Balanced modulation of neuromuscular synaptic transmission via M1 and M2 muscarinic receptors during inhibition of cholinesterases.

Organophosphorus (OP) compounds that inhibit acetylcholinesterase are a common cause of poisoning worldwide, resulting in several hundred thousand deaths each year. The pathways activated during OP compound poisoning via overstimulation of muscarinic acetylcholine receptors (mAChRs) play a decisive role in toxidrome. The antidotal therapy includes atropine, which is a nonspecific blocker of all mAChR subtypes. Atropine is efficient for mitigating depression in respiratory control centers but does not benefit patients with OP-induced skeletal muscle weakness. By using an ex vivo model of OP-induced muscle weakness, we studied the effects of the M1/M4 mAChR antagonist pirenzepine and the M2/M4 mAChR antagonist methoctramine on the force of mouse diaphragm muscle contraction. It was shown that weakness caused by the application of paraoxon can be significantly prevented by methoctramine (1 µM). However, neither pirenzepine (0.1 µM) nor atropine (1 µM) was able to prevent muscle weakness. Moreover, the application of pirenzepine significantly reduced the positive effect of methoctramine. Thus, balanced modulation of neuromuscular synaptic transmission via M1 and M2 mAChRs contributes to paraoxon-induced muscle weakness. It was shown that methoctramine (10 µmol/kg, i.p.) and atropine (50 µmol/kg, i.p.) were equieffective toward increasing the survival of mice poisoned with a 2xLD50 dose of paraoxon.

Sensitivity of dose-estimations for acute acetaminophen overdose in predicting hepatotoxicity risk using the Rumack-Matthew Nomogram.

Timely assessment of acetaminophen concentration in overdose situations is not always available in resource-poor settings. The 150 mg/kg dose-estimate for acetaminophen is widely considered as criterion for acetaminophen overdose. Its sensitivity and specificity when compared to the 150 mg/L treatment line on the Rumack-Matthew Nomogram (150-treatment line) has rarely been evaluated. This is a retrospective chart review of acute acetaminophen overdose patients. We evaluated the sensitivity and specificity of the 150, 200 mg/kg and 8- and 10-g dose-estimates by plotting the serum acetaminophen levels and using 150-treatment line on the Nomogram as the treatment cut-off. A comparison of medical care costs was performed. We enrolled 784 cases for analysis. Median (IQR) age was 23 (20-28) years (81.9% female). There were 545 cases (69.5%) where the estimated ingested acetaminophen dose were ≥150 mg/kg and 406 cases (51.8%) with concentrations ≥150-treatment line. Hepatotoxicity and acute liver injury (ALI) occurred in 7.3% and 23.9%, respectively. The sensitivity and specificity of 150 mg/kg dose-estimate for the 150-treatment line were 92.6% (95% CI 89.6, 94.8) and 55.3% (95% CI 50.3, 60.2). Among patients with dose-estimate below150 mg/kg, none developed hepatotoxicity and 17 (7.1%) develop ALI. The administration of activated charcoal significantly decreased the risk of being above the 150-treatment line by half. In resource-poor setings, the use of 150 mg/kg dose-estimate as a stand-alone criteria for initiation of N-acetylcysteine therapy is satisfactory, especially when combined with decontamination with activated charcoal and follow up of aminotransferase at 24 h.

A novel aqueous dimethyl trisulfide formulation is effective at low doses against cyanide toxicity in non-anesthetized mice and rats.

