Russell's Viper Envenoming Research Articles

A simple mortality risk prediction score for viper envenoming in India (VENOMS): A model development and validation study.

Snakebite is a neglected problem with a high mortality in India. There are no simple clinical prognostic tools which can predict mortality in viper envenomings. We aimed to develop and validate a mortality-risk prediction score for patients of viper envenoming from Southern India. We used clinical predictors from a prospective cohort of 248 patients with syndromic diagnosis of viper envenoming and had a positive 20-minute whole blood clotting test (WBCT 20) from a tertiary-care hospital in Puducherry, India. We applied multivariable logistic regression with backward elimination approach. External validation of this score was done among 140 patients from the same centre and its performance was assessed with concordance statistic and calibration plots. The final model termed VENOMS from the term "Viper ENvenOming Mortality Score included 7 admission clinical parameters (recorded in the first 48 hours after bite): presence of overt bleeding manifestations, presence of capillary leak syndrome, haemoglobin <10 g/dL, bite to antivenom administration time > 6.5 h, systolic blood pressure < 100 mm Hg, urine output <20 mL/h in 24 h and female gender. The lowest possible VENOMS score of 0 predicted an in-hospital mortality risk of 0.06% while highest score of 12 predicted a mortality of 99.1%. The model had a concordance statistic of 0·86 (95% CI 0·79-0·94) in the validation cohort. Calibration plots indicated good agreement of predicted and observed outcomes. The VENOMS score is a good predictor of the mortality in viper envenoming in southern India where Russell's viper envenoming burden is high. The score may have potential applications in triaging patients and guiding management after further validation.

Comparison of rotational thromboelastometry parameters with 20-minute whole blood clotting test as a predictor of envenoming in Russell's viper bite patients.

Coagulopathy is an important and common systemic clinical syndrome caused by snake envenoming. The major clinical effect of Russell's viper (RV) envenoming is haematotoxicity. The 20-min whole blood clotting test (WBCT20) is the standard test for identification of envenoming in resource-limited settings. However, its reliability as a diagnostic test has been questioned. Rotational thromboelastometry (ROTEM) assays different phases of clot formation from initiation to fibrinolysis. Our objective was to compare parameters of ROTEM with WBCT20 and the international normalized ratio (INR) as predictors of envenoming in RV bite patients. Fifty-three patents with RV bite presenting to Anuradhapura Hospital, Sri Lanka were recruited. Epidemiological and clinical data were obtained. Venous blood samples were collected at admission for ROTEM, INR and WBCT20. A total of 46 of 53 patients with RV bites received antivenom serum (AVS); 74% had a non-clottable WBCT20. All 46 had at least one abnormal ROTEM parameter and 93% had a prolonged EXTEM clotting time (EXTEM-CT). The sensitivity of a prolonged INR was only 55%. EXTEM-CT is a better predictor of envenoming and the need for AVS than WBCT20 in RV bites (p=0.02). It provides a numerical value that can be used post-AVS to objectively assess the response and decide on further treatment.

A Bayesian phase 2 model based adaptive design to optimise antivenom dosing: Application to a dose-finding trial for a novel Russell's viper antivenom in Myanmar.

For most antivenoms there is little information from clinical studies to infer the relationship between dose and efficacy or dose and toxicity. Antivenom dose-finding studies usually recruit too few patients (e.g. fewer than 20) relative to clinically significant event rates (e.g. 5%). Model based adaptive dose-finding studies make efficient use of accrued patient data by using information across dosing levels, and converge rapidly to the contextually defined 'optimal dose'. Adequate sample sizes for adaptive dose-finding trials can be determined by simulation. We propose a model based, Bayesian phase 2 type, adaptive clinical trial design for the characterisation of optimal initial antivenom doses in contexts where both efficacy and toxicity are measured as binary endpoints. This design is illustrated in the context of dose-finding for Daboia siamensis (Eastern Russell's viper) envenoming in Myanmar. The design formalises the optimal initial dose of antivenom as the dose closest to that giving a pre-specified desired efficacy, but resulting in less than a pre-specified maximum toxicity. For Daboia siamensis envenoming, efficacy is defined as the restoration of blood coagulability within six hours, and toxicity is defined as anaphylaxis. Comprehensive simulation studies compared the expected behaviour of the model based design to a simpler rule based design (a modified '3+3' design). The model based design can identify an optimal dose after fewer patients relative to the rule based design. Open source code for the simulations is made available in order to determine adequate sample sizes for future adaptive snakebite trials. Antivenom dose-finding trials would benefit from using standard model based adaptive designs. Dose-finding trials where rare events (e.g. 5% occurrence) are of clinical importance necessitate larger sample sizes than current practice. We will apply the model based design to determine a safe and efficacious dose for a novel lyophilised antivenom to treat Daboia siamensis envenoming in Myanmar.

