Fomepizole use reported to United States Poison Centers from 2010 to 2021.

BACKGROUND: The diagnosis of toxic alcohol poisoning is often based on clinical presentation and nonspecific surrogate laboratory studies due to limited testing availability. Fomepizole is the recommended antidote and often administered empirically. The objective of this study is to identify substances that mimic toxic alcohols and compare key clinical factors between toxic alcohol and non-toxic alcohol exposures when fomepizole was administered. METHODS: This study was a retrospective evaluation using the National Poison Data System from January 1, 2010 through December 31, 2021. Exposures were included if fomepizole was administered. Toxic alcohol exposures had ethylene glycol or methanol as a coded substance. For exposures not coded as a toxic alcohol, the first substance was described. Paracetamol (acetaminophen) exposures from 2020 and 2021 were excluded. RESULTS: Fomepizole was reportedly used 25,110 times over 12 years. Use increased from 1,955 in 2010 to 2,710 in 2021. Most administrations were for reported toxic alcohol poisoning (60 percent) but use in reported non-toxic alcohol poisoning was greater starting in 2020. Toxic alcohol exposures were older (43.3 versus 39.8 years; P < 0.001) and more likely male (65.7 percent versus 58.2 percent). Level of care was mostly a critical care unit (67.7 percent), which was less common in toxic alcohol (63.3 percent) than non-toxic alcohol exposures (74.2 percent). The most common non-toxic alcohol substances were ethanol (24.9 percent) or an unknown drug (17.5 percent). Acidosis, increased creatinine concentration, anion gap, and osmolal gap, and kidney failure were coded in a lower proportion of toxic alcohol exposures than non-toxic alcohol exposures (P < 0.001). DISCUSSION: The inability to provide rapid clinical confirmation of toxic alcohol poisoning results in the empiric administration of fomepizole to many patients who will ultimately have other diagnoses. Although fomepizole is relative well tolerated we estimated that this practice costs between $1.5 to $2.5 million. The major limitations of this work include the biases associated with retrospective record review, and the inability to confirm the exposures which may have resulted in allocation error. CONCLUSION: Most fomepizole use was for a presumed toxic alcohol. This recently shifted to greater use in likely non-toxic alcohol poisoning. Key difference between the groups suggest fomepizole administration was likely due to the difficulty in diagnosis of toxic alcohol poisoning along with the efficacy and safety of fomepizole. Increased toxic alcohol laboratory testing availability could improve timely diagnosis, reserving fomepizole use for toxic alcohol poisoning.

Spatial analysis of renal acetaminophen metabolism and its modulation by 4-methylpyrazole with DESI mass spectrometry imaging.

Acute kidney injury (AKI) is a common complication in acetaminophen (APAP) overdose patients and can negatively impact prognosis. Unfortunately, N-acetylcysteine, which is the standard of care for the treatment of APAP hepatotoxicity does not prevent APAP-induced AKI. We have previously demonstrated the renal metabolism of APAP and identified fomepizole (4-methylpyrazole, 4MP) as a therapeutic option to prevent APAP-induced nephrotoxicity. However, the kidney has several functionally distinct regions, and the dose-dependent effects of APAP on renal response and regional specificity of APAP metabolism are unknown. These aspects were examined in this study using C57BL/6J mice treated with 300-1200 mg/kg APAP and mass spectrometry imaging (MSI) to provide spatial cues relevant to APAP metabolism and the effects of 4MP. We find that renal APAP metabolism and generation of the nonoxidative (APAP-GLUC and APAP-SULF) and oxidative metabolites (APAP-GSH, APAP-CYS, and APAP-NAC) were dose-dependently increased in the kidney. This was recapitulated on MSI which revealed that APAP overdose causes an accumulation of APAP and APAP GLUC in the inner medulla and APAP-CYS in the outer medulla of the kidney. APAP-GSH, APAP-NAC, and APAP-SULF were localized mainly to the outer medulla and the cortex where CYP2E1 expression was evident. Interestingly, APAP also induced a redistribution of reduced GSH, with an increase in oxidized GSH within the kidney cortex. 4MP ameliorated these region-specific variations in the formation of APAP metabolites in renal tissue sections. In conclusion, APAP metabolism has a distinct regional distribution within the kidney, the understanding of which provides insight into downstream mechanisms of APAP-induced nephrotoxicity.