BACKGROUND: Cyanide (CN) is a metabolic poison that is capable of intoxicating individuals through accidental or intentional means. With high concentration exposures, death can occur in minutes. In cases of mass casualty exposures, there is a need for a rapid-acting countermeasure capable of being administered in a short period of time in a pre-hospital setting to treat victims. OBJECTIVE: These studies evaluate the safety and efficacy of a novel aqueous formulation of dimethyl trisulfide (DMTS) as an intramuscular (IM) CN countermeasure using non-anesthetized rodent models. METHODS: Non-anesthetized rodents (mice and rats) were exposed to hydrogen cyanide (HCN) or potassium cyanide (KCN) along with immediate IM 10% DMTS treatment or vehicle treatment. Survival and other parameters, such as the time to recovery and assessment of clinical toxic signs (e.g., gasping, loss of righting reflex, convulsions, etc.), were quantified to determine the effectiveness of 10% DMTS treatment (12.5, 25, 75 mg/kg IM) compared to vehicle control treatment. A rat KCN delayed-treatment model with a 15-minute treatment delay was also utilized to simulate a real-life exposure/treatment scenario with 10% DMTS treatment. The stability of the 10% DMTS formulation was also assessed. RESULTS: A 25 mg/kg IM dose of 10% DMTS exhibits potent efficacy against subcutaneous (SC) KCN challenge in both mice and rats and inhalational HCN exposure in mice. 10% DMTS treatment also shortens the time to recovery in rats using a delayed-treatment model. CONCLUSION: IM treatment with 10% DMTS improves survival and clinical outcomes in non-anesthetized rodent models of acute CN toxicity. Additionally, the use of an SC KCN delayed-treatment model in rats is advised to assess the performance of a candidate CN countermeasure in a more realistic exposure/treatment scenario.

Indirect antiplatelet effects of rivaroxaban in a patient with intracranial hemorrhage: An underappreciated coagulopathy of factor Xa inhibitors?

Rivaroxaban is a direct oral anticoagulant (DOAC) used for prophylaxis and treatment of many prothrombotic states. The anticoagulation effects of rivaroxaban are produced by selectively binding and inhibiting factor Xa, causing delayed thrombin generation. Additionally, the delay in thrombin generation produces an indirect, dose dependent antiplatelet effect via reduction in tissue factor platelet aggregation. As with any anticoagulant, rivaroxaban use increases a patient's risk for major and minor hemorrhagic events. With mortality rates reported as high as 25% for those who experience an intracranial hemorrhage (ICH), immediate mitigation of hematoma and hemorrhage volume expansion is imperative. Management strategies include utilizing prothrombin complex concentrates (PCC) and factor Xa inhibitor specific antidotes, such as coagulation factor Xa recombinant, inactivated-zhzo. Routine monitoring or management of DOAC induced antiplatelet effects is ill-defined and not a part of routine standard of care. We report the first case, to our knowledge, of rivaroxaban's indirect antiplatelet effects identified by platelet function assays and managed with four-factor PCC and desmopressin in a patient experiencing an ICH. Further exploration is needed to determine the true clinical impact attributed to rivaroxaban's antiplatelet effects.

The three biological gaps and hyperoxaluria in ethylene glycol poisoning: case presentation and review.

Ethylene glycol is a toxic alcohol which may induce significant toxicity when ingested accidentally or intentionally. The main clinical complications of EG poisoning include central nervous system depression, cardiorespiratory instability and renal failure, which may be lethal if improperly treated. Although the demonstration of high plasma levels of ethylene glycol confirms the intoxication, such measurements are generally not obtained in the acute setting and can be misleading due to the rapid metabolism of EG. This implies the need for alternative, indirect, diagnostic methods, which reflect the metabolic fate of EG. These include an early and transient osmolar gap, followed by an anion gap metabolic acidosis and hyperoxaluria. Another frequent finding is a lactate gap between various methods of lactate measurements. An appropriate knowledge of these laboratory findings is essential for the diagnosis of EG poisoning, and for the initiation of antidote therapy (fomepizole) and hemodialysis in selected cases. These features are illustrated by the presentation of a prototypical case of EG poisoning, in which an incomplete diagnostic workup on hospital admission resulted in an unnecessary laparotomy and a significant delay in the management of the intoxication.

Protective effect of a new generation of activated and purified bentonite in combination with yeast and phytogenic substances on mycotoxin challenge in pigs.

