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Objective Rapidly and safely managing severe acute behavioural disturbance (ABD) in the prehospital setting is important for the welfare of both patient and prehospital clinician alike. We investigated the safety and effectiveness of ketamine as rescue sedation in patients with severe ABD. Methods This prospective observational study investigated ketamine use by a state ambulance service as rescue sedation for patients with severe ABD who remained agitated following droperidol administration. The primary outcome was the proportion of adverse events (vomiting, hypersalivation, emergence, over-sedation, airway obstruction, laryngospasm, hypoxia, bradypnoea and intubation). Secondary outcomes included time to sedation, requirement for additional sedation and rate of successful sedation. Results There were 105 presentations (males 69/102 [69%]; median age 31 years (16-83 years). The commonest causes of ABD were illicit drug (39%) and alcohol (33%) intoxication. The median total dose of intramuscular ketamine was 200 mg (interquartile range [IQR] 150-200 mg). There were 64 adverse events in 40 (38%) patients. Four had vomiting, two had hypersalivation, two had emergence, 15 were oversedated, four had hypoxia, three had bradypnoea and 16 were intubated. Sedation was achieved in 103 (98%) patients at a median time post-ketamine of 8 min (IQR 5-13 min). Additional sedation was administered to 41 patients (nine prehospital and 37 within 1 h of arriving to hospital). In 44 (42%) patients, ketamine successfully sedated the patient with no adverse effects and no ongoing sedation requirement. Conclusion The use of ketamine as rescue sedation in prehospital patients with severe ABD is effective. Adverse events are common but can be managed supportively.

Myotoxicity is a recognised but poorly characterised effect of snake envenoming worldwide. We aimed to describe the clinical effects, complications and effectiveness of antivenom in myotoxicity from Australian snake envenoming.Patients were recruited to the Australian Snakebite Project (ASP), a prospective, observational study of patients with suspected or proven snakebite countrywide. After informed consent data is collected and stored in a dedicated database and blood samples are taken and stored. We included patients with envenoming and biochemical evidence of myotoxicity (peak creatine kinase [CK] 1000 U/L). Snake species was determined by expert identification or venom specific enzyme immunoassay. Analysis included patient demographics, clinical findings, pathology results, treatment and outcomes (length of hospital stay, complications).1638 patients were recruited January 2003-December 2016, 935 (57%) were envenomed, 148 developed myotoxicity (16%). Snake species most commonly associated with myotoxicity wereMyotoxicity from Australian snakes is relatively common and has systemic effects, with significant associated morbidity and mortality. CK is not a good early biomarker of mytoxicity. Early antivenom may play a role in reducing severity.

Amlodipine, a dihydropyridine calcium channel blocker (CCB), is the leading cause of cardiovascular drug-related overdose deaths in the USA. In contrast, angiotensin-II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) cause minimal toxicity in overdose. ACEIs/ARBs are often combined with dihydropyridines in hypertension treatment. Co-ingested ARBs/ACEIs may significantly contribute to the toxicity of dihydropyridine, but this has not been investigated.To investigate the clinical outcomes from dihydropyridine overdoses with ARBs/ACEIs versus dihydropyridine overdoses alone.This was a retrospective study of patients reported to the New South Wales Poisons Information Centre (NSW PIC) and 3 toxicology units (Jan 2016 to Jun 2019) in Australia. Patients14 years who took an overdose of dihydropyridines (amlodipine, felodipine, lercanidipine, nifedipine) were included. Concurrent overdoses with non-dihydropyridine CCBs, alpha-blockers and beta-blockers were excluded. Patient demographics, drugs exposure details, serial vital signs, treatments and outcome were collected.There were 100 patients. 68 took mixed overdoses of dihydropyridines with ARBs/ACEIs and 32 took single overdoses of dihydropyridines without ARBs/ACEIs. The mixed group had lower median nadir mean arterial pressures (62 vs 75 mmHg,Combined overdoses of dihydropyridines with ARBs/ACEIs caused more significant hypotension and required more haemodynamic support than overdoses of dihydropyridines alone.

AIMS: With rising use worldwide, pregabalin is increasingly implicated in poisoning deaths. We aimed to investigate the clinical effects and complications of pregabalin poisoning. METHODS: This is a retrospective review of patients presenting with pregabalin poisoning to two tertiary toxicology units from 1 July 2014 to 30 June 2019. Patients were identified from prospective databases maintained by both units and data were extracted from these in addition to medical records. RESULTS: There were 488 presentations in 413 patients (237 [57%] male) over the five‐year period. The median age was 41 years (IQR 31–50 years). Deliberate self‐poisonings accounted for 342 (70%) presentations, with 121 (25%) recreational exposures. Recreational exposures increased over the period from 2 (4%) in the first year to 54 (39%) presentations in the final year. The median dose of pregabalin was 1200 mg (IQR 600‐3000 mg, range 75‐16 800 mg). Co‐ingestions occurred in 427 (88%) presentations, with sedating agents being co‐ingested in 387 (79%)—most commonly opioids and benzodiazepines in 201 (41%) and 174 (36%) presentations respectively. Coma (GCS < 9) occurred in 89 (18%) cases, with 52 (11%) patients being intubated. Only one (0.2%) of these patients had not co‐ingested a sedating agent. Hypotension occurred in 26 (5%) cases, all with co‐ingestants. Seizures occurred in 11 (2%) cases, 3/59 (5%) in pregabalin‐only overdoses. The median length of stay was 16.5 hours (IQR 10–25 hours). CONCLUSIONS: Pregabalin overdose does not cause severe toxicity, but rather mild sedation and, uncommonly, seizures. Coma is common in the presence of sedating co‐ingestants. Recreational use is increasing.

Russell's viper envenoming causes venom-induced consumption coagulopathy (VICC) within hours of a bite, which is associated with thrombotic microangiopathy (TMA) and acute kidney injury (AKI) in a proportion of cases. We report a juvenile Russell's viper bite in which a patient developed mild VICC after the usual 24-h observation period, which was subsequently associated with severe AKI due to TMA. This shows the clinical importance of detecting and treating mild VICC, which may be delayed or not detected with bedside clotting tests.

Large doses of intramuscular (IM) naloxone are commonly used in out-of-hospital settings to reverse opioid toxicity; however, they are used less commonly in hospitals because of concerns about opioid withdrawal, particularly agitation. We aimed to determine the frequency of severe agitation following a single 1.6 mg IM naloxone dose.We undertook a prospective study of adult (15 years) patients treated by an Australian state ambulance service with 1.6 mg IM administration of naloxone for respiratory depression (respiratory rate11 breaths/min and/or oxygen saturation93% in room air) caused by presumed opioid poisoning. The primary outcome was the proportion of presentations with severe agitation (Sedation Assessment Tool score1) within 1 hour of naloxone administration. Secondary outcomes were the proportion of presentations with acute opioid withdrawal (tachycardia [pulse rate100 beats/min], hypertension [systolic140 mm Hg], vomiting, agitation, seizure, myocardial infarction, arrhythmia, or pulmonary edema), and reversal of respiratory depression (respiratory rate10 breaths/min and saturation92% or Glasgow Coma Scale score 15).From October 2019 to July 2021, there were 197 presentations in 171 patients, with a median age of 41 years (range, 18 to 80 years); of the total patients, 119 were men (70%). The most common opioids were heroin (131 [66%]), oxycodone (14 [7%]), and morphine (11 [6%]). Severe agitation occurred in 14 (7% [95% confidence interval {CI} 4% to 12%]) presentations. Opioid withdrawal occurred in 76 presentations (39% [95% CI 32% to 46%]), most commonly in the form of tachycardia (18%), mild agitation/anxiety (18%) and hypertension (14%). Three presentations (1.5%) received chemical sedation for severe agitation within 1 hour of naloxone administration. A single 1.6 mg dose of naloxone reversed respiratory depression in 192 (97% [95% CI: 94% to 99%]) presentations.Severe agitation was uncommon following the administration of 1.6 mg IM naloxone and rarely required chemical sedation.

