Poisoning and envenomation linkage to evaluate outcomes and clinical variation in Australia (PAVLOVA): a longitudinal data-linkage cohort of acute poisonings, envenomations, and adverse drug reactions in New South Wales, Australia, 2011-2020.

INTRODUCTION: Poisoning is a leading cause of morbidity and mortality that is increasing in many countries. Better data are needed to understand epidemiology and outcomes of poisoning. This work describes a new poisoning data linkage cohort in New South Wales, Australia (population approximately 8 million). METHODS: This is a longitudinal health record linkage, 2011-2020, including data from: ambulance call-outs, emergency department presentations, hospital admissions, death registrations, the poisons centre, and four tertiary toxicology units. Individuals with poisoning, venomous animal/plant exposures, or adverse drug reaction events were included. RESULTS: There were 845,217 linkable events relating to 400,642 ambulance, 688,484 emergency department, 682,013 admission, 40,456 toxicology, and 11,879 death records. There were 572,841 people with events; the median age at the time of first event was 57 years, and 51.9% were female. Events leading to patient admission were most commonly adverse drug reactions (n = 511,263), intentional poisonings (n = 68,646), unintentional poisonings (n = 54,840) and animal/plant exposures (n = 11,092). Demographics varied by cause: intentional poisoning (median age 33 years, 64% female); unintentional poisoning/animals/plants (median age 43 years, 45%); and adverse drug reactions (median age 70 years, 54%). Adolescent females had highest rates of intentional poisoning, while unintentional poisoning had a bimodal distribution, highest in children <5 years old and males aged 20 to 50 years. Substance use disorders were documented comorbidities for 44% of intentional poisoning, 29% of unintentional poisoning, and 13% of adverse drug reaction-related admissions; mood disorders were documented for 54%, 17% and 10% of these admissions, respectively. DISCUSSION: Poisonings and hospitalised adverse drug reactions are common in New South Wales, affecting approximately 8% of the population in 10 years. This linkage improves understanding of poisoning risks and outcomes in Australia. CONCLUSIONS: This novel data linkage provides a unique opportunity to study poisoning across multiple settings for an individual over an extended period.

Calcium channel blocker overdose: Not all the same toxicity.

AIMS: Calcium channel blocker (CCB) overdose remains an important poisoning, with increasing availability of dihydropyridines. We aimed to compare the severity and treatment of CCB overdoses. METHODS: We reviewed CCB overdoses presenting to two toxicology services from 2014 to 2023. We extracted prospectively collected data from a clinical database, including demographics, dose, co-ingestants, complications, treatments and outcomes, to compare different CCBs. RESULTS: There were 236 overdoses; median age 55 years (interquartile range [IQR]: 41-65 years); 130 (55%) were females. Dihydropyridine overdoses increased significantly: median of nine cases annually (IQR: 8.8-12.3) during the study compared to a median of three cases annually (IQR: 1-4.3; P < 0.001) in the 10 years prior. The commonest agent was amlodipine (147), then lercanidipine (28), diltiazem (27), verapamil (23) and felodipine (11). Median defined daily dose ingested was higher for dihydropyridines, and cardiac co-ingestants were common except verapamil. Median length of stay was 21 h (IQR: 13-43 h), which was similar except longer for diltiazem (median, 39 h). Fifty-six patients (24%) were admitted to intensive care, more often for diltiazem (14; 52%) and verapamil (7; 30%). Dysrhythmias occurred in 19 patients (diltiazem [9], verapamil [8], amlodipine [2]), and included 13 junctional dysrhythmias. Hypotension occurred in 91 patients (39%), 62 (26%) received inotropes/vasopressors (adrenaline 32 [52%], noradrenaline 48 [77%]), 21 (9%) high-dose insulin and 44 (19%) calcium. Adrenaline and high-dose insulin were more commonly given in diltiazem and verapamil overdoses, compared to vasopressors in dihydropyridine overdoses. Acute kidney injury occurred in 39 patients. Seven (3%) patients died. CONCLUSIONS: Dihydropyridines were the commonest CCB overdoses, with amlodipine making up half. More severe toxicity occurred with diltiazem and verapamil.

Taipan envenoming south of the border.

