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Schistocytosis is the morphological hallmark of the microangiopathic haemolytic anaemia of thrombotic microangiopathy (TMA). Consensus guidelines for manual schistocyte quantitation are available, but limited research has evaluated them. The 2012 International Council for Standardization in Haematology (ICSH) recommends a schistocyte quantitation of 1% as a robust cut-off for significance, with the quantitation including helmet, crescent, triangle and keratocyte poikilocytes; and microspherocytes only in the presence of helmets, crescents/triangles, and keratocytes. We aimed to evaluate the relative contribution of these different poikilocytes to schistocyte counting; compare the ICSH method with our proposed method which counts only cells most specific for red cell fragmentation (helmet, crescent and triangular schistocytes); and evaluate inter- and intra-observer agreement. Blood films were sourced from the Australian Snakebite Project, including non-envenomed and envenomed cases, with and without TMA. In blood films across the range of schistocytosis, the predominant poikilocytes present were helmets and crescents. Triangles, keratocytes and microspherocytes were typically only present when ICSH schistocyte count was1%. With results dichotomised as1.0% or ≥1.0%, our proposed new method versus the ICSH method showed almost perfect agreement [observed agreement 95%, Cohen's kappa (κ)=0.84, SE 0.04, 95% CI 0.76-0.92, p0.005]. Inter-observer strength of agreement for our method was moderate (Fleiss' κ for comparisons between three non-unique microscopists κ=0.50, SE 0.05, 95% CI 0.41-0.59, p0.005). Intra-observer reproducibility assessed in two microscopists ranged from substantial (Cohen's κ=0.71, SE 0.08, 95% CI 0.55-0.86, p0.005) to borderline almost perfect agreement (Cohen's κ=0.81, SE 0.07, 95% CI 0.68-0.93, p0.005). Schistocyte quantitation using our new method is simpler than the 2012 ICSH method and had almost perfect agreement. Our finding of moderate inter-observer agreement in quantitating helmet, triangle and crescent schistocytes is applicable to both the ICSH and our newly proposed method. This finding underscores the importance of clinicopathological correlation and repeated examinations in the context of a clinically suspected TMA.

The objectives are to determine the effect of NaHCO and/or mechanical ventilation on the biochemical profile and serum alkalinisation in tricyclic antidepressant (TCA) poisoning and investigate the impact of effective alkalinisation therapy on the QRS interval in TCA poisoning. This was a retrospective review of TCA poisonings from three Australian toxicology units and a poisons information centre (Jan 2013-Jan 2019). We included patients with TCA toxicity who ingested>10mg/kg or had clinically significant toxicities consistent with TCA poisoning, and analysed patients' clinical, electrocardiogram and biochemical data. Of 210 patients, 84 received NaHCO and ventilation (dual therapy), 12 NaHCO , 46 ventilation and 68 supportive care treatment. When compared with single/supportive groups, patients who received dual therapy had taken a significantly higher median dose of TCA(1.5g vs.1.3g,p A combination of NaHCO and mechanical ventilation was most effective in achieving serum alkalinisation and was associated with a more rapid narrowing of the QRS interval. We would advise the maximal dose of NaHCO should be

Background Snakebite-associated thrombotic microangiopathy (TMA) occurs in a subset of patients with venom-induced consumption coagulopathy (VICC) following snakebite. Acute kidney injury (AKI) is the commonest end-organ manifestation of TMA. The epidemiology, diagnostic features, outcomes, and effectiveness of interventions including therapeutic plasma-exchange (TPE), in snakebite-associated TMA are poorly understood. Methods We reviewed all patients with suspected or confirmed snakebite recruited to the Australian Snakebite Project (2004-2018 inclusive), a prospective cohort study, from 202 participating Australian hospitals across the country. TMA was defined as anemia with schistocytosis. Results 2069 patients with suspected snakebite were enrolled, with 1158 (56.0%) systemically envenomed, of which 842 (72.7%) developed VICC, from which 104 (12.4%) developed TMA. Of those systemically envenomed, TMA occurred in 26% (13/50) taipan, 17% (60/351) brown, and 8% (16/197) tiger snakebites. Thrombocytopenia was present in 90% (94/104) of TMA cases, and a further eight (8%) had a > 25% decrease in platelets from the presentation. Patients with TMA were significantly older than non-TMA patients with VICC (53 [35-61] versus 41 [24-55] years, median [IQR], p 90-day follow-up for 25 D-AKI cases (130 person-years) showed no end-stage kidney disease but 52% (13/25) had ≥ stage 3 chronic kidney disease (CKD). Conclusion Our findings support a definition of snakebite-associated TMA as anemia with schistocytosis and either thrombocytopenia or >25% drop in platelet count. AKI occurring with snakebite-associated TMA varied in severity, with most achieving DFS, but with a risk of long-term CKD in half. We found no evidence of benefit for TPE in D-AKI.

