Cognitive impairment following sedative overdose.

INTRODUCTION: Patients with sedative overdose may have residual cognitive impairment at the time they are deemed medically cleared for discharge. Impairment could affect the performance of high-risk activities, including driving. The Trail Making Test is an alpha-numeric assessment that can be performed at the bedside to assess cognitive function. We examined whether there were differences in cognitive function when medically cleared between patients that overdosed on sedative and non-sedative drugs. METHODS: A prospective, observational study assessed cognitive function using the Trail Making Test between 2018 and 2021. Patients (16 years and greater) completed testing upon medical clearance if they spoke English and had no previous neurological injury. Continuous covariates were compared using t-tests or Mann-Whitney U tests and multiple linear regression; binary variables were modelled using logistic regression. RESULTS: Of 171 patients enrolled, 111 (65 per cent) had sedative overdose; they were older (median 32.1 versus 22.2 years) and more likely to be male (58.6 per cent versus 36.7 per cent). Benzodiazepines and paracetamol were the commonest drug overdoses. Patients with sedative overdose performed worse on Trail Making Test part A (37.0 versus 33.1 seconds, P = 0.017) and Trail Making Test part B (112.4 versus 81.5 seconds, P = 0.004). Multiple linear regression analysis indicated that patient age (P < 0.001, 1.7 seconds slower per year, 95 per cent confidence interval: 0.9-2.6 seconds) and perception of recovery (P = 0.006, 36.4 seconds slower if perceived not recovered, 95 per cent confidence interval: 10.8-62.0 seconds) were also associated with Trail Making Test part B times. Patients with sedative overdose were more likely to be admitted to the intensive care unit (Odds Ratio: 4.9, 95 percent confidence interval: 1.1-22.0; P = 0.04). DISCUSSION: Our results are broadly in keeping with previously published work, but include a wider range of drug overdose scenarios (polypharmacy and recreational drugs). While patients demonstrated some perception of their cognitive impairment, our model could not reliably be used to provide individual discharge advice. The study design did not allow us to prove causation of cognitive impairment, or to make comparison between the strength of an overdose to the trail making test time. CONCLUSIONS: Trail Making Test results suggested that patients who had sedative drug overdoses may have significant cognitive deficits even when medically cleared. Risk of harm may be minimised with advice to avoid high-risk activities such as driving. More profound impacts seen on the Trail Making Test part B than A may mean higher-order thinking is more affected than simple cognitive function.

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.

Acetaminophen Poisoning.

Acetaminophen is a common medication taken in deliberate self-poisoning and unintentional overdose. It is the commonest cause of severe acute liver injury in Western countries. The optimal management of most acetaminophen poisonings is usually straightforward. Patients who present early should be offered activated charcoal and those at risk of acute liver injury should receive acetylcysteine. This approach ensures survival in most. The acetaminophen nomogram is used to assess the need for treatment in acute immediate-release overdoses with a known time of ingestion. However, scenarios that require different management pathways include modified-release, large/massive, and repeated supratherapeutic ingestions.

Hepatotoxicity in a child following an accidental overdose of liquid paracetamol.

Introduction: Accidental pediatric liquid paracetamol exposure is common. Most children do not require treatment with acetylcysteine and acute liver injury is rare.Case report: An otherwise well 3-year-old (15.4 kg) girl with recent vomiting and low-grade fever presented 1 h post-accidental ingestion of up to 150 mL of 24 mg/mL (240 mg/kg) of liquid paracetamol. Paracetamol concentrations 2 and 4 h post-ingestion were 105 and 97 mg/L, respectively, both below the nomogram treatment threshold so acetylcysteine was not administered. The ALT was elevated to 52 U/L 4 h post-ingestion, and then 219 U/L at 17 h, so intravenous acetylcysteine was commenced at 25 h. ALT peaked at 1393 U/L 5d post-ingestion, and INR peaked at 1.5 at 44 h post-ingestion. Acetylcysteine continued for 64 h and she made an uneventful recovery. Paracetamol metabolites were measured including, nontoxic glucuronide and sulphate conjugates and toxic cytochrome P450 (CYP) metabolites (cysteine and mercapturate). The apparent paracetamol half-life was 6.3 h. Her CYP metabolites were higher than usual, 11% of total metabolites. Glucuronide and sulphate conjugates accounted for 71 and 18% of total metabolites, respectively.Conclusion: This uncommon case of hepatotoxicity in a child following accidental liquid paracetamol ingestion may have been due to increased susceptibility from a recent viral illness with decreased oral intake, as evidenced by the higher proportion of CYP metabolites.