The study aimed to investigate the efficacy of new mycotoxin adsorbents based on purified and activated bentonites combined with yeast and phytogenic compounds in fattening pigs. The experiment involved 96 pigs (31.2±2.4 kg). Control (C) group was fed a diet naturally contaminated with mycotoxins (5 mg/kg deoxynivalenol, DON) without an adsorbent. Treated groups received the feed with mycotoxin adsorbents: purified and activated bentonite (T1), purified and activated bentonite, yeast derivatives, phytogenic substances (T2), and purified, activated, and sulphurated bentonite with phytogenic substances (T3). Evaluated parameters involved growth performance, organ weight, small intestine and liver histopathology, complete blood count, serum biochemistry, antioxidant status of the organism and total and free DON content in urine. In all treated groups, an significant increase in intestinal GSH and GSH/GSSG ratio was observed when compared to C. No significant effects on liver and kidney weight, complete blood count, serum or intestinal malondialdehyde concentration, or total/free DON content in urine were observed. All adsorbents improved histopathological findings in the liver when compared to C. Moreover, T1, and T2 groups showed no presence of inflammatory reaction or necrotic changes in the livers. Although, mycotoxin adsorbents investigated in this study had no significant impact on pig growth performance, they reduced the oxidative stress, and on the tissue level they protected the jejunal tissue and liver parenchyma under deoxynivalenol challenge.

Brain-targeting delivery of MMB4 DMS using carrier-free nanomedicine CRT-MMB4@MDZ.

Brain-targeting delivery of 1,1'-methylenebis[4-[(hydroxyimino)methyl]-pyridinium] dimethanesulfonate (MMB4 DMS) is limited by its hydrophilic property and chemical instability. In order to solve this problem, herein, we develop a facile protocol through combining antisolvent precipitation and emulsion-solvent evaporation method to synthesize midazolam (MDZ) coated MMB4 DMS (MMB4@MDZ) nanoparticles. The as-prepared MMB4@MDZ had a MMB4 DMS nanocrystal (MMB4-NC) core and a MDZ shell. The MDZ shell prevented the MMB4-NC core from contacting the aqueous environment, and thus, guaranteed the chemical stability of MMB4 DMS. Most charmingly, the iron mimic cyclic peptide CRTIGPSVC (CRT) was modified on MMB4@MDZ surfaces to produce CRT-MMB4@MDZ which was endowed with ability to absorb transferrin (Tf)-abundant corona. Taking advantages of the Tf-abundant corona, CRT-MMB4@MDZ achieved transferrin receptor (TfR)-mediated brain-targeting delivery. With the fascinating chemical stability and brain-targeting delivery effect, CRT-MMB4@MDZ showed great clinical transform prospect as a brand-new nanomedicine. Of particular importance, this work promised not only a core-shell carrier-free nanomedicine platform for effective delivery of unstable water-soluble drug, but also a protein corona-manipulating strategy for targeting delivery.

Time to Peak International Normalized Ratio Rise in Acute and Acute-on-Chronic Warfarin Overdoses.

ABSTRACT: Guidelines exist on the management of supratherapeutic/subtherapeutic international normalized ratio (INR) values for patients on warfarin. However, there is a paucity of the literature relating to an acute overdose of warfarin. This is a retrospective cohort study for all acute and acute-on-chronic (AOC) warfarin overdoses reported to the Maryland Poison Center in patients ≥12 years between January 1st, 2000, until October 31st, 2019, managed in a health care facility. The primary outcome was to determine the time after presentation to peak INR. Secondary outcomes included risk factors associated with INR >10 and describing patient characteristics. A total of 163 overdoses were included, 68 acute and 95 AOC. In patients who did not receive reversal therapies, INR peaked at a median value of 3.8 (interquartile range 2.6-5.5) between 24 and 36 hours. The median time to phytonadione was 22.0 hours. Most patients received phytonadione (62.0%), with fewer receiving blood products (16.6%). The median warfarin dose ingested was 75 mg. The AOC group had a greater mean age (56 vs. 43 years), median INR value (2.4 vs. 1.4), and men (62.1% vs. 41.2%). Factors associated with an INR > 10 included initial INR and reported quantity ingested. Peak INR was greater in the AOC than the acute overdose group (6.1 vs. 3.4), although the bleeding rate was similar. Peak INR values after warfarin overdose occur between 24 and 36 hours after presentation. Initial INRs and reported quantity ingested may be useful to predict those needing treatment.

Safety and toxicology assessment of sodium nitrite administered by intramuscular injection.