Lack of mitochondrial Cyp2E1 drives acetaminophen-induced ER stress-mediated apoptosis in mouse and human kidneys: Inhibition by 4-methylpyrazole but not N-acetylcysteine.

Acetaminophen (APAP) overdose causes liver injury and acute liver failure, as well as acute kidney injury, which is not prevented by the clinical antidote N-acetyl-L-cysteine (NAC). The absence of therapeutics targeting APAP-induced nephrotoxicity is due to gaps in understanding the mechanisms of renal injury. APAP metabolism through Cyp2E1 drives cell death in both the liver and kidney. We demonstrate that Cyp2E1 is localized to the proximal tubular cells in mouse and human kidneys. Virtually all the Cyp2E1 in kidney cells is in the endoplasmic reticulum (ER), not in mitochondria. By contrast, hepatic Cyp2E1 is in both the ER and mitochondria of hepatocytes. Consistent with this subcellular localization, a dose of 600 mg/kg APAP in fasted C57BL/6J mice induced the formation of APAP protein adducts predominantly in mitochondria of hepatocytes, but the ER of the proximal tubular cells of the kidney. We found that reactive metabolite formation triggered ER stress-mediated activation of caspase-12 and apoptotic cell death in the kidney. While co-treatment with 4-methylpyrazole (4MP; fomepizole) or the caspase inhibitor Ac-DEVD-CHO prevented APAP-induced cleavage of procaspase-12 and apoptosis in the kidney, treatment with NAC had no effect. These mechanisms are clinically relevant because 4MP but not NAC also significantly attenuated APAP-induced apoptotic cell death in primary human kidney cells. We conclude that reactive metabolite formation by Cyp2E1 in the ER results in sustained ER stress that causes activation of procaspase-12, triggering apoptosis of proximal tubular cells, and that 4MP but not NAC may be an effective antidote against APAP-induced kidney injury.

An international survey of the treatment of massive paracetamol overdose in 2023.

INTRODUCTION: Changes in the commercialization of nonprescription drugs have made large quantities of paracetamol available to individuals, resulting in larger overdoses than previously observed. Although most patients with paracetamol overdose can be managed with acetylcysteine, patients with a massive overdose may become critically ill earlier and fail standard antidotal therapy. Several strategies are proposed for the management of these patients, including using increased doses of acetylcysteine, extracorporeal removal, and fomepizole. However, the benefits of these strategies remain largely theoretical, with sparse evidence for efficacy in humans. METHODS: This cross-sectional study surveys international practice patterns of medical toxicology providers regarding the management of a hypothetical patient with a massive paracetamol overdose. RESULTS: A total of 342 responses from 31 different nations were obtained during the study period. Sixty-one percent of providers would have increased their acetylcysteine dosing when treating the hypothetical massive overdose. Thirty percent of respondents recommended an indefinite infusion of acetylcysteine at 12.5 mg/kg/hour after the bolus dose, whereas 20 percent recommended following the "Hendrickson" protocol, which advocates for a stepwise increase in acetylcysteine dosing to match high paracetamol concentrations at the 300 mg/L, 400 mg/L, and 600 mg/L lines on the Rumack-Matthew nomogram. Ten percent of respondents stated they would have given "double dose acetylcysteine" but did not specify what that entailed. Forty-seven percent of respondents indicated that they would have given fomepizole, and 28 percent of respondents recommended extracorporeal removal. DISCUSSION: Our survey study assessed the approach to a hypothetical patient with a massive paracetamol overdose and demonstrated that, at minimum, most respondents would increase the dose of acetylcysteine. Additionally, almost half would also include fomepizole, and nearly one-third would include extracorporeal removal. CONCLUSIONS: There is considerable international variation for the treatment of both non-massive and massive paracetamol overdoses. Future research is needed to identify and standardize the most effective treatment for both non-massive and massive paracetamol overdoses.

