Compliance with national snakebite treatment guidelines in rural Sri Lankan hospitals: a cluster randomized controlled trial of a brief educational intervention.

BACKGROUND: Snakebite is a global health problem that predominantly occurs in rural areas. In Sri Lanka, the majority of snakebite patients first present to smaller rural primary hospitals. Improving care delivered at rural hospitals has the potential to reduce morbidity and mortality from snakebites. OBJECTIVE: In this study, we evaluated whether an educational intervention would increase compliance with national snakebite treatment guidelines in primary hospitals. METHODS: The hospitals were randomized into educational intervention (n = 24) and control groups (n = 20). The intervention hospitals received a brief educational intervention based on Sri Lankan Medical Association (SLMA) guidelines on the management of snakebites. Control hospitals had free access to the guidelines but no additional promotion. Four outcomes were assessed: pre- and post-test knowledge at the completion of a one-day workshop of educational intervention (intervention group only); improvement in the quality of the patient's medical records; appropriateness of transfers to higher hospitals; and quality of overall management graded by a blinded expert. The data was collected over a period of 12 months. RESULTS: All case notes of snakebite hospital admissions were reviewed. There were 1021 cases in the intervention group hospitals and 1165 cases in the control hospitals. Four hospitals in the intervention group and three hospitals in the control group did not have snakebite admissions and were excluded from the cluster analysis. The absolute quality of care was high in both groups. Post-test knowledge was improved (p < 0.0001) following the intervention group's educational workshop. There was no statistical difference between the two groups in terms of clinical data documentation in hospital notes (scores, p = 0.58) or transfer appropriateness (p = 0.68)-both of which were significantly different from the guidelines. CONCLUSION: Education of primary hospital staff improved the immediate knowledge gained but did not improve record-keeping or the appropriateness of inter-hospital patient transfer. TRIAL REGISTRATION: The study was registered with Sri Lanka Medical Associations' clinical trial registry. Reg. No SLCTR -2013-023. Registered: 30/07/2013.

Epidemiology and renal injury following 2-methyl-4-chlorophenoxyacetic acid (MCPA) poisoning.

2-Methyl-4-chlorophenoxyacetic acid (MCPA) is a widely used chlorophenoxy herbicide. MCPA poisoning causes mitochondrial dysfunction, which can lead to kidney injury and death. The objective of this study is to describe the epidemiology, case fatality and extent of renal injury in a large cohort of MCPA self-poisonings. The study consists of two parts: (1) A report of epidemiological data and clinical outcomes in MCPA poisoned patients in Sri Lanka between 2002 and 2019; (2) Evaluation of acute kidney injury (AKI) using renal biomarkers in a subset from this cohort. Serum creatinine (sCr) and biomarkers were measured soon after hospitalization (2 [IQR 1-3] h) and at different time intervals. We measured serum biomarkers: sCr, cystatin C (sCysC), creatine kinase (CK), and urinary biomarkers: creatinine, kidney injury molecule-1 (KIM-1), clusterin, albumin, beta-2-microglobulin (ß2M), cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), trefoil factor 3 (TFF3) and cytochrome C (CytoC). Kidney Disease Improving Global Outcomes (KDIGO) criteria was used to define acute kidney injury (AKI). There were 1653 patients; 65% were male. The median time from ingestion to examination was 3:54 (IQR 2:19-6:57) h. The overall case-fatality rate was 5.3%. Patients who died were older (42 [IQR 33.5-54] vs 27 [IQR 20-37] for survivors). The median estimated amount of MCPA ingested by patients who died was also greater (88 [IQR 34-200] vs. 30 [IQR 15-63] ml in survivors). Moderate to severe AKI (AKI2/3) was uncommon (6/59 patients in the biomarker study had KDIGO stage 2 or 3). Most patients in AKI2/3 group with increased sCr were older (median age 35 years [IQR 27-41]) compared to No AKI (23 years (19-29) years) or AKI1 (26 years (21-40) years) group who had no or mild increase in sCr. These patients had no pre-existing kidney diseases. In these patients, serum creatinine (maximum medium concentration; 1.12 [IQR 0.93-1.67] mg/dl) and CK (maximum medium concentration; 284 [IQR 94-428] U/l) were increased but sCysC (maximum medium concentration; 0.79 [IQR 0.68-0.81] mg/l) remained in the normal range within 72 h. All urinary biomarkers performed poorly in diagnosing AKI (area under the receiver operating characteristic curve < 0.68). The higher numbers of men with MCPA poisoning likely reflects greater occupational access to pesticides. Fatal outcome and higher ingested dose were more common in the elderly. Significant AKI with tubular injury biomarkers was uncommon. Most people with raised sCr were older and appeared to have no pre-existing kidney disease.

