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Opposing evidence exists for the source of the hydrogen ions (H+) during ketoacidosis. Organic and computational chemistry using dissociation constants and alpha equations for all pertinent ionizable metabolites were used to (1) document the atomic changes in the chemical reactions of ketogenesis and ketolysis and (2) identify the sources and quantify added fractional (~) H+ exchange (~H+e). All computations were performed for pH conditions spanning from 6.0 to 7.6. Summation of the ~H+e for given pH conditions for all substrates and products of each reaction of ketogenesis and ketolysis resulted in net reaction and pathway ~H+e coefficients, where negative revealed ~H+ release and positive revealed ~H+ uptake. Results revealed that for the liver (pH = 7.0), the net ~H+e for the reactions of ketogenesis ending in each of acetoacetate (AcAc), β-hydroxybutyrate (β-HB), and acetone were −0.9990, 0.0026, and 0.0000, respectively. During ketogenesis, ~H+ release was only evident for HMG CoA production, which is caused by hydrolysis and not ~H+ dissociation. Nevertheless, there is a net ~H+ release during ketogenesis, though this diminishes with greater proportionality of acetone production. For reactions of ketolysis in muscle (pH = 7.1) and brain (pH = 7.2), net ~H+ coefficients for β-HB and AcAc oxidation were −0.9649 and 0.0363 (muscle), and −0.9719 and 0.0291 (brain), respectively. The larger ~H+ release values for β-HB oxidation result from covalent ~H+ release during the oxidation–reduction. For combined ketogenesis and ketolysis, which would be the metabolic condition in vivo, the net ~H+ coefficient depends once again on the proportionality of the final ketone body product. For ketone body production in the liver, transference to blood, and oxidation in the brain and muscle for a ratio of 0.6:0.2:0.2 for β-HB:AcAc:acetone, the net ~H+e coefficients for liver ketogenesis, blood transfer, brain ketolysis, and net total (ketosis) equate to −0.1983, −0.0003, −0.2872, and −0.4858, respectively. The traditional theory of ketone bodies being metabolic acids causing systemic acidosis is incorrect. Summation of ketogenesis and ketolysis yield H+ coefficients that differ depending on the proportionality of ketone body production, though, in general, there is a small net H+ release during ketosis. Products formed during ketogenesis (HMG-CoA, acetoacetate, β-hydroxybutyrate) are created as negatively charged bases, not acids, and the final ketone body, acetone, does not have pH-dependent ionizable groups. Proton release or uptake during ketogenesis and ketolysis are predominantly caused by covalent modification, not acid dissociation/association. Ketosis (ketogenesis and ketolysis) results in a net fractional H+ release. The extent of this release is dependent on the final proportionality between acetoacetate, β-hydroxybutyrate, and acetone.

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.

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.

OBJECTIVES Pharmacogenomic testing (PGX) implementation is rapidly expanding, including pre-emptive testing funded by health systems. PGX continues to develop an evidence base that it saves money and improves clinical outcomes. Identifying the potential impact of pre-emptive testing in specific populations may aid in the development of a business case. METHODS We utilized a software tool that can evaluate patient drug lists and identified groups of patients most likely to benefit from implementation of a PGX testing program in a major medical system population. RESULTS Medication lists were obtained for sixteen patient groups with a total of 82 613 patients. The percent of patients in each group with testing 'Recommended', 'Strongly recommended', or 'Required' ranged from 12.7% in the outpatient pediatric psychiatry group to 75.7% in the any adult inpatient age >50 years group. Some of the highest yield drugs identified were citalopram, simvastatin, escitalopram, metoprolol, clopidogrel, tramadol, and ondansetron. CONCLUSION We demonstrate a significant number of patients in each group may have benefit, but targeting certain ones for pre-emptive testing may result in the initial highest yield for a health system.

BACKGROUND & AIMS: Acetaminophen (APAP) overdose remains a frequent cause of acute liver failure, which is generally accompanied by increased levels of serum bile acids (BAs). However, the pathophysiological role of BAs remains elusive. Herein, we investigated the role of BAs in APAP-induced hepatotoxicity. METHODS: We performed intravital imaging to investigate BA transport in mice, quantified endogenous BA concentrations in the serum of mice and patients with APAP overdose, analyzed liver tissue and bile by mass spectrometry and MALDI-mass spectrometry imaging, assessed the integrity of the blood-bile barrier and the role of oxidative stress by immunostaining of tight junction proteins and intravital imaging of fluorescent markers, identified the intracellular cytotoxic concentrations of BAs, and performed interventions to block BA uptake from blood into hepatocytes. RESULTS: Prior to the onset of cell death, APAP overdose causes massive oxidative stress in the pericentral lobular zone, which coincided with a breach of the blood-bile barrier. Consequently, BAs leak from the bile canaliculi into the sinusoidal blood, which is then followed by their uptake into hepatocytes via the basolateral membrane, their secretion into canaliculi and repeated cycling. This, what we termed 'futile cycling' of BAs, led to increased intracellular BA concentrations that were high enough to cause hepatocyte death. Importantly, however, the interruption of BA re-uptake by pharmacological NTCP blockage using Myrcludex B and Oatp knockout strongly reduced APAP-induced hepatotoxicity. CONCLUSIONS: APAP overdose induces a breach of the blood-bile barrier which leads to futile BA cycling that causes hepatocyte death. Prevention of BA cycling may represent a therapeutic option after APAP intoxication. LAY SUMMARY: Only one drug, N-acetylcysteine, is approved for the treatment of acetaminophen overdose and it is only effective when given within ∼8 hours after ingestion. We identified a mechanism by which acetaminophen overdose causes an increase in bile acid concentrations (to above toxic thresholds) in hepatocytes. Blocking this mechanism prevented acetaminophen-induced hepatotoxicity in mice and evidence from patients suggests that this therapy may be effective for longer periods after ingestion compared to N-acetylcysteine.

