Search

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

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

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

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

Methotrexate toxicity following intravenous (IV) methotrexate is well reported, but there is less information on accidental daily dosing of a prescribed weekly dose of oral methotrexate. A 70 year old female presented following accidentally taking 20 mg methotrexate for five days, with multiple oral ulcers, thrombocytopenia (platelets 80 x 109/L [reference range[RR]:150-400 x 109/L]) and an alanine aminotransferase 820 U/L [RR:10-35 U/L]. Methotrexate was undetectable [<0.04 µmol/L]. She was treated with folinic acid, 15 mg orally and then 15 mg IV every six hours. She became progressively pancytopenic, with the lowest counts occurring days 3-6: Hb, 87 g/L, platelets, 22 x 109/L, neutrophils, 0.0 x 109/L [RR:2-8 x 109/L] and white cell count, 0.6 x 109/L [RR:4-11 x 109/L]. She received 2 units of platelets, filgrastim 300 mcg daily for days 3-7 and IV ceftazidime/gentamicin for a fever. On day 6, her platelet and neutrophil counts began to recover, and her ALT was almost normal on discharge day 9. She had alopecia in the 3 months post-discharge. Our patient developed severe toxicity, consistent with complete absorption and cellular uptake of methotrexate, with slow cellular elimination. She was treated with folinic acid, granulocyte-colony stimulating factor and blood product transfusions. [ABSTRACT FROM AUTHOR]

Serum sickness is a poorly reported delayed adverse reaction following snake antivenom therapy. We aimed to assess the frequency of serum sickness associated with administering Indian polyvalent antivenom in Sri Lanka. We recruited patients from the Anuradhapura snakebite cohort who were admitted to a rural tertiary care hospital in Sri Lanka over one year period. Patients were interviewed over the phone 21 to 28 days post-envenoming to collect data on clinical effects: fever/chills, arthralgia/myalgia, rash, malaise, headache, abdominal pain, and nausea/vomiting. The presence of three or more symptoms between the 5th to 20th days after snake envenoming was defined as serum sickness. We were able to contact 98/122 (80%) patients who received antivenom and 423/588 (72%) who did not receive antivenom during the study period. The treated patients received a median dose of 20 vials (interquartile range: 20–30) of Indian polyvalent antivenom and of them, 92 (92%) received premedication. However, 67/98 (68%) developed acute adverse reactions to antivenom, including 19/98 (19%) developing anaphylaxis. Only 4/98 (4%) who received antivenom met the criteria for serum sickness, compared to none who did not receive antivenom therapy. All patients who developed serum sickness were envenomed by Russell's vipers, were premedicated, and received VINS Bioproducts antivenom. Three of them were treated with hydrocortisone in the acute stage, as premedication or as a treatment for acute adverse reactions of antivenom. Although all four patients sought medical advice for their symptoms, only one was clinically suspected to be serum sickness and treated, while the others were treated for infections. We confirmed that Indian polyvalent antivenom use in Sri Lanka is associated with high rates of acute adverse reactions. In contrast to studies of other antivenoms only a small proportion of patients developed serum sickness. [ABSTRACT FROM AUTHOR]

Snakebite is a neglected public health issue causing death and disability, disproportionately affecting tropical and subtropical resource poor countries globally. Snakebite-associated thrombotic microangiopathy (TMA) occurs in a subset of snakebites and is associated with acute kidney injury (sometimes requiring renal replacement therapy) and a risk of chronic kidney disease. This expert review synthesizes current evidence on therapeutic interventions in snakebite-associated TMA via PubMed search for cohort studies and randomized controlled trials (RCTs) in snakebite-associated TMA from 1970 to October 2022. There are no interventional RCTs in snakebite-associated TMA. Recent cohort studies from Sri Lanka, India, and Australia report clinical and laboratory endpoint outcomes for intervention with antivenom and therapeutic plasma-exchange (TPE). TPE is a resource intense and costly treatment using large volumes of blood donor plasma. There is no consistent evidence supporting TPE in snakebite-associated TMA with respect to patient survival, dialysis-free survival, or hospital length of stay. Antivenom is the standard of care for patients with snake envenoming, but there is no specific evidence of benefit in snakebite-associated TMA. Emerging new therapies in snakebite more broadly are untested in snakebite-associated TMA. RCTs are needed to improve the evidence for treatment of snakebite-associated TMA. [ABSTRACT FROM AUTHOR]