We present a case of severe taipan envenoming in northern New South Wales in a 68-year-old man. He developed severe neurotoxicity requiring intubation and ventilation, venom-induced consumption coagulopathy, myotoxicity and thrombotic microangiopathy with acute kidney injury requiring dialysis. He was administered brown and tiger snake antivenom consistent with guidelines and snake occurrence in the region. Taipan venom was detected in serum (72 ng/ml) following concern about the severity of neurotoxicity, clinical toxicology consultation and a concurrent report of a taipan in the area. Based on this it would be prudent to stock and consider treating with polyvalent antivenom in north-eastern New South Wales and south-eastern Queensland.

Effectiveness of intramuscular naloxone 1,600 µg in addition to titrated intravenous naloxone 100 µg for opioid poisoning: a randomised controlled trial.

INTRODUCTION: Naloxone is an effective antidote, but its short half-life means repeated doses, and infusions are often required. We investigated the effectiveness of adding intramuscular naloxone to titrated intravenous naloxone in opioid overdose in preventing recurrence of respiratory depression. METHODS: This double-blinded randomised placebo-controlled trial was conducted in patients with suspected opioid poisoning and respiratory depression (respiratory rate <10 breaths/min or oxygen saturation <93%). Patients were randomised to receive either intramuscular naloxone 1,600 µg or saline placebo. All patients received titrated intravenous naloxone 100 µg and were managed on an opioid poisoning care pathway. The primary outcome was recurrence of respiratory depression within 4 h. Secondary outcomes were the proportion receiving naloxone infusions, number of naloxone boluses administered, reversal of respiratory depression at 10 min, and precipitation of opioid withdrawal (any symptom). RESULTS: Recurrence of respiratory depression within 4 h was less common in 28/69 (41%) patients receiving intramuscular naloxone versus 48/67 (72%) patients receiving placebo (difference 31%, 95% CI: 13-46%; P < 0.001). Fewer naloxone infusions (5/69; 7% versus 25/67; 37%, difference 30%, 95% CI: 15 to 55%; P < 0.001) and fewer naloxone doses were administered (median 2, IQR: 1 to 5, versus median 5, IQR: 2 to 8; P = 0.001) in the intramuscular group. Reversal of respiratory depression at 10 min was similar between groups (51/69; 74% intramuscular naloxone versus 47/67; 70% placebo; P = 0.703). Opioid withdrawal occurred in 35/69 (51%) given intramuscular naloxone compared to 28/67 (42%) in the placebo group (difference 9%; 95% CI: -8 to 27%; P = 0.308). DISCUSSION: The favourable pharmacokinetics of intramuscular naloxone, particularly its longer duration of activity, likely explains the improved effectiveness with lower recurrence of respiratory depression. CONCLUSION: The addition of intramuscular naloxone 1,600 µg to titrated intravenous naloxone prolonged effective reversal of respiratory depression, with fewer naloxone doses and infusions given, and no significant difference in patients developing withdrawal.

Handheld point-of-care devices for snakebite coagulopathy: a scoping review.

Venom induced consumption coagulopathy (VICC) is a common complication of snakebite that is associated with hypofibrinogenaemia, bleeding, disability, and death. In remote tropical settings, where most snakebites occur, the 20-minute whole blood clotting test is used to diagnose VICC. Point-of-care (POC) coagulation devices could provide an accessible means of detecting VICC that is better standardised, quantifiable, and more accurate. In this scoping review, the mechanistic reasons that previously studied POC devices have failed in VICC are considered, and evidence-based recommendations are made to prioritise certain devices for clinical validation studies. Four small studies have evaluated a POC international normalised ratio (INR) device in patients with Australian Elapid, Daboia russelii and Echis carinatus envenoming. All of these studies used POC INR devices that rely on a thrombin substrate endpoint, which, unlike laboratory-based INR measurement, is known to underestimate INR in patients with hypofibrinogenaemia. Seventeen commercially available POC devices for measuring INR, activated clotting time (ACT), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, and fibrin(ogen) degradation products (FDP) have been reviewed. POC INR devices that detect fibrin clot formation, as well as a novel POC device that quantifies fibrinogen were identified, that show promise for use in patients with VICC. These devices could support more accurate allocation of antivenom, reduce the time to antivenom administration, and provide improved clinical trial outcome measurement instruments. There is an urgent need for these promising POC coagulation devices to be validated in prospective clinical snakebite studies.

Effectiveness of pharmacological treatments for severe agitation in real-world emergency settings: protocol of individual-participant-data network meta-analysis.

