Jeffrey Brent

Fomepizole for the Treatment of Methanol Poisoning

BACKGROUND Methanol poisoning may result in metabolic acidosis, blindness, and death. The inhibition of alcohol dehydrogenase is fundamental to the treatment of methanol poisoning. We performed a multicenter study to evaluate fomepizole, an inhibitor of alcohol dehydrogenase, in the treatment of patients with methanol poisoning. METHODS We administered intravenous fomepizole to 11 consecutive patients who presented with methanol poisoning at a participating center. Serial clinical and laboratory studies, including measurements of plasma formic acid and fomepizole, were performed. The outcomes measured were the preservation of visual acuity, the resolution of metabolic acidosis, the inhibition of formic acid production, the achievment of therapeutic plasma concentrations of fomepizole with the dosing regimen, residual illness or disability, and death. RESULTS Plasma formic acid concentrations were detectable in eight patients, and these concentrations were closely correlated with the initial arterial pH values (r=0.92, P<0.001). In response to fomepizole, plasma formic acid concentrations fell and metabolic abnormalities resolved in all patients. Nine patients survived. Seven patients initially had visual abnormalities, but at the end of the trial no surviving patient had any detectable visual deficits related to methanol poisoning. Fomepizole had few adverse effects. The two patients who died had anoxic brain injury that was present at the time of enrollment. During treatment, methanol had an elimination half-life of 54 hours. CONCLUSIONS Fomepizole appears to be safe and effective in the treatment of methanol poisoning.

Fomepizole for Ethylene Glycol and Methanol Poisoning

A 35-year-old man is brought to the emergency department after ingesting automobile antifreeze. His pH is 7.30, and his urinalysis reveals calcium oxalate crystals, findings consistent with ethylene glycol poisoning. Treatment with fomepizole is recommended. Fomepizole is a competitive inhibitor of alcohol dehydrogenase that prevents the formation of the toxic metabolites of ethylene glycol and methanol.

Current Management of Ethylene Glycol Poisoning

Ethylene glycol, a common antifreeze, coolant and industrial solvent, is responsible for many instances of accidental and intentional poisoning annually. Following ingestion, ethylene glycol is first hepatically metabolised to glycoaldehyde by alcohol dehydrogenase. Glycoaldehyde is then oxidised to glycolic acid, glyoxylic acid and finally oxalic acid. While ethylene glycol itself causes intoxication, the accumulation of toxic metabolites is responsible for the potentially fatal acidosis and renal failure, which characterises ethylene glycol poisoning.Treatment of ethylene glycol poisoning consists of emergent stabilisation, correction of metabolic acidosis, inhibition of further metabolism and enhancing elimination of both unmetabolised parent compound and its metabolites. The prevention of ethylene glycol metabolism is accomplished by the use of antidotes that inhibit alcohol dehydrogenase. Historically, this has been done with intoxicating doses of ethanol. At a sufficiently high concentration, ethanol saturates alcohol dehydrogenase, preventing it from acting on ethylene glycol, thus allowing the latter to be excreted unchanged by the kidneys. However, ethanol therapy is complicated by its own inherent toxicity, and the need to carefully monitor serum ethanol concentrations and adjust the rate of administration.A recent alternative to ethanol therapy is fomepizole, or 4-methylpyrazole. Like ethanol, fomepizole inhibits alcohol dehydrogenase; however it does so without producing serious adverse effects. Unlike ethanol, fomepizole is metabolised in a predictable manner, allowing for the use of a standard, validated administration regimen. Fomepizole therapy eliminates the need for the haemodialysis that is required in selected patients who are non-acidotic and have adequate renal function.

