Does Antivenom Work?

OVERVIEW

• Antivenom is widely used for Australian envenoming syndromes
• Antivenoms are generally perceived, by both clinicians and the general public, as highly effective treatments
• However, there is little evidence to support this widely held view, in fact, the weight of evidence suggests that some antivenoms are ineffective in clinical practice
• Worldwide, snake antivenoms are the most important due to the severity and number of cases of snakebite envenoming worldwide

This page is largely based on this excellent review:

Isbister GK. Antivenom efficacy or effectiveness: the Australian experience. Toxicology. 2010 Feb 9;268(3):148-54. [PMID: 19782716]

DEFINITIONS

• Venoms are mixtures of toxins administered by specialised apparatus by one organism that causes a harmful envenoming syndrome in another organism.
• Antivenoms (AV) are polyclonal antibody preparations that are produced from the plasma of animals, usually horses or sheep, by injecting the animals with venoms. They contain numerous antibodies of varying titre and affinity to the various different toxins in the venom. All Australian antivenoms are IgG Fab fragments.
• A monovalent antivenom is specific to one type of venomous organism (e.g. brown snake) whereas a polyvalent antivenom can be used for multiple types of venomous organism (e.g. polyvalent snake antivenom is designed to be used for all types of Australian venous snake). Both monovalent and polyvalent antivenoms contain polyclonal antibodies.
• Antivenom efficacy is the ability to bind and neutralise venom-mediated effects under ideal conditions (in vitro studies and animal studies of binding and neutralisation)
• Antivenom effectiveness is the ability to reverse or prevent envenoming in human patients

EVIDENCE SUMMARY

Efficacy:

• Numerous preclinical and in vitro studies have demonstrated that antivenoms can bind venoms and prevent appropriate venom-mediated effects in vitro if premixed with venom

Studies demonstrating antivenom effectiveness:

• Venom induced consumption coagulopathy (VICC) in West African saw-scaled viper (Echis carinatus) and Russell’s viper envenoming (Myint et al, 1985; Warrell et al, 1977)
• Neurotoxicity in taipan (Oxyuranus canni) bites in Papua New Guinea (Currie, 2006; Lalloo et al, 1995; Trevett et al, 1995)
• Scorpion envenoming (Boyer et al., 2009; Calderon-Aranda et al, 1995)
• Funnel-web spider envenoming (Hartman and Sutherland, 1984)

Studies suggesting antivenom is not effective:

• Delayed use in neurotoxicity (Kularatne, 2002; Phillips et al, 1988; Pochanugool et al, 1997; Theakston et al, 1990)
• Venom-induced consumptive coagulopathy in Australasian elapid envenoming (Isbister et al, 2009; Tanos et al, 2008)
• Myotoxicity and renal failure (Myint et al, 1985)
• Local tissue effects (Dart et al 2001; Warrell et al, 1976, and 1977).

Most RCTs were not placebo-controlled, instead they have compared types, routes and routes of antivenom.

POSSIBLE REASONS FOR ANTIVENOM FAILURE

• Anti-venom inefficacy
  • antibodies in the antivenom are unable to bind the toxins in the venom (rare)
• Irreversible venom-mediated effects
  • toxin injury that is irreversible such as pre-synaptic neurotoxicity (nerve terminal destruction), myotoxicity or renal injury
• Inability of antivenom to reach venom target
  • venom-mediated injury at the bite site, or
  • toxin molecules are much smaller than antivenom molecules (e.g. short chain neurotoxins compared to IgG molecules)
• Rapid venom onset
  • rapid onset of envenoming such that antivenom is unable to prevent or reverse severe or life-threatening effects, such as cardiac toxicity from box jellyfish envenoming
• Mismatch of venom and antivenom pharmacokinetics
  • manifests as “recurrence” and is thought to occur when there is ongoing venom absorption after antivenom has been eliminated
  • this is usually only a problem with the rapidly eliminated Fab type antivenoms

Lack of effectiveness does not imply lack of efficacy — assumptions of reduced efficacy may led to:

• excess doses of antivenom being administered
• increased cost
• increase adverse events
• neglect of other treatments that may be beneficial (e.g. supportive care and monitoring)

SNAKE ANTIVENOM Brown snake AV efficacy is high efficacious — but this has only recently been proven

