Professor Geoff Isbister

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

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

We studied the neutralisation of Sri Lankan Russell¿s viper (Daboia russelii) and Australian mulga snake (Pseudechis australis) venom-induced myotoxicity by Indian (Vins and Bharat) and Australian (Seqirus) polyvalent antivenoms, using the in vitro chick biventer skeletal muscle prepara-tion. Prior addition of Bharat or Vins antivenoms abolished D. russelii venom (30 µg/mL)-mediated inhibition of direct twitches, while Australian polyvalent antivenom was not protective. Bharat antivenom prevented, while Vins and Australian polyvalent antivenoms partially prevented, the inhibition of responses to exogenous KCl. Myotoxicity of Mulga venom (10 µg/mL) was fully neutralised by the prior addition of Australian polyvalent antivenom, partially neutralised by Vins antivenom but not by Bharat antivenom. Although the myotoxicity of both venoms was partially prevented by homologous antivenoms when added 5 min after the venom, with an increasing time delay between venom and antivenom, the reversal of myotoxicity gradually decreased. However, antivenoms partially prevented myotoxicity even 60 min after venom. The effect of antivenoms on already initiated myotoxicity was comparable to physical removal of the toxins by washing the bath at similar time points, indicating that the action of the antivenoms on myotoxicity is likely to be due to trapping the toxins or steric hindrance within the circulation, not allowing the toxins to reach target sites in muscles.

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 Hoplo-cephalus stephensii (Stephen¿s banded snake) is an arboreal snake with a unique morphology. Human envenoming results in venom-induced consumption coagulopathy, without neurotoxicity. Using transcriptomics and a multi-step fractionation method involving reverse-phase high-performance liquid chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis and bottom-up proteomics, we characterized the venom proteome of H. stephensii. 92% of the total protein component of the venom by weight was characterized, and included all dominant protein families and 4 secondary protein families. Eighteen toxins made up 76% of the venom, four previously characterized and 14 new toxins. The four dominant protein families made up 77% of the venom, including snake venom metalloprotease (SVMP; 36.7%; three identified toxins), phospholipase A2 (PLA2; 24.0%; five identified toxins), three-finger toxin (3FTx; 10.2%; two toxins) and snake venom serine protease (SVSP; 5.9%; one toxin; Hopsarin). Secondary protein families included L-amino acid oxidase (LAAO; 10.8%; one toxin), natriuretic peptide (NP; 0.8%; two toxins), cysteine-rich secretory protein (CRiSP; 1.7%; two toxins), c-type lectin (CTL; 1.1%; one toxin), and one minor protein family, nerve growth factor (NGF; 0.8%; one toxin). The venom composition of H. stephensii differs to other elapids, with a large proportion of SVMP and LAAO, and a relatively small amount of 3FTx. H. stephensii venom appeared to have less toxin diversity than other elapids, with only 18 toxins making up three-quarters of the venom.

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 let-ters, 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 foot-wear 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 regres-sion, 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.

Background: Sea snakes are venomous snakes found in the warm parts of the Indo-Pacific, including around Australia. Most sea snake envenoming causes myotoxicity, but previous Australian case reports describe neurotoxicity. We aimed to describe the epidemiology and clinical presentation of Australian sea snake envenoming and the effectiveness of antivenom. Methods: Patients were recruited to the Australian Snakebite Project (ASP), an Australia-wide prospective observational study recruiting all patients with suspected or confirmed snakebite >2¿years. Information about demographics, bite circumstances, species involved, clinical and laboratory features of envenoming, and treatment is collected and entered into a purpose-built database. Results: Between January 2002 and August 2020, 13 patients with suspected sea snake bite were recruited to ASP, 11 were male; median age was 30¿years. Bites occurred in Queensland and Western Australia. All patients were in or around, coastal waters at the time of bite. The species involved was identified in two cases (both Hydrophis zweifeli). Local effects occurred in 9 patients: pain (5), swelling (5), bleeding (2), bruising (1). Envenoming occurred in eight patients and was characterised by non-specific systemic features (6) and myotoxicity (2). Myotoxicity was severe (peak CK 28200 and 48100 U/L) and rapid in onset (time to peak CK 13.5 and 15.1¿h) in these two patients. Non-specific systemic features included nausea (6), headache (6), abdominal pain (3), and diaphoresis (2). Leukocytosis, neutrophilia, and lymphopenia occurred in both patients with myotoxicity and was evident on the first blood test. No patients developed neurotoxicity or coagulopathy. Early Seqirus antivenom therapy was associated with a lower peak creatine kinase. Conclusion: While relatively rare, sea snake envenoming is associated with significant morbidity and risk of mortality. Early antivenom appears to have a role in preventing severe myotoxicity and should be a goal of therapy.

Aims: The objectives were to determine the effect of NaHCO3 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. Methods: This was a retrospective review of TCA poisonings from three Australian toxicology units and a poisons information centre (Jan 2013 to Jan 2019). We included patients with TCA toxicity who ingested>10¿mg/kg or had clinically significant toxicities consistent with TCA poisoning, and analysed patients' clinical, electrocardiogram and biochemical data. Results: Of 210 patients, 84 received NaHCO3 and ventilation (dual therapy), 12 NaHCO3, 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 (1.5¿g vs1.3¿g, P <.001), a longer median maximum QRS interval (124 ms, interquartile ranges [IQR] 108-138 vs106 ms, IQR 98-115, P <.001) and were more likely to have seizures (14% vs3%, P =.006) and arrhythmias (17% vs1%, P <.001). The dual therapy group demonstrated greater increases in serum pH (median 0.11, IQR 0.04-0.17) compared to the single/supportive therapy group (median 0.03, IQR -0.01-0.09, p <.001). A greater proportion of patients reached the target pH¿7.45-7.55 in the dual therapy group (59%) compared to the single/supportive therapy group (10%) (P <.001). For each 100 mmol bolus of NaHCO3 given, the median increase in serum sodium was 2.5¿mmol/L (IQR 1.5-4.0). QRS narrowing occurred twice as quickly in the dual therapy vs single/supportive therapy group. Conclusions: A combination of NaHCO3 and mechanical ventilation was most effective in achieving serum alkalinisation and was associated with a more rapid narrowing of the QRS interval. We advise that the maximal dose of NaHCO3 should be <400 mmol (6¿mmol/kg).

Understanding snake venom proteomes is becoming increasingly important to understand snake venom biology, evolution and especially clinical effects of venoms and approaches to antivenom development. To explore the current state of snake venom proteomics and transcriptomics we investigated venom proteomic methods, associations between methodological and biological variability and the diversity and abundance of protein families. We reviewed available studies on snake venom proteomes from September 2017 to April 2021. This included 81 studies characterising venom proteomes of 79 snake species, providing data on relative toxin abundance for 70 species and toxin diversity (number of different toxins) for 37 species. Methodologies utilised in these studies were summarised and compared. Several comparative studies showed that preliminary decomplexation of crude venom by chromatography leads to increased protein identification, as does the use of transcriptomics. Combining different methodological strategies in venomic approaches appears to maximize proteome coverage. 48% of studies used the RP-HPLC ¿1D SDS-PAGE ¿in-gel trypsin digestion ¿ ESI -LC-MS/MS pathway. Protein quantification by MS1-based spectral intensity was used twice as commonly as MS2-based spectral counting (33¿15 studies). Total toxin diversity was 25¿225 toxins/species, with a median of 48. The relative mean abundance of the four dominant protein families was for elapids; 3FTx¿52%, PLA2¿27%, SVMP¿2.8%, and SVSP¿0.1%, and for vipers: 3FTx¿0.5%, PLA2¿24%, SVMP¿27%, and SVSP¿12%. Viper venoms were compositionally more complex than elapid venoms in terms of number of protein families making up most of the venom, in contrast, elapid venoms were made up of fewer, but more toxin diverse, protein families. No relationship was observed between relative toxin diversity and abundance. For equivalent comparisons to be made between studies, there is a need to clarify the differences between methodological approaches and for acceptance of a standardised protein classification, nomenclature and reporting procedure. Correctly measuring and comparing toxin diversity and abundance is essential for understanding biological, clinical and evolutionary implications of snake venom composition.

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.

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 was >1%. With results dichotomised as <1.0% or =1.0%, our proposed new method versus the ICSH method showed almost perfect agreement [observed agreement 95%, Cohen's kappa (¿)=0.84, SE 0.04, 95% CI 0.76¿0.92, p<0.005]. Inter-observer strength of agreement for our method was moderate (Fleiss' ¿ for comparisons between three non-unique microscopists ¿=0.50, SE 0.05, 95% CI 0.41¿0.59, p<0.005). Intra-observer reproducibility assessed in two microscopists ranged from substantial (Cohen's ¿=0.71, SE 0.08, 95% CI 0.55¿0.86, p<0.005) to borderline almost perfect agreement (Cohen's ¿=0.81, SE 0.07, 95% CI 0.68¿0.93, p<0.005). 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.

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.