The clinical toxicity of imidacloprid self-poisoning following the introduction of newer formulations.

BACKGROUND: Self-poisoning with imidacloprid has been previously shown to have low toxicity in humans. Since 2007 newer formulations of Imidacloprid with unknown solvents have been introduced and the potential clinical consequences of these products have not been described. METHODS: Clinical and demographic data were prospectively collected from admissions following oral ingestion of imidacloprid from seven hospitals in Sri Lanka. Data was collected from 2002 to 2007 in an already published study. We compared this data on poisonings collected from 2010 to 2016 following the introduction of new formulations of imidacloprid. RESULTS: From 2002-2007, there were 56 patients with ingestion to imidacloprid compared to 67 patients post 2010 The median time to presentation prior to 2007 was 4 h (IQR 2.3-6.0 hrs) and post 2010 was only 2.0 hr (IQR 1.5 to 3.1 hrs). The median amount ingested was 15 ml (IQR 10.0-50.0mls) prior to 2007 and 27.5mls (IQR 5.0-71.8mls) post 2010. In both studies most patients developed non-specific symptoms including nausea, vomiting, epigastric pain and headache. However, prior to 2007 only 1.9% of the cohort required mechanical ventilation due to respiratory failure and there were no reported deaths. In contrast, post 2010; deaths occurred in 3.0% of the cohort and 6.0% required mechanical ventilation for respiratory failure. The cause of mortality was due to one case of cardiorespiratory failure and the other due to a prolonged admission complicated with lobar pneumonia leading to decompensated liver failure on the background of undiagnosed liver cirrhosis. CONCLUSION: Although acute exposure to imidacloprid is usually associated with mild non-specific symptoms, since the introduction of new formulations of imidacloprid, the toxic profile has changed with reported cases of death as well as an increase in cases requiring mechanical ventilation. The change in toxicity could be due to the solvents used in the newer formulations but also due to higher dose of imidacloprid described in our latter cohort. Further research into these solvents needs to be done and continued toxicovigilance is required.

A pilot clinical study of the neuromuscular blocker rocuronium to reduce the duration of ventilation after organophosphorus insecticide poisoning.

Background: A common manifestation of organophosphorus insecticide self-poisoning is prolonged respiratory failure due to neuromuscular junction dysfunction and likely nicotinic receptor overstimulation. We aimed at collecting preliminary data on whether addition of the competitive nicotinic antagonist rocuronium to standard early therapy might be clinically feasible and associated with reduced duration of ventilation.Methods: A pilot three-arm dose-response phase II trial was set up to compare bolus doses of rocuronium bromide titrated to produce initial >95% or 50% inhibition of neuromuscular function, measured using acceleromyography, plus standard treatment, versus standard treatment alone. After attaining inhibition, patients receiving bolus rocuronium then received rocuronium infusions for a maximum of 120 h. Primary outcome was duration of intubation; secondary outcome was case fatality. Plasma butyrylcholinesterase activity was measured throughout the inpatient stay. Blood was analysed to confirm the organophosphorus insecticide ingested.Results: Forty-five patients were randomised to receive: rocuronium to initially attain 95% inhibition (Roc>95, n = 15), rocuronium to initially attain 50% inhibition (Roc50, n = 14), or no rocuronium (control, n = 16). The most commonly ingested pesticide was profenofos (29/45, 64.4%). Butyrylcholinesterase activity remained severely inhibited for the duration of the study for most patients. Case fatality was 9/45 (20%) and similar across study arms: control 3/16 (18.8%), Roc50 4/14 (28.6%) and Roc>95 2/15 (13.3%) (p = .5842). When excluding patients who died, median [IQR] duration of intubation was significantly longer in the Roc50 (259.5 [176-385] h) and Roc>95 (226.8 [186-355] h) groups compared to controls (88.5 [47-160] h, p = .0162 and p = .0016, respectively).Conclusions: In this pilot dose-response study, we found no evidence that rocuronium in addition to standard therapy reduced the duration of intubation. It is possible that it worsened neuromuscular junction function. Further clinical research, including testing of shorter duration regimens, needs to be performed before nicotinic antagonists can be used in the clinical management of OP poisoning.

