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.

Differentiating Ischemic Hepatitis from Acetaminophen Overdose in Acute Liver Failure: Role of Acetaminophen Adducts-Ischemic Hepatitis vs Acetaminophen Overdose.

BACKGROUND AND AIMS: Acetaminophen (APAP) hepatotoxicity and ischemic hepatic injury (IH) demonstrate remarkably similar biochemical patterns. Deciding between these two etiologies in the setting of acute liver failure (ALF) can be challenging. We reviewed all cases in the Acute Liver Failure Study Group (ALFSG) registry where these diagnoses were considered, to determine reasons for, and frequency of, difficulties making these diagnoses. We hypothesized that the newly developed APAP-CYS adduct assay could help in discerning the correct diagnosis. METHODS: Among 3364 patients with ALF or acute liver injury (ALI: INR ≥ 2.0 but without encephalopathy) between 1998 and 2019, 1952 (58%) received a final diagnosis of either APAP (1681) or IH (271). We utilized a review committee of senior hepatologists as well as the APAP-CYS assay (where sera were available), measuring the presence of toxic by-products of APAP injury to optimize adjudication. RESULTS: With these methods, a total of 575 adduct positive APAP cases included 488 recognized APAP, as well as an additional 87 patients previously diagnosed as other etiologies. Nine cases initially attributed to IH were deemed combination APAP-IH injuries. Conversely, 215 of the 280 IH subjects tested for adducts disclosed 173 confirmed as IH with adduct testing below the toxicity threshold, while 9 cases were revised from APAP to the IH-APAP combination phenotype, where both hypotension and APAP likely played a role. CONCLUSIONS: Discerning APAP from IH can be difficult-in rare cases, combined injury is observed (18/1952). APAP-CYS testing resulted in revising the diagnosis in 14.6% of cases.

Adolescent Acetaminophen and Ibuprofen Self-Poisoning, 2017-2022.

BACKGROUND: Acetaminophen and ibuprofen are the most common agents involved in adolescent self-poisoning. With increasing suicidality observed during the COVID-19 pandemic, we sought to compare overdose trends, severity, and outcomes for both agents. METHODS: We performed a retrospective analysis of the National Poison Data System for acetaminophen and ibuprofen single-substance exposures in teenagers 13-19 years of age from 2017-2022. Acetaminophen and ibuprofen overdoses (per 100,000 persons) were plotted by year. Medical outcomes, clinical effects, and therapies were compared to determine if there were differences in overdose severity between the 2 agents. RESULTS: From 2017 to 2022, US poison centers recorded 50,902 single-substance acetaminophen exposures and 41,674 single-substance ibuprofen exposures in teenagers. Cases peaked in 2021 with 40.0 versus 29.1 cases (per 100,000 persons) for acetaminophen and ibuprofen, respectively. Acetaminophen self-poisoning was significantly more likely to result in death (odds ratio, 13.92; 95% confidence interval, 2.18-581.75; P < 0.001) or inpatient admission (odds ratio, 7.38; 95% confidence interval, 7.10-7.66; P < 0.001) compared with ibuprofen. Abdominal pain and vomiting were the most common clinical effects for both agents, and unsurprisingly, acetaminophen was more likely to cause transaminitis and liver dysfunction, whereas ibuprofen was more likely to cause central nervous system depression and metabolic acidosis. For the acetaminophen group, 19 teenagers underwent organ transplantation. CONCLUSIONS: Given the increased hospitalization and treatment resources needed for acetaminophen overdoses compared with ibuprofen, it is time to implement acetaminophen packaging policy change to protect US adolescents.

The Insidious Enemy of the Liver: The Situation in Childhood Acetaminophen Poisoning and Early N-AC Treatment.