INTRODUCTION: Crotalidae immune F(ab’)(2) (Fab2AV) became available in the USA in 2019 for treatment of rattlesnake envenomation. In the clinical trial comparing Fab2AV to crotalidae immune polyvalent fab (FabAV), Fab2AV was associated with less late hemotoxicity. The purpose of this study was to describe outcomes following use of Fab2AV in patients with rattlesnake envenomation in Arizona. METHODS: This is an observational study of patients admitted to a medical toxicology service at two hospitals in Arizona between January 1, 2019 and December 31, 2020. Patients with rattlesnake envenomation who received Fab2AV were included. Patients who received FabAV, alone or in combination with Fab2AV, were excluded. The main outcomes of interest were antivenom dose, adverse reactions, late hemotoxicity, and hospital readmission or retreatment. RESULTS: Forty-six patients were included. The mean age was 40 years, with 15% under 12 years of age. All exhibited swelling, 20% thrombocytopenia, and 35% coagulopathy. Median time to treatment was 3 h and median total Fab2AV dose was 20 vials. Three patients had an acute reaction to Fab2AV which was non-life-threatening and resolved with antihistamines and/or steroids. In the follow-up period, one case of delayed thrombocytopenia (platelets = 108 K/mm(3)) and one case of recurrent thrombocytopenia (platelets = 111 K/mm(3)) were identified. There was no late coagulopathy. Five patients reported symptoms consistent with mild serum sickness. CONCLUSIONS: In this series of patients with rattlesnake envenomation in Arizona who were treated with Fab2AV, there were no cases of clinically significant late hemotoxicity, and no patients required late retreatment with antivenom. Acute and delayed reactions did occur in some patients but were mild and easily treated.

INTRODUCTION: Acetaminophen (APAP) is commonly ingested in both accidental and suicidal overdose. Oxidative metabolism by cytochrome P450 2E1 (CYP2E1) produces the hepatotoxic metabolite, N-acetyl-p-benzoquinone imine. CYP2E1 inhibition using 4-methylpyrazole (4-MP) has been shown to prevent APAP-induced liver injury in mice and human hepatocytes. This study was conducted to assess the effect of 4-MP on APAP metabolism in humans. METHODS: This crossover trial examined the ability of 4-MP to inhibit CYP2E1 metabolism of APAP in five human volunteers. Participants received a single oral dose of APAP 80 mg/kg, both with and without intravenous 4-MP, after which urinary and plasma oxidative APAP metabolites were measured. The primary outcome was the fraction of ingested APAP excreted as total oxidative metabolites (APAP-CYS, APAP-NAC, APAP-GSH). RESULTS: Compared with APAP alone, co-treatment with 4-MP decreased the percentage of ingested APAP recovered as oxidative metabolites in 24-hour urine from 4.48 to 0.51% (95% CI = 2.31–5.63%, p = 0.003). Plasma concentrations of these oxidative metabolites also decreased. CONCLUSIONS: These results show 4-MP effectively reduced oxidative metabolism of APAP in human volunteers ingesting a supratherapeutic APAP dose. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03878693

INTRODUCTION: Measurement of serum acetaminophen-protein adducts (APAP-CYS) has been suggested to support or refute a diagnosis of acetaminophen (APAP)-induced hepatotoxicity when ingestion histories are unreliable or unavailable and when circulating APAP concentrations are low or undetectable. Non-APAP overdose patients commonly have used APAP products in non-toxic quantities and, thus, will have measurable APAP-CYS concentrations, even when hepatic injury results from other causes, such as ischemic hepatitis. The relationship between alanine aminotransferase (ALT) activity and APAP-CYS concentration might assist in distinguishing between toxic and non-toxic APAP doses in patients suspected of drug overdose. METHODS: We measured serial levels of serum APAP-CYS and ALT activities in 500 overdose patients in whom APAP toxicity was suspected on inpatient admission, but who were then classified at time of discharge and before results of APAP-CYS concentrations were available into three groups: 1) definite APAP group; 2) definitely not APAP group; and 3) indeterminate group. Subjects in the definite and definitely not APAP groups were selected in whom a plasma ALT activity was measured within ± 4 h of a serum APAP-CYS concentration. Regressions with correlation coefficients between APAP-CYS and ALT were calculated for repeat measures in the 335 subjects (908 blood samples) in the definite APAP group and 79 subjects (231 samples) in the definitely not APAP group, with an emphasis on APAP-CYS concentrations and calculation of 95% prediction intervals when ALT was ≥ 1000 IU/L. RESULTS: A strong correlation was found between APAP-CYS and ALT in the definite APAP group over all ALT activities (r = 0.93, p 1000 IU/L (r = 0.82, p

The heparin-induced thrombocytopenia computerised risk (HIT-CR) score is designed to aid in the diagnosis of HIT. We sought to evaluate its potential clinical utility. In this retrospective cohort study, we collected HIT-CR scores on all inpatients receiving heparin over a 4-month period and performed chart reviews on the subset who independently underwent clinical diagnostic testing for HIT to identify patients with HIT. In all, 34 342 patients received heparin, 1744 had high-risk HIT-CR scores of ≥3 and 220 had the maximal risk score of 4. Only 6% of high-risk and 10% of maximal-risk patients underwent testing for HIT. Conversely, among all 317 patients who underwent independent testing for HIT, 67% had low-risk HIT-CR scores (

