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Bite Me!An Overview of AustralianSnakebite Envenomation
Paul Harris
Introduction
Australia has a lot of dangerous creaturesA lot of these are venomousA lot of these venomous creatures are snakesA lot of these venomous snakes look a bit similarA lot of these similar looking, venomous snakeshave potentially lethal bites and different treatmentsA lot of this makes managing them all a bit tricky
Contents of PresentationEpidemiology of snake bite in WASnake ClassificationComposition of Snake VenomPhysiology of NMJ and Coagulation CascadeAction and clinical picture of envenomation fromdifferent snake speciesPractical management of snake biteVenom detection and anti-venomsSummary
Australian Poison CentreBites/Stings Information
Spiders: 54%5-10,000 bites/yearMostly Red Back spider bites (<20% requiring specific treatment)Funnel Web spider bites (<50/yr)Necrotic Arachnadism (<100/yr)Paralysis Ticks (very common but paralysis very few)
Insects: 38%Ants, bees, wasps
Marine: 4%Box Jellyfish (<50/yr)Blue-ringed Octopus (10/yr)Venomous fish stings (Stonefish <10/yr)
Snake Bite InformationAustralian Poisons Centre:
1,000 – 3,000 cases per year = 3%Up to 200 requiring anti-venomNot a notifiable diseaseSutherland SK & Leonard RL. MJA 1995;163:616-618
World Health Organisation Data:Global mortality 50-100,000 hospital deaths / yearSignificant chronic disability in survivors
Physical handicap (necrosis, amputations)Systemic disease
Size of the ProblemDespite advances in the past 20 years with first-aid, venomdetection, supportive care and the use of anti-venom, thenumber of snakebite fatalities appears to have risen
White J. Emergency Med 2000;12:204-6
Between 1982 – 1992, 1.8 deaths per yearSutherland SK. MJA 1992;157:734-739.
Between 1992-1994, 3.7 deaths per yearSutherland SK, Leonard RL. MJA 1995;163:616-8
Epidemiology ofSnake Bite in Perth
Admissions for suspected snake bite to the Perth adultteaching hospitals, 1979 to 1988
Jelinek A. et al. Med J Aust 1991 155;(2):761-499 definite bites, 193 cases total
53 envenomations (3 in snake handlers)30 equivocal envenomationsDugite commonest snake bite (often coagulopathy only)Tiger and Gwardar common
36% of snake genus identified by venom detection kitsAll brown or tiger snake genus
At least 5 fatalities in last 10 years
Epidemiology ofSnake Bite in Perth
Use of Anti-venom:RPH:46 patients received anti-venom34 patients definitely envenomedSCGH:15 patients received anti-venom13 patients definitely envenomedFH:11 patients received anti-venom11 patients definitely envenomed
Snake ClassificationKingdom: AnimaliaPhylum: ChordataSubphylum: VertebrataClass: ReptiliaOrder: SquamataSuborder: Serpentes
Serpent Superfamilies
Henophidia:Boas, pythons andrelatives
Typhlopoidea:Blind snakes
Xenophidia:Colubridae (back fanged)Elapidae (front fanged)Hydrophiidae
Australian Species86 species of elapids33 species of hydrophiidae seasnakes2 species of acrochordidae seasnakes11 species of colubridae15 species of boas31 insectivorous blind snakes178 in total
Australian Snakes
25% of world land snakes = venomous70% of Australian land snakes = venomous
200 species of elapids, worldwide86 of these are specific to Australia20 of these are deadly12+ are potentially dangerous
Elapid Land Snakes of Australia
Brown snakesBlack snakesTiger snakesTaipansDeath adders
All ‘orrible
Snake VenomVenom is a substance which is capable ofproducing toxic reactions when introduced intoanother animalPurpose:
Incapacitates preyAids digestion of preyDeterrent to predators
