Acetaminophen Metabolites on Presentation Following an Acute Acetaminophen Overdose (ATOM-7).

Acetaminophen (APAP) is commonly taken in overdose and can cause acute liver injury via the toxic metabolite NAPQI formed by cytochrome (CYP) P450 pathway. We aimed to evaluate the concentrations of APAP metabolites on presentation following an acute APAP poisoning and whether these predicted the subsequent onset of hepatotoxicity (peak alanine aminotransferase > 1,000 U/L). The Australian Toxicology Monitoring (ATOM) study is a prospective observational study, recruiting via two poison information centers and four toxicology units. Patients following an acute APAP ingestion presenting < 24 hours post-ingestion were recruited. Initial samples were analyzed for APAP metabolites, those measured were the nontoxic glucuronide (APAP-Glu) and sulfate (APAP-Sul) conjugates and NAPQI (toxic metabolite) conjugates APAP-cysteine (APAP-Cys) and APAP-mercapturate (APAP-Mer). The primary outcome was hepatotoxicity. In this study, 200 patients were included, with a median ingested dose of 20 g, 191 received acetylcysteine at median time of 5.8 hours post-ingestion. Twenty-six patients developed hepatotoxicity, one had hepatotoxicity on arrival (excluded from analysis). Those who developed hepatotoxicity had significantly higher total CYP metabolite concentrations: (36.8 µmol/L interquartile range (IQR): 27.8-51.7 vs. 10.8 µmol/L IQR: 6.9-19.5) and these were a greater proportion of total metabolites (5.4%, IQR: 3.8-7.7) vs. 1.7%, IQR: 1.3-2.6, P < 0.001)]. Furthermore, those who developed hepatotoxicity had lower APAP-Sul concentrations (49.1 µmol/L, IQR: 24.7-72.2 vs. 78.7 µmol/L, IQR: 53.6-116.4) and lower percentage of APAP-Sul (6.3%, IQR: 4.6-10.9 vs. 13.1%, IQR, 9.1-20.8, P < 0.001)]. This study found that those who developed hepatotoxicity had higher APAP metabolites derived from CYP pathway and lower sulfation metabolite on presentation. APAP metabolites may be utilized in the future to identify patients who could benefit from increased acetylcysteine or newer adjunct or research therapies.

Overdose and off-label psychotropic prescribing in patients with borderline personality disorder: A retrospective series.

OBJECTIVE: Borderline personality disorder (BPD) is common and poses many clinical challenges. Despite limited evidence of effectiveness, psychotropic medications are often prescribed. We aimed to characterise overdose presentations in patients with BPD. METHOD: This is a retrospective observational series of patients with BPD presenting to a tertiary hospital following an overdose from January 2019 to December 2020. Medical records were reviewed to determine baseline characteristics, overdose details, clinical features, treatment, and disposition. RESULTS: There were 608 presentations in 370 people (76% female), median age 28 years (range 16-75 years). The majority (331[89%]) of patients were prescribed at least one psychotropic medication, with 129 (35%) being prescribed three or more different psychotropic agents. Of the total prescribed psychotropics, 520/1459 (36%) were for off-label indications. The majority of agents (860/1487[58%]) taken in overdose were prescribed. The commonest drug classes taken in overdose were benzodiazepines (241[16%]) and antipsychotics (229[15%]). Severe toxicity occurred in 99 (16%) cases with either coma (GCS<9) or hypotension (systolic BP <90 mmHg). The commonest agent associated with severe toxicity was quetiapine 39/99 (39%). CONCLUSIONS: Psychotropic polypharmacy is common in BPD, often with off-label indications. Prescribed medications are commonly taken in overdose. Quetiapine is over-represented both in off-label prescribing and associated harm.

Unintentional paediatric iron poisoning: A retrospective case series.

