In a factorial randomized trial conducted in Sri Lanka, de Silva and colleagues evaluate the safety and efficacy of pretreatments intended to reduce the risk of serious reactions to antivenom following snakebite.
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.
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.
Please see later in the article for the Editors' Summary
Of the 3,000 or so snake species in the world, about 600 are venomous. Venomous snakes, which are particularly common in equatorial and tropical regions, immobilize their prey by injecting modified saliva (venom) into their prey's tissues through their fangs—specialized hollow teeth. Snakes also use their venoms for self-defense and will bite people who threaten, startle, or provoke them. A bite from a highly venomous snake such as a pit viper or cobra can cause widespread bleeding, muscle paralysis, irreversible kidney damage, and tissue destruction (necrosis) around the bite site. All these effects of snakebite are potentially fatal; necrosis can also result in amputation and permanent disability. It is hard to get accurate estimates of the number of people affected by snakebite, but there may be about 2 million envenomings (injections of venom) and 100,000 deaths every year, many of them in rural areas of South Asia, Southeast Asia, and sub-Saharan Africa.
Why Was This Study Done?
The best treatment for snakebite is to give antivenom (a mixture of antibodies that neutralize the venom) as soon as possible. Unfortunately, in countries where snakebites are common (for example, Sri Lanka), antivenoms are often of dubious quality, and acute allergic reactions to them frequently occur. Although some of these reactions are mild (for example, rashes), in up to 40% of cases, anaphylaxis—a potentially fatal, whole-body allergic reaction—develops. The major symptoms of anaphylaxis—a sudden drop in blood pressure and breathing difficulties caused by swelling of the airways—can be treated with adrenaline. Injections of antihistamines (for example, promethazine) and hydrocortisone can also help. In an effort to prevent anaphylaxis, these drugs are also widely given before antivenom, but there is little evidence that such “prophylactic” treatment is effective or safe. In this randomized double-blind controlled trial (RCT), the researchers test whether low-dose adrenaline, promethazine, and/or hydrocortisone can prevent acute adverse reactions to antivenom. In an RCT, the effects of various interventions are compared to a placebo (dummy) in groups of randomly chosen patients; neither the patients nor the people caring for them know who is receiving which treatment until the trial is completed.
What Did the Researchers Do and Find?
The researchers randomized 1,007 patients who had been admitted to secondary referral hospitals in Sri Lanka after snakebite to receive low-dose adrenaline, promethazine, hydrocortisone, or placebo alone and in all possible combinations immediately before treatment with antivenom. The patients were monitored for at least 96 hours for adverse reactions to the antivenom; patients who reacted badly were given adrenaline, promethazine, and hydrocortisone as “rescue medication.” Three-quarters of the patients had acute reactions—mostly moderate or severe—to the antivenom. Most of the acute reactions occurred within an hour of receiving the antivenom, and nearly half of all the patients were given rescue medication during the first hour. Compared with placebo, pretreatment with adrenaline reduced severe reactions to the antivenom by 43% at one hour and by 38% over 48 hours. By contrast, neither hydrocortisone nor promethazine given alone reduced the rate of adverse reactions to the antivenom. Moreover, adding hydrocortisone negated the beneficial effect of adrenaline.
What Do These Findings Mean?
These findings show that pretreatment with low-dose adrenaline is safe and reduces the risk of acute severe reactions to snake antivenom, particularly during the first hour after infusion. They do not provide support for pretreatment with promethazine or hydrocortisone, however. Indeed, the findings suggest that the addition of hydrocortisone could negate the benefits of adrenaline, although this finding needs to be treated with caution because of the design of the trial, as does the observed increased risk of death associated with pretreatment with hydrocortisone. More generally, the high rate of acute adverse reactions to antivenom in this trial highlights the importance of improving the quality of antivenoms available in Sri Lanka and other parts of South Asia. The researchers note that the recent World Health Organization guidelines on production, control, and regulation of antivenom should help in this regard but stress that, for now, it is imperative that physicians carefully monitor patients who have been given antivenom and provide prompt treatment of acute reactions when they occur.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000435.
The MedlinePlus Encyclopedia has pages on snakebite and on anaphylaxis (in English and Spanish)
The UK National Health Service Choices website also has pages on snakebite and on anaphylaxis
The World Health Organization has information on snakebite and on snake antivenoms (in several languages); its Guidelines for the Production, Control and Regulation of Snake Antivenom Immunoglobulins are also available
The Global Snakebite Initiative has information on snakebite
A PLoS Medicine Research Article by Anuradhani Kasturiratne and colleagues provides data on the global burden of snakebite
A PLoS Medicine Neglected Diseases Article by José María Gutiérrez and colleagues discusses the neglected problem of snakebite envenoming