Management of Acetaminophen Poisoning in the US and Canada: A Consensus Statement.

Importance: The US and Canada currently have no formal published nationwide guidelines for specialists in poison information or emergency departments for the management of acetaminophen poisoning, resulting in significant variability in management. Objective: To develop consensus guidelines for the management of acetaminophen poisoning in the US and Canada. Evidence Review: Four clinical toxicology societies (America's Poison Centers, American Academy of Clinical Toxicology, American College of Medical Toxicology, and Canadian Association of Poison Control Centers) selected participants (n = 21). Led by a nonvoting chairperson using a modified Delphi method, the panel created a decision framework and determined the appropriate clinical management of a patient with acetaminophen poisoning. Unique to this effort was the collection of guidelines from most poison centers in addition to systematic collection and review of the medical literature. Comments from review by external organizations were incorporated before the guideline was finalized. The project began in March 2021 and ended in March 2023. Findings: The search retrieved 84 guidelines and 278 publications. The panel developed guidelines for emergency department management of single or repeated ingestion of acetaminophen. In addition, the panel addressed extended-release formulation, high-risk ingestion, coingestion of anticholinergics or opioids, age younger than 6 years, pregnancy, weight greater than 100 kg, and intravenous acetaminophen use. Differences from current US practice include defining acute ingestion as an ingestion presentation from 4 to 24 hours after overdose was initiated. A revised form of the Rumack-Matthew nomogram was developed. The term massive ingestion was replaced with the term high-risk ingestion and denoted by a specific nomogram line. Other recommendations include specific criteria for emergency department triage, laboratory evaluation and monitoring parameters, defining the role of gastrointestinal decontamination, detailed management of acetylcysteine treatment, associated adverse effects, and stopping criteria for acetylcysteine treatment, as well as criteria for consultation with a clinical toxicologist. Finally, specific treatment considerations, including acetylcysteine dosing, fomepizole administration, and considerations for extracorporeal elimination and transplant evaluation, were addressed. Conclusions and Relevance: This qualitative study provides a consensus statement on consistent evidence-based recommendations for medical, pharmacy, and nursing education and practice to optimize care of patients with acetaminophen poisoning.

Ninety-Day Stroke or Transient Ischemic Attack Recurrence in Patients Prescribed Anticoagulation in the Emergency Department With Atrial Fibrillation and a New Transient Ischemic Attack or Minor Stroke.

Background For patients with atrial fibrillation seen in the emergency department (ED) following a transient ischemic attack (TIA) or minor stroke, the impact of initiating oral anticoagulation immediately rather than deferring the decision to outpatient follow-up is unknown. Methods and Results We conducted a planned secondary data analysis of a prospective cohort of 11 507 adults in 13 Canadian EDs between 2006 and 2018. Patients were eligible if they were aged 18 years or older, with a final diagnosis of TIA or minor stroke with previously documented or newly diagnosed atrial fibrillation. The primary outcome was subsequent stroke, recurrent TIA, or all-cause mortality within 90 days of the index TIA diagnosis. Secondary outcomes included stroke, recurrent TIA, or death and rates of major bleeding. Of 11 507 subjects with TIA/minor stroke, atrial fibrillation was identified in 11.2% (1286, mean age, 77.3 [SD 11.1] years, 52.4% male). Over half (699; 54.4%) were already taking anticoagulation, 89 (6.9%) were newly prescribed anticoagulation in the ED. By 90 days, 4.0% of the atrial fibrillation cohort had experienced a subsequent stroke, 6.5% subsequent TIA, and 2.6% died. Results of a multivariable logistic regression indicate no association between prescribed anticoagulation in the ED and these 90-day outcomes (composite odds ratio, 1.37 [95% CI, 0.74-2.52]). Major bleeding was found in 5 patients, none of whom were in the ED-initiated anticoagulation group. Conclusions Initiating oral anticoagulation in the ED following new TIA was not associated with lower recurrence rates of neurovascular events or all-cause mortality in patients with atrial fibrillation.

Prospective Validation of Computed Tomography to Identify Patients at High Risk for Stroke After Transient Ischemic Attack or Minor Stroke.

