Kalana Maduwage

Current Treatment for Venom-Induced Consumption Coagulopathy Resulting from Snakebite

Venomous snakebite is considered the single most important cause of human injury from venomous animals worldwide. Coagulopathy is one of the commonest important systemic clinical syndromes and can be complicated by serious and life-threatening haemorrhage. Venom-induced consumption coagulopathy (VICC) is the commonest coagulopathy resulting from snakebite and occurs in envenoming by Viperid snakes, certain elapids, including Australian elapids, and a few Colubrid (rear fang) snakes. Procoagulant toxins activate the clotting pathway, causing a broad range of factor deficiencies depending on the particular procoagulant toxin in the snake venom. Diagnosis and monitoring of coagulopathy is problematic, particularly in resource-poor countries where further research is required to develop more reliable, cheap clotting tests. MEDLINE and EMBASE up to September 2013 were searched to identify clinical studies of snake envenoming with VICC. The UniPort database was searched for coagulant snake toxins. Despite preclinical studies demonstrating antivenom binding toxins (efficacy), there was less evidence to support clinical effectiveness of antivenom for VICC. There were no placebo-controlled trials of antivenom for VICC. There were 25 randomised comparative trials of antivenom for VICC, which compared two different antivenoms (ten studies), three different antivenoms (four), two or three different doses or repeat doses of antivenom (five), heparin treatment and antivenom (five), and intravenous immunoglobulin treatment and antivenom (one). There were 13 studies that compared two groups in which there was no randomisation, including studies with historical controls. There have been numerous observational studies of antivenom in VICC but with no comparison group. Most of the controlled trials were small, did not use the same method for assessing coagulopathy, varied the dose of antivenom, and did not provide complete details of the study design (primary outcomes, randomisation, and allocation concealment). Non-randomised trials including comparison groups without antivenom showed that antivenom was effective for some snakes (e.g., Echis), but not others (e.g., Australasian elapids). Antivenom is the major treatment for VICC, but there is currently little high-quality evidence to support effectiveness. Antivenom is not risk free, and adverse reactions can be quite common and potentially severe. Studies of heparin did not demonstrate it improved outcomes in VICC. Fresh frozen plasma appeared to speed the recovery of coagulopathy and should be considered in bleeding patients.

Epidemiology and clinical effects of Hump-nosed pit viper (Genus: Hypnale) envenoming in Sri Lanka

Hump-nosed pit vipers of Genus Hypnale are the commonest cause of snake bite in Sri Lanka. Although there are many reports of local effects, coagulopathy and acute kidney injury, it remains unclear how frequent these clinical effects are and therefore the medical importance of this snake genus. The genus has been recently revised to include Hypnale hypnale from Sri Lanka and Western Ghats of Southern India, and the two endemic species to Sri Lanka, Hypnale zara and Hypnale nepa. This was a prospective hospital-based clinical study of definite Hypnale spp. bites from July 2008 to July 2010 in six Sri Lankan hospitals. There were 114 patients included and all snakes were correctly identified by hospital staff as Hypnale spp. Of these, 93 snakes were identified as H. hypnale by an expert, 16 as H. zara and five as H. nepa. Most bites occurred on the lower limbs in the daytime. There was no difference in the clinical effects between the three species. Pain and fang marks were present in all patients, 101 had local swelling and only 16 (14%) developed extensive local swelling that spread proximally and involved more than half of the bitten limb. Systemic symptoms occurred in 18 patients; four patients had an abnormal 20 min whole blood clotting test and one patient developed an acute kidney injury that required haemodialysis. All patients were discharged alive with a median length of stay of 2 days. This study confirms that hump-nosed viper bites cause only minor effects in most cases. Future studies need to undertake formal coagulation studies and identify important early indicators of renal impairment.