Acetaminophen-protein adducts are specific biomarkers of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (alanine aminotransferase [ALT]1,000 U/L), an adduct concentration ≥1.0 nmol/ml is sensitive and specific for identifying cases secondary to acetaminophen. Our aim was to characterise acetaminophen-protein adduct concentrations in patients following acetaminophen overdose and determine if they predict toxicity.We performed a multicentre prospective observational study, recruiting patients 14 years of age or older with acetaminophen overdose regardless of intent or formulation. Three serum samples were obtained within the first 24 h of presentation and analysed for acetaminophen-protein adducts. Acetaminophen-protein adduct concentrations were compared to ALT and other indicators of toxicity.Of the 240 patients who participated, 204 (85%) presented following acute ingestions, with a median ingested dose of 20 g (IQR 10-40), and 228 (95%) were treated with intravenous acetylcysteine at a median time of 6 h (IQR 3.5-10.5) post-ingestion. Thirty-six (15%) patients developed hepatotoxicity, of whom 22 had an ALT ≤1,000 U/L at the time of initial acetaminophen-protein adduct measurement. Those who developed hepatotoxicity had a higher initial acetaminophen-protein adduct concentration compared to those who did not, 1.63 nmol/ml (IQR 0.76-2.02, n = 22) vs. 0.26 nmol/ml (IQR 0.15-0.41; n = 204; p0.0001), respectively. The AUROC for hepatotoxicity was 0.98 (95% CI 0.96-1.00; n = 226; p0.0001) with acetaminophen-protein adduct concentration and 0.89 (95% CI 0.82-0.96; n = 219; p0.0001) with ALT. An acetaminophen-protein adduct concentration of 0.58 nmol/ml was 100% sensitive and 91% specific for identifying patients with an initial ALT ≤1,000 U/L who would develop hepatotoxicity. Adding acetaminophen-protein adduct concentrations to risk prediction models improved prediction of hepatotoxicity to a level similar to that obtained by more complex models.Acetaminophen-protein adduct concentration on presentation predicted which patients with acetaminophen overdose subsequently developed hepatotoxicity, regardless of time of ingestion. An adduct threshold of 0.58 nmol/L was required for optimal prediction.Acetaminophen poisoning is one of the most common causes of liver injury. This study examined a new biomarker of acetaminophen toxicity, which measures the amount of toxic metabolite exposure called acetaminophen-protein adduct. We found that those who developed liver injury had a higher initial level of acetaminophen-protein adducts than those who did not.Australian Toxicology Monitoring (ATOM) Study-Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.

The Merrem's hump-nosed viper (H. hypnale) causes many snakebites in South India and Sri Lanka. At present no antivenom is available for envenomings by this snake. A 42-year-old male bitten by a large H. hypnale, presented within 30 min of the bite and had a cardiac arrest soon after admission. This responded to standard advanced life support, but he had an unrecordably high international normalised ratio (INR), activated partial thromboplastin time and unrecordably low fibrinogen, consistent with a complete venom-induced consumption coagulopathy. In the absence of antivenom, a total of 1680ml of fresh frozen plasma (FFP) was transfused 5.5 and 16 h post-bite. The coagulopathy did not improve with the administration of FFP and a further elevation of D-Dimer after FFP suggested consumption of transfused clotting factors. The coagulopathy resolved after 72 h. The patient did not develop any bleeding complications, acute kidney injury or evidence of thrombotic microangiopathy and was discharged 8 days after the bite. This case suggests that early FFP for VICC in H. hypnale envenoming may worsen the coagulopathy in the absence of antivenom and cannot be recommended.

Understanding the time course of venom exposure in snakebite patients is important for the optimisation of treatment including antivenom dose and timing. We aimed to investigate the pharmacokinetics of red-bellied black snake (RBBS;Timed venom concentration data were obtained from patients with RBBS envenomation recruited to the Australian Snakebite Project (ASP), including demographics and antivenom treatment. Venom concentrations were measured using an enzyme immunoassay. Data were modelled using NONMEM version 7.3. Uncertainty in venom "dose" was accounted for by arbitrarily fixing the average amount to 1 mg and incorporating between-subject variability on relative bioavailability. A scale parameter for venom clearance was implemented to account for the rapid venom clearance following antivenom dosing. A sensitivity analysis was performed to determine the magnitude of venom clearance amplification.There were 457 venom concentrations in 114 patients (median age 41, 2-90 y; 80 male). Antivenom was administered to 54 patients a median of 4.2 h post-bite (0.67 to 32 h). A one-compartment model with first-order absorption and elimination provided the best description of the data. The estimated clearance and volume of distribution were 5.21 L/h and 39.9 L, respectively. The calculated elimination half-life ofThe information on the exposure time of venom in the body following envenomation will help improve treatment and the timing of antivenom.

Introduction The major systemic manifestation of hemotoxicity in human snakebite envenoming is venom‐induced consumption coagulopathy (VICC). A subset of patients with VICC develop thrombotic microangiopathy (TMA), in which acute kidney injury (AKI) occurs. We aimed to investigate the association between schistocytosis in snakebite patients with VICC and AKI, compared to non‐envenomed patients. Methods Serial blood films collected from a prospective cohort of snakebite patients (Australian Snakebite Project) were examined. Cases were classified a priori as non‐envenomed snakebites (normal controls), envenomed without VICC, partial VICC without AKI, complete VICC without AKI, and VICC with AKI based on defined clinical and laboratory criteria. The percentage of schistocytes between groups was compared and correlated by Kendall's tau b test. Results Seven hundred and eighty blood films from 234 snakebite cases were analyzed. There was a statistically significant correlation (τ = .69, SE .03, P

AIM The aim of this study is to describe the epidemiology and health-care utilisation of paediatric emergency department (ED) presentations due to poisoning. METHODS A retrospective review of all ED presentations of paediatric poisoning cases (

Background Myotoxicity is one of the common clinical manifestations of red-bellied black snake (Pseudechis porphyriacus) envenomation characterised by elevated creatine kinase (CK) concentrations of greater than 1000 U/L. This study aimed to investigate the occurrence of myotoxicity in patients following envenomation. Methods/Principal findings Patient characteristics and serial blood samples (timed venom concentrations and CK concentrations, pre- and post- antivenom) from 114 patients (median age 41, 2-90y; 80 male) were extracted from the Australian Snakebite Project database. Patients were categorised into three groups based on peak CK concentrations [no myotoxicity (10,000 U/L)]. The odds of (mild or severe) myotoxicity was lower in patients that received early antivenom (within 6 hours post-bite) compared to those that received late or no antivenom (odd ratio was 0.186; 95% confidence interval, 0.052–0.664). A population pharmacokinetic-pharmacodynamic (PKPD) model was developed to describe the relationship between the time course of venom (a mixture of toxins) and effect (elevated CK). In addition, a kinetic-pharmacodynamic (KPD) model was developed to describe the relationship between time course of a theoretical toxin and effect. Model development and parameter estimation was performed using NONMEM v7.3. No single set of parameter values from either the PKPD or KPD models were found that could accurately describe the time course of different levels of severity of myotoxicity. The predicted theoretical toxin half-life from the KPD model was 11 ± 3.9 hours compared to the half-life of venom of 5.3 ± 0.36 hours. This indicates that the putative causative toxin’s concentration-time profile does not parallel that of venom. Conclusion Early antivenom administration reduces the incidence of myotoxicity. The venom concentration profile does not appear to be the driver for myotoxicity following envenomation. Additional factors that affect the sensitivity of the patient to snake venom/toxins must be explored to understand the relationship with myotoxicity.