Intramuscular (IM) injection of nitrite (1-10 mg/kg) confers survival benefit and protects against lung injury after exposure to chlorine gas in preclinical models. Herein, we evaluated safety/toxicity parameters after single, and repeated (once daily for 7 days) IM injection of nitrite in male and female Sprague Dawley rats and Beagle dogs. The repeat dose studies were performed in compliance with the Federal Drug Administration's (FDA) Good Laboratory Practices Code of Federal Regulations (21 CFR Part 58). Parameters evaluated consisted of survival, clinical observations, body weights, clinical pathology, plasma drug levels, methemoglobin and macroscopic and microscopic pathology. In rats and dogs, single doses of ≥100 mg/kg and 60 mg/kg resulted in death and moribundity, while repeated administration of ≤30 or ≤ 10 mg/kg/day, respectively, was well tolerated. Therefore, the maximum tolerated dose following repeated administration in rats and dogs were determined to be 30 mg/kg/day and 10 mg/kg/day, respectively. Effects at doses below the maximum tolerated dose (MTD) were limited to emesis (in dogs only) and methemoglobinemia (in both species) with clinical signs (e.g. blue discoloration of lips) being dose-dependent, transient and reversible. These signs were not considered adverse, therefore the No Observed Adverse Effect Level (NOAEL) for both rats and dogs was 10 mg/kg/day in males (highest dose tested for dogs), and 3 mg/kg/day in females. Toxicokinetic assessment of plasma nitrite showed no difference between male and females, with Cmax occurring between 5 mins and 0.5 h (rats) or 0.25 h (dogs). In summary, IM nitrite was well tolerated in rats and dogs at doses previously shown to confer protection against chlorine gas toxicity.

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.

Alginate-coated activated charcoal enhances fecal excretion of 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice, with fewer side effects than uncoated one.

Activated charcoal (AC) is a potential candidate antidote against dioxins. However, it is difficult to take AC as a supplement on a daily basis, because its long-term ingestion causes side effects such as constipation and deficiency of fat-soluble essential nutrients and hypocholesterolemia. Alginate-coated AC, termed Health Carbon (HC), was developed to decrease the side effects of AC, but its pharmacological effects, including side effects, remains unclear. Here, we show that HC enhanced fecal excretion of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and decreased some side effects of unmodified AC, such as hypocholesterolemia, in male mice. Basal diet mixed with HC or unmodified AC at various concentrations was fed to mice for 16 days following a single intraperitoneal administration of [3H]TCDD. Both HC and unmodified AC at 3% or more significantly increased fecal excretion of [3H]TCDD in comparison with the control basal diet. Consistent with this, [3H]TCDD radioactivity in the liver-a major TCDD storage organ-was markedly decreased by HC at concentrations of 3% and 10%. In an examination of potential side effects, unmodified AC at 10% or more caused significant body weight reduction and at 20% caused significant hypocholesterolemia. In contrast, HC caused weight gain reduction only at a concentration of 20%, and there was no evidence of hypocholesterolemia at any dietary HC concentration. HC not only retains the ability of AC to enhance fecal excretion of TCDD but also reduces some of the side effects of AC.

Aging erythrocyte membranes as biomimetic nanometer carriers of liver-targeting chromium poisoning treatment.

Chromium poisoning has become one of the most common heavy metal poisoning occupational diseases with high morbidity and mortality. However, most antidotes detoxify the whole body and are highly toxic. To achieve hepato-targeted chromium poisoning detoxification, a novel hepato-targeted strategy was developed using aging erythrocyte membranes (AEMs) as biomimetic material coated with a dimercaptosuccinic acid (DMSA) nanostructured lipid carrier to construct a biomimetic nano-drug delivery system. The particle size, potential, drug loading, encapsulation rate, in vitro release, and stability of the nanoparticles (NPs) were characterized. Confocal microscopy and flow cytometry showed that the prepared NPs could be phagocytized by RAW264.7 macrophage cells. The efficacy of AEM-DMSA-NPs for targeted liver detoxification was evaluated by in vitro MTT analysis and an in vivo model of chromium poisoning. The results showed that the NPs could safely and efficiently achieve targeted liver chromium poisoning detoxification. All the results indicated that the biomimetic nano-drug delivery system mediated by aging erythrocyte membranes and containing DMSA nanoparticles could be used as a novel therapeutic drug delivery system potentially targeting liver detoxification.

Efficacy and expenses of succimer vs. d-penicillamine plus garlic in the treatment of lead poisoning: a retrospective cross-sectional study.

