Navigating methotrexate toxicity: Examining the therapeutic roles of folinic acid and glucarpidase.

Methotrexate (MTX) toxicity varies depending on factors such as dosing frequency (acute or repeated), dosage (low or high) and the administration route (oral, parenteral or intrathecal). Renal impairment can trigger or exacerbate MTX toxicity. Acute oral low-dose MTX (LDMTX) overdoses seldom lead to toxicity due to the saturable maximal bioavailable dose, but toxicity risks increase with repeated low doses (>3 days), high-dose MTX (HDMTX) or intrathecal poisoning. Folinic acid shares MTX transporters in the gut and cells and bypasses the MTX-induced dihydrofolate reductase inhibition. The required folinic acid dosage differs for low-dose and high-dose MTX toxicities. Acute LDMTX poisoning rarely requires folinic acid, while chronic LDMTX poisoning needs low-dose folinic acid until cellular function is restored. In HDMTX toxicities, early intravenous folinic acid administration is recommended, with dose and duration being guided by MTX concentrations and clinical improvement. In intrathecal MTX poisoning, folinic acid should be administered intravenously. Glucarpidase, a recombinant bacterial enzyme, has a high affinity for MTX and folate analogues in the intravascular or intrathecal systems. It decreases serum MTX concentrations by 90%-95% within 15 min. Its primary indication is for intrathecal MTX poisoning. It is rarely indicated in HDMTX toxicity unless patients have renal injury. However, there is no literature evidence supporting its use in HDMTX poisoning. Its use is limited by its significant cost and lack of availability. Haemodialysis can be potentially useful for MTX removal in cases where glucarpidase is not available. Additionally, fluid hydration, renal support and urine alkalinization are important adjunctive therapies for managing MTX toxicities.

The impact of tightened prescribing restrictions for PBS-subsidised opioid medicines and the introduction of half-pack sizes, Australia, 2020-21: an interrupted time series analysis.

OBJECTIVES: To evaluate the impact of the tightened Pharmaceutical Benefits Scheme (PBS) prescribing rules for immediate release (IR) and controlled release (CR) opioid medicines (1 June 2020), which also eliminated repeat dispensing without authorisation for codeine/paracetamol and tramadol IR and introduced half-pack size item codes for IR formulations. DESIGN, SETTING: Population-based interrupted time series analysis of PBS dispensing data claims for a 10% sample of PBS-eligible residents and IQVIA national opioid medicine sales data (PBS-subsidised and private prescriptions), 28 May 2018 - 6 June 2021. MAIN OUTCOME MEASURES: Mean amount of PBS-subsidised opioid medicines dispensed per day and mean overall amount sold per day - each expressed as oral morphine equivalent milligrams (OME) - overall, by formulation type (IR, CR), and by specific formulation. RESULTS: During the twelve months following the PBS changes, daily PBS-subsidised opioid medicine dispensing was 81 565 OME lower (95% CI, -106 146 to -56 984 OME) than the mean daily level for 2018-20, a decline of 3.8% after adjusting for the pre-intervention trend; the relative reduction was greater for IR (8.4%) than CR formulations (2.6%). Total daily sales of all, IR formulation, and CR formulation opioid medicines did not change significantly after the PBS changes. Repeat dispensing of prescriptions comprised 7.4% of PBS-subsidised opioid dispensing before 1 June 2020, and 1.3% after the changes. Half-pack sizes comprised 8.4% of PBS-subsidised IR opioid medicine dispensing and 2.8% of all opioid medicines sold in the twelve months after the PBS changes. CONCLUSIONS: The introduction of new PBS rules for subsidised opioid medicines was followed by a decline in PBS-subsidised dispensing. Some people may have bypassed the new restrictions by switching to private prescriptions, but our findings suggest that opioid medicine use in Australia declined as a result of the new restrictions.

Intestinal injury in paracetamol overdose (ATOM-8).

