title: Antivenom for European Vipera species envenoming.
abstract: BACKGROUND
  European viper bite is relatively uncommon but can cause serious envenoming, particularly swelling and hemorrhage 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 many hundreds of 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
  A systematic review of articles relating to antivenom in Europe was performed using the Medline medical database. The following keywords "Europ*" or the individual names of each European country and "antiven*" or "immun*" or "envenom*" and "snake" or "viper*" or "adder" were used. Articles published between 1 January 1996 and 11 March 2016 pertaining to clinical outcome, including case reports, were selected. Referenced articles in the indexed articles were explored for suitability and included if they met any of the criteria: specific antivenom used, route of antivenom administration, adverse reactions to antivenom therapy and length of hospital admission. All accepted abstracts from EAPCCT conferences since 2000 were searched and abstracts relating to Vipera spp envenoming were assessed for suitability. We 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. We identified 40 papers and six published abstracts, and one unpublished paper that reported clinical cases and case series of envenomed patients treated with antivenom. No publication reported randomized controlled trials comparing any European Vipera antivenom with either placebo or another antivenom. 25 reports were of retrospective hospital- (n = 13) or poison center-based (n = 12) case series including five or more patients; a further 12 reports were either case reports or case series with less than five patients and one paper was a limited literature review. An additional nine papers reported prospective data; seven collected data remotely through poison service telephone communication with the attending physicians. Antivenoms available in Europe: Eight antivenoms are available 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 recommended intramuscular administration while two recommended intravenous administration. No randomized control trials comparing the effectiveness of antivenoms were identified. Pre-clinical data: We found two papers presenting comparative preclinical data. Clinical 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. Repeated use of antivenom: Repeat doses were reported in 230/1491 of cases (15.4%) where this information was recorded. Outcome and length of hospital stay: Intravenous administration of antivenom was associated with shorter length of hospital stay (median length of hospital stay in studies of intravenous ViperFAV or ViperaTAb ranged from 1 to 4.8 days versus 2 to 18 days for intramuscular Bulbio or Zagreb antivenoms). Antivenom versus no antivenom: Some small studies demonstrated no difference in the length of hospital stay in patients with equivalent envenomation grading who either did or did not receive antivenom. Adverse events: Adverse reactions were reported in 37 of 2408 cases (1.5%) including seven cases of anaphylaxis.
  
  
  CONCLUSIONS
  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 the efficacy of Zagreb, ViperFAV and ViperaTAb antivenoms by the intravenous route but not intramuscular route, although this is level D evidence. Reported adverse reactions were rare, suggesting that the modern intravenous antivenoms are of good quality. Better and more systematic data, including perhaps randomized controlled trials comparing different antivenoms, are required for the many hundreds of antivenom administrations that occur annually across Europe.
authors.affiliation: a Department of Pharmacology, Toxicology, and Therapeutics , University/BHF Centre for Cardiovascular Science, University of Edinburgh , Edinburgh , UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lamb
authors.affiliation: b Centre Antipoison , Hôpital Sainte Marguerite , Marseilles , France.
authors.forename: Luc
authors.initials: L
authors.lastname: de Haro
authors.affiliation: c Poison Control Centre and National Toxicology Information Centre - Toxicology Unit, Istituti Clinici Scientifici Maugeri , IRCCS Maugeri Hospital and University of Pavia , Pavia , Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Lonati
authors.affiliation: d Centre for Clinical Toxicology and Pharmacology , University Medical Centre Ljubljana , Ljubljana , Slovenia.
authors.forename: Miran
authors.initials: M
authors.lastname: Brvar
authors.affiliation: a Department of Pharmacology, Toxicology, and Therapeutics , University/BHF Centre for Cardiovascular Science, University of Edinburgh , Edinburgh , UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Eddleston
mesh_terms: D000818:Animals; D000997:Antivenins / Q000008:administration & dosage*; D005060:Europe; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D007902:Length of Stay; D011039:Poison Control Centers / Q000706:statistics & numerical data; D012909:Snake Bites / Q000503:physiopathology / Q000628:therapy*; D014757:Viper Venoms / Q000037:antagonists & inhibitors* / Q000633:toxicity; D017819:Viperidae
chemical_list: D000997:Antivenins; D014757:Viper Venoms
keywords: Antivenom; Vipera snakes; effectiveness