BACKGROUND: Computed tomography (CT) findings of acute and chronic ischemia are associated with subsequent stroke risk in patients with transient ischemic attack. We sought to validate these associations in a large prospective cohort of patients with transient ischemic attack or minor stroke. METHODS: This prospective cohort study enrolled emergency department patients from 13 hospitals with transient ischemic attack who had CT imaging. Primary outcome was stroke within 90 days. Secondary outcomes were stroke within 2 or 7 days. CT findings were abstracted from radiology reports and classified for the presence of acute ischemia, chronic ischemia, or microangiopathy. Multivariable logistic regression was used to test associations with primary and secondary end points. RESULTS: From 8670 prospectively enrolled patients between May 2010 and May 2017, 8382 had a CT within 24 hours. From this total population, 4547 (54%) patients had evidence of acute ischemia, chronic ischemia, or microangiopathy on CT, of whom 175 had a subsequent stroke within 90 days (3.8% subsequent stroke rate; adjusted odds ratio [aOR], 2.33 [95% CI, 1.62-3.36]). This was in comparison to those with CT imaging without ischemia. Findings associated with an increased risk of stroke at 90 days were isolated acute ischemia (6.0%; aOR, 2.42 [95% CI, 1.03-5.66]), acute ischemia with microangiopathy (10.7%; aOR, 3.34 [95% CI, 1.57-7.14]), chronic ischemia with microangiopathy (5.2%; aOR, 1.83 [95% CI, 1.34-2.50]), and acute ischemia with chronic ischemia and microangiopathy (10.9%; aOR, 3.49 [95% CI, 1.54-7.91]). Acute ischemia with chronic ischemia and microangiopathy were most strongly associated with subsequent stroke within 2 days (aOR, 4.36 [95% CI, 1.31-14.54]) and 7 days (aOR, 4.50 [95% CI, 1.73-11.69]). CONCLUSIONS: In patients with transient ischemic attack or minor stroke, CT evidence of acute ischemia with chronic ischemia or microangiopathy significantly increases the risk of subsequent stroke within 90 days of index visit. The combination of all 3 findings results in the greatest early risk.

Predictors of neurologists confirming or overturning emergency physicians' diagnosis of TIA or stroke.

BACKGROUND: Transient ischemic attack (TIA) and non-disabling stroke are common emergency department (ED) presentations. Currently, there are no prospective multicenter studies determining predictors of neurologists confirming a diagnosis of cerebral ischemia in patients discharged with a diagnosis of TIA or stroke. The objectives were to (1) calculate the concordance between emergency physicians and neurologists for the outcome of diagnosing TIA or stroke, and (2) identify characteristics associated with neurologists diagnosing a stroke mimic. METHODS: This was a planned sub-study of a prospective cohort study at 14 Canadian EDs enrolling patients diagnosed with TIA or non-disabling stroke from 2006 to 2017. Logistic regression was used to identify factors associated with neurologists' diagnosis of cerebral ischemia. Our primary outcome was the composite outcome of cerebral ischemia (TIA or non-disabling stroke) based on the neurologists' assessment. RESULTS: The diagnosis of cerebral ischemia was confirmed by neurologists in 5794 patients (55.4%). The most common identified stroke mimics were migraine (18%), peripheral vertigo (7%), syncope (4%), and seizure (3%). Over a third of patients (38.4%) ultimately had an undetermined aetiology for their symptoms. The strongest predictors of cerebral ischemia confirmation were infarct on CT (OR 1.83, 95% CI 1.65-2.02), advanced age (OR comparing 75th-25th percentiles 1.67, 1.55-1.80), language disturbance (OR 1.92, 1.75-2.10), and smoking (OR 1.67, 1.46-1.91). The strongest predictors of stroke mimics were syncope (OR 0.59, 0.48-0.72), vertigo (OR 0.52, 0.45-0.59), bilateral symptoms (OR 0.60, 0.50-0.72), and confusion (OR 0.50, 0.44-0.57). CONCLUSION: Physicians should have a high index of suspicion of cerebral ischemia in patients with advanced age, smoking history, language disturbance, or infarcts on CT. Physicians should discriminate in which patients to pursue stroke investigations on when deemed at minimal risk of cerebral ischemia, including those with isolated vertigo, syncope, or bilateral symptoms.

