Considerations for the treatment of ethylene glycol poisoning based on analysis of two cases

The clinical picture as well as the principles of treatment in ethylene glycol poisoning differ with the time after ingestion. These time-related differences are illustrated by two case reports. During the first hours of ethylene glycol poisoning, the patient suffers from drunkenness, vomiting and somnolence due to the intoxicant effect of ethylene glycol on the central nervous system. In the following hours a poisoning with glycolate and oxalate develops, with increasing acidosis, renal and brain damage. A patient admitted within a few hours of an overdose, with no or only slight metabolic acidosis, may be successfully treated with ethanol. If the serum concentration of ethylene glycol is very high, hemodialysis may be deferred until the necessary staff and equipment are available. If the patient is admitted with severe metabolic acidosis, hemodialysis must be started immediately. The need for ethanol administration during hemodialysis merits reevaluation.     

Treatment of severe pediatric ethylene glycol intoxication without hemodialysis

BACKGROUND: There is limited experience treating severe ethylene glycol poisoning in children without hemodialysis. The objective of this study was to describe the clinical course and outcome of severe pediatric ethylene glycol poisoning treated without hemodialysis. METHODS: Patient records were identified retrospectively by hospital discharge diagnosis (ICD-9 code) of ethylene glycol poisoning from 1999 through 2002 at a pediatric medial center. Patients with initial serum ethylene glycol concentrations less than 50 mg/dL or those who received hemodialysis were excluded. RESULTS: Six patients with an age range of 22 months to 14 years were admitted for treatment of ethylene glycol poisoning over a four-year period. Initial serum ethylene glycol concentrations ranged from 62 to 304 mg/dL (mean 174.0 mg/dL). The lowest-measured individual serum bicarbonates ranged from 4 to 17 mEq/L. All patients were initially admitted to intensive care. One patient received ethanol only, two patients received fomepizole only, and three patients received a loading dose of ethanol and then were converted to fomepizole therapy. None of the patients received hemodialysis. Treatment was continued until the serum ethylene glycol was less than 10 mg/dL. Metabolic acidosis resolved with intravenous fluid and supplemental bicarbonate within 24h. All patients had a normal creatinine upon presentation and at discharge. The mean length of stay in intensive care was 21h and on the ward was 33.7h. One episode of hypoglycemia occurred in a 22-month-old. All patients recovered without evidence of renal insufficiency or other major complications at discharge. CONCLUSION: Six pediatric patients with severe ethylene glycol intoxication and normal renal function were successfully treated without hemodialysis.     

急性乙二醇中毒3例报告及文献回顾

乙二醇为防冻剂的主要成分。乙二醇主要在肝脏内先后代谢为羟乙醛、乙醇醛、乙醇酸及草酸。这些代谢特可导致代谢性酸中毒。典型临床表现通常为3个阶段：第1阶段在摄入后12h内，乙二醇致中枢神经系统抑制；第2阶段在摄入12～24h后，出现代谢性酸中毒和心肺疾病；第3阶段在摄入后24～72h。出现肾小管坏死和肾衰竭。乙二醇致死量为1．4-1．6ml／kg[成人（70kg）约为100m1]。一旦怀疑乙二醇中毒，应尽快测定乙二醇和乙醇酸血浓度明确诊断。中毒治疗原则包括早期及时洗胃，给予乙醇或甲吡唑解毒剂，血液透析，碳酸氢钠vitB6等。大多数乙二醇中毒患者经早期诊断治疗后可恢复正常。本文报告3例急性乙醇中毒，3例患者均为男性（48岁），每人服用防冻液约为150ml。2倒出现头痛有，1例出现上腹不适、兴奋、躁动。3倒患者在摄入乙醇后12～18h出现代谢性酸中毒，24h出现血尿。经洗胃和血液透析，给予法莫替丁40mg，10％葡萄糖酸钙20ml。4％碳酸氢钠静脉注射，38％白酒200ml口服。2倒治愈，1例于摄入乙二醇后29h死亡。     