Russell's viper bite and the empty sella syndrome.

Snake bites are very common in India especially in rural areas. Empty sella syndrome is a relatively uncommon sequela of Russell's viper bite. Here, we describe a case of 22-year-old female who was seriously envenomed by Russell's viper bite at the age of 14 years. Diagnosis of hypopituitarism following Russell's viper bite was significantly delayed. We attribute her empty sella syndrome and hypopituitarism to Russell's viper envenoming.

Thai Russell's viper monospecific antivenom is immunoreactive and effective in neutralizing the venom of Daboia siamensis from Java, Indonesia

Daboia siamensis monovalent antivenom (DSMAV, Thailand) exhibited comparable immunoreactivity toward the venoms of eastern Russell's vipers from Thailand and Indonesia. It also effectively neutralized the procoagulant and lethal effects of both venoms, showing high potency. The Indonesian heterologous trivalent antivenom SABU (Serum Anti Bisa Ular), however, has very weak immunoreactivity and it failed to neutralize the Russell's viper venoms. DSMAV appears to be the appropriate choice of antivenom to treat Russell's viper envenoming.

Clinico-epidemiology and management of Russell's viper (Daboia russelii) envenoming in dogs in Sri Lanka.

Russell's viper envenoming in dogs is a significant problem in Sri Lanka. The current study focused on investigating clinical profile, laboratory findings of three selected tests and to develop a treatment strategy with Indian polyvalent Anti-Venom Serum (AVS). It was also intended to report adverse effects and complications caused by both Russell's viper venom (RVV) and AVS in Russell's Viper (RV) envenomed dogs. To evaluate and report the clinical manifestations, to find out the minimum effective vials of AVS and to record AVS induced adverse reactions of RV envenoming in dogs. A prospective study was conducted on Russell's viper bitten dogs (n = 65) admitted to the Veterinary Teaching Hospital (VTH) in Sri Lanka. Indian polyvalent AVS was used to treat all the envenomed dogs. The number of vials of AVS that was administered to a patient was decided upon by a second degree polynomial model with a number of vials of AVS in the X axis verses Prothrombine Time (PT), Activated Partial Thromboplastine Time (aPTT) and Clotting Time (CT) in the Y axis respectively. Varying degrees of pain were exhibited by all the victim dogs. Mild swelling and necrosis at the site of bite was seen in 54% (n = 35) and 37% (n = 24) of dogs respectively. Prolonged values of, PT, aPTT and CT were seen from all the RV envenomed dogs. The mean leukocyte count in these dogs was 39.79 × 103/μL (normal range; 4-20 × 103/μL) (IQR:29.05 × 103/μL-45.92 × 103/μL). Statistical analysis showed that the initial vials of 7 AVS would be the minimum required vials. Therefore, a range of 6-15 AVS vials in total were administered to these dogs and in 7.6% (n = 5) of dogs, the results of PT, aPTT and CT became normal with 6 AVS vials at 32-97 minutes. Acute Renal Failure (ARF) was detected from 29% (n = 19) of dogs as a complication. Systemic clinical signs of haemorrhagic lesions, cardio respiratory toxicities were common in Russell's viper envenomed dogs. Initially 6 vials of AVS must be administered. AVS induced reactions were reported commonly. Russell's viper envenoming was found to be lethal in dogs.