BACKGROUND AND AIM: Paracetamol, a widely used medication, is known for its delayed hepatotoxicity in cases of overdose. However, the potential for intestinal toxicity resulting from very high paracetamol concentrations during absorption is not well explored. This study aims to investigate the presence of intestinal toxicity and its correlation with observations in early and late paracetamol toxicity. METHODS: Serial samples of 30 patients with acute paracetamol overdose (> 10 g or 200 mg/kg) were prospectively tested. Markers of enterocyte damage, including plasma intestinal fatty acid binding protein (IFABP) and selected gut-related microRNAs (miR-21, miR-122, miR-194, and miR-215), were analyzed. Sub-analysis was performed on patients presenting with hyperlactatemia defined as a lactate greater than 2 mmol/L within 12 h post ingestion. RESULTS: In paracetamol overdose patients, median plasma IFABP was significantly elevated compared with healthy controls (720 µg/L [interquartile range, IQR, 533-1644] vs 270 µg/L [IQR 153-558], P < 0.001). Four patients had early hyperlactatemia and had significantly higher median plasma IFABP compared with those without early hyperlactatemia (3028 µg/L [IQR 1399-3556] vs 574 µg/L [IQR 526-943], P = 0.007). Furthermore, two microRNAs (miR-122 and miR-215) were downregulated in early hyperlactatemia (P = 0.019 and P = 0.006, respectively). Plasma IFABP concentrations correlated with paracetamol concentration (Spearman's r = 0.55) and lactate (r = 0.60). CONCLUSIONS: Paracetamol overdose causes concentration-related intestinal toxicity, and this is a possible explanation for the early hyperlactatemia syndrome. Intestinal toxicity has potential impacts on pharmacokinetics of other agents ingested and on the evolution of hepatotoxicity. Further studies are required to explore the mechanisms and prognostic implications of intestinal toxicity.

Quality use of publicly subsidised tapentadol in Australia: a population-based analysis.

BACKGROUND: Sustained-release (SR) tapentadol was listed on Australia's Pharmaceutical Benefits Scheme (PBS) in 2014 for chronic severe pain requiring long-term opioid treatment. Dispensings have increased since listing despite declining trends in other PBS-listed opioids. Preferential prescribing of SR opioids may increase the risk of dependence and accidental overdose, particularly when used to treat acute pain. AIMS: To explore the quality use of publicly subsidised tapentadol in Australia. METHODS: We examined annual initiation rates and patterns of use of tapentadol (SR) in the dispensing records of a 10% random sample of PBS-eligible Australians (2014-2021). We used national tapentadol sales data to assess the proportion of sales attributable to the PBS. RESULTS: Tapentadol initiation increased from 2014, peaking at 7.5/1000 adult population in 2019 before declining to 5.3/1000 in 2021. We identified 63 766 new users between 2014 and 2020, of whom 92.8% discontinued in the first year following initiation, 58.0% had only a single dispensing and 34.3% had no other opioids dispensed in the 3 months before or after initiation. 27.8% of new users were dispensed tapentadol on the same day as potentially interacting medicines. There was a sustained drop in the proportion of sales attributable to the PBS from June 2020 onwards, from an average of 69.1%, to 63.9% of pack sales. CONCLUSIONS: Patterns of use suggest tapentadol (SR) is generally used for short duration. Although most tapentadol sold in Australia is subsidised, there is evidence of a shift towards private sales.

Patterns of suboptimal antipsychotic use and misuse in Australia: What can routinely collected data tell us?

AIMS: There are increasing concerns about harms related to suboptimal antipsychotic use. Here we describe recent population-based trends in antipsychotic use and harms in Australia and identify population groups exhibiting patterns of use likely to contribute to these harms. METHODS: Using population-based data from the Australian Pharmaceutical Benefits Scheme (2015-2020), poisoning calls to the New South Wales (NSW) Poisons Information Centre (2015-2020) and poisoning deaths in all coronial records (2005-2018) in Australia, we measured trends in the prevalence of antipsychotic use and related deaths and poisonings. We applied latent class analyses to identify patterns of antipsychotic use that may contribute to harms. RESULTS: Quetiapine and olanzapine had the highest prevalence of use between 2015 and 2020. Noteworthy trends included increases of 9.1% and 30.8% in quetiapine use and poisonings, while olanzapine use decreased by 4.5% but poisonings increased by 32.7%. Quetiapine and olanzapine poisonings and related deaths had the highest rates of co-ingestion of opioids, benzodiazepines and pregabalin compared to other antipsychotics. We identified six distinct population groups using antipsychotics: (i) ongoing high-dose use with sedatives (8%), (ii) ongoing use (42%), (iii) ongoing use with analgesics and sedatives (11%), (iv) long-term low-dose use (9%), (v) sporadic use (20%) and (vi) sporadic use with analgesics (10%). CONCLUSION: Ongoing potentially suboptimal antipsychotic use and associated harms highlight the need to monitor such patterns of use, for example through prescription monitoring systems.