RéSUMé: CONTEXTE: L'accident ischémique transitoire (AIT) et l'accident vasculaire cérébral (AVC) non invalidant sont des présentations courantes dans les services d'urgence. Actuellement, il n'existe pas d'études prospectives multicentriques déterminant les facteurs prédictifs de la confirmation par les neurologues d'un diagnostic d'ischémie cérébrale chez les patients sortis de l'hôpital avec un diagnostic d'AIT ou d'AVC. Les objectifs étaient de (1) calculer la concordance entre les urgentistes et les neurologues pour le résultat du diagnostic de l'AIT ou de l'AVC, et (2) identifier les caractéristiques associées au diagnostic par les neurologues d'une imitation d'AVC. MéTHODES: Il s'agissait d'une sous-étude planifiée d'une étude de cohorte prospective dans 14 services d'urgence canadiens recrutant des patients diagnostiqués avec un AIT ou un AVC non invalidant de 2006 à 2017. Une régression logistique a été utilisée pour identifier les facteurs associés au diagnostic d'ischémie cérébrale par les neurologues. Notre résultat principal était le résultat composite de l'ischémie cérébrale (AIT ou accident vasculaire cérébral non invalidant) selon l'évaluation des neurologues. RéSULTATS: Le diagnostic d'ischémie cérébrale a été confirmé par des neurologues chez 5 794 patients (55,4 %). Les imitateurs d'AVC identifiés les plus courants étaient la migraine (18 %), le vertige périphérique (7 %), la syncope (4 %) et les convulsions (3 %). Plus d'un tiers des patients (38,4 %) avaient finalement une étiologie indéterminée pour leurs symptômes. Les prédicteurs les plus forts de la confirmation de l'ischémie cérébrale étaient l'infarctus au scanner (OR 1.83, IC 95 % 1.65­2.02), l'âge avancé (OR comparant les 75e et 25e percentiles 1.67, 1.55­1.80), les troubles du langage (OR 1.92, 1.75­2.10) et le tabagisme (OR 1.67, 1.46­1.91). Les prédicteurs les plus forts d'imitateurs d'AVC étaient la syncope (OR 0.59, 0.48­0.72), le vertige (OR 0.52, 0.45­0.59), les symptômes bilatéraux (OR 0.60, 0.50­0.72) et la confusion (OR 0.50, 0.44­0.57). CONCLUSION: Les médecins devraient avoir un indice élevé de suspicion d'ischémie cérébrale chez les patients ayant un âge avancé, des antécédents de tabagisme, des troubles du langage ou des infarctus au scanner. Les médecins doivent distinguer les patients sur lesquels poursuivre des investigations sur un AVC lorsqu'ils sont jugés à risque minimal d'ischémie cérébrale, y compris ceux présentant des vertiges isolés, une syncope ou des symptômes bilatéraux.

Code Status Documentation Availability and Accuracy Among Emergency Patients with End-stage Disease.

INTRODUCTION: Some patients with end-stage disease who may neither want nor benefit from aggressive resuscitation receive such treatment if they cannot communicate in an emergency. Timely access to patients' current resuscitation wishes, or "code status," should be a key metric of electronic health records (EHR). We sought to determine what percentage of a cohort of patients with end-stage disease who present to the emergency department (ED) have accessible, code status documents, and for those who do, how quickly can this documentation be retrieved. METHODS: In this cross-sectional study of ED patients with end-stage disease (eg, palliative care, metastatic malignancy, home oxygen, dialysis) conducted during purposefully sampled random accrual times we performed a standardized, timed review of available health records, including accompanying transfer documents. We also interviewed consenting patients and substitute decision makers to compare available code status documents to their current wishes. RESULTS: Code status documentation was unavailable within 15 minutes of ED arrival in most cases (54/85, or 63%). Retrieval time was under five minutes in the rest, especially when "one click deep" in the EHR. When interviewed, 20/32 (63%) expressed "do not resuscitate" wishes, 10 of whom had no supporting documentation. Patients from assisted-living (odds ratio [OR] 6.7; 95% confidence interval [CI], 1.7-26) and long-term care facilities (OR 13; 95% CI, 2.5-65) were more likely to have a documented code status available compared to those living in the community. CONCLUSION: The majority of patients with end-stage disease, including half of those who would not wish resuscitation from cardiorespiratory arrest, did not have code status documents readily available upon arrival to our tertiary care ED. Patients living in the community with advanced disease may be at higher risk for unwanted resuscitative efforts should they present to hospital in extremis. While easily retrievable code status documentation within the EHR shows promise, its accuracy and validity remain important considerations.