Albuminuria and other renal damage biomarkers detect acute kidney injury soon after acute ingestion of oxalic acid and potassium permanganate.

BACKGROUND: Deliberate self-poisoning with a combination washing powder containing oxalic acid (H2C2O4) and potassium permanganate (KMnO4) is a significant medical problem in the Southern Province of Sri Lanka. Acute kidney injury (AKI) is a frequent consequence. Biomarkers for early diagnosis of nephrotoxicity could guide appropriate supportive therapies. METHODS: We investigated the performance of three serum biomarkers and nine urinary biomarkers in 85 patients in an ongoing multicenter prospective cohort study in Sri Lanka exploring AKI following poisoning. RESULTS: Sixty two (62/85, 73%) patients developed AKI (acute kidney injury network, AKIN, criteria). Early and rapid increases in serum creatinine (sCr) peaking on day 3 were observed in AKIN stage 2 and 3 patients. In these patients, serum cystatin C (sCysC) rose more gradually but also peaked on day 3. Biomarker concentrations (normalized to urinary creatinine) of urinary albumin (uAlbumin), clusterin (uClusterin), beta-2-microglobulin (uB2M), osteopontin (uOPN), neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (uKIM-1) in the AKIN2/3 group increased above the 95th centile concentration of the healthy population. Within 8 h of ingestion, the normalized uAlbumin and sCysC predicted AKIN2/3 with respective area under receiver operating characteristic curve, AUC-ROC values, of 0.94 (95% CI 0.86-1.00) and 0.85 (95% CI 0.76-0.95). CONCLUSIONS: Urinary albumin was the best performing AKI biomarker following ingestion of H2C2O4/KMnO4. This may reflect glomerular injury and/or proximal tubular injury. The urinary albumin concentrations observed in this study could generally be detected using albumin specific dipstick methods, easily available even in resource poor settings.

Clinico-epidemiology of arthropod stings and bites in primary hospitals of North Western province of Sri Lanka.

OBJECTIVE: Arthropod stinging and bites are common environmental hazards in Sri Lanka. However, their medical importance has not been fully evaluated yet. This study aims to study the burden, epidemiology, and outcome of stings and bites in primary hospitals in the Kurunegala district in North Western Province (NWP) of Sri Lanka. METHODOLOGY: The study was conducted one year from 25th May 2013 to 25th May 2014. Details of all stings and bites admissions and their outcomes were retrospectively extracted from hospital records in all 44 primary hospitals in the district. RESULTS: There were 623 stings and bites with population incidence of 38/100,000 (95% CI 27-52). There were no deaths. Median age was 38 years (IQR: 19-53 years), and 351 (56%) were males. Most of stings and bites (75%) occurred in the daytime. Median time to hospital arrival was 55 minutes (IQR: 30 min to 2 h). The offending arthropods had been identified in 557 (89%) cases, of them, 357 (57%) were Hymenoptera (hornet and bees), 99 centipedes, 61 spiders and 40 scorpions. Local pain occurred in 346 (56%) cases - centipede 69 (70%), Scorpion 24 (60%), spider 36 (59%), Hymenoptera 187 (52%) and unidentified 30 (45%). Hymenoptera stings and spider bites occurred between 06 am to 12 noon, and scorpion stings and centipede bites mostly occurred between 06 pm to 12 midnight. Mild, moderate to severe anaphylaxis reactions occurred in 173 (28%) patients including 110 Hymenoptera stings - mild 39, moderate 62 and severe 9. From primary hospitals, 53(9%) cases had been transferred to tertiary care units for further management. Of them, 41 cases were Hymenoptera stings and 24 (58%) of them had mild, moderate to severe anaphylaxis. In the entire group, 27% severe cases received adrenaline. CONCLUSIONS: The primary hospitals in NW province of Sri Lanka manage large numbers of arthropod stings and bites. These include Hymenoptera (hornet and bee), centipedes, spiders, and scorpions. Pain, swellings and anaphylactic reactions were the most common adverse effects.

A prospective cohort study of the effectiveness of the primary hospital management of all snakebites in Kurunegala district of Sri Lanka.