We aimed to investigate the frequency of serotonin toxicity following overdose of antidepressants that inhibit serotonin reuptake and the factors that influence the probability of serotonin toxicity occurring. This was a retrospective cohort study of overdoses that included selective serotonin reuptake inhibitors (SSRIs) (70%) and serotonin norepinephrine reuptake inhibitors (SNRIs) (30%) admitted to a tertiary toxicology unit over 23 years. A multivariate mixed effects logistic regression model using NONMEM (7.2.0) was used to determine factors that influenced the probability of serotonin toxicity occurring. There were 1978 overdoses in 1520 patients; median age 33 y (range: 13–86 years) and 64% female. Median defined daily dose equivalent (DDD) was 15 (1–420). Co-ingestants were taken in 1678/1978 (85%) overdoses: 11 co-ingested the monoamine oxidase-A inhibitor (MAOI) moclobemide, 99 (5%) co-ingested olanzapine, 58 (3%) co-ingested risperidone and 417 co-ingested a benzodiazepine (21%). Serotonin toxicity occurred in 269 overdoses (13.6%). The probability of serotonin toxicity increased slightly per 10 DDD units dose [OR, 1.01; 95% confidence intervals (CIs): 0.93–1.10], increased for an SNRI vs. an SSRI [OR, 1.07; 95% CI: 0.99–1.15], and markedly increased with co-ingestion of moclobemide [OR, 33.12; 95% CI: 7.5–147]. The probability decreased per 10 y age [OR, 0.84; 95% CI: 0.74–0.95], and with co-ingestion of the serotonin 2 A receptor (5-HT2A) antagonists olanzapine [OR, 0.40; 95% CI: 0.17–0.94] or risperidone [OR, 0.13; 95% CI: 0.02–0.99]. The probability of serotonin toxicity was 12.5% at 1 DDD (therapeutic), 12.7% at 15 DDDs and 19% at 420 DDDs. In overdoses of the median dose of 15 DDDs, co-ingestion of moclobemide increased the probability to 83%, and co-ingestion of olanzapine or risperidone decreased it to 5.5% and 1.8%, respectively. Serotonin toxicity is common following SSRI/SNRI overdose. Although dose increases probability, this was only a small effect. Co-ingestion with olanzapine or risperidone reduced the risk 2–6-fold, and moclobemide increased the risk 5-fold. [ABSTRACT FROM AUTHOR]

There is limited information on the risk of chronic kidney disease (CKD) following snakebite and its relationship with chronic interstitial nephritis in agricultural communities (CINAC). We aimed to investigate CKD in patients with a confirmed snakebite in rural Sri Lanka. Patients prospectively recruited to the Anuradhapura snakebite cohort with authenticated bites were followed up. Two groups of patients were followed up: 199 patients in group I with a snakebite (August 2013–October 2014), reviewed after 4 years, and 168 patients in group II with a snakebite (May 2017–August 2018), reviewed after one year, with serum creatinine (estimated glomerular filtration rate [eGFR]) and urinary albumin to creatinine ratio (ACR). There were 12/199 (6%) in group I and 9/168 (5%) in group II with AKI following snakebite; 3/12 in group I and 2/9 in group II had haemodialysis. On review after 1 and 4 years, no patient had CKD and all had an eGFR ≥60 mL/min/1.73m2. Of 234 patients with a creatinine measured on discharge, 17/140 in group I and 11/94 in group II had a low eGFR (<60mL/min/1.73m2). In group I, 14/17 had a normal eGFR after four years, including 11/12 who had AKI following snakebite, and the 3/17 with a low eGFR on review had CKD or co-morbidities for CKD. In group II, 10/11 had a normal eGFR after one year, including all nine patients with AKI following snakebite, and the one patient with a low eGFR on review had CKD. Fifty patients (25%) in group I and 43 (26%) in group II had a high urinary ACR on review, all but two in each group had microalbuminuria. Multivariate logistic regression showed in group I that only comorbidities for CKD were associated with high urinary ACR, and in group II comorbidities for CKD, snakebite associated AKI and snake type were associated with high urinary ACR. All nine patients from both groups with a low eGFR (CKD stages 3–5) had CKD prior to the snakebite or treatment for hypertension or diabetes. There was no significant association between snakebite-associated AKI and CKD in patients followed up from a snakebite cohort post-bite. Microalbuminuria was common in these patients but likely associated with hypertension, diabetes mellitus and CINAC in this rural farming population. [ABSTRACT FROM AUTHOR]

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

The whole blood clotting test (WBCT) is commonly used for diagnosing venom-induced consumption coagulopathy (VICC) in resource-poor settings. We aimed to investigate the diagnostic accuracy of the WBCT and capillary blood clotting test (CBCT) for detecting VICC in viper envenoming in Sri Lanka. All confirmed snakebites admitted to Teaching Hospital Anuradhapura from July 2020 to June 2021 were included. On admission, WBCTs after 15, 20 and 25 min observation times (WBCT-15, WBCT-20 and WBCT-25) and CBCT observed in 30 s intervals (CBCT-t), 5 and 10 min CBCT (CBCT-5 and CBCT-10) were done. Blood was collected simultaneously for prothrombin time (PT)/international normalized ratio (INR) and plasma fibrinogen. We defined VICC as an INR >1.5 (Incomplete VICC = INR>1.5 and complete VICC = ≥3.0). A total of 272 confirmed snakebites (Russell's viper[76], hump-nosed viper[89], non-venomous snakes[51] and unidentified bites[56]) were recruited (median age: 42 y [interquartile range: 30- 53 y]; 189 males [69%]). On admission, 82 (30%) had incomplete VICC (INR >1.5 and <3) and 77 (28%) had complete VICC (INR ≥3). Sixteen (6%) developed clinically apparent bleeding. The WBCT-15 had the best sensitivity of 47% for detecting VICC and 68% for complete VICC. The sensitivities of the WBCT-20, WBCT-25, CBCT-5 and CBCT-10 was 30–35%. The sensitivities of all tests were better in detecting complete VICC, VICC in Russell's viper bites and more than 2 h post-bite. The WBCT-15 test had a sensitivity of 76% for VICC in confirmed Russell's viper bites. For detection of VICC, CBCT-t had an an excellent sensitivity of 97%, but a poor specificity of 35% for an optimal cut-off of >6.25 min. WBCTs are poorly diagnostic for VICC in Russell's viper and hump-nosed viper envenoming, missing up to two-thirds of patients for some tests. The WBCT-15 was the best test, improving for more severe VICC and greater than 2 h post-bite. [ABSTRACT FROM AUTHOR]