Acetaminophen (APAP) hepatotoxicity is the most common cause of acute liver failure in the United States, and while a significant percentage of APAP overdose patients develop kidney injury, molecular mechanisms involved in APAP-induced nephrotoxicity are relatively unknown. We have shown that 4-methylpyrazole (4MP, Fomepizole) protects against APAP-induced liver injury by inhibiting reactive metabolite formation through Cyp2E1, and analysis of data from APAP overdose patients indicated that kidney dysfunction strongly correlated with severe liver injury. Since Cyp2E1 is also expressed in the kidney, this study explored protection by 4MP against APAP-induced nephrotoxicity. Male C57BL/6 J mice were treated with either 300 or 600 mg/kg APAP with or without 4MP for 2, 6 or 24 h, followed by measurement of APAP metabolism and tissue injury. Interestingly, levels of APAP and its non-oxidative metabolites were significantly higher in kidneys when compared to the liver. APAP-protein adducts were present in both tissues within 2 h, but were absent in kidney mitochondria, unlike in the liver. While GSH depletion was seen in both tissues, activation of c-jun N-terminal kinase and its translocation to the mitochondria, which is a critical feature of APAP-induced liver injury, was not detected in the kidney. Treatment with 4MP attenuated APAP oxidative metabolite generation, GSH depletion as well as kidney injury indicating its potential use in protection against APAP-induced nephrotoxicity. In conclusion, since reactive metabolite formation seems to be common in both liver and kidney, 4MP mediated inhibition of Cyp2E1 protects against APAP-induced nephrotoxicity. However, downstream mechanisms of APAP-induced nephrotoxicity seem distinct from the liver. © 2020 Elsevier Inc., National Institutes of Health, NIH: R01 DK102142 National Institutes of Health, NIH: F31 DK120194-01 National Institute of General Medical Sciences, NIGMS: P20 GM103549, P30 GM118247, This work was supported by a grant from McNeil Consumer Health Care, Inc. , the National Institutes of Health grant R01 DK102142 , and the National Institute of General Medical Sciences ( P20 GM103549 and P30 GM118247 ) from the National Institutes of Health . J.Y.A. was supported by a NIH Predoctoral Fellowship F31 DK120194-01 .

Purpose To determine whether tidal volume/predicted body weight (TV/PBW) or driving pressure (DP) are associated with mortality in a heterogeneous population of hypoxic mechanically ventilated patients. Methods A retrospective cohort study involving 18 intensive care units included consecutive patients ≥18 years old, receiving mechanical ventilation for ≥3 days, with a PaO2/FiO2 ratio ≤300 mmHg, whether or not they met full criteria for ARDS. The main outcome was hospital mortality. Multiple logistic regression (MLR) incorporated TV/PBW, DP, and potential confounders including age, APACHE IVa® predicted hospital mortality, respiratory system compliance (CRS), and PaO2/FiO2. Predetermined strata of TV/PBW were compared using MLR. Results Our cohort comprised 5,167 patients with mean age 61.9 years, APACHE IVa® score 79.3, PaO2/FiO2 166 mmHg and CRS 40.5 ml/cm H2O. Regression analysis revealed that patients receiving DP one standard deviation above the mean or higher (≥19 cmH20) had an adjusted odds ratio for mortality (ORmort) = 1.10 (95% CI: 1.06–1.13, p = 0.009). Regression analysis showed a U-shaped relationship between strata of TV/PBW and adjusted mortality. Using TV/PBW 4–6 ml/kg as the referent group, patients receiving >10 ml/kg had similar adjusted ORmort, but those receiving 6–7, 7–8 and 8–10 ml/kg had lower adjusted ORmort (95%CI) of 0.81 (0.65–1.00), 0.78 (0.63–0.97) and 0.80 0.67–1.01) respectively. The adjusted ORmort in patients receiving 4–6 ml/kg was 1.26 (95%CI: 1.04–1.52) compared to patients receiving 6–10 ml/kg. Conclusions Driving pressures ≥19 cmH2O were associated with increased adjusted mortality. TV/PBW 4-6ml/kg were used in less than 15% of patients and associated with increased adjusted mortality compared to TV/PBW 6–10 ml/kg used in 82% of patients. Prospective clinical trials are needed to prove whether limiting DP or the use of TV/PBW 6–10 ml/kg versus 4–6 ml/kg benefits mortality.

A review of the typical clinical course, diagnosis and treatment of acetaminophen toxicity is provided. For an acute overdose, most adults must ingest about 12g or more acetaminophen (APAP) before risk of serious hepatotoxicity is of concern. A nomogram of serum APAP concentration vs hours post-ingestion can assist in determining risk of liver injury and need for treatment. However, histories concerning the time of ingestion and the amount of drug ingested are usually unreliable. Peak serum transaminase activities usually occur 48-96h after acute ingestion. It is possible for patients to present in liver failure days after ingestion with undetectable serum APAP concentrations. Patients who have chronically ingested excessive APAP doses and develop hepatotoxicity usually present with such, and renal failure is more common in this population. Current treatment centers on administration of N-acetylcysteine (NAC) to prevent hepatotoxicity, though NAC also improves outcomes in patients who present with acute liver failure. When given early after APAP ingestion, NAC's main mechanism of action is to maintain intracellular glutathione stores so to detoxify the electrophilic APAP metabolite, NAPQI. NAC is generally well-tolerated when given intravenously, with the main concern being anaphylactoid reactions. These reactions usually occur during loading doses and are easily treated with discontinuation of the NAC infusion, administration of antihistamines, and then restarting the loading dose at a slower infusion rate. There is concern that current NAC dosing is not large enough to adequately treat large APAP ingestions. Patients with acute liver failure may be candidates for orthotopic liver transplantation.