50% snake bites are dry bites (no venom injected)
Snake Venom Toxicity
Standard measure = LD50 in miceVarious routes of administrationNumber / weights of test animalsVenom binding to lab glasswareMilking may not produce in vivo venom compositionQuantity of venom important
Australia has dubious distinction of holding mostdangerous snakes in the world (18/25):
Inland Taipan LD50 = 0.025mg/Kg (250,000 mice, 100 men)Common Brown snake = 0.053mg/KgTaipan = 0.099mg/Kg
Composition ofSnake Venom
Enzymes:PhospholipasesPhosphodiesterasesAmino acid oxidasesAcetylcholinesteraseProteolytic enzymesArginine esterasesNucleosidasesHyaluronidase
PeptidesNeurotoxinsCytotoxinsMyotoxinsCardiotoxinsDisintegrins
Snake Venom ToxicityLocal effectsSystemic effects:
NeurotoxicityPre- and post-synaptic
HaemotoxicityMyotoxicityNephrotoxicity(Cardiotoxicity)
Neuromuscular Junction:Summary
Interchange between somatic nerve ending and muscularend-plateNerve synthesises Acetylcholine and stores it withinvesiclesNerve stimulation causes vesicle migration to nervesurface, rupture and ACh release into cleftACh receptors open post-junctional voltage gated Na+
channelsNa+ influx initiates skeletal muscle contractionACh detaches from receptor and is destroyed by acetylcholinesterase
NMJ MorphologyMotor neurones (group α fibres) run from ventral horn of spinalcord (monosynaptic)Branches repeatedly on muscle approach = motor unitMyelin sheath lost and replaced by Schwann cell coverNerve separated from muscle by 20nm junctional cleftNerve and muscle held in tight alignment by basal laminaMuscle layer corrugated into primary and secondary cleftsACh receptors on cleft shoulders (5 million per junction)Na+ channels exist deep within the clefts
NMJ: Nerve Action PotentialNerve action potential begins with sodium propagationdown axon = saltatory conductionThis depolarising voltage opens Ca2+ channelsCa2+ influx into cell causes ACh release into synaptic spacevia mobilisation of vesiclesECF [Ca2+ ] controls quantal release of AChCa2+ release is limited by Ca2+-activated K+ channelsCa2+ entry explains post-tetanic potentiationCalcium channels (P-type and L-type) responsible for AChrelease
NMJ: Calcium ChannelsVoltage dependent P channels are found only at nerveterminalsLocated immediately adjacent to active zonesTargeted in Eaton-Lambert SyndromeAntagonised by bivalent inorganic cations eg Mg2+
Explains rationale behind Mg2+ use in pre-eclampsiaNot affected by calcium channel blockers, which blockL-type channels? Prolonged n.m block with non-depolarising agents andcalcium channel blockers
NMJ: Synaptic Vesicles
2 pools of vesicles:VP1 = reserve storeVP2 = readily releasable store
Calcium docks to vesicle wall and causes ACh exocytosisMost vesicles fuse with release sites (VP2 stores)SNARE protein mediated (soluble N-ethylmaleimide-sensitive attachment protein receptors)
Synaptobrevin = vesicle proteinSyntaxins = plasma membrane proteinsSynaptotagmin = neuronal calcium receptor bridge
NMJ: ACh Release
NMJ: Acetylcholine Receptor
Mature / junctional form:2 α, β, δ and ε sub-unitsε = shorter open times, high-amplitude channel currents
Immature / extra-junctional form:2 α, β, γ and δ sub-unitsγ = long open times, low amplitude channel currents
Receptor = 250,000Da molecular weightα units = ACh binding sitesAnchored to end-plate membrane by protein = rapsyn
ACh Receptor
NMJ: Electrophysiology ofNeurotransmission
ACh receptor normally closed by approximation of sub-unitsACh binds both α sub-units to open channelCations flow down concentration gradients:
