myonecrosis at the site of the bite. How to tell whether your snake is royalty?  Apparently it is difficult even for snake afficionados. Apart from being a bit wider, the distinctions rest in subtle things like paired subcaudal scales on one and singles on the other. It would be unreasonable to expect the "junior colleague" from Question 1 to be able to confidently identify the reptilian enemy, and so it would be reasonable to instruct them that they may expect rhabdomyolysis.
  • Mild neurotoxicity: This is a possible consequence of the presynaptic and postsynaptic effects of the brown snake venom, but it is very rare. In the review by Allen et al (2012), only 1% of the patients (2 victims) had neurotoxicity: one developed ptosis, and the other had weird migratory cranial nerve signs including diplopia and bulbar weakness. Given that coagulopathy is a major problem here, any sudden onset neurological signs would probably need to be interpreted as an intracranial haemorrhage. You'd scan the head before putting things down to neurotoxicity.
  • Cardiovascular consequences: The VICC tends to create cardiovascular collapse with decreased cardiac output and severe hypotension (which in some human cases has concluded with cardiac arrest in the prehospital setting).  Tibballs et al (1992) were able to demonstrate this in a bunch of dogs they envenomed for science. The culprit appears to be the prothrombin-activating component of the venom, as all cardiovascular badness was prevented completely by premedicating the dogs with heparin. 
  • Thrombotic microangiopathy,  which appears to be unrelated to the VICC.  The microscopic clots which form everywhere in the process of VICC might be expected to have a cheesegrater-like effect on the endothlium of small vessels (like in TTP-HUS) but in fact the DIC has usually resolved by the time this micorangiopathy takes place. Isbister et al (2007) found that microangiopathic haemolytic anaemia tends to develop in about 13% of the victims, with the nadir of severe thrombocytopenia (platelet count less than <20 × 109/L) occurring around 4-5 days after the bite. The authors likened the effect to that of HUS-indicung E.coli, commenting that "it is conceivable that the venom (or a toxin in the venom) induces similar endothelial damage and initiates the thrombotic microangiopathy".

Specific management steps should include:

  • Urgent antivenom
  • FFP and cryoprecipitate to help correct coagulopathy more rapidly

ICU-level management should consist of the following supportive steps:

  • A - assess the need for airway protection and intubate the patient
  • B - there may be hypoxia; perform a CXR to assess pulmonary haemorrhage or pulmonary oedema 
  • C - haemodynamic instability is likely and hydration probably has merit if myotoxicity is going to develop - fluid resusictation should be vigorous.
  • D - analgesia is probably going to be required
  • E - electrolyte derangement may be present due to prehospital exposure (dehydration, this is 'Straya) and rhabdomyolysis
  • F - Renal replacement therapy may be indicated as acute kidney injury develops
  • H - Nonessential invasive procedures should be delayed until after the coagulopathy subsides
  • I - Antibiotics are not indicated

Question 1 from the second paper of 2017 asked about the possible causes of renal failure with brown snake venom, which is not classically nephrotoxic. Though the examiners complained bitterly about templated answers being used to mask the candidates' unfamiliarity with snake bites, one cannot help but note that in the absence of specific nephrotoxins the patient's renal failure could be due to any of the normal things which cause renal failure. These things are typically categorised as pre-renal, post-renal and intra-renal. With the exception of VICC-induced microangiopathy, the college list of differentials is certainly no different to a normal list of causes for renal failure in critical illness, featuring such favourites as "sepsis" and "ATN secondary to prolonged hypotension/arrest". In response, here is a classically organised list of plausible-sounding reasons for renal failure in a patient with a brown snake bite:

Causes of Acute Renal Failure
Following a Brown Snake Bite

Pre-renal

Intra-renal

Post-renal

  • Hypovolemia:
    • Haemorrhage
    • Dehydration in the outback
  • Redistribution of fluid
    • Sepsis
    • Aseptic SIRS, eg. anaphylaxis due to antivenom
  • Decreased cardiac output
    • Cardiac failure due to VICC
  • Renal microvascular obstruction
    • Thrombotic microangiopathy
  • Acute Tubular Necrosis
    • Vascular insufficiency (pre-renal)
    • Drug-related
    • Myoglobin (rhabdomyolysis)
    • Haem (haemolysis)
    • Sepsis
  • Upper tract obstruction
    • Renal haemorrhage due to coagulopathy
  • Bladder outlet obstruction
    • Clots due to haematuria (traumatic IDC insertion, coagulopathy etc)

 

References

Isbister, Geoffrey K., et al. "Snakebite in Australia: a practical approach to diagnosis and treatment." Med J Aust 199 (2013): 763-768.

Bücherl, Wolfgang, Eleanor E. Buckley, and Venancio Deulofeu, eds. Venomous Animals and Their Venoms: Venomous Vertebrates. Vol. 1. Elsevier, 2013.

Russell, Findlay E., and Harold W. Puffer. "Pharmacology of snake venoms." Clinical toxicology 3.3 (1970): 433-444.

Daltry, Jennifer C., Wolfgang Wüster, and Roger S. Thorpe. "Diet and snake venom evolution." Nature 379.6565 (1996): 537-540.

Allen, George E., et al. "Clinical effects and antivenom dosing in brown snake (Pseudonaja spp.) envenoming—Australian snakebite project (ASP-14)." PLoS One 7.12 (2012): e53188.

Brown, Simon GA, et al. "Clotting factor replacement and recovery from snake venom-induced consumptive coagulopathy." Intensive care medicine 35.9 (2009): 1532-1538.

Isbister, Geoffrey K., et al. "Thrombotic microangiopathy from Australian brown snake (Pseudonaja) envenoming." Internal medicine journal 37.8 (2007): 523-528.

Tibballs, J., et al. "The cardiovascular and haematological effects of purified prothrombin activator from the common brown snake (Pseudonaja textilis) and their antagonism with heparin." Anaesthesia and intensive care 20.1 (1992): 28-32.

Ponraj, Durairaj, and Ponnambalam Gopalakrishnakone. "Establishment of an animal model for myoglobinuria by use of a myotoxin from Pseudechis australis (king brown snake) venom in mice." Laboratory animal science 46.4 (1996): 393-398.

White, Julian. "Factor replacement for Australian snakebite coagulopathy: a re-evaluation?." (2009): Intensive Care Med (2009) 35:1503–1504