Adverse Events Among Emergency Department Patients With Cardiovascular Conditions: A Multicenter Study.

STUDY OBJECTIVE: We aim to determine incidence and type of adverse events (adverse outcomes related to emergency care) among emergency department (ED) patients discharged with recent-onset atrial fibrillation, acute heart failure, and syncope. METHODS: This 5-year prospective cohort study included high-acuity adult patients discharged with the 3 sentinel diagnoses from 6 tertiary care Canadian EDs. We screened all ED visits for eligibility and performed telephone interviews 14 days postdischarge to identify flagged outcomes: death, hospital admission, return ED visit, health care provider visit, and new or worsening symptoms. We created case summaries describing index ED visit and flagged outcomes, and trained emergency physicians reviewed case summaries to identify adverse events. We reported adverse event incidence and rates with 95% confidence intervals and contributing factor themes. RESULTS: Among 4,741 subjects (mean age 70.2 years; 51.2% men), we observed 170 adverse events (3.6 per 100 patients; 95% confidence interval 3.1 to 4.2). Patients discharged with acute heart failure were most likely to experience adverse events (5.3%), followed by those with atrial fibrillation (2.0%) and syncope (0.8%). We noted variation in absolute adverse event rates across sites from 0.7 to 6.0 per 100 patients. The most common adverse event types were management issues, diagnostic issues, and unsafe disposition decisions. Frequent contributing factor themes included failure to recognize underlying causes and inappropriate management of dual diagnoses. CONCLUSION: Among adverse events after ED discharge for patients with these 3 sentinel cardiovascular diagnoses, we identified quality improvement opportunities such as strengthening dual diagnosis detection and evidence-based clinical practice guideline adherence.

Adducts Post Acetaminophen Overdose Treated with a 12-Hour vs 20-Hour Acetylcysteine Infusion.

INTRODUCTION: Acetaminophen protein adducts in the circulation are a specific biomarker of acetaminophen oxidation, and may be a more sensitive measure of impending hepatic injury following overdose than alanine transaminase (ALT). We performed an exploratory analytical substudy of adducts during a clinical trial (NACSTOP) of abbreviated (12-hour) versus control (20-hour) acetylcysteine to identify any signal of diminished antidotal effectiveness with shortened therapy. METHODS: We measured adducts at 0, 12, and 20 hours from a convenience sample of subjects enrolled in the cluster-controlled NACSTOP trial evaluating a 12-hour ("abbreviated"; 200 mg/kg over 4 hours, 50 mg/kg over 8 hours) vs 20-hour acetylcysteine regimen ("control"; 200 mg/kg over 4 hours, 100 mg/kg over 16 hours). Adducts were assayed using high-performance liquid chromatography/mass spectrometry. RESULTS: Median ALT 20 hours after the initiation of acetylcysteine was 12 U/L (IQR 8,14) in the abbreviated 12-hour regimen group (N = 8), compared with the control group 16 U/L (IQR 11,21; N = 21) (p = 0.46). Adduct concentrations were similarly low in both groups: abbreviated [(0.005 µmol/L, IQR (0,0.14)] and control [(0.005 µmol/L, IQR (0,0.05)] (p = 0.61). CONCLUSIONS: There were minimal to no acetaminophen protein adducts detected. These findings further support discontinuing acetylcysteine when acetaminophen concentrations are low and liver function tests normal after 12 hours of treatment.

ST-elevation in ethylene glycol toxicity mimicking myocardial infarction.

Electrocardiographic changes due to ethylene glycol toxicity are described in a 37-year-old woman who presented with intentional overdose. She received prompt treatment with dialysis and fomepizole, which reversed profound metabolic acidosis. ST-elevation in leads I, aVL, and aVR were observed 87 h after admission along with diffuse repolarization abnormalities. Coronary angiography found no evidence of coronary artery disease, and echocardiogram revealed normal left ventricle size and a mildly hypokinetic basal inferior wall. Diffuse repolarization abnormalities persisted for several days. Review of literature supports the diagnosis of myocarditis induced by toxic metabolites of ethylene glycol in context of hepatic and renal failure.