Delays in treatment seeking and antivenom administration remain problematic for snake envenoming. We aimed to describe the treatment seeking pattern and delays in admission to hospital and administration of antivenom in a cohort of authenticated snakebite patients. Adults (> 16 years), who presented with a confirmed snakebite from August 2013 to October 2014 were recruited from Anuradhapura Hospital. Demographic data, information on the circumstances of the bite, first aid, health-seeking behaviour, hospital admission, clinical features, outcomes and antivenom treatment were documented prospectively. There were 742 snakebite patients [median age: 40 years (IQR:27–51; males: 476 (64%)]. One hundred and five (14%) patients intentionally delayed treatment by a median of 45min (IQR:20-120min). Antivenom was administered a median of 230min (IQR:180–360min) post-bite, which didn’t differ between directly admitted and transferred patients; 21 (8%) receiving antivenom within 2h and 141 (55%) within 4h of the bite. However, transferred patients received antivenom sooner after admission to Anuradhapura hospital than those directly admitted (60min [IQR:30-120min] versus 120min [IQR:52-265min; p, Author summary Snakebite is a neglected tropical disease which is closely associated with underdevelopment. Poor accessibility to safe and effective antivenoms is a major issue in some regions highest-affected by snakebites. Antivenom can prevent severe effects of envenoming if given early. Therefore, educating communities and health care workers to improve treatment seeking after snakebite is a global priority. Many factors are associated with delayed presentation to hospital and early administration of antivenom. We found that most snakebite patients in Sri Lanka present to the first hospital within an hour of the bite. However, there remains a delay of about two more hours until the first dose of antivenom is administered. This delay is a reflection of a delay in the appearance of observable or measurable features of envenoming and a lack of reliable early diagnostic tests. We emphasise the need for reliable, rapid diagnostics for systemic envenoming.

Acute kidney injury (AKI) is the most serious clinical manifestation of the Sri Lankan hump-nosed pit viper (We conducted a prospective observational study of suspected viper bites and included 103 confirmed cases ofTen patients developed AKI: seven AKI stage 1 and three AKI stage 3. Ten patients (10%) developed thrombocytopaenia while 11 (11%) had MAHA. All three AKI stage 3 had thrombocytopaenia and MAHA fulfilling the criteria for TMA. Two of them presented with oliguria/anuria and all three required haemodialysis. Serum creatinine within 4 h post-bite was the best predictor of AKI with AUC-ROC of 0.83 (95% CI: 0.67-0.99) and was no better within 8 h of the bite.We found that AKI is uncommon in

Intra-specific venom variation has the potential to provide important insights into the evolution of snake venom, but remains a relatively neglected aspect of snake venom studies. We investigated the venom from 13 individual coastal taipans Oxyuranus scutellatus from four localities on the north-east coast of Australia, spanning a distance of 2000km. The intra-specific variation in taipan venom was considerably less than the inter-specific variation between it and the other Australian elapids to which it was compared. The electrophoretic venom profile of O. scutellatus was visually different to six other genera of Australian elapids, but not to its congener inland taipan O. microlepidotus. There was minimal geographical variation in taipan venom, as the intra-population variation exceeded the inter-population variation for enzymatic activity, procoagulant activity, and the abundance of neurotoxins. The pre-synaptic neurotoxin (taipoxin) was more abundant than the post-synaptic neurotoxins (3FTx), with a median of 11.0% (interquartile range (IQR): 9.7% to 18.3%, range: 6.7% to 23.6%) vs. a median of 3.4% (IQR: 0.4% to 6.7%, range: 0% to 8.1%). Three taipan individuals almost completely lacked post-synaptic neurotoxins, which was not associated with geography and occurred within two populations. We found no evidence of sexual dimorphism in taipan venom. Our study provides a basis for evaluating the significance of intra-specific venom variation within a phylogenetic context by comparing it to the inter-specific and inter-generic variation. The considerable intra-population variation we observed supports the use of several unpooled individuals from each population when making inter-specific comparisons.

Reporting of snakebite is poor in areas where they are most common. Comparatively, bites by snakes of high medical importance are likely to be documented than snakes of lesser medical importance. This study aims to describe the demographic, epidemiological and, clinical data of patients who were presented during a 49-month study period to a tertiary care center in rural Sri Lanka following authenticated bites by snakes of lesser medical importance. Of the total of 2362 confirmed snakebite patients during the study period, 517 (22%) presented with the offending snake specimen. Of them, 76 (15%) were identified as snakes of lesser medical importance and were included in this study. There were 41 (54%) females. The median ages of females and males were 35 and 43 years respectively. Most patients (86%) were bitten indoors or at home gardens. More than half of them were bitten between 1800 and 0000 h. Most bites (54%) had occurred to the ankle or below. The patients were bitten by 12 species of colubrids, one pythonid (Python molurus), and one viperid (Trimeresurus trigonocephalus). The snake species that caused the most-number of bites was the Trinket snake (Coelognathus helena) (n = 15). Three species of wolf-snakes, Lycodon aulicus, L. anamallensis, and L. striatus were responsible for 12, 11, and 5 bites respectively. Most of the patients (55%) presented to the local hospital and subsequently transferred to the study hospital for further management. None of the patients developed systemic envenoming and five developed mild local pain and swelling. Fifty-six (74%) patients were discharged on the following day, while 18 (24%) were discharged on the third day. There is a need to educate medical personnel working the peripheral hospital on how to identify medically lesser important snakes to avoid unnecessary transfers.

Background: Repeated supratherapeutic ingestion (RSTI) of paracetamol can result in acute liver injury. Management guidelines vary worldwide and in Australia, acetylcysteine treatment is recommende...

Study objective: Although uncommon, children ( = 2 determined by the attending paramedic. The primary outcome was the proportion of adverse effects (need for airway intervention, oxygen saturation

Background: Modified-release (MR) paracetamol is available in many countries as 665 mg tablets of which 69% is MR and 31% is immediate release. There are concerns that MR paracetamol overdose has higher rates of liver injury despite standard treatment algorithms. The objective of this study was to describe the clinical characteristics and outcomes of acute MR paracetamol overdose. Methods: Prospective observational study, recruiting patients from January 2013 to June 2017, from five clinical toxicology units and calls to two Poisons Information Centres in Australia. Included were patients >14 years who ingested ≥10 g or 200 mg/kg (whichever is less) of MR paracetamol. Data collected included demographics, ingestion history, pathology results, treatments, and outcomes including hepatotoxicity (ALT >1000 U/L). Results: In total, 116 patients were recruited, 85(73%) were female. The median dose ingested was 32 g (IQR: 20–49 g) and median time to presentation was 3 h (IQR: 2–9 h). 78(67%) had an initial paracetamol concentration above the nomogram line (150 mg/L at 4 h). A further 12(10%) crossed the nomogram after repeat paracetamol measurements, of which five crossed after two non-toxic levels 4 h apart. Six had a double paracetamol peak, in three occurring >24 h post-ingestion. 113(97%) received acetylcysteine of which 67 received prolonged treatment beyond the standard 21 h. This was because of an elevated paracetamol concentration at the completion of acetylcysteine in 39 (median paracetamol concentration 25 mg/L, IQR: 16–62 mg/L). 21 (18%) developed hepatotoxicity, including six treated within 8 h of ingestion. Activated charcoal and double doses of acetylcysteine did not significantly decrease the risk of hepatotoxicity. Conclusions: Drug regulatory authorities are considering restrictions on MR paracetamol preparations. Following an acute MR paracetamol overdose, this study found that many patients had a persistently elevated paracetamol concentrations, many required prolonged treatment and some developed liver injury despite early acetylcysteine treatment. Furthermore, activated charcoal and increased acetylcysteine did not appear to significantly alter the risk of liver injury. Hence, research into better treatment strategies is required. Trial registration: Australian Toxicology Monitoring (ATOM) Study – Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.