High risk and low prevalence diseases: Toxic alcohol ingestion.

INTRODUCTION: Toxic alcohol ingestion is a rare but serious condition that carries with it a high rate of morbidity and mortality. OBJECTIVE: This review highlights the pearls and pitfalls of toxic alcohol ingestion, including presentation, diagnosis, and management in the emergency department (ED) based on current evidence. DISCUSSION: Toxic alcohols include ethylene glycol, methanol, isopropyl alcohol, propylene glycol, and diethylene glycol. These substances can be found in several settings including hospitals, hardware stores, and the household, and ingestion can be accidental or intentional. Toxic alcohol ingestion presents with various degrees of inebriation, acidemia, and end-organ damage depending on the substance. Timely diagnosis is critical to prevent irreversible organ damage or death and is based primarily on clinical history and consideration of this entity. Laboratory evidence of toxic alcohol ingestion includes worsening osmolar gap or anion-gap acidemia and end organ injury. Treatment depends on the ingestion and severity of illness but includes alcohol dehydrogenase blockade with fomepizole or ethanol and special considerations for the initiation of hemodialysis. CONCLUSIONS: An understanding of toxic alcohol ingestion can assist emergency clinicians in diagnosing and managing this potentially deadly disease.

Fomepizole should not be used more liberally in paracetamol overdose.

Fomepizole is a promising new treatment for preventing liver injury following paracetamol (acetaminophen) overdose. However, we need robust clinical trials to be performed to demonstrate its effect on clinical outcomes that are important to our patients and important to healthcare providers. Until such trials are performed, the toxicology community should learn the lessons from the COVID pandemic-potential novel therapeutic options may be theoretically appealing, but their effectiveness needs to be assessed in robust clinical trials before they are used in clinical practice.

Fomepizole should be used more liberally in paracetamol overdose.

Growing clinical and basic science data support the use of fomepizole as an adjunct to N-acetylcysteine in paracetamol poisoning. This safe antidote may be helpful in severely poisoned patients.

Desorption Electrospray Ionization Mass Spectrometry Imaging Allows Spatial Localization of Changes in Acetaminophen Metabolism in the Liver after Intervention with 4-Methylpyrazole.

Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the US, and hepatotoxicity is initiated by a reactive metabolite which induces characteristic centrilobular necrosis. The only clinically available antidote is N-acetylcysteine, which has limited efficacy, and we have identified 4-methylpyrazole (4MP, Fomepizole) as a strong alternate therapeutic option, protecting against generation and downstream effects of the cytotoxic reactive metabolite in the clinically relevant C57BL/6J mouse model and in humans. However, despite the regionally restricted necrosis after APAP, our earlier studies on APAP metabolites in biofluids or whole tissue homogenate lack the spatial information needed to understand region-specific consequences of reactive metabolite formation after APAP overdose. Thus, to gain insight into the regional variation in APAP metabolism and study the influence of 4MP, we established a desorption electrospray ionization mass spectrometry imaging (DESI-MSI) platform for generation of ion images for APAP and its metabolites under ambient air, without chemical labeling or a prior coating of tissue which reduces chemical interference and perturbation of small molecule tissue localization. The spatial intensity and distribution of both oxidative and nonoxidative APAP metabolites were determined from mouse liver sections after a range of APAP overdoses. Importantly, exclusive differential signal intensities in metabolite abundance were noted in the tissue microenvironment, and 4MP treatment substantially influenced this topographical distribution.

Symptomatic Diethylene Glycol Ingestion Successfully Treated with Fomepizole Monotherapy.