Context: Acute kidney injury (AKI) is the most serious clinical manifestation of the Sri Lankan hump-nosed pit viper (Hypnale spp.) bites. Thrombotic microangiopathy (TMA) is increasingly recognized in association with AKI in cases of Hypnale spp envenomation. We investigated AKI in a cohort of cases of Hypnale envenomation, its association with TMA and the early diagnostic value of common biomarkers for AKI occurring. Materials and methods: We conducted a prospective observational study of suspected viper bites and included 103 confirmed cases of Hypnale envenomation, based on venom specific enzyme immunoassay of blood. AKI was defined using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Thrombotic microangiopathy was diagnosed based on thrombocytopenia (platelet count < 150,000 × 103/µL) and microangiopathic haemolytic anaemia (MAHA). We investigated the diagnostic performance of creatinine, platelet count and INR for AKI within 4 h and 8 h post-bite by area under the receiver operator characteristic curve (AUC¿ROC). Results: Ten 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. Conclusions: We found that AKI is uncommon in Hypnale spp. envenomation, but an important serious complication. Severe AKI was associated with TMA. A creatinine within 4 h post-bite was the best predictor of AKI.

Background: 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. Methods: 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). Results: 1638 patients were recruited January 2003¿December 2016, 935 (57%) were envenomed, 148 developed myotoxicity (16%). Snake species most commonly associated with myotoxicity were Notechis spp. (30%), Pseudechis porphyriacus (20%) and Pseudechis australis (13%). Bite site effects occurred in 19 patients. Non-specific systemic symptoms occurred in 135 patients (91%), specific signs and symptoms in 83. In 120 patients with early serial CK results, the median peak CK was 3323 U/L (IQR;1050¿785100U/L), the median time to first CK >500 U/L was 11.1 h and median time to peak CK of 34.3 h. White cell count was elevated in 136 patients (93%; median time to elevation, 4.9 h). 37 patients had elevated creatinine, six were dialysed. Two patients died from complications of severe myotoxicity. Antivenom given before the first abnormal CK (>500 U/L) was associated with less severe myotoxicity (2976 versus 7590 U/L). Non-envenomed patients with elevated CK had rapid rise to abnormal CK (median 3.5 h) and less had elevated WCC (32%). Conclusion: Myotoxicity 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.

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 < 0.0001) and receiver operator characteristics area-under-curve (ROC-AUC) > 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.

Context: Thrombotic microangiopathy (TMA) resulting in acute kidney injury (AKI) is an important complication of venomous snakebites. We aimed to describe TMA secondary to Russell¿s viper (Daboia russelli) and hump-nosed viper (Hypnale spp.) bites and assess the effect of different treatments. Materials and methods: We undertook a prospective observational study of patients with AKI secondary to snakebite over a two-year period. Data recorded included: demographic details, clinical and laboratory features, treatment, complications and outcomes, until hospital discharge and at three months post-discharge. TMA was defined as the development of microangiopathic hemolytic anemia and thrombocytopenia along with AKI. Treatment with therapeutic plasma exchange (TPE; also known as plasmapheresis) and/or fresh frozen plasma (FFP) was determined by the treating clinician. Antivenom was given to all patients with evidence of systemic envenoming following Russell¿s viper bites. Results: Fifty-nine patients were included in the analysis. Thirty-three (56%) were males and median age was 56 years. Forty-five (76%) developed TMA while a further 11 and two developed isolated thrombocytopenia and microangiopathic hemolytic anemia, respectively. Presence of TMA was associated with increased dialysis requirements (5 vs. 3) and longer hospital stay (18 vs. 12 days). Of the patients with TMA, nine received TPE with or without FFP infusions. The use of TPE was not associated with improved outcomes in patients with TMA based on requirement for blood transfusion, recovery of thrombocytopenia, requirement of dialysis and duration of hospital stay. Patients who did not receive TPE had better renal function at three months compared to patients who received this treatment. Conclusion: Presence of TMA in patients with Daboia and Hypnale bites was associated with a more prolonged course of AKI. Patients with TMA who were treated with TPE did not have improved early or late outcomes compared to patients who were not treated with TPE.

Background & Aims: 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. Methods: 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. Results: 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; p <0.0001), respectively. The AUROC for hepatotoxicity was 0.98 (95% CI 0.96¿1.00; n = 226; p <0.0001) with acetaminophen-protein adduct concentration and 0.89 (95% CI 0.82¿0.96; n = 219; p <0.0001) 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. Conclusion: 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. Lay summary: 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. Clinical Trial registration: Australian Toxicology Monitoring (ATOM) Study¿Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.

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 collection tool allowing data to be captured on inpatient and remote consultations. Methods: Retrospective review of all cases entered in the database from 1 March 2014 to 28 February 2016. Data collected included demographics (age, sex), clinical details (exposure category), presentation facility and disposition. Results: The database included 3616 cases: 59 (1.6%) were excluded due to inadequate details, 122 (3.4%) had no electronic medical record available, 1985 (54.9%) presented to the inpatient unit facility and 1450 (40.1%) were external consultations. Of these 1450, 223 (6.2%) were paediatric (aged less than 12¿years), 395 (10.9%) adolescent (12¿17¿years) and 832 (23.0%) adults (18¿years and over). The proportion of paediatric cases (median age 2¿y; 45.7% females) with pharmaceutical ingestions was 122 (54.7%; 95% confidence intervals (CIs): 48.2¿61.1) compared with 345 (87.3%; 95% CI: 83.7¿90.3) in adolescents (median age 15¿y; 79.5% females). Of the adult presentations, 659 (18.2%) were metropolitan/regional facility presentations and 173 (4.8%) rural facilities with 125 (3.4%) adults subsequently transferred to the inpatient facility. Median age was 38¿years (interquartile range (IQR) 35¿52) with 338 (51.4%) females in the metropolitan group and 37¿years (IQR 26¿48) with 51 (30.5%) females in the rural group. There were more bites and stings in the rural group, 41 (23.7%; 95% CI: 18.0¿30.6) versus 54 (8.2%; 95% CI: 6.3¿10.5), more recreational substance exposures 27 (15.6%; 95% CI: 11.0¿21.8) versus 40 (6.1%; 95% CI: 4.5¿8.2) and less pharmaceutical exposures 93 (53.8%; 95% CI: 46.3¿61.0) versus 462 (70.1%; 95% CI: 66.5¿73.5). Conclusions: The tablet based database provided useful information on populations of poisoned patients not accessible previously. It demonstrated important differences in the types of patients presenting to rural versus metropolitan hospitals.

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 '90% and/or respiratory rate '12/min, systolic blood pressure '90 mmHg, sedation assessment tool score of -3 and dystonic reactions). Secondary outcomes included time to sedation, additional sedation, proportion with successful sedation. Results: There were 149 patients (males 78 [52%], median age 78 years; 65¿101 years) presenting on 162 occasions. Dementia was the commonest cause (107/164 [65%]) of acute behavioural disturbance. There were six AEs in five patients (5/162 [3%]; 95% confidence interval 1¿7). Three had hypotension, one with associated hypoxia (80%); and two had respiratory AEs (respiratory rate, 10/min [no hypoxia] and hypoxia [88%] which required oxygen). Median time to sedation was 19 min (interquartile range 12¿29 min). Additional sedation was given in 2/162 patients during ambulance transfer and 16/162 within an hour of hospital arrival; 24/162 (15%) failed to sedate in the ambulance; 16 subsequently settled in ED and 8/24 received additional sedation. Of 162, 123 (76%) patients successfully sedated, without AEs or additional sedation. Of 162, 114 (70%) patients received 5 mg, 46 (29%) received two doses of 5 mg and two patients (1%) received three doses. Conclusions: Droperidol appeared to be safe and effective for pre-hospital sedation of acute behavioural disturbance in elderly patients.

Poisoning by venomous creatures is common. Most is benign, causing only minor irritation or pain, but rarely significant morbidity and mortality can occur. Medically important venomous creatures include snakes, spiders, scorpions and marine creatures. For suspected cases of severe envenoming, seek early expert advice from a clinical toxicologist or poisons information centre. First aid measures include pressure bandaging of the affected limb with immobilization in suspected snakebite and funnel web spider bite, and administration of vinegar after removing tentacles in box jellyfish stings. Management of severe envenoming requires resuscitation with early provision of antivenom where available. Ensure the patient has adequate tetanus prophylaxis. Pain is often prominent and adequate analgesia should be provided. Primary prevention of bites and stings is crucial to reduce the impact of envenoming.

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.

Background: 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. Methods: 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. Results: 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. Limitations: The study was unable to differentiate between suicide attempts and self-harm self-poisonings. Conclusions: 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.

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(ab0)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.

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.

Aims: We aim to calculate 2 metrics of relative lethal toxicity; the fatal toxicity index (FTI; number of deaths per year of a daily dose) and the case fatality (CF; number of deaths per overdose) with a focus on opioids, antidepressants, antipsychotics, benzodiazepines and illicit drugs. Methods: This descriptive cohort study used the Australian National Coronial Information System (NCIS) to identify a population of individuals with drug-associated deaths in the Greater Newcastle Hunter Area between January 2002 and December 2016. This was combined with Australian medicine dispensing data and corresponding data from the Hunter Area Toxicology Service to calculate FTI and CF. Results: There were 444 drug-related deaths and 21,296 overdoses during the study period. FTI and CF were well correlated (Spearman's rho 0.64, P¿<.001). Of the classes of interest, opioids had the highest FTI (40.3 95% confidence interval [CI] 35.2¿45.4 deaths per 100¿years of use at the defined daily dose or deaths/DDD/100¿years) and CF (12.4% 95%CI 11.0¿13.9). Fentanyl, methadone and morphine had the highest relative fatal toxicity within this class. Tricyclic antidepressants had the highest relative fatal toxicity of all antidepressants (FTI 14.5 95%CI 9.7¿19.3 deaths/DDD/100¿years and CF 7.1% [95%CI 4.8¿9.3]) and benzodiazepines appeared to be more associated with multiple agent deaths than single. Of the illicit drugs, heroin had the highest CF (26.4%, 95%CI 19.1¿33.7). Conclusion: Knowledge of relative lethal toxicity is useful to prescribers and medicines and public health policy makers in restricting access to more toxic drugs and may also assist coroners in determining cause of death.