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

For acute digoxin poisoning, it has been recommended to give bolus doses of 10–20 vials or potentially larger than needed doses calculated from dose ingested or the measured concentration. However, a recent revision of internal Poisons Information Centre guidelines prompted a change of our recommendations, specifically instead of large boluses, to use titrating repeated low doses of digoxin antibodies(Digoxin-Fab) based on bedside assessment of cardiac toxicity. This is a prospective observational study of patients with acute digoxin poisoning identified through two Poisons Information Centres and three toxicology units. Patient demographics, signs and symptoms of digoxin toxicity, doses and response to Digoxin-Fab, free and bound serum digoxin concentrations. Outcomes were recorded and analysed. From September 2013 to September 2020, 23 patients with 25 presentations (median age 56 years, females 56%) were recruited. Median dose ingested was 13 mg(IQR: 9.5–25). Median heart rate (HR) was 41 beats/min before treatment. Initial median digoxin and potassium concentrations were 14.5 nmol/L (IQR: 10.9–20) [11.2 µg/L(IQR: 8.4–15.4)] and 5 mmol/L (IQR: 4.5–5.4 mmol/L), respectively. Gastrointestinal symptoms and acute kidney injury were present in 22 patients (88%) and 5 patients (20%), respectively. Four patients received an initial bolus dose of Digoxin-Fab of 5–20 vials. Twenty-one patients received repeated titrated doses (1–2 vials) of Digoxin-Fab and the median total dose was 4 vials (IQR: 2–7.5). Median maximal change in HR post-Digoxin-Fab was 19 beats/min. The median potassium concentration decrease post-Digoxin-Fab was 0.3 mmol/L. Total dose used in the titration group was 25% and 35% of the predicted doses based on the amount of digoxin ingested or measured serum concentration, respectively. Twelve had free digoxin concentrations measured. Free digoxin concentrations dropped to almost zero after any dose of Digoxin-Fab. Ten patients had a rebound of digoxin >2.6 nmol/L (2 µg/L). There were no deaths from acute digoxin toxicity. The new practice of using small, titrated doses of Digoxin-Fab led to a considerable reduction in total usage and major savings. The clinical response to titrated doses was safe and acceptable in acute digoxin poisoning. [ABSTRACT FROM AUTHOR]

Snakebite-associated thrombotic microangiopathy (TMA) occurs in a subset of patients with venom-induced consumption coagulopathy (VICC) following snakebite. Acute kidney injury (AKI) is the commonest end-organ manifestation of TMA. The epidemiology, diagnostic features, outcomes, and effectiveness of interventions including therapeutic plasma-exchange (TPE), in snakebite-associated TMA are poorly understood. We reviewed all patients with suspected or confirmed snakebite recruited to the Australian Snakebite Project (2004-2018 inclusive), a prospective cohort study, from 202 participating Australian hospitals across the country. TMA was defined as anemia with schistocytosis. 2069 patients with suspected snakebite were enrolled, with 1158 (56.0%) systemically envenomed, of which 842 (72.7%) developed VICC, from which 104 (12.4%) developed TMA. Of those systemically envenomed, TMA occurred in 26% (13/50) taipan, 17% (60/351) brown, and 8% (16/197) tiger snakebites. Thrombocytopenia was present in 90% (94/104) of TMA cases, and a further eight (8%) had a > 25% decrease in platelets from the presentation. Patients with TMA were significantly older than non-TMA patients with VICC (53 [35–61] versus 41 [24–55] years, median [IQR], p < 0.0001). AKI developed in 94% (98/104) of TMA patients, with 34% (33/98) requiring dialysis (D-AKI). There were four deaths. In D-AKI TMA cases, eventual dialysis-free survival (DFS) was 97% (32/33). TPE was used in five D-AKI cases, with no significant difference in DFS or time to independence from dialysis. >90-day follow-up for 25 D-AKI cases (130 person-years) showed no end-stage kidney disease but 52% (13/25) had ≥ stage 3 chronic kidney disease (CKD). Our findings support a definition of snakebite-associated TMA as anemia with schistocytosis and either thrombocytopenia or >25% drop in platelet count. AKI occurring with snakebite-associated TMA varied in severity, with most achieving DFS, but with a risk of long-term CKD in half. We found no evidence of benefit for TPE in D-AKI. [ABSTRACT FROM AUTHOR]

Overdose with paracetamol modified-release (MR) formulation, a bilayer tablet containing 69% slow-release component, has been increasing since its introduction to the market. However, little evidence exists for the management of MR paracetamol overdose. We aimed to develop a population pharmacokinetic (PK) model for immediate-release (IR) and MR paracetamol and its major metabolism, and quantitatively understand the formulation difference in toxicity assessment based on the nomogram line. Data from a cross-over study design in nine healthy volunteers administered a single supratherapeutic oral dose (80 mg/kg) of either IR and MR paracetamol were available from a published study. Plasma concentrations for paracetamol and its metabolites glucuronide (APAPG) and sulfate conjugate (APAPS) for both formulations were measured and analysed with population pharmacokinetic (PK) method using NONMEM. Toxicity in both formulations was assessed by comparing the simulated paracetamol concentrations under different paracetamol dose levels with the 150 mg/L nomograms. The difference in the assessment was compared between the two formulations. Paracetamol concentrations for the IR formulation were described with a two-compartment model with first-order input and a lag time. The delayed time-course of MR paracetamol concentrations was best captured by a parallel absorption model in which the slow-release component was a serial zero-order then the first-order process. The formation of APAPG was linear, while APAPS concentrations were best fitted by a Michaelis-Menten process. The relative bioavailability of MR paracetamol compared to IR ( F M R / I R ) was estimated as 0.81. The simulated probability of making different toxicity assessments based on nomogram line was increased with dose levels and was as high as 14.6% after 22 g IR or MR paracetamol ingested. A joint parent-metabolite model to describe time-course profiles of both IR and MR paracetamol and its metabolites APAPG and APAPS concentrations was developed. Simulations from the model showed that toxicity assessment based on the 150 mg/L nomograms is not suitable in MR paracetamol overdoses. [ABSTRACT FROM AUTHOR]