METHODS: This study was designed as a cross-sectional, observational, retrospective study. The variables of the study were paracetamol overdose, demographic information, poisoning mechanisms, clinical, laboratory findings, and clinical progression of the cases. The cases compared in whom treatment was initiated within the first 8 hours after poisoning and those in whom it was not. χ 2 , t test, and logistic regression analyses were conducted at appropriate facilities. RESULTS: Three hundred forty-eight cases were included in the study. N-AC treatment was initiated within the first 8 hours after poisoning in 322 cases (92.5%), and 26 cases received N-AC treatment after 8 hours after poisoning. Liver toxicity developed in 6 cases (1.7%), and indications for liver transplantation were met in 36 cases (10.3%). Among the 26 cases for which treatment was not initiated within the first 8 hours, 18 cases (69.2%) had indications for liver transplantation ( P < 0.01). It was found that N-AC within the first 8 hours reduced the risk by 43 times ( P = 0.02) and being older than 6 years, being admitted to the intensive care unit, and having alanine aminotransferase values above 1000 U/L increased the risk significantly ( P = 0.009, P = 0.005, P < 0.001). When a receiver operating characteristic curve was plotted for the 4th-hour blood acetaminophen level to predict liver transplantation, a value of 684.5 µg/mL emerged with 89% sensitivity and 93% specificity (area under the curve, 0.951). CONCLUSIONS: As a result, this study demonstrates the protective effect of early-initiated N-AC therapy on liver toxicity in pediatric acetaminophen poisoning cases. It also highlights a significant impact of gastrointestinal decontamination methods.

Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose.

Acetaminophen (APAP) overdose can cause hepatotoxicity and even liver failure. N-acetylcysteine (NAC) is still the only FDA-approved antidote against APAP overdose 40 years after its introduction. The standard oral or intravenous dosing regimen of NAC is highly effective for patients with moderate overdoses who present within 8 h of APAP ingestion. However, for late-presenting patients or after ingestion of very large overdoses, the efficacy of NAC is diminished. Thus, additional antidotes with an extended therapeutic window may be needed for these patients. Fomepizole (4-methylpyrazole), a clinically approved antidote against methanol and ethylene glycol poisoning, recently emerged as a promising candidate. In animal studies, fomepizole effectively prevented APAP-induced liver injury by inhibiting Cyp2E1 when treated early, and by inhibiting c-jun N-terminal kinase (JNK) and oxidant stress when treated after the metabolism phase. In addition, fomepizole treatment, unlike NAC, prevented APAP-induced kidney damage and promoted hepatic regeneration in mice. These mechanisms of protection (inhibition of Cyp2E1 and JNK) and an extended efficacy compared to NAC could be verified in primary human hepatocytes. Furthermore, the formation of oxidative metabolites was eliminated in healthy volunteers using the established treatment protocol for fomepizole in toxic alcohol and ethylene glycol poisoning. These mechanistic findings, together with the excellent safety profile after methanol and ethylene glycol poisoning and after an APAP overdose, suggest that fomepizole may be a promising antidote against APAP overdose that could be useful as adjunct treatment to NAC. Clinical trials to support this hypothesis are warranted.

Successful orthotopic liver transplantation in a patient with a positive SARS-CoV2 test and acute liver failure secondary to acetaminophen overdose.

SARS-CoV2, first described in December 2019, was declared a pandemic by the World Health Organization in March 2020. Various surgical and medical societies promptly published guidelines, based on expert opinion, on managing patients with COVID-19, with a consensus to postpone elective surgeries and procedures. We describe the case of an orthotopic liver transplantation (OLT) in a young female who presented with acute liver failure secondary to acetaminophen toxicity to manage abdominal pain and in the setting of a positive SARS-CoV2 test. Despite a positive test, she had no respiratory symptoms at time of presentation. The positive test was thought to be residual viral load. The patient had a very favorable outcome, likely related to multiple factors including her young age, lack of respiratory COVID-19 manifestations and plasma exchange peri-operatively. We recommend a full work-up for OLT in COVID-19 patients with uncomplicated disease according to standard of care, with careful interpretation of COVID-19 testing in patients presenting with conditions requiring urgent or emergent surgery as well as repeat testing even a few days after initial testing, as this could alter management.

Routine Laboratory Screening for Acetaminophen and Salicylate Ingestion in Preadmission Psychiatric Patients Is Unnecessary.