Study objective: Although uncommon, children (<16 years) with acute behavioral disturbance are a significant issue for emergency medical service providers. In this study, we aimed to investigate the safety and effectiveness of droperidol in children with prehospital acute behavioral disturbance. Methods: This was a prospective observational study over 1 year investigating the use of droperidol (0.1¿0.2 mg/kg) for children (< 16 years) with acute behavioral disturbance. Inclusion criteria for acute behavioral disturbance were defined by a sedation assessment tool score of =2 determined by the attending paramedic. The primary outcome was the proportion of adverse effects (need for airway intervention, oxygen saturation <90% and/or respiratory rate <12, systolic blood pressure <90 mmHg, sedation assessment tool score of -3 and dystonic reactions). Secondary outcomes included time to sedation (sedation assessment tool score decreased by 2 or more, or a score of zero), requirement for additional sedation, failure to sedate and proportion of sedation success defined as the number of patients successfully sedated who did not suffer any adverse events or receive additional sedation. Results: There were 96 patients (males 51 [53%], median age 14 years [range 7¿15 years]) who presented on 102 occasions over the one year study period. Self-harm and/or harm to others was the commonest (74/105 [70%]) cause of acute behavioral disturbance followed by alcohol (16/105 [15%]). There were 9 adverse events in 8 patients (8/102 [8%]; 95% confidence intervals [CI]: 3¿13%) Five patients had hypotension, all asymptomatic and only one required treatment; 2 dystonic reactions managed with benztropine and one patient with respiratory depression. Median time to sedation was 14 min (interquartile range (IQR): 10¿20 min; range: 3¿85 min). There was no requirement for prehospital additional sedation (0/102 [0%]; 95% CI: 0¿4%) and additional sedation in the first hour of arrival to hospital was required by 4 patients (4/102 [4%]; 95% CI: 1¿10%). Overall successful sedation was achieved in 89 (87%) patients. Conclusions: The use of droperidol in children for acute behavioral disturbance in the prehospital setting is both safe and effective.

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.

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.

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.

Background: Snakebite 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. Methods: A 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. Results: Snakebite 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. Conclusions: Snakebite 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.

Context: 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. Methods: 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. Results: 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 or <63 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 or <45 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. Discussion: 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.

Snake venom a-neurotoxins potently inhibit rodent nicotinic acetylcholine receptors (nAChRs), but their activity on human receptors and their role in human paralysis from snakebite remain unclear. We demonstrate that two short-chain a-neurotoxins (SaNTx) functionally inhibit human muscle-type nAChR, but are markedly more reversible than against rat receptors. In contrast, two long-chain a-neurotoxins (LaNTx) show no species differences in potency or reversibility. Mutant studies identified two key residues accounting for this. Proteomic and clinical data suggest that paralysis in human snakebites is not associated with SaNTx, but with LaNTx, such as in cobras. Neuromuscular blockade produced by both subclasses of a-neurotoxins was reversed by antivenom in rat nerve¿muscle preparations, supporting its effectiveness in human post-synaptic paralysis.

Study Objective: 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. Methods: 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 saturation < 90%, respiratory rate < 12, systolic blood pressure < 90¿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. Results: 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. Conclusions: 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.

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 t90 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.

Context: 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. Methods: 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 (ALT >1000 U/L). Results: 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. Conclusion: 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.

Objective: To investigate the effectiveness of hot water immersion for relieving the pain of major box jellyfish (Chironex fleckeri) stings. Design, interventions: Open label, randomised controlled trial comparing the effects of hot water immersion (45°C) and icepacks. Setting, participants: 42 patients with suspected C. fleckeri stings treated in the emergency department of the Royal Darwin Hospital during September 2005 e October 2008. Main outcome measures: The primary outcome was pain severity, assessed with a visual analogue scale (VAS). Secondary outcomes included crossover to the alternative treatment, use of opioid analgesia, emergency department length of stay (LOS), and delayed urticaria. Results: Of 42 patients (26 males; median age, 19 years; IQR, 13e27 years), 25 were allocated to icepack treatment and 17 to hot water immersion. The demographic and baseline VAS data for the two groups were similar. After 30 minutes of treatment, 11 patients (65%) treated with hot water and 14 (56%) treated with icepacks had clinically improved pain scores (absolute difference, 9%; 95% CI, e22% to 39%; P = 0.75). One patient treated with icepacks crossed over to heat immersion. Two patients in each arm received intravenous opioid analgesia. Median emergency department LOS was 1.6 h (IQR, 1.0e1.8 h) for icepack patients and 2.1 h (IQR, 1.6e2.8 h) for heat immersion patients (P = 0.07). Five of seven patients who were followed up developed delayed urticaria. Conclusion: Hot water immersion was no more effective than icepacks for reducing the acute pain of box jellyfish stings, but increased emergency department LOS by about 30 minutes.

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.

Aims: Methadone is a widely used opioid agonist treatment associated with QT prolongation and torsades de pointes. We investigated the QT interval in patients treated with methadone or buprenorphine using continuous 12-lead Holter recordings. Methods: We prospectively made 24-h Holter recordings in patients prescribed methadone or buprenorphine, compared to controls. After their normal dose a continuous 12-lead Holter recorder was attached for 24¿h. Digital electrocardiograms were extracted hourly from the Holter recordings. The QT interval was measured automatically (H-scribe software, Mortara Pty Ltd) and checked manually. The QT interval was plotted against heart rate (HR) on the QT nomogram to determine abnormality. Demographics, dosing, medical history and laboratory investigations were recorded. Results: There were 58 patients (19 methadone, 20 buprenorphine and 19 control); median age 35¿years (20¿56¿years); 33 males. Baseline characteristics were similar. Median dose of methadone was 110¿mg¿day¿1 (70¿170¿mg¿day¿1) and buprenorphine was 16¿mg¿day¿1 (12¿32¿mg¿day¿1). Seven participants had abnormal QT intervals. There was a significant difference in the proportion of prescribed methadone with abnormal QT intervals, 7/19 (37%; 95% confidence interval: 17¿61%), compared to controls 0/19 (0%; 95% confidence interval: 0¿21%; P¿=¿0.008), but no difference between buprenorphine and controls (0/20). QT vs. HR plots showed patients prescribed methadone had higher QT-HR pairs over 24¿h compared to controls. There was no difference in dose for patients prescribed methadone with abnormal QT intervals and those without. Conclusions: Methadone is associated with prolonged QT intervals, but there was no association with dose. Buprenorphine did not prolong the QT interval. Twenty four-hour Holter recordings using the QT nomogram is a feasible method to assess the QT interval in patients prescribed methadone.

Context: There are limited reports of adult clonidine overdose. We aimed to describe the clinical effects and treatment of clonidine overdose in adults. Methods: This was a retrospective review of a prospective cohort of poisoned patients who took clonidine overdoses (>200 µg). Demographic information, clinical effects, treatment, complications (central nervous system and cardiovascular effects) and length of stay (LOS) were extracted from a clinical database or medical records. Results: From 133 admissions for clonidine poisoning (1988¿2015), no medical record was available in 14 and 11 took staggered ingestions. Of 108 acute clonidine overdoses (median age 27 years; 14¿65 years; 68 females), 40 were clonidine alone ingestions and 68 were clonidine with co-ingestants. Median dose taken was 2100 µg (interquartile range [IQR]: 400¿15,000 µg). Median LOS was 21h (IQR: 14¿35 h) and there were no deaths. Glasgow coma score [GCS] <15 occurred in 73/108 (68%), and more patients taking co-ingestants (8/68; 12%) had coma (GCS <9) compared to clonidine alone (2/40; 5%). Miosis occurred in 31/108 (29%) cases. Median minimum HR was 48 bpm (IQR: 40¿57 bpm), similar between clonidine alone and co-ingestant overdoses. There was a significant association between dose and minimum HR for clonidine alone overdoses (p = 0.02). 82/108 (76%) had bradycardia, median onset 2.5 h post-ingestion (IQR: 1.7¿5.5 h) and median duration 20 h (2.5¿83 h), similar for clonidine alone and co-ingestant overdoses. There were no arrhythmias. Three patients ingesting 8000¿12,000 µg developed early hypertension. Median minimum systolic BP was 96 mmHg (IQR: 90¿105 mmHg) and hypotension occurred in 26/108 (24%). 12/108 patients were intubated, but only 2 were clonidine alone cases. Treatments included activated charcoal (24), atropine (8) and naloxone (23). The median total naloxone dose was 2 mg (IQR: 1.2¿2.4 mg), but only one patient given naloxone was documented to respond with partial improvement in GCS. Discussion: Clonidine causes persistent but not life-threatening clinical effects. Most patients develop mild central nervous system depression and bradycardia. Naloxone was not associated with improved outcomes.

The 20-minute whole blood clotting test (WBCT20) is used as a bedside 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.

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.