Psychotropic and other medicine use at time of death by suicide: a population-level analysis of linked dispensing and forensic toxicology data.

OBJECTIVES: To determine the numbers and types of medicines dispensed around the time of death to people who die by suicide; to compare the medicines recently dispensed and those recorded in post mortem toxicology reports. DESIGN, SETTING, PARTICIPANTS: Analysis of linked National Coronial Information System (NCIS) and Pharmaceutical Benefits Scheme (PBS) data from the Australian Suicide Prevention using Health Linked Data (ASHLi) study, a population-based case series study of closed coronial cases for deaths of people in Australia aged ten years or more during 1 July 2013 - 10 October 2019 deemed by coroners to be the result of intentional self-harm. MAIN OUTCOME MEASURES: Proportions of people to whom medicines were dispensed around the time of death, by medicine group, class, and specific medicine; comparison of medicines recently dispensed and those detected by post mortem toxicology. RESULTS: Toxicology reports were available for 13 541 of 14 206 people who died by suicide (95.3%; 10 246 men, 75.7%); poisoning with medicines contributed to 1163 deaths (8.6%). At least one PBS-subsidised medicine had been dispensed around the time of death to 7998 people (59.1%). For three medicine classes, the proportions of people in whom the medicines were detected post mortem and their death was deemed medicine-related were larger for those without records of recent dispensing than for people for whom they had been dispensed around the time of death: antidepressants (17.7% v 12.0%), anxiolytics (16.3% v 14.8%), and sedatives/hypnotics (24.3% v 16.5%). At least one recently dispensed medicine not detected post mortem was identified for 6208 people (45.8%). CONCLUSIONS: A considerable proportion of people who died by suicide were not taking psychotropic medicines recently dispensed to them, suggesting non-adherence to pharmacotherapy, and a smaller than expected proportion were using antidepressants. Conversely, medicines that had not recently been dispensed were detected post mortem in many people for whom poisoning with medicines was a contributing factor, suggesting medicine stockpiling.

Prescribing trend of tapentadol in a Sydney local health district.

AIMS: Tapentadol, an opioid with mu-opioid receptor agonism and noradrenaline reuptake inhibition, has been increasingly used in Australia since 2011. However, data on hospital prescribing trends and indications are scarce. This study aimed to investigate hospital prescribing trends of tapentadol, oxycodone and tramadol in a Sydney local health district (LHD) and the indications for tapentadol hospital prescriptions in an Australian tertiary hospital. METHODS: We analysed 5-year patient dispensing for tapentadol, oxycodone and tramadol from four hospitals in a Sydney LHD with data expressed as oral morphine equivalents (OME). We also conducted a retrospective review of 140 and 54 patients prescribed tapentadol at a tertiary hospital's surgical and spinal units in 2020. RESULTS: Over 5 years in the Sydney LHD, there was a 19.5% reduction in total dispensing of these opioids from 1 225 210 to 986 477.5 OME milligrams. Decreases were specifically for oxycodone (-37.8% immediate-release, -65.2% sustained-release) and tramadol (-74.6% immediate-release, -70.1% sustained-release). Contrastingly, hospital prescriptions of tapentadol immediate-release increased by 223.2% between 2018-19 and 2020-21 while sustained-release increased by 17.9% from 2016-17 to 2020-21. By 2020-21, tapentadol overtook oxycodone to become the most prescribed opioid in the Sydney LHD (51.4%). At the hospital's surgical units, 137 (97.9%) patients were prescribed tapentadol for acute post-operative pain with the majority (54.0%) prescribed both immediate-release and sustained-release tapentadol, while 71.1% were prescribed for neuropathic pain in the spinal units. CONCLUSION: In a Sydney LHD, tapentadol prescriptions increased significantly to become the preferred opioid analgesic. At the hospital's surgical units, off-label prescriptions of tapentadol sustained-release for acute post-operative pain were observed.