• poor efficacy of commercially available AV, based on a number of animal and laboratory studies, was previously thought to account for cases of antivenom failure in humans and a need for increasing doses of AV.
• Sprivulis et al. (1996) investigated the ability of Australian snake antivenom to prevent the in vitro procoagulant clotting effects of their respective venoms
  • assumed that the venom concentration in patients can be simply calculated from the average venom yield of the snake
  • found that up to 25 times the recommended amount of antivenom (1 vial) was insufficient to prevent clotting for brown snake
  • similar results found in an earlier study by Tibballs and Sutherland (1991))
• The laboratory studies by Sprivulis et al. (1996) and Tibballs and Sutherland (1991) — which suggested that snake antivenoms lacked efficacy — are flawed
  • the amount of venom administered would result in a blood concentration approximately 100–1000 times that seen in patients
• Lack of snake AV efficacy was supported by observational studies such as Yeung et al, 2004
  • up to 10 ampoules of brown snake AV were recommended based on the amount of AV given before correction of coagulopathy in clinical case series
  • however, recovery from VICC takes up to 12–18 h to occur after antivenom administration due to the time needed to resynthesis consumed clotting factors.
  • the dose of antivenom thus correlates with the frequency of clotting studies until resynthesis occurs!
  • the study measured inappropriate AV administration, not the dose of AV actually needed
• Evidence that brown snake AV is highly efficacious comes from Isbister et al, 2007
  • used clinically relevant concentrations of venom (4–95 ng/mL), determined from a study of patients with brown snake envenoming (Isbister et al., 2007b; O’Leary et al., 2006)
  • one ampoule of brown snake AV was sufficient to neutralise the in vitro procoagulant effect of brown snake venom at these venom concentrations
  • one ampoule of brown snake AV was able to bind all free venom in solution at venom concentrations equivalent to those seen with human envenoming
• The ASP project (Allen et al ,2012)

Based on these studies an initial dose of brown snake antivenom should be 1 vial and repeat doses are not required, and it will take 12–18 h for the coagulopathy to recover.

Tiger snake antivenom

• Sprivulis et al. (1996) also found that large doses of antivenom were required to prevent the in vitro procoagulant effect of Tiger snake venom
• Again, very high venom doses were used — about 1000-fold those expected in human envenoming (5–200 ng/mL) (O’Leary et al., 2008)
• Tiger snake AV is able to prevent the procoagulant effect of tiger snake venom in vitro (O’Leary et al., 2007)

Venom-induced consumptive coagulopathy (VICC)

• Tanos et al., 2008 developed a semi-mechanistic systems model of the coagulation pathway that suggests that Taipan antivenom neutralisation needs to occur soon after venom enters the circulation to have an impact on the recovery of the coagulopathy (Tanos et al., 2008). If true, unless antivenom is administered rapidly (e.g. <1 hour) it is unlikely to be effective for VICC caused by Taipans
• Clinical studies suggest that antivenom does not speed up the recovery from VICC in Australia and PNG:
  • PNG taipan envenoming (Lalloo et al., 1995a)
  • brown snakes and tiger snakes in Australia (Isbister et al., 2009)

Other snakes and venom effects

• Observational studies show that the coagulopathy in Echis spp. bites may last for many days untreated, but will resolve a mean of 12 h after antivenom treatment (Warrell et al, 1977)
• Administration of Taipan AV within 6 h of the bite in taipan envenoming appears to reduce the number of patients requiring endotracheal intubation (Lalloo et al, 1995a), suggesting the AV may be useful for preventing delayed neurotoxicity

References

• Allen GE, Brown SG, Buckley NA. Clinical effects and antivenom dosing in brown snake (Pseudonaja spp.) envenoming–Australian snakebite project (ASP-14). PloS one. 7(12):e53188. 2012. [pubmed] [free full text]
• Yeung JM, Little M, Murray LM, Jelinek GA, Daly FF. Antivenom dosing in 35 patients with severe brown snake (Pseudonaja) envenoming in Western Australia over 10 years. Med J Aust. 2004 Dec 6-20;181(11-12):703-5. PubMed PMID: 15588174.

BOX JELLYFISH ANTIVENOM

Clinical experience

• severe envenoming is highly lethal due to toxin-induced cardiovascular compromise and cardiac arrest (usually within 10-20 minutes)
• An ovine antivenom has been in use for over 30 years
• There have been at least 4 deaths despite antivenom administration, but there are also cases of antivenom use where patients survived.
• Prior to the introduction of antivenom, there were reports of patient survival with early CPR.

Efficacy

• Chironex antivenom is highly efficacious
• Western blot analysis using box jellyfish antivenom or antibodies raised to the venom preparation showed that both could detect the majority of the protein bands in the venom ranging from 10 to 200 kDa (Winter et al., 2009).
• Pre-mixing antivenom (and antibodies) with the venom prevented toxicity in a cell-based assay (Konstantakopoulos et al., 2009) and also prevented cardiovascular collapse in an in vivo rat model (Winter et al., 2009).