Context: Desvenlafaxine is used to treat major depression. Desvenlafaxine is also the active metabolite of venlafaxine. Venlafaxine overdose can cause serotonin toxicity, seizures and cardiovascular effects, but there is limited information on desvenlafaxine overdose. Objective: We aimed at investigating the clinical effects and complications from desvenlafaxine overdose. Materials and methods: This was a retrospective observational study of desvenlafaxine overdoses over a six-year period. Demographic details, dose and timing of the overdose, together with clinical effects, treatment and complications were extracted from a local hospital network database or the medical records of patients following hospital admission with a desvenlafaxine overdose. Results: There were 182 cases of desvenlafaxine overdose included in the study. From the 182 cases, 75 were desvenlafaxine (± alcohol) only ingestions and 107 included one or more co-ingested drugs. In single-agent desvenlafaxine ingestions, median age was 25 years (range: 13¿68 years) with a median ingested dose of 800 mg (range: 250¿3500 mg; interquartile range (IQR): 600¿1400 mg), and 54/75 (72%) were female. The Glasgow Coma Score (GCS) was 15 in 68/74 (92%) patients, 13¿14 in 5/74 (7%), and was seven in one patient following aspiration. Mild hypertension (systolic blood pressure [BP] > 140¿180 mmHg) occurred in 23/71 patients (32%), and tachycardia occurred in 29/74 (39%) patients. There were no abnormal QT intervals and no QRS >120 m s. Serotonin toxicity was diagnosed by the treating physician in 7/75 (9%) patients, but only one of these met the Hunter Serotonin Toxicity Criteria. None of the 75 patients who took desvenlafaxine only (± alcohol) had seizures, were admitted to intensive care or died. In comparison, the 107 patients taking desvenlafaxine in overdose with other medications developed more pronounced toxicity. Generalised seizures occurred in 5/107 (5%), but in three of these cases co-ingestants were possible proconvulsants. Fifteen patients had a GCS =9 and none had an abnormal QT or QRS. Severe effects appeared to be associated with coingestants. Conclusion: Desvenlafaxine overdose causes minor effects with mild hypertension and tachycardia. The risk of seizures or serotonin toxicity is low.

Context: 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. Methods: 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. Results: 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. Discussion: 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.

Purpose We aimed to determine the incidence of esophageal strictures in corrosive ingestions and potential predictors of severe injury. Basic procedures This was a retrospective cohort study of corrosive ingestions from a toxicology unit (1987¿2013) with telephone follow-up at least 1 y post-ingestion. Clinical data and investigations were obtained from a toxicology admission database. The primary outcome was esophageal stricture. Other outcomes included in-hospital mortality, endoscopy grade and early complications. Main findings There were 89 corrosive ingestions; median age, 31 y [1¿87 y; 46 females], including 13 strong alkalis (pH¿>¿12), 8 strong acids (pH¿<¿2), 29 domestic bleaches, 30 other domestic products, 6 non-domestic products and three unknown. Three patients died in hospital within 24 h (phenol, sodium azide, HCl). Two developed strictures (both strong alkalis): one had complete esophageal destruction; another developed a stricture after 25 d (inpatient grade 2A endoscopy). 24 patients were asymptomatic and discharged without complication. 65 patients were symptomatic (4 catastrophic injuries). 61 reported sore mouth/throat (50), abdominal pain (21), chest pain (17), dysphagia (13); 28 had an abnormal oropharyngeal examination. 25/61 symptomatic patients underwent inpatient endoscopy: normal (3), grade 1 (5), grade 2 (15) and grade 3 (2). Of 88 patients, 12 died (3 inpatients, 9 unrelated), 28 couldn't be contacted and 48 were contacted after 1.7¿24 y, including two with strictures. Five couldn't be interviewed (normal endoscopy (1), no dysphagia (3) and stroke (1). 4/41 interviewed reported dysphagia but no objective evidence of stricture. Principal conclusions All inpatient deaths and severe complications were apparent within hours of ingestion, and occurred with highly corrosive substances. One delayed stricture occurred, not predicted by inpatient endoscopy.

Aims: Codeine containing analgesics are commonly taken in overdose, but the frequency of respiratory depression is unknown. We investigated whether paracetamol-codeine combination overdoses caused respiratory depression more than paracetamol alone. Methods: We reviewed deliberate self-poisoning admissions with paracetamol (>2¿g) and paracetamol-codeine combinations presenting to a tertiary toxicology unit (1987¿2013). Demographic information, clinical effects, treatment (naloxone, length of stay [LOS], mechanical ventilation) were extracted from a prospective database. Primary outcome was naloxone requirement or ventilation for respiratory depression. Results: From 4488 presentations, 1376 admissions were included with paracetamol alone (929), paracetamol-codeine combinations (346) or paracetamol-codeine-doxylamine combinations (101) without co-ingestants. Median age was 23 years (12¿89 years); 1002 (73%) were female. Median dose was 12¿g (interquartile range [IQR]: 7.5¿20¿g). Median LOS was 16¿h (IQR: 6.5¿27¿h) and 564 (41%) were given acetylcysteine. Significantly larger paracetamol doses were ingested and more acetylcysteine given in paracetamol alone versus paracetamol combination overdoses. Seven out of 1376 patients were intubated or received naloxone (0.5%; 95% CI: 0.2¿1.1%), three intubated, three given naloxone and one both. Three out of 929 patients ingesting paracetamol alone (0.3%; 95% CI: 0.1¿1%) required intubation or naloxone, compared to two out of 346 ingesting paracetamol-codeine combinations (0.6%; 95% CI: 0.1¿2.3%; absolute difference, 0.26%; 95% CI: -0.7¿1.2%; P¿=¿0.62). Two out of 101 patients ingesting paracetamol-codeine-doxylamine combinations (2%; 95% CI: 0.3¿8%) required intubation or naloxone. Four patients were intubated for reasons other than respiratory depression: hepatotoxicity (2), retrieval (1), no data (1). Two out of 929 (0.2%) paracetamol alone overdoses had a Glasgow coma score < 9 compared to three out of 346 (0.9%) in the paracetamol-codeine group. Conclusions: Paracetamol-codeine combination overdoses are rarely associated with severe respiratory depression, with only two given naloxone and none intubated for respiratory depression.

Background: Acute alcohol consumption is a major risk factor for suicide, therefore investigating factors associated with alcohol-related self-harm warrant attention. Aims: To investigate the influence of prescribed psychotropic medications on the odds of coingesting alcohol preceding or during intentional efforts to self-poison. Method: A cross-sectional analysis of consecutive hospital presentations following intentional self-poisoning was conducted. A total of 7270 patients (4363 women) aged 18-96 were included. Results: The odds of alcohol coingestion were increased in those not prescribed any medication (odds ratio (OR)= 1.27, 99% CI 1.10-1.46, P50.001) and in impulsive self-poisonings (OR= 1.39, 99% CI 1.11-1.74, P50.001). Odds were decreased in those prescribed anticonvulsants (OR=0.69, 99% CI 0.51-0.93), antipsychotics (OR =0.55, 99% CI 0.45-0.66) and antidepressants (OR= 0.87, 99% CI 0.77-0.99). Conclusions: Findings indicate that being medicated for a psychiatric illness may reduce the likelihood of alcohol consumption during times of acute distress, hence perhaps may reduce the risk of intentional self-poisoning.

Background: Pneumatic tube transport of pathology specimens from the emergency department to the laboratory for analysis is a widely used practice. When compared to manual specimen transport, it results in savings in both time and labour. Sampling of cerebrospinal fluid still forms part of the workup of patients with suspected subarachnoid haemorrhage. There are claims in the literature that transport of cerebrospinal fluid samples by pneumatic tube results in excess haemolysis, which interferes with cerebrospinal fluid analysis for the presence of bilirubin. The aim of our study was to ascertain whether pneumatic tube transport of blood-stained cerebrospinal fluid to the laboratory, results in clinically significantly higher levels of haemolysis compared with manual transport of the same specimens. Methods: Stored cerebrospinal fluid was spiked with varying amounts of red blood cells creating 72 specimens of varying red cell concentration. Half of these specimens were transported to the laboratory manually while the other half were sent by pneumatic tube transport. The rates of haemolysis were compared between the pneumatic tube and manual transport samples. Results: There was no clinically significant difference in the rates of haemolysis between the samples transported to the laboratory by pneumatic tube compared with those moved manually. Conclusions: Pneumatic tube transport of cerebrospinal fluid to the laboratory is not associated with clinically significantly higher rates of haemolysis when compared to manual transport.

Background Animal models are used to test toxic effects of snake venoms/toxins and the antivenom required to neutralise them. However, venoms that cause clinically relevant coagulopathy in humans may have differential effects in animals. We aimed to investigate the effect of different procoagulant snake venoms on various animal plasmas. Methods Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and D-dimer levels were measured in seven animal plasmas (human, rabbit, cat, Guinea pig, pig, cow and rat). In vitro clotting times were then used to calculate the effective concentration (EC50) in each plasma for four snake venoms with different procoagulant toxins: Pseudonaja textilis, Daboia russelli, Echis carinatus and Calloselasma rhodostoma. Results Compared to human, PT and aPTT were similar for rat, rabbit and pig, but double for cat and cow, while Guinea pig had similar aPTT but double PT. Fibrinogen and D-dimer levels were similar for all species. Human and rabbit plasmas had the lowest EC50 for P. textilis (0.1 and 0.4 µg/ml), D. russelli (0.4 and 0.1 µg/ml), E. carinatus (0.6 and 0.1 µg/ml) venoms respectively, while cat plasma had the lowest EC50 for C. rhodostoma (11 µg/ml) venom. Cow, rat, pig and Guinea pig plasmas were highly resistant to all four venoms with EC50 10-fold that of human. Conclusions Different animal plasmas have varying susceptibility to procoagulant venoms, and excepting rabbits, animal models are not appropriate to test procoagulant activity. In vitro assays on human plasma should instead be adopted for this purpose.

