A Randomised Controlled Trial of Two Infusion Rates to Decrease Reactions to Antivenom

Background: Snake envenoming is a major clinical problem in Sri Lanka, with an estimated 40,000 bites annually. Antivenom is only available from India and there is a high rate of systemic hypersensitivity reactions. This study aimed to investigate whether the rate of infusion of antivenom reduced the frequency of severe systemic hypersensitivity reactions. Methods and findings: This was a randomized comparison trial of two infusion rates of antivenom for treatment of non-pregnant adult patients (>14 y) with snake envenoming in Sri Lanka. Snake identification was by patient or hospital examination of dead snakes when available and confirmed by enzyme-immunoassay for Russell’s viper envenoming. Patients were blindly allocated in a 11 randomisation schedule to receive antivenom either as a 20 minute infusion (rapid) or a two hour infusion (slow). The primary outcome was the proportion with severe systemic hypersensitivity reactions (grade 3 by Brown grading system) within 4 hours of commencement of antivenom. Secondary outcomes included the proportion with mild/moderate hypersensitivity reactions and repeat antivenom doses. Of 1004 patients with suspected snakebites, 247 patients received antivenom. 49 patients were excluded or not recruited leaving 104 patients allocated to the rapid antivenom infusion and 94 to the slow antivenom infusion. The median actual duration of antivenom infusion in the rapid group was 20 min (Interquartile range[IQR]:20–25 min) versus 120 min (IQR:75–120 min) in the slow group. There was no difference in severe systemic hypersensitivity reactions between those given rapid and slow infusions (32% vs. 35%; difference 3%; 95%CI:−10% to +17%;p = 0.65). The frequency of mild/moderate reactions was also similar. Similar numbers of patients in each arm received further doses of antivenom (30/104 vs. 23/94). Conclusions: A slower infusion rate would not reduce the rate of severe systemic hypersensitivity reactions from current high rates. More effort should be put into developing better quality antivenoms

The time of onset of the reaction after antivenom comparing the rapid and slow infusion groups.

<p>(The whiskers are the minimum and maximum, the box the interquartile range, and the median line across the box).</p

Demographic features, snake type and clinical effects for patients randomised to the rapid infusion arm and the slow infusion arm.

<p>Demographic features, snake type and clinical effects for patients randomised to the rapid infusion arm and the slow infusion arm.</p

Secondary outcomes for patients randomised to the rapid infusion arm and the slow infusion arm.

<p>Secondary outcomes for patients randomised to the rapid infusion arm and the slow infusion arm.</p

Comparison of patients with and without antivenom reactions, subdividing into severe and mild/moderate reactions. Proportions are reported with 95% confidence intervals.

1<p>Venom concentration for Russell’s viper patients only.</p

Consort diagram showing all patient recruitments, exclusions and outcomes in each of the arms of the study. *

<p>Exclusion criteria were age <14 years, pregnancy, clinician excluded, premedication given, prior administration of antivenom, were missed or did not consent to the study.</p

Dataset for "Venom concentrations and clotting factor levels in a prospective cohort of Russell’s viper bites with coagulopathy"

The dataset supports the published paper, all patients and their coagulation studies

Immune response to snake envenoming and treatment with antivenom; complement activation, cytokine production and mast cell degranulation

Background: Snake bite is one of the most neglected public health issues in poor rural communities worldwide. In addition to the clinical effects of envenoming, treatment with antivenom frequently causes serious adverse reactions, including hypersensitivity reactions (including anaphylaxis) and pyrogenic reactions. We aimed to investigate the immune responses to Sri Lankan snake envenoming (predominantly by Russell’s viper) and antivenom treatment. Methodology/Principal Findings: Plasma concentrations of Interleukin (IL)-6, IL-10, tumor necrosis factor α (TNFα), soluble TNF receptor I (sTNFRI), anaphylatoxins (C3a, C4a, C5a; markers of complement activation), mast cell tryptase (MCT), and histamine were measured in 120 Sri Lankan snakebite victims, both before and after treatment with antivenom. Immune mediator concentrations were correlated with envenoming features and the severity of antivenom-induced reactions including anaphylaxis. Envenoming was associated with complement activation and increased cytokine concentrations prior to antivenom administration, which correlated with non-specific systemic symptoms of envenoming but not with coagulopathy or neurotoxicity. Typical hypersensitivity reactions to antivenom occurred in 77/120 patients (64%), satisfying criteria for a diagnosis of anaphylaxis in 57/120 (48%). Pyrogenic reactions were observed in 32/120 patients (27%). All patients had further elevations in cytokine concentrations, but not complement activation, after the administration of antivenom, whether a reaction was noted to occur or not. Patients with anaphylaxis had significantly elevated concentrations of MCT and histamine. Conclusions/Significance: We have demonstrated that Sri Lankan snake envenoming is characterized by significant complement activation and release of inflammatory mediators. Antivenom treatment further enhances the release of inflammatory mediators in all patients, with anaphylactic reactions characterised by high levels of mast cell degranulation but not further complement activation. Anaphylaxis is probably triggered by non allergen-specific activation of mast cells and may be related to the quality of available antivenom preparations, as well as a priming effect from the immune response to the venom itself

Plots of median venom concentrations (open circles [○] and dashed lines; all panels), clotting times and factor concentrations (filled circles [●]) versus time post-antivenom for 146 patients with Russell’s viper envenoming including INR [A], aPTT (sec) [B], fibrinogen (g/L) [C], iD-dimer (mg/L FEU) [D], factor V (%) [E] and factor X (%) [F].

<p>Black lines represent the interpolated median factor concentration time curves and the shaded area is the normal range for each test. INR—international normalised ratio; aPTT—activated partial thromboplastin time; RVV—Russell’s viper venom.</p

Peak mediator levels within the first four hours post-antivenom; comparisons between no reaction, skin-only reactions and anaphylaxis.

*<p>Calculated from assays conducted in our laboratory on healthy controls.</p>†<p>p<0.001 comparing all groups (Kruskal-Wallis), p<0.001 for anaphylaxis versus no reaction, p = 0.050 for anaphylaxis versus skin-only reaction (Mann Whitney).</p>‡<p>p<0.001 comparing all groups (Kruskal-Wallis), p<0.001 for anaphylaxis versus no reaction, p = 0.064 for anaphylaxis versus skin-only reaction (Mann Whitney).</p