BACKGROUND: Diethylene glycol (DEG) is an industrial solvent with many uses, including brake fluids. It has also caused mass poisonings after use as an inappropriate substitute for propylene glycol or glycerin, though individual ingestions are rare. Like other toxic alcohols, DEG is metabolized by alcohol dehydrogenase and aldehyde dehydrogenase, with toxicity likely mediated by the resulting metabolites. Fomepizole, an alcohol dehydrogenase inhibitor, is used to prevent metabolite formation with other toxic alcohol exposures. Fomepizole is recommended for DEG poisoning, though supporting clinical evidence is limited. CASE REPORT: A 31-year-old man presented after ingestion of DEG-containing brake fluid and hydrocarbon-containing "octane booster." He was noted to be clinically intoxicated, with a mildly elevated anion gap metabolic acidosis and no osmolar gap. DEG level was later found to be elevated, consistent with his ingestion. He was treated with fomepizole alone, with resolution of metabolic acidosis and clinical findings over the next 2 days. No delayed neurologic sequelae were present at 52-day follow-up. Our case provides additional evidence supporting the use of fomepizole for DEG poisoning. Consistent with other toxic alcohols, DEG poisoning, especially early presentations, may benefit from empiric fomepizole administration. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: DEG poisoning is potentially life threatening, but treatable if identified early. An ingestion can be toxic despite a normal osmolar gap, leading to false reassurance. Finally, it is rare, so emergency physicians must be made aware of its potential dangers.

Treating ethylene glycol poisoning with alcohol dehydrogenase inhibition, but without extracorporeal treatments: a systematic review.

CONTEXT: Ethylene glycol is metabolized to toxic metabolites that cause acute kidney injury, metabolic acidemia, and death. The treatment of patients with ethylene glycol poisoning includes competitively inhibiting alcohol dehydrogenase with ethanol or fomepizole to prevent the formation of toxic metabolites, and extracorporeal treatments such as hemodialysis to remove ethylene glycol and its metabolites. In the absence of significant metabolic acidemia or kidney injury, it is hypothesized that extracorporeal treatments may be obviated without adverse outcomes to the patient if alcohol dehydrogenase inhibitors are used. OBJECTIVES: The objectives of this study are to: (1) identify indicators predicting ADH inhibitor failure in patients with ethylene glycol poisoning treated with either ethanol or fomepizole for whom extracorporeal treatment was not performed (aside from rescue therapy, see below) (prognostic study), and (2) validate if the anion gap, shown in a previous study to be the best surrogate for the glycolate concentration, is associated with acute kidney injury and mortality (anion gap study). METHODS: We conducted a systematic review to identify all reported patients with ethylene glycol poisoning treated without extracorporeal treatments but with either fomepizole (fomepizole monotherapy) or ethanol (ethanol monotherapy). Analyses were performed using both one case per patient and all cases (if multiple events were reported for a single patient). Data were compiled regarding poisoning, biochemistry, and outcomes. Treatment failure was defined as mortality, worsening of acid-base status, extracorporeal treatments used as rescue, or a worsening of kidney or neurological function after alcohol dehydrogenase inhibition was initiated. Also, we performed an analysis of previously described anion gap thresholds to determine if they were associated with outcomes such as acute kidney injury and mortality. RESULTS: Of 115 publications identified, 96 contained case-level data. A total of 180 cases were identified with ethanol monotherapy, and 231 with fomepizole monotherapy. Therapy failure was noted mostly when marked acidemia and/or acute kidney injury were present prior to therapy, although there were cases of failed ethanol monotherapy with minimal acidemia (suggesting that ethanol dosing and/or monitoring may not have been optimal). Ethylene glycol dose and ethylene glycol concentration were predictive of monotherapy failure for ethanol, but not for fomepizole. In the anion gap study (207 cases), death and progression of acute kidney injury were almost nonexistent when the anion gap was less than 24 mmol/L and mostly observed when the anion gap was greater than 28 mmol/L. CONCLUSION: This review suggests that in patients with minimal metabolic acidemia (anion gap <28 mmol/L), fomepizole monotherapy without extracorporeal treatments is safe and effective regardless of the ethylene glycol concentration. Treatment failures were observed with ethanol monotherapy which may relate to transient subtherapeutic ethanol concentrations or very high ethylene glycol concentrations. The results are limited by the retrospective nature of the case reports and series reviewed in this study and require prospective validation.