Changing nomogram risk zone classification with serial testing after acute acetaminophen overdose: a retrospective database analysis.

CONTEXT: The Rumack-Matthew nomogram stratifies patients into discrete risk zones following acetaminophen (APAP) overdose. Treatment decisions have traditionally been based on the initial risk zone. "Line-crossing" between zones occurs and is poorly understood. The study objective was to characterize line-crossing behavior in acute APAP overdose patients, especially moving from below to above the nomogram treatment threshold. METHODS AND MATERIALS: The study was a secondary analysis of the Canadian Acetaminophen Overdose Study (CAOS) database, a large medical record review of patients hospitalized in eight large Canadian cities (1980-2005) following APAP poisoning. Population consisted of acute APAP overdose patients with at least two serum concentrations performed during hospitalization. Using ordinal logistic regression, we studied the effects of patient demographics, ingestion size/timing, APAP concentrations, time to N-acetylcysteine (NAC), and co-ingestants on a three-level dependent variable: patients whose risk increased two or more zones, those remaining in the same or adjacent zone, and those whose risk fell by two or more zones. RESULTS: Of the 3201 eligible hospitalizations with 7705 APAP concentrations, half (1679, 52.5%) crossed at least one zone (up or down) within 24 h of acute ingestion, including 190 (5.9%), who crossed at least two lines into a higher risk zone, and 516 (16.1%) at least two lines into a lower risk zone. Of the 1251 patients initially below the nomogram treatment line of 150 µg/mL, 131 (10.8%) patients crossed above this line. Being older, male, and co-ingesting opioids, antimuscarinics, or NSAIDs were independently associated with line-crossing. CONCLUSIONS: Patients commonly crossed nomogram risk zones, including from below to above the current treatment threshold. These findings support recommendations for serial APAP testing until the individual risk of hepatic injury is clearly established.

Anaphylactoid Reactions to Intravenous N-Acetylcysteine during Treatment for Acetaminophen Poisoning.

BACKGROUND: Anaphylactoid reactions to intravenous (IV) N-acetylcysteine (NAC) are well-recognized adverse events during treatment for acetaminophen (APAP) poisoning. Uncertainty exists regarding their incidence, severity, risk factors, and management. We sought to determine the incidence, risk factors, and treatment of anaphylactoid reactions to IV NAC in a large, national cohort of patients admitted to hospital for acetaminophen overdose. METHODS: This retrospective medical record review included all patients initiated on the 21-h IV NAC protocol for acetaminophen poisoning in 34 Canadian hospitals between February 1980 and November 2005. The primary outcome was any anaphylactoid reaction, defined as cutaneous (urticaria, pruritus, angioedema) or systemic (hypotension, respiratory symptoms). We examined the incidence, severity and timing of these reactions, and their association with patient and overdose characteristics using multivariable analysis. RESULTS: An anaphylactoid reaction was documented in 528 (8.2%) of 6455 treatment courses, of which 398 (75.4%) were cutaneous. Five hundred four (95.4%) reactions occurred during the first 5 h. Of 403 patients administered any medication for these reactions, 371 (92%) received an antihistamine. Being female (adjusted OR 1.24 [95%CI 1.08, 1.42]) and having taken a single, acute overdose (1.24 [95%CI 1.10, 1.39]) were each associated with more severe reactions, whereas higher serum APAP concentrations were associated with fewer reactions (0.79 [95%CI 0.68, 0.92]). CONCLUSION: Anaphylactoid reactions to the 21-h IV NAC protocol were uncommon and involved primarily cutaneous symptoms. While the protective effects of higher APAP concentrations are of interest in understanding the pathophysiology, none of the associations identified are strong enough to substantially alter the threshold for NAC initiation.

Accuracy of the paracetamol-aminotransferase product to predict hepatotoxicity in paracetamol overdose treated with a 2-bag acetylcysteine regimen.