Objective: Investigating diurnal variation in the timing of suicidal behaviours offers opportunity to better understand its various proximal risk factors. Acute use of alcohol is a potent proximal risk factor for suicidal behaviour, though the nature of this risk is poorly understood. The aim of this study was to compare the diurnal variation in time of poison ingestion between deliberate self-poisonings that involve alcohol versus those that do not. Methods: A retrospective analysis of consecutive presentations to a toxicology service following deliberate self-poisoning, 1996–2016. An independent samples Kolmogorov–Smirnov test was performed to test the null hypothesis that the diurnal distribution of poison ingestion time was equal across self-poisonings that did and did not involve alcohol co-ingestion. Presence of circadian rhythmicity was established using cosinor analysis. Results: A total of 11,088 deliberate self-poisoning records, for 7467 patients (60.8% females), were included in the analysis. In all, 31.3% of the total records involved alcohol co-ingestion. Distribution of exposure time was significantly different between deliberate self-poisonings that did and did not involve alcohol ( p Conclusion: This study exposed the differential diurnal patterns in deliberate self-poisoning according to the presence of alcohol co-ingestion. This analysis adds to the accumulating evidence that suicidal behaviour that involves alcohol co-ingestion represents a distinct subtype, which may be driven by alcohol consumption patterns in society. This also means that this large proportion of deliberate self-poisonings may not otherwise have occurred if it were not for alcohol consumption, underscoring the importance of drug and alcohol services for alcohol-related self-harm.

A well-accepted test for monitoring anticoagulation by enoxaparin is not currently available. As inadequate dosing may result in thrombosis or bleeding, a clinical need exists for a suitable test. Previous in silico and in vitro studies have identified factor Xa as an appropriate activating agent, and the phospholipid Actin FS as a cofactor for a Xa clotting time (TenaCT) test. A proof-of-concept study was designed to (1) explore the reproducibility of the TenaCT test and (2) explore factors that could affect the performance of the test. In vitro clotting time tests were carried out using plasma from 20 healthy volunteers. The effect of enoxaparin was determined at concentrations of 0.25, 0.50, and 1.0 IU/mL. Clotting times for the volunteers were significantly prolonged with increasing enoxaparin concentrations. Clotting times were significantly shortened for frozen plasma samples. No significant differences in prolongation of clotting times were observed between male and female volunteers or between the 2 evaluated age groups. The clotting times were consistent between 2 separate occasions. The TenaCT test was able to distinguish between the subtherapeutic and therapeutic concentrations of enoxaparin. Plasma should not be frozen prior to performing the test, without defining a frozen plasma reference range. This study provided proof-of-concept for a Xa-based test that can detect enoxaparin dose effects, but additional studies are needed to further develop the test.

Paracetamol is commonly taken in overdose, with increasing concerns that those taking "massive" overdoses have higher rates of hepatotoxicity and may require higher doses of acetylcysteine. The objective was to describe the clinical characteristics and outcomes of "massive" (≥ 40 g) paracetamol overdoses.Patients were identified through the Australian Paracetamol Project, a prospective observational study through Poisons Information Centres in NSW and Queensland, over 3 and 1.5 years, respectively, and retrospectively from three clinical toxicology unit databases (over 2.5 to 20 years). Included were immediate-release paracetamol overdoses ≥ 40 g ingested over ≤ 8 h. Outcomes measured included paracetamol ratio[defined as the ratio of the first paracetamol concentration taken 4-16 h post-ingestion to the standard (150 mg/L at 4 h) nomogram line at that time] and hepatotoxicity (ALT1000 U/L).Two hundred paracetamol overdoses were analysed, reported median dose ingested was 50 g (interquartile range (IQR): 45-60 g) and median paracetamol ratio 1.9 (IQR: 1.4-2.9, n = 173). One hundred and ninety-three received acetylcysteine at median time of 6.3 h (IQR: 4-9.3 h) post-ingestion. Twenty-eight (14%) developed hepatotoxicity, including six treated within 8 h of ingestion. Activated charcoal was administered to 49(25%), at median of 2 h post-ingestion (IQR:1.5-5 h). Those receiving activated charcoal (within 4 h of ingestion), had significantly lower paracetamol ratio versus those who did not: 1.4 (n = 33, IQR: 1.1-1.6) versus 2.2 (n = 140, IQR: 1.5-3.0) (p .0001) (paracetamol concentration measured ≥ 1 h after charcoal). Furthermore, they had lower rates of hepatotoxicity [unadjusted OR: 0.12 (95% CI:0.001-0.91); adjusted for time to acetylcysteine OR: 0.20 (95%CI: 0.002-1.74)]. Seventy-nine had a paracetamol ratio ≥2, 43 received an increased dose of acetylcysteine in the first 21 h; most commonly a double dose in the last bag (100 to 200 mg/kg/16 h). Those receiving increased acetylcysteine had a significant decrease risk of hepatotoxicity [OR:0.27 (95% CI: 0.08-0.94)]. The OR remained similar after adjustment for time to acetylcysteine and paracetamol ratio.Massive paracetamol overdose can result in hepatotoxicity despite early treatment. Paracetamol concentrations were markedly reduced in those receiving activated charcoal within 4 h. In those with high paracetamol concentrations, treatment with increased acetylcysteine dose within 21 h was associated with a significant reduction in hepatotoxicity.

This was a before and after study which sought to assess the impact of opening an ED short stay unit (ESSU) on the ED performance of poisoned patients.Data was collected from two groups of adult patients presenting to an ED with a tertiary referral inpatient Toxicology unit from the 2009 and 2012 calendar years, to assess the impact of the ESSU. The toxicology unit clinical database and hospital electronic medical records were interrogated for demographic, clinical and hospital flow details of presentations. The primary outcome was ED length of stay (LOS). Other outcomes included proportion of patients remaining in ED for their admission, 28day re-presentations and hospital LOS.During 2009, 795 patients met inclusion criteria, and during 2012, 762. The median LOS in ED was reduced from 8.5 h (IQR: 4.7-14 h) to 2.7 h (IQR: 1.6-4.6; p0.0001). The proportion of patients remaining in ED for their entire hospital stay was reduced from 515/795 (65%) to 56/762 (7.3%) [Absolute difference: 57%; 95% CI: 53 to 62%; p0.0001]. Total hospital LOS increased from 14.5 h (IQR: 8.4-21.8 h) to 16.7 h (IQR: 11.5-23; p0.0001), but there was a decrease in re-presentations with self-poisoning within 28days from 6.9% in 2009 to 4.5% in 2012 (p0.038). There was no difference between disposition destination or toxins causing exposure between the two groups.The ESSU led to a significant improvement in ED performance of poisoned patients. It also potentially assisted in reducing ED overcrowding.

Warfarin acts by inhibiting the reduction of vitamin K (VK) to its active form, thereby decreasing the production of VK-dependent coagulation proteins. The aim of this research is to develop a joint model for the VK-dependent clotting factors II, VII, IX and X, and the anticoagulation proteins, proteins C and S, during warfarin initiation. Data from 18 patients with atrial fibrillation who had warfarin therapy initiated were available for analysis. Nine blood samples were collected from each subject at baseline, and at 1–5, 8, 15 and 29 days after warfarin initiation and assayed for factors II, VII, IX and X, and proteins C and S. Warfarin concentration–time data were not available. The coagulation proteins data were modelled in a stepwise manner using NONMEM® Version 7.2. In the first stage, each of the coagulation proteins was modelled independently using a kinetic-pharmacodynamic model. In the subsequent step, the six kinetic-pharmacodynamic models were combined into a single joint model. One patient was administered VK and was excluded from the analysis. Each kinetic-pharmacodynamic model consisted of two parts: (1) a common one-compartment pharmacokinetic model with first-order absorption and elimination for warfarin; and (2) an inhibitory E max model linked to a turnover model for coagulation proteins. In the joint model, an unexpected pharmacodynamic lag was identified and the estimated degradation half-life of VK-dependent coagulation proteins were in agreement with previously published values. The model provided an adequate fit to the observed data. The joint model represents the first work to quantify the influence of warfarin on all six VK-dependent coagulation proteins simultaneously. Future work will expand the model to predict the influence of exogenously administered VK on the time course of clotting factor concentrations after warfarin overdose and during perioperative warfarin reversal procedures.