A randomized controlled trial of fresh frozen plasma for coagulopathy in Russell's viper (Daboia russelii) envenoming

Essentials Russell's viper envenoming is a major health issue in South Asia and causes coagulopathy.We studied the effect of fresh frozen plasma and two antivenom doses on correcting coagulopathy.Fresh frozen plasma did not hasten recovery of coagulopathy.Low‐dose antivenom did not worsen coagulopathy. SummaryBackgroundRussell's viper (Daboia russelii) envenoming is a major health issue in South Asia and causes venom‐induced consumption coagulopathy (VICC).ObjectivesTo investigate the effects of fresh frozen plasma (FFP) and two antivenom doses in correcting VICC.MethodsWe undertook an open‐label randomized controlled trial in patients with VICC at two Sri Lankan hospitals. Patients with suspected Russell's viper bites and coagulopathy were randomly allocated (1 : 1) to high‐dose antivenom (20 vials) or low‐dose antivenom (10 vials) plus 4 U of FFP. The primary outcome was the proportion of patients with an International Normalized Ratio (INR) of < 2 at 6 h after antivenom administration. Secondary outcomes included anaphylaxis, major hemorrhage, death, and clotting factor recovery.ResultsFrom 214 eligible patients, 141 were randomized: 71 to high‐dose antivenom, and 70 to low‐dose antivenom/FFP; five had no post‐antivenom blood tests. The groups were similar except for a delay of 1 h in antivenom administration for FFP patients. Six hours after antivenom administration, 23 of 69 (33%) patients allocated to high‐dose antivenom had an INR of < 2, as compared with 28 of 67 (42%) allocated to low‐dose antivenom/FFP (absolute difference 8%; 95% confidence interval − 8% to 25%). Fifteen patients allocated to FFP did not receive it. Severe anaphylaxis occurred equally frequently in each group. One patient given FFP developed transfusion‐related acute lung injury. Three deaths occurred in low‐dose antivenom/FFP patients, including one intracranial hemorrhage. There was no difference in recovery rates of INR or fibrinogen, but there was more rapid initial recovery of factor V and FX in FFP patients.Conclusion FFP after antivenom administration in patients with Russell's viper bites did not hasten recovery of coagulopathy. Low‐dose antivenom/FFP did not worsen VICC, suggesting that low‐dose antivenom is sufficient.

Clinical and Pharmacological Investigation of Myotoxicity in Sri Lankan Russell's Viper (Daboia russelii) Envenoming.

BackgroundSri Lankan Russell’s viper (Daboia russelii) envenoming is reported to cause myotoxicity and neurotoxicity, which are different to the effects of envenoming by most other populations of Russell’s vipers. This study aimed to investigate evidence of myotoxicity in Russell’s viper envenoming, response to antivenom and the toxins responsible for myotoxicity.Methodology and FindingsClinical features of myotoxicity were assessed in authenticated Russell’s viper bite patients admitted to a Sri Lankan teaching hospital. Toxins were isolated using high-performance liquid chromatography. In-vitro myotoxicity of the venom and toxins was investigated in chick biventer nerve-muscle preparations. Of 245 enrolled patients, 177 (72.2%) had local myalgia and 173 (70.6%) had local muscle tenderness. Generalized myalgia and muscle tenderness were present in 35 (14.2%) and 29 (11.8%) patients, respectively. Thirty-seven patients had high (>300 U/l) serum creatine kinase (CK) concentrations in samples 24h post-bite (median: 666 U/l; maximum: 1066 U/l). Peak venom and 24h CK concentrations were not associated (Spearman’s correlation; p = 0.48). The 24h CK concentrations differed in patients without myotoxicity (median 58 U/l), compared to those with local (137 U/l) and generalised signs/symptoms of myotoxicity (107 U/l; p = 0.049). Venom caused concentration-dependent inhibition of direct twitches in the chick biventer cervicis nerve-muscle preparation, without completely abolishing direct twitches after 3 h even at 80 μg/ml. Indian polyvalent antivenom did not prevent in-vitro myotoxicity at recommended concentrations. Two phospholipase A2 toxins with molecular weights of 13kDa, U1-viperitoxin-Dr1a (19.2% of venom) and U1-viperitoxin-Dr1b (22.7% of venom), concentration dependently inhibited direct twitches in the chick biventer cervicis nerve-muscle preparation. At 3 μM, U1-viperitoxin-Dr1a abolished twitches, while U1-viperitoxin-Dr1b caused 70% inhibition of twitch force after 3h. Removal of both toxins from whole venom resulted in no in-vitro myotoxicity.ConclusionThe study shows that myotoxicity in Sri Lankan Russell’s viper envenoming is mild and non-life threatening, and due to two PLA2 toxins with weak myotoxic properties.