STUDY OBJECTIVE: Screening preadmission psychiatric patients for acetaminophen or salicylate overdose is unnecessary in the absence of specific clinical concern for medication ingestion. METHODS: This was a multicenter retrospective cohort study of 3 Veteran's Administration emergency departments that medically evaluate patients prior to psychiatric admission. During the 10-year study period, these departments followed screening protocols that required the measurement of acetaminophen and salicylate levels on every patient prior to psychiatric admission. We examined all the acetaminophen and salicylate assays performed to see if any that were sent for screening led to a diagnosis of overdose and/or the administration of antidotal therapy. RESULTS: A total of 33,439 combined acetaminophen and salicylate assays were sent on 10,482 unique patients over approximately 17,000 patient encounters. An estimated 29,000 assays were sent for screening purposes only-87% (95% confidence interval [CI] 85% to 89%) of salicylate assays and 85% (95% CI 83% to 87%) of acetaminophen assays. We identified 43 patients with elevated acetaminophen levels and 11 with elevated salicylate levels. Among these patients, only 6 in total had their levels drawn for screening purposes only, with no history of suspected ingestion; in all but 1 patient, the levels were only slightly above the reference range. None of the patients with elevated levels identified by screening had clinical toxicity or received antidotal therapy. CONCLUSION: Over a 10-year period, 3 Veteran's Administration emergency departments performed psychiatric preadmission screening protocols with acetaminophen and salicylate assays approximately 17,000 times without diagnosing a single case of toxicity. Our results suggest that this practice is unnecessary and wasteful.

Delayed administration of N-acetylcysteine blunts recovery after an acetaminophen overdose unlike 4-methylpyrazole.

N-acetylcysteine (NAC) is the only clinically approved antidote against acetaminophen (APAP) hepatotoxicity. Despite its efficacy in patients treated early after APAP overdose, NAC has been implicated in impairing liver recovery in mice. More recently, 4-methylpyrazole (4MP, Fomepizole) emerged as a potential antidote in the mouse APAP hepatotoxicity model. The objective of this manuscript was to verify the detrimental effect of NAC and its potential mechanism and assess whether 4MP has the same liability. C57BL/6J mice were treated with 300 mg/kg APAP; 9 h after APAP and every 12 h after that, the animals received either 100 mg/kg NAC or 184.5 mg/kg 4MP. At 24 or 48 h after APAP, parameters of liver injury, mitochondrial biogenesis and cell proliferation were evaluated. Delayed NAC treatment had no effect on APAP-induced liver injury at 24 h but reduced the decline of plasma ALT activities and prevented the shrinkage of the areas of necrosis at 48 h. This effect correlated with down-regulation of key activators of mitochondrial biogenesis (AMPK, PGC-1α, Nrf1/2, TFAM) and reduced expression of Tom 20 (mitochondrial mass) and PCNA (cell proliferation). In contrast, 4MP attenuated liver injury at 24 h and promoted recovery at 48 h, which correlated with enhanced mitochondrial biogenesis and hepatocyte proliferation. In human hepatocytes, 4MP demonstrated higher efficacy in preventing cell death compared to NAC when treated at 18 h after APAP. Thus, due to the wider treatment window and lack of detrimental effects on recovery, it appears that at least in preclinical models, 4MP is superior to NAC as an antidote against APAP overdose.

Patterns of transaminase elevation in rhabdomyolysis versus acetaminophen toxicity.

BACKGROUND: Transaminase elevations can occur from liver injury or in the setting of rhabdomyolysis. The goal of this study is to evaluate indices that could differentiate acetaminophen toxicity from muscle injury in the setting of transaminase elevations. METHODS: A retrospective chart review of consecutive cases reported to our regional poison center. Patients with transaminase (AST and ALT) elevation were grouped as those with acetaminophen exposure (AT) and those with elevated creatine phosphokinase (CPK) without evidence of acetaminophen exposure (RHB). RESULTS: Of the 345 patients included in the study, elevated AST/ALT levels were attributed to rhabdomyolysis in 168 patients and attributed to acetaminophen toxicity in 177 patients. The median AST: ALT values also differed between groups, with patients in the RHB group had higher median ratios (p < 0.001). Using an AST: ALT value of 2.02 as a diagnostic cutoff produced a specificity of 0.52 (95% CI: 0.37, 0.64) and sensitivity of 0.84 (95% CI: 0.73, 0.94) for acetaminophen detection in the test dataset (N = 104). CONCLUSIONS: Elevated transaminases due to liver injury from acetaminophen ingestion had a different pattern than elevated transaminases due to rhabdomyolysis. Lower AST:ALT ratios were found in acetaminophen cases, however, the specificity using a ratio threshold of ≤1 would be 83%.