INTRODUCTION: Paracetamol concentration is a highly accurate risk predictor for hepatotoxicity following overdose with known time of ingestion. However, the paracetamol-aminotransferase multiplication product can be used as a risk predictor independent of timing or ingestion type. Validated in patients treated with the traditional, "three-bag" intravenous acetylcysteine regimen, we evaluated the accuracy of the multiplication product in paracetamol overdose treated with a two-bag acetylcysteine regimen. METHODS: We examined consecutive patients treated with the two-bag regimen from five emergency departments over a two-year period. We assessed the predictive accuracy of initial multiplication product for the primary outcome of hepatotoxicity (peak alanine aminotransferase ≥1000IU/L), as well as for acute liver injury (ALI), defined peak alanine aminotransferase ≥2× baseline and above 50IU/L). RESULTS: Of 447 paracetamol overdoses treated with the two-bag acetylcysteine regimen, 32 (7%) developed hepatotoxicity and 73 (16%) ALI. The pre-specified cut-off points of 1500 mg/L × IU/L (sensitivity 100% [95% CI 82%, 100%], specificity 62% [56%, 67%]) and 10,000 mg/L × IU/L (sensitivity 70% [47%, 87%], specificity of 97% [95%, 99%]) were highly accurate for predicting hepatotoxicity. There were few cases of hepatotoxicity irrespective of the product when acetylcysteine was administered within eight hours of overdose, when the product was largely determined by a high paracetamol concentration but normal aminotransferase. CONCLUSIONS: The multiplication product accurately predicts hepatotoxicity when using a two-bag acetylcysteine regimen, especially in patients treated more than eight hours post-overdose. Further studies are needed to assess the product as a method to adjust for exposure severity when testing efficacy of modified acetylcysteine regimens.

Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose.

CONTEXT: The paracetamol-aminotransferase multiplication product (APAP × ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses. OBJECTIVE: The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose. METHODS: We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase ≥1000 IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L. RESULTS: Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product <10,000 mg/L × IU/L developed hepatotoxicity (sensitivity 100% [95%CI 48%, 100%], specificity 97% [90%, 100%]). Specificity fell to 54% (95%CI: 34, 59%) at a product cut-off point <1500 mg/L × IU/L. When calculated within eight hours of ingestion, mild elevations of the multiplication product fell quickly on repeat testing in patients without ALI or hepatotoxicity. CONCLUSIONS: In modified-release paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000 mg/L × IU/L, it was very strongly associated with the development of acute liver injury and hepatotoxicity, especially when calculated more than eight hours post-ingestion. When below 1500 mg/L × IU/L the likelihood of developing hepatotoxicity was very low. Persistently high serial multiplication product calculations were associated with the greatest risk of hepatotoxicity.

Can a serum acetaminophen concentration obtained less than 4 hours post-ingestion determine which patients do not require treatment with acetylcysteine?

CONTEXT: The interpretation of acetaminophen concentrations obtained prior to 4 hours after an acute, single overdose remains unclear. Patient care decisions in the Emergency Department could be accelerated if such concentrations could reliably exclude the need for treatment. OBJECTIVE: To determine the agreement between a serum acetaminophen concentration obtained less than 4 hours after an acute ingestion and the subsequent 4 + hour concentration, and the predictive accuracy of early concentrations for identifying patients with potentially toxic exposures. METHODS: A secondary analysis of patients admitted for acetaminophen poisoning at one of the 34 hospitals in eight Canadian cities from 1980 to 2005. We examined serum acetaminophen concentrations obtained less than 4 hours post-ingestion, and again 4 or more hours post-ingestion. For the diagnostic accuracy analysis, we specified a cutpoint of 100 µg/mL (662 µmol/L) obtained between 2 and 4 hours and a subsequent 4 to 20 hour acetaminophen concentration above the nomogram treatment line of 150 µg/mL (993 µmol/L). RESULTS: Of 2454 patients identified, 879 (36%) had a subsequent acetaminophen concentration above the nomogram treatment line. The 2-4 hour concentration demonstrated a sensitivity of 0.96 [95% CI; 0.94, 0.97] and a negative likelihood ratio of 0.070 [0.048, 0.10]. Coingested opioids reduced this sensitivity to 0.91 [0.83, 0.95], and antimuscarinics to 0.86 [0.72, 0.94]. Only very low to undetectable acetaminophen concentrations prior to 4 hours reliably excluded a subsequent concentration over the treatment line. CONCLUSIONS: Applying an acetaminophen concentration cutpoint of 100 µg/mL (662 µmol/L) at 2-4 hours after an acute ingestion as a threshold for repeat testing and/or treatment would occasionally miss potentially toxic exposures. Absorption of acetaminophen is only slightly delayed by coingested opioids or antimuscarinics. Our analysis validates the practice of not retesting when the first post-ingestion acetaminophen concentration is below the lower limit of quantification.