INTRODUCTION: Sri Lanka records substantial numbers of snakebite annually. Primary rural hospitals are important contributors to health care. Health care planning requires a more detailed understanding of snakebite within this part of the health system. This study reports the management and epidemiology of all hospitalised snakebite in the Kurunegala district in Sri Lanka. METHODOLOGY: The district has 44 peripheral/primary hospitals and a tertiary care hospital-Teaching Hospital, Kurunegala (THK). This prospective study was conducted over one year. All hospitals received copies of the current national guidelines on snakebite management. Clinical and demographic details of all snakebite admissions to primary hospitals were recorded by field researchers and validated by comparing with scanned copies of the medical record. Management including hospital transfers was independently assessed against the national guidelines recommendation. Population rates were calculated and compared with estimates derived from recent community based surveys. RESULTS: There were 2186 admissions of snakebites and no deaths in primary hospitals. An additional 401 patients from the district were admitted directly to the teaching hospital, 2 deaths were recorded in this group. The population incidence of hospitalized snakebite was 158/100,000 which was significantly lower than community survey estimates of 499/100,000. However there was no significant difference between the incidence of envenomation of 126/100,000 in hospitalised patients and 184/100,000 in the community survey. The utilisation of antivenom was appropriate and consistent with guidelines. Seventy patients received antivenom. Anaphylactic reactions to antivenom occurred in 22 patients, treatment reactions was considered to be outside the guidelines in 5 patients. Transfers from the primary hospital occurred in 399(18%) patients but the majority (341) did not meet the guideline criteria. A snake was identified in 978 cases; venomous snakebites included 823 hump-nosed viper (Hypnalespp), 61 Russell's viper, 14 cobra, 13 common krait, 03 saw scaled viper. CONCLUSIONS: Primary hospitals received a significant number of snakebites that would be missed in surveys conducted in tertiary hospitals. Adherence to guidelines was good for the use of antivenom but not for hospital transfer or treatment of anaphylaxis. The large difference in snakebite incidence between community and hospital studies could possibly be due to non-envenomed patients not presenting. As the majority of snakebite management occurs in primary hospitals education and clinical support should be focused on that part of the health system.

Serum creatinine and cystatin C provide conflicting evidence of acute kidney injury following acute ingestion of potassium permanganate and oxalic acid.

AIM: Acute kidney injury (AKI) is common following deliberate self-poisoning with a combination washing powder containing oxalic acid (H2C2O4) and potassium permanganate (KMnO4). Early and rapid increases in serum creatinine (sCr) follow severe poisoning. We investigated the relationship of these increases with direct nephrotoxicity in an ongoing multicenter prospective cohort study in Sri Lanka exploring AKI following poisoning. METHODS: Multiple measures of change in kidney function were evaluated in 48 consenting patients who had serial sCr and serum cystatin C (sCysC) data available. RESULTS: Thirty-eight (38/48, 79%) patients developed AKI (AKIN criteria). Twenty-eight (58%) had AKIN stage 2 or 3. Initial increases in urine creatinine (uCr) excretion were followed by a substantial loss of renal function. The AKIN stage 2 and 3 (AKIN2/3) group had very rapid rises in sCr (a median of 118% at 24 h and by 400% at 72 h post ingestion). We excluded the possibility that the rapid rise resulted from the assay used or muscle damage. In contrast, the average sCysC increase was 65% by 72 h. CONCLUSIONS: In most AKI, sCysC increases to the same extent but more rapidly than sCr, as sCysC has a shorter half-life. This suggests either a reduction in Cystatin C production or, conversely, that the rapid early rise of sCr results from increased production of creatine and creatinine to meet energy demands following severe oxidative stress mediated by H2C2O4 and KMnO4. Increased early creatinine excretion supports the latter explanation, since creatinine excretion usually decreases transiently in AKIN2/3 from other causes.

Mechanism-specific injury biomarkers predict nephrotoxicity early following glyphosate surfactant herbicide (GPSH) poisoning.

