title: Low-dose adrenaline, promethazine, and hydrocortisone in the prevention of acute adverse reactions to antivenom following snakebite: a randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Envenoming from snakebites is most effectively treated by antivenom. However, the antivenom available in South Asian countries commonly causes acute allergic reactions, anaphylactic reactions being particularly serious. We investigated whether adrenaline, promethazine, and hydrocortisone prevent such reactions in secondary referral hospitals in Sri Lanka by conducting a randomised, double-blind placebo-controlled trial.
  
  
  RESULTS
  In total, 1,007 patients were randomized, using a 2 × 2 × 2 factorial design, in a double-blind, placebo-controlled trial of adrenaline (0.25 ml of a 1∶1,000 solution subcutaneously), promethazine (25 mg intravenously), and hydrocortisone (200 mg intravenously), each alone and in all possible combinations. The interventions, or matching placebo, were given immediately before infusion of antivenom. Patients were monitored for mild, moderate, or severe adverse reactions for at least 96 h. The prespecified primary end point was the effect of the interventions on the incidence of severe reactions up to and including 48 h after antivenom administration. In total, 752 (75%) patients had acute reactions to antivenom: 9% mild, 48% moderate, and 43% severe; 89% of the reactions occurred within 1 h; and 40% of all patients were given rescue medication (adrenaline, promethazine, and hydrocortisone) during the first hour. Compared with placebo, adrenaline significantly reduced severe reactions to antivenom by 43% (95% CI 25-67) at 1 h and by 38% (95% CI 26-49) up to and including 48 h after antivenom administration; hydrocortisone and promethazine did not. Adding hydrocortisone negated the benefit of adrenaline.
  
  
  CONCLUSIONS
  Pretreatment with low-dose adrenaline was safe and reduced the risk of acute severe reactions to snake antivenom. This may be of particular importance in countries where adverse reactions to antivenom are common, although the need to improve the quality of available antivenom cannot be overemphasized.
authors.affiliation: Clinical Trials Unit, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka. asita@sltnet.lk
authors.forename: H Asita
authors.initials: HA
authors.lastname: de Silva
authors.forename: Arunasalam
authors.initials: A
authors.lastname: Pathmeswaran
authors.forename: Channa D
authors.initials: CD
authors.lastname: Ranasinha
authors.forename: Shaluka
authors.initials: S
authors.lastname: Jayamanne
authors.forename: Senarath B
authors.initials: SB
authors.lastname: Samarakoon
authors.forename: Ariyasena
authors.initials: A
authors.lastname: Hittharage
authors.forename: Ranjith
authors.initials: R
authors.lastname: Kalupahana
authors.forename: G Asoka
authors.initials: GA
authors.lastname: Ratnatilaka
authors.forename: Wimalasiri
authors.initials: W
authors.lastname: Uluwatthage
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Aronson
authors.forename: Jane M
authors.initials: JM
authors.lastname: Armitage
authors.forename: David G
authors.initials: DG
authors.lastname: Lalloo
authors.forename: H Janaka
authors.initials: HJ
authors.lastname: de Silva
mesh_terms: D000293:Adolescent; D000328:Adult; D000707:Anaphylaxis / Q000517:prevention & control; D000997:Antivenins / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004837:Epinephrine / Q000008:administration & dosage* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D010919:Placebos; D011398:Promethazine / Q000008:administration & dosage* / Q000627:therapeutic use; D012909:Snake Bites / Q000188:drug therapy*; D012910:Snake Venoms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013188:Sri Lanka; D016896:Treatment Outcome
chemical_list: D000997:Antivenins; D010919:Placebos; D012910:Snake Venoms; D011398:Promethazine; D006854:Hydrocortisone; D004837:Epinephrine