Understanding the time course of venom exposure in snakebite patients is important for the optimisation of treatment including antivenom dose and timing. We aimed to investigate the pharmacokinetics of red-bellied black snake (RBBS; Pseudechis porphyriacus) venom in envenomed patients. Timed venom concentration data were obtained from patients with RBBS envenomation recruited to the Australian Snakebite Project (ASP), including demographics and antivenom treatment. Venom concentrations were measured using an enzyme immunoassay. Data were modelled using NONMEM version 7.3. Uncertainty in venom "dose" was accounted for by arbitrarily fixing the average amount to 1 mg and incorporating between-subject variability on relative bioavailability. A scale parameter for venom clearance was implemented to account for the rapid venom clearance following antivenom dosing. A sensitivity analysis was performed to determine the magnitude of venom clearance amplification. There were 457 venom concentrations in 114 patients (median age 41, 2–90 y; 80 male). Antivenom was administered to 54 patients a median of 4.2 h post-bite (0.67 to 32 h). A one-compartment model with first-order absorption and elimination provided the best description of the data. The estimated clearance and volume of distribution were 5.21 L/h and 39.9 L, respectively. The calculated elimination half-life of P. porphyriacus venom from the final pharmacokinetic model was 5.35 ± 0.36 h. The variability in the relative dose of injected venom was 140%. Antivenom administration increased venom clearance by 40-fold. Ten patients showed evidence of a double peak in the absorption profile. The information on the exposure time of venom in the body following envenomation will help improve treatment and the timing of antivenom. [ABSTRACT FROM AUTHOR]

Myotoxicity is a recognised but poorly characterised effect of snake envenoming worldwide. We aimed to describe the clinical effects, complications and effectiveness of antivenom in myotoxicity from Australian snake envenoming. Patients were recruited to the Australian Snakebite Project (ASP), a prospective, observational study of patients with suspected or proven snakebite countrywide. After informed consent data is collected and stored in a dedicated database and blood samples are taken and stored. We included patients with envenoming and biochemical evidence of myotoxicity (peak creatine kinase [CK] > 1000 U/L). Snake species was determined by expert identification or venom specific enzyme immunoassay. Analysis included patient demographics, clinical findings, pathology results, treatment and outcomes (length of hospital stay, complications). 1638 patients were recruited January 2003–December 2016, 935 (57%) were envenomed, 148 developed myotoxicity (16%). Snake species most commonly associated with myotoxicity 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%). 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. [ABSTRACT FROM AUTHOR]

Amlodipine, a dihydropyridine calcium channel blocker (CCB), is the leading cause of cardiovascular drug-related overdose deaths in the USA. In contrast, angiotensin-II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) cause minimal toxicity in overdose. ACEIs/ARBs are often combined with dihydropyridines in hypertension treatment. Co-ingested ARBs/ACEIs may significantly contribute to the toxicity of dihydropyridine, but this has not been investigated. To investigate the clinical outcomes from dihydropyridine overdoses with ARBs/ACEIs versus dihydropyridine overdoses alone. This was a retrospective study of patients reported to the New South Wales Poisons Information Centre (NSW PIC) and 3 toxicology units (Jan 2016 to Jun 2019) in Australia. Patients >14 years who took an overdose of dihydropyridines (amlodipine, felodipine, lercanidipine, nifedipine) were included. Concurrent overdoses with non-dihydropyridine CCBs, alpha-blockers and beta-blockers were excluded. Patient demographics, drugs exposure details, serial vital signs, treatments and outcome were collected. There were 100 patients. 68 took mixed overdoses of dihydropyridines with ARBs/ACEIs and 32 took single overdoses of dihydropyridines without ARBs/ACEIs. The mixed group had lower median nadir mean arterial pressures (62 vs 75 mmHg, p < 0.001), more frequently had hypotension (OR 4.5, 95%CI: 1.7–11.9) or bradycardia (OR 8.8, 95%CI: 1.1–70). Multivariable analysis indicated the mixed overdoses had an 11.5 mmHg (95%CI: 4.9–18.1) lower minimum systolic blood pressure (SBP) compared with the single group; other factors associated with a lower minimum SBP were higher doses [2.3 mmHg (95%CI: 1.1–3.5) lower per 10 defined daily doses] and younger age [2.2 mmHg (95%CI: 0.3–4.2) higher per decade]. A larger proportion of the mixed ingestion group received intravenous fluids (OR 5.7, 95%CI: 1.8–18.6) and antidotes and/or vasopressors (OR 2.9, 95%CI: 1.004–8.6). Combined overdoses of dihydropyridines with ARBs/ACEIs caused more significant hypotension and required more haemodynamic support than overdoses of dihydropyridines alone. [ABSTRACT FROM AUTHOR]