A general model for cell death and biomarker release from injured tissues.

Cellular response to insults may result in the initiation of different cell death processes. For many cases the cell death process will result in an acute release of cellular material that in some circumstances provides valuable information about the process (i.e. may represent a biomarker). The characteristics of the biomarker release is often informative and plays critical roles in clinical practice and toxicology research. The aim of this study is to develop a general, semi-mechanistic model to describe cell turnover and biomarker release by injured tissue that can be used for estimation in pharmacokinetic and (toxicokinetic)-pharmacodynamic studies. The model included three components: (1) natural tissue turnover, (2) biomarker release from cell death and its movement from the cell through the tissue into the blood, (3) different target insult mechanisms of cell death. We applied the general model to biomarker release profiles for four different cell insult causes. Our model simulations showed good agreements with reported data under both delayed release and rapid release cases. Additionally, we illustrate the use of the model to provide different biomarker profiles. We also provided details on interpreting parameters and their values for other researchers to customize its use. In conclusion, our general model provides a basic structure to study the kinetic behaviour of biomarker release and disposition after cellular insult.

Chrysanthemi Flos extract alleviated acetaminophen-induced rat liver injury via inhibiting oxidative stress and apoptosis based on network pharmacology analysis.

CONTEXT: Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury. Bianliang ziyu, a variety of Chrysanthemum morifolium Ramat. (Asteraceae), has potential hepatoprotective effect. However, the mechanism is not clear yet. OBJECTIVE: To investigate the hepatoprotective activity and mechanism of Bianliang ziyu flower ethanol extract (BZE) on APAP-induced rats based on network pharmacology. MATERIALS AND METHODS: Potential pathways of BZE were predicted by network pharmacology. Male Sprague-Dawley rats were pre-treated with BZE (110, 220 and 440 mg/kg, i.g.) for eight days, and then APAP (800 mg/kg, i.g.) was used to induce liver injury. After 24 h, serum and liver were collected for biochemical detection and western blot measurement. RESULTS: Network pharmacology indicated that liver-protective effect of BZE was associated with its antioxidant and anti-apoptotic efficacy. APAP-induced liver pathological change was alleviated, and elevated serum AST and ALT were reduced by BZE (440 mg/kg) (from 66.45 to 22.64 U/L and from 59.59 to 17.49 U/L, respectively). BZE (440 mg/kg) reduced the ROS to 65.50%, and upregulated SOD and GSH by 212.92% and 175.38%, respectively. In addition, BZE (440 mg/kg) increased levels of p-AMPK, p-GSK3ß, HO-1 and NQO1, ranging from 1.66- to 10.29-fold compared to APAP group, and promoted nuclear translocation of Nrf2. BZE also inhibited apoptosis induced by APAP through the PI3K-Akt pathway and restored the ability of mitochondrial biogenesis. DISCUSSION AND CONCLUSIONS: Our study demonstrated that BZE protected rats from APAP-induced liver injury through antioxidant and anti-apoptotic pathways, suggesting BZE could be further developed as a potential liver-protecting agent.

Alternatively activated macrophages promote resolution of necrosis following acute liver injury.