Outcomes of Patients With Premature Discontinuation of the 21-h Intravenous N-Acetylcysteine Protocol After Acute Acetaminophen Overdose.

BACKGROUND: The minimum recommended treatment duration for i.v. N-acetylcysteine (NAC) after an acute, single acetaminophen (APAP) overdose is 21 h. Some have questioned whether shorter courses may be sufficient in carefully selected cases. OBJECTIVE: We sought to describe the incidence of hepatotoxicity in a cohort of acute APAP overdose patients who received <21 h of i.v. NAC for any reason. METHODS: We performed a secondary analysis of a large multicenter retrospective cohort of patients hospitalized for APAP poisoning. We selected patients with a potentially toxic serum APAP concentration measured between 4 and 24 h post ingestion, in whom i.v. NAC was initiated but discontinued before completing the full 21-h course. We further characterized outcomes in these patients as a function of two novel risk-prediction tools, the psi (ψ) parameter and APAP × aminotransferase (AT) product. The ψ parameter is an estimate of the cellular burden of injury based on the area under the concentration-time curve before treatment, and calculated with respect to the APAP concentration and time to initiation of NAC. RESULTS: Fifty-nine patients met inclusion criteria. Intravenous NAC was initiated a median of 11.3 h post ingestion and administered for a median of 11.0 h. Hepatotoxicity (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] > 1,000 IU/L) occurred in one patient (1.7%; 95% confidence interval 0.04-9.1), and eight additional patients developed hepatic injury (AST or ALT > 100 IU/L). No fatalities occurred. A multiplication product of APAP and AT (APAP × AT) that falls below 10,000 µmol/L/IU-L, or pretreatment ψ < 5 mmol/L-h suggested a low risk of hepatic injury. CONCLUSIONS: In this retrospective analysis of patients treated with < 21 h of i.v. NAC for acute APAP overdose, the incidence of hepatotoxicity and coagulopathy was low, despite delays to NAC treatment.

A descriptive analysis of aspartate and alanine aminotransferase rise and fall following acetaminophen overdose.

CONTEXT: Risk prediction following acetaminophen (paracetamol, APAP) overdose is based on serum APAP, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels. One recently proposed risk stratification tool, the APAPxAT multiplication product, uses either AST or ALT, whichever is higher, yet their interrelation is not well known following APAP-induced hepatic injury. OBJECTIVE: To describe the kinetics of AST and ALT release into and disappearance from the circulation following APAP overdose. MATERIALS AND METHODS: An observational case series of adult patients with peak AST or ALT > 100 IU/L attributable to APAP toxicity. Cases were identified by electronic search of hospital laboratory database and by discharge diagnosis corroborated by structured explicit medical record review. RESULTS: Of 68 cases identified (mean age (SD): 39 (18) years, 63% female, and 21% ethanol co-ingested), 28 (41%) developed hepatotoxicity (peak AST or ALT > 1000 IU/L), 28 (41%) coagulopathy (international normalized ratio or INR > 2), and 21 (31%) both. Three patients (4%) were transferred for liver transplantation and ultimately six (8.8%) died. Serum AST and ALT activity rose in a closely aligned 1:1 AST:ALT ratio, but fell at distinctly different rates: AST activity fell with a half-life (interquartile range [IQR]) of 15.1 (12.2, 19.4) hours, and ALT 39.6 (32.9, 47.6) hours. Using an aminotransferase falling to below 50% of peak as the basis for discontinuing acetylcysteine would have resulted in antidotal treatment being stopped 24 (IQR: 9.6, 40) hours earlier (and in no cases later) using AST rather than ALT. Only six patients had an AST:ALT ratio greater than 2:1 at the time of acetylcysteine administration; of these six, four died and one survivor developed coagulopathy. DISCUSSION: AST and ALT release into the circulation appears tightly linked and numerically similar, except in the sickest patients. Once the aminotransferases peak, AST returns to baseline more quickly. CONCLUSION: Either AST or ALT can be used for early risk stratification tools when only one is known. Any criterion for N-AC discontinuation should be based on the decline of AST rather than ALT, with a potential benefit measured in days.