OBJECTIVE: Iron poisoning is a historically important cause of paediatric morbidity and mortality. In recent decades, public health measures have considerably reduced paediatric iron exposures. We investigated unintentional paediatric iron poisoning in children with the aim of developing an assessment approach specific for this group. METHODS: This was a retrospective observational study of unintentional iron poisoning in children (<7 years old) referred to either a state-wide poisons information service or a tertiary clinical toxicology unit from 1 January 2015 to 16 February 2020. Patients were identified from prospective databases maintained by both services, and data were extracted from these in addition to the medical record. RESULTS: There were 54 children included in the study (29 [54%] male; median age 2 years (range 8 months to 4 years). The median suspected dose of elemental iron ingested was 72 mg/kg (IQR 41-140 mg/kg). Seventeen (31%) children were symptomatic. There were no cases of severe toxicity. Children symptomatic with gastrointestinal toxicity had a median suspected dose ingested of 60 mg/kg (IQR 38-150 mg/kg) that was similar to asymptomatic children (81 mg/kg [IQR 41-143 mg/kg], P = 0.809). The median peak iron concentration was 49 µmol/L (IQR 13.5-67.5 µmol/L, range 4-75 µmol/L). Symptomatic children had a significantly higher median peak serum iron concentration of 66 µmol/L (IQR 54-68 µmol/L) compared to 12 µmol/L (IQR 9-15 µmol/L) in asymptomatic children (P < 0.001). CONCLUSION: Unintentional paediatric iron poisoning is uncommon and largely benign. Suspected dose ingested is a poor predictor of toxicity. Targeting investigations and interventions to symptomatic children should reduce unnecessary assessment and management while still safely managing the exposure.

Oral potassium overdose: a case series.

OBJECTIVE: Severe toxicity from ingestions of oral sustained-release potassium is rare. While acute hyperkalaemia requires urgent intervention given the risk of cardiac toxicity, there is a lack of clinical consensus on optimal management. The aim of this study was to characterise the clinical manifestations of acute potassium overdose and its management approach. METHODS: This is a retrospective case series of patients presenting following oral potassium overdose of ≥6000mg between January 2009 and December 2020 in Queensland, Australia as recorded in the state's Poisons Information Centre database and a tertiary Clinical Toxicology Unit database. Patients were identified from prospective databases maintained by both units and data were extracted from these in addition to medical records. RESULTS: Thirteen presentations in eleven patients occurred in the twelve-year period. The median age was 35 years (range 14-55 years). The median dose ingested was 6.4 mmol/kg (range 0.9-30.8 mmol/kg). Severe hyperkalaemia >7mmol/L occurred in five patients, four with ingestions ≥60,000mg. All patients with hyperkalaemia received multiple modes of intracellular potassium shifting therapy. Four patients had endoscopic removal of pharmacobezoars. One also underwent whole bowel irrigation. Three presentations were managed with haemodialysis. All patients were discharged home with a median length of stay of 20 h. CONCLUSION: Aggressive medical therapy to shift potassium into cells appears to be the mainstay of treatment in patients with normal renal function. Early decontamination may limit peak potassium concentrations. It is unclear if haemodialysis provides significant additional benefit in patients with normal renal function.

Methamphetamine intoxication and acute kidney injury: A prospective observational case series.