Context: The current 3-phase acetylcysteine infusion for paracetamol poisoning delivers half the dose over 15-60 min and frequently results in adverse reactions. Objective: We aimed to determine adverse reaction frequency with a modified 2-phase infusion protocol with a longer initial infusion. Materials and methods: A prospective observational study of a modified 2-phase acetylcysteine protocol was undertaken at two hospitals. Acetylcysteine was commenced on admission and ceased if paracetamol concentrations were low-risk (below the nomogram line). The first infusion was 200 mg/kg over 4-9 h based on ingestion time or 4 h for staggered/chronic ingestions. The second infusion was 100 mg/kg over 16 h. Pre-defined outcomes were frequency of adverse reactions (systemic hypersensitivity reactions or gastrointestinal); proportion with alanine transaminase (ALT) > 1000 U/L or abnormal ALT. Results: 654 paracetamol poisonings were treated with the new protocol; median age 29 y (15-98 y); 453 females; 576 acute and 78 staggered/chronic ingestions. In 420 (64%) acetylcysteine was stopped for low-risk paracetamol concentrations. An adverse reaction occurred in 229/654 admissions (35%; 95% CI: 31-39%): 173 (26.5%; 95% CI: 23-30%) only gastrointestinal, 50 (8%; 95% CI: 6-10%) skin only systemic hypersensitivity reactions; and three severe anaphylaxis (0.5%; 95% CI: 0.1-1.5%; all hypotension). Adverse reactions occurred in 111/231 (48%) receiving full treatment compared to 116/420 (28%) in whom the infusion was stopped early (absolute difference 20%; 95% CI: 13-28%; p < 0.0001). In 200 overdoses < 10 g, one had toxic paracetamol concentrations, but 53 developed reactions. Sixteen patients had an ALT > 1000 U/L and 24 an abnormal ALT attributable to paracetamol; all but one had treatment commenced >12 h post-ingestion. Conclusion: A 2-phase acetylcysteine infusion protocol results in a fewer reactions in patients with toxic paracetamol concentrations, but is not justified in patients with low-risk paracetamol concentrations.

Study objective We investigate the effectiveness and safety of ketamine to sedate patients with severe acute behavioral disturbance who have failed previous attempts at sedation. Methods This was a prospective study of patients given ketamine for sedation who had failed previous sedation attempts. Patients with severe acute behavioral disturbance requiring parenteral sedation were treated with a standardized sedation protocol including droperidol. Demographics, drug dose, observations, and adverse effects were recorded. The primary outcome was the number of patients who failed to sedate within 120 minutes of ketamine administration or requiring further sedation within 1 hour. Results Forty-nine patients from 2 hospitals were administered rescue ketamine during 27 months; median age was 37 years (range 20-82 years); 28 were men. Police were involved with 20 patients. Previous sedation included droperidol (10 mg; 1), droperidol (10+10 mg; 33), droperidol (10+10+5 mg; 1), droperidol (10+10+10 mg; 11), and combinations of droperidol and benzodiazepines (2) and midazolam alone (1). The median dose of ketamine was 300 mg (range 50 to 500 mg). Five patients (10%; 95% confidence interval 4% to 23%) were not sedated within 120 minutes or required additional sedation within 1 hour. Four of 5 patients received 200 mg or less. Median time to sedation postketamine was 20 minutes (interquartile range 10 to 30 minutes; 2 to 500 minutes). Three patients (6%) had adverse effects, 2 had vomiting, and a third had a transient oxygen desaturation to 90% after ketamine that responded to oxygen. Conclusion Ketamine appeared effective and did not cause obvious harm in this small sample and is a potential option for patients who have failed previous attempts at sedation. A dose of 4 to 5 mg/kg is suggested, and doses less than 200 mg are associated with treatment failure.

Paracetamol overdose prior to the introduction of acetylcysteine was associated with significant morbidity. Acetylcysteine is now the mainstay of treatment for paracetamol poisoning and has effectively reduced rates of hepatotoxicity and death. The current three-bag intravenous regimen with an initial high loading dose was empirically derived four decades ago and has not changed since. This regimen is associated with a high rate of adverse effects due mainly to the high initial peak acetylcysteine concentration. Furthermore, there are concerns that the acetylcysteine concentration is not adequate for 'massive' overdoses and that the dose and duration may need to be altered. Various novel regimens have been proposed, looking to address these issues. Many of these modified regimens aim to decrease the rate of adverse reactions by slowing the loading dose and thereby decrease the peak concentration. We used a published population pharmacokinetic model of acetylcysteine to simulate these modified regimens. We determined mean peak and 20 h acetylcysteine concentrations and area under the under the plasma concentration-time curve to compare these regimens. Those regimens that resulted in a lower peak acetylcysteine concentration have been shown in studies to have a lower rate of adverse events. However, these studies were too small to show whether they are as effective as the traditional regimen. Further research is still needed to determine the optimum dose and duration of acetylcysteine that results in the fewest side-effects and treatment failures. Indeed, a more patient-tailored approach might be required, whereby the dose and duration are altered depending on the paracetamol dose ingested or paracetamol concentrations.

An understanding of mechanisms, potential benefits and risks of antidotes is essential for clinicians who manage poisoned patients. Of the dozens of antidotes currently available, only a few are regularly used. These include activated charcoal, acetylcysteine, naloxone, sodium bicarbonate, atropine, flumazenil, therapeutic antibodies and various vitamins. Even then, most are used in a minority of poisonings. There is little randomized trial evidence to support the use of most antidotes. Consequently, decisions about when to use them are often based on a mechanistic understanding of the poisoning and the expected influence of the antidote on the patient's clinical course. For some antidotes, such as atropine and insulin, the doses employed can be orders of magnitude higher than standard dosing. Importantly, most poisoned patients who reach hospital can recover with supportive care alone. In low risk patients, the routine use of even low risk antidotes such as activated charcoal is unwarranted. In more serious poisonings, decisions regarding antidote use are generally guided by a risk/benefit assessment based on low quality evidence.

Background: Intramuscular droperidol is used increasingly for sedation of aggressive and violent patients. This study aimed to characterise the pharmacokinetics of intramuscular droperidol in these patients to determine how rapidly it is absorbed and the expected duration of measurable drug concentrations. Methods: We undertook a population pharmacokinetic analysis of a subgroup of patients from a clinical trial comparing droperidol and midazolam: 17 receiving 5¿mg and 24 receiving 10¿mg droperidol. Droperidol was measured using high-performance liquid chromatography. Pharmacokinetic modelling was performed under a nonlinear mixed effects modelling framework (NONMEM v7.2). The model was used to simulate concentration time profiles of three typical doses, 5¿mg, 10¿mg and 10¿mg¿+¿10¿mg repeated at 15¿min. Results: A two-compartment first-order input with first-order output model fitted the data best. The absorption rate constant was poorly characterised by the data and an estimate of the first order rate constant of absorption when fixed to 10¿h¿1provided a stable model and lowest objective function. This represents extremely rapid absorption with a half-life of 5¿min. The final model had a clearance of 41.9¿l¿h¿1and volume of distribution of the central compartment of, 73.6¿l. Median and interquartile range of initial (alpha) half-life was 0.32¿h (0.26¿0.37¿h) and second (beta) half-life was 3.0¿h (2.5¿3.6¿h). Simulations indicate that 10¿mg alone provides an 80% probability of being above the lower limit of quantification (5¿µg¿l¿1) for 7¿h, 2¿h longer than for 5¿mg. Giving two 10¿mg doses increased this duration to 10¿h. Conclusions: Intramuscular droperidol is rapidly absorbed with high therapeutic concentrations after 5 and 10¿mg doses, and supports clinical data in which droperidol sedates rapidly for up to 6¿h.

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

abstract: Context: We hypothesized that in chronic digoxin toxicity, anti-digoxin antibodies (Fab) would be efficacious in binding digoxin, but this may not translate into improved clinical outcomes. Objective: This study aims to investigate changes in free digoxin concentrations and clinical effects on heart rate and potassium concentrations in chronic digoxin poisoning when anti-digoxin Fab are given. Materials and methods: This is a prospective observational study. Patients were recruited if they have been treated with anti-digoxin Fab for chronic digoxin poisoning. Data was entered into a standardised prospective form, supplemented with medical records. Their serum or plasma was collected, analysed for free and bound digoxin and free anti-digoxin Fab concentrations. Results: From September 2013 to February 2015, 36 patients (median age, 78 years; 22 females) were recruited from 18 hospitals. Median heart rate (HR) was 49 beats/min. Initial median digoxin and potassium concentrations were 4.7 nmol/L (3.6 µg/L) (range: 2.3¿11.2 nmol/L) and 5.3 mmol/L (range: 2.9¿9.2 mmol/L) respectively. Beta-blockers (n = 18), calcium antagonists (n = 6), spironolactone and/or angiotensin blocking agents (n = 24) were also used concomitantly. Renal impairment and gastrointestinal symptoms were present in 31 (86%) and 22 (63%) patients respectively. Five patients died from conditions unrelated to digoxin toxicity. Median change in HR was 8 beats/min post-Fab with no effect on blood pressure; they were 4, 10 and 17 beats/min for the 1, 2 and =3 vials of anti-digoxin Fab groups respectively. Concomitant treatments with potassium lowering agents (12/36) and inotropic drugs (7/36) were used. Gastrointestinal effects resolved in all 22 patients. The median decrease for potassium was 0.3 mmol/L. Digoxin concentration reduced from 3.8 to 0 nmol/L post-Fab. There was a rebound observed in the free digoxin concentration in 25 patients but none had associated clinical deterioration. Conclusions: One to two vials of anti-digoxin Fab initially bound all free digoxin confirming Fab efficacy. However, this was associated with only a moderate improvement in HR and potassium, suggesting bradyarrhythmia and hyperkalaemia may be from other co-morbidities.