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

BACKGROUND 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. AIM We aimed to investigate the diagnostic utility of the WBCT20 for coagulopathy in Russells viper envenoming. DESIGN Prospective observational study. METHODS Adult patients with snake envenoming were recruited. Age, sex, bite information, clinical effects, serial WBCT20 and antivenom treatment were recorded. Definite Russells viper envenoming was confirmed with venom specific enzyme immunoassay. We assessed sensitivity of admission WBCT20 to coagulopathy (international normalized ratio, INR > 1.5) in Russells viper envenoming, the specificity of negative WBCT20 in non-envenomed patients and directly compared paired WBCT20 and INR. RESULTS Admission WBCT20 was done in 140 Russells 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. CONCLUSION 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.

Neuromuscular Effects of Common Krait (Bungarus caeruleus) Envenoming in Sri Lanka.

Objective We aimed to investigate neurophysiological and clinical effects of common krait envenoming, including the time course and treatment response. Methodology Patients with definite common krait (Bungarus caeruleus) bites were recruited from a Sri Lankan hospital. All patients had serial neurological examinations and stimulated concentric needle single-fibre electromyography (sfEMG) of orbicularis oculi in hospital at 6wk and 6–9mth post-bite. Principal Findings There were 33 patients enrolled (median age 35y; 24 males). Eight did not develop neurotoxicity and had normal sfEMG. Eight had mild neurotoxicity with ptosis, normal sfEMG; six received antivenom and all recovered within 20–32h. Seventeen patients developed severe neurotoxicity with rapidly descending paralysis, from ptosis to complete ophthalmoplegia, facial, bulbar and neck weakness. All 17 received Indian polyvalent antivenom a median 3.5h post-bite (2.8–7.2h), which cleared unbound venom from blood. Despite this, the paralysis worsened requiring intubation and ventilation within 7h post-bite. sfEMG showed markedly increased jitter and neuromuscular blocks within 12h. sfEMG abnormalities gradually improved over 24h, corresponding with clinical recovery. Muscle recovery occurred in ascending order. Myotoxicity was not evident, clinically or biochemically, in any of the patients. Patients were extubated a median 96h post-bite (54–216h). On discharge, median 8 days (4–12days) post-bite, patients were clinically normal but had mild sfEMG abnormalities which persisted at 6wk post-bite. There were no clinical or neurophysiological abnormalities at 6–9mth. Conclusions Common krait envenoming causes rapid onset severe neuromuscular paralysis which takes days to recover clinically consistent with sfEMG. Subclinical neuromuscular dysfunction lasts weeks but was not permanent. Antivenom effectively cleared venom but did not prevent worsening or reverse neuromuscular paralysis.

Revisiting Russell's viper (Daboia russelii) bite in Sri Lanka: is abdominal pain an early feature of systemic envenoming?

The Russells viper (Daboia russelii) is responsible for 30–40% of all snakebites and the most number of life-threatening bites of any snake in Sri Lanka. The clinical profile of Russells viper bite includes local swelling, coagulopathy, renal dysfunction and neuromuscular paralysis, based on which the syndromic diagnostic tools have been developed. The currently available Indian polyvalent antivenom is not very effective in treating Russells viper bite patients in Sri Lanka and the decision regarding antivenom therapy is primarily driven by clinical and laboratory evidence of envenoming. The non-availability of early predictors of Russells viper systemic envenoming is responsible for considerable delay in commencing antivenom. The objective of this study is to evaluate abdominal pain as an early feature of systemic envenoming following Russells viper bites. We evaluated the clinical profile of Russells viper bite patients admitted to a tertiary care centre in Sri Lanka. Fifty-five patients were proven Russells viper bite victims who produced the biting snake, while one hundred and fifty-four were suspected to have been bitten by the same snake species. Coagulopathy (159, 76.1%), renal dysfunction (39, 18.7%), neuromuscular paralysis (146, 69.9%) and local envenoming (192, 91.9%) were seen in the victims, ranging from mono-systemic involvement to various combinations. Abdominal pain was present in 79.5% of these patients, appearing 5 minutes to 4 hours after the bite. The severity of the abdominal pain, assessed using a scoring system, correlated well with the severity of the coagulopathy (p<0.001) and the neurotoxicity (p<0.001). Its diagnostic validity to predict systemic envenoming is – Sensitivity 81.6%, Specificity 82.4%, Positive predictive value 91.2%. Thus, abdominal pain is an early clinical feature of systemic Russells viper bite envenoming in Sri Lanka. However, it is best to judge abdominal pain together with other clinical manifestations on decision making.