Optimising alkalinisation and its effect on QRS narrowing in tricyclic antidepressant poisoning.

AIMS: The objectives were to determine the effect of NaHCO3 and/or mechanical ventilation on the biochemical profile and serum alkalinisation in tricyclic antidepressant (TCA) poisoning and investigate the impact of effective alkalinisation therapy on the QRS interval in TCA poisoning. METHODS: This was a retrospective review of TCA poisonings from three Australian toxicology units and a poisons information centre (Jan 2013 to Jan 2019). We included patients with TCA toxicity who ingested>10 mg/kg or had clinically significant toxicities consistent with TCA poisoning, and analysed patients' clinical, electrocardiogram and biochemical data. RESULTS: Of 210 patients, 84 received NaHCO3 and ventilation (dual therapy), 12 NaHCO3 , 46 ventilation and 68 supportive care treatment. When compared with single/supportive groups, patients who received dual therapy had taken a significantly higher median dose of TCA (1.5 g vs1.3 g, P < .001), a longer median maximum QRS interval (124 ms, interquartile ranges [IQR] 108-138 vs106 ms, IQR 98-115, P < .001) and were more likely to have seizures (14% vs3%, P = .006) and arrhythmias (17% vs1%, P < .001). The dual therapy group demonstrated greater increases in serum pH (median 0.11, IQR 0.04-0.17) compared to the single/supportive therapy group (median 0.03, IQR -0.01-0.09, p < .001). A greater proportion of patients reached the target pH 7.45-7.55 in the dual therapy group (59%) compared to the single/supportive therapy group (10%) (P < .001). For each 100 mmol bolus of NaHCO3 given, the median increase in serum sodium was 2.5 mmol/L (IQR 1.5-4.0). QRS narrowing occurred twice as quickly in the dual therapy vs single/supportive therapy group. CONCLUSIONS: A combination of NaHCO3 and mechanical ventilation was most effective in achieving serum alkalinisation and was associated with a more rapid narrowing of the QRS interval. We advise that the maximal dose of NaHCO3 should be <400 mmol (6 mmol/kg).

Prescribed medicine use and extent of off-label use according to age in a nationwide sample of Australian children.

BACKGROUND: Medicine prescribing for children is impacted by a lack of paediatric-specific dosing, efficacy and safety data for many medicines. OBJECTIVES: To estimate the prevalence of medicine use among children and the rate of 'off-label' prescribing according to age at dispensing. METHODS: We used population-wide primarily outpatient dispensing claims data for 15% of Australian children (0-17 years), 2013-2017 (n = 840,190). We estimated prescribed medicine use and 'off-label' medicine use according to the child's age (<1 year, 1-5 years, 6-11 years, 12-17 years) defined as medicines without age-appropriate dose recommendations in regulator-approved product information. Within off-label medicines, we also identified medicines with and without age-specific dose recommendations in a national prescribing guide, the Australian Medicines Handbook Children's Dosing Companion (AMH CDC). RESULTS: The overall dispensing rate was 2.0 dispensings per child per year. The medicines with the highest average yearly prevalence were systemic antibiotics (435.3 per 1000 children), greatest in children 1-5 years (546.9 per 1000). Other common medicine classes were systemic corticosteroids (92.7 per 1000), respiratory medicines (91.2 per 1000), acid-suppressing medicines in children <1 year (47.2 per 1000), antidepressants in children 12-17 years (40.3 per 1000) and psychostimulants in children 6-11 years (27.0 per 1000). We identified 12.2% of dispensings as off-label based on age, but 66.3% of these had age-specific dosing recommendations in the AMH CDC. Among children <1 year, off-label dispensings were commonly acid-suppressing medicines (35.5%) and topical hydrocortisone (33.1%); in children 6-11 years, off-label prescribing of clonidine (16.0%) and risperidone (13.1%) was common. Off-label dispensings were more likely to be prescribed by a specialist (21.7%) than on-label dispensings (7.5%). CONCLUSIONS: Prescribed medicine use is common in children, with off-label dispensings for medicines without paediatric-specific dosing guidelines concentrated in classes such as acid-suppressing medicines and psychotropics. Our findings highlight a need for better evidence to support best-practice prescribing.