Envenoming by the Australian red-bellied black snake (Pseudechis porphyriacus) causes non-specific systemic symptoms, anticoagulant coagulopathy, myotoxicity and local effects. Current management for systemic envenoming includes administration of one vial of tiger snake antivenom within 6 h of the bite to prevent myotoxicity. We present a case of severe rhabdomyolysis in a 16 year old male which developed despite early administration of one vial of tiger snake antivenom. Free venom was detected after the administration of antivenom concurrent with rapidly decreasing antivenom concentrations. The case suggests that insufficient antivenom was administered and the use of larger doses of antivenom need to be explored for red-bellied black snake envenoming.

Background: There is a paucity of robust epidemiological data on snakebite, and data available from hospitals and localized or time-limited surveys have major limitations. No study has investigated the incidence of snakebite across a whole country. We undertook a community-based national survey and model based geostatistics to determine incidence, envenoming, mortality and geographical pattern of snakebite in Sri Lanka. Methodology/Principal Findings: The survey was designed to sample a population distributed equally among the nine provinces of the country. The number of data collection clusters was divided among districts in proportion to their population. Within districts clusters were randomly selected. Population based incidence of snakebite and significant envenoming were estimated. Model-based geostatistics was used to develop snakebite risk maps for Sri Lanka. 1118 of the total of 14022 GN divisions with a population of 165665 (0.8%of the country¿s population) were surveyed. The crude overall community incidence of snakebite, envenoming and mortality were 398 (95% CI: 356¿441), 151 (130¿173) and 2.3 (0.2¿4.4) per 100000 population, respectively. Risk maps showed wide variation in incidence within the country, and snakebite hotspots and cold spots were determined by considering the probability of exceeding the national incidence. Conclusions/Significance: This study provides community based incidence rates of snakebite and envenoming for Sri Lanka. The within-country spatial variation of bites can inform healthcare decision making and highlights the limitations associated with estimates of incidence from hospital data or localized surveys. Our methods are replicable, and these models can be adapted to other geographic regions after re-estimating spatial covariance parameters for the particular region.

Context: Serum sickness is a delayed immune reaction resulting from the injection of foreign protein or serum. Antivenom is known to cause serum sickness but the incidence and characteristics are poorly defined. Objective: To investigate the incidence and clinical features of serum sickness following the administration of Australian snake antivenoms. Materials and methods: This was a prospective cohort study of patients recruited to the Australian Snakebite Project who received snake antivenom from November 2012 to March 2014. Demographics, clinical information, laboratory tests and antivenom treatment were recorded prospectively. Patients administered antivenom were followed up at 7-10 days and 6 weeks post-antivenom. The primary outcome was the proportion with serum sickness, pre-defined as three or more of: fever, erythematous rash/urticaria, myalgia/arthralgia, headache, malaise, nausea/vomiting 5-20 days post-antivenom. Results: During the 16-month period, 138 patients received antivenom. 23 were not followed up (unable to contact, tourist, child, bee sting) and 6 died in hospital. Of 109 patients followed up, the commonest reason for antivenom was venom induced consumption coagulopathy in 77 patients. An acute systemic hypersensitivity reaction occurred post-antivenom in 25 (23%) and 8 (7%) were severe with hypotension. Serum sickness occurred in 32/109 (29%) patients, including 15/37 (41%) given tiger snake, 6/15 (40%) given polyvalent and 4/23 (17%) given brown snake antivenom. There was no association between the volume of antivenom and serum sickness, p = 0.18. The commonest effects were lethargy, headache, muscle/joint aches and fever. Discussion: The incidence of serum sickness after snake antivenom in Australia was higher than earlier investigations which failed to define symptoms or follow-up patients, but similar to more recent studies of antivenoms in the United States. Conclusion: Serum sickness is common with Australian snake antivenom but does not appear to be predictable based on the volume of antivenom administered.

The most common toxicity associated with sulfonylureas and insulin is hypoglycaemia. The article reviews existing evidence to better guide hypoglycaemia management. Sulfonylureas and insulin have narrow therapeutic indices. Small doses can cause hypoglycaemia, which may be delayed and persistent. All children and adults with intentional overdoses need to be referred for medical assessment and treatment. Unintentional supratherapeutic ingestions can be initially managed at home but if symptomatic or if there is persistent hypoglycaemia require medical referral. Patients often require intensive care and prolonged observation periods. Blood glucose concentrations should be assessed frequently. Asymptomatic children with unintentional sulfonylurea ingestions should be observed for 12 h, except if this would lead to discharge at night when they should be kept until the morning. Prophylactic intravenous dextrose is not recommended. The goal of therapy is to restore and maintain euglycaemia for the duration of the drug's toxic effect. Enteral feeding is recommended in patients who are alert and able to tolerate oral intake. Once insulin or sulfonylurea-induced hypoglycaemia has developed, it should be initially treated with an intravenous dextrose bolus. Following this the mainstay of therapy for insulin-induced hypoglycaemia is intravenous dextrose infusion to maintain the blood glucose concentration between 5.5 and 11 mmol l-1. After sulfonylurea-induced hypoglycaemia is initially corrected with intravenous dextrose, the main treatment is octreotide which is administered to prevent insulin secretion and maintain euglycaemia. The observation period varies depending on drug, product formulation and dose. A general guideline is to observe for 12 h after discontinuation of intravenous dextrose and, if applicable, octreotide.

Aims: Morbidity and mortality from drug overdose has decreased over three decades. This is credited to safer drugs and therefore better outcomes in overdose. We aimed to investigate changing prescriptions of antipsychotic medications and associated changes in antipsychotic overdoses over a 26-year period. Methods: All antipsychotic poisoning presentations to a tertiary referral toxicology unit between 1987 and 2012 were reviewed. Data were collected prospectively on demographics, ingestion information, clinical effects, complications and treatment. Rates of antipsychotic drug use in Australia were obtained from Australian government publications for 1990¿2011 and linked to overdose admissions by postcode. Results: There were 3180 antipsychotic overdoses: 1235 first generation antipsychotics, 1695 ¿atypical¿ second generation antipsychotics and 250 lithium overdoses. Over 26 years, antipsychotic overdoses increased 1.8-fold, with first generation antipsychotics decreasing to one-fifth of their peak (¿80/year to 16) and second generation antipsychotics increasing to double this (¿160/year), olanzapine and quetiapine accounting for 78%. All antipsychotic overdoses had a median length of stay of 18.6 h, 15.7% admitted to intensive care unit, 10.4% ventilated and 0.13% died in hospital, which was the same for first generation compared to second generation antipsychotics. There was a 2.3-fold increase in antipsychotic prescriptions over the same period; first generation antipsychotics declined whereas there was a dramatic rise in second generation antipsychotics, mainly olanzapine, quetiapine and risperidone (79%). Conclusion: Over 26 years there was an increase in antipsychotic prescribing associated with an increase in antipsychotic overdoses. Although the type of antipsychotics changed, the morbidity and mortality remained the same, so that antipsychotics are an increasing proportion of overdose admissions.

Context: Many bites from mildly venomous elapids occur but identification or presence of systemic envenoming is rarely confirmed. Objective: 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. Case: 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 × 109/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. Materials and methods: 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. Results: 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 g/mL and even weaker anticoagulant activity. Conclusions: 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.

Study objective: We investigate the safety and effectiveness of droperidol for sedation of acute behavioral disturbance in the emergency department (ED). Methods: This was a prospective observational study in 6 EDs (August 2009 to April 2013). Adult patients requiring parenteral sedation for acute behavioral disturbance received droperidol 10 mg. If this did not sedate the patient within 15 minutes, further sedation was allowed but droperidol 10 mg was recommended as part of a sedation protocol. The primary outcome was the proportion of patients with an abnormal QT interval, defined by the at-risk line on the QT nomogram. Secondary outcomes were effectiveness determined by the time to sedation measured on the Sedation Assessment Tool, use of additional sedation, adverse events, and injury to staff or patients. Results: There were 1,009 patients with an ECG performed within 2 hours of droperidol administration, with a median dose of 10 mg (interquartile range [IQR]10 to 17.5 mg). Thirteen of the 1,009 patients had an abnormal QT (1.3%; 95% confidence interval 0.7% to 2.3%), but 7 of these had another cause attributed for prolonged QT (methadone, escitalopram, amiodarone, or preexisting). In 1,403 patients sedated with a median total dose of droperidol of 10 mg (IQR 10 to 20 mg), the median time to sedation was 20 minutes (IQR 10 to 30 minutes) and 97% were sedated within 120 minutes. Additional sedation was required for 435 patients (31.0%; 95% confidence interval 28.6% to 33.5%). Adverse events occurred in 70 patients (5%) and oversedation without complications in 109 (8%), the latter more common for patients receiving benzodiazepines as additional sedation (16/109 [15%]). There were no cases of torsades de pointes. Injuries occurred in 34 staff members and 4 patients. Conclusion: The study supports the use of high-dose droperidol as a safe sedating agent for patients with acute behavioral disturbance in the ED. There is no evidence of increased risk for QT prolongation with the doses used in this study.