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. SUMMARY: Background Russell's viper (Daboia russelii) envenoming is a major health issue in South Asia and causes venom-induced consumption coagulopathy (VICC). Objectives To investigate the effects of fresh frozen plasma (FFP) and two antivenom doses in correcting VICC. Methods We 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. Results From 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. NHMRC. Grant Numbers: 631073, 1061041, 1059542

Cellular response to insults may result in the initiation of different cell death processes. For many cases the cell death process will result in an acute release of cellular material that in some circumstances provides valuable information about the process (i.e. may represent a biomarker). The characteristics of the biomarker release is often informative and plays critical roles in clinical practice and toxicology research. The aim of this study is to develop a general, semi-mechanistic model to describe cell turnover and biomarker release by injured tissue that can be used for estimation in pharmacokinetic and (toxicokinetic)-pharmacodynamic studies. The model included three components: (1) natural tissue turnover, (2) biomarker release from cell death and its movement from the cell through the tissue into the blood, (3) different target insult mechanisms of cell death. We applied the general model to biomarker release profiles for four different cell insult causes. Our model simulations showed good agreements with reported data under both delayed release and rapid release cases. Additionally, we illustrate the use of the model to provide different biomarker profiles. We also provided details on interpreting parameters and their values for other researchers to customize its use. In conclusion, our general model provides a basic structure to study the kinetic behaviour of biomarker release and disposition after cellular insult.

Introduction: In our previous study on chronic digoxin poisoning, there was a minor improvement after treatment with digoxin-specific antibody (digoxin-Fab). We hypothesised patients with elevated digoxin concentrations may derive little benefit from digoxin-Fab because their presenting complaint was more closely related to their multiple co-morbidities. We aimed to compare the outcome of patients who were initially treated with digoxin-Fab with those that received supportive care. Method: Patients were prospectively recruited to the study if they had an elevated digoxin concentration, signs or symptoms of toxicity thought to be from digoxin. Patients who were initially managed with digoxin-Fab were compared with those not initially receiving digoxin-Fab (observation group). Patients presented with ventricular arrhythmias before initial assessment were excluded from the analysis. Primary outcome was mortality. Secondary outcomes were length of stay (LOS), change in heart rate (HR) and potassium concentration. Results: From September 2013 to January 2018, 128 patients were recruited of which 78 (61%) received initial digoxin-Fab. Digoxin-Fab and supportive care groups had an initial median heart rate of 46 (range: 20–120) vs 52 bpm (range: 29–91) (p = .06), systolic blood pressure of 110 mmHg (range: 65–180) vs 125 mmHg (range: 90–184) (p = .009), respectively. Digoxin concentrations 4.4 nmol/L (range: 3.3–9) vs 4.2 (range: 2–11.2) (p = .42) and potassium concentrations 5.4 mmol/L (range: 3–11) vs 5.1 mmol/L (range: 3.5–8.2) (p = .33) were similar. Median dose of digoxin-Fab used was 1.5 vials (IQR: 1–2). There were 9 (12%) deaths in the Fab group compared to 7 (14%) in those treated with supportive care (risk difference −2.5%; 95% CI: −14 to 9%; p = .68). The median LOS was six days in both groups. Mean changes in potassium concentration [−0.5 ± 0.1 vs. −0.4 ± 0.1 mmol/L; difference −0.1 (95% CI: −.02, 0.4), p = .70] and HR within 4 h [8 ± 1 vs. 7 ± 3 bpm; difference −1.0 (95% CI: −6.7, 4.8), p = 0.74] were similar in the two groups. Conclusions: This study did not appear to show any benefit from the routine use of digoxin-Fab in patients thought to have chronic digoxin poisoning. These patients have multiple co-morbidities that may be contributing to their clinical features, other treatments are often equally effective.

Wistar rats were administered increasing doses of Russell's viper venom (RVV; 0.025–0.4 mg/kg) intraperitoneally to investigate acute kidney injury (AKI) by measuring creatinine (1.5-fold increase in serum creatinine above baseline) and examining kidney histology. Approximately 50% of rats receiving 0.25–0.4 mg/kg venom died within 72 h. An increase in serum creatinine only occurred at a venom dose of 0.4 mg/kg, except in two rats. Acute tubular necrosis, glomerular necrosis, cortical necrosis and interstitial inflammation were observed at venom doses of ≥0.25 mg/kg in 12/36 rats. However, of those 12 rats only four survived to 48 h compared to the 24 rats not developing nephrotoxicity, in which 18 were alive at 48 h. There was poor correlation between histological nephrotoxicity and AKI based on creatinine measurement. The early death in rats with AKI makes this a poor model for studying RVV-induced AKI.

We investigated the cardiovascular effects of venoms from seven medically important species of snakes: Australian Eastern Brown snake (Pseudonaja textilis), Sri Lankan Russell’s viper (Daboia russelii), Javanese Russell’s viper (D. siamensis), Gaboon viper (Bitis gabonica), Uracoan rattlesnake (Crotalus vegrandis), Carpet viper (Echis ocellatus) and Puff adder (Bitis arietans), and identified two distinct patterns of effects: i.e. rapid cardiovascular collapse and prolonged hypotension. P. textilis (5 µg/kg, i.v.) and E. ocellatus (50 µg/kg, i.v.) venoms induced rapid (i.e. within 2 min) cardiovascular collapse in anaesthetised rats. P. textilis (20 mg/kg, i.m.) caused collapse within 10 min. D. russelii (100 µg/kg, i.v.) and D. siamensis (100 µg/kg, i.v.) venoms caused ‘prolonged hypotension’, characterised by a persistent decrease in blood pressure with recovery. D. russelii venom (50 mg/kg and 100 mg/kg, i.m.) also caused prolonged hypotension. A priming dose of P. textilis venom (2 µg/kg, i.v.) prevented collapse by E. ocellatus venom (50 µg/kg, i.v.), but had no significant effect on subsequent addition of D. russelii venom (1 mg/kg, i.v). Two priming doses (1 µg/kg, i.v.) of E. ocellatus venom prevented collapse by E. ocellatus venom (50 µg/kg, i.v.). B. gabonica, C. vegrandis and B. arietans (all at 200 µg/kg, i.v.) induced mild transient hypotension. Artificial respiration prevented D. russelii venom induced prolonged hypotension but not rapid cardiovascular collapse from E. ocellatus venom. D. russelii venom (0.001–1 μg/ml) caused concentration-dependent relaxation (EC50 = 82.2 ± 15.3 ng/ml, Rmax = 91 ± 1%) in pre-contracted mesenteric arteries. In contrast, E. ocellatus venom (1 µg/ml) only produced a maximum relaxant effect of 27 ± 14%, suggesting that rapid cardiovascular collapse is unlikely to be due to peripheral vasodilation. The prevention of rapid cardiovascular collapse, by ‘priming’ doses of venom, supports a role for depletable endogenous mediators in this phenomenon.

Context: Inpatient toxicology services undertake remote as well as inpatient management of poisoned patients. The aim of this study is to describe the introduction of a tablet-based electronic data...

Here we test and refute the hypothesis that venom toxins from an Australian elapid, the Eastern Brown snake (Pseudonaja textilis, PTx), solely require lymphatic transport to enter the circulation. Studies were made using anaesthetised non-recovery rats in which a marker dye (India ink) or highly potent PTx venom was injected into the hind paw. The studies required a means of inhibiting lymphatic function, as achieved by cooling of the test hind limb to low temperatures (~3 °C). Maintained entry of a non-lethal dose (0.15 mg/kg) and respiratory arrest consequent to injection of a lethal dose (1 mg/kg) of PTx venom at these low temperatures indicate that venom including toxin components enter the circulation directly via the vascular system, a process facilitated by, but not dependent on, lymphatic transport. Notably, the venom had a direct effect on vascular permeability markedly increasing this to allow extravasation of plasma albumin (MWt ~60 kDa).