Therapy of Brown Spider Envenomation: A Controlled Trial of Hyperbaric Oxygen, Dapsone, and Cyproheptadine

STUDY OBJECTIVE To determine whether hyperbaric oxygen (HBO), dapsone, or cyproheptadine decreases the severity of skin lesions resulting from experimental Loxosceles envenomation. DESIGN Randomized, blinded, controlled study. SETTING Animal care facility. INTERVENTIONS We used New Zealand white rabbits. All groups received 20 micrograms of pooled L deserta venom intradermally. Our control group received 4 ml of a 5% ethanol solution by oral gavage every 12 hours for 4 days. The HBO group received hyperbaric oxygen at 2.5 ATA for 65 minutes every 12 hours for 2 days, plus 5% ethanol solution for 4 days. The dapsone group received dapsone 1.1 mg/kg in 5% ethanol by gavage every 12 hours for 4 days. The cyproheptadine group received cyproheptadine .125 mg/kg in 5% ethanol by gavage every 12 hours for 4 days. RESULTS Total lesion size and ulcer size were followed for 10 days. The lesions were then excised, examined microscopically, and ranked by the severity of the histopathology. The groups did not differ significantly with respect to lesion size, ulcer size, or histopathologic ranking. CONCLUSION Given the negative result in this study with adequate power to detect meaningful treatment benefits, we cannot recommend hyperbaric oxygen, dapsone, or cyproheptadine in the treatment of Loxosceles envenomation.

Toxicokinetics of ethylene glycol during fomepizole therapy: Implications for management

STUDY OBJECTIVE The elimination kinetics of ethylene glycol (EG) in human subjects treated with fomepizole (4-methylpyrazole) were analyzed to establish the efficacy of alcohol dehydrogenase (ADH) inhibition and to characterize elimination pathways. METHODS Drug concentration data from patients enrolled in the EG arm of the Methylpyrazole for Toxic Alcohols trial, a prospective, multicenter, open-label trial of fomepizole, were analyzed and compared with published estimates. RESULTS In 19 patients analyzed (EG concentrations of 3.5 to 211 mg/dL), elimination was first order during fomepizole monotherapy (half-life of 19.7±1.3 hours) and was not affected by the presence of ethanol. The elimination rate was significantly faster (half-life of <8.6±1.1 hours, P <.001) in the absence of fomepizole and ethanol. EG elimination by the kidneys was directly proportional to remaining renal function as estimated by creatinine clearance, with a fractional excretion of 25.5%±9.4%. Renal elimination and hemodialysis were the only significant routes of EG elimination as long as fomepizole concentrations were maintained well above 10 μmol/L (EG/fomepizole molar ratio, <100:1). All patients with normal serum creatinine concentrations at the initiation of fomepizole treatment had rapid rates of renal elimination (half-life of 16.8±0.8 hours). CONCLUSION At doses used, fomepizole effectively inhibits ADH-mediated metabolism of EG. Serum creatinine concentration at presentation and creatinine clearance can be used to predict EG elimination during fomepizole therapy and can help determine which patients will require hemodialysis to expedite EG elimination. An absolute EG concentration above 50 mg/dL should no longer be used as an independent criterion for hemodialysis in patients treated with fomepizole. [Sivilotti MLA, Burns MJ, McMartin KE, Brent J, for the Methylpyrazole for Toxic Alcohols Study Group. Toxicokinetics of ethylene glycol during fomepizole therapy: implications for management. Ann Emerg Med. August 2000;36:114-125.].