Ethylene Glycol Toxicity Presenting with Non‐Anion Gap Metabolic Acidosis

Abstract: Ethylene glycol classically produces an elevated anion gap metabolic acidosis. We report a series of patients with ethylene glycol toxicity with a component of non‐anion gap metabolic acidosis without known associated confounding factors. A retrospective review of Poison Control Center records were searched more than 8 years (2000–2007) for ethylene glycol and antifreeze. Cases were reviewed and excluded for miscoding, information calls, animal exposures, or non‐ingestion exposures. The bicarbonate gap, or delta ratio (DR), was calculated using the formula: DR = (AG ? 12)/[24 – measured serum where anion gap (AG) = [Na⁺] ? [Cl^?] ? , all in mEq/l. Non‐anion gap metabolic acidosis was considered present when the DR < 1. Of 254 cases, 175 were excluded. Of the remaining 79 cases, 14 had a component of non‐anion gap metabolic acidosis at presentation. Their calculated anion gap was 14–28, and measured serum ranged from 2–20 mEq/l. A normal anion gap was present in two patients who presented with non‐anion gap metabolic acidosis. The DR ranged from 0.28–0.95. Seven out of 14 patients with non‐anion gap metabolic acidosis had elevated serum [Cl^?]. In the other cases, no explanation for the non‐anion gap metabolic acidosis could be determined. The absence of a significant anion gap elevation in the setting of metabolic acidosis after ethylene glycol ingestion without other confounding factors (such as ethanol, lithium carbonate or bromide) has not previously been recognized. Clinicians should be aware of the potential for non‐anion gap metabolic acidosis in patients with ethylene glycol toxicity, and should not exclude the diagnosis in patients who present with a non‐anion gap metabolic acidosis. Further study is needed to determine the mechanisms by which this occurs.     

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.     

Massive Ethylene Glycol Ingestion Treated with Fomepizole Alone—A Viable Therapeutic Option

Fomepizole is used to treat and prevent toxicity from ethylene glycol poisoning. Treatment with fomepizole without hemodialysis in massive ethylene glycol ingestion has been rarely reported in the literature; however, published literature and practice guidelines recommend considering dialysis for ethylene glycol levels >50 mg/dL. We report a case of massive ethylene glycol ingestion resulting in the highest serum ethylene glycol concentration in a patient without ethanol co-ingestion who was treated with fomepizole and was not hemodialyzed. A 48-year-old male presented to the emergency department after reportedly ingesting >1liter of antifreeze in an attempt at self-harm. He denied concomitant ethanol consumption. His initial presenting serum ethylene glycol level was 700 mg/dL, with normal renal function, and a metabolic acidosis with a high anion gap. One hour after presentation, he was started on intravenous fomepizole. Treatment with fomepizole continued until the patient's plasma ethylene glycol concentration was 16 mg/dL. His metabolic acidosis quickly resolved, he had no adverse reactions to the treatment, and his renal function remained normal. Ultimately, he was discharged to a psychiatric unit without sequelae. Published literature and practice guidelines suggests considering hemodialysis initiation in patients with an ethylene glycol level >50 mg/dL. This recommendation is anecdotally, rather than evidence, based. With the potential risks inherent in hemodialysis, our case provides evidence that treatment with fomepizole without hemodialysis appears to be a viable alternative option in patients with even extremely high plasma ethylene glycol concentrations as long as their renal function is intact.     

Severe central nervous system damage and profound acidosis in persons exposed to pentaborane

Three cases of pentaborane intoxication resulting from a common exposure are presented. These cases were characterized by the rapid onset of seizures and opisthotonic spasms accompanied by severe metabolic acidosis without respiratory compensation. Rhabdomyolysis occurred, serum transaminase levels were elevated, and liver damage was demonstrated histologically. One patient died and another sustained severe neurologic damage. These poisonings are unique with respect to the rapid and devastating neurologic consequences. Pentaborane is an extremely toxic compound and a major hazard not only to exposed workers but also to the medical personnel dealing with them.     

Ethylene glycol ingestion treated only with fomepizole

Introduction

Ethylene glycol is a widely used chemical that is capable of causing significant injury if ingested. Treatment for ethylene glycol poisoning typically includes basic supportive care, alcohol dehydrogenase inhibition, and hemodialysis. Recent data have suggested that hemodialysis may not be necessary for cases of ethylene glycol poisoning that can be treated with fomepizole as blocking therapy before acidosis or renal dysfunction develops.

Case Report

A 33-year-old man presented to the emergency department 1 hour after drinking approximately 1/2 gallon of ethylene glycol antifreeze and an unknown quantity of beer. On arrival he was mildly inebriated but otherwise displayed no other features of ethylene glycol poisoning. Fomepizole therapy was initiated and initial laboratory studies later revealed an osmol gap of 157 mOsm and an ethylene glycol concentration of 706 mg/dL. Nephrology and toxicology services were consulted. Over the next 3 days, fomepizole therapy was continued while the patient’s acid-base status and renal function were closely monitored. No evidence of acid-base abnormalities or renal impairment was ever observed and the patient was discharged to psychiatric care on the fourth hospital day.

