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.

Methods and findings: 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.

Trial registration: ClinicalTrials.gov NCT00270777.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1. Trial profile.

Figure 2. Progression of type of reaction over 48 h.

Numbers within boxes indicate the number of patients according to the highest category of reaction they had experienced by that time. Numbers above the boxes indicate the number of patients who experienced a higher category of reaction during the preceding interval. Those who changed from no reaction to a reaction category are indicated by numbers highlighted in yellow. Those who changed from mild reaction to a higher category are indicated by numbers highlighted in green. Those who changed from moderate to severe reaction are indicated by numbers highlighted in turquoise. For example the above numbers can be interpreted as follows. At 1 h, there were 315 patients with moderate reaction, and by 6 h, 336 patients were classified as moderate reactions; 33 patients who had had no reaction in 1 h had a moderate reaction during this interval, six patients who had had mild reaction in 1 h had a moderate reaction during this interval, and 18 patients who had had moderate reaction in 1 h had a severe reaction during this interval: 336 = (315+33+6)−18.