BACKGROUND: Severe psychomotor agitation and aggression often require immediate pharmacological intervention, but clear evidence-based recommendations for choosing among the multiple options are lacking. To address this gap, we plan a systematic review and individual-participant-data network meta-analysis to investigate their comparative effectiveness in real-world emergency settings with increased precision. METHODS: We will include randomized controlled trials investigating intramuscular or intravenous pharmacological interventions, as monotherapy or in combination, in adults with severe psychomotor agitation irrespective of the underlying diagnosis and requiring rapid tranquilization in general or psychiatric emergency settings. We will exclude studies before 2002, those focusing on specific reasons for agitation and placebo-controlled trials to avoid concerns related to the transitivity assumption and potential selection biases. We will search for eligible studies in BIOSIS, CENTRAL, CINAHL Plus, Embase, LILACS, MEDLINE via Ovid, PubMed, ProQuest, PsycINFO, ClinicalTrials.gov, and WHO-ICTRP. Individual-participant data will be requested from the study authors and harmonized into a uniform format, and aggregated data will also be extracted from the studies. At least two independent reviewers will conduct the study selection, data extraction, risk-of-bias assessment using RoB 2, and applicability evaluation using the RITES tool. The primary outcome will be the number of patients achieving adequate sedation within 30 min after treatment, with secondary outcomes including the need for additional interventions and adverse events, using odds ratios as the effect size. If enough individual-participant data will be collected, we will synthesize them in a network meta-regression model within a Bayesian framework, incorporating study- and participant-level characteristics to explore potential sources of heterogeneity. In cases where individual-participant data are unavailable, potential data availability bias will be explored, and models allowing for the inclusion of studies reporting only aggregated data will be considered. We will assess the confidence in the evidence using the Confidence in Network Meta-Analysis (CINeMA) approach. DISCUSSION: This individual-participant-data network meta-analysis aims to provide a fine-tuned synthesis of the evidence on the comparative effectiveness of pharmacological interventions for severe psychomotor agitation in real-world emergency settings. The findings from this study can greatly be provided clearer evidence-based guidance on the most effective treatments. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023402365.

Utility of Three Serum Biomarkers for Early Detection of Systemic Envenoming Following Viper Bites in Sri Lanka.

STUDY OBJECTIVE: Early detection of systemic envenoming is critical for early antivenom therapy to minimize morbidity and mortality from snakebite. We assessed the diagnostic utility of 3 serum biomarkers in the early detection of systemic envenoming in viper bites in rural Sri Lanka. METHODS: All confirmed snakebite patients admitted to Teaching Hospital Anuradhapura from July 2020 to June 2021 were included. On admission, blood was collected for venom concentrations, prothrombin time/international normalized ratio, fibrinogen concentration, serum creatinine concentration, and 3 serum biomarkers, namely secretory phospholipase A2 (sPLA2) activity, neutrophil gelatinase-associated lipocalin (sNGAL) concentration, and clusterin (sClu) concentration. Systemic envenoming was defined by the presence of venom-induced consumption coagulopathy, neurotoxicity, acute kidney injury, or the presence of nonspecific clinical effects. RESULTS: A total of 237 confirmed snakebite patients (Russell's viper, 72; hump-nosed viper, 80; nonvenomous snakes, 31; and unidentified bites, 54) with sufficient preantivenom serum samples were recruited [median age: 42 years (interquartile range [IQR] 29 to 53 years); 173 men (73%)]. Systemic envenoming occurred in 68 (94%) Russell's viper bites, 48 (60%) hump-nosed viper bites, and 45 (83%) unidentified bites. The median sPLA2 activity was 72 nmol/mL/min (IQR 30 to 164) for Russell's viper envenoming, 12 nmol/mL/min (IQR 9 to 16) for hump-nosed viper envenoming, and 11 nmol/mL/min (IQR 9 to 14) for nonvenomous bites. There was no difference in sNGAL and sCLu concentrations among the 3 groups. The median sPLA2 activity of patients with systemic envenoming was 16 nmol/min/mL (IQR 11 to 59) compared to 11 nmol/min/mL (IQR 9 to 14) in patients without systemic envenoming; the difference between medians was 5 nmol/min/mL (95% confidence interval [CI] 4 to 12). The area under the receiver operator characteristic curve (AUC-ROC) of admission sPLA2 activity was the best predictor of systemic envenoming in all snakebites (AUC-ROC 0.72, 95% CI 0.66 to 0.79), whereas sNGAL and sClu concentrations were poor predictors. sPLA2 activity was a better predictor of systemic envenoming in Russell's viper bites (AUC-ROC 0.90, 95% CI 0.76 to 1.00) and in those presenting within 2 hours of a bite. A sPLA2 activity more than 23.5 nmol/min/mL had a sensitivity of 41% (95% CI 34% to 49%), and a specificity of 97% (95% CI 91% to 99.5%) in predicting systemic envenoming. A sPLA2 activity of more than 46 nmol/min/mL on admission had a sensitivity of 67% (95% CI 55% to 77%) and a specificity of 100% (95% CI 51% to 100%) in predicting systemic envenoming in Russell's viper bites. CONCLUSIONS: sPLA2 activity is an early predictor of systemic envenoming following snakebite, particularly in Russell's viper bites and in those who present early.