Overdose with paracetamol modified-release (MR) formulation, a bilayer tablet containing 69% slow-release component, has been increasing since its introduction to the market. However, little evidence exists for the management of MR paracetamol overdose. We aimed to develop a population pharmacokinetic (PK) model for immediate-release (IR) and MR paracetamol and its major metabolism, and quantitatively understand the formulation difference in toxicity assessment based on the nomogram line.Data from a cross-over study design in nine healthy volunteers administered a single supratherapeutic oral dose (80 mg/kg) of either IR and MR paracetamol were available from a published study. Plasma concentrations for paracetamol and its metabolites glucuronide (APAPG) and sulfate conjugate (APAPS) for both formulations were measured and analysed with population pharmacokinetic (PK) method using NONMEM. Toxicity in both formulations was assessed by comparing the simulated paracetamol concentrations under different paracetamol dose levels with the 150 mg/L nomograms. The difference in the assessment was compared between the two formulations.Paracetamol concentrations for the IR formulation were described with a two-compartment model with first-order input and a lag time. The delayed time-course of MR paracetamol concentrations was best captured by a parallel absorption model in which the slow-release component was a serial zero-order then the first-order process. The formation of APAPG was linear, while APAPS concentrations were best fitted by a Michaelis-Menten process. The relative bioavailability of MR paracetamol compared to IR (A joint parent-metabolite model to describe time-course profiles of both IR and MR paracetamol and its metabolites APAPG and APAPS concentrations was developed. Simulations from the model showed that toxicity assessment based on the 150 mg/L nomograms is not suitable in MR paracetamol overdoses.

MicroRNAs in biofluids are potential biomarkers for detecting kidney and other organ injuries. We profiled microRNAs in urine samples from patients with Russell’s viper envenoming or acute self-poisoning following paraquat, glyphosate, or oxalic acid [with and without acute kidney injury (AKI)] and on healthy controls. Discovery analysis profiled for 754 microRNAs using TaqMan OpenArray qPCR with three patients per group (12 samples in each toxic agent). From these, 53 microRNAs were selected and validated in a larger cohort of patients (Russell’s viper envenoming = 53, paraquat = 51, glyphosate = 51, oxalic acid = 40) and 27 healthy controls. Urinary microRNAs had significantly higher expression in patients poisoned/envenomed by different nephrotoxic agents in both discovery and validation cohorts. Seven microRNAs discriminated severe AKI patients from no AKI for all four nephrotoxic agents. Four microRNAs (miR-30a-3p, miR-30a-5p, miR-92a, and miR-204) had > 17 fold change (p 0.72. Pathway analysis of target mRNAs of these differentially expressed microRNAs showed association with the regulation of different nephrotoxic signaling pathways. In conclusion, human urinary microRNAs could identify toxic AKI early after acute injury. These urinary microRNAs have potential clinical application as early non-invasive diagnostic AKI biomarkers.

Paracetamol-induced hepatotoxicity is the leading cause of acute liver failure in many countries, including North America and the United Kingdom. Among the three dominant paracetamol metabolism pathways (i.e. glucuronidation, sulfation and oxidation), the importance of sulfation is often underestimated because of the general thinking that the sulfation pathway is saturated at therapeutic doses and ultimately accounts for a limited proportion of the fate of a paracetamol dose. We illustrate that insufficient sulfation leads to a shift in biotransformation of paracetamol to toxic oxidation pathways and patients with low sulfate reserves are at higher risk of paracetamol toxicity. Here, we propose that sulfation is of critical importance in understanding the risk of liver toxicity secondary to paracetamol overdose. Serum inorganic sulfate, a measurable substrate on the causal path of paracetamol-induced liver toxicity, should be considered a biomarker for potential toxicity as well as a target for treatment.