PURPOSE: Lead Poisoning is a major health problem in Iran. We aimed to compare efficacy of a standard regimen (Succimer) with that of a low-priced combination of D-penicillamine and Garlic in outpatients with lead poisoning. METHODS: In this retrospective cross-sectional study, year-long clinical files of outpatients with lead poisoning in two referral toxicology clinics in Mashhad, Iran were reviewed. A total of 79 patients (all men), received either Succimer or a combination of D-penicillamen plus garlic (DPN + Gar), for 19 and 30 days, respectively. Clinical and laboratory data, including blood lead level (BLL), were analyzed and treatment expanses were compared between the two regimens. RESULTS: Of 79 male patients, 42 were treated by DPN + Gar and 37 received Succimer. Mean BLL of DPN + Gar group before treatment (965.73 ± 62.54 µg/L) was higher than that of the Succimer group (827.59 ± 24.41) (p < 0.001). After treatment, BLL in both groups significantly reduced to 365.52 ± 27.61 µg/L and 337.44 ± 26.34 µg/L, respectively (p < 0.001). The price of a 19-day treatment with Succimer was approximately 28.6 times higher than a one-month course of treatment with garlic plus DPN. None of the treatments caused serious side effects in the patients. CONCLUSION: Combination therapy with DPN + Gar is as effective as Succimer in Pb poisoning, while treatment with Succimer is significantly more expensive.

A review of alternative intravenous acetylcysteine regimens for acetaminophen overdose.

INTRODUCTION: Acetylcysteine is the standard treatment for preventing hepatotoxicity caused by acetaminophen overdose. Several novel approaches to the management of acetaminophen overdose have been suggested to improve patient safety by reducing adverse drug reactions and dosing errors. This article reviews these alternative treatment regimens and intends to offer a detailed assessment of the available options to assist providers in managing cases of acetaminophen overdose. AREAS COVERED: This review article covers observational and experimental studies that assessed the efficacy and safety of alternative intravenous acetylcysteine regimens for acetaminophen overdose. A literature search was conducted using PubMed, ProQuest, and Scopus to identify the studies, which included results through April 2021. The assessment of alternative regimens consists of a discussion on the limitations and benefits, barriers to implementation, and important considerations for each regimen. EXPERT OPINION: Several alternative regimens have been studied and implemented in various institutions. Many of these dosing regimens have supporting safety data but most lack robust data. A reduction in infusion-related side effects is an important outcome, but established efficacy, local poison center familiarity with the regimen, institutional resources, and patient-specific factors should be equally considered when deciding on implementing and using an alternative dosing strategy.

Formate test for bedside diagnosis of methanol poisoning.

Methanol poisoning kills thousands of people every year and remains a diagnostic challenge, especially where the resources are scarce, but also in high-income countries worldwide. We are in the course of developing a bedside strip to detect formate - the toxic metabolite of methanol. We hereby present the first clinical methanol case where formate was detected bedside from a drop of blood: The patient, a 61-year-old male, was admitted with a suspect methanol poisoning and severe metabolic acidosis. The test strip was positive after 3 minutes. Sodium bicarbonate (500 mmol/L), fomepizole, dialysis and folinic acid were given based on the positive test. The diagnosis was some hours later confirmed by GC-MS, showing a methanol concentration of 62 mmol/L (200 mg/dL) and a formate concentration of 19 mmol/L. Implementation of this technology into routine clinical use can potentially offer an opportunity for a step change in the management of methanol poisoning.

RETROSPECTIVE REVIEW OF COPPER SULFATE IMMERSION TREATMENT IN MARINE TELEOSTS DURING QUARANTINE AT THE NATIONAL AQUARIUM OF BALTIMORE FROM 2004 TO 2016.

