Rapid availability of ethylene glycol test results with enzymatic assay.

BACKGROUND: Ethylene glycol poisoning causes metabolic acidosis, organ injury, and death. Ethylene glycol testing is unavailable in many areas. Our laboratory uses an automated glycerol dehydrogenase enzymatic assay to screen for ethylene glycol. We sought to determine how often ethylene glycol results were available within 12 h of the first dose of fomepizole. METHODS: Records from a single poison center were reviewed from December 2016 to December 2019. Cases were identified by searching for cases that received fomepizole. Outcomes included whether results were available within 12 h, and the turnaround time from time of laboratory order to result. RESULTS: Of the 125 cases of suspected toxic alcohol poisoning identified, 73 had screening for ethylene glycol by enzymatic assay. Results were available within 12 h of the initial fomepizole dose in 58 (79%) cases with a median turnaround time of 391 min. DISCUSSION: We have demonstrated clinically acceptable turnaround times using an automated screening ethylene glycol assay. The major limitations include lack of approval for this test at this time, the use of voluntarily reported poison center data, and lack of assessment of patient outcomes. CONCLUSION: Enzymatic screening for ethylene glycol yielded results within 12 h in 79% of cases.

Real-world safety and effectiveness of intravenous fomepizole in patients with ethylene glycol and methanol poisoning in Japan: results of a 7-year post-marketing surveillance study.

BACKGROUND: Fomepizole is a competitive alcohol dehydrogenase inhibitor used for the treatment of ethylene glycol and methanol poisoning. We evaluated the safety and effectiveness of fomepizole in patients with ethylene glycol or methanol poisoning in Japan. RESEARCH DESIGN AND METHODS: This retrospective post-marketing surveillance study conducted in Japan registered patients who received fomepizole intravenous infusion per the package insert (January 2015-June 2022). Endpoints included adverse drug reactions/infections (ADRs), arterial blood pH, and treatment outcomes. RESULTS: Of 147 patients registered (91 institutions), 131 and 126 were included in the safety and effectiveness analysis sets, respectively. Mean age was 43.6 years, and 66.4% were male. Mean time from poison ingestion to treatment was 15.1 hours; 66.4% received concomitant hemodialysis. No serious ADRs were reported. ADRs were reported in seven patients; the most-reported ADR was vomiting (2.3%). Seven patients died, 105 survived without sequelae, and 19 survived with sequelae. Most common sequelae were renal failure or renal dysfunction. Mean arterial blood pH increased to 7.4 by 4 hours of treatment, remaining stable for 24 hours post-treatment. CONCLUSIONS: Fomepizole is well tolerated and helps improve clinical outcomes in patients with ethylene glycol or methanol poisoning in Japan. TRIAL REGISTRATION: Japanese Pharmaceutical Information Center (JapicCTI-152817).

Ethylene Glycol Poisoning: A Case Study of a 71-Year-Old Male with a History of Alcohol Abuse and Suicide Attempts.

A 71-year-old male with a history of alcohol abuse and multiple suicide attempts was brought to the emergency department in an unconscious state. Initial assessment revealed profound obtundation and malnutrition. Laboratory findings demonstrated a significant anion gap metabolic acidosis with a high osmolar gap, suggestive of possible toxic alcohol ingestion. Despite negative serum alcohol levels, ethylene glycol poisoning was confirmed with a level of 226. Treatment included fluid resuscitation, bicarbonate therapy, and fomepizole administration. However, due to progressive multi-organ failure, continuous veno-venous hemodialysis was initiated. Despite interventions, the patient deteriorated rapidly, leading to a decision for hospice care, ultimately resulting in death. Ethylene glycol poisoning presents significant challenges in management, with potential complications including renal failure and multi-organ dysfunction. Fomepizole remains the cornerstone of treatment, but additional therapies such as ethanol administration were considered but ultimately deemed unnecessary due to associated risks. This case highlights the complexity and severity of ethylene glycol poisoning, emphasizing the need for early recognition and aggressive management strategies.