BACKGROUND & AIM: Following acetaminophen (APAP) overdose, acute liver injury (ALI) can occur in patients that present too late for N-acetylcysteine treatment, potentially leading to acute liver failure, systemic inflammation, and death. Macrophages influence the progression and resolution of ALI due to their innate immunological function and paracrine activity. Syngeneic primary bone marrow-derived macrophages (BMDMs) were tested as a cell-based therapy in a mouse model of APAP-induced ALI (APAP-ALI). METHODS: Several phenotypically distinct BMDM populations were delivered intravenously to APAP-ALI mice when hepatic necrosis was established, and then evaluated based on their effects on injury, inflammation, immunity, and regeneration. In vivo phagocytosis assays were used to interrogate the phenotype and function of alternatively activated BMDMs (AAMs) post-injection. Finally, primary human AAMs sourced from healthy volunteers were evaluated in immunocompetent APAP-ALI mice. RESULTS: BMDMs rapidly localised to the liver and spleen within 4 h of administration. Injection of AAMs specifically reduced hepatocellular necrosis, HMGB1 translocation, and infiltrating neutrophils following APAP-ALI. AAM delivery also stimulated proliferation in hepatocytes and endothelium, and reduced levels of several circulating proinflammatory cytokines within 24 h. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was demonstrated by reduced infiltrating host Ly6Chi macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice, underscoring the translational potential of these findings. CONCLUSION: We identify that AAMs have value as a cell-based therapy in an experimental model of APAP-ALI. Human AAMs warrant further evaluation as a potential cell-based therapy for APAP overdose patients with established liver injury. LAY SUMMARY: After an overdose of acetaminophen (paracetamol), some patients present to hospital too late for the current antidote (N-acetylcysteine) to be effective. We tested whether macrophages, an injury-responsive leukocyte that can scavenge dead/dying cells, could serve as a cell-based therapy in an experimental model of acetaminophen overdose. Injection of alternatively activated macrophages rapidly reduced liver injury and reduced several mediators of inflammation. Macrophages show promise to serve as a potential cell-based therapy for acute liver injury.

Acute liver failure.

Acute liver failure is a rare and severe consequence of abrupt hepatocyte injury, and can evolve over days or weeks to a lethal outcome. A variety of insults to liver cells result in a consistent pattern of rapid-onset elevation of aminotransferases, altered mentation, and disturbed coagulation. The absence of existing liver disease distinguishes acute liver failure from decompensated cirrhosis or acute-on-chronic liver failure. Causes of acute liver failure include paracetamol toxicity, hepatic ischaemia, viral and autoimmune hepatitis, and drug-induced liver injury from prescription drugs, and herbal and dietary supplements. Diagnosis requires careful review of medications taken, and serological testing for possible viral exposure. Because of its rarity, acute liver failure has not been studied in large, randomised trials, and most treatment recommendations represent expert opinion. Improvements in management have resulted in lower mortality, although liver transplantation, used in nearly 30% of patients with acute liver failure, still provides a life-saving alternative to medical management.

The NACSTOP Trial: A Multicenter, Cluster-Controlled Trial of Early Cessation of Acetylcysteine in Acetaminophen Overdose.

Historically, intravenous acetylcysteine has been delivered at a fixed dose and duration of 300 mg/kg over 20 to 21 hours to nearly every patient deemed to be at any risk for hepatotoxicity following acetaminophen overdose. We investigated a 12-hour treatment regimen for selected low-risk patients. This was a multicenter, open-label, cluster-controlled trial at six metropolitan emergency departments. We enrolled subjects following single or staggered acetaminophen overdose with normal serum alanine transaminase (ALT) and creatinine on presentation and at 12 hours, and less than 20 mg/L acetaminophen at 12 hours. Patients were allocated to intervention (250 mg/kg over 12-hour) or control (300 mg/kg over 20-hour) regimens by site. The primary outcome was incidence of "hepatic injury" 20 hours following initiation of acetylcysteine treatment, defined as ALT doubling and peak ALT greater than 100 IU/L, indicating the need for further antidotal treatment. Secondary outcomes included incidence of hepatotoxicity (ALT > 1,000 IU/L), peak international normalized ratio (INR), and adverse drug reactions. Of the 449 acetaminophen overdoses receiving acetylcysteine, 100 were recruited to the study. Time to acetylcysteine (median 7 hours [interquartile ratio 6,12] versus 7 hours [6,10]) and initial acetaminophen (124 mg/L [58,171] versus 146 mg/L [66,204]) were similar between intervention and control groups. There was no difference in ALT (18 IU/L [13,22] versus 16 IU/L [13,21]) or INR (1.2 versus 1.2) 20 hours after starting acetylcysteine between groups. No patients developed hepatic injury or hepatotoxicity in either group (odds ratio 1.0 [95% confidence interval 0.02, 50]). No patients represented with liver injury, none died, and 96 of 96 were well at 14-day telephone follow-up. Conclusion: Discontinuing acetylcysteine based on laboratory testing after 12 hours of treatment is feasible and likely safe in selected patients at very low risk of liver injury from acetaminophen overdose.

p53 Up-regulated Modulator of Apoptosis Induction Mediates Acetaminophen-Induced Necrosis and Liver Injury in Mice.