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. 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). 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. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Envenoming by hump-nosed pit vipers (genus Hypnale) causes local effects, mild coagulopathy, and rarely, acute kidney injury. Neuromuscular dysfunction has not been clinically reported but, in vitro studies show a weak, reversible, neurotoxic effect on the neuromuscular junction. We investigated the neuromuscular dysfunction in H. hypnale envenoming. Eighteen patients with authenticated H. hypnale envenoming were included. All 18 had serial clinical and neurological examinations. We evaluated neuromuscular dysfunction using stimulated concentric needle single-fibre electromyography (sfEMG) of orbicularis oculi in the patients within two days of the bite and compared to 29 normal subjects. Patients with abnormal jitter were reviewed six weeks later. All 18 patients had local effects and one-third had non-specific systemic symptoms. No patient had clinical features of neuromuscular paralysis. Median jitter values of patients were statistically significantly higher than normal subjects (19.6 ± 13.0 µs compared with 15.6 ± 7.4 µs.). None of the patients or normal subjects had neuromuscular blocks. Three patients had median jitter values higher than the maximum in normal subjects, which returned to normal by six weeks. H. hypnale envenoming leads to sub-clinical neuromuscular dysfunction, despite patients not showing any clinically detectable neurotoxicity. [ABSTRACT FROM AUTHOR]

Background: Repeated supratherapeutic ingestion (RSTI) of paracetamol can result in acute liver injury. Management guidelines vary worldwide and in Australia, acetylcysteine treatment is recommended in patients with a paracetamol concentration ≥20 mg/L and/or alanine transaminase (ALT) ≥50 U/L. Objectives: To investigate patients with RSTI of paracetamol and determine whether admission ALT <50 U/L rules out those who develop hepatotoxicity (ALT >1000 U/L). Method: Retrospective review of paracetamol RSTI presentations to two toxicology services over a four-year period. Patients were included if they ingested >4 g per 24 h of paracetamol for a period >8 h, regardless of intent. Data collected included demographics, ingestion history, pathology results, treatments and outcomes. Results: 266 patients were identified with median ingested dose of 9 g per 24 h (IQR: 6–12 g) over a median of 2 days (IQR: 1–5 days). On presentation, paracetamol was detected in 192 (72%), with median concentration of 14 mg/L (IQR: 7–27 mg/L). Median ALT on admission in those developing hepatotoxicity was significantly higher, 1182 U/L (IQR: 598–4251 U/L), compared to 30 U/L (IQR: 18–59 U/L; p <.0001) in those who did not. All 17 who developed hepatotoxicity had an ALT ≥50 U/L on presentation. Five patients presenting with an ALT <50 U/L developed a peak ALT between 50 and 1000 U/L, of which three had a paracetamol concentration <20 mg/L. 139 (52%) received acetylcysteine, of which 64 received an abbreviated course (<20 h), with a median length of infusion of 11 h (IQR: 7–14 h). 127 (48%) patients were not treated with acetylcysteine, none of these patients returned to hospital. Conclusions: Our results confirm that those developing hepatotoxicity from RSTI of paracetamol have an elevated ALT on presentation. Presenting ALT <50 U/L appears to be a safe threshold not to administer acetylcysteine, provided the paracetamol concentration is low. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

Context: Ingestion of bromoxynil and 2-methyl-4-chlorophenoxyacetic acid (MCPA) in combination is associated with high mortality. Toxicity is characterised by hyperthermia and metabolic acidosis. Dialysis is a proposed treatment, but little data exist regarding its effectiveness. Case details: Case 1: A 50-year-old female presented 18 h post-ingestion of 200  mL of bromoxynil(200 g/L) and MCPA(200 g/L). She was agitated, tachycardic and tachypnoeic. She was intubated and continuous venovenous haemodiafiltration (CVVHDF) was commenced. She deteriorated, becoming hypotensive, hyperthermic (39.5 °C) and hypercapnic (80 mmHg). She was cooled, paralysed, received CVVHDF for 2d and was extubated on day 4 making a full recovery. Case 2: A 60-year-old male presented 6 h post-ingestion of an unknown amount of bromoxynil (200 g/L) and MCPA (200 g/L). On arrival, he was tachycardic and tachypneic (pCO2 25 mmHg). At 8h post-ingestion he became hyperthermic, hypercapnic and acidotic (pH 7.15), and was intubated, paralysed, cooled and received CVVHDF for 36 h. He was extubated after 42 h and made a full recovery. Bromoxynil and MCPA serum and effluent concentrations were measured. Peak MCPA serum concentrations were 161 µg/ml and 259 µg/ml and peak bromoxynil concentrations were 119 µg/ml and 155 µg/ml in case 1 and 2, respectively. The estimated clearance of both herbicides by CVVHDF was low (<10 mL/min). Conclusion: CVVHDF did not result in significant clearance of either herbicide but may have assisted with hyperthermia control. Both patients survived with vigorous cooling, paralysis and ventilatory support. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Context:Taipans (Oxyuranusspp.) 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. [ABSTRACT FROM PUBLISHER]