This cohort study investigates whether the Sequential Organ Failure Assessment (SOFA) score is accurate enough to discriminate death from survival, and thus perhaps be a ventilator triage tool, for US patients with coronavirus disease 2019 (COVID-19) hospitalized in intensive care units and requiring mechanical ventilation.

Study objective To evaluate the efficacy and safety of a new F(abʹ)2 antivenom preparation in the treatment of Crotalinae envenomation in children. Methods We present a case series of children younger than 16 years who suffered Crotalinae envenomation and were treated with a new F(abʹ)2 antivenom. Envenomated children treated with the new antivenom were assessed for efficacy of the product, defined as improvement of any hemotoxicity (hypofibrinogenemia, defined as fibrinogen Results Twenty-one children received the F(abʹ)2 antivenom. Efficacy was achieved in all children receiving the product with initial control of swelling and improvement in those with hemotoxicity. No patients suffered anaphylaxis or any other serious adverse events from the F(abʹ)2 treatment. There were no cases of recurrent hemotoxicity recorded in the study between time of initial control and postinfusion day 15. Conclusions In this series of children, the F(abʹ)2 antivenom appeared to be both safe and effective in the treatment of hemotoxicity and local tissue toxicity (swelling) from Crotalinae envenomation.

Background & aims Hypoxic hepatitis is a clinical condition precipitated by prolonged periods of oxygen deprivation to the liver. It can have several underlying causes. Despite its prevalence in critically ill patients, which can reach upwards of 10%, very little is known about the mechanisms of injury. Thus, we set out to measure previously identified circulating biomarkers in an attempt to describe mechanisms of injury following hypoxic hepatitis. Methods Plasma from patients diagnosed with hypoxic hepatitis was collected for this study. Biomarkers of hepatocellular injury, mitochondrial damage and cell death were measured. These results were compared against results obtained from well-characterized acetaminophen overdose patients. Results At peak injury, ALT measured 4082±606 U/L and gradually decreased over 5 days, corresponding to the clinically observed pattern of hypoxic hepatitis. Levels of GDH showed a similar pattern, but neither ALT nor GDH were significantly higher in these patients than in acetaminophen patients. Plasma levels of DNA fragments mimicked hepatocellular injury as measured by ALT and miRNA-122. Interestingly, we found a significant increase in caspase-cleaved cytokeratin-18; however, the full-length form greatly exceeded the cleaved form at the time of maximum injury (45837±12085 vs 2528±1074 U/L). We also found an increase in acHMGB1 at later time points indicating a possible role of inflammation, but cytokine levels at these times were actually decreased relative to early time points. Conclusions The mechanism of injury following hypoxic hepatitis involves mitochondrial damage and DNA fragmentation. Importantly, necrosis, rather than apoptosis, is the main mode of cell death.

Essentials We previously published a diagnostic algorithm for heparin-induced thrombocytopenia (HIT). In this study, we validated the algorithm in an independent large healthcare system. The accuracy was 98%, sensitivity 82% and specificity 99%. The algorithm has potential to improve accuracy and efficiency in the diagnosis of HIT. SummaryBackground Heparin-induced thrombocytopenia (HIT) is a life-threatening drug reaction caused by antiplatelet factor 4/heparin (anti-PF4/H) antibodies. Commercial tests to detect these antibodies have suboptimal operating characteristics. We previously developed a diagnostic algorithm for HIT that incorporated ‘four Ts’ (4Ts) scoring and a stratified interpretation of an anti-PF4/H enzyme-linked immunosorbent assay (ELISA) and yielded a discriminant accuracy of 0.97 (95% confidence interval [CI], 0.93–1.00). Objectives The purpose of this study was to validate the algorithm in an independent patient population and quantitate effects that algorithm adherence could have on clinical care. Methods A retrospective cohort comprised patients who had undergone anti-PF4/H ELISA and serotonin release assay (SRA) testing in our healthcare system from 2010 to 2014. We determined the algorithm recommendation for each patient, compared recommendations with the clinical care received, and enumerated consequences of discrepancies. Operating characteristics were calculated for algorithm recommendations using SRA as the reference standard. Results Analysis was performed on 181 patients, 10 of whom were ruled in for HIT. The algorithm accurately stratified 98% of patients (95% CI, 95–99%), ruling out HIT in 158, ruling in HIT in 10 and recommending an SRA in 13 patients. Algorithm adherence would have obviated 165 SRAs and prevented 30 courses of unnecessary antithrombotic therapy for HIT. Diagnostic sensitivity was 0.82 (95% CI, 0.48–0.98), specificity 0.99 (95% CI, 0.97–1.00), PPV 0.90 (95% CI, 0.56–0.99) and NPV 0.99 (95% CI, 0.96–1.00). Conclusions An algorithm incorporating 4Ts scoring and a stratified interpretation of the anti-PF4/H ELISA has good operating characteristics and the potential to improve management of suspected HIT patients.