External validation of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity from paracetamol overdose.

CONTEXT: Risk prediction in paracetamol (acetaminophen, or APAP) poisoning treated with acetylcysteine helps guide initial patient management and disposition. The paracetamol-aminotransferase multiplication product may be a useful and less time-sensitive risk predictor. OBJECTIVE: The aim of this study was to validate this multiplication product in an independent cohort of patients with paracetamol overdose. MATERIALS AND METHODS: Using an existing toxicology dataset of poisoned patients from two large inner-city United Kingdom teaching hospitals, we retrospectively identified by electronic search all paracetamol overdoses from February 2005 to March 2013. We assessed the diagnostic accuracy of the multiplication product (serum APAP concentration × alanine transaminase [ALT] activity), especially at the pre-specified cut-off points of 1 500 mg/L × IU/L (10 000 micromol/L × IU/L) and 10 000 mg/L × IU/L (66 000 micromol/L × IU/L). The primary outcome was hepatotoxicity defined by a peak ALT > 1000 IU/L. RESULTS: Of 3823 total paracetamol overdose presentations, there were 2743 acute single, 452 delayed single (> 24 h post overdose), 426 staggered (ingestion over > 1 h), and 202 supratherapeutic ingestions. Altogether, 34 patients developed hepatotoxicity. Among the acute single-ingestion patients, a multiplication product > 10 000 mg/L × IU/L had a sensitivity of 80% (95% confidence interval [CI]: 44%, 96%) and specificity of 99.6% [99.3%, 99.8%], while a product > 1 500 mg/L × IU/L had a sensitivity of 100% [66%, 100%] and specificity of 92% [91%, 93%]. Overall, 16 patients with a multiplication product > 10 000 mg/L × IU/L developed hepatotoxicity (likelihood ratio: 250, 95% CI: 130, 480), and 4 patients with a multiplication product between 1 500 and 10 000 (likelihood ratio: 2.5, 95% CI: 1.0, 6.0). No patient with a product < 1 500 mg/L × IU/L who received acetylcysteine developed hepatotoxicity. CONCLUSIONS: Regardless of ingestion type, a product > 10 000 mg/L × IU/L was associated with a very high likelihood, and < 1 500 mg/L × IU/L with a very low likelihood, of developing hepatotoxicity in patients treated with acetylcysteine.

Multiplying the serum aminotransferase by the acetaminophen concentration to predict toxicity following overdose.

CONTEXT: The first available predictors of hepatic injury following acetaminophen (APAP) overdose are the serum APAP and aminotransferases [AT, i.e., aspartate (AST) aminotransferase or alanine (ALT) aminotransferase]. OBJECTIVE: We describe the initial value, rate of change, and interrelationship between these biomarkers in patients who develop hepatotoxicity despite treatment following acute overdose. A new parameter, the APAP × AT multiplication product, is proposed for early risk stratification. METHODS: We conducted a descriptive study of individuals selected from a multicenter retrospective cohort of patients hospitalized for APAP poisoning. We selected those acute APAP overdose patients who subsequently developed AT > 1,000 IU/L. Rising serum AT values were compared to simultaneously measured (or estimated) falling serum APAP. The APAP × AT was expressed relative to initiation of acetylcysteine therapy and grouped by time to meeting hepatotoxicity criteria. RESULTS: In the 94 cases studied, serum APAP concentrations were still appreciable [median 570 (interquartile range (IQR) 314-983) µmol/L] at the time of the first measured AT [211 (77-511) IU/L at 15.3 (12.1-19.2) h post-ingestion], yielding an initial APAP × AT of 99,000 (52,000-240,000) µmol × IU/L(2). Because serum AT rose rapidly (doubling time 9.5 h ) and APAP fell slowly (half-life 4.8 h), the multiplication product remained elevated during the first 12-24 h of antidotal therapy, especially among patients who developed earlier hepatotoxicity (AT > 1,000 IU/L). DISCUSSION AND CONCLUSIONS: The APAP × AT multiplication product, calculated at the time of presentation and after several h of antidotal therapy, holds promise as a new risk predictor following APAP overdose. It requires neither graphical interpretation nor accurate time of ingestion, two limitations to current risk stratification.