Health issues and related health-seeking behaviours of snakebite patients after hospital discharge: A cohort study from rural Sri Lanka.

We aimed to assess the unresolved health issues experienced by a cohort of snakebite survivors and their health-seeking behaviours during the first three months after the snakebite. Patients from the Anuradhapura snakebite cohort admitted to the Teaching Hospital Anuradhapura, Sri Lanka, from July 2021 to June 2022 were recruited. Patients were interviewed over the telephone three weeks and three months post-bite to collect data on unresolved health problems post-discharge, patient's adherence to the review plan, newly experienced health issues, health-seeking behaviours and the effect on daily routine. Only snakebite survivors who could be contacted at both three weeks and three months were included. Of 710 eligible patients, 384 (54%) were contactable at both reviews. On discharge from the hospital, 248/384 (65%) had unresolved effects of the snakebite, including 224/384 (58%) who had local effects. The unresolved health problems were reported by patients bitten by H. hypnale (54%), D. russelii (23%), and unidentified snakes (19%). At three weeks and three months, 98/384 (26%) and 52/384 (14%) still had unresolved local effects of envenoming, respectively. Of 144/384 (38%) who were advised to attend review visits post-discharge, mostly to assess renal function, 118 (82%) complied. 112/384 (29%) patients reported self-motivated treatment seeking for unresolved effects of snakebite over the three months. Of them, 87 (78%) visited Sri Lankan indigenous medical practitioners. Patients missed a median of two working days (IQR: 2-4 days) post-discharge. 26 (6.7%) were unable to return to work at 3 weeks, and five patients at 3 months. In rural Sri Lanka, a significant number of viper bite patients leave hospital with mild persistent local effects, which commonly leads to them seeking further treatment. Despite that, almost all snakebite survivors had returned to work at three months post-bite.

Growing burden of gamma-hydroxybutyrate intoxication on emergency department resource utilisation.

OBJECTIVE: Recreational gamma-hydroxybutyrate (GHB) use is rising in Australia. We aimed to describe ED presentation patterns related to GHB over time and the impact this has on ED resource use. METHODS: Retrospective review of prospective data collection from two clinical toxicology units based in Queensland and New South Wales. RESULTS: There were 751 GHB-related presentations to the two units (Newcastle, 127; Princess Alexandria, 624), with marked increases in presentations occurring in 2019 and 2023. The major intervention was intubation, with 95 (13%) patients intubated. CONCLUSION: GHB presentations to ED are rising and the impact on acute bed space and clinical resources is significant.

Management of serotonin syndrome (toxicity).

Serotonin syndrome (toxicity), resulting from an excessive accumulation of serotonin in the central nervous system, it can occur due to various factors such as the initiation of medication, overdose or drug interactions. Diagnosing serotonin toxicity presents challenges as there are no definitive criteria. This review delves into the pathophysiology, incidence, clinical assessment and management of serotonin toxicity, stressing the significance of promptly recognizing and managing severe cases. Diagnosis relies primarily relies on clinical assessment due to the absence of specific laboratory tests. The Hunter Serotonin Toxicity criteria are commonly utilized but have only been validated in the overdose setting. Assessing the severity of toxicity is crucial for guiding management decisions. Supportive care, discontinuation of causative agents and symptomatic treatment are prioritized in management. Mild toxicity often requires withdrawal or reduction of the serotonergic agent, while more severe toxicity requires more aggressive resuscitative and supportive care. Severe serotonin toxicity characterized by hyperthermia and rigidity requires aggressive supportive measures, including benzodiazepines, intubation, paralysis and active cooling. Animal studies suggest potential benefits of 5-HT2A receptor antagonists in preventing hyperthermia and fatalities, but only at high doses. Their clinical effectiveness remains uncertain, and evidence is predominately from case series and case reports. Although commonly used, serotonin antagonists like cyproheptadine lack conclusive evidence of efficacy. Other serotonin antagonists such as chlorpromazine and olanzapine have been explored but evidence is limited to case reports. Hence, the cornerstone of treating severe cases does not lie in 'antidote' administration or even diagnosis but in effective early resuscitative and supportive care.