Acute kidney injury (AKI) is common following glyphosate surfactant herbicide (GPSH) self-poisoning. Serum creatinine (sCr) is the most widely used renal biomarker for diagnosis of AKI although a recent study in rats suggested that urinary kidney injury molecule-1 predicted AKI earlier and better after GPSH-induced nephrotoxicity. We explored the utility of a panel of biomarkers to diagnose GPSH-induced nephrotoxicity in humans. In a prospective multi-centre observational study, serial urine and blood samples were collected until discharge and at follow-up. The diagnostic performance of each biomarker at various time points was assessed. AKI was diagnosed using the Acute Kidney Injury Network (AKIN) definitions. The added value of each biomarker to sCr to diagnose AKI was assessed by the integrated discrimination improvement (IDI) metric. Of 90 symptomatic patients, 51% developed AKI and 5 patients who developed AKIN≥2 died. Increased sCr at 8 and 16h predicted moderate to severe AKI and death. None of the 10 urinary biomarkers tested increased above normal range in patients who did not develop AKI or had mild AKI (AKIN1); most of these patients also had only minor clinical toxicity. Absolute concentrations of serum and urinary cystatin C, urinary interleukin-18 (IL-18), Cytochrome C (CytoC) and NGAL increased many fold within 8h in patients who developed AKIN≥2. Maximum 8 and 16h concentrations of these biomarkers showed an excellent diagnostic performance (AUC-ROC ≥0.8) to diagnose AKIN≥2. However, of these biomarkers only uCytoC added value to sCr to diagnose AKI when assessed by IDI metrics. GPSH-induced nephrotoxicity can be diagnosed within 24h by sCr. Increases in uCytoC and uIL-18 confirm GPSH-induces apoptosis and causes mitochondrial toxicity. Use of these biomarkers may help to identify mechanism specific targeted therapies for GPSH nephrotoxicity in clinical trials.

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

BACKGROUND: Russell'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 FINDINGS: In 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 39 y (16-82 y) and 111 were male. The median peak INR was 6.8 (interquartile range [IQR]: 3.7 to >13), associated with low fibrinogen [median,<0.01 g/L; IQR: <0.01-0.9 g/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 48 h post-antivenom. The median INR remained >3 at 6 h post-antivenom but had reduced to <2, by 24 h. The aPTT had also returned to close to normal (<50 sec) at 24 h. 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). CONCLUSIONS: Russell's viper coagulopathy results in prolonged aPTT, INR, low fibrinogen, factors V, VIII and X which recover over 48 h. Severity of clotting abnormalities was associated with venom concentrations.

Mechanisms underlying early rapid increases in creatinine in paraquat poisoning.

BACKGROUND: Acute kidney injury (AKI) is common after severe paraquat poisoning and usually heralds a fatal outcome. The rapid large increases in serum creatinine (Cr) exceed that which can be explained by creatinine kinetics based on loss of glomerular filtration rate (GFR). METHODS AND FINDINGS: This prospective multi-centre study compared the kinetics of two surrogate markers of GFR, serum creatinine and serum cystatin C (CysC), following paraquat poisoning to understand and assess renal functional loss after paraquat poisoning. Sixty-six acute paraquat poisoning patients admitted to medical units of five hospitals were included. Relative changes in creatinine and CysC were monitored in serial blood and urine samples, and influences of non-renal factors were also studied. RESULTS: Forty-eight of 66 patients developed AKI (AKIN criteria), with 37 (56%) developing moderate to severe AKI (AKIN stage 2 or 3). The 37 patients showed rapid increases in creatinine of >100% within 24 hours, >200% within 48 hours and >300% by 72 hours and 17 of the 37 died. CysC concentration increased by 50% at 24 hours in the same 37 patients and then remained constant. The creatinine/CysC ratio increased 8 fold over 72 hours. There was a modest fall in urinary creatinine and serum/urine creatinine ratios and a moderate increase in urinary paraquat during first three days. CONCLUSION: Loss of renal function contributes modestly to the large increases in creatinine following paraquat poisoning. The rapid rise in serum creatinine most probably represents increased production of creatine and creatinine to meet the energy demand following severe oxidative stress. Minor contributions include increased cyclisation of creatine to creatinine because of acidosis and competitive or non-competitive inhibition of creatinine secretion. Creatinine is not a good marker of renal functional loss after paraquat poisoning and renal injury should be evaluated using more specific biomarkers of renal injury.

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

BACKGROUND: Venom 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 FINDINGS: The 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). CONCLUSION: Recurrence 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.

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.

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. TRIAL REGISTRATION: www.slctr.lk SLCTR/2007/005.