The thrombopoietin mimetic JNJ-26366821 reduces the late injury and accelerates the onset of liver recovery after acetaminophen-induced liver injury in mice.

Acetaminophen (APAP)-induced hepatotoxicity is comprised of an injury and recovery phase. While pharmacological interventions, such as N-acetylcysteine (NAC) and 4-methylpyrazole (4-MP), prevent injury there are no therapeutics that promote recovery. JNJ-26366821 (TPOm) is a novel thrombopoietin mimetic peptide with no sequence homology to endogenous thrombopoietin (TPO). Endogenous thrombopoietin is produced by hepatocytes and the TPO receptor is present on liver sinusoidal endothelial cells in addition to megakaryocytes and platelets, and we hypothesize that TPOm activity at the TPO receptor in the liver provides a beneficial effect following liver injury. Therefore, we evaluated the extent to which TPOm, NAC or 4-MP can provide a protective and regenerative effect in the liver when administered 2 h after an APAP overdose of 300 mg/kg in fasted male C57BL/6J mice. TPOm did not affect protein adducts, oxidant stress, DNA fragmentation and hepatic necrosis up to 12 h after APAP. In contrast, TPOm treatment was beneficial at 24 h, i.e., all injury parameters were reduced by 42-48%. Importantly, TPOm enhanced proliferation by 100% as indicated by PCNA-positive hepatocytes around the area of necrosis. When TPOm treatment was delayed by 6 h, there was no effect on the injury, but a proliferative effect was still evident. In contrast, 4MP and NAC treated at 2 h after APAP significantly attenuated all injury parameters at 24 h but failed to enhance hepatocyte proliferation. Thus, TPOm arrests the progression of liver injury by 24 h after APAP and accelerates the onset of the proliferative response which is essential for liver recovery.

Transcriptome Study of Bursaphelenchus xylophilus Treated with Fomepizole Reveals a Serine/Threonine-Protein Phosphatase Gene that Is Substantially Linked with Vitality and Pathogenicity.

Bursaphelenchus xylophilus, the pine wood nematode (PWN), is the causal agent of pine wilt disease (PWD), which causes enormous economic loss annually. According to our previous research, fomepizole, as a selective inhibitor of PWN alcohol dehydrogenase (ADH), has the potential to be a preferable lead compound for developing novel nematicides. However, the underlying molecular mechanism is still unclear. The result of molecular docking showed that the stronger interactions between fomepizole and PWN ADH at the active site of ADH were attributed to hydrogen bonds. Low-dose fomepizole had a substantial negative impact on the egg hatchability, development, oviposition, and lifespan of PWN. Transcriptome analysis indicated that 2,124 upregulated genes and 490 downregulated genes in fomepizole-treated PWN were obtained. Kyoto Encyclopedia of Genes and Genomes enrichment analysis of differentially expressed genes indicated that fomepizole could be involved in controlling PWN vitality mainly by regulating key signaling pathways, such as the ribosome, hippo signaling pathway, and lysosome. Remarkably, the results of RNA interference indicated that the downregulated serine/threonine-protein phosphatase gene (stpp) could reduce the egg hatchability, development, oviposition, and lifespan of PWN, which was closely similar to the consequences of nematodes with low-dose fomepizole treatment. In addition, the silencing of stpp resulted in weakness of PWN pathogenicity, which indicated that stpp could be a potential drug target to control PWN.

Massive acetaminophen ingestion managed successfully with N-acetylcysteine, fomepizole, and renal replacement therapy.