Neurotoxicity in Russell’s viper (Daboia russelii) envenoming in Sri Lanka: a clinical and neurophysiological study

Abstract Context: Russell’s viper is more medically important than any other Asian snake, due to number of envenoming’s and fatalities. Russell’s viper populations in South India and Sri Lanka (Daboia russelii) cause unique neuromuscular paralysis not seen in other Russell’s vipers. Objective: To investigate the time course and severity of neuromuscular dysfunction in definite Russell’s viper bites, including antivenom response. Methodology: We prospectively enrolled all patients (>16 years) presenting with Russell’s viper bites over 14 months. Cases were confirmed by snake identification and/or enzyme immunoassay. All patients had serial neurological examinations and in some, single fibre electromyography (sfEMG) of the orbicularis oculi was performed. Results: 245 definite Russell’s viper bite patients (median age: 41 years; 171 males) presented a median 2.5 h (interquartile range: 1.75–4.0 h) post-bite. All but one had local envenoming and 199 (78%) had systemic envenoming: coagulopathy in 166 (68%), neurotoxicity in 130 (53%), and oliguria in 19 (8%). Neurotoxicity was characterised by ptosis (100%), blurred vision (93%), and ophthalmoplegia (90%) with weak extraocular movements, strabismus, and diplopia. Neurotoxicity developed within 8 h post-bite in all patients. No bulbar, respiratory or limb muscle weakness occurred. Neurotoxicity was associated with bites by larger snakes (p < 0.0001) and higher peak serum venom concentrations (p = 0.0025). Antivenom immediately decreased unbound venom in blood. Of 52 patients without neurotoxicity when they received antivenom, 31 developed neurotoxicity. sfEMG in 27 patients with neurotoxicity and 23 without had slightly elevated median jitter on day 1 compared to 29 normal subjects but normalised thereafter. Neurological features resolved in 80% of patients by day 3 with ptosis and weak eye movements resolving last. No clinical or neurophysiological abnormality was detected at 6 weeks or 6 months. Conclusion: Sri Lankan Russell’s viper envenoming causes mild neuromuscular dysfunction with no long-term effects. Indian polyvalent antivenom effectively binds free venom in blood but does not reverse neurotoxicity.

Revisiting saw-scaled viper (Echis carinatus) bites in the Jaffna Peninsula of Sri Lanka: Distribution, epidemiology and clinical manifestations

In Sri Lanka, the saw-scaled viper (Echis carinatus) is distributed in the arid, dry and sandy coastal plains and in a prospective study we describe its bites in the Jaffna peninsula. Of the 304 snake bite admissions to the Jaffna Hospital in 2009, 217 (71.4%) were bitten by either venomous species or envenomed by unidentified snakes. There were 99 (45.6%) reported saw-scaled viper bites, of which 26 were confirmed cases. The length of the offending snakes ranged from 228-310mm and bites mainly occurred in the nearby islands. The median age of the confirmed cases was 34 years (range 1.5-72 years); occupations included housewives (8, 31%), school children (4, 15%) and farmers (2, 8%). In 18 patients (69%), bites occurred in daylight and in 8 (31%) within or near the compounds. The fingers were bitten in 8 (31%) and toes/foot in 11 (42%) cases. There were 2 (8%) dry bites and 19 patients (73%) developed local swelling; one patient developed haemorrhagic blisters. In 24 patients (92%), blood incoagulability manifested between 40 and 1095min after the bite, and three patients (12%) developed spontaneous bleeding. One patient (4%) developed mild acute renal dysfunction. The median time for correction of coagulopathy was 802min (range 180-1669min) with Indian polyvalent antivenom. All recovered. The saw scaled viper is responsible for most venomous bites in the Jaffna peninsula.

Coagulopthy, acute kidney injury and death following Hypnale zara envenoming: the first case report from Sri Lanka.