Understand factors related to related to tobacco smoking amongst individuals who present with deliberate self-harm is important. This article explores the relationship between tobacco use with mental health diagnoses and substance use in a cohort of overdose admissions.Secondary analysis of an existing health service database with 7133 patients admitted for deliberate self-poisonings from 1997 to 2013 was conducted. A data collection form was used on admission to capture information on patient demographics, drugs ingested, use of drugs of misuse, regular medications and management and complications of poisoning. The data was analysed using a multiple logistic regression model.Within a deliberate self-poisoning population, those diagnosed with: an amphetamine substance use disorder (OR = 1.84, p .001), alcohol use disorder (OR = 1.68, p .001), other substance use disorder (OR = 1.77, p .001), psychotic diagnoses (OR = 1.17, p = .032), or had a history of self-harm (OR = 1.15, p = .011) were more likely to be a current tobacco smoker. Those who were older (OR = 0.99, p .001) or diagnosed with a mood disorder (OR = 0.87, p = .018) were less likely to smoke tobacco.The study was unable to differentiate between suicide attempts and self-harm self-poisonings.Among a deliberate self-poisoning population those who were younger, diagnosed with a variety of substance use disorders, or had a history of previous self-poisoning were more likely to use tobacco. Those with a mood disorder were less likely to smoke tobacco.

Objectives To assess the numbers of paracetamol overdose-related hospital admissions and deaths in Australia since 2007-08, and the overdose size of intentional paracetamol overdoses since 2004. Design, setting Retrospective analysis of data on paracetamol-related exposures, hospital admissions, and deaths from the Australian Institute of Health and Welfare National Hospital Morbidity Database (NHMD; 2007-08 to 2016-17), the New South Wales Poisons Information Centre (NSWPIC; 2004-2017), and the National Coronial Information System (NCIS; 2007-08 to 2016-17). Participants People who took overdoses of paracetamol in single ingredient preparations. Main outcome measures Annual numbers of reported paracetamol-related poisonings, hospital admissions, and deaths; number of tablets taken in overdoses. Results The NHMD included 95 668 admissions with paracetamol poisoning diagnoses (2007-08 to 2016-17); the annual number of cases increased by 44.3% during the study period (3.8% per year; 95% CI, 3.2-4.6%). Toxic liver disease was documented for 1816 of these patients; the annual number increased by 108% during the study period (7.7% per year; 95% CI, 6.0-9.5%). The NSWPIC database included 22 997 reports of intentional overdose with paracetamol (2004-2017); the annual number increased by 77.0% during the study period (3.3% per year; 95% CI, 2.5-4.2%). The median number of tablets taken increased from 15 (IQR, 10-24) in 2004 to 20 (IQR, 10-35) in 2017. Modified release paracetamol ingestion report numbers increased 38% between 2004 and 2017 (95% CI, 30-47%). 126 in-hospital deaths were recorded in the NHMD, and 205 deaths (in-hospital and out of hospital) in the NCIS, with no temporal trends. Conclusions The frequency of paracetamol overdose-related hospital admissions has increased in Australia since 2004, and the rise is associated with greater numbers of liver injury diagnoses. Overdose size and the proportion of overdoses involving modified release paracetamol have each also increased.

Objective: To examine the epidemiology and severity of self-poisoning by older people in Australia; to compare these data with those for overdoses in younger adults. Design, setting, participants: A cohort study of people presenting to a tertiary toxicology centre after self-poisoning over 26 years (1987–2012). Main outcome measures: Hospital length of stay (LOS); types of drug ingested; intensive care unit (ICU) admissions; in-hospital deaths. Results: Of 17 276 admissions, 626 patients (3.6%) were at least 65 years old. There was a steady decline in the number of overdoses with age. Most self-poisoning by older people was intentional (80% of admissions), but the proportion of unintentional poisonings increased with age (P < 0.001). Median LOS for older patients was 34 h (interquartile range [IQR], 16–75 h), longer than for younger patients (16 h; IQR, 9–25 h; P < 0.001). 133 older patients (21.2%) were admitted to an ICU, compared with 1976 younger patients (11.9%; P < 0.001). 24 older patients (3.8%) and 93 younger patients (0.6%) died; mortality among older patients declined over time. Hypotension and arrhythmias were more common in patients over 65. Benzodiazepines (24%) were the drugs most commonly ingested by older patients, but opioids the most frequently taken drugs in fatal cases. Toxic ingestion of cardiovascular drugs increased threefold over the 26 years; about one-third of poisonings were unintentional or iatrogenic. Recreational drugs were implicated in the admissions of four older patients (0.6%), but in 7.8% of those of people under 65. Conclusion: Older patients treated for self-poisoning differ in several important respects from patients under 65. They are more severely affected by self-poisoning: LOS is greater, and ICU admission and mortality rates are higher.

SummaryThe 20-minute whole blood clotting test (WBCT20) is used as a bed-side diagnostic test for coagulopathic snake envenoming. We aimed to assess the performance of the WBCT20 in diagnosis of venom induced consumption coagulopathy (VICC) in Russell’s viper envenoming. Adult patients admitted with suspected snake bites were recruited from two hospitals. WBCT20 and prothrombin time (PT) test were performed on admission. WBCT20 was done by trained clinical research assistants using 1 ml whole blood in a 5 ml borosilicate glass tube with a 10 mm internal diameter. The PT was measured by a semi-automated coagulation system and international normalised ratio (INR) calculated. VICC was defined as present if the INR was >1.4. The diagnostic utility of WBCT20 was determined by calculating the sensitivity and specificity of the WBCT20 on admission for detecting VICC. There were 987 snake bites where both WBCT20 and PT were done on admission samples. This included 79 patients (8 %) with VICC. The WBCT20 was positive in 65/79 patients with VICC (sensitivity 82 %; 95 % confidence interval [CI]: 72–90 %) and was falsely positive in 13/908 with no coagulopathy. The WBCT20 was negative in 895/908 snake bites with no coagulopathy (specificity: 98 % 95 % CI: 97–99 %) and was falsely negative in 14/79 with VICC. Using trained clinical staff, the WBCT20 test had a relatively good sensitivity for the detection of VICC, but still missed almost one fifth of cases where antivenom was potentially indicated.Supplementary Material to this article is available online at www.thrombosis-online.com.

Taipans (Oxyuranus spp.) are medically important venomous snakes from Australia and Papua New Guinea. The objective of this study was to describe taipan envenoming in Australian and its response to antivenom.Confirmed taipan bites were recruited from the Australian Snakebite Project. Data were collected prospectively on all snakebites, including patient demographics, bite circumstances, clinical effects, laboratory results, complications and treatment. Blood samples were taken and analysed by venom specific immunoassay to confirm snake species and measure venom concentration pre- and post-antivenom.There were 40 confirmed taipan bites: median age 41 years (2-85 years), 34 were males and 21 were snake handlers. Systemic envenoming occurred in 33 patients with neurotoxicity (26), complete venom induced consumption coagulopathy (VICC) (16), partial VICC (15), acute kidney injury (13), myotoxicity (11) and thrombocytopenia (7). Venom allergy occurred in seven patients, three of which had no evidence of envenoming and one died. Antivenom was given to 34 patients with a median initial dose of one vial (range 1-4), and a median total dose of two vials (range 1-9). A greater total antivenom dose was associated with VICC, neurotoxicity and acute kidney injury. Early antivenom administration was associated with a decreased frequency of neurotoxicity, acute kidney injury, myotoxicity and intubation. There was a shorter median time to discharge of 51 h (19-432 h) in patients given antivenom 4 h post-bite, compared to 175 h (27-1104 h) in those given antivenom 4 h. Median peak venom concentration in 25 patients with systemic envenoming and a sample available was 8.4 ng/L (1-3212 ng/L). No venom was detected in post-antivenom samples, including 20 patients given one vial initially and five patients bitten by inland taipans.Australian taipan envenoming is characterised by neurotoxicity, myotoxicity, coagulopathy, acute kidney injury and thrombocytopenia. One vial of antivenom binds all measurable venom and early antivenom was associated with a favourable outcome.

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 (13.6 kDa), 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 ± 7 min only at 1 μM. 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.