Acetaminophen (APAP)-induced acute liver failure (ALF) remains a major clinical problem. Although a majority of patients recovers after severe liver injury, a subpopulation of patients proceeds to ALF. Bile acids are generated in the liver and accumulate in blood during liver injury, and as such, have been proposed as biomarkers for liver injury and dysfunction. The goal of this study was to determine whether individual bile acid levels could determine outcome in patients with APAP-induced ALF (AALF). Serum bile acid levels were measured in AALF patients using mass spectrometry. Bile acid levels were elevated 5–80-fold above control values in injured patients on day 1 after the overdose and decreased over the course of hospital stay. Interestingly, glycodeoxycholic acid (GDCA) was significantly increased in non-surviving AALF patients compared with survivors. GDCA values obtained at peak alanine aminotransferase (ALT) and from day 1 of admission indicated GDCA could predict survival in these patients by receiver-operating characteristic analysis (AUC = 0.70 for day 1, AUC = 0.68 for peak ALT). Of note, AALF patients also had significantly higher levels of serum bile acids than patients with active cholestatic liver injury. These data suggest measurements of GDCA in this patient cohort modestly predicted outcome and may serve as a prognostic biomarker. Furthermore, accumulation of bile acids in serum or plasma may be a result of liver cell dysfunction and not cholestasis, suggesting elevation of circulating bile acid levels may be a consequence and not a cause of liver injury.

Context: New biomarkers are needed in acetaminophen (APAP) hepatotoxicity. Plasma argininosuccinate synthetase (ASS) is a promising candidate.Objective: Characterize ASS in APAP hepatotoxicity.Methods: ASS was measured in plasma from rodents and humans with APAP hepatotoxicity.Results: In mice, ASS increased before injury, peaked before alanine aminotransferase (ALT) and decreased rapidly. Fischer rats had a greater increase in ASS relative to ALT. Patients with abnormal liver test results had very high ASS compared to controls. ASS appeared to increase early in some patients, and declined rapidly in all.Conclusions: ASS may be a useful biomarker of acute cell death in APAP hepatotoxicity.

Background Heparin-induced thrombocytopenia (HIT) is diagnosed using clinical criteria and detection of platelet-activating anti-platelet factor 4/heparin (anti-PF4/H) antibodies, usually through a surrogate enzyme-linked immunosorbent assay (ELISA). The high false-positive rate (FPR) of this ELISA prompted us to reexamine its interpretation. Methods We analyzed anti-PF4/H ELISA results from a previously published dataset of 1,958 patients, using clinical suspicion and serotonin-release assay (SRA) to diagnose HIT. We performed receiver operating characteristic (ROC) analysis using stratum-specific likelihood ratios (SSLRs) and used Bayes theorem to construct a clinical decision-support algorithm. Results The most discriminant single cutoff by anti-PF4/H ELISA for the diagnosis of HIT was found to be 0.8 optical density (OD) units, not 0.4 OD (currently accepted practice). This change reduced the FPR from 31% to 6% (95% CI, 5%-8%). ELISA results were grouped into five strata, which yielded SSLRs ranging from 0.02 (strongly ruling HIT out) to 104.4 (strongly ruling HIT in). Comparison of ROC curves demonstrated that this five-strata approach is statistically more accurate than current accepted practice at discriminating whether patients have HIT or not (area under the ROC curve, 0.97 [95% CI, 0.93-1.00] vs 0.83 [95% CI, 0.80-0.89]). Our decision-support algorithm incorporated clinical assessment into this stratified model and clarified HIT diagnosis with a high degree of certainty and without the need for SRA testing in approximately 90% of patients. Conclusions Diagnostic accuracy of the anti-PF4/H ELISA can be optimized by using a higher cutoff and a stratified interpretation of the results. Our algorithm should significantly reduce overdiagnosis of HIT and the need for SRA testing.

To evaluate the efficacy and safety of a new F(ab')We present a case series of children younger than 16 years who suffered Crotalinae envenomation and were treated with a new F(ab')Twenty-one children received the F(ab')In this series of children, the F(ab')

Study objective Ethylene glycol remains an important toxic cause of metabolic acidosis and acute renal failure. Traditionally, inhibition of alcohol dehydrogenase along with hemodialysis has been used for treatment. Because of reported long elimination half-life of ethylene glycol during alcohol dehydrogenase inhibition, hemodialysis has been used in patients who are otherwise doing well to clear ethylene glycol. We study ethylene glycol elimination kinetics in patients treated with fomepizole, but without hemodialysis. Methods This was a retrospective, multicenter cohort study of patients older than 15 years who were treated at one of 3 medical centers during an 8-year period. Inclusion criteria were peak serum ethylene glycol concentration greater than 20 mg/dL, lack of renal failure on admission, treatment with fomepizole but without hemodialysis, and availability of serial serum ethylene glycol concentrations, allowing calculation of elimination half-life. The primary outcome variable was ethylene glycol elimination half-life; mortality and onset of renal failure were secondary outcome variables. Results During the study period, 85 patients were treated for ethylene glycol toxicity, of whom 40 met inclusion criteria. The mean serum ethylene glycol elimination half-life was 14.2 hours (SD=3.7 hours; 95% confidence interval 13.1 to 15.3 hours). One patient presented with metabolic acidosis on admission and developed mild transient renal insufficiency but did not require hemodialysis. No patient died. Conclusion The mean elimination half-life of ethylene glycol in this population was shorter than previously reported without hemodialysis, and this select group of patients did well without enhanced elimination by hemodialysis.

This is the third article of a three-part series that reviews the care of poisoned patients in the ICU. This article focuses on natural toxins, such as heavy metals and those produced by plants, mushrooms, arthropods, and snakes. The first article discussed the general approach to the patient, including laboratory testing; the second article focused on specific toxic agents, grouped into categories.