D-dimer testing for early detection of venom-induced consumption coagulopathy after snakebite in Australia (ASP-29).

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

The impact of tightened prescribing restrictions on proton pump inhibitor use in Australia: An evaluation using interrupted time series analysis.

AIM: In May 2019, Australia's Pharmaceutical Benefits Scheme (PBS) tightened the prescribing restrictions for publicly subsidized high and standard strength proton-pump inhibitors (PPIs). We aimed to determine the impacts on PPI use in Australia. METHODS: Population-based interrupted time series analysis of PBS dispensing claims for a 10% sample of PBS-eligible Australian residents from January 2017 to December 2020 and national prescription and over-the-counter sales to pharmacies from January 2017 to October 2020. We examined trends in monthly PPI dispensings, switches from higher to lower strength formulations, and volume (kg) dispensed and sold. RESULTS: From May 2019, we observed a small, immediate decrease (-7830 [95%CI: -8818 to -6842]) in standard strength PPI dispensings/month, which rebounded to exceed pre-intervention levels by December 2020. High strength dispensings decreased until the end of the study period to less than half their pre-intervention average/month; low strength dispensings/month increased until the end of the study period to more than double their pre-intervention average/month. We observed transient increases in switches to lower strength formulations post-intervention. The kilograms of PPIs sold/month followed a similar pattern to PBS kilograms dispensed/month with the exception of standard strength formulations where PBS dispensings decreased by -74 (95%CI: -93 to -55) but total sales remained unchanged (comprising PBS and private prescriptions, and over-the-counter sales). CONCLUSIONS: Tightened prescribing restrictions had an immediate and sustained impact on PPI use in Australia, with decreased high strength use and increased low strength use. Some patients likely switched to private market prescriptions for standard strength PPI, given the observed patterns in total volume sold/dispensed.

Just 'nanging' around - harmful nitrous oxide use: a retrospective case series and review of Internet searches, social media posts and the coroner's database.

BACKGROUND: The chronic recreational inhalation of nitrous oxide (N2 O) 'nanging', can have adverse neurological and psychiatric effects. AIM: To evaluate cases of chronic N2 O use presenting to two hospitals, as well as to evaluate nationally N2 O deaths reported to the coroner and trends in Internet searches and social media posts related to N2 O. METHODS: Retrospective review of two toxicology units, from July 2017 to October 2020, of patients presenting with chronic N2 O use and neurological and/or psychiatric symptoms. We evaluated 10 years (2010-2019) of Internet search and social media trends involving N2 O and the National Coronial Information System (NCIS) database for deaths across Australia. RESULTS: Twenty-two patients were identified: median age 22 years, half female, 17 Asian background and 15 students. Presentations included decreased mobility or unsteady gait (n = 15) and psychiatric symptoms (n = 5). The median reported bulb use/day was 300 (interquartile range (IQR): 200-370), for a median of 6 months (IQR: 3-24). On magnetic resonance imaging, 10/18 had subacute combined degeneration of the spinal cord and 7/7 sensorimotor neuropathy on nerve conduction studies. All received high-dose intramuscular vitamin B12 and 11 methionine. Despite prolonged rehabilitation, nine required walking aids on discharge. Since 2017, social media posts and Internet searches for N2 O increased rapidly, the latter mostly directed at obtaining N2 O canisters. From the NCIS, 36 deaths were identified, 12 unintentional (recreational drug use), 20 intentional self-harm and 4 traumatic. CONCLUSION: We report a case series of symptomatic chronic N2 O use, many with ongoing neurological sequelae. Furthermore, a sharp increase in Internet searches to obtain N2 O cannisters was noted. Education of high-risk student groups on the long-term sequelae is important.