Acetaminophen (APAP) overdose is one of the leading causes of hepatotoxicity and acute liver failure in the United States. Accumulating evidence suggests that hepatocyte necrosis plays a critical role in APAP-induced liver injury (AILI). However, the mechanisms of APAP-induced necrosis and liver injury are not fully understood. In this study, we found that p53 up-regulated modulator of apoptosis (PUMA), a B-cell lymphoma-2 (Bcl-2) homology domain 3 (BH3)-only Bcl-2 family member, was markedly induced by APAP in mouse livers and in isolated human and mouse hepatocytes. PUMA deficiency suppressed APAP-induced mitochondrial dysfunction and release of cell death factors from mitochondria, and protected against APAP-induced hepatocyte necrosis and liver injury in mice. PUMA induction by APAP was p53 independent, and required receptor-interacting protein kinase 1 (RIP1) and c-Jun N-terminal kinase (JNK) by transcriptional activation. Furthermore, a small-molecule PUMA inhibitor, administered after APAP treatment, mitigated APAP-induced hepatocyte necrosis and liver injury. Conclusion: Our results demonstrate that RIP1/JNK-dependent PUMA induction mediates AILI by promoting hepatocyte mitochondrial dysfunction and necrosis, and suggest that PUMA inhibition is useful for alleviating acute hepatotoxicity attributed to APAP overdose.

Mice deficient in pyruvate dehydrogenase kinase 4 are protected against acetaminophen-induced hepatotoxicity.

Though mitochondrial oxidant stress plays a critical role in the progression of acetaminophen (APAP) overdose-induced liver damage, the influence of mitochondrial bioenergetics on this is not well characterized. This is important, since lifestyle and diet alter hepatic mitochondrial bioenergetics and an understanding of its effects on APAP-induced liver injury is clinically relevant. Pyruvate dehydrogenase (PDH) is critical to mitochondrial bioenergetics, since it controls the rate of generation of reducing equivalents driving respiration, and pyruvate dehydrogenase kinase 4 (PDK4) regulates (inhibits) PDH by phosphorylation. We examined APAP-induced liver injury in PDK4-deficient (PDK4-/-) mice, which would have constitutively active PDH and hence elevated flux through the mitochondrial electron transport chain. PDK4-/- mice showed significant protection against APAP-induced liver injury when compared to wild type (WT) mice as measured by ALT levels and histology. Deficiency of PDK4 did not alter APAP metabolism, with similar APAP-adduct levels in PDK4-/- and WT mice, and no difference in JNK activation and translocation to mitochondria. However, subsequent amplification of mitochondrial dysfunction with release of mitochondrial AIF, peroxynitrite formation and DNA fragmentation were prevented. Interestingly, APAP induced a rapid decline in UCP2 protein levels in PDK4-deficient mice. These data suggest that adaptive changes in mitochondrial bioenergetics induced by enhanced respiratory chain flux in PDK4-/- mice render them highly efficient in handling APAP-induced oxidant stress, probably through modulation of UCP2 levels. Further investigation of these specific adaptive mechanisms would provide better insight into the control exerted by mitochondrial bioenergetics on cellular responses to an APAP overdose.

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.

Suicide-related over-the-counter analgesic exposures reported to United States poison control centers, 2000-2018.