This is the second of a three-part series that reviews the generalized care of poisoned patients in the ICU. This article focuses on specific agents grouped into categories, including analgesics, anticoagulants, cardiovascular drugs, dissociative agents, carbon monoxide, cyanide, methemoglobinemia, cholinergic agents, psychoactive medications, sedative-hypnotics, amphetamine-like drugs, toxic alcohols, and withdrawal states. The first article discussed the general approach to the toxicology patient, including laboratory testing; the third article will cover natural toxins.

Amitriptyline and its metabolite, nortriptyline, are metabolized, in part, by CYP2D6, a polymorphic enzyme. About 8% of Caucasians are deficient in CYP2D6 activity.We present the case of a comatose woman who intentionally overdosed on amitriptyline and displayed rising serum total tricyclic antidepressant concentrations for at least 6 days after admission. Serial immunoassay total tricyclic antidepressant concentrations in our patient showed gradual decline beginning day 7, although the patient did not regain normal mental status until day 12. Genotyping revealed the patient to be homozygous for the CYP2D6*4 allele, the most common explanation of CYP2D6 enzymatic deficiency among Caucasians. Patients taking tricyclic antidepressants who are homozygous for CYP2D6*4 demonstrate3 times concentration-time curve (AUCs) and prolonged elimination half-lives, especially of secondary amines such as nortriptyline.We believe this is the first report describing toxicokinetics after tricyclic antidepressant overdose in a CYP2D6-deficient patient.

Background North American rattlesnake envenomations commonly produce defibrination, coagulopathy and/or thrombocytopenia, which may be reversed following treatment with Crotalidae Polyvalent Immune Fab Ovine (FabAV). Despite initial resolution with FabAV, late onset or recurrence of venom-induced hematologic effects may occur. Time at which onset of late hematotoxicity may first be detected is unknown. The purpose of this study was to identify the incidence and time of onset of recurrent or new late hypofibrinogenemia, coagulopathy, or thrombocytopenia in a cohort of rattlesnake envenomation patients seen in outpatient follow-up after treatment with FabAV, and to report hematologic outcomes in these patients. Methods Review of 66 charts of patients with rattlesnake envenomation who were treated with FabAV, and subsequently had outpatient follow-up evaluation at least 48 h after last FabAV, was performed. Demographic information, rattlesnake and bite characteristics, dose and timing of antivenom administration, adverse events, in-patient laboratory values, length of hospital stay, and follow-up laboratory values were collected. The primary outcome parameters were recurrent or delayed onset coagulopathy, hypofibrinogenemia, or thrombocytopenia identified no sooner than 48 h after last dose of FabAV. Results Prior to control of the envenomation with FabAV, 42 patients (63.6%) experienced hematologic toxicity. At follow-up, 21 patients (32%) were found to have late coagulopathy, hypofibrinogenemia, or thrombocytopenia. Of twenty-three patients (35%) with more than one follow-up visit, fifteen had normal laboratory findings at the first follow-up visit. Five of these 15 patients (8% of total study group; 33% of this subgroup) with normal hematologic studies at first follow-up exhibited late hematologic toxicity at second follow-up. Severe late hematologic toxicity developed in five of 66 (8%) patients. One patient was retreated with FabAV for late severe thrombocytopenia. Conclusion Recurrent and delayed onset of hematologic toxicity in rattlesnake envenomation victims treated with FabAV is common. Follow-up more than three days after treatment is necessary to detect all cases of late hematologic toxicity.

Anticonvulsant hypersensitivity syndrome is a rare disorder which occurs after administration of phenytoin, phenobarbitone or carbamazepine. It may be distinguished from a simple drug rash by the presence of fever, hepatitis, haematological abnormalities and other signs of systemic disease. These drugs all contain a benzene ring which is thought to form a toxic metabolite called arene oxide. This highly electrophilic molecule covalently binds to molecules and causes cell death. This compound is normally detoxified by the enzyme epoxide hydroxylase. Those individuals with impaired or absent activity of the enzyme will manifest the syndrome. In the unborn foetus, lack of this enzyme will predispose the child to developing foetal hydantoin syndrome. Treatment consists of removing the offending agent and supportive care. The use of steroids remains controversial.

Patient home management by a regional poison control center has potential to save public healthcare dollars by preventing unnecessary utilization of emergency department services. We wished to conservatively quantify such savings at a large regional poison center and compare savings to funds received in state support.Banner Poison Control Center (BPCC) serves a population of about four million in central AZ. A telephone survey of callers who were managed at home in February and March of 2007 after nontoxic exposures was used to calculate what percentage of such callers would have sought unnecessary medical care in emergency departments. Twelve emergency departments geographically dispersed in the region were surveyed, and a state database of hospital charges was queried to determine hospital charges and physician professional charges for conservative management of a patient who would have been advised to remain at home by BPCC.BPCC managed 28,883 callers at home in 2007. Seventy percent of home-managed patients would have sought unnecessary care in emergency departments. Using most conservative assumptions, a median of $33 million [range $18 million to $45 million] in unnecessary health care charges were prevented by BPCC home-management in 2007. A median of about $36 in unnecessary health care charges were prevented for each dollar of state funding BPCC received.Home management by BPCC provides large dollar savings to residents compared to dollars received in state support.