A cross sectional study of psychotropic medicine use in Australia in 2018: A focus on polypharmacy.

AIMS: To examine prescribed psychotropic medicine use on a given day in Australia (25 September 2018; World Pharmacists Day), with a focus on psychotropic polypharmacy. METHODS: We used a 10% sample of individual-level nationwide dispensing claims to examine psychotropic medicine use on a given day. We estimated the prevalence of psychotropic medicine use in all ages stratified by age and sex. We also calculated the observed vs expected (had medicines been randomly combined) prevalence of psychotropic combinations used. We focused on combinations of clinical significance as well combinations of psychotropics with medicines prescribed to manage cardiovascular risk and disease. RESULTS: Serotonin reuptake inhibitors, serotonin-noradrenalin reuptake inhibitors/noradrenaline reuptake inhibitors, tricyclic antidepressants and gabapentinoids dominated psychotropic use. The use of any psychotropic as a proportion of people in the Australian population increased with age, peaking at the 85-89 year age group and declining thereafter. Combinations of medicines from the same subclass generally occurred at lower than expected frequencies. However, combinations including atypical antipsychotics occurred more frequently than expected; e.g. 7.4× with anticonvulsants and 2.2× with other atypical antipsychotics. This was also the case for combinations of sedatives, e.g. anxiolytic with hypnotic benzodiazepines (3.8×). Lipid-lowering drugs and antidiabetic medicines were combined with psychotropics at frequencies close to those expected had they been randomly combined. CONCLUSION: Psychotropic use in older adults and certain psychotropic combinations that are not well supported with evidence remain prevalent and greater consideration of the drivers of this potentially inappropriate prescribing is required.

Long-term trajectories of medicine use among older adults experiencing polypharmacy in Australia.

AIMS: To explore longitudinal changes in the number and type of medicines used among older people who experience polypharmacy. METHODS: We used pharmaceutical claims for a 10% sample of Australian Pharmaceutical Benefits Scheme beneficiaries to identify people aged 70 years and older who were exposed to 5 or more medicines on 15 February 2014. Using group-based trajectory modelling, we explored changes in the quarterly number and type of medicines used over a 5-year period (2014-2018). RESULTS: In our cohort of 98 539 people, we identified 2 predominant groups of medicine use: sustained polypharmacy (77% of people, 4 trajectories); and decreasing medicine use (23%, 3 trajectories). Within the sustained polypharmacy group, people in trajectories with a lower mean number of medicines (e.g. 6 unique medicines) had relatively stable trajectories, while those using a higher number of medicines (e.g. 15 unique medicines) experienced greater seasonal variation in the number and type of medicines used. On average, people continued to use 2/3 of their medicines (chemical substance level) across adjacent quarters. Within groups of decreasing medicine use, the most common trajectory was a slight drop in medicines within 3 months. Overall, 79% of people still experienced polypharmacy after 1 year. CONCLUSION: Polypharmacy among older people is a sustained phenomenon, reflecting the chronic nature of multimorbidity within this population. However, there is an underlying volatility in the nature of medicines involved, reflecting both changes in treatment and seasonal fluctuation in dispensing. Ongoing prescribing vigilance is required, particularly for patients using very large amounts of medicines.

Machine read frontal QRS-T angle and QTc is no substitute for manual measurement of QTc in pro-arrhythmic drug overdose.

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

Early acetaminophen-protein adducts predict hepatotoxicity following overdose (ATOM-5).