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.

The Australasian region is home to the most diverse elapid snake radiation on the planet (Hydrophiinae). Many of these snakes have evolved into unique ecomorphs compared to elapids on other continents; however, their venom compositions are poorly known. The Australian elapid

To assess the accuracy and marginal value of quantitative D-dimer testing for diagnosing venom-induced consumption coagulopathy (VICC) in people bitten by Australian snakes.Analysis of data for suspected and confirmed cases of snakebite collected prospectively by the Australian Snakebite Project, 2005-2019, from 200 hospitals across Australia.1363 patients for whom D-dimer was quantitatively assessed within 24 hours of suspected or confirmed snakebite.Diagnostic performance of quantitative D-dimer testing for detecting systemic envenoming with VICC (area under the receiver operating characteristic curve, AUC); optimal D-dimer cut-off value (maximum sum of sensitivity and specificity).D-dimer values exceeded 2.5 mg/L within three hours of the bite for 95% of patients who developed VICC, and were lower than 2.5 mg/L for 95% of non-envenomed patients up to six hours after snakebite. The AUC for diagnosing envenoming with VICC on the basis of quantitative D-dimer testing within six hours of snakebite was 0.97 (95% CI, 0.96-0.98; 944 patients). Diagnostic performance increased during the first three hours after snakebite; for quantitative D-dimer testing at 2-6 hours, the AUC was 0.99 (95% CI, 0.99-1.0); with a cut-off of 2.5 mg/L, sensitivity was 97.1% (95% CI, 95.0-98.3%) and specificity 99.0% (95% CI, 97.6-99.6%) for VICC. For 36 patients with normal international normalised ratio (INR) and activated partial thromboplastin time (aPTT) values 2-6 hours after snakebite, the AUC was 0.97 (95% CI, 0.93-1.0); with a cut-off of 1.4 mg/L, sensitivity was 94% (95% CI, 82-99%) and specificity 96% (95% CI, 94-97%). In all but one of 84 patients who developed VICC-related acute kidney injury, D-dimer values exceeded 4 mg/L within 24 hours of the bite.D-dimer concentrations assessed 2-6 hours after snakebite, with a cut-off value of 2.5 mg/L, could be useful for diagnosing envenoming with VICC.

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.

Duloxetine is a commonly used antidepressant that is a serotonin and norepinephrine reuptake inhibitor. We aimed to investigate the frequency and severity of clinical effects following duloxetine overdose. We undertook a retrospective review of duloxetine overdoses (>120 mg) admitted to two tertiary toxicology units between March 2007 and May 2021. Demographic information, details of ingestion (dose, co-ingestants), clinical effects, investigations (ECG parameters including QT interval), complications (coma [GCS < 9], serotonin toxicity, seizures and cardiovascular effects), length of stay [LOS] and intensive care unit [ICU] admission were extracted from a clinical database. There were 241 duloxetine overdoses (>120 mg), median age 37 years (interquartile range [IQR]: 25–48 years) and there were 156 females (65%). The median dose was 735 mg (IQR: 405–1200 mg). In 177 patients, other medications were co-ingested, most commonly alcohol, paracetamol, quetiapine, diazepam, ibuprofen, pregabalin and oxycodone. These patients were more likely to be admitted to ICU (12 [7%] vs. none; p = 0.040), develop coma (16 [9%] vs. none; p = 0.008) and hypotension [systolic BP < 90 mmHg] (15 [8%] vs. one; p = 0.076). Sixty four patients ingested duloxetine alone with a median dose of 840 mg (180–4200 mg). The median LOS, in the duloxetine only group, was 13 h (IQR:8.3–18 h), which was significantly shorter than those taking coingestants, 19 h (IQR:12–31 h; p = 0.004). None of these patients were intubated. Six patients developed moderate serotonin toxicity, without complications and one had a single seizure. Tachycardia occurred in 31 patients (48%) and mild hypertension (systolic BP > 140 mmHg) in 29 (45%). One patient had persistent sympathomimetic toxicity, and one had hypotension after droperidol. Two patients of 63 with an ECG recorded had an abnormal QT: one QT 500 ms, HR 46 bpm, which resolved over 3.5 h and a second with tachycardia (QT 360 ms, HR 119 bpm). None of the 64 patients had an arrhythmia. Duloxetine overdose most commonly caused sympathomimetic effects and serotonin toxicity, consistent with its pharmacology, and did not result in coma, arrhythmias or intensive care admission, when taken alone in overdose.