We have noticed increased prescribing of tramadol by emergency physicians for breakthrough pain in patients chronically taking oxycodone. Both oxycodone and tramadol undergo oxidative metabolism by CYP2D6 and CYP3A4, suggesting the possibility that tramadol may compete with oxycodone for metabolism. A randomized controlled trial in 10 human volunteers was performed to determine if single-dose tramadol therapy would impair oxycodone clearance. Subjects were randomized whether to enter the control or experimental arm of the study first, with each subject serving as his or her own control. In the control arm, each subject received 10 mg immediate-release oxycodone orally and had serial plasma oxycodone and oxymorphone concentrations measured over 8 h. The experimental arm was identical except that 100 mg tramadol was ingested 1.5 h before oxycodone. Clearance divided by fraction absorbed (CL/f) was calculated using the dose and the area under the 8-h time-plasma oxycodone concentration curve. Peak plasma oxycodone concentrations (C(max)) and time until peak oxycodone concentrations (T(max)) were secondary outcome parameters. Group size was chosen to produce a power of 0.8 to detect a 20% difference in CL/f between study arms. Values for CL/f, C(max), and T(max) were compared between study arms using two-tailed, paired t-tests. No statistically significant difference between groups was demonstrated for any parameter. We failed to demonstrate that single doses of tramadol impaired oxycodone clearance.

Background:Salicylate poisoning appears to result in death, despite supportive care, once a critical brain salicylate concentration is reached. The binding of salicylate to albumin is saturable; free plasma salicylate concentrations rise disproportionately to total drug levels. Because unbound salicylate distributes into the brain, the authors questioned whether an intravenous (IV) infusion of albumin would cause a redistribution of salicylate from the brain back into the plasma, which might allow enough time for hemodialysis to be instituted. Objectives:To determine if IV albumin infusion would lower brain salicylate concentrations through redistribution in a porcine model of acute salicylate poisoning. Methods:In a randomized controlled trial, 17 swine under anesthesia and controlled ventilation received 400 mg/kg of sodium salicylate IV over 15 minutes. At 60 minutes, nine animals received 1.25 g/kg albumin (25% solution) IV over 15 minutes, while eight control animals received an equal volume of normal saline (5 mL/kg). Arterial pH was maintained between 7.45 and 7.55. Serial measurements of serum albumin as well as free and total salicylate concentrations were obtained, and urine was collected for measurement of total salicylate excretion. At 180 minutes, animals were killed and brains harvested for measurement of brain salicylate concentrations. Results:Average peak serum total salicylate concentrations of 105.5 and 109 mg/dL were achieved in control and albumin-treated animals, respectively. Albumin infusion was accompanied by statistically significant increases in serum total salicylate concentrations (median from 79.5 to 86.9 mg/dL at 75 minutes), while levels decreased slightly in control animals. Serum free salicylate concentrations decreased slightly in albumin-treated animals, but the difference was not statistically significant. Median brain salicylate concentrations were about 14% lower in the albumin treatment group (17.8 mg/100 g brain) compared with controls (20.5 mg/100 g brain); this approached statistical significance (p = 0.075). Median urinary salicylate excretion was higher in the albumin-treated group (0.83 vs. 0.48 g; p = 0.072), with similar urinary pH and volumes in both groups. Conclusions:In this animal model of salicylate poisoning, IV infusion of 1.25 g/kg albumin was accompanied by a 14% decline in median brain salicylate concentrations, which approached statistical significance.

Bupropion overdose mainly is characterized by tachycardia, agitation, and seizures. The few reports of QRS complex widening after bupropion overdose that have been published in peer-reviewed literature are notable for failure to have confirmed elevated plasma bupropion concentrations or failure to have excluded other causes of QRS widening. We describe two patients in whom bupropion overdose was confirmed with elevated plasma bupropion concentrations and in whom other cardiotoxic ingestions were excluded with comprehensive analytical toxicology testing. Our findings are in keeping with ex vivo studies in which bupropion antagonizes cardiac voltage-gated sodium channels. Bupropion overdose should be considered in the differential diagnosis of unexpected QRS widening.

Serum acetaminophen determination is frequently necessary in patients with hepatic failure. We observed two patients (#1, #2) with elevated serum total bilirubin levels (26.5 mg/dL and 40.1 mg/dL) who had multiple false positive acetaminophen levels using the kinetic method of the GDS Diagnostics enzymatic acetaminophen assay (GDS Diagnostics, Elkhart, IN). We investigated the magnitude, threshold, and linearity of this effect using the GDS Diagnostics assay and an EMIT acetaminophen assay on two other hyperbilirubinemic patients (#3, #4) and a commercial solubilized bilirubin standard. Samples were diluted using fresh frozen plasma, and acetaminophen levels were analyzed twice using the kinetic method of the GDS Diagnostic acetaminophen assay and twice with the EMIT assay. The absence of acetaminophen in all samples was verified by gas chromatography/mass spectroscopy (GC/MS). The kinetic GDS assay resulted in a positive acetaminophen assay (cutoff for a positive result= 10 mg/L) with patient #3, patient #4, and in the bilirubin standard when the total bilirubin levels were 28.2 mg/dL, 22.5 mg/dL, and 18.3 mg/dL, respectively. One sample was interpolated to give a positive acetaminophen reading when diluted to a total bilirubin concentration of 15 mg/L. None of the samples tested with GC/MS or the EMIT assay resulted in any detectable acetaminophen. In conclusion, caution must be taken utilizing the GDS Diagnostic assay for the quantification of acetaminophen with concomitant hyperbilirubinemia. Alternatives such as EMIT or GC/MS should be employed to assess acetaminophen levels in such patients.