Neurotoxicity in Sri Lankan Russell's Viper (Daboia russelii) Envenoming is Primarily due to U1-viperitoxin-Dr1a, a Pre-Synaptic Neurotoxin.

Russell's vipers are snakes of major medical importance in Asia. Russell's viper (Daboia russelii) envenoming in Sri Lanka and South India leads to a unique, mild neuromuscular paralysis, not seen in other parts of the world where the snake is found. This study aimed to identify and pharmacologically characterise the major neurotoxic components of Sri Lankan Russell's viper venom. Venom was fractionated using size exclusion chromatography and reverse-phase high-performance liquid chromatography (RP-HPLC). In vitro neurotoxicities of the venoms, fractions and isolated toxins were measured using chick biventer and rat hemidiaphragm preparations. A phospholipase A2 (PLA2) toxin, U1-viperitoxin-Dr1a (13.6kDa), which constitutes 19.2% of the crude venom, was isolated and purified using HPLC. U1-viperitoxin-Dr1a produced concentration-dependent in vitro neurotoxicity abolishing indirect twitches in the chick biventer nerve-muscle preparation, with a t 90 of 55±7min only at 1μM. The toxin did not abolish responses to acetylcholine and carbachol indicating pre-synaptic neurotoxicity. Venom, in the absence of U1-viperitoxin-Dr1a, did not induce in vitro neurotoxicity. Indian polyvalent antivenom, at the recommended concentration, only partially prevented the neurotoxic effects of U1-viperitoxin-Dr1a. Liquid chromatography mass spectrometry analysis confirmed that U1-viperitoxin-Dr1a was the basic S-type PLA2 toxin previously identified from this venom (NCBI-GI: 298351762; SwissProt: P86368). The present study demonstrates that neurotoxicity following Sri Lankan Russell's viper envenoming is primarily due to the pre-synaptic neurotoxin U1-viperitoxin-Dr1a. Mild neurotoxicity observed in severely envenomed Sri Lankan Russell's viper bites is most likely due to the low potency of U1-viperitoxin-Dr1a, despite its high relative abundance in the venom.

Venom Concentrations and Clotting Factor Levels in a Prospective Cohort of Russell's Viper Bites with Coagulopathy.

BackgroundRussell’s viper envenoming is a major problem in South Asia and causes venom induced consumption coagulopathy. This study aimed to investigate the kinetics and dynamics of venom and clotting function in Russell’s viper envenoming.Methodology/Principal FindingsIn a prospective cohort of 146 patients with Russell’s viper envenoming, we measured venom concentrations, international normalised ratio [INR], prothrombin time (PT), activated partial thromboplastin time (aPTT), coagulation factors I, II, V, VII, VIII, IX and X, and von Willebrand factor antigen. The median age was 39y (16–82y) and 111 were male. The median peak INR was 6.8 (interquartile range[IQR]:3.7 to >13), associated with low fibrinogen [median,<0.01g/L;IQR:<0.01–0.9g/L), low factor V levels [median,<5%;IQR:<5–4%], low factor VIII levels [median,40%;IQR:12–79%] and low factor X levels [median,48%;IQR:29–67%]. There were smaller reductions in factors II, IX and VII over time. All factors recovered over 48h post-antivenom. The median INR remained >3 at 6h post-antivenom but had reduced to <2, by 24h. The aPTT had also returned to close to normal (<50sec) at 24h. Factor VII, VIII and IX levels were unusually high pre-antivenom, median peak concentrations of 393%, 307% and 468% respectively. Pre-antivenom venom concentrations and the INR (r = 0.20, p = 0.02) and aPTT (r = 0.19, p = 0.03) were correlated (non-parametric Spearman analysis).ConclusionsRussell’s viper coagulopathy results in prolonged aPTT, INR, low fibrinogen, factors V, VIII and X which recover over 48h. Severity of clotting abnormalities was associated with venom concentrations.

Detection of venom after antivenom is not associated with persistent coagulopathy in a prospective cohort of Russell's viper (Daboia russelii) envenomings.