Redback spider envenoming causes severe pain lasting several days. A recent clinical trial found that antivenom is not effective. We investigated ketamine for pain in redback spider envenoming. Ten adult patients with severe pain from redback spider envenoming were administered 15 mg intravenous ketamine after standard analgesia, then up to 4 oral doses of ketamine 25- 50 mg. Three patients had a clinically significant improvement in pain compared to baseline after intravenous ketamine. Five patients had a minimal decrease in pain and 2 had no improvement. Eight patients received oral ketamine: 4 doses in 5 and 2 doses in 3. At 24 h, 3/6 patients assessed had clinically significant improvement in pain and 4/5 patients assessed at 48 h, had clinically significant improvement in pain. Six patients reported side effects, including dissociation (4) and hallucinations (2). Five patients required rescue opioids and 2 were readmitted to hospital. We found that ketamine provided no additional pain relief in redback spider envenoming, compared to standard analgesia, and resulted in unacceptable adverse effects.

Many bites from mildly venomous elapids occur but identification or presence of systemic envenoming is rarely confirmed.To confirm systemic envenoming and binding of venom components to a commercial antivenom in a definite bite by the Ornamental Snake (Denisonia maculata) using enzyme immunoassays.A 9-year old boy was bitten by an identified Ornamental Snake. He developed nausea, vomiting, local pain, and swelling. He had a leucocytosis (white cell count, 20.8 × 10(9)/L), an elevated international normalised ratio (INR) of 1.6, but otherwise normal blood tests including D-Dimer and activated partial thromboplastin time. He was treated with Australian Black Snake antivenom because the commercial venom detection kit was positive for Black snake. He was admitted for 36 h with continuing local pain and swelling requiring parenteral analgesia.Blood samples were collected with informed consent for measurement of venom and antivenom concentrations. Venom-specific enzyme immunoassays were developed using the closely related D. devisi venom with Rabbit anti-Notechis (Tiger Snake) and anti-Tropidechis (Rough-scaled Snake) IgG antibodies to detect venom in serum. Standard curves for measured venom versus actual venom concentrations were made to interpolate Denisonia venom concentrations. In vitro procoagulant and anticoagulant activity of venom was assayed.Denisonia venom was detected in the pre-antivenom sample as 9.6 ng/mL D. devisi venom. No antigenic venom components were detected in post-antivenom samples and there were high antivenom concentrations. D. devisi venom had mild in vitro procoagulant activity with a minimum concentration required to clot after 5 min of 2.5-5 μg/mL and even weaker anticoagulant activity.Denisonia bites appear to cause local effects and possibly mild systemic envenoming (with only non-specific systemic symptoms and leucocytosis), confirmed by detection of antigenic venom components in blood. A significant coagulopathy does not appear to occur.

Intracranial haemorrhage (ICH) is a rare life-threatening consequence of venom induced consumption coagulopathy in snake-bite. It is unclear why certain patients haemorrhage. We aimed to investigate ICH in snake envenoming. Cases of venom-induced consumption coagulopathy from July 2005–June 2014 were identified from the Australian Snakebite Project, a prospective multicentre cohort of snake-bites. Cases with venom-induced consumption coagulopathy were extracted with data on the snake-bite, clinical effects, laboratory investigations, treatment and outcomes. 552 cases had venom-induced consumption coagulopathy; median age, 40 y (2–87 y), 417 (76%) males, 253 (46%) from brown snakes and 17 died (3%). There were 6/552 (1%) cases of ICH; median age, 71 y (59–80 y), three males and five from brown snakes. All received antivenom and five died. All six had a history of hypertension. Time to onset of clinical effects consistent with ICH was 8–12 h in four cases, and within 3 h in two. Difficult to manage hypertension and vomiting were common. One patient had a normal cerebral CT on presentation and after the onset of focal neurological effects a repeat CT showed an ICH. ICH is rare in snake-bite with only 1% of patients with coagulopathy developing one. Older age and hypertension were associated with ICH.

Acute behavioral disturbance is a common problem for emergency medical services. We aimed to investigate the safety and effectiveness of droperidol compared to midazolam in the prehospital setting.This was a prospective before and after study comparing droperidol to midazolam for prehospital acute behavioral disturbance, when the state ambulance service changed medications. The primary outcome was the proportion of adverse effects (airway intervention, oxygen saturation90%, respiratory rate12, systolic blood pressure90 mmHg, sedation assessment tool score -3 and dystonic reactions) in patients receiving sedation. Secondary outcomes included time to sedation, requirement for additional sedation, staff and patient injuries, and prehospital time.There were 141 patients administered midazolam and 149 patients administered droperidol in the study. Alcohol was the most common cause of acute behavioral disturbance. Fewer patient adverse events occurred with droperidol (11/149) compared to midazolam (33/141) (7% vs. 23%; absolute difference 16%; 95% confidence interval [CI]: 8% to 24%; p = 0.0001). Median time to sedation was 22 min (interquartile range [IQR]:18 to 35 min) for droperidol compared to 30 min (IQR:20 to 45 min) for midazolam. Additional prehospital sedation was required in 6/149 (4%) droperidol patients and 20/141 (14%) midazolam patients, and 11 (7%) droperidol and 59 (42%) midazolam patients required further sedation in the emergency department. There were no differences in patient or staff injuries, or prehospital time.The use of droperidol for acute behavioral disturbance in the prehospital setting is associated with fewer adverse events, a shorter time to sedation, and fewer requirements for additional sedation.

Context: Ingestion of bromoxynil and 2-methyl-4-chlorophenoxyacetic acid (MCPA) in combination is associated with high mortality. Toxicity is characterised by hyperthermia and metabolic acidosis. Dialysis is a proposed treatment, but little data exist regarding its effectiveness. Case details: Case 1: A 50-year-old female presented 18 h post-ingestion of 200 mL of bromoxynil(200 g/L) and MCPA(200 g/L). She was agitated, tachycardic and tachypnoeic. She was intubated and continuous venovenous haemodiafiltration (CVVHDF) was commenced. She deteriorated, becoming hypotensive, hyperthermic (39.5 °C) and hypercapnic (80 mmHg). She was cooled, paralysed, received CVVHDF for 2d and was extubated on day 4 making a full recovery. Case 2: A 60-year-old male presented 6 h post-ingestion of an unknown amount of bromoxynil (200 g/L) and MCPA (200 g/L). On arrival, he was tachycardic and tachypneic (pCO 2 25 mmHg). At 8h post-ingestion he became hyperthermic, hypercapnic and acidotic (pH 7.15), and was intubated, paralysed, cooled and received CVVHDF for 36 h. He was extubated after 42 h and made a full recovery. Bromoxynil and MCPA serum and effluent concentrations were measured. Peak MCPA serum concentrations were 161 µg/ml and 259 µg/ml and peak bromoxynil concentrations were 119 µg/ml and 155 µg/ml in case 1 and 2, respectively. The estimated clearance of both herbicides by CVVHDF was low ( < 10 mL/min). Conclusion: CVVHDF did not result in significant clearance of either herbicide but may have assisted with hyperthermia control. Both patients survived with vigorous cooling, paralysis and ventilatory support. Refereed/Peer-reviewed

