To the Editor: Gawarammana et al present an interesting study of premedication to prevent adverse reactions to snake antivenom,1 but I have concerns with the data presentation and analysis. The 95% confidence intervals presented in Box 3 of their article are impossibly narrow. For example, recalculation of the first cell (hypotension rate for treatment A) by the binomial method gives a 95% confidence interval of 12%–62%, not 30%–36% as presented. Also, my analysis of the aggregate endpoint differs. Using the Fisher exact test to compare reaction rates in the hydrocortisone + antihistamine group (11/21) with placebo (13/16), for the difference in proportions of 0.29 I obtain a 95% confidence interval of 2 0.04 to 0.58. This has a P value of 0.14 using a 2-tailed test, according to the program Analyse-it.2

This comes as no surprise given that steroids take hours to work, and that histamine is just one of many mediators released during anaphylaxis, rising early and only transiently during severe and protracted anaphylactic reactions.3 Although antihistamines reverse the effects of histamine infusions which mimic anaphylaxis, animal studies indicate that they are ineffective for treating anaphylaxis mediated by mast-cell degranulation.4,5

Human studies have shown that H1 blockade is useful in preventing mild reactions to immunotherapy that are confined to the skin, but do not appear to prevent severe reactions.6,7 One human study has compared H1 + H2 blockade with H1-only blockade for the management of mild allergic reactions, finding a small benefit of combined H1 + H2 blockade.8 However, a confounder was that adrenaline was administered more frequently in the combined H1 + H2 antihistamine treatment group. A study of reactions to immunotherapy has failed to show any benefit from H1 + H2 blockade.7

I suspect that, instead of proceeding to study combination prophylaxis with antihistamines, steroids and adrenaline, it might be better to examine the preparation for and management of allergic reactions to antivenom. Many doctors fear intravenous adrenaline infusions, but in our experience this approach to managing anaphylaxis is safe, well tolerated and immediately effective, without the unpredictable, unpleasant, and (in the setting of venom-induced coagulopathy) potentially dangerous side effects sometimes seen with intramuscular, subcutaneous and intravenous bolus injections.9 Perhaps it is time for a trial of premedication with subcutaneous adrenaline versus an “as required” approach using a carefully titrated intravenous infusion.

In reply: Brown has pointed out some interesting observations about antihistamines and mediators such as histamine, released during anaphylactic reactions.

First, we must address the statistical issues. We are grateful to Brown for detecting an important error in Box 3 of our article.1 When we were asked to calculate confidence intervals for the percentages, we used a formula recommended by Spiegel.2 As this formula was not available in our software packages, we programmed it ourselves. We made an error in our programming and we apologise for this. (See Correction, page 428.)

For the difference in reaction rates for the treatment regimens, we used the following calculation.

The difference P1 – P2 = − 0.2887

To calculate the confidence interval, we calculated the standard error (SE) of the difference by the following formula.

This interval does not include 0, so Brown’s P value of 0.14 is not reasonable. We do accept that the statistical significance is marginal.

We agree that antihistamine is ineffective as a prophylactic agent in anaphylaxis. This was observed in studies in Sri Lanka and Brazil, where chlorpheniramine and promethazine, respectively, were used to prevent reactions to antivenom.3,4 However, we defended the observed reduction of mild to moderate acute reactions to antivenom in our study by highlighting the counter-effect of antihistamine on released histamine after mast-cell degranulation.1

Our study was to test the usefulness of an established practice in Sri Lanka, where steroid infusion is used to counter reactions to antivenom. The crux of the problem is the highly antigenic antivenom preparations used in Sri Lanka, despite ever-increasing reaction rates, because of the lack of facilities for developing purified antivenom.

The proposal of using intravenous adrenaline infusion to reduce allergic reactions is novel and exciting. This should be tested by randomised controlled trials.

Comment: Kularatne and Gawarammana compared the proportion of side-effects given in their table above using the well-known (and easily understood) test of the difference between two proportions using the normal distribution. However, as each of these proportions follows a binomial distribution (13 “successes” out of 16 trials and 11 “successes” out of 21 trials), the normal approximation is only useful if the number of trials is greater than 30.

Because of the small sample sizes, “exact” methods better reflect the true difference (in terms of P values and confidence intervals) between the two proportions. The more complicated methods (different formulations of the exact test) and the resulting confidence intervals provide a clearer indication of whether the proportions are indeed different (statistically). In this instance, the evidence is not sufficient to declare the two proportions statistically different.