Influx: Na+, Ca2+
Outflux: K+
Anions excluded from channel
Ion current depolarises muscle membraneEach quantum of ACh opens 500,000 channels (picoamps)Non-depolarising blockers competitively block this action
Neurotoxicityß-Neurotoxins
Highly specific pre-synaptic calcium channel blockers (P-type)Inhibit vesicle availability irreversiblyMultiple agents from different species:
Single chain: Notexin (tiger snake) Pseudexins (black snake) Acanthoxin (death adder)
Multi-chain: Taipoxin, Taicatoxin (taipan)Textilotoxin (brown snake)
All phospholipase A2 inhibitorsa-Neurotoxins
Non-lethal post-synaptic acetylcholine receptor antagonists“curare-mimetic” agents
Coagulation Cascade
Role of Clotting FactorsFactor I: Fibrinogen
Activates fibrin clotFactor II: Pro-thrombin
IIa activates factors I,V,VII,XIII, protein C, plateletsFactor III: Tissue factor
Co-factor for VIIaFactor IV: Calcium
Required for clotting factors to bind phospholipidFactor V: Pro-accelerin, labile factor
Co-factor of X, forms pro-thrombinase complexFactor VI: Defunct
Role of Clotting FactorsFactor VII: Stable factor (cothromboplastin)
Activates IX, XFactor VIII: Anti-haemophilic factor
Co-factor of IX, with which it forms the tenase complexFactor IX: Christmas factorFactor X: Stuart-Prower factor
Activates II, forming pro-thrombinase complex with VFactor XI: Plasma thromboplastin antecedent
Activates XII, IX and pre-kallikreinFactor XII: Hageman factor
Activates pre-kallikrein and fibrinolysisFactor XIII: Fibrin-stabilising factor
Cross-links fibrin
Role of Clotting Co-factorsVon Willebrand Factor:
Binds VIII, mediates platelet adhesion
Pre-Kallikrein: Activates XII and self; Cleaves HMWK
High Molecular Weight Kininogen (HMWK):Supports reciprocal activation of XII, XI and pre-kallikrein
Fibronectin:Mediates cell adhesion
Anti-thrombin III:Inhibits IIa, Xa and other proteases
Fibrinolysis
Role of Clotting Co-factorsProtein C:
Inactivates Va, VIIIaProtein S:
Co-factor for activated protein C (inactive bound to C4b)Protein Z:
Mediates thrombin adhesion to phospholipids, degrades XPlasminogen:
Converts to plasmin, lyses fibrin and other proteinsTissue plasminogen activator, urokinase
Activate plasmina2-antiplasmin
Inhibits plasmin
HaemotoxinsFibrinogen clotting enzymesFibrinogen degrading enzymesPlasminogen activatorsProtein C activatorsActivators of factors V, IX, X and prothrombinAnticoagulantsGIIb/IIIa receptor antagonismComplete defibrination can be seen in <20minutesProfound secondary haemorrhagic effects
Australian ElapidsGroup 1:
Eastern Brown snakeWestern Brown snake(Gwardar)DugitePeninsula Brown snakeSpeckled Brown snakeIngram’s Brown snake
Eastern Brown SnakePseudonaja textilis
Gwardar (Western Brown)Pseudonaja nuchalis
DugitePseudonaja affinis
Speckled Brown SnakePseudonaja guttata
Brown Snake VenomLeading cause of snakebite deaths throughout Australia
White J. Toxicon 1998;36:1483-1492.
Coagulopathy, renal failure and haemolytic anaemiaEarly deaths from shock and ?coronary thrombus
Tibballs J et al. Anaesthetics and Intensive Care 1989;17:466-469.
Tibballs J & Sutherland SK. Anaesthetics and Intensive Care1992;20:33-37.
Johnston M et al. MJA 2002; 177:646-649.
Paralysis and neurotoxicity incredibly rare
Brown Snake VenomVenom-induced activation of coagulation cascadeBrown snake venom contains a factor X-like protein thatactivates prothrombin in the presence of factor V, calciumand phospholipid.Leads to production of thrombin and consumption offibrinogen (i.e. consumption coagulopathy).