Context:Poisoning due to chloroform ingestion is rare. The classic features of acute chloroform toxicity include central nervous system (CNS) and respiratory depression, and delayed hepatotoxicity. Case details:A 30-year-old female ingested 20–30 mL of 99% chloroform solution, which caused rapid loss of consciousness, transient hypotension and severe respiratory depression requiring endotracheal intubation and ventilation. She was alert by 12 h and extubated 16 h post-overdose. At 38-h post-ingestion, her liver function tests started to rise and she was commenced on intravenous acetylcysteine. Her alanine transaminase (1283 U/L), aspartate transaminase (734 U/L) and international normalized ratio (2.3) peaked 67- to 72-h post-ingestion. She also developed severe abdominal pain, vomiting and diarrhoea. An abdominal CT scan was consistent with severe enterocolitis, and an upper gastrointestinal endoscopy showed erosive oesophagitis, severe erosive gastritis and ulceration. She was treated with opioid analgesia, proton pump inhibitors, sucralfate and total parenteral nutrition. Secretions caused a contact dermatitis of her face and back. Nine days post-ingestion she was able to tolerate food. Her liver function tests normalized and the dermatitis resolved. Chloroform was measured using headspace gas chromatograph mass spectrometry, with a peak concentration of 2.00 μg/mL, 4 h 20 min post-ingestion. The concentration-time data fitted a 1-compartment model with elimination half-life 6.5 h. Discussion:In addition to early CNS depression and delayed hepatotoxicity, we report severe gastrointestinal injury and dermatitis with chloroform ingestion. Recovery occurred with good supportive care, acetylcysteine and management of gastrointestinal complications. [ABSTRACT FROM PUBLISHER]

Objective:Acute beta-blocker overdose can cause severe cardiac dysfunction. Chronic toxicity is rare but potentially severe. We report therapeutic dosing of metoprolol resulting in unusual pharmacokinetics and toxicity, given high-dose insulin therapy for treatment. Case details:A 90-year-old female presented with hypotension, tachycardia and severe cardiac dysfunction after commencing a rapidly increasing metoprolol dose of 250 mg split daily. She was admitted to intensive care and given high-dose insulin therapy (10 U/kg/h), noradrenaline, adrenaline and dobutamine for severe cardiac dysfunction (cardiac index, 0.76 L/min/m2). She developed acute renal failure, ischaemic hepatitis and disseminated intravascular coagulopathy. Inotropes and high-dose insulin were weaned over four days with complete recovery. Metoprolol was quantified with liquid chromatography-tandem mass spectrometry and concentration-time data were analysed using MONOLIX®vs 4.3 (www.lixoft.com). Admission metoprolol concentration was 2.39 μg/mL (therapeutic reference range: 0.035–0.5 μg/mL). Data best fitted a one compartmental model with Michaelis–Menten kinetics and zero order elimination at high concentrations. Final parameter estimates were V, 63.4 L, maximum rate [Vm], 9.57 mg h−1, Michaelis constant [Km], 1.97 mg L−1. Predicted elimination half-life decreased from 20 h over time until there was first order elimination with a half-life 9 h. Conclusion:The time course of cardiac dysfunction was longer than acute overdose but consistent with prolonged zero order elimination of metoprolol, suggesting the patient was a poor CYP2D6 metaboliser. High-dose insulin euglycaemia appeared to be effective in combination with vasoconstrictors/inotropes. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM PUBLISHER]

Context: Russell’s viper is more medically important than any other Asian snake, due to number of envenoming’s and fatalities. Russell’s viper populations in South India and Sri Lanka (Daboia russelii) cause unique neuromuscular paralysis not seen in other Russell’s vipers.Objective: To investigate the time course and severity of neuromuscular dysfunction in definite Russell’s viper bites, including antivenom response.Methodology: We prospectively enrolled all patients (>16 years) presenting with Russell’s 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 Russell’s 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 Russell’s 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 FROM PUBLISHER]

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 relatedD. devisivenom 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 interpolateDenisoniavenom concentrations.In vitroprocoagulant and anticoagulant activity of venom was assayed.Results:Denisoniavenom was detected in the pre-antivenom sample as 9.6 ng/mLD. devisivenom. No antigenic venom components were detected in post-antivenom samples and there were high antivenom concentrations.D. devisivenom had mildin vitroprocoagulant activity with a minimum concentration required to clot after 5 min of 2.5–5 μg/mL and even weaker anticoagulant activity.Conclusions:Denisoniabites 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. [ABSTRACT FROM AUTHOR]

Context: Funnel-web spider (AtraxandHadronychespp.) envenoming is rare but causes severe neuromuscular, autonomic, and cardiac effects. A rabbit-derived IgG antivenom is available, but venom detection in patients has not been reported.Objective: To use serial venom and antivenom concentrations to better define envenoming and antivenom effectiveness.Materials and methods: Serum was collected from nine patients with suspected funnel-web spider bites and clinical effects were recorded. Venom-specific enzyme immunoassays were developed to measure funnel-web spider venom and antivenom concentrations. Goat anti-rabbit whole serum was coupled to UltraLink resin and added to samples to remove bound venom and measure free venom. Antivenom efficacy was defined as antivenom binding all free venom and antivenom effectiveness as resolution of clinical features.Results: Venom was detectable in samples from six of nine patients. In three patients without venom detected, there were only moderate effects, which did not completely respond to antivenom in all cases and no spider was identified. In five of six cases, a maleAtraxspp. (Sydney funnel-web) spider was identified. Three patients had moderate envenoming which responded to antivenom. Three patients had severe envenoming and developed catecholamine-induced myocarditis and acute pulmonary oedema. Although cholinergic and non-specific clinical features appeared to respond to antivenom, myocarditis and pulmonary oedema lasted 2–4 days. Median venom concentration pre-antivenom in five patients with samples was 5.6 ng/ml (3–35 ng/ml), and immediately post-antivenom decreased to a median of 0 ng/ml (0–1.8 ng/ml). Post-antivenom venom concentrations decreased when bound venom was removed; median, 0 ng/ml (0–0.9 ng/ml), indicating that most venom detected post-antivenom was bound. There was recurrence of venom and clinical features in one patient when a pressure bandage was removed.Conclusions: Detection of venom in suspected funnel-web spider bites identified definite cases with characteristic envenoming and a spider was identified. Measurement of venom concentrations pre- and post-antivenom demonstrated that venom was bound by antivenom, but in severe cases cardiac toxicity was not reversed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

The article presents a case study of the toxicity caused by Bromoxynil and 2-methyl-4-chlorophenoxyacetic acid (MCPA) poisoning in several patients. The article discusses how MCPA and bromoxynil can cause cellular dysfunction with MCPA appearing to cause gastrointestinal effects resulting in hypovolemia, rhabdomyolysis, renal failure and hepatitis.