Glycolate Kinetics and Hemodialysis Clearance in Ethylene Glycol Poisoning

OBJECTIVE Toxic manifestations following ethylene glycol exposure are due to accumulation of metabolites, particularly glycolate. We characterized glycolate elimination kinetics and dialysis properties in a series of ethylene glycol poisonings. METHODS Patients who ingested ethylene glycol and received fomepizole (4-methylpyrazole; 4-MP) +/- hemodialysis were prospectively evaluated. Serial blood samples for ethylene glycol, glycolate, pH, and bicarbonate were drawn to determine glycolate elimination rate, t1/2, and correlations between initial glycolate and initial markers of acidosis. Dialyzer inlet and outlet samples were obtained to measure hemodialysis glycolate clearance. Plasma ethylene glycol and glycolate were determined by gas chromatography. RESULTS Ten patients, mean age 49 years (range 28-73 years), presented a mean of 10.5 hours (range 3.5-21.5 hours) after ethylene glycol ingestion. Mean initial ethylene glycol was 18.5 mmol/L (range 0.8-62.2 mmol/L) (115 mg/dL; range 5-386 mg/dL) and glycolate was 17.0 mmol/L (range 10.0-23.7 mmol/L). Nine of 10 underwent hemodialysis. Nonhemodialysis (n = 4) elimination rate was 1.08 +/- 0.67 mmol/L/h (mean +/- SD) and t1/2 was 626 +/- 474 minutes. Elimination t1/2 during hemodialysis (n = 8) was 155 +/- 42 minutes. Hemodialysis clearance (n = 5) was 170 +/- 23 mL/min with flow rates 250-400 mL/min. Pearson correlation coefficients were: anion gap vs glycolate r2 = 0.65 (p = 0.005), bicarbonate vs glycolate r2 = 0.10 (NS) and pH vs glycolate r2 = 0.06 (NS). CONCLUSION Glycolate has a slow elimination rate and long half-life. Hemodialysis effectively clears glycolate. An increased anion gap correlates with the presence of glycolate. Hemodialysis is projected as useful for ethylene glycol-poisoned patients with anion gap acidosis and low ethylene glycol blood levels.

Treatment of Methanol Poisoning With Intravenous 4-Methylpyrazole

Treatment of human methanol poisoning with the alcohol dehydrogenase inhibitor, 4-methylpyrazole (fomepizole), has not been previously described. We report the clinical and toxicokinetic data of a patient with methanol poisoning who was treated with fomepizole. Formic acid levels remained undetectable during fomepizole treatment, the toxic effects of methanol were prevented, and the patient made a full recovery.

Formate Kinetics in Methanol Poisoning

Objective: We sought to describe the kinetics, dialysis clearance, and laboratory markers of formate (FA), the toxic metabolite of methanol (meOH). Methods: Data were obtained from a prospective, multicenter study of fomepizole±dialysis for methanol poisoning. Inclusion criteria confirmed methanol exposure or suspicion of exposure plus either acidemia or abnormal osmolar gap. Dialysis indications were [meOH]>50 mg/dL, pH<7.1, refractory acidosis, or visual toxicity. Serial plasma formate, methanol, pH, and electrolyte measurements were made. Formate was determined by gas chromatography. Endogenous and dialysis elimination half-lives were calculated as t1/2=0.693/Ke, with Ke (elimination constant) derived from the slope of log (FA) vs. time. Half-lives were compared with an unpaired Students t-test. Dialysis clearance was calculated using the Fick Principle. Pearson correlation analysis compared initial formate with initial pH, serum bicarbonate, and anion gap. Results: Eleven patients were treated in the study. Eight had detectable formate with mean [FA] of 15.1 mmol/L (range 0.5–34.8). Endogenous elimination half-life was 205±90 minutes. Elimination half-life during dialysis (n=5) was 150±37 minutes, which was not different (t=0.22; NS). The overall dialysis formate clearance rate was 223±25 mL/min. Correlation coefficients were: pH vs. formate r2=0.93; bicarbonate vs. formate r2=0.81; and anion gap vs. formate r2=0.76 (all p<0.05). Conclusions: Although dialysis clears formate, it did not significantly enhance endogenous elimination in our series of patients. Low pH, low bicarbonate, and elevated anion gap correlate independently with formate presence.

Vitreous humor cocaine and metabolite concentrations: do postmortem specimens reflect blood levels at the time of death?