High-dose insulin euglycaemia (HIE) is recommended in the management of toxin-induced cardiac toxicity, with increasing insulin doses now being used. We aimed to investigate the safety of HIE in toxin-induced cardiac toxicity.This was a retrospective review of cases from two clinical toxicology units. Demographics, toxin(s) ingested, clinical effects, investigations (serum glucose, electrolytes), treatments (insulin, glucose, electrolyte replacement), length of stay (LOS) and outcomes were extracted from the patients' medical records. Associations between insulin and glucose/electrolyte homeostasis were explored by comparing insulin administration and glucose or electrolyte concentrations and replacement.There were 22 patients (12 females), median age 57 years (15-88 years) treated with HIE. There were 12 beta-blocker, six calcium channel blocker and three combined beta-blocker and calcium channel blocker ingestions. A total of 19 patients had a systolic blood pressure 80mmHg and 18 patients required inotropes in addition to HIE. There were three deaths. Despite glucose and electrolyte replacement, 16 patients (73%) developed hypoglycaemia (Reference range [RR] 3.5 mmol/L or63 mg/dl). In 7 patients, hypoglycaemia was mild (2.5-3.4 mmol/L or 45-62 mg/dl) and in nine was severe (2.5 mmol/L or45 mg/dl). There were no neurological effects from hypoglycaemia. A total of 18 patients (82%) developed hypokalaemia (3.5 mEq/L). In 16 patients, this was mild (2.5-3.4 mEq/L). There were no cardiac arrhythmias associated with this hypokalaemia. There was no apparent association between insulin dosing and severity of hypoglycaemia or hypokalaemia, or in glucose or potassium replacement. Median insulin loading dose was 80U (range 50-125 U) and the median maximum insulin infusion rate was 150 U/h (range 38-1500 U/h). Median glucose infusions rates were 37.5g/h (range 4-75g/h). There was no apparent association between insulin and glucose administration. Glucose was administered for a median of 18h after ceasing insulin. The duration of glucose administration after ceasing insulin increased with the rate and total insulin administered during HIE.Despite the benefits of HIE in toxin-induced cardiac toxicity, it caused significant disruption to glucose and electrolyte homeostasis, although there were no apparent complications from this. There was no association by comparing the amount of insulin administered on adverse effects or glucose administered, suggesting higher doses of insulin are associated with no more adverse effects.

Myotoxicity is a common clinical effect of snake envenoming and results from either local or systemic myotoxins in snake venoms. Although numerous myotoxins have been isolated from snake venoms, there has been limited study on the relationship between the time course of venom concentrations (pharmacokinetics) and the time course of muscle injury measured as a rise in creatine kinase (CK) (pharmacodynamics).The aim of this study was to develop an in vivo model of myotoxicity to investigate the time course of myotoxicity and the effect of antivenom.Anesthetised rats were administered Pseudechis australis (mulga snake) venom either through i.v., i.m. or s.d. route, including a range of doses (5-100 μg/kg). Serial blood samples were collected for measurement of venom using enzyme immunoassay and measurement of CK and creatinine. Antivenom was administered before, 1 and 6 h after venom administration to investigate its effect on muscle injury. Plots of venom and CK versus time were made and the area under the curve (AUC) was calculated.There was a significant dose-dependent increase in CK concentration after administration of P. australis venom, which was greatest for i.v. administration. Timed measurement of venom concentrations showed a rapid absorption through s.d. and i.m. routes and a delayed rise in CK concentrations following any route. Antivenom prevented myotoxicity shown by a decrease in the CK AUC, which was most effective if given earliest. There was a rise in creatinine following i.v. venom administration.The study shows the delayed relationship between venom absorption and the rise in CK, consistent with the delayed onset of myotoxicity in human envenoming. Antivenom prevented myotoxicity more effectively if given earlier.

Aims To investigate the QT interval after high dose droperidol using continuous 12-lead Holter recordings. Methods This was a prospective study of patients given droperidol with a continuous Holter recording. Patients were recruited from the DORM II study which included patients with aggression presenting to the emergency department. Patients initially received 10 mg droperidol as part of a standardized sedation protocol. An additional 10 mg dose was given after 15 min if required and further doses at the clinical toxicologist's discretion. Continuous 12-lead Holter recordings were obtained for 2–24 h utilizing high resolution digital recordings with automated QT interval measurement. Electrocardiograms were extracted hourly from Holter recordings. The QT interval was plotted against heart rate (HR) on the QT nomogram to determine if it was abnormal. QTcF (Fridericia's HR correction) was calculated and >500 ms was defined as abnormal. Results Forty-six patients had Holter recordings after 10–40 mg droperidol and 316 QT–HR pairs were included. There were 32 abnormal QT measurements in four patients, three given 10 mg and one 20 mg. In three of the four patients QTcF >500 ms but only in one taking methadone was the timing of QTcF >500 ms consistent with droperidol dosing. Of the three other patients, one took amphetamines, one still had QT prolongation 24 h after droperidol and one took a lamotrigine overdose. No patient given >30 mg had a prolonged QT. There were no arrhythmias. Conclusion QT prolongation was observed with high dose droperidol. However, there was little evidence supporting droperidol being the cause and QT prolongation was more likely due to pre-existing conditions or other drugs.

Background Acute kidney injury (AKI) is a major complication of snake envenoming, but early diagnosis remains problematic. We aimed to investigate the time course of novel renal biomarkers in AKI following Russell’s viper (Daboia russelii) bites. Methodology/Principal findings We recruited a cohort of patients with definite Russell’s viper envenoming and collected serial blood and urine samples on admission (, Author summary Snake envenoming is a neglected tropical disease that causes death and severe effects in the rural tropics. Acute kidney injury is a major cause of morbidity in snake envenoming, but continues to be poorly recognised and early diagnosis is difficult. We aimed to investigate the time course of renal biomarkers in acute kidney injury, following Russell’s viper (Daboia russelii) envenoming. In a group of 65 definite Russell’s viper bites in Sri Lanka, acute kidney injury was common and sometimes severe. The severity of the acute kidney injury was associated with the blood venom concentrations. Three novel biomarkers, serum cystatin C, urine neutrophil gelatinase-associated lipocalin and urine clusterin became abnormal before serum creatinine, the current standard biomarker for kidney injury. These three novel biomarkers will be useful to diagnose snake envenoming and acute kidney injury. They provide insight into the time course of snakebite associated acute kidney injury.

CASE REPORT: We report a fatal case of a 37 year old gentleman who ingested a MCPA/bromoxynil co-formulation herbicide. Although clinically well on initial examination, our patient declined dramatically over his 18 h admission with increasing CO2 production, hyperthermia and metabolic derangement to eventually die from cardiac asystole 20 h post ingestion. Two hours after ingestion the MCPA concentration was 83.9 μg/mL and bromoxynil concentration was 137 μg/mL. DISCUSSION: The patients' mechanism of death appeared to be uncoupling of oxidative phosphorylation, excess CO2 production and hyperthermia. There is limited knowledge on the acute toxicity of these herbicides, in particular bromoxynil, and this case highlights the relentless progression of severe toxicity in humans. The collaboration was supported by an NHMRC Program Grant (1055176). Geoff Isbister is supported by an NHMRC Senior Research Fellowship ID 1061041 and Mike Roberts is supported by an NHMRC Senior Principal Research Fellowship ID 1002611.

The Pseudonaja genus (Brown snakes) is widely distributed across Australia and bites account for significant mortality. Venom-induced consumption coagulopathy (VICC) and, less often, early cardiovascular collapse occur following envenoming by these snakes. We have previously examined possible mechanism(s) behind the early cardiovascular collapse following Papuan taipan (Oxyuranus scutellatus) envenoming. In the present study, we investigate early cardiovascular collapse in anaesthetized rats following administration of eastern brown snake (Pseudonaja textilis) venom, and prevention of this effect with prior administration of ‘priming’ doses (i.e. doses of venom which caused a transient hypotensive response) of venom. P. textilis venom (5–10 μg/kg, i.v.) induced cardiovascular collapse in anaesthetized rats, characterized by a rapid decrease in systolic blood pressure until non recordable. Prior administration of ‘priming’ doses of P. textilis venom (2 and 3 μg/kg) or, at least, 4–5 doses of O. scutellatus (2 μg/kg, i.v.) or Daboia russelii limitis (20 μg/kg, i.v.) venoms prevented cardiovascular collapse induced by P. textilis venom. Moreover, early collapse was also inhibited by prior administration of 2 discrete doses of Acanthophis rugosus venom. Prior administration of commercial polyvalent snake antivenom (500–3000 units/kg, i.v.) or heparin (300 units/kg, i.v.) also inhibited P. textilis venom-induced cardiovascular collapse. Our results indicate that P. textilis venom-induced cardiovascular collapse can be prevented by prior administration of sub-lethal doses of venom from P. textilis, O. scutellatus, A. rugosus and D. russelii limitis. This suggests that sudden cardiovascular collapse following envenoming is likely to involve a common mechanism/pathway activated by different snake venoms.