Low-dose adrenaline, promethazine, and hydrocortisone in the prevention of acute adverse reactions to antivenom following snakebite: a randomised, double-blind, placebo-controlled trial

• Published in: PLoS medicine 2011-05, Vol.8 (5), p.e1000435
• Main Authors: de Silva, H Asita, Pathmeswaran, Arunasalam, Ranasinha, Channa D, Jayamanne, Shaluka, Samarakoon, Senarath B, Hittharage, Ariyasena, Kalupahana, Ranjith, Ratnatilaka, G Asoka, Uluwatthage, Wimalasiri, Aronson, Jeffrey K, Armitage, Jane M, Lalloo, David G, de Silva, H Janaka
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Adverse and side effects; Anaphylaxis - prevention & control; Antivenins; Antivenins - administration & dosage; Antivenins - adverse effects; Antivenins - therapeutic use; Bites and stings; Blood pressure; Complications and side effects; Critical Care and Emergency Medicine; Dosage and administration; Dose-Response Relationship, Drug; Double-Blind Method; Drugs; Epinephrine; Epinephrine - administration & dosage; Epinephrine - therapeutic use; Evidence-Based Healthcare/Bedside Evidence-Based Medicine; Female; Health aspects; Hospitals; Humans; Hydrocortisone; Hydrocortisone - administration & dosage; Hydrocortisone - therapeutic use; Infectious Diseases/Neglected Tropical Diseases; Male; Medical research; Physiological aspects; Placebos; Prevention; Promethazine; Promethazine - administration & dosage; Promethazine - therapeutic use; Snake bites; Snake Bites - drug therapy; Snake Venoms - antagonists & inhibitors; Snake Venoms - metabolism; Sri Lanka; Studies; Treatment Outcome; Venom
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.1000435

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. 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. 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.