Decreased fibrinogen and platelets (sometimes)
Raised INR, APTT, FDPsOuyang C et al. Toxicon 1992;30:945-966.
Australian ElapidsGroup 2:
Common Tiger snakeBlack Tiger snakeWestern Tiger snakeLowlands CopperheadHighlands CopperheadPygmy CopperheadRough scaled snakeBroad-headed snakePale-headed snakeStephen’s Banded snakeEastern Small-eyed snake
Black Tiger SnakeNotechis ater
Mainland Tiger SnakeNotechis scutatus
Perth’s Tiger Snake
CopperheadAustrelaps superbus
Rough Scaled SnakeTropidechis carinatus
Broad Headed SnakeHoplocephalus bungaroides
Pale Headed SnakeHoplocephalus bitoquatus
Stephen’s Banded SnakeHoplocephalus stephensi
Eastern Small Eyed SnakeRhinocephalus nigrescens
Tiger Snake VenomVenom-induced activation of coagulation cascade
Rapid onset, factor V-like prothrombin activator
Isbister et al. Pathology 2002;34(6):588-590.
Neurotoxicity and paralysis
Slow in onset (up to 24 hours)
Associated with rise in creatine kinase
Descending flaccid paralysis
Anti-venom arrests progression but not reversible
Gavaghan CF & Sparkes G. Emerg Med 2003;15:497-499.
Australian ElapidsGroup 3:
Mulga (King Brown snake)Butler’s MulgaCollett’s snakeRed-bellied Black snakeSpotted / blue-bellied Black snake
Mulga (King Brown)Pseudechis australis
Red-Bellied Black SnakePseudechis porphyriacus
Collett’s snakePseudechis colletti
Blue-bellied Black SnakePseudechis guttatus
Black Snake VenomMild anti-coagulant effect but NO pro-coagulation
Normal fibrinogen and FDPsMildly raised INR, APTT
MyolysisCauses renal failureLocal swelling and necrosis at bite site
ParalysisVariable extent
Possible direct cardiotoxin with Mulga envenomation
Australian ElapidsGroup 4:
Common TaipanInland Taipan (fierce snake)
Group 5:Common Death AdderDesert Death AdderNorthern death Adder
Common TaipanOxyuranus scutellatus
Fierce Snake (Inland Taipan)Oxyuranus microlepidotus
Death AddersAcanthophis antarcticus, A. praelongus,A. pyrrhus
Other Elapid Snake Venoms
TaipansAggressive snakes with highrate of envenomationSimilar spectrum of toxicity totiger snakes
Activation of coagulationcascadeFactor V-like prothrombinactivationNeurotoxicity and progressiveflaccid paralysisMyotoxicity with raised CK
Death AddersNeurotoxicity
Potent post-synaptic blockadeNo CK rise
Paralysis:Reversed with anti-venomTemporarily reversed withneostigmine
No effect on coagulation cascadeNo myolytic toxinLittle M et al. MJA 1998;169: 229-30
Limitation of DataExtensively studied:
Common death adderMainland tiger snakeCoastal taipanMulgaEastern brown snake
Lethal and not studied:Black headed death adderNorthern death adderDesert death adderHighland copperheadIngram’s brown snakeBroad headed snakeStephen’s banded snakeButler’s snake
Clinical Manifestations of Snake Bite
Local effects:Local necrosisOedema
Systemic effects:Anti-haemostatic and thromboticCoagulopathyProgressive paralysisShock, hypovolaemiaDirect cardiac toxicityRhabdomyolysis, acute renal failure
Management of Snake BiteFirst aid:
Pressure-immobilisation principle (lymphatic spread)Pressure bandage over entire limbImmobilisation of limb and whole patientSutherland SK et al. Lancet 1979;1:183.