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.

Objective: Acute behavioural disturbance in the elderly (≥65 years) is a significant issue for emergency medical services with increasing prevalence of dementia and aging populations. We investigated the pre-hospital safety and effectiveness of droperidol in the elderly with acute behavioural disturbance. Methods: This was a pre-hospital prospective observational 1-year study of elderly patients with acute behavioural disturbance. The primary outcome was proportion of adverse events (AEs) (airway intervention, oxygen saturation

Snakebite is a major public health issue in the rural tropics. Antivenom is the only specific treatment currently available. We review the history, mechanism of action and current developments in snake antivenoms. In the late nineteenth century, snake antivenoms were first developed by raising hyperimmune serum in animals, such as horses, against snake venoms. Hyperimmune serum was then purified to produce whole immunoglobulin G (IgG) antivenoms. IgG was then fractionated to produce F(ab) and F(ab′)2 antivenoms to reduce adverse reactions and increase efficacy. Current commercial antivenoms are polyclonal mixtures of antibodies or their fractions raised against all toxin antigens in a venom(s), irrespective of clinical importance. Over the last few decades there have been small incremental improvements in antivenoms, to make them safer and more effective. A number of recent developments in biotechnology and toxinology have contributed to this. Proteomics and transcriptomics have been applied to venom toxin composition (venomics), improving our understanding of medically important toxins. In addition, it has become possible to identify toxins that contain epitopes recognized by antivenom molecules (antivenomics). Integration of the toxinological profile of a venom and its composition to identify medically relevant toxins improved this. Furthermore, camelid, humanized and fully human monoclonal antibodies and their fractions, as well as enzyme inhibitors have been experimentally developed against venom toxins. Translation of such technology into commercial antivenoms requires overcoming the high costs, limited knowledge of venom and antivenom pharmacology, and lack of reliable animal models. Addressing such should be the focus of antivenom research.

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.

The acute effects of snakebite are often emphasized, with less information on long-term effects. We aimed to describe the long-term health effects perceived by patients followed up after confirmed snakebites. Two groups of snakebite patients (>18y) from the Anuradhapura snakebite cohort were reviewed: Group I had a snakebite during August 2013-October 2014 and was reviewed after 4 years, and group II had a snakebite during May 2017-August 2018, and was reviewed after one year. Patients were invited by telephone, by sending letters, or doing home visits, including 199 of 736 patients (27%) discharged alive from group I and 168 of 438 patients (38%) from group II, a total of 367 followed up. Health effects were categorised as musculoskeletal, impact on daily life, and medically unexplained. Health issues were attributed to snakebite in 107/199 patients (54%) from group I and 55/168 patients (33%) from group II, suggesting the proportion with health issues increases with time. Sixteen patients (all viperine bites) had permanent musculoskeletal problems, none with a significant functional disability affecting daily routine. 217/367 reported being more vigilant about snakes while working outdoors, but only 21/367 were using protective footwear at review. Of 275 farmers reviewed, only six (2%) had restricted farming activities due to fear of snakebite, and only one stopped farming. 104/199 (52%) of group I and 42/168 (25%) of group II attributed non-specific symptoms (fatigue, body aches, pain, visual impairment) and/or oral cavity-related symptoms (avulsed teeth, loose teeth, receding gums) to the snakebite, which cannot be explained medically. In multivariate logistic regression, farming, type of snake, antivenom administration, and time since snakebite were associated with medically unexplained symptoms. The latter suggests medically unexplained effects increased with time. Based on two groups of snakebite patients reviewed one and four years post-bite, we show that long-term musculoskeletal disabilities are uncommon and not severe in snakebite survivors in rural Sri Lanka. However, a large portion of patients complain of various non-specific general and oral symptoms, not explainable based on the known pathophysiology of snakebite. These perceived effects of snakebite were more common in patients with systemic envenoming, and were more frequent the longer the time post-bite.