Chlorpromazine overdose: a case series.

INTRODUCTION: Chlorpromazine, one of the oldest antipsychotic medications, remains widely available and is still taken in overdose. We aimed to investigate the clinical effects of chlorpromazine overdose and determine if there is a relationship between the reported dose ingested and intensive care unit admission or endotracheal intubation. METHODS: We performed a retrospective analysis of patients admitted to our toxicology tertiary referral hospital with chlorpromazine overdose (reported dose ingested greater than 300 mg) between 1987 and 2023. We extracted demographic information, details of ingestion, clinical effects and complications (Glasgow Coma Scale, hypotension [systolic blood pressure less than 90 mmHg], delirium, dysrhythmias), length of stay, intensive care unit admission, and endotracheal intubation. RESULTS: There were 218 chlorpromazine overdose cases, with presentations decreasing in frequency over the 36 years. The median age at presentation was 32 years (interquartile range: 25-40 years) and 143 (61 per cent) were female. The median reported dose ingested was 1,250 mg (interquartile range; 700-2,500 mg). The majority of presentations (135; 62 per cent) involved reported co-ingestion of other medications, typically benzodiazepines, paracetamol or antipsychotics. There were 76 (35 per cent) chlorpromazine alone ingestions in which there was a slightly higher median reported dose ingested of 1,650 mg (interquartile range: 763-3,000 mg) compared to the reported co-ingestion group, median reported dose ingested of 1,200 mg (interquartile range: 700-2,100 mg). Of all presentations, 36 (27 per cent) had a Glasgow Coma Scale less than 9, 50 (23 per cent) were admitted to the intensive care unit, and 32 (15 per cent) were endotracheally intubated. There was a significant difference in the median reported dose ingested between patients intubated (2,000 mg; interquartile range: 1,388-3,375 mg) and those not intubated (1,200 mg; interquartile range: 644-2,050mg; P < 0.001), and between those admitted to the intensive care unit and not admitted to the intensive care unit (P < 0.0001). The median reported dose ingested in seven chlorpromazine alone presentations who were intubated was 2,500 mg (interquartile range: 2,000-8,000 mg, range: 1,800-20,000 mg). Eighteen (8 per cent) patients developed delirium, eight (4 per cent) had hypotension, three had seizures, and there was one death. DISCUSSION: Almost one quarter of cases were admitted to the intensive care unit and over half of these were intubated. Whist the decision to admit to an intensive care unit or intubate a patient is based on clinical need, there was a significant association between reported dose ingested and requirement for endotracheal intubation. Both the frequency of presentation and reported dose ingested declined after 2013. The major limitations of the study were a retrospective design and no analytical confirmation of ingestion. CONCLUSIONS: We found that the most common effect of chlorpromazine overdose was central nervous system depression and that endotracheal intubation was associated with larger reported doses ingested, particularly in single chlorpromazine ingestions.

A randomized controlled trial and prospective cohort investigating antivenom for red-bellied black snake envenomation.