Do not wash snake bite areaAim of first aid is to delay absorption of venom frombite site until the patient is in a facility that canadminister adequate doses of anti-venom if required
Sutherland SK & Leonard RL. MJA 1995;163:616-620.
Hospital ManagementFirst aid and non-removal of PIBTransfer to appropriate facility
Clinical expertise, laboratory facility, sufficient anti-venomAssessment of likely envenomation
Coagulation, neurological examination, respiratory functionEnvenomation is a clinical decision, not from venom detection kits
HistoryGeographical area, snake description, bite characteristics
Lab tests:Coagulation, CK, U&Es, myoglobinuria
Anti-venomAncillary therapy
Snake Species DetectionSnake captured or correctly identifiedGeographical locationLocal and systemic effectsPresence or absence of paralysisCoagulopathy (defibrination or anti-coagulation)Snake venom detection kits
ELISA test (affinity-purified venom specific antibodies)Urine / bite site / bloodDetects 2.5ng/ml venom in 25min
Australia has only commercially available test in worldSutherland SK & Leonard RL. MJA 1995;163:616-620.
VDK
Differences in Snake VenomBrown:
Life threatening coagulopathyParalysisThrombocytopenia
Black (including Mulga):No pro-coagulants in Mulga (anticoagulant toxin only)ParalysisMyolytic toxinsPossible cardiotoxin (Mulga)Less toxic but high volume
Differences in Snake VenomTiger snake:
Pro-coagulantParalysisMyolytic toxin
Taipan:Profound paralysisPotent pro-coagulantMyolytic toxin
Death Adder:Paralysis – commonCoagulopathy - rare
Anti-venomFab fraction of immunised horse serumFirst utilised in 189721 labs produce anti-venom worldwidePowerfully immunogenic to humans but more costeffective because of high yieldLiquid or lyophilised preparationMono-specific: Safer, smaller dose, species dependentPoly-specific: Higher risk of reaction, species independent
Anti-venom
Types available:Death adder (6,000u/vial: $1,582.25)Brown snake (1,000u/vial: $381.96)Black snake (18,000u/vial: $1,963.14)Taipan (12,000u/vial: $2,395.49)Tiger snake (3,000u/vial: $480.78)Sea snake (1,000u/vial: $1314.61)Polyvalent (40,000u/vial: $2,621.96)
Amount standardised to neutralise in vitro averageyield of venom for each snake
Indications for Anti-venomShockSpontaneous systemic bleedingIncoaguable bloodParalysisAcute renal failure or myoglobinuriaExtensive, progressive local swelling
Especially in digits or fascial compartments and necrotic venom
Anti-venoms all highly immunogenicControversy over use of adrenaline pre-medication
Anti-Venom Adverse Effects
Amount required highly variable depending on degree ofenvenomationEquine serum:
Risk of anaphylaxis highViral transmission possibleAnaphylactoid reactions with other equine serum
Complement fixationDelayed serum sickness
Anti-Venom Hypersensitivity1978 – 2003: 17 anti-venom adverse reactions
Polyvalent: 6Brown: 4Tiger: 3Black: 3Death Adder: 2Taipan: 0Sea snake: 2 minor
No deaths
Ancillary Therapy
Thorough supportive care required to maintaincardiovascular, respiratory and renal function whiledefinitive treatment (anti-venom) is given.ICU managementIntubation and ventilationCVVHF / haemodialysisControversies:
Use of blood productsAdrenaline and anaphylaxis precautions before anti-venomRole of fasciotomy in local necrosis
SummarySnakes are rare cause of venomous creature bites but carry highmortality if incorrectly treatedUp to 50% bites may be dry (no venom)6 broad categories of dangerous snakesIdentification of snake difficult and may be avoidableMixed neuro- and haemo-toxicity most serious effectsEnvenomation and need for anti-venom <50% casesManagement of envenomed patients is an enormous challengeand requires transfer to adequate facility and ICUAppropriate first aid therapy can be life savingLimited data available on venom composition and pharmacology
Any Questions?