Acetaminophen ingestion is routinely managed with the antidote, N-acetylcysteine (NAC). Massive acetaminophen poisoning has been treated successfully with adjunctive therapies such as fomepizole and hemodialysis. Fomepizole functions by inhibiting cytochrome p560, which prevents tylenol from forming its toxic metabolite, NAPQI. Prior cases have demonstrated favorable outcomes and a significant drop in acetaminophen levels after a single session of intermittent hemodialysis and continuous veno-venous hemofiltration (CVVH). However, the recommended dosage adjustments of NAC and fomepizole while a patient is undergoing CVVH has not been well reported. We present a case of an 18-year-old male who presented after ingesting 125 g of tylenol. His 4-hour acetaminophen level was 738.6 µg/mL. He was treated with NAC, fomepizole, and a single 4-hour session of hemodialysis. His acetaminophen level remained elevated at 730 µg/mL despite the hemodialysis session. CVVH was initiated, and he was given intravenous NAC at 12.5 mg/kg/h, oral NAC at 70 mg/kg every 4 hours, and intravenous fomepizole at 10 mg/kg every 6 hours. His tylenol levels became undetectable 57 hours after ingestion, and he did not develop permanent liver toxicity. This case encourages the use of CVVH for massive tylenol ingestion when a single run of intermittent hemodialysis is not effective in lowering the tylenol level. NAC, fomepizole, and CVVH can prevent unfavorable outcomes in massive acetaminophen ingestion when provided at an appropriate dose and frequency.

Clinically relevant therapeutic approaches against acetaminophen hepatotoxicity and acute liver failure.

Liver injury and acute liver failure caused by an acetaminophen (APAP) overdose is a significant clinical problem in western countries. With the introduction of the mouse model of APAP hepatotoxicity in the 1970 s, fundamental mechanisms of cell death were discovered. This included the recognition that part of the APAP dose is metabolized by cytochrome P450 generating a reactive metabolite that is detoxified by glutathione. After the partial depletion of glutathione, the reactive metabolite will covalently bind to sulfhydryl groups of proteins, which is the initiating event of the toxicity. This insight led to the introduction of N-acetyl-L-cysteine, a glutathione precursor, as antidote against APAP overdose in the clinic. Despite substantial progress in our understanding of the pathomechanisms over the last decades viable new antidotes only emerged recently. This review will discuss the background, mechanisms of action, and the clinical prospects of the existing FDA-approved antidote N-acetylcysteine, of several new drug candidates under clinical development [4-methylpyrazole (fomepizole), calmangafodipir] and examples of additional therapeutic targets (Nrf2 activators) and regeneration promoting agents (thrombopoietin mimetics, adenosine A2B receptor agonists, Wharton's Jelly mesenchymal stem cells). Although there are clear limitations of certain therapeutic approaches, there is reason to be optimistic. The substantial progress in the understanding of the pathophysiology of APAP hepatotoxicity led to the consideration of several drugs for development as clinical antidotes against APAP overdose in recent years. Based on the currently available information, it is likely that this will result in additional drugs that could be used as adjunct treatment for N-acetylcysteine.

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.

Developing new antidotes for poisons with existing effective treatments: a case study of fomepizole in paracetamol poisoning.