Background: Marine stings are common but most are minor and do not require medical intervention. Severe and systemic marine envenoming is uncommon, but includes box jellyfish stings, Irukandji syndrome, major stingray trauma and blue-ringed octopus envenoming. Almost all marine injuries are caused by jellyfish stings, and penetrating injuries from spiny fish, stingrays or sea urchins. Objective: This article describes the presentation and management of marine envenomations and injuries that may occur in Australia. Discussion: First aid for jellyfish includes tentacle removal, application of vinegar for box jellyfish, and hot water immersion (45°C for 20 min) for bluebottle jellyfish stings. Basic life support is essential for severe marine envenomings that result in cardiac collapse or paralysis. Irukandji syndrome causes severe generalised pain, autonomic excess and minimal local pain, which may require large amounts of analgesia, and, uncommonly, myocardial depression and pulmonary oedema occur. Penetrating marine injuries can cause significant trauma depending on location of the injury. Large and unclean wounds may have delayed healing and secondary infection if not adequately irrigated, debrided and observed.

Hematologic abnormalities are the most common effects of snake envenoming globally. Venom-induced consumption coagulopathy (VICC) is the commonest and most important. Other hematologic abnormalities are an anticoagulant coagulopathy and thrombotic microangiopathy. Venom-induced consumption coagulopathy is a venom-induced activation of the clotting pathway by procoagulant toxins, resulting in clotting factor consumption and coagulopathy. The type of procoagulant toxin differs between snakes and can activate prothrombin, factor X, and factor V or consume fibrinogen. The most useful investigation in VICC is a prothrombin time/international normalized ratio. The d-dimer may assist in early diagnosis, but fibrinogen levels often add little in the clinical setting. Bedside investigations would be ideal, but point-of-care testing international normalized ratio and whole blood clotting tests have been shown to be unreliable in VICC. The major complication of VICC is hemorrhage, including intracranial hemorrhage which is often fatal. The role of antivenom in VICC is controversial and may only be beneficial for some types of snakes including Echis spp where the duration of abnormal clotting is reduced from more than a week to 24 to 48 hours. In contrast, antivenom does not appear to speed the recovery of VICC in Australian snake envenoming. Other treatments for VICC include factor replacement, observation and prevention of trauma, and heparin. An Australian study showed that fresh-frozen plasma speeds recovery of VICC, but early use may increase consumption. There is no evidence to support heparin.

Background Russell¿s viper envenoming is a major problem in South Asia and causes venom induced consumption coagulopathy. This study aimed to investigate the kinetics and dynamics of venom and clotting function in Russell¿s viper envenoming. Methodology/Principal Findings In a prospective cohort of 146 patients with Russell¿s viper envenoming, we measured venom concentrations, international normalised ratio [INR], prothrombin time (PT), activated partial thromboplastin time (aPTT), coagulation factors I, II, V, VII, VIII, IX and X, and von Willebrand factor antigen. The median age was 39y (16¿82y) and 111 were male. The median peak INR was 6.8 (interquartile range[IQR]:3.7 to >13), associated with low fibrinogen [median,<0.01g/L;IQR:<0.01¿0.9g/L), low factor V levels [median,<5%;IQR:<5¿4%], low factor VIII levels [median,40%;IQR:12¿79%] and low factor X levels [median,48%; IQR:29¿67%]. There were smaller reductions in factors II, IX and VII over time. All factors recovered over 48h post-antivenom. The median INR remained >3 at 6h post-antivenom but had reduced to <2, by 24h. The aPTT had also returned to close to normal (<50sec) at 24h. Factor VII, VIII and IX levels were unusually high pre-antivenom, median peak concentrations of 393%, 307% and 468% respectively. Pre-antivenom venom concentrations and the INR (r = 0.20, p = 0.02) and aPTT (r = 0.19, p = 0.03) were correlated (non-parametric Spearman analysis). Conclusions Russell¿s viper coagulopathy results in prolonged aPTT, INR, low fibrinogen, factors V, VIII and X which recover over 48h. Severity of clotting abnormalities was associated with venom concentrations.

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.

Brown snake (Pseudonaja spp.)-induced early cardiovascular collapse is a life-threatening medical emergency in Australia. We have previously shown that this effect can be mimicked in animals and is mediated via the release of endogenous mediators. In the present study, we aimed to purify and characterize the component in Pseudonaja textilis venom which induces cardiovascular collapse following envenoming. The component (fraction 3) was isolated using a combination of techniques including hydroxyapatite and reverse phase chromatography. Fraction 3 (10 or 20 µg/kg, i.v.) produced a rapid decrease in mean arterial pressure (MAP) followed by cardiovascular collapse. Fraction 3-induced early collapse was abolished by prior administration of smaller priming doses of fraction 3 (i.e. 2 and 5 µg/kg, i.v.) or heparin (300 units/kg, i.v.). P. textilis whole venom (1 and 3 µg/ml), but not fraction 3 (1 or 3 µg/ml), induced endothelium-dependent relaxation in isolated rat mesenteric arteries. SDS-PAGE gel indicated the presence of 9-10 protein bands of fraction 3. Using proteomic based analysis some protein bands of fraction 3 were identified as subunits of venom prothrombin activator, pseutarin C of P. textilis venom. Our results conclude that prothrombin activator-like toxin is likely to be a contributor to the rapid collapse induced by P. textilis venom.

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.

Aims To investigate the pharmacokinetics (PK) of sertraline in overdose and the effect of single dose activated charcoal (SDAC). Methods Patients presenting to a toxicology unit with sertraline overdoses had demographic and clinical information recorded, and serial serum collected for measurement of sertraline concentrations. Monolix® version 4.2 was used to develop a population PK model of sertraline overdose and the effect of SDAC. Uncertainty in dose time was accounted for by shifting dose time using lag time with between subject variability (BSV). BSV on relative fraction absorbed was used to model uncertainty in dose. Results There were 77 timed sertraline concentrations measured in 28 patients with sertraline overdoses with a median dose of 1550 mg (250-5000 mg). SDAC was given to seven patients between 1.5 and 4 h post-overdose. A one compartment model with lag time of 1 h and first order input and elimination adequately described the data. Including BSV on both lag time and relative fraction absorbed improved the model. The population PK parameter estimates for absorption rate constant, volume of distribution and clearance were 0.895 h-1, 5340 l and 130 l h-1, respectively. The calculated half-life of sertraline following overdose was 28 h (IQR 19.4-30.6h). When given up to 4 h post-overdose, SDAC significantly increased the clearance of sertraline by a factor of 1.9, decreased the area under the curve and decreased the maximum plasma concentration (Cmax). Conclusions Sertraline had linear kinetics in overdose with parameter values similar to those in therapeutic use. SDAC is effective in increasing clearance when given 1.5 to 4 h post-overdose.

Purpose: Dosing of enoxaparin, like other anticoagulants, may result in bleeding following excessive doses and clot formation if the dose is too low. We recently showed that a factor Xa based clotting time test could potentially assess the effect of enoxaparin on the clotting system. However, the test did not perform well in subsequent individuals and effectiveness of an exogenous phospholipid, Actin FS, in reducing the variability in the clotting time was assessed. The aim of this work was to conduct an adaptive pilot study to determine the range of concentrations of Xa and Actin FS to take forward into a proof-of-concept study. Methods: A nonlinear parametric function was developed to describe the response surface over the factors of interest. An adaptive method was used to estimate the parameters using a D-optimal design criterion. In order to provide a reasonable probability of observing a success of the clotting time test, a P-optimal design criterion was incorporated using a loss function to describe the hybrid DP-optimality. Results: The use of adaptive DP-optimality method resulted in an efficient estimation of model parameters using data from only 6 healthy volunteers. The use of response surface modelling identified a range of sets of Xa and Actin FS concentrations, any of which could be used for the proof-of-concept study. Conclusions: This study shows that parsimonious adaptive DP-optimal designs may provide both precise parameter estimates for response surface modelling as well as clinical confidence in the potential benefits of the study.

Context. Tramadol is a commonly used centrally acting analgesic associated with seizures and suspected to cause serotonin toxicity in overdose. Objective. This study sought to investigate the effects of tramadol overdose, and included evaluation for serotonin toxicity based on the Hunter Serotonin Toxicity Criteria where the seven clinical features of spontaneous clonus, inducible clonus, ocular clonus, agitation, diaphoresis, tremor and hyperreflexia are examined for in all patients taking serotonergic medications; seizures and central nervous system depression. Materials and methods. This was an observational cases series based on a retrospective review of tramadol overdoses (> 400 mg) admitted to a tertiary toxicology unit from November 2000 to June 2013. Demographic details, information on ingestion (dose and co-ingestants), clinical effects, complications (seizures, serotonin toxicity and cardiovascular effects) and intensive care unit (ICU) admission were extracted from a clinical database. Results. There were 71 cases of tramadol overdose (median age: 41 years, range: 17-69 years; and median ingested dose: 1000 mg, interquartile range [IQR]: 800-2000 mg). Seizures were dose related and occurred in 8 patients, one of them co-ingested a benzodiazepine compared with 16 patients without seizures. There were no cases of serotonin toxicity meeting the Hunter Serotonin Toxicity Criteria. Tachycardia occurred in 27 and mild hypertension occurred in 32. The Glasgow Coma Score was < 15 in 29 and < 9 in 5 patients; three co-ingested tricyclic antidepressants and two tramadol alone (3000 mg and 900 mg). Respiratory depression occurred in 13, median dose: 2500 (IQR: 1600-3000) mg which was significantly different (p = 0.003) to patients without respiratory depression, median dose: 1000 (IQR: 750-1475) mg. Eight patients were admitted to ICU, five due to co-ingestant toxicity and three for respiratory depression. Discussion. Tramadol overdose was associated with a significant risk of seizures and respiratory depression in more severe cases, both which appear to be related to the ingested dose. There were no cases of serotonin toxicity, while opioid-like effects and adrenergic effects were prominent. Conclusion. Tramadol overdose is associated with seizures and respiratory depression, but is unlikely to cause serotonin toxicity.