The article presents abstracts on medical topics which include an online poison information web resource, Russell's viper envenomation, and alcohol-related emergency department visits.

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. [ABSTRACT FROM AUTHOR]

Context. Methanol and ethylene glycol cause significant mortality post-ingestion. Predicting prognosis based on the biomarkers osmolal gap, anion gap and pH is beneficial. Objective. To evaluate the relationship between biomarkers, measured post-methanol and ethylene glycol exposure, and clinical outcomes. Methods. A review of the literature identified cases where methanol or ethylene glycol had been ingested and clinical outcomes were recorded. Biomarkers were extracted including osmolal gap, anion gap and pH, with clinical outcomes categorised as recovered, recovered with adverse sequelae and death. Biomarkers were analysed using the Mann-Whitney test for two samples; sensitivity and specificity were evaluated using receiver operating characteristic (ROC) curves. Results. In total, 119 cases of methanol and 88 of ethylene glycol poisoning were identified; 21 methanol and 19 ethylene glycol patients died. For methanol ingestion the mean values, for survival compared to death, were 48 (range: 6-138) and 90 (range: 49-159) mOsm/kg water for osmolal gap (p==0.0052), 31 (range: 11-50) and 41 (range: 30-53) mmol/L for anion gap (p==0.0065) and 7.21 (range: 6.60-7.50) and 6.70 (range: 6.34-7.22) for arterial pH (p<0.0001). The area under the ROC curve was highest for arterial pH, 0.94 (95% CI: 0.89-0.99). For ethylene glycol, these were 49 (range: 0-189) and 79 (range: 25-184) mOsm/kg water for osmolal gap (p==0.050), 28 (range: 6-48) and 38 (range: 20-66) mmol/L for anion gap (p==0.0037) and 7.08 (range: 6.46-7.39) and 6.98 (range: 6.50-7.16) for pH (p==0.072), for survival compared to death. The area under the ROC curve was highest for anion gap, 0.73 (95% CI: 0.60-0.87). Conclusion. Post-methanol ingestion a large osmolal gap, anion gap and low pH (<7.22) were associated with increased mortality; and pH has the highest predictive value. Post-ethylene glycol ingestion, both osmolal gap and anion gap were associated with increased mortality. [ABSTRACT FROM AUTHOR]

Context. Current treatment of paracetamol (acetaminophen) poisoning involves initiating a 3-phase N-acetylcysteine (NAC) infusion after comparing a plasma concentration, taken ≥4 h post-overdose, to a nomogram. This may result in dosing errors, a delay in treatment, or possibly more adverse effects - due to the use of a high dose rate for the first infusion when treatment is initiated. Objective . Our aim was to investigate a novel dosing regimen for the immediate administration of NAC on admission at a lower infusion rate. Methods . We used a published population pharmacokinetic model of NAC to simulate a scenario where a patient presents to the hospital 2 h post-overdose. The conventional regimen is commenced 6 h post-overdose when the 4-h plasma paracetamol concentration is available. We investigated an NAC infusion using a lower dosing rate initiated immediately on presentation. We determined a dosing rate that gave an area under the curve (AUC) of the concentration-time curve that was the same or greater than that from the conventional regimen on 90% of occasions. Results . Lower dosing rates of NAC initiated immediately resulted in a similar exposure to NAC. An infusion of 110 mg/kg over the first 5 h (22 mg/kg/h) followed by the last two phases of the conventional regimen, or 200 mg/kg over 9 h (22.6 mg/kg/h) followed by the last phase of the conventional regimen could be used. Conclusion . The novel dosing regimen allowed immediate treatment of a patient using a lower dosing rate. This greatly simplifies the current dosing regimen and may reduce NAC adverse effects while ensuring the same amount of NAC is delivered. [ABSTRACT FROM AUTHOR]

Objective: To describe the cardiovascular toxicity and pharmacokinetics of levetiracetam in overdose.Case Report: A 43-year-old female presented 8 h post ingestion of 60–80 g of levetiracetam with mild central nervous system depression, bradycardia, hypotension and oliguria. Her cardiovascular toxicity transiently responded to atropine and intravenous fluids. A bedside echocardiogram demonstrated normal left and right ventricular contractility. Despite her cardiovascular toxicity and oliguria, she had normal serial venous lactates and renal function; and made a complete recovery over 48 h. Her levetiracetam concentration was 463 mcg/ml 8 h post ingestion (therapeutic range 10–40 mcg/ml) and her concentration–time data best fitted a one-compartment model with first-order input and an elimination half-life of 10.4 h.Discussion: Levetiracetam in large ingestions appears to cause bradycardia and hypotension that is potentially responsive to atropine and intravenous fluids. Based on a normal echocardiogram, the mechanism for this effect may be levetiracetam acting at muscarinic receptors at high concentration. The pharmacokinetics of levetiracetam in overdose appeared to be similar to therapeutic levetiracetam dosing. [ABSTRACT FROM AUTHOR]