Oxidative stress and biochemical indicators in blood of patients addicted to alcohol treated for acute ethylene glycol poisoning.

Ethylene glycol (EG), in addition to its neurotoxic and nephrotoxic effects, evokes oxidative stress. The aim of this study was to assess the influence of the ethylene glycol on the biochemical indicators and oxidoreductive balance of patients treated for acute poisoning. The total study group consisted of 56 persons including 26 alcoholics who took EG as a substitute for ethyl alcohol in the course of alcohol dependence syndrome and 30 controls. Severity of poisoning, results of acid-base parameters, biochemical, and toxicological tests as well as biomarkers of the oxidative stress in blood were analyzed during the patients' hospitalization. The key issue was to assess the oxidative stress and biochemical disturbances caused by EG and the type of treatment applied in the course of poisoning. Significant changes in some parameters were found both at time of diagnosis and after treatment initiation (ethanol as an antidote and hemodialysis). The most important differences included the activity of hepatic parameters (aspartate aminotransferase, AST) and oxidative stress markers like catalase (CAT); correlation of the lipid peroxidation products level (TBARS) with urea concentration has been shown. On the last day of the hospitalization, in some cases, the mutual correlation between the evaluated markers were observed, for example, between alanine transaminase (ALT) and glutathione reductase (GR), and urea concentration and glutathione level (GSH/GSSG). The concentration of ions (H+) had a major impact on the oxidoreductive balance, correlating with the elevated GR and GSH/GSSG levels.

Use of fomepizole (4-methylpyrazole) for acetaminophen poisoning: A scoping review.

INTRODUCTION: Acetaminophen (paracetamol, APAP) poisoning is a prominent global cause of drug-induced liver injury. While N-acetylcysteine (NAC) is an effective antidote, it has therapeutic limitations in massive overdose or delayed presentation. The objective is to comprehensively review the literature on fomepizole as a potential adjunct antidote for acetaminophen toxicity. METHODS: A scoping review was performed using standardized search terms from inception through July 2021. RESULTS: Reports on fomepizole as a therapeutic adjunct for APAP toxicity span heterogeneous types of evidence. Eleven preclinical studies (in vitro and animal), fourteen case reports/series, and one human volunteer study were included. Fomepizole's action is mediated by inhibition of CYP2E1 to prevent oxidant stress generation, and inhibition of c-Jun N-terminal kinase (JNK) to decrease amplification of oxidant stress signaling to mitochondria. Studies have shown a reduction in oxidative metabolites likely by shunting metabolism away from CYP2E1 and a resultant decrease in liver injury in animals, independent of CYP2E1 interactions. Fomepizole has been linked to few adverse effects. CONCLUSION: Based on in vitro and animal studies, and bolstered by case reports, fomepizole likely offers benefit as an adjunct antidote for APAP toxicity, however this remains to be shown in a human trial. NAC remains the standard of care antidote, but given that fomepizole is approved and generally safe, it may be considered for APAP toxicity as off-label use by experienced clinicians, in rare circumstances associated with increased risk of hepatotoxicity despite standard NAC dosing. The marginal clinical benefit of fomepizole adjunct therapy beyond NAC monotherapy remains to be clearly defined, and routine use for APAP overdose is premature based on current evidence.

Toxic alcohol poisoning characteristics and treatments from 2000 to 2017 at a United States regional poison center.