BackgroundVenom recurrence or persistence in the circulation after antivenom treatment has been documented many times in viper envenoming. However, it has not been associated with clinical recurrence for many snakes, including Russell's viper (Daboia spp.). We compare the recovery of coagulopathy to the recurrence or persistence of venom in patients with Russell's viper envenoming.Methodology/Principal FindingsThe study included patients with Russell's viper (D. russelii) envenoming presenting over a 30 month period who had Russell's viper venom detected by enzyme immunoassay. Demographics, information on the snake bite, and clinical effects were collected for all patients. All patients had serum collected for venom specific enzyme immunoassay and citrate plasma to measure fibrinogen levels and prothrombin time (international normalised ratio; INR). Patients with venom recurrence/persistence were compared to those with no detectable recurrence of venom. There were 55 patients with confirmed Russell's viper envenoming and coagulopathy with low fibrinogen concentrations: 31 with venom recurrence/persistence, and 24 with no venom detected post-antivenom. Fibrinogen concentrations increased and INR decreased after antivenom in both the recurrence and non-recurrence patients. Clinical features, laboratory parameters, antivenom dose and length of hospital were similar for both groups. Pre-antivenom venom concentrations were higher in patients with venom recurrence/persistence with a median venom concentration of 385 ng/mL (16–1521 ng/mL) compared to 128 ng/mL (14–1492 ng/mL; p = 0.008).ConclusionRecurrence of Russell's viper venom was not associated with a recurrence of coagulopathy and length of hospital stay. Further work is required to determine if the detection of venom recurrence is due to the venom specific enzyme immunoassay detecting both venom-antivenom complexes as well as free venom.

Detection of venom–antivenom (VAV) immunocomplexes in vitro as a measure of antivenom efficacy

The measurement of free venom with enzyme immunoassay in serum of patients with snake envenoming is used to confirm snake identification and to determine if sufficient antivenom has been given. Recent studies with Russell's viper (RV; Daboia russelii) envenoming have detected free venom post-antivenom despite recovery of coagulopathy. This raises the question as to whether this assay also measures venom–antivenom (VAV) complexes. In this study we developed an assay to measure VAV complexes and investigate the binding of venom and antivenom in vitro. The assay consisted of rabbit anti-snake venom IgG attached to a microplate which binds the venom component of VAV and anti-horse IgG antibodies conjugated to horseradish peroxidase to detect the antivenom portion of VAV. A known amount of venom or toxin was incubated with increasing antivenom concentrations and VAV was detected as absorbance at 450 nm and plotted against AV concentration. Pseudonaja textilis (brown snake), Notechis scutatus (tiger snake), Oxyuranus scutellatus (taipan), Tropidechis carinatus (rough-scaled snake), Pseudechis porphyriacus (red-bellied black snake) and D. russelii mixtures with appropriate antivenoms were assayed. Measured VAV initially increased with increasing antivenom concentration until it reached a maximum after which the VAV concentration decreased with further increasing antivenom concentrations. The VAV curves for two Australian snake venom–antivenom mixtures, Hoplocephalus stephensii and Ancanthophis antarcticus, had broad VAV peaks with two maxima. Two fractions isolated from N. scutatus venom and Russell's viper factor X activator toxin produced similar VAV curves to their whole venoms. The antivenom concentration for which the maximum VAV occurred was linearly related to the venom concentration, and this slope or ratio was consistent with that used to define the neutralisation units for Australian antivenoms. The maximal VAV point appears to represent the antivenom concentration where every venom molecule (toxin) is attached to at least one antivenom molecule (antibody) on average and may be a useful measure of antivenom efficacy. In vivo this would mean that for a defined antivenom concentration, venom components will be eliminated and are trapped in the central compartment.

Diagnostic 20-min whole blood clotting test in Russell's viper envenoming delays antivenom administration