AIM: The effects of methamphetamine intoxication on the kidney are not well reported. We aimed to investigate acute kidney injury (AKI) associated with methamphetamine intoxication, in particular its severity, duration and association with rhabdomyolysis. METHODS: This is a prospective observational series of methamphetamine-intoxicated patients presenting to an Emergency Department. Patients self-reporting recent methamphetamine use, with a positive urine drug screen and an elevated creatinine, were eligible for the study. Urinary neutrophil gelatinase-associated lipocalin (NGAL) was measured, and serum creatinine, creatine kinase and cystatin C concentrations were performed on arrival and at several time points until discharge from hospital. Demographic and clinical data were obtained from the medical records. RESULTS: There were 634 presentations with methamphetamine intoxication over a 10-month period, with 73/595(12%) cases having an elevated serum creatinine concentration on arrival. Fifty presentations in 48 patients were included in the study. Most patients (85%) were male with a median age of 32 years. The median serum creatinine concentration on presentation was 125 µmol/L (IQR:113-135 µmol/L) with 45 (90%) presentations meeting diagnostic criteria for AKI. Concurrent rhabdomyolysis occurred in 22 (44%) presentations with a median CK of 2695 U/L (IQR:1598-5060 U/L). Cystatin C was elevated (> 0.98 mg/L) in 18 cases. An elevated NGAL concentration (>150 µg/L) was present in five (10%) cases. No patients required dialysis. The median length of stay was 19 hours (IQR 14-24 hours). CONCLUSION: AKI is common in methamphetamine intoxication. The kidney injury is relatively mild and short-lived, resolving with crystalloid therapy.

Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand.

INTRODUCTION: Paracetamol is a common agent taken in deliberate self-poisoning and in accidental overdose in adults and children. Paracetamol poisoning is the commonest cause of severe acute liver injury. Since the publication of the previous guidelines in 2015, several studies have changed practice. A working group of experts in the area, with representation from all Poisons Information Centres of Australia and New Zealand, were brought together to produce an updated evidence-based guidance. MAIN RECOMMENDATIONS (UNCHANGED FROM PREVIOUS GUIDELINES): The optimal management of most patients with paracetamol overdose is usually straightforward. Patients who present early should be given activated charcoal. Patients at risk of hepatotoxicity should receive intravenous acetylcysteine. The paracetamol nomogram is used to assess the need for treatment in acute immediate release paracetamol ingestions with a known time of ingestion. Cases that require different management include modified release paracetamol overdoses, large or massive overdoses, accidental liquid ingestion in children, and repeated supratherapeutic ingestions. MAJOR CHANGES IN MANAGEMENT IN THE GUIDELINES: The new guidelines recommend a two-bag acetylcysteine infusion regimen (200 mg/kg over 4 h, then 100 mg/kg over 16 h). This has similar efficacy but significantly reduced adverse reactions compared with the previous three-bag regimen. Massive paracetamol overdoses that result in high paracetamol concentrations more than double the nomogram line should be managed with an increased dose of acetylcysteine. All potentially toxic modified release paracetamol ingestions (≥ 10 g or ≥ 200 mg/kg, whichever is less) should receive a full course of acetylcysteine. Patients ingesting ≥ 30 g or ≥ 500 mg/kg should receive increased doses of acetylcysteine.

Acute bone marrow suppression and gastrointestinal toxicity following acute oral methotrexate overdose.

OBJECTIVE: Acute methotrexate overdose rarely causes systemic toxicity due to saturable absorption and rapid renal elimination. We present a case of methotrexate toxicity following acute overdose. CASE REPORT: A 56-year-old female presented soon after an overdose of 1250 mg of methotrexate, zopiclone and tramadol. The methotrexate was initially under-reported (500 mg) and folinic acid was not provided. Despite normal renal function, the patient developed toxicity. She represented 5 days following the overdose with mucositis, bone marrow suppression and prolonged febrile neutropenia. Treatment included folinic acid, broad-spectrum antibiotics, filgrastim, red cell and platelet transfusion. Her bone marrow began to recover 12 days following the overdose. She was discharged home on Day 17. DISCUSSION: Severe toxicity following an acute ingestion of a large amount of methotrexate is rarely reported. The development of toxicity was unexpected in this case given methotrexate's pharmacokinetics and the patient's normal renal function. The serum methotrexate concentrations were below the treatment threshold of the folinic acid rescue therapy nomogram suggesting that the nomogram should not be relied on in acute ingestions. Large acute oral methotrexate poisoning can result in systemic toxicity and folinic acid therapy should be provided in ingestions >1000 mg.