INTRODUCTION: Antivenom is first line treatment for snake envenomation worldwide, despite few placebo controlled clinical trials demonstrating effectiveness. We aimed to investigate whether early antivenom in red-bellied black snake (Pseudechis porphyriacus) bites would prevent systemic myotoxicity. METHODS: We undertook a multicentre randomized placebo-controlled trial of antivenom for red-bellied black snake bites with patients recruited from the Australian Snakebite Project (July 2014 to June 2020). In addition, we report all patients with red-bellied black snake bites during the same period, comparing the same outcomes. Patients over 2 years of age with definite red-bellied black snake bites and early systemic effects were randomized to receive 50 per cent glucose (placebo) or tiger snake antivenom within 6 hours post-bite, or in the cohort group received antivenom determined by the treating clinician. The primary outcome was the proportion of patients with myotoxicity (peak creatine kinase activity >1,000 U/L). Secondary outcomes were: area under the curve of total creatine kinase elevation over 48 hours, presence of venom post-antivenom, and adverse reactions. We analyzed both the randomized control trial patients and the combination of randomized control trial and cohort patients. RESULTS: Fifteen patients were recruited to the randomized controlled trial, and a cohort of 68 patients who were not randomized were included in the analysis. After treatment, two of seven patients given placebo had a peak creatine kinase activity >1,000 U/L versus none of the eight given antivenom (difference in favour of antivenom; 29 per cent; 95 per cent confidence interval:-18 per cent to +70 per cent; P = 0.2). The median area under the curve of total creatine kinase elevation over 48 hours in patients given placebo was 0 U/L*h (interquartile range: 0-124 U/L*h), which was not significantly different to those given antivenom: 197 U/L*h (interquartile range: 0-66,353 U/L*h; P = 0.26). Venom was not detected post-antivenom in six patients with measured venom concentrations given antivenom. Two patients given antivenom had immediate hypersensitivity reactions, one severe anaphylaxis, and another had serum sickness. Combining randomized and not randomized patients, three of 36 (8 per cent) administered antivenom less than 6 hours post-bite had a peak creatine kinase activity >1,000 U/L versus 17/47 (36 per cent) patients not receiving antivenom less than 6 hours post-bite (difference in favour of antivenom 29 per cent; 95 per cent confidence interval: 8 per cent to 44 per cent; P < 0.004). Overall, 13/36 (36 per cent) patients administered antivenom within 6 hours had hypersensitivity reactions, six severe anaphylaxis (17 per cent). DISCUSSION: We found that early antivenom was effective in red-bellied black snake bites, and only three patients need to be given antivenom within 6 hours to prevent myotoxicity in one (number needed to treat = 3). However, one in three patients administered antivenom developed a hypersensitivity reaction, and one in six had severe anaphylaxis. The major limitation of this study was the small number of patients recruited to the randomized controlled trial. CONCLUSION: Administration of antivenom in red-bellied black snake envenomation within 6 hours post-bite appeared to decrease the proportion of patients with myotoxicity, but a third of patients had adverse reactions.

Anticoagulant activity in Australasian elapid snake venoms and neutralisation with antivenom and varespladib.

The venoms of Australasian elapid snakes are known to possess coagulant activity, including some with strong procoagulant activity and others with anticoagulant activity, although the latter are less well known. This study investigates the anticoagulant activity of Australasian elapid snake venoms, and whether this activity is neutralised by commercial snake antivenom and varespladib (PLA2 inhibiting agent). Clotting assays were completed for 34 species of Australasian elapids. Antivenom neutralisation assays with tiger snake antivenom (TSAV) were performed on five species to determine if there was cross-neutralisation. Varespladib neutralisation assays were also completed for the same five species. All Pseudechis species venoms had anticoagulant activity, except P. porphyriacus, which was procoagulant. Pseudechis species venoms had similar anticoagulant potency ranging from the most potent P. colletti venom to the least potent P. butleri venom. The three Austrelaps (copperhead) species venoms were the next most potent anticoagulants. Six further snakes, Elapognathus coronatus, Acanthophis pyrrhus, A. antarcticus, Suta suta, Denisonia devisi and D. maculata, had weaker anticoagulant activity, except for D. maculata which had similar anticoagulant activity to Pseudechis species. Tiger Snake Antivenom (1200mU/mL) neutralised the anticoagulant effect of P. australis for concentrations up to 1 mg/mL. TSAV (1200mU/mL) also neutralised P. colletti, D. maculata, A. superbus and A. pyrrhus venoms at their EC50, demonstrating cross neutralisation. Varespladib neutralised the anticoagulant effect of P. australis venom at 5 µM and for venoms of P. colletti, D. maculata, A. superbus and A. pyrrhus. We found anticoagulant activity to be present in six genera of Australasian snakes at low concentrations, which can be completely neutralised by both antivenom and varespladib. Anticoagulant activity in Australian elapid venoms was associated with species possessing high PLA2 activity without procoagulant snake venom serine proteases.

Investigating skeletal muscle biomarkers for the early detection of Australian myotoxic snake envenoming: an animal model pilot study.