BACKGROUND & AIMS: Acetaminophen-protein adducts are specific biomarkers of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (alanine aminotransferase [ALT] >1,000 U/L), an adduct concentration ≥1.0 nmol/ml is sensitive and specific for identifying cases secondary to acetaminophen. Our aim was to characterise acetaminophen-protein adduct concentrations in patients following acetaminophen overdose and determine if they predict toxicity. METHODS: We performed a multicentre prospective observational study, recruiting patients 14 years of age or older with acetaminophen overdose regardless of intent or formulation. Three serum samples were obtained within the first 24 h of presentation and analysed for acetaminophen-protein adducts. Acetaminophen-protein adduct concentrations were compared to ALT and other indicators of toxicity. RESULTS: Of the 240 patients who participated, 204 (85%) presented following acute ingestions, with a median ingested dose of 20 g (IQR 10-40), and 228 (95%) were treated with intravenous acetylcysteine at a median time of 6 h (IQR 3.5-10.5) post-ingestion. Thirty-six (15%) patients developed hepatotoxicity, of whom 22 had an ALT ≤1,000 U/L at the time of initial acetaminophen-protein adduct measurement. Those who developed hepatotoxicity had a higher initial acetaminophen-protein adduct concentration compared to those who did not, 1.63 nmol/ml (IQR 0.76-2.02, n = 22) vs. 0.26 nmol/ml (IQR 0.15-0.41; n = 204; p <0.0001), respectively. The AUROC for hepatotoxicity was 0.98 (95% CI 0.96-1.00; n = 226; p <0.0001) with acetaminophen-protein adduct concentration and 0.89 (95% CI 0.82-0.96; n = 219; p <0.0001) with ALT. An acetaminophen-protein adduct concentration of 0.58 nmol/ml was 100% sensitive and 91% specific for identifying patients with an initial ALT ≤1,000 U/L who would develop hepatotoxicity. Adding acetaminophen-protein adduct concentrations to risk prediction models improved prediction of hepatotoxicity to a level similar to that obtained by more complex models. CONCLUSION: Acetaminophen-protein adduct concentration on presentation predicted which patients with acetaminophen overdose subsequently developed hepatotoxicity, regardless of time of ingestion. An adduct threshold of 0.58 nmol/L was required for optimal prediction. LAY SUMMARY: Acetaminophen poisoning is one of the most common causes of liver injury. This study examined a new biomarker of acetaminophen toxicity, which measures the amount of toxic metabolite exposure called acetaminophen-protein adduct. We found that those who developed liver injury had a higher initial level of acetaminophen-protein adducts than those who did not. CLINICAL TRIAL REGISTRATION: Australian Toxicology Monitoring (ATOM) Study-Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.

Haemodialysis for lithium poisoning: Translating EXTRIP recommendations into practical guidelines.

OBJECTIVES: This study aimed to determine the impact on practice of applying the Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup criteria to lithium toxicity. METHOD: We retrospectively examined the medical records of patients from three hospitals who presented with chronic or acute on chronic lithium poisoning with a lithium concentration ≥1.3 mmol/L (2008-2018). We determined which criteria were met by patients and their subsequent course. We developed and validated a method to predict if lithium concentration would be >1mmol/L at 36 hours. RESULTS: There were 111 acute on chronic and 250 chronic lithium toxic patients. Nine patients (2.5%) were treated with haemodialysis. Six chronic patients had neurological sequelae. The "estimated lithium concentration at 36 hours > 1 mmol/L" criterion required pharmacokinetic calculations. A simple nomogram was developed using Estimated Glomerular Filtration Rate (eGFR) and lithium concentration. For chronic toxicity, the nomogram would have correctly predicted lithium concentration >1.4 mmol/L at 36 hours in all except two patients. If EXTRIP criteria were followed, dialysis would have been instituted for 211 patients (58%). However, only 51 patients with chronic toxicity fulfilled both a concentration and a clinical criterion. Late neurological sequelae were observed in five out of six patients who fulfilled a concentration and a clinical criterion on admission, with the sixth meeting these criteria shortly after admission. CONCLUSIONS: The EXTRIP criteria are too broad, but minor modifications allow haemodialysis to be targeted to those most at risk of sequelae. Most acute on chronic poisonings do not need haemodialysis, but it might shorten hospital stay in those with very high concentrations. The nomogram accurately predicts the fall in lithium concentration for chronic poisoning.

Buprenorphine to reverse respiratory depression from methadone overdose in opioid-dependent patients: a prospective randomized trial.