The 20-min whole blood clotting test (WBCT20) is widely used for the identification of coagulopathy in snake envenoming, but its performance in practice has not been evaluated. We aimed to investigate the diagnostic utility of the WBCT20 for coagulopathy in Russell's viper envenoming. Prospective observational study. Adult patients with snake envenoming were recruited. Age, sex, bite information, clinical effects, serial WBCT20 and antivenom treatment were recorded. Definite Russell's viper envenoming was confirmed with venom specific enzyme immunoassay. We assessed sensitivity of admission WBCT20 to coagulopathy (international normalized ratio, INR > 1.5) in Russell's viper envenoming, the specificity of negative WBCT20 in non-envenomed patients and directly compared paired WBCT20 and INR. Admission WBCT20 was done in 140 Russell's viper bites with coagulopathy and was positive in 56/140 [sensitivity 40% (95% confidence interval (CI): 32-49%)]. A negative WBCT20 led to delayed antivenom administration [WBCT20-ve tests: median delay, 1.78 h (interquartile range (IQR): 0.83-3.7 h) vs. WBCT20 + ve tests: median delay, 0.82 h (IQR: 0.58-1.48 h); P = 0.0007]. Delays to antivenom were largely a consequence of further WBCT20 being performed and more common if the first test was negative (41/84 vs. 12/56). Initial WBCT20 was negative in 9 non-envenomed patients and 48 non-venomous snakebites [specificity: 100% (95% CI: 94-100%)]. In 221 paired tests with INR > 1.5, the WBCT20 was positive in 91(41%). The proportion of positive WBCT20 only increased slightly with higher INR. In clinical practice, the WBCT20 has low sensitivity for detecting coagulopathy in snake envenoming and should not over-ride clinical assessment-based decisions about antivenom administration. There is an urgent need to develop a simple bedside test for coagulopathy in snake envenoming.

Acute pituitary insufficiency and hypokalaemia following envenoming by Russell's viper (Daboia russelii) in Sri Lanka: Exploring the pathophysiological mechanisms

Russell's viper envenoming is associated with a high incidence of morbidity and mortality. Hypopituitarism following envenoming by Russell's vipers is a well recognized sequel in Burma and parts of India but has been reported only once in Sri Lanka. Hypokalaemia following envenoming by Russell's viper has not been described. Here we describe the association of acute pituitary insufficiency and hypokalaemia following Russell's viper envenoming in Sri Lanka and review the literature in order to understand its pathophysiological basis. A previously healthy 21-year-old man was envenomed by a Russell's viper and treated with antivenom. Ten hours after the bite, he developed persistent hypotension, which responded promptly to intravenous dexamethasone. His hormone profiles were consistent with hypocortisolism secondary to acute pituitary insufficiency. He also developed hypokalaemia. Analysis of urine and serum electrolytes suggested redistribution of potassium in to the cells rather than renal loss. Hypotension and hypoglycaemic coma are life-threatening manifestations of acute pituitary insufficiency. Therefore prompt steroid administration in these setting is life saving. Awareness of these complications among physicians would help to make prompt diagnosis and initiate immediate life saving treatment.

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

BackgroundSnake 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 FindingsThis 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).ConclusionsA 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.Trial Registration www.slctr.lk SLCTR/2007/005

An open, randomized comparative trial of two antivenoms for the treatment of envenoming by Sri Lankan Russell's viper ( Daboia russelii russelii)

Russell's viper ( Daboia russelii russelii) is an important cause of morbidity and mortality in Sri Lanka. In a study in 1985, Haffkine equine polyspecific antivenom in doses up to 20 g proved ineffective in clearing antigenaemia and caused a high incidence of anaphylactoid reactions. A new, monospecific ovine Fabantivenom (PolongaTAb ™) has been developed against the venom of Sri Lankan Russell's viper and, to assess its safety and efficacy, we carried out (in 1997) an open, randomized comparison of this with the Hafikine antivenom currently in use in the country. Patients with systemic envenoming following Russell's viper bite were randomized to receive an initial intravenous dose of either 1 g of PolongaTAb ( n = 23) or 10g of Haffkine antivenom ( n = 20). One dose of PolongaTAb permanently restored blood coagulability in only 9 (41%) of 22 patients and 13 needed repeated doses, whereas the majority ( 14 20 ; 70%) had restored coagulability after 1 dose of Haffkine antivenom. There was a tendency towards more rapid resolution of local swelling and systemic manifestations in the Hafifkine group. Venom antigenaemia was eliminated more quickly in the Haffkine group and ovine Fab was cleared from the circulation more rapidly than equine F(ab′) 2. To evaluate safety, patients were closely observed for adverse reactions. Following a severe reaction with Haffkine antivenom all subsequent patients in this group were treated prophylactically with hydrocortisone and chlorpheniramine. Despite this, the incidence of adverse reactions was significantly higher in the Haffkine group compared with the PolongaTAb group (81% compared with 48%) and 4 patients had a severe anaphylactic reaction in the former group. In conclusion, the new antivenom is safer than Haffkine antivenom but, to avoid repeated doses, an initial dose higher than 1 g is needed in the treatment of Sri Lankan Russell's viper envenoming. The safety of this larger dose is the subject of further studies.