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.

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.

Clinical decision rule for non-traumatic computed tomography of the brain.

OBJECTIVE: The aims of the present study were to derive and validate a clinical decision rule (CDR) to rule out the need for computed tomography of the brain (CTB) in non-traumatic patients who present to the ED. METHODS: This is a retrospective review of non-traumatic patients who presented to the EDs in two urban hospitals and received CTB from January 2014 to December 2016. Data from one hospital were used to develop a CDR for clinically significant CTB findings. Clinically significant CTB findings were defined as acute infarction, intracranial neoplasm, intracranial haemorrhage, acute hydrocephalus, cerebral oedema and intracranial infection. Patients from another hospital were used as a validation cohort to evaluate the CDR and compare it to four previously derived CDRs. RESULTS: There were 5296 cases in the derivation cohort, with 345 (6.5%) clinically significant CTB findings. Identified risk factors were: focal neurological deficit (adjusted odds ratio [OR] 3.4, 95% confidence interval [CI] 2.6-4.4), Glasgow Coma Scale <15 (adjusted OR 3.5, 95% CI 2.6-4.6), history of malignancy (adjusted OR 3.2, 95% CI 2.4-4.2), nausea and/or vomiting (adjusted OR 1.6, 95% CI 1.1-2.1), headache (adjusted OR 1.1, 95% CI 0.9-1.5) and coagulopathy (adjusted OR 9.2, 95% CI 2.1-41.5). These criteria and four pre-existing CDRs were applied to the validation cohort of 5098 patients from the second hospital, which had 338 (6.6%) clinically significant CTB findings. Our criteria were found to have a sensitivity of 99.7% (95% CI 99.1-100.0) and a specificity of 11.0% (95% CI 10.1-11.9). The risk of having a clinically significant CTB finding is 0.3% if patients do not meet any of the criteria. CONCLUSION: The CDR derived in the present study achieved the highest sensitivity and a moderate specificity when compared with four other pre-existing CDRs for non-traumatic brain injury patients.

Retrospective evaluation of repeated supratherapeutic ingestion (RSTI) of paracetamol †.

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.

Interventions for paracetamol (acetaminophen) overdose.