The interpretation of postmortem cocaine concentrations is made in an attempt to estimate drug concentrations present at the time of death and thus infer not only drug presence but drug toxicity. Previous data suggest that changes in postmortem blood cocaine concentrations over time are not predictable and interpretation of cocaine levels should be done with caution. However, these data come from autopsy case series where vital information, such as blood cocaine concentration at the time of death, dose and time since last use, and postmortem interval is often not known. The purpose of this study was to characterize postmortem changes in cocaine and metabolite concentrations relative to premortem concentrations over time at two anatomic sites: peripheral blood and vitreous humor, in a controlled, large animal model. Juvenile swine were given cocaine HCl 10 mg/kg as an IV bolus which resulted in seizures and wide complex tachycardia. Five minutes after cocaine administration, animals were euthanized. At time of death and eight hours postmortem, femoral venous blood and vitreous humor (VH) samples were obtained for quantitation of cocaine, benzoyl ecgonine (BE), and ecgonine methyl ester (EME) by GC/MS. There were no significant increases over time in mean femoral vein concentrations of cocaine or BE. However, a large interanimal variability in direction and magnitude of concentration changes was seen. Mean EME concentrations at the femoral site increased significantly over 8 hours (P < 0.03). Mean VH cocaine concentrations at time of death were significantly lower than corresponding blood concentrations (P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Fomepizole for the treatment of pediatric ethylene and diethylene glycol, butoxyethanol, and methanol poisonings

Introduction. The use and clinical efficacy of the alcohol dehydrogenase inhibitor fomepizole is well established for the treatment of ethylene glycol and methanol poisonings in adults. Methods. A computerized search of the U.S. National Academy of medicine and EMBase databases was undertaken to identify published cases of patients treated with fomepizole. This search strategy identified 14 published cases related to the topic of this review: 10 due to ethylene glycol poisoning, 1 due to diethylene glycol poisoning, 1 due to butoxyethanol ingestion, and 2 due to methanol poisoning. The median age of these cases was 5.5 years old. Fomepizole in glycol and glycol ether poisoning. For the 10 ethylene glycol poisoned patients, the median recorded values of their arterial pH was 7.27 (range 7.03–7.38), serum bicarbonate concentration was 13 mEq/L (range 2–25), and ethylene glycol concentration was 2,140 mg/L (range 130–3,840). Eight of these patients were not hemodialyzed. The eight patients who were not hemodialyzed had ethylene glycol concentrations as high as 3,500 mg/L and serum bicarbonate concentrations as low as 4 mEq/L. All 10 patients had resolution of their metabolic acidosis and recovered without sequelae. The half-times of ethylene glycol elimination ranged from 9 to 15 h during fomepizole therapy, which is faster than the 19.7 h reported in adults. The two patients who ingested diethylene glycol or butoxyethanol all recovered without sequelae. The patient who ingested the butoxyethanol had a serum bicarbonate concentration of 13 mEq/L and was not hemodialyzed. Fomepizole in methanol poisoning. One of the two children who ingested methanol was hemodialyzed. Both cases had a similar degree of severity. Does fomepizole obviate the need for hemodialysis? Based on the experience reviewed herein it appears that, as in adults, hemodialysis may not be necessary in most cases of pediatric ethylene glycol poisoning if treated with fomepizole. Fomepizole pharmacokinetics. Plasma fomepizole concentrations were measured in three cases and were found to be therapeutic with apparent Michaelis–Menton kinetics, having a zero-order elimination rate of 0.6–1 mg/L/h at higher concentrations and a first-order elimination with an apparent elimination half-time of 3.9 h at lower concentrations. Fomepizole regimen. Most cases used the current U.S.-approved regimen. Adverse effects of fomepizole. The one adverse effect reported during fomepizole therapy was transient nystagmus in a 6-year-old with a serum ethylene glycol concentration of 130 mg/L and a serum bicarbonate concentration of 2 mEq/L; it is likely that ethylene glycol itself was the cause. Comparison of fomepizole with ethanol therapy. Two cases were originally treated with ethanol but switched to fomepizole because of adverse effects. In both cases, the adverse reactions to ethanol resolved once fomepizole treatment was initiated. Conclusions. The limited data available suggest that fomepizole, using the same dosage regimen as that used for adults, is efficacious and well tolerated in pediatric patients. In many cases of pediatric ethylene glycol poisoning treated with fomepizole, hemodialysis may not be necessary despite high concentrations and the presence of metabolic acidosis.