Therapeutic effects of antivenom supplemented by antithrombin III in rats experimentally envenomated with Russell's viper ( Daboia russelli siamensis) venom

The effects of equine antivenom and antithrombin III (AT-III) on the coagulopathy induced by Russell's viper venom (RVV, Daboia russelli siamensis) were investigated in the rat. After taking blood samples from the femoral vein for determination of simple blood clotting time and AT-III activity, all anaesthetized rats received an intramuscular injection of venom (2 μg/g). Treatment (antivenom or AT-III or both) was given intravenously through another femoral vein 30 min after venom injection. All untreated rats ( n = 7) developed AT-III depletion (<70%) [mean (S.D.)] 70 (36) min, and incoagulable blood 85 (53) min after venom injection. Supplementation with AT-III (either 0.25 U/g or 0.5 U/g) had no effect on the RVV induced coagulopathy ( n = 20). Treatment with antivenom alone (10 μg/g) reduced the incidence of abnormal clotting significantly (8/15, 53%) ( P = 0.03). When antivenom was given in combination with AT-III (0.5 U/g), abnormal clotting was prevented in all but one animal (1/15, 7%) ( P = 0.007). AT-III activity declined progressively in all rats which developed non-clotting blood. These results suggest that coagulopathy in Russell's viper envenoming is associated with activation of coagulation and consumption of AT-III. Antivenom can prevent coagulopathy, but its neutralizing activity is augmented significantly by AT-III supplementation.

Synergy of antithrombin III concentrate and antivenom in preventing coagulopathy in a rat model of Thai Russell's viper envenoming: A. Nontprasert, S. Pukrittayakamee, R. Clemens, P. Charoenlarp and N. J. White (Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; and Nuffield Department of Clinical Medicine, Oxford University, Oxford, U.K.)

Synergy of antithrombin III concentrate and antivenom in preventing coagulopathy in a rat model of Thai Russell's viper envenoming: A. Nontprasert, S. Pukrittayakamee, R. Clemens, P. Charoenlarp and N. J. White (Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; and Nuffield Department of Clinical Medicine, Oxford University, Oxford, U.K.)

Neutralization of pathophysiological manifestations of Russell's viper envenoming by antivenom raised against gamma-irradiated toxoid

Rabbits were immunized against gamma-irradiated (100 krads) Russell's viper venom toxoid adsorbed to aluminium phosphate gel. The antivenom (0.1 ml) neutralized 5 ld 50, 8 minimum hemorrhagic doses (MHD) and 14 minimum necrotic doses (MND) of venom. The coagulant and protease activities of the viper venom were neutralized more effectively than phospholipase A activity, by the toxoid antivenom.

Bites by Russell's vipers ( Daboia russelii siamensis) in Myanmar: effect of the snake's length and recent feeding on venom antigenaemia and severity of envenoming

An improved enzyme immunoassay technique (EIA) was used in the diagnosis of 311 suspected Russell's viper bite cases in Myanmar [Burma], 181 of whom (58%) had systemic envenoming. Russell's viper venom was detected in the sera of 175 (56·3%), cobra or green pit viper venoms in 4 (1·3%), and no venom in the remaining 132 (42·4). Among 175 of these patients who failed to bring the dead snake, EIA achieved a specific diagnosis of Russell's viper envenoming in 101 (58%). The serum venom antigen concentration was higher in patients with systemic envenoming than in those with local or no envenoming and it increased with the development of coagulopathy. Stomach contents were examined in 101 Russell's vipers responsible for bites. The presence of prey, usually a rodent, in the snake's stomach, indicating that it had eaten recently, did not influence the severity of envenoming, the initial venom level, or the percentage circumference increase and the extent of local swelling in the bitten limb. One hundred and fifty-five Russell's vipers responsible for bites showed a bimodal distribution of total lengths. The smaller snakes had probably been born that year. Longer snakes were responsible for more severe envenoming, a shorter interval between the bite and the detection of incoagulable blood, and more extensive local swelling with a greater percentage circumference increase of the bitten limb; but their bites were not associated with higher initial venom antigenaemia or a greater risk of developing acute renal failure.