BACKGROUND: Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or unintentionally. In high-income countries, paracetamol toxicity is a common cause of acute liver injury. There are various interventions to treat paracetamol poisoning, depending on the clinical status of the person. These interventions include inhibiting the absorption of paracetamol from the gastrointestinal tract (decontamination), removal of paracetamol from the vascular system, and antidotes to prevent the formation of, or to detoxify, metabolites. OBJECTIVES: To assess the benefits and harms of interventions for paracetamol overdosage irrespective of the cause of the overdose. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (January 2017), CENTRAL (2016, Issue 11), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), and Science Citation Index Expanded (1900 to January 2017). We also searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov database (US National Institute of Health) for any ongoing or completed trials (January 2017). We examined the reference lists of relevant papers identified by the search and other published reviews. SELECTION CRITERIA: Randomised clinical trials assessing benefits and harms of interventions in people who have ingested a paracetamol overdose. The interventions could have been gastric lavage, ipecacuanha, or activated charcoal, or various extracorporeal treatments, or antidotes. The interventions could have been compared with placebo, no intervention, or to each other in differing regimens. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included trials. We used fixed-effect and random-effects Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of the review outcomes. We used the Cochrane 'Risk of bias' tool to assess the risks of bias (i.e. systematic errors leading to overestimation of benefits and underestimation of harms). We used Trial Sequential Analysis to control risks of random errors (i.e. play of chance) and GRADE to assess the quality of the evidence and constructed 'Summary of findings' tables using GRADE software. MAIN RESULTS: We identified 11 randomised clinical trials (of which one acetylcysteine trial was abandoned due to low numbers recruited), assessing several different interventions in 700 participants. The variety of interventions studied included decontamination, extracorporeal measures, and antidotes to detoxify paracetamol's toxic metabolite; which included methionine, cysteamine, dimercaprol, or acetylcysteine. There were no randomised clinical trials of agents that inhibit cytochrome P-450 to decrease the activation of the toxic metabolite N-acetyl-p-benzoquinone imine.Of the 11 trials, only two had two common outcomes, and hence, we could only meta-analyse two comparisons. Each of the remaining comparisons included outcome data from one trial only and hence their results are presented as described in the trials. All trial analyses lack power to access efficacy. Furthermore, all the trials were at high risk of bias. Accordingly, the quality of evidence was low or very low for all comparisons. Interventions that prevent absorption, such as gastric lavage, ipecacuanha, or activated charcoal were compared with placebo or no intervention and with each other in one four-armed randomised clinical trial involving 60 participants with an uncertain randomisation procedure and hence very low quality. The trial presented results on lowering plasma paracetamol levels. Activated charcoal seemed to reduce the absorption of paracetamol, but the clinical benefits were unclear. Activated charcoal seemed to have the best risk:benefit ratio among gastric lavage, ipecacuanha, or supportive treatment if given within four hours of ingestion. There seemed to be no difference between gastric lavage and ipecacuanha, but gastric lavage and ipecacuanha seemed more effective than no treatment (very low quality of evidence). Extracorporeal interventions included charcoal haemoperfusion compared with conventional treatment (supportive care including gastric lavage, intravenous fluids, and fresh frozen plasma) in one trial with 16 participants. The mean cumulative amount of paracetamol removed was 1.4 g. One participant from the haemoperfusion group who had ingested 135 g of paracetamol, died. There were no deaths in the conventional treatment group. Accordingly, we found no benefit of charcoal haemoperfusion (very low quality of evidence). Acetylcysteine appeared superior to placebo and had fewer adverse effects when compared with dimercaprol or cysteamine. Acetylcysteine superiority to methionine was unproven. One small trial (low quality evidence) found that acetylcysteine may reduce mortality in people with fulminant hepatic failure (Peto OR 0.29, 95% CI 0.09 to 0.94). The most recent randomised clinical trials studied different acetylcysteine regimens, with the primary outcome being adverse events. It was unclear which acetylcysteine treatment protocol offered the best efficacy, as most trials were underpowered to look at this outcome. One trial showed that a modified 12-hour acetylcysteine regimen with a two-hour acetylcysteine 100 mg/kg bodyweight loading dose was associated with significantly fewer adverse reactions compared with the traditional three-bag 20.25-hour regimen (low quality of evidence). All Trial Sequential Analyses showed lack of sufficient power. Children were not included in the majority of trials. Hence, the evidence pertains only to adults. AUTHORS' CONCLUSIONS: These results highlight the paucity of randomised clinical trials comparing different interventions for paracetamol overdose and their routes of administration and the low or very low level quality of the evidence that is available. Evidence from a single trial found activated charcoal seemed the best choice to reduce absorption of paracetamol. Acetylcysteine should be given to people at risk of toxicity including people presenting with liver failure. Further randomised clinical trials with low risk of bias and adequate number of participants are required to determine which regimen results in the fewest adverse effects with the best efficacy. Current management of paracetamol poisoning worldwide involves the administration of intravenous or oral acetylcysteine which is based mainly on observational studies. Results from these observational studies indicate that treatment with acetylcysteine seems to result in a decrease in morbidity and mortality, However, further evidence from randomised clinical trials comparing different treatments are needed.

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.

Evidence for the changing regimens of acetylcysteine.

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