BACKGROUND: Toxic alcohol exposures are an ongoing concern in the United States. In the US, few studies characterize the local epidemiology of toxic alcohols over time. OBJECTIVES: The objective was to examine the incidence of toxic alcohol ingestions and changes in management over time. METHODS: This retrospective cohort study evaluates toxic alcohol ingestion phone calls to a regional poison center in the United States covering four states. Data were queried for this poison center from the National Poison Data System (NPDS) using generic codes for each toxic alcohol. Inclusion criteria were ingestion of toxic alcohol, age ≥ 13 years, from January 1, 2000 to Dec 31, 2017. Exclusion criteria were unrelated effects coded in the medical outcome, duplicate data, or incomplete demographic data. RESULTS: Of 926 subjects (adults and teenagers), 71.5% were male, and the mean age was 34.5 years. Toxic alcohol ingestion was more common in individuals younger than 40 years, with a significant relationship between age and intentional abuse or misuse (p = 0.001). There was also a significant relationship between age and reason for ingestion, with younger patients more likely to be suicidal (p < 0.001). Ethyleneglycol was the most common toxic alcohol. There was no change in the incidence of toxic alcohol ingestions over the study period. The mortality rate was 1.7%, and 31.2%of patients were hospitalized in a critical care unit. Major effects and death were more common in younger patients (p < 0.001). There was a significant difference in medical outcomes based on the type of toxic alcohol(p = 0.03). Fomepizole was the most common treatment. A Poisson regression model found no change in fomepizole use during the study period (p = 0.1). Ethanol administration over the study period increased (p = 0.02), while hemodialysis decreased (p = 0.02). CONCLUSION: Data obtained from a single regional United States poison center showed low mortality related to toxic alcohol ingestions. The most prevalent toxic alcohol was Ethylene glycol. In all cases, toxic alcohol ingestion was higher in the 20-29-year-old age group. Reasons for ingestion, in most cases, were suicidal. Fomepizole was the most common treatment, ethanol administration as an antidote is rising, and hemodialysis utilization is decreasing. Data may not be nationally representative.

Spurious point-of-care lactate elevation in ethylene glycol intoxication: rediscovering a clinical pearl.

A 76-year-old man was found unresponsive and brought to the emergency department. Initial workup showed profound lactic acidosis on a point-of-care arterial blood gas, without clinical signs of hypoperfusion. Investigations for types A and B lactic acidosis revealed no unifying diagnosis to explain both his altered mental status and profound lactic acidosis. A toxicology workup revealed an increased osmolar gap and an elevated ethylene glycol level. The lactic acidosis and his mental status completely normalised within 8 hours of renal replacement therapy initiation and fomepizole administration. Ethylene glycol metabolites have similar molecular structure with L-lactate. Some blood gas analysers are unable to differentiate them, resulting in an artefactual lactate elevation. Our case highlights the importance of recognising a falsely elevated lactate, which should raise clinical suspicion of ethylene glycol poisoning, as the treatment is time-sensitive to prevent complications and mortality.

Subchronic administration of mitoxantrone and the influence of enzyme inhibitors on its induced cardiotoxicity in mice: role of NRF-2/CYP2E1.

OBJECTIVE: Mitoxantrone (MTX)- induced cardiotoxicity is a clinical concern that is limiting its use. The aim of this paper, therefore, was to investigate the subchronic administration of MTX plus nonspecific/specific inhibitors of CYP450/2E1, to assess the extent of oxidative-induced injury by measuring levels of oxidative cardiac and injury biomarkers in mice and to evaluate the effects of CYP2E1 on caspase 3 activity and nuclear factor erythroid 2-related factor-2 (NRF-2). MATERIALS AND METHODS: Mice (n = 32) were divided into four treatment groups of eight: control, MTX, MTX + 4-methlypyrazole (4MP) and MTX + disulfiram (Disf). After 6 weeks of treatments, blood and heart samples were collected. RESULTS: Liquid chromatography-mass spectrometry (LCMS) analysis of MTX-treated plasma samples revealed several metabolites with different retention times. Cardiac antioxidant enzymes and creatine kinase (CK) levels were not significantly different among the groups. However, cardiac troponin and caspase 3 activity were significantly raised, with increased CYP2E1 expressions and reduced NRF-2 expression. Tissue damage was observed in all the treatment groups, including MTX, leading to the conclusion that MTX-induced cardiotoxicity was mediated by CYP2E1 activity, which initiated caspase 3 production, and decreased NRF-2 expression. CONCLUSIONS: Therefore, agents that inhibit CPY2E1 expression might attenuate MTX-induced cardiotoxicity by increasing NRF-2 expression.