PURPOSE: To investigate suicide-related over-the-counter (OTC) analgesic medication exposures among individuals ≥6 years old reported to United States (US) poison control centers. METHODS: Data from the National Poison Data System for the years 2000-2018 were retrospectively analyzed. RESULTS: From 2000 to 2018, US poison control centers recorded 549 807 suicide-related cases involving OTC analgesics, including 327 781 cases (59.6%) admitted to the hospital and 1745 deaths (0.3%). Most cases involved a single substance (67.5%) and occurred among females (72.7%) and individuals 6-19 years old (49.7%). Overall, the rate of exposures increased significantly by 33.5% from 2000 to 2018, primarily driven by the increasing exposure rate among 6- to 19-year-old females. From 2000 to 2018, exposure rates for acetaminophen and ibuprofen increased, while that for acetylsalicylic acid decreased. Additionally, the proportion of cases resulting in a serious medical outcome or healthcare facility admission increased for all types of OTC analgesics. Acetaminophen and acetylsalicylic acid accounted for 48.0% and 18.5% of cases, respectively, and 64.5% and 32.6% of deaths, respectively. Both acetaminophen and acetylsalicylic acid had greater odds of healthcare facility admission (ORs 2.56 and 2.63, respectively) and serious medical outcomes (ORs 2.54 and 4.90, respectively) compared with ibuprofen. CONCLUSIONS: The rate of suicide-related OTC analgesic cases is increasing. Acetaminophen and acetylsalicylic acid cases are associated with greater morbidity and mortality. Prevention efforts should include implementing unit-dose packaging requirements and restrictions on package sizes and purchase quantities for acetaminophen and acetylsalicylic acid products to reduce access to large quantities of these analgesics.

Polyethylene glycol electrolyte lavage solution increases tablet dissolution of acetaminophen in an in vitro model mimicking acute poisoning.

INTRODUCTION: Polyethylene glycol electrolyte lavage solution (PEG-ELS) is similar to pharmaceutical solvent propylene glycol and used following acute poisonings for whole bowel irrigation (e.g., "body stuffing"). This raises concern of PEG-ELS increasing solubility following acute ingestions of non-sustained release xenobiotics in the stomach. We theorized PEG-ELS increases solubility of acetaminophen in an in vitro stomach model. MATERIAL AND METHODS: An in vitro artificial stomach with 500 mL simulated gastric fluid and either 500 mL of sodium chloride 0.9% (group A) or 500 mL of PEG-ELS (group B). Ten non-sustained release acetaminophen tablets added with concentrations 0, 15, 45 and 90 min in triplicate. Mean concentrations and mean area under the curve (AUC) (mg-min/L to 90 min). RESULTS: In control group A (normal saline + simulated gastric fluid) mean acetaminophen concentrations 0, 3, 13 and 36 mg/L at 0, 15, 45 and 90 min, respectively. In group B (PEG-ELS + simulated gastric fluid) mean acetaminophen concentrations 0, 34, 109 and 136 mg/L at 0, 15, 45 and 90 min, respectively (p < 0.05). Mean AUC 0-90 1385 [95% C.I. 990.5-1779] mg-min/L in control group A compared to mean AUC 0-90 in group B (PEG-ELS) 7673 mg-min/L [95% C.I. 4832-10513] (p < 0.05). DISCUSSION: Group B (PEG-ELS) with significantly higher mean acetaminophen concentrations and greater mean AUC compared to control group A (normal saline). CONCLUSION: We demonstrated increased mean acetaminophen concentrations and increased mean AUC of following exposure of PEG-ELS in an artificial stomach model.

Fomepizole as an Adjunctive Treatment in Severe Acetaminophen Toxicity.

A 33-year-old male presented to the emergency department with a chief complaint of abdominal pain after taking #50 500 mg acetaminophen tablets over the preceding two days. He was tachycardic and tachypneic, and the initial labs were notable for acetaminophen level, 337 mg/L; AST, 137 IU/L; ALT, 194 IU/L; ABG pH, 7.24; and lactate, 4.1 mmol/L. The patient was started on IV N-Acetylcysteine (NAC) as well as given a single dose of 15 mg/kg fomepizole. The patient did remarkably well, with a peak AST of 198 IU/L, peak ALT of 301 IU/L, and peak INR of 3.1. Biochemical and animal data support fomepizole having hepatoprotective effects in acetaminophen poisoning. To our knowledge, this is the first human case of an intentional dual NAC/fomepizole regimen for severe acetaminophen toxicity.