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.

Introduction To investigate whether there is an association between the blocking of cardiac potassium channels, which is characterised by a prolonged QTc interval and the frontal QRS-T angle after overdose by QT prolonging drugs. Methods We obtained patient medical records associated with QT prolonging drugs from 3 different hospitals: the Calvary Mater Newcastle Hospital (CMNH), Royal Prince Alfred Hospital (RPAH) and Prince of Wales Hospital (POWH). RPAH and POWH admissions were taken between 4/01/2017 to 1/11/2019, and CMNH admissions were taken between 4/01/2013 to 24/06/2018. Demographic information and details of overdose were collected. All admission ECGs were manually measured. Linear regression was used to assess the relationship between various QTc formulas and the frontal QRS-T angle. A Bland-Altman plot was used to examine agreement between manual and machine QT intervals. Results 144 patients met the inclusion criteria for analysis. None of the patients developed torsades de pointes (TdP). There was no linear association between the QRS-T angle and the various QTc formulas (For QRS-T angle: QTcRTH: p = 0.76, QTcB: p = 0.83, QTcFri: p = 0.90, QTcFra: p = 0.13, QTcH: p = 0.97; For square root transformation of the QRS-T angle: QTcRTH: p = 0.18, QTcB: p = 0.33, QTcFri: p = 0.95, QTcFra: p = 0.47, QTcH: p = 0.33). Agreement between machine and manual QT measurements was low. Conclusions The frontal QRS-T angle cannot substitute the QTc in assessing the blockage of cardiac potassium channels in drug induced long QT syndrome. We also support the consensus that despite the availability of machine measurements of the QT interval, manual measurements should also be performed.

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...

The Chinese Cobra (Naja atra) is an elapid snake of major medical importance in southern China. Although previous studies have shown that postsynaptic neurotoxins account for 11–23% of N. atra venom, envenomed patients do not display marked signs of neurotoxicity. We have previously shown that the lack of clinical neurotoxicity following snake envenoming by some species with ‘neurotoxic’ venoms may be related to the high prevalence of short-chain postsynaptic neurotoxins in these venoms. In this study, we describe the isolation and characterization of α-Elapitoxin-Na1a (α-EPTX-Na1a; 6949 Da), a short-chain postsynaptic neurotoxin, which accounts for approximately 9% of N. atra crude venom. α-EPTX-Na1a (30–300 nM) produced concentration-dependent inhibition of indirect-twitches, with a t90 value of 17 ± 2 min at 300 nM, and abolished contractile responses to exogenous acetylcholine and carbachol, in the chick biventer cervicis nerve-muscle preparation. The prior addition of either Chinese N. atra monovalent antivenom (0.3 U/ml) or Australian polyvalent snake antivenom (2.4 U/ml), prevented the in vitro neurotoxic effects of α-EPTX-Na1a (30 nM). Addition of each of these antivenoms at the t90 time point partially reversed the in vitro neurotoxicity caused by α-EPTX-Na1a (30 nM). The inhibition of indirect twitches by α-EPTX-Na1a (30 nM) was not reversed by repeatedly washing the tissue. α-EPTX-Na1a displayed pseudo-irreversible antagonism of concentration-response curves to carbachol with a pA2 value of 8.21. De novo protein sequencing of α-EPTX-Na1a revealed a typical short-chain postsynaptic neurotoxin profile of 62 amino acids which shared >98% amino acid sequence similarity with short-chain postsynaptic neurotoxins from other Naja species. When compared to short-chain neurotoxins isolated from cobras in China, α-EPTX-Na1a contained novel residues K47Q (i.e. lysine to glutamine), N48T (i.e. asparagine to threonine) and G49A (i.e. glycine to alanine). In conclusion, α-EPTX-Na1a is a potent, pseudo-irreversible, short-chain neurotoxin. The high prevalence of α-EPTX-Na1a in Chinese N. atra venom is likely to explain the mild neurotoxicity experienced by envenomed patients.