INTRODUCTION: Myotoxicity is an important toxidrome that can occur with envenoming from multiple Australian snake types. Early antivenom administration is an important strategy to reduce the incidence and severity of myotoxicity. The current gold standard biomarker, serum creatine kinase activity, does not rise early enough to facilitate early antivenom administration. Several other skeletal muscle biomarkers have shown promise in other animal models and scenarios. The aim of this study was to examine the predictive values of six skeletal muscle biomarkers in a rat model of Australian snake myotoxicity. METHODS: Sprague-Dawley rats were anaesthetised and administered either Pseudechis porphyriacus (red-bellied black snake) or Notechis scutatus (tiger snake) venom, or normal saline via intramuscular injection. Blood samples were collected. Assays were performed for serum creatine kinase skeletal muscle troponin-I concentration, skeletal muscle troponin-C concentration, myoglobin activity, skeletal muscle myosin light chain-1 concentration, and creatine kinase-MM activity. Serum markers were plotted against time, with comparison of area under the concentration (or activity)-time curve. The predictive values of six skeletal muscle biomarkers were examined using receiver operating characteristic curves. RESULTS: There was no difference in area under the serum creatine kinase activity-time curve between venom and control groups. Serum creatine kinase-MM activity rose early in the venom treated rats, which had a significantly greater area under the serum activity-time curve. No difference in area under the serum concentration-time curve was demonstrated for the other biomarkers. Creatine kinase-MM activity had a superior predictive values than creatine kinase activity at 0-4 hours and 0-10 hours after venom administration, as indicated by area under the receiver operating characteristic curves (95 per cent confidence intervals) of 0.91 (0.78-1.00) and 0.88 (0.73-1.00) versus 0.79 (0.63-0.95) and 0.66 (0.51-0.80). DISCUSSION: The limitations of serum creatine kinase activity in early detection of myotoxicity were demonstrated in this rat model. CONCLUSION: Serum creatine kinase-MM activity was superior for early detection of Australian myotoxic snake envenoming.

The critical time period for administering antivenom: golden hours and missed opportunities.

INTRODUCTION: Antivenom is widely accepted as an effective treatment for snake envenomation. This is despite very limited evidence supporting clinical effectiveness for major envenomation syndromes, and is mainly based on pre-clinical studies and observational studies without control groups. EFFECTIVENESS OF EARLY ANTIVENOM: Although antivenom exhibits efficacy by binding to snake toxins and preventing toxic injury in animals if pre-mixed with venom, this efficacy does not always translate to clinical effectiveness. There are many irreversible venom mediated effects that antivenom cannot neutralise or reverse, such as pre-synaptic neurotoxicity and myotoxicity. Fortunately, early antivenom appears to prevent some of these. PRACTICALITIES OF ADMINISTERING ANTIVENOM EARLY: With good evidence that early antivenom prevents some envenomation syndromes, the time between bite and antivenom administration must be reduced. This requires improving the initial assessment of snakebite patients, and improving early decision making based on clinical effects. CONCLUSION: Until there are improved, simplified, easy to use, rapid and inexpensive tests, whether available in the laboratory or preferably at the bedside that identify systemic envenomation, the key to early antivenom administration is early assessment and decision making based on systemic symptoms, including nausea, vomiting, headache and abdominal pain.

The Eastern Bandy Bandy Vermicella annulata, expresses high abundance of SVMP, CRiSP and Kunitz protein families in its venom proteome.

The Australian elapid snake radiation (Hydrophiinae) has evolved in the absence of competition from other advanced snakes. This has resulted in ecological specialisation in Australian elapids and the potential for venom proteomes divergent to other elapids. We characterised the venom of the Australian elapid Vermicella annulata (eastern bandy bandy). The venom was analysed using a two-dimensional fractionation process consisting of reverse-phase high-performance liquid chromatography then sodium dodecyl sulphate polyacrylamide gel electrophoresis, followed by bottom-up proteomics. Resulting peptides were matched to a species-specific transcriptome and 87% of the venom was characterised. We identified 11 toxins in the venom from six families: snake venom metalloproteinases (SVMP; 24.2%; two toxins) that are class P-III SVMPs containing a disintegrin-like domain, three-finger toxins (3FTx; 21.6%; five toxins), kunitz peptides (KUN; 19.5%; one toxin), cysteine-rich secretory proteins (CRiSP; 18%; one toxin), and phospholipase A2 (PLA2; 4%; two toxins). The venom had low toxin diversity with five protein families having one or two toxins, except for 3FTx with five different toxins. V. annulata expresses an unusual venom proteome, with high abundances of CRiSP, KUN and SVMP, which are not normally highly expressed in elapid venoms. This unusual venom composition could be an adaptation to its specialised diet. BIOLOGICAL SIGNIFICANCE: Although the Australian elapid radiation represents the most extensive speciation event of elapids on any continent, with 100 terrestrial species, the venom composition of these snakes has rarely been investigated, with only five species currently characterised. Here we provide the venom proteome of a sixth species, Vermicella annulata. The venom of this species could be particularly informative from an evolutionary perspective, as it is an extreme dietary specialist, only preying on blind snakes (Typhlopidae). We show that V. annulata expresses a highly unusual venom for an elapid, due to the high abundance of the protein families SVMP, CRiSP, and KUN, which together make up 61% of the venom. When averaged across all species, a typical elapid venom is 82% PLA2 and 3FTx. This is the second recorded instance of an Australian elapid having evolved highly divergent venom expression.