Objective. To describe the clinical effects, pharmacokinetics, and pharmacodynamics of plasma and acetylcholinesterase in an aldicarb overdose. Case Report. A 57-year-old female was found unconscious and incontinent of urine after ingesting aldicarb. She was bradycardic, hypotensive, hypersalivating, clammy, had small pupils, and generalized weakness. She was intubated, ventilated, and treated with large atropine doses (50 mg and 20 mg/h infusion) and adrenaline. She improved hemodynamically over 24 h, but remained comatose for another 24 h, before recovering without sequela. Aldicarb concentration at admission was 2.18 µg/ml and concentration-time data best fitted a two compartmental model with first order absorption and a time of ingestion 4.5 h preadmission. The half-life of distribution was 0.4 h and half-life of elimination, 13 h. Plasma cholinesterase concentration at admission was 0.3 kU/L (Reference range[RR]:4.3-10.6 kU/L) and red cell cholinesterase was 10 U/gHb (RR:38-66 U/gHb). The IC50 was 0.15 µg/ml and 0.26 µg/ml for plasma and red cell cholinesterase, respectively. Discussion. Aldicarb poisoning causes rapid onset severe toxicity with muscarinic and nicotinic excess, seizures, and decreased consciousness. Cholinesterases rapidly recover once aldicarb concentrations decrease and precede clinical recovery.

Context. Toxicity from recreational substances marketed for other purposes is a well-documented clinical entity. We present two cases of phenibut toxicity procured via the internet. Case Details. A 20-year-old female presented to the emergency department (ED) having used phenibut the prior day. The main finding was a decreased level of consciousness, however when roused she became delirious. Supportive care only was required with no specific intervention. The patient made a full recovery over a 24-hour period and admitted to use of phenibut purchased online. Plasma phenibut concentration was 29.7 µg/ml. A 38-year-old male presented to ED with an agitated delirium. The prior evening he had used tetrahydrocannabinol or THC, alcohol and phenibut, the latter purchased via the internet. His behavioural state had a suboptimal response to parenteral sedation. He was subsequently intubated for airway protection in the context of ongoing sedation to optimally manage his behavioural state. Post extubation the next morning he admitted using phenibut. Plasma phenibut concentration was 36.5 µg/ml. Discussion. Altered mental status was the predominant manifestation of phenibut toxicity in these cases. Clinicians to be aware of how phenibut toxicity may present as the internet has widened access to such substances.

Serum sickness is a delayed immune reaction in which the immune system responds to a protein in antiserum as a potentially harmful substance and mounts an IgG-mediated antibody response. A 32 year-old female patient had systemic envenoming following a bite by a red-bellied black snake (Pseudechis porphyriacus). She was treated with Tiger snake antivenom and recovered over 24 h and did not develop myotoxicity. She then presented with local pain, itching and swelling, which was partially treated with antihistamines. Eleven days after the bite she presented again with symptoms of worsening serum sickness including rash on the upper legs, joint and muscle pain in arms, ankles and knees, and nausea. The patient was prescribed five days of prednisone 50 mg/day, antihistamine 10 mg/day and analgesia 1000 mg/day and improved over 2 days. She had no further problems on follow up at 4 months. This case highlights that serum sickness can cause significant effects after the treatment of snake envenoming. It develops 5-14 days after antivenom administration and has characteristic clinical and laboratory features. Severe cases of serum sickness can result in morbidity but it appears to respond well to corticosteroid treatment.

Objectives: Measuring the QT interval on an electrocardiogram (ECG) is integral to risk assessment of Torsade de Pointes (TdP). This study aimed to investigate the accuracy of the 1/2 RR rule as a risk assessment tool for drug-induced TdP, comparing it to the QT nomogram, Bazett's corrected QT (QTcB), and Fridericia's corrected QT (QTcF). Methods: The authors calculated sensitivity and specificity of the 1/2 RR rule using a published data set of 129 cases of drug-induced TdP and 316 controls (noncardiotoxic overdoses), compared to the QT nomogram, QTcB > 500 msec and QTcF > 500 msec. To further determine the value of the 1/2 RR rule, its observed positive, and negative agreement were calculated when compared to the QT nomogram for determining an abnormal QT in eight samples of different drugs in overdose. Results: The sensitivity and specificity of the 1/2 RR rule were 88% (95% confidence interval [CI] = 80% to 93%) and 53% (95% CI = 47% to 58%), respectively, compared to the QT nomogram (sensitivity = 97%, 95% CI = 92% to 99%; specificity = 99%, 95% CI = 97% to 100%). It was also less sensitive than QTcB > 500 msec and had a lower specificity than QTcB > 500 msec and QTcF > 500 msec. In drug overdose patients, the 1/2 RR rule had poor observed agreement averaging 41%, which was mainly due to poor positive agreement, except for amisulpride where there was good agreement. Conclusions: The 1/2 RR rule was not as sensitive as the QT nomogram or QTcB > 500 msec for drug-induced TdP. It had poor positive agreement in almost all overdose patients, resulting in over half of patients receiving unnecessary cardiac monitoring and repeat ECGs.

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of antivenom for the recovery from VICC in people with snake envenoming.

Study objective Latrodectism is the most important spider envenomation syndrome worldwide. There remains considerable controversy over antivenom treatment. We aimed to investigate whether antivenom resulted in resolution of pain and systemic effects in patients with latrodectism who received standardized analgesia.

Study objective: Antipsychotic drugs are frequently reported to cause QT prolongation and torsade de pointes. We aim to investigate the potential risk of torsade de pointes in antipsychotic overdose by assessing the QT interval with the QT nomogram. Methods: All presentations to a toxicology service between January 1987 and May 2013 were reviewed. Admissions with single ingestions of an antipsychotic greater than maximum daily dose were extracted. Demographics, dose, ECG, and outcomes (arrhythmias and death) were obtained. QT intervals in multiple leads were manually measured and the median taken. QT-heart rate (QT-HR) pairs were plotted on the QT nomogram and defined as prolonged if above the abnormal line. The QTcF (Fridericia's HR correction) was calculated and compared with dose. Results: From 2,356 antipsychotic overdoses, 494 were included. There were no abnormal QT-HR pairs in 4 aripiprazole, 31 pericyazine, 14 trifluoperazine, and 7 haloperidol overdoses. Abnormal QT intervals occurred in 9 of 16 amisulpride overdoses (56%; 95% confidence interval [CI] 31% to 79%), 16 of 57 thioridazine overdoses (28%; 95% CI 17% to 42%), and 5 of 29 chlorpromazine overdoses (17%; 95% CI 7% to 36%). Abnormal QT intervals occurred in 5 of 41 risperidone overdoses (12%; 95% CI 5% to 27%), 10 of 202 quetiapine overdoses (5%; 95% CI 3% to 9%), and 2 of 76 olanzapine overdoses (3%; 95% CI 0.5% to 10%), but there was no correlation between dose and QTcF, and most abnormal QT intervals were at fast HR. An additional 186 single antipsychotic ingestions with noncardiotoxic coingestants had similar proportions of abnormal QT. There was 1 case of torsade de pointes in a thioridazine overdose. Conclusion: There appeared to be significant risk of QT prolongation with amisulpride and thioridazine overdoses. Although there were abnormal QT intervals for quetiapine, olanzapine, and risperidone overdoses, they were associated with tachycardia and not dose dependent, and so were unlikely to be associated with increased torsade de pointes risk.

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

Snakebite is a potential medical emergency and must receive high-priority assessment and treatment, even in patients who initially appear well. Patients should be treated in hospitals with onsite laboratory facilities, appropriate antivenom stocks and a clinician capable of treating complications such as anaphylaxis. All patients with suspected snakebite should be admitted to a suitable clinical unit, such as an emergency short-stay unit, for at least 12 hours after the bite. Serial blood testing (activated partial thromboplastin time, international normalised ratio and creatine kinase level) and neurological examinations should be done for all patients. Most snakebites will not result in significant envenoming and do not require antivenom. Antivenom should be administered as soon as there is evidence of envenoming. Evidence of systemic envenoming includes venom-induced consumption coagulopathy, sudden collapse, myotoxicity, neurotoxicity, thrombotic microangiopathy and renal impairment. Venomous snake groups each cause a characteristic clinical syndrome, which can be used in combination with local geographical distribution information to determine the probable snake involved and appropriate antivenom to use. The Snake Venom Detection Kit may assist in regions where the range of possible snakes is too broad to allow the use of monovalent antivenoms. When the snake identification remains unclear, two monovalent antivenoms (eg, brown snake and tiger snake antivenom) that cover possible snakes, or a polyvalent antivenom, can be used. One vial of the relevant antivenom is sufficient to bind all circulating venom. However, recovery may be delayed as many clinical and laboratory effects of venom are not immediately reversible. For expert advice on envenoming, contact the National Poisons Information Centre on 13 11 26.