INTRODUCTION: Acetylcysteine is the only effective and licensed therapy for paracetamol poisoning. However, acetylcysteine loses efficacy if treatment is delayed 8-12 hours after paracetamol ingestion, and there is also uncertainty as to whether the dose should be increased in high-risk paracetamol ingestions. Studies have identified potential therapeutic targets, including enzymes that metabolize paracetamol; the pathways causing mitochondrial toxicity via c-Jun N-terminal kinases or superoxide generation; and other specific targets, such as nuclear factor-erythroid factor 2-dependent gene induction and autophagy. With this range of potential additional therapies, how should the speciality of clinical toxicology approach the development of new antidotes for this common poisoning? HISTORICAL BACKGROUND: When the first treatments for paracetamol toxicity were developed, the clinical trial and ethical basis of practice were different from today. Acetylcysteine was never subjected to placebo-controlled studies, even by the United States Food and Drug Administration, as it was presumed that the toxicity of high paracetamol concentrations was so evident that placebo-controlled studies were unethical. Thus, the absolute benefit of acetylcysteine remains unknown. In addition, no dose-ranging studies of acetylcysteine in patients were ever done. The weakness of assessing the efficacy of additional antidotes in small groups of patients with moderate poisoning is illustrated by the use of cimetidine in paracetamol poisoning. CURRENT APPROACHES TO DRUG (AND ANTIDOTE) DEVELOPMENT: The approach required by regulatory authorities today relies on several important steps. First, a clear target for therapeutic effect is sought, normally in a laboratory model. Next, a 'proof of principle' study is required to demonstrate that the target is 'druggable'. Finally, clinical studies to confirm proof of principle applies in humans, followed by a controlled trial with matched patient groups with sufficient power to demonstrate the clinical outcome being sought. Such patient studies can be expensive to conduct, and non-commercial groups suffer the risk of not being funded. FOMEPIZOLE: Fomepizole prevents paracetamol-induced hepatic toxicity in mice by inhibiting cytochrome P4502E1, thereby preventing the conversion of paracetamol to its toxic metabolite. Fomepizole also inhibits c-Jun N-terminal kinases, a key pathway in the downstream toxicity on the mitochondria. The present evidence of efficacy in humans is based on small case series with no control groups. The availability of a licensed indication has facilitated off-label use of fomepizole in an unproven indication. CONCLUSIONS: Paracetamol poisoning is common, and randomized, controlled clinical trials are possible. The benefit of fomepizole can only be shown by such a study. As clinical trials using fomepizole as an added therapy to acetylcysteine are recruiting in the United States, these should be supported by all clinical toxicologists. In the interim, the publication of small case series using fomepizole should be discouraged by journals.

Severe Acetaminophen Toxicity From the Use of Oxycodone-Acetaminophen With Normal Liver Function Tests and a Completely Asymptomatic Course of Hospitalization.

Acetaminophen (N-acetyl-p-aminophenol, APAP), after being metabolized to toxic N-acetyl-p-benzoquinone imine, can cause irreversible hepatic necrosis. The mainstay of treatment includes N-acetylcysteine and fomepizole or liver transplant in patients who further deteriorate. Currently, many overdoses unintentionally occur in the setting of ingesting combined products that contain APAP. We report a rare case of a 60-year-old woman who presented with altered mental status and APAP toxicity in the setting of oxycodone-APAP overdose. She had a toxic serum APAP level on arrival. During hospitalization, her APAP level remained at the toxic level on the Rumack-Matthew nomogram. However, her liver function tests remained within normal limits, and she remained completely asymptomatic. To our best knowledge, this is the second case report with asymptomatic APAP toxicity and normal liver function tests. We will explore the effect of concomitant oxycodone ingestion on possibly delaying APAP absorption and thus resulting in a more favorable prognosis without hepatotoxicity.

Nrf2 as a therapeutic target in acetaminophen hepatotoxicity: A case study with sulforaphane.

Acetaminophen (APAP) overdose can cause severe liver injury and acute liver failure. The only clinically approved antidote, N-acetylcysteine (NAC), is highly effective but has a narrow therapeutic window. In the last 2 decades, activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates acute phase proteins and antioxidant defense genes, has emerged as a putative new therapeutic target against APAP hepatotoxicity. However, virtually all studies that propose Nrf2 activation as mechanism of protection used prolonged pretreatment, which is not a clinically feasible approach to treat a drug overdose. Therefore, the objective of this study was to assess if therapeutic activation of Nrf2 is a viable approach to treat liver injury after APAP overdose. We used the water-soluble Nrf2 activator sulforaphane (SFN; 5 mg/kg) in a murine model of APAP hepatotoxicity (300 mg/kg). Our results indicate that short-term treatment (≤3 h) with SFN alone did not activate Nrf2 or its target genes. However, posttreatment with SFN after APAP partially protected at 6 h likely due to more rapid activation of the Nrf2-target gene heme oxygenase-1. A direct comparison of SFN with NAC given at 1 h after APAP showed a superior protection with NAC, which was maintained at 24 h unlike with SFN. Thus, Nrf2 activators have inherent problems like the need to create a cellular stress to activate Nrf2 and delayed adaptive responses which may hamper sustained protection against APAP hepatotoxicity. Thus, compared to the more direct acting antidote NAC, Nrf2 activators are less suitable for this indication.

