You have received a phone call from a junior colleague at a remote location. A previously well 32-year-old male has presented with nausea and hypotension following a confirmed bite on his leg from a brown snake. A retrieval team will arrive in approximately three hours; until then your colleague is the only medical officer available.

a) Outline the telephone advice you would give them. Include guidance on what complications they might expect to arise and how to manage them. (80% marks)

b) Several days after arrival in your Intensive Care Unit (ICU) the patient develops oliguric renal failure. List the possible causes. (20% marks)

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College answer

a)                                                                                                                                  

  • Ensure patient is in an appropriate monitored area
  • Give face mask oxygen, obtain iv access. Fluid resuscitation if hypotensive.
  • Apply pressure bandage over the bite site and aim to cover entire leg. Splint limb and keep immobile.
  • Patient has features of systemic envenomation and should therefore receive appropriate antivenom, one vial is adequate dose. No requirement for premedication with adrenaline or steroids.
  • Ideally take baseline blood tests, including coagulation studies U&E, FBE, CK, LFTs.
  • Given the circumstances it would be reasonable to either release the pressure bandage after antivenom administration or keep it in place until the patient has been retrieved (Note to examiners – some mention of what to do with the PB expected, although either option acceptable)
  • Discussion with National Poisons Information Centre

Complications include:

  • Anaphylaxis to antivenom – manage by stopping infusion, airway management as indicated and fluid resuscitation. May require adrenaline – use with caution due to concern of raised blood pressure and potential coagulopathy.
  • Coagulopathy: - likely very high INR, undetectable fibrinogen
  • If no active bleeding does not require specific management other than antivenom. If severe or life-threatening bleeding, reasonable to give FFP after antivenom.
  • May develop severe hypotension or cardiac arrest. Manage according to basic ALS principles
  • Neurotoxicity and cardiotoxicity rare and mild with brown snake envenomation

        b)                                                                                                                                       

  • Potential causes of renal failure.
  • Thrombotic microangiopathy secondary to consumptive coagulopathy
  • Rhabdomyolysis
  • ATN secondary to prolonged hypotension/arrest.
  • Secondary sepsis
  • Transfusion mismatch

Examiners Comments:

 Many candidates ignored the setting of a remote location completely, and gave a management plan that was applicable to a tertiary centre (e.g., TEG and ROTEM; "intubate" without reference to the skill of the junior doctor, etc.).

 Some candidates appeared unaware of even the most basic aspects of snake bite management e.g., pressure immobilization, VDK, monovalent versus polyvalent etc.

 Many candidates used an ABCDE template which prioritized airway and breathing above the first-aid of snake bite; also, it resulted in not covering the coagulopathy aspects well enough.

The answer for the renal failure again seemed templated (pre-renal, renal, post-renal) and lacked context - there were very few references to the snake bite and antivenom as possible causes of renal failure

Discussion

The venom itself is a mixture of presynaptic and postsynaptic neurotoxins and procoagulants. There is nothing myotoxic or nephrotoxic in the venom. 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:

  • Pressure bandage
  • Splint limb
  • Urgent antivenom
    • Polyvalent or monovalent, depending on whether the species has been confidently identified
  • FFP and cryoprecipitate to help correct coagulopathy more rapidly (if available)

Distant back-of-Bourke management should consist of:

  • Immobilisation
  • Airway support
  • Basic blood tests
  • Vascular access 
  • Organisation of retrieval
  • Liason with Poisons Centre

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

  • A - assess the need for airway protection; intubate the patient if needed or if appropriate skills are available
  • 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 resuscitation 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

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 venom nephrotoxins the patient's renal failure could be due to any of the normal things which cause renal failure. And 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