Antivenom for European Vipera species envenoming

Background: European viper bite is relatively uncommon but can cause serious envenoming, particularly swelling and haemorrhage spreading from limb to trunk that can cause long term disability. Systemic features are relatively mild compared to many other venomous species. Moderate-to-severe envenoming requires antivenom, which is given an estimated 4,000 times each year across the continent. Several Vipera spp antivenoms are produced in Europe but there is little comparative information available for the antivenoms and none is licensed with the European Medicines Agency. We aimed to collect descriptive data on European viper antivenoms and assess their relative effectiveness.
Methods: We performed a systematic review of publications from 1996 to 2016 on Vipera antivenoms and extracted data on study type, safety and effectiveness. We sought information on antivenoms from manufacturers and individual patient data from authors of publications. Since individual patient data were only rarely available, we compared median length of stay between case series reporting each antivenom.
Results: Eight antivenoms are currently produced for European Vipera spp envenoming; a material safety data sheet providing information on manufacture was available for seven. Six are raised against V berus or V ammodytes venom; the seventh is raised against a mixture of V ammodytes, V aspis and V berus venom and the eighth is raised against V ammodytes, Macrovipera lebetina and Montivipera xanthina venom. Six manufacturers recommend intramuscular (IM) administration while two recommend intravenous (IV) administration. No randomized control trials comparing the effectiveness of antivenoms were identified. We found two papers presenting comparative preclinical data. Clinical studies were predominantly retrospective and contained clinical data on antivenom used in 2602 patients; where the antivenom was identified (n=2174), 2061 (94.8%) received Zagreb, ViperFAV or ViperaTAb antivenoms. There were few published data on the other antivenoms. IV administration of antivenom was associated with shorter length of hospital stay (median length of hospital stay in studies of IV ViperFAV or ViperaTAb ranged from 1 to 4.8 days versus 2 to 18 days for IM Bulbio or Zagreb antivenoms). Repeat doses were reported in 230/1491 of cases (15.4%) where this information was recorded. Adverse reactions were reported in 37 of 2408 cases (1.5%) including seven cases of anaphylaxis.
Conclusion: There are very limited pre-clinical comparative data and no randomised controlled trials assessing effectiveness of the antivenoms against different Vipera species. Most descriptive data suggest efficacy of Zagreb, ViperFAV and ViperaTAb antivenoms by the IV route but not IM route, although this is level D evidence. Reported adverse reactions were rare, suggesting that the modern IV antivenoms are of good quality. Better and more systematic data, including perhaps RCTs comparing different antivenoms, are required for the thousands of antivenom administrations that occur annually across Europe.