[A global core outcome measurement set for snakebite clinical trials]. / Définition d'un jeu universel de critères de décision de base pour les essais cliniques sur les morsures de serpent.

Background: Snakebite clinical trials have often used heterogeneous outcome measures and there is an urgent need for standardisation. Method: A globally representative group of key stakeholders came together to reach consensus on a globally relevant set of core outcome measurements. Outcome domains and outcome measurement instruments were identified through searching the literature and a systematic review of snakebite clinical trials. Outcome domains were shortlisted by use of a questionnaire and consensus was reached among stakeholders and the patient group through facilitated discussions and voting. Results: Five universal core outcome measures should be included in all future snakebite clinical trials: mortality, WHO disability assessment scale, patient-specific functional scale, acute allergic reaction by Brown criteria, and serum sickness by formal criteria. Additional syndrome-specific core outcome measures should be used depending on the biting species. Conclusion: This core outcome measurement set provides global standardisation, supports the priorities of patients and clinicians, enables meta-analysis, and is appropriate for use in low-income and middle-income settings.

Lack of cholinergic features in healthcare workers caring for a patient with organophosphate poisoning.

INTRODUCTION: Controversy exists with regard to risk of secondary exposure of health care workers caring for patients who have ingested an organophosphate insecticide. We aim to report clinical effects of staff members caring for an organophosphate poisoned patient. INCIDENT: A 76-year-old male presented to the Emergency Department exhibiting a cholinergic toxidrome requiring atropine, intubation and mechanical ventilation. METHODS: We undertook a retrospective chart review of any Emergency Department presentations for medical assessment in relation to the incident and conducted telephone interviews of any healthcare workers who did not present but were deemed to be closely involved with patient care. We collected data including age, gender, symptoms reported and plasma cholinesterase activity measurement. RESULTS: We collected data from 13 individuals, of whom nine presented for medical assessment, including the patient's spouse. Five additional staff members were interviewed, having been identified via Emergency Department rostering documentation. The 13 healthcare workers comprised five nurses, four paramedics and four doctors. Dizziness and nausea were reported in two and the patient's spouse reported one episode of vomiting. Of the nine patients who had plasma cholinesterase activity measured, none were below the laboratory reference range, including those who experienced symptoms. CONCLUSIONS: We found no clinical nor biochemical evidence of toxicity in healthcare workers caring for a critically ill patient with organophosphate ingestion. These findings are consistent with previously published guidelines advocating standard/Level D personal protective equipment. We believe that emergency departments should not be closed as a safety measure.

Advances in the understanding of acetaminophen toxicity mechanisms: a clinical toxicology perspective.

INTRODUCTION: Acetaminophen (paracetamol) is a commonly used analgesic and antipyretic agent, which is safe in therapeutic doses. Acetaminophen poisoning due to self-harm or repeated supratherapeutic ingestion is a common cause of acute liver injury. Acetylcysteine has been a mainstay of treatment for acetaminophen poisoning for decades and is efficacious if administered early. However, treatment failures occur if administered late, in 'massive' overdoses or in high-risk patients. AREAS COVERED: This review provides an overview of the mechanisms of toxicity of acetaminophen poisoning (metabolic and oxidative phase) and how this relates to the assessment and treatment of the acetaminophen poisoned patient. The review focuses on how these advances offer further insight into the utility of novel biomarkers and the role of proposed adjunct treatments. EXPERT OPINION: Advances in our understanding of acetaminophen toxicity have allowed the development of novel biomarkers and a better understanding of how adjunct treatments may prevent acetaminophen toxicity. Newly proposed adjunct treatments like fomepizole are being increasingly used without robust clinical trials. Novel biomarkers (not yet clinically available) may provide better assessment of these newly proposed adjunct treatments, particularly in clinical trials. These advances in our understanding of acetaminophen toxicity and liver injury hold promise for improved diagnosis and treatment.