Effectiveness

• Chironex antivenom is unlikely to be effective in the clinical setting, possibly due to the extremely rapid onset of venom-mediated cardiovascular collapse
• administration of the antivenom after venom addition in the in vivo rat model did not prevent cardiovascular collapse (Winter et al., 2009)
• administration of antivenom to the rat prior to venom (not pre- mixed with venom) also did not prevent cardiovascular collapse (Winter et al., 2009)

FUNNELWEB SPIDER ANTIVENOM

Funnelweb spider (FWS) envenoming is rare but prior to antivenom was highly lethal, even despite intensive care treatments of the late 1970s

• lapine antivenom became available in the early 1980s
• no RCT performed in humans
• dramatic response seen in the first few cases treated, consistent with animal studies
• marked reduction in LOS, organ failure and ICU admission since the introduction of FWS AV — and no deaths have occurred in patients administered FWS AV
• Miller et al (2016) showed that FWS AV reversed some clinical features in confirmed cases, and was found to bind venom, but did not reverse all cardiotoxic effects.

References

• Isbister GK, Gray MR, Balit CR, Raven RJ, Stokes BJ, Porges K, Tankel AS, Turner E, White J, Fisher MM. Funnel-web spider bite: a systematic review of recorded clinical cases. Med J Aust. 2005 Apr 18;182(8):407-11. Review. PubMed PMID: 15850438.
• Miller M, O’Leary MA, Isbister GK. Towards rationalisation of antivenom use in funnel-web spider envenoming: enzyme immunoassays for venom concentrations. Clinical toxicology (Philadelphia, Pa.). 54(3):245-51. 2016. [pubmed]

REDBACK SPIDER ANTIVENOM

This equine antivenom is the most commonly used antivenom in Australia

• Two RCTs of IV versus IM route of AV adminstration in redback envoming (Ellis et al, 2005; Isbister et al’s RAVE study, 2008)
  • both showed no difference between the routes of administration
  • in the RAVE trial AV concentrations were measured showing that AV could only be detected in blood after IV administration (Isbister et al., 2008c)
  • these results suggest that the AV by either route is equally effective — or perhaps more accurately (given the pharmacokinetic data), equally ineffective!
• The subsequent RAVE-II study, a multicenter RCT found no benefit for redback AV compared to placebo for the treatment of pain or systemic features of lactrodectism (Isbister et al, 2014)

References

• Ellis RM, Sprivulis PC, Jelinek GA, Banham ND, Wood SV, Wilkes GJ, Siegmund A, Roberts BL. A double-blind, randomized trial of intravenous versus intramuscular antivenom for red-back spider envenoming. Emerg Med Australas. 2005 Apr;17(2):152-6. PubMed PMID: 15796730.
• Isbister GK, O’Leary M, Miller M, Brown SG, Ramasamy S, James R, Schneider JS. A comparison of serum antivenom concentrations after intravenous and intramuscular administration of redback (widow) spider antivenom. Br J Clin Pharmacol. 2008 Jan;65(1):139-43. doi: 10.1111/j.1365-2125.2007.03004.x. Epub 2007 Aug 9. PubMed PMID: 18171334; PubMed Central PMCID: PMC2291270.
• Isbister GK, Brown SG, Miller M, Tankel A, Macdonald E, Stokes B, Ellis R, Nagree Y, Wilkes GJ, James R, Short A, Holdgate A. A randomised controlled trial of intramuscular vs. intravenous antivenom for latrodectism–the RAVE study. QJM. 2008 Jul;101(7):557-65. doi: 10.1093/qjmed/hcn048. Epub 2008 Apr 8. PubMed PMID: 18400776.
• Isbister GK, Page CB, Buckley NA. Randomized controlled trial of intravenous antivenom versus placebo for latrodectism: the second Redback Antivenom Evaluation (RAVE-II) study. Annals of emergency medicine. 64(6):620-8.e2. 2014. [pubmed]

CONCLUSION

It is likely that many of the antivenoms in current clinical use are ineffective (e.g. brown snake AV for VICC, Chironex AV for box jellyfish envenoming for toxin-induced cardiovascular collapse).

• Apparent antivenom ineffectiveness in specific cases does not imply that all antivenoms are ineffective (e.g. snake AV might still work for MAHA, Chironex AV might work for pain)
• Knowing the reasons why an antivenom does not work is important to ensure that management is appropriate

There is still a role for properly performed observational studies:

• serial venom concentrations should be measured
• ensure that clinically appropriate venom concentrations are used for in vitro studies
• provide an understanding of the time course and likely reversibility of venom-mediated effects

References and Links

Individual studies are referenced in the relevant sections above.

• Isbister GK. Antivenom efficacy or effectiveness: the Australian experience. Toxicology. 2010 Feb 9;268(3):148-54. PMID: 19782716.
• Maduwage K, Buckley NA, de Silva HJ, Lalloo DG, Isbister GK. Snake antivenom for snake venom induced consumption coagulopathy. The Cochrane database of systematic reviews. 6:CD011428. 2015. [pubmed]