Objectives. To assess interobserver agreement when trained healthcare staff measure the QT interval using a standardized approach across a range of QT lengths. Methods. A sample of 110 electrocardiograms (ECGs) was taken from general and psychotropic overdose admissions to the emergency department including drugs known to cause QT prolongation and Torsades de Pointes. Four of the authors measured the QT interval in all ECGs using a previously developed approach. Each rater was blinded to the ECG admission details and the measurements of the other raters. The primary outcome was the inter-rater agreement for the median QT and interobserver classification as to whether the QT interval was abnormal or not, based on the QT nomogram. Results. There was good agreement between raters (intraclass correlation coefficient, 0.61; 95% CI = 0.53 to 0.69). When classifying the QT as abnormal there was good agreement between the raters with a Fleiss' kappa of 0.61. There was perfect agreement between all four raters on 86 of 110 ECGs (78.2%), agreement between three raters on 18 of 110 (16.3%), and a split between the four on 6 of 110 (5.5%). Disagreement between the automated QT measurement and the majority of the raters was slightly more than within raters. Conclusions. The study demonstrates that there is good agreement between trained observers when manually measuring the QT interval using a standardized approach. This provides an inexpensive method for the measurement of QT in clinical studies of drug overdose and a potentially useful approach in the clinical assessment of patients with possible QT prolongation. [ABSTRACT FROM AUTHOR]

Traditionally animals and cell cultures have been used to assess the toxic potential of xenobiotics on cell membranes. In search for more reproducible, quantitative, cost- and time-effective assays, toxicologists have recently become interested in biomimetic lipid vesicle-based test systems. Lipid vesicles (liposomes) have long been appreciated as simple cell membrane models in biochemical and biophysical studies providing a good understanding of the physicochemical properties of liposome systems. More recently a number of reports have been published on the interactions of toxic substances with vesicles. Literature reports on liposome assays have appeared for widely different classes of xenobiotics, such as dental materials, antibiotics, detergents, and peptides. In this review we focus on those reports that contain a quantitative and significant correlation with more established toxicological tests like cell culture assays. We provide an introduction to the structure and main characteristics of vesicles and related lipid aggregates. The two main assays presented are leakage of fluorescence dyes and differential scanning calorimetry (DSC) measurements of the solid-ordered/liquid-disordered main phase transition temperature (Tm). [ABSTRACT FROM AUTHOR]

Background. Methyl parathion is classed as an extremely hazardous pesticide with a rodent LD50 of 6 to 24 mg/kg. It has been banned in numerous countries, but there are few reports of acute methyl parathion poisoning. Methods. Plasma cholinesterase and acetylcholinesterase were measured in blood. Methyl parathion and the major metabolite 4-nitrophenol where measured in serum and urine. Based on the available concentration-time data, the pharmacokinetic parameters of methyl parathion were estimated for this patient. Case Report and Results. A 29-year-old male ingested 50 to 100mL (12 to 24 g) of methyl parathion causing delayed and prolonged suppression of acetylcholinesterase but almost no clinical effects. Absorption was predicted to last for 30 hours and the bioavailability appeared to be very low. Conclusions. Although it is feasible the patient ingested much less, a tenth of his alleged ingestion dose is more than the oral LD50 in rats. Methyl parathion appears to be less toxic in humans than parathion for similar amounts ingested, which is not consistent with the two pesticides having similar rodent LD50. [ABSTRACT FROM AUTHOR]

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have increasingly replaced tricyclic antidepressants (TCAs) in the treatment of depression. They appear to be safer in overdose, but there is little information on their spectrum of toxicity in overdose, or relative toxicity of each agent. OBJECTIVE: To determine the effect of SSRIs in overdose, as a group, and the relative toxicity of five different SSRIs. METHODS: A review of consecutive SSRI poisoning admissions to a single toxicology unit. Outcomes examined were length of stay [LOS], intensive care [ICU] admission rate, coma, seizures, electrocardiographic [ECG] abnormalities, and presence of serotonin syndrome [SS]. Logistic regression was used to model the outcome QTc > 440 msec. RESULTS: There were 469 SSRI poisoning admissions analyzed after exclusions. The median LOS for all SSRI overdose admissions was 15.3 h (IQR: 10.5–21.3) and 30 of 469 (6.4%; 95% CI 4.3–9.0%) cases were admitted to ICU. The incidence of seizures was 1.9% and coma was 2.4%. Serotonin syndrome occurred in 14% of overdoses. Comparison of median QTc intervals of the five SSRIs was significantly different (p = 0.0002); citalopram (450 IQR: 436–484) was individually different to fluoxetine (p = 0.045), fluvoxamine (p = 0.022), paroxetine (p = 0.0002), and sertraline (p = 0.001). The proportion of citalopram overdoses with a QTc > 440 msec was 68%, differing significantly from sertraline (adjusted OR: 5.11 95% CI 2.32–11.27). Comparison of median QT intervals of the five SSRIs was statistically different (p = 0.026); citalopram (400 IQR: 380–440) was individually different from sertraline (p = 0.023). CONCLUSIONS: This study shows SSRIs are relatively safe in overdose despite serotonin syndrome being common. The exception was citalopram, which was significantly associated with QTc prolongation. We believe that cardiac monitoring should be considered in citalopram overdose, particularly with large ingestions and patients with associated cardiac disease. [ABSTRACT FROM AUTHOR]