Copper sulfate immersion is common for the prevention and treatment of Cryptocaryon irritans during quarantine of marine teleosts. The National Aquarium in Baltimore has followed a consistent copper sulfate protocol for marine teleost quarantine since 2004. The protocol used copper sulfate pentahydrate as a slow drip to increase copper ions over 3-5 days to a level of 0.18-0.21 mg/L. This level was maintained for 21 days, and then copper ions were rapidly removed with activated carbon filtration and water changes. Quarantine records from 2004-2016 were used to examine mortality of marine teleosts during copper treatment and identify factors that might have influenced mortality. The following records were excluded: brackish and freshwater teleosts (salinity <25 g/L); long-term treatment at subtherapeutic levels (<0.18 mg/L); intentional short courses (<14 days); and use outside of quarantine. Species, system volume, temperature, parasitic outbreaks, concurrent medications, and water quality concerns were evaluated. During this period, 4,835 individual teleosts belonging to 347 different species were treated. From 2004 to 2016, mortality during copper treatment was 4.1% (199/4,835 individuals) and was higher when treatment was started during the first week of quarantine (7.7%, 68/884) rather than later (3.3%, 131/3,951 individuals). Of the mortalities, 24.1% (48/199) occurred during the initial subtherapeutic period, and 75.9% (151/199) occurred during the therapeutic period. No mortalities occurred in 75.5% (262/347) of species during copper treatment. When using a similar methodology, copper sulfate is a safe immersion for quarantine of marine teleosts. Mortalities during copper treatment can be reduced by increasing copper ion levels to therapeutic ranges more slowly (e.g., over 7 days) and starting copper treatment after the first week of quarantine.

A metabolomic analysis of thiol response for standard and modified N-acetyl cysteine treatment regimens in patients with acetaminophen overdose.

N-acetylcysteine (NAC) is an antidote to prevent acetaminophen (paracetamol-APAP)-induced acute liver injury (ALI). The 3-bag licensed 20.25 h standard regimen, and a 12 h modified regimen, are used to treat APAP overdose. This study evaluated the redox thiol response and APAP metabolites, in patients with a single APAP overdose treated with either the 20.25 h standard or 12 h modified regimen. We used liquid chromatography tandem mass spectrometry to quantify clinically important oxidative stress biomarkers and APAP metabolites in plasma samples from 45 patients who participated in a randomized controlled trial (SNAP trial). We investigated the time course response of plasma metabolites at predose, 12 h, and 20.25 h post-start of NAC infusion. The results showed that the 12 h modified regimen resulted in a significant elevation of plasma NAC and cysteine concentrations at 12 h post-infusion. We found no significant alteration in the metabolism of APAP, mitochondrial, amino acids, and other thiol biomarkers with the two regimens. We examined APAP and purine metabolism in overdose patients who developed ALI. We showed the major APAP-metabolites and xanthine were significantly higher in patients with ALI. These biomarkers correlated well with alanine aminotransferase activity at admission. Receiver operating characteristic analysis showed that at admission, plasma APAP-metabolites and xanthine concentrations were predictive for ALI. In conclusion, a significantly higher redox thiol response with the modified NAC regimen at 12 h postdose suggests this regimen may produce greater antioxidant efficacy. At baseline, plasma APAP and purine metabolites may be useful biomarkers for early prediction of APAP-induced ALI.

Clinical outcome of massive acetaminophen overdose treated with standard-dose N-acetylcysteine.

BACKGROUND: Recent recognition of "massive" acetaminophen (APAP) overdoses has led to the question of whether standard dosing of N-acetylcysteine (NAC) is adequate to prevent hepatoxicity in these patients. The primary aim of this study was to evaluate the clinical outcome for patients with massive APAP overdose who received standard intravenous NAC dosing of 300 mg/kg over 21 h. METHODS: This was a single-center retrospective cohort study conducted by chart review of APAP overdoses reported to a regional poison center from 1 January 2010 to 31 December 2019. Massive APAP overdose was defined by single, acute overdose resulting in an APAP concentration exceeding 300 mcg/mL at 4 h post-ingestion. Standard univariate statistical analysis was conducted to describe the cohort, and a multivariate logistic model was utilized to calculate adjusted odds ratios for risk of hepatoxicity. RESULTS: 1425 cases of APAP overdose were reviewed. 104 cases met the inclusion criteria of massive APAP overdose. Overall, 79 cases (76%) had no acute liver injury or hepatotoxicity, and 25 (24%) developed hepatoxicity. Nine percent (n = 4) of cases receiving NAC within 8 h developed hepatotoxicity. Crude odds for hepatoxicity was 5.5-fold higher for cases who received NAC after 8 h. CONCLUSIONS: Standard NAC dosing received within 8 h prevented hepatoxicity in 91% (n = 40) of cases in our series of massive APAP overdoses. Additional data is needed to determine the clinical outcomes of massive APAP overdose using current intravenous NAC dosing.