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

BackgroundSnakebite is a neglected tropical disease that has been overlooked by healthcare decision makers in many countries. Previous studies have reported seasonal variation in hospital admission rates due to snakebites in endemic countries including Sri Lanka, but seasonal patterns have not been investigated in detail.MethodsA national community-based survey was conducted during the period of August 2012 to June 2013. The survey used a multistage cluster design, sampled 165 665 individuals living in 44 136 households and recorded all recalled snakebite events that had occurred during the preceding year. Log-linear models were fitted to describe the expected number of snakebites occurring in each month, taking into account seasonal trends and weather conditions, and addressing the effects of variation in survey effort during the study and of recall bias amongst survey respondents.ResultsSnakebite events showed a clear seasonal variation. Typically, snakebite incidence is highest during November-December followed by March-May and August, but this can vary between years due to variations in relative humidity, which is also a risk factor. Low relative-humidity levels are associated with high snakebite incidence. If current climate-change projections are correct, this could lead to an increase in the annual snakebite burden of 31.3% (95% confidence interval: 10.7-55.7) during the next 25-50 years.ConclusionsSnakebite in Sri Lanka shows seasonal variation. Additionally, more snakebites can be expected during periods of lower-than-expected humidity. Global climate change is likely to increase the incidence of snakebite in Sri Lanka.

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.

Snake venom is comprised of a combination of different proteins and peptides with a wide range of molecular weights and different disposition processes inherent to each compound. This causes venom to have a complex exposure profile. Our study investigates 1) how each molecular weight fraction (toxin) of venom contributes to the overall time course of the snake venom, and 2) the ability to determine toxin profiles based on the profile of the overall venom only. We undertook an in silico simulation and modelling study. Sixteen variations of venom, comprising of two to nine toxins with different molecular weights were investigated. The pharmacokinetic parameters (i.e., clearance,, and volume of distribution,) of each toxin were generated based on a log-linear relationship with molecular weight. The concentration&ndash, time data of each toxin were simulated for 100 virtual patients using MATLAB and the total concentration&ndash, time data of each toxin were modelled using NONMEM. We found that the data of sixteen mixtures were best described by either two- or three-compartment models, despite the venom being made up of more than three different toxins. This suggests that it is generally not possible to determine individual toxin profiles based on measurements of total venom concentrations only.

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.

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...

Background Thrombotic microangiopathy is an uncommon complication of snake envenoming associated with a subset of snakebite cases presenting with venom-induced consumption coagulopathy. It presents with microangiopathic haemolytic anaemia and thrombocytopenia. Available studies are predominantly small retrospective observational studies only. Renal end organ injury appears common. It has variably been likened to either thrombotic thrombocytopenic purpura or atypical haemolytic uraemic syndrome. Many studies report acute kidney injury, with dialysis required in a subset of patients. Some studies suggest a role for treatment with plasmapheresis. Interpretation of the literature is complicated by variable nomenclature and historically poor case definitions of both venom-induced consumption coagulopathy and thrombotic microangiopathy associated with snake envenoming. Methods The main objective of this systematic review is to synthesise the worldwide experience of snakebite-associated thrombotic microangiopathy with respect to its features and outcomes, and collate any evidence for the role of plasmapheresis as treatment. A predetermined case definition of confirmed or suspected snakebite with either blood film evidence of microangiopathic haemolytic anaemia or histological evidence of thrombotic microangiopathy will be used. This case definition will determine the search terms and study inclusion criteria. Relevant studies will be identified by electronic database, published conference abstracts, and grey literature search. This systematic review will be performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. The quality of included studies will be assessed by a proposed tool for evaluating the methodological quality of case reports and case series. Results will be reported by a descriptive synthesis with a focus on the presenting features; outcomes of acute kidney injury, dialysis-free survival, other end organ damage, and overall survival; and any evidence of a role for treatment with plasmapheresis. The quality of accumulated evidence will be assessed via the Grading of Recommendations, Assessment, Development, and Evaluations framework. Discussion It is anticipated that eligible studies will consist of small observational studies. Evidence gathered from this review will provide the first broader understanding of the clinical features, outcomes, prognosis, and management of snakebite-associated thrombotic microangiopathy. Systematic review registration PROSPERO CRD42019121436 Electronic supplementary material The online version of this article (10.1186/s13643-019-1133-2) contains supplementary material, which is available to authorized users.

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.