Outcome of Methanol Toxicity Outbreak In Saudi Arabia: Case Series Study.

Introduction Methanol poisoning is an acute medical emergency. If not recognized in time and treated properly, it can lead to a considerable magnitude of morbidity as well as mortality. This article aims to report cases of methanol toxicity, focusing on clinical presentation, management, and outcomes. Method Nine ICU-admitted patients with confirmed positive serum methanol levels were analyzed in a case series at King Fahad General Hospital in Jeddah, Saudi Arabia, between November 2022 and January 2023. Results Among the nine patients admitted to the ICU due to methanol poisoning, the majority were middle-aged males, with two females included. Gastrointestinal symptoms were seen in two-thirds of patients, while three patients required immediate mechanical ventilation due to a low Glasgow Coma Scale. Severe metabolic acidosis was observed in most cases. All patients received sodium bicarbonate and hemodialysis, with six patients also receiving fomepizole. However, two patients in the study with low initial low Glasgow Coma Scale (GCS), severe metabolic acidosis, and diffuse brain edema, did not survive. One patient reported acute complete vision loss. Conclusion This case series highlights the importance of promptly recognizing and managing methanol toxicity in ICU settings. The clinical presentation of methanol toxicity can be challenging, and early diagnosis and treatment are crucial to prevent irreversible damage.

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.

[When a Gap Leads to an Answer]. / Wenn eine Lücke zur Lösung führt.

When a Gap Leads to an Answer Abstract. We report the case of a 22-year-old patient who was found somnolent after previously complaining of nausea, abdominal pain, and vomiting. The main findings were high anion gap metabolic acidosis and lactatemia. Causative was the ingestion of ethylene glycol using a car antifreeze agent with suicidal intent.

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.

Fomepizole as an adjunctive therapy for acetaminophen poisoning: cases reported to the toxicology investigators consortium (ToxIC) database 2015-2020.

INTRODUCTION: Fomepizole inhibits formation of toxic acetaminophen (APAP) metabolites and may prevent or reverse mitochondrial toxicity. Given these mechanisms, it may be beneficial in patients with severe APAP toxicity. Current patterns of use for this indication are not well-studied. METHODS: This is a secondary analysis of patients enrolled in the Toxicology Investigators Consortium (ToxIC) database from January 2015 to July 2020. We queried cases in which APAP was listed as an ingested agent and fomepizole was also administered. We excluded cases in which APAP was not the primary agent, N-acetylcysteine (NAC) was not administered, or fomepizole was explicitly administered for another indication. Additionally, we sent a survey to each ToxIC site that administered fomepizole for APAP toxicity to better understand when, why, and how they were using it for this indication. RESULTS: Twenty-five cases of fomepizole administration following an APAP ingestion met our inclusion criteria. There were one to four cases per year between 2015 and 2019 and eight cases in 2020. Seventeen of 25 (68%) cases were for a known acute ingestion. Eighteen of 25 (72%) patients developed hepatotoxicity (AST or ALT > 1000 IU/L) and 10 of 25 (40%) developed coagulopathy (PT > 15s). This was an ill patient population, with 18 of 25 (72%) developing metabolic acidosis (pH <7.20), 12 of 25 (48%) were intubated, 9 of 25 (36%) receiving vasopressors, and 6 of 25 (24%) receiving continuous renal replacement therapy. Overall, mortality was 24%. CONCLUSION: The use of fomepizole is increasing in frequency in a small subset of critically ill and acutely APAP-poisoned patients.