In October 2002, the Russian military used a mysterious "gas" to incapacitate Chechen rebels at a Moscow theater. Despite increased interest in the potential use of lethal chemical weapons in recent years, the medical community has paid little attention to the development of incapacitating, calmative, and "less than lethal" technologies. In this analysis, we review the events surrounding the use of a calmative "gas" during the Russian military action and discuss what is currently known about fentanyl derivatives, their aerosolization, and the rationale for their use as incapacitating agents. Collectively, the available evidence strongly suggests that a combination of a potent aerosolized fentanyl derivative, such as carfentanil, and an inhalational anesthetic, such as halothane, was used. The paper also assesses potential errors leading to the loss of a substantial number of hostages. Several lessons can be learned from this surprising and novel use of an incapacitating gas.

A patient with nonspecific complaints had four previous venous blood samples showing elevated methemoglobin fractions of 15.6-20.1%. Cooximetry on a fresh specimen revealed a methemoglobin fraction of 0.8%, while that reported by the original laboratory on the simultaneously collected specimen was 14.9%. The laboratory assayed the specimen after holding it in frozen storage. Venous blood from a healthy volunteer was assayed by cooximetry after storage under conditions of room temperature (22-24 degrees C), refrigeration (1-4 degrees C), and freezing (-14 to -12 degrees C). Methemoglobin level in frozen-thawed specimens rose over time from 1.8% (0.29 g/dL) at 6 hour to 10.9% (1.71 g/dL) after 6 days. With the exception of a single specimen stored in an EDTA-containing tube at room temperature for 6 days, methemoglobin in nonfrozen specimens never exceeded 0.8% (0.12 g/dL).

Elevated concentrations of serum acetaminophen-protein adducts, measured as protein-derived acetaminophen-cysteine (APAP-CYS), have been used to support a diagnosis of APAP-induced liver injury when histories and APAP levels are unhelpful. Adducts have been reported to undergo first-order elimination, with a terminal half-life of about 1.6 days. We wondered whether renal failure would affect APAP-CYS elimination half-life and whether continuous venovenous hemodiafiltration (CVVHDF), commonly used in liver failure patients, would remove adducts to lower their serum concentrations. Terminal elimination half-lives of serum APAP-CYS were compared between subjects with and without renal failure in a prospective cohort study of 168 adults who had ingested excessive doses of APAP. APAP-CYS concentrations were measured in plasma ultrafiltrate during CVVHDF at times of elevated serum adduct concentrations. Paired samples of urine and serum APAP-CYS concentrations were examined to help understand the potential importance of urinary elimination of serum adducts. APAP-CYS elimination half-life was longer in 15 renal failure subjects than in 28 subjects with normal renal function (41.3 ± 2.2 h versus 26.8 ± 1.1 h [mean ± SEM], respectively, p

The aims of this study were to develop, validate, and apply a high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method for quantification of protein-derived 3-(cystein-S-yl)-acetaminophen (APAP-Cys) in human serum. Formation of acetaminophen (APAP) protein adducts is thought to be a critical, early event in the development of APAP-induced hepatotoxicity, and quantification of these protein adducts in human serum represents a valuable tool for assessment of APAP exposure, metabolism, and toxicity. In the reported procedure, serum samples were first dialyzed or passed through gel filtration columns to remove APAP-Cys not covalently bound to proteins. Serum eluates were then subjected to enzymatic protease digestion to liberate protein-bound APAP-Cys. Norbuprenorphine-D3 was utilized as an internal standard (IS). APAP-Cys and IS were recovered from digested serum by protein precipitation with acetonitrile, and sample extracts were analyzed by HPLC-ESI-MS/MS. The method was validated by assessment of intra- and inter-assay accuracy and imprecision on two different analytical instrument platforms. APAP-Cys could be accurately quantified from 0.010 to 10μM, and intra- and inter-assay imprecision were

There are no published studies that have compared quality outcomes of hospitalized poisoned patients primarily under the care of physician medical toxicologists to patients treated by non-toxicologists. We hypothesized that inpatients primarily cared for by medical toxicologists would exhibit shorter lengths of stay (LOS), lower costs, and decreased mortality. Patients discharged in 2010 and 2011 from seven hospitals within the same health care system and greater metropolitan area with Medicare severity diagnosis-related groups for “poisoning and toxic effects of drugs” with and without major comorbidities or complications (917 & 918, respectively) were identified from a Premier® database. The database contained severity-weighted comparisons between expected and observed outcomes for each patient. Outcome parameters were differences between expected and observed LOS, cost, and percent mortality. These were then compared among groups of patients primarily admitted and cared for by (1) medical toxicologists at one hospital (Banner Good Samaritan Medical Center, BGS), (2) non-toxicologists at BGS, and (3) non-toxicologists at six other hospitals. Records of 3,581 patients contained complete data for assessment of at least one outcome measure. Patients cared for by medical toxicologists experienced favorable differences in LOS, costs, and mortality compared with other patient groups (p

Significance Hundreds of microRNAs become dramatically elevated in the plasma or serum of acetaminophen (APAP) overdose patients and then recover back toward normal during successful treatment with the APAP antidote, N -acetyl cysteine (NAC). Importantly, the elevation of these circulating miRNAs can precede the rise in the standard biomarker, alanine aminotransferase (ALT), and the recovery of these miRNAs during NAC treatment is more rapid than ALT. We identify a set of 11 miRNAs whose profiles and dynamics in circulation during NAC treatment can discriminate APAP hepatotoxicity from another common hepatotoxic condition, ischemic hepatitis. These findings suggest that miRNAs are sensitive diagnostic and prognostic biomarkers for liver injury with broad potential for use in monitoring drug-induced liver injury in clinical and research contexts.