Rivastigmine for the management of anticholinergic delirium.

INTRODUCTION: Anticholinergic agents are commonly taken in overdose, often causing delirium. The spectrum of anticholinergic delirium ranges from mild agitation to severe behavioural disturbance. Physostigmine is an effective treatment for anticholinergic delirium, but its availability is limited. As rivastigmine is readily available, it has been used to manage anticholinergic delirium; however, there is limited research investigating its use. METHOD: This was a retrospective review of patients with anticholinergic delirium treated in two toxicology units with rivastigmine (oral capsule or transdermal patch) from January 2019 to June 2023. The primary outcome was the use of further parenteral treatment (sedation or physostigmine) for delirium post rivastigmine administration. RESULTS: Fifty patients were administered rivastigmine for the management of anticholinergic delirium. The median age was 36 years (interquartile range: 25-49 years) and 27 (54 per cent) were females. Features consistent with anticholinergic toxicity included tachycardia in 44 (88 per cent) and urinary retention requiring catheterisation in 40 (80 per cent). Forty-three patients (86 per cent) were treated with physostigmine before rivastigmine administration. Twenty-two were managed with transdermal rivastigmine (most commonly 9.5 mg/24 hour patch), and 28 with oral rivastigmine 6 mg. Further parenteral sedation and/or physostigmine treatment were required more often in patients given transdermal than oral rivastigmine [16/22 (73 per cent) versus 9/28 (32 per cent), P = 0.010)]. No patients had bradycardia or gastrointestinal symptoms following rivastigmine administration. One patient with a history of epilepsy had a seizure, 1.5 hours post physostigmine administration and 7 hours post transdermal rivastigmine. DISCUSSION: Rivastigmine has been increasingly used for the management of patients with anticholinergic delirium, due to the lack of availability of physostigmine. In this case series, rivastigmine transdermal patch appeared to be less effective than oral rivastigmine capsules, likely due to its slow onset of action and/or insufficient dose. CONCLUSION: Rivastigmine can be used to treat anticholinergic delirium. In our case series oral rivastigmine appeared more effective than transdermal rivastigmine.

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.

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.

Physiologically based pharmacokinetic modelling of acute digoxin toxicity and the effect of digoxin-specific antibody fragments.

CONTEXT: Recommended doses of digoxin-specific antibody fragments (digoxin-Fab) for treatment of acute digoxin poisoning are pharmacokinetically unsubstantiated and theoretically excessive. Physiologically based pharmacokinetic (PBPK) modelling creates clinical simulations which are closely related to physiological and pharmacokinetic behaviour. This paper details the formulation of a PBPK model of digoxin and explores its use as a simulation tool for acute digoxin toxicity and its management. MATERIALS AND METHODS: A PBPK model of digoxin was constructed and validated for acute digoxin poisoning management by comparing simulations with observed individual acute overdose patients. These simulations were compared with standard two-compartment PK model simulations. RESULTS: PBPK model simulations showed good agreement with post-absorption plasma concentrations of digoxin measured in 6 acute overdose patients. PBPK predictions were accurate to 1.5-fold or less of observed clinical values, proving to be more accurate than two-compartment simulations of the same patients which produced up to a 4.9-fold change. CONCLUSIONS: Compared to conventional two-compartment modelling, PBPK modelling is superior in generating realistic simulations of acute digoxin toxicity and the response to digoxin-Fab. Simulation capacity provides realistic, continuous data which has the potential to substantiate alternative, less expensive, and safer digoxin-Fab dosing strategies for the treatment of acute digoxin toxicity.

Comparison of Wells and YEARS clinical decision rules with D-dimer for low-risk pulmonary embolus patients.

BACKGROUND: Assessment of pulmonary embolism (PE) remains a diagnostic and investigative burden to emergency departments. The decision of which D-dimer cut-off to use in low-risk patients remains controversial. AIMS: To compare the sensitivity and specificity of varying D-dimer cut-offs in the diagnosis of PE for Wells low-risk patients. METHODS: Retrospective review of patients presenting to a tertiary emergency department over 42 months who had a D-dimer performed for PE risk stratification. Wells scores were calculated for each patient, those with Wells score of ≤4 ('PE unlikely') were analysed. Four D-dimer thresholds were compared, including traditional threshold (≥0.5 µg/mL), age-adjusted (≥age in years × 0.01 µg/mL), doubled-traditional threshold and YEARS criteria. RESULTS: During the study period, 2291 D-dimers were ordered for suspected PE, of which 2125 were low risk for PE. Of these low-risk patients 46 (2.2%) were found to have a PE. The sensitivity and specificity for each D-dimer threshold were traditional threshold (95.6% and 65.6%), age-adjusted (93.5% and 71.7%), doubled traditional (69.6% and 85.5%) and YEARS criteria (80.4% and 84.0%). Utilising an age-adjusted threshold, YEARS criteria or doubled-traditional threshold would have resulted in 70, 217 and 245 fewer imaging investigations. CONCLUSIONS: The prevalence of PE in this low-risk cohort was very low. Utilising an age-adjusted D-dimer would have reduced imaging tests performed while maintaining good sensitivity. Although The YEARS criteria and doubled-traditional threshold would have reduced scanning considerably both had sensitivities of less than 90%.

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.

Modified release paracetamol overdose: a prospective observational study (ATOM-3).

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.

Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2).

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.

Use of multi-dose activated charcoal in phenytoin toxicity secondary to genetic polymorphism.

INTRODUCTION: Phenytoin is metabolised in the liver by cytochrome (CYP)2C9 and 2C19 enzymes. Due to saturation of enzyme capacity, the elimination half-life is prolonged at supratherapeutic levels. Genetic polymorphisms of CYP2C9 and 2C19 are reasonably common and further prolong the elimination of phenytoin. There are conflicting reports regarding whether multiple-dose activated charcoal (MDAC) significantly increases the clearance of phenytoin in poisoning. CASE REPORT: We present 3 patients with phenytoin toxicity and very slow elimination secondary to reduced CYP enzyme function from genetic polymorphisms. MDAC was used in two patients and led to rapid and large reductions in the measured elimination half-lives. This is contrasted with very prolonged elimination in a third patient who did not receive MDAC. CONCLUSION: MDAC may play a role in the management of chronic phenytoin toxicity, especially in those with very slow endogenous elimination secondary to genetic polymorphisms.

Comparison of intermittent haemodialysis, prolonged intermittent renal replacement therapy and continuous renal replacement haemofiltration for lithium toxicity: a case report.

This case report compares three types of renal replacement therapy for acute severe lithium toxicity and is the first to use prolonged intermittent renal replacement therapy (PIRRT). A peak lithium level of 13.2mmol/L was recorded after a 51- year-old man attempted suicide. He was treated with intermittent haemodialysis (IHD), PIRRT and continuous venovenous haemofiltration (CVVH) over 55 hours. Lithium clearance was shown to be comparable between IHD and PIRRT, both of which were superior to CVVH. Expected efficacy of treatment with a single daily session of PIRRT was higher than IHD or CVVH. PIRRT is a useful strategy for dialysis among patients with acute lithium intoxication.