Prevention of acute adverse reactions to snake antivenom after snakebite: multi-centre, randomized, controlled clinical trial

Abstract

BACKGROUND: Antivenom is the most effective treatment for snakebite envenoming. Acute adverse reactions to the polyvalent antivenom (PAV) are common; anaphylactk reactions are particularly serious. OBJECTIVE: To determine whether promethazine, hydrocortisone, and low-dose adrenaline, alone and in all possible combinations, prevent reactions to antivenom. METHODS: The study was conducted in 3 hospitals in Sri Lanka from March 2005 to April 2008. It required 1000 patients to detect a 25% reduction in reactions at p<0.01 with 80% power. After informed consent, patients were randomized in a 2x2x2 factorial blinded design to receive each active intervention versus matching placebo immediately before administration of PAV. They were monitored for adverse reactions categorized as mild, moderate, severe, for at least 96 hours. The pre-specified primary analyses were of effects of each intervention on the incidence of severe reactions over 48 hours. Results: Of 1007 randomized subjects 776 (77.2%) were males, mean (sd) age 36.5 (13.6) yrs. Median time between snakebite and PAV administration was 4.25 hours. 752 (75%) patients developed acute reactions to PAV; 9% mild, 48% moderate and 43% severe. None of the drugs significantly reduced severe reactions to PAV at any time point. However, there was an 18% reduction in the rate of severe reactions at 1 hour with adrenaline (p-0.052) and a 33-3% reduction in signs of allergy (pruritus, urticaria, facial oedema, bronchospasm) with promethazine at 1 and 24 hours (p<0.001). CONCLUSIONS: Pre-treatment with promethazine, hydrocortisone, and low-dose adrenaline alone and in different combinations do not significantly reduce acute reactions to PAV.