BACKGROUND: Naloxone is the usual drug used in opioid-induced respiratory depression but it has a short half-life, precipitates withdrawal in dependent patients, and thus for persistent reversal of long-acting opioids has to be given by titrated doses and infusions. The partial agonist buprenorphine has a much longer duration of action and causes less severe withdrawal, but still should largely reverse respiratory depression induced by full agonist opioids. We aimed to compare the efficacy/safety of buprenorphine and naloxone in reversing respiratory depression in methadone-poisoned opioid-dependent patients. METHODS: Patients with methadone-induced respiratory depression were randomized to receive naloxone (titrated doses), or lower or higher doses of buprenorphine (10 µg/kg or 15 µg/kg). The primary outcome was immediate reversal of respiratory depression. We also recorded acute opioid withdrawal, need for intubation/recurrent apnea, repeated doses of opioid antagonists, length of hospital stay, other morbidity, and mortality. The study was registered with the Iranian Registry of Clinical Trials (Trial ID: 18265; Approval code: IRCT2015011020624N1). RESULTS: Eighty-five patients were randomized; 55/56 patients who received buprenorphine had rapid reversal of respiratory depression, which persisted for at least 12 h. Naloxone was effective in 28/29 patients, but often required very high titrated doses (thus delaying time to respond) and prolonged infusions. Intubation (8/29 vs 5/56) and opioid withdrawal (15/29 vs 7/56) were less common with buprenorphine. There were no serious complications or deaths in those receiving buprenorphine. The 15-µg/kg buprenorphine dose appeared to provide a longer duration of action, but precipitated withdrawal more frequently than the 10-µg/kg dose. CONCLUSION: Buprenorphine appears to be a safe and effective substitute for naloxone in overdosed opioid-dependent patients. Further studies are warranted to explore the optimal dosing strategy for buprenorphine to consistently maintain reversal of respiratory depression but not precipitate withdrawal. TRIAL REGISTRATION NUMBER: IRCT2015011020624N1. Registered 30 September 2015.

Changes in sales of analgesics to pharmacies after codeine was rescheduled as a prescription only medicine.

OBJECTIVE: To investigate changes in sales to pharmacies of over-the-counter (OTC) and prescription analgesics, cold and flu products, and cough suppressants after the rescheduling of codeine as a prescription only medicine in February 2018. DESIGN: Interrupted time series analysis of sales to pharmacies. SETTING: Pharmaceutical sales to community pharmacies in Australia, March 2015 - March 2019. The period January 2017 (month after rescheduling was announced) to January 2018 (month before rescheduling was implemented) was excluded from the time series analysis. MAIN OUTCOME MEASURES: Monthly pack and tablet sales per 10 000 population of OTC and prescription analgesics, cold and flu products, and cough suppressants. RESULTS: During 2016, 7586 packs and 248 127 tablets of OTC codeine per 10 000 population were sold to pharmacies; in the 14 months after rescheduling, a small level increase in monthly prescription codeine sales was evident (2247 tablets/capsules per 10 000 population; 95% CI, 1231-3264 per 10 000 population). Monthly OTC analgesic sales increased by 258 (95% CI, 151-365) packs per 10 000 population and 37 856 (95% CI, 26 143-49 569) tablet/capsules per 10 000 population. Monthly sales of single ingredient paracetamol (41 415 [95% CI, 31 374-51 456] tablets/capsules per 10 000 population), ibuprofen (1392 [95% CI 916-1868] tablets/capsules per 10 000 population), paracetamol/ibuprofen (1618 tablets [95% CI, 1567-1669] tablets/capsules per 10 000 population), and other paracetamol combinations (233 [95% CI, 112-353] tablets/capsules per 10 000 population) all increased, but not those of prescription analgesic products not containing codeine. Rises for OTC cold/flu products containing the opioid derivative dextromethorphan were small; sales of OTC cough suppressants containing opioid derivatives (dextromethorphan, pholcodine, dihydrocodeine) did not change. CONCLUSIONS: The rescheduling of codeine was followed by increased sales to pharmacies of paracetamol, ibuprofen, and paracetamol combination products. While these products carry no risk of dependence, their inappropriate use is also associated with harms that warrant adverse event monitoring.

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.