Snakebite is a major medical problem in developing Asia. Hump-nosed pit viper (Genus Hypnale) causes the most number of snakebites with significant morbidity and mortality in Sri Lanka. Even though there are three species (Hypnale hypnale, Hypnale zara and Hypnale nepa) in Sri Lanka there are few published literature on species-specific clinico-epidemiological data. This report describes an authenticated fatal case of a 47 years old male due to coagulopthy and acute kidney injury following envenoming by H. zara in Sri Lanka.

Hump-nosed pit viper (Hypnale hypnale) envenoming causes mild coagulopathy with incomplete clotting factor consumption

Context. Limited information exists on the coagulopathy caused by hump-nosed pit viper (Hypnale hypnale) envenoming. Objectives. This study aimed to characterise the coagulopathy in hump-nosed pit viper bites by measuring laboratory clotting times and factor studies. Materials and methods. Cases of hump-nosed pit viper envenoming were included from a prospective cohort study of Sri Lankan snake-bite patients. Patient age, sex, snake identification, time of bite and clinical effects were recorded. Patients did not receive anti-venom because no specific anti-venom to hump-nosed vipers exists. All patients received supportive care and serial 20-min whole blood clotting tests (WBCT20). The prothrombin time (PT), international normalised ratio (INR), activated partial thromboplastin time (aPTT), coagulation factors I, II, V, VII, VIII, IX and X, von Willebrand factor (vWF) antigen and D-Dimer concentrations were measured. The median of highest or lowest test result for each patient was reported with interquartile range (IQR). Results. There were 80 hump-nosed pit viper bites, median age was 37 years (IQR: 26–51 years) and 48 were male. The WBCT20 was positive in one patient. The median highest INR was 1.9 (1.5–2.2; Range: 1.3 to > 12) and median highest aPTT was 54 s (46–72 s; Range: 35–170 s). There was low fibrinogen [median: 1.3 g/L;1, –1.8 g/L; Range: < 0.2–2.9], low factor VIII levels [median: 23%; 16–37%] and low factor V levels [median: 43%; 23–74%]. D-Dimer concentrations [median: 3.4 mg/L; 2–7.4 mg/L] were slightly elevated. Factors II, VII and X and vWF antigen concentrations were normal. Discussion and Conclusions. Hump-nosed pit viper bites result in a mild coagulopathy which is usually not detected by a WBCT20. It is characterised by mild elevation of INR, low fibrinogen and Factors V and VIII which may be consistent with the venom containing a thrombin-like enzyme.

Parallels between Russell's viper (Daboia russelii) and hump–nosed viper (Hypnale species) bites in the central hills of Sri Lanka amidst the heavy burden of unidentified snake bites

OBJECTIVE To describe the epidemiology of snake bite in the region and attempt to compare proven Russells viper with hump-nosed viper bites. METHODS All snake bite admissions to the Toxicology Unit of Teaching Hospital Peradeniya over three year from 2006 were included. RESULTS Of the 776 snakebites, 665(86%) were unidentified and non-envenomed. Hump-nosed viper and Russells viper accounted for 55(7%) and 40(5%) bites respectively, of them, incriminated snakes were found in 36(65%) and 19(48%) cases. The cobra bites-5, krait bites-0. The median ages: Russells viper bites-41(range 16-66), hump-nosed viper bites-42(range 15-75). The gender incidence, time of bite (>58% daytime) were similar. In hump-nosed viper bite; upper limb involved in 13(36%), happened at home garden in 22(61%), none in paddy fields. In Russells viper bite; 6(33%) occurred in paddy fields. Dry bites were similar at 5%. In hump-nosed viper bite: local effects 94%, coagulopathy 3%, acute renal failure 3% and one patient died. In Russells viper bite; local effects 84%, coagulopathy 53%, neurotoxicity 21%. Abdominal pain occurred only in Russells viper bites 10(53%). CONCLUSIONS Overwhelming numbers of unidentified, non-envenomed snakebites are common in the central hills. Some distinctive differences were observed between Russells viper and hump-nosed viper bites.