Discussion

This report describes the case of a patient who presented soon after a massive ingestion of ethylene glycol with very high serum concentrations. He was successfully treated using fomepizole and basic supportive care. Our patient developed neither renal insufficiency nor metabolic acidosis. His concomitant ethanol consumption, early presentation, and treatment likely contributed to his favorable outcome. This case report underscores the effectiveness of supportive care and fomepizole in the treatment of ethylene glycol poisoning.     

Clinical evaluation of pediatric ethylene glycol monobutyl ether poisonings.

Ethylene glycol butyl ether, CAS 111-76-2, an ingredient in many popular commercial window/glass cleaners, is known to produce equal if not greater toxicity than ethylene glycol when administered to animals. Treatment recommendations for human poisonings are based upon animal data and include the use of ethanol therapy to inhibit the production of toxic metabolites. No human experiential data exist to accurately assess human toxicity or to verify treatment modalities. A 5 month retrospective review of all glass cleaner ingestions reported to a regional poison information center disclosed 24 pediatric patients, ages 7 mo to 9 y, who ingested 5-300 mL of a liquid glass cleaning product containing ethylene glycol butyl ether. All ingestions were reported within 5 min of ingestion, and all 24 children were asymptomatic at that time and subsequently. The product concentrations of ethylene glycol butyl ether ranged from 0.5% to 9.9%. Two of the 24 children ingested > 15 mL and were treated by gastric emptying and 24 h hospital observation. Neither hospitalized child suffered symptoms consistent with hemolysis, nervous system depression, acidosis, or renal compromise. Dilution with oral fluids at home is considered appropriate treatment of pediatric ingestions of < 10 mL of a commercial liquid glass/window cleaners containing < 10% ethylene glycol butyl ether.     

Mode of action: oxalate crystal-induced renal tubule degeneration and glycolic acid-induced dysmorphogenesis--renal and developmental effects of ethylene glycol

Ethylene glycol can cause both renal and developmental toxicity, with metabolism playing a key role in the mode of action (MOA) for each form of toxicity. Renal toxicity is ascribed to the terminal metabolite oxalic acid, which precipitates in the kidney in the form of calcium oxalate crystals and is believed to cause physical damage to the renal tubules. The human relevance of the renal toxicity of ethylene glycol is indicated by the similarity between animals and humans of metabolic pathways, the observation of renal oxalate crystals in toxicity studies in experimental animals and human poisonings, and cases of human kidney and bladder stones related to dietary oxalates and oxalate precursors. High-dose gavage exposures to ethylene glycol also cause axial skeletal defects in rodents (but not rabbits), with the intermediary metabolite, glycolic acid, identified as the causative agent. However, the mechanism by which glycolic acid perturbs development has not been investigated sufficiently to develop a plausible hypothesis of mode of action, nor have any cases of ethylene glycol-induced developmental effects been reported in humans. Given this, and the variations in sensitivity between animal species in response, the relevance to humans of ethylene glycol-induced developmental toxicity in animals is unknown at this time.     

Mode of Action: Oxalate Crystal-Induced Renal Tubule Degeneration and Glycolic Acid-Induced Dysmorphogenesis—Renal and Developmental Effects of Ethylene Glycol

Ethylene glycol can cause both renal and developmental toxicity, with metabolism playing a key role in the mode of action (MOA) for each form of toxicity. Renal toxicity is ascribed to the terminal metabolite oxalic acid, which precipitates in the kidney in the form of calcium oxalate crystals and is believed to cause physical damage to the renal tubules. The human relevance of the renal toxicity of ethylene glycol is indicated by the similarity between animals and humans of metabolic pathways, the observation of renal oxalate crystals in toxicity studies in experimental animals and human poisonings, and cases of human kidney and bladder stones related to dietary oxalates and oxalate precursors. High-dose gavage exposures to ethylene glycol also cause axial skeletal defects in rodents (but not rabbits), with the intermediary metabolite, glycolic acid, identified as the causative agent. However, the mechanism by which glycolic acid perturbs development has not been investigated sufficiently to develop a plausible hypothesis of mode of action, nor have any cases of ethylene glycol-induced developmental effects been reported in humans. Given this, and the variations in sensitivity between animal species in response, the relevance to humans of ethylene glycol-induced developmental toxicity in animals is unknown at this time.     

Clearance of ethylene glycol by kidneys and hemodialysis

A patient with acute ethylene glycol poisoning was treated with ethanol administration and hemodialysis, and his renal function remained consistently normal. Serial measurements of serum and urine levels of urea, creatinine, ethylene glycol, and ethanol were performed to compare the relative contributions of the hemodialyzer and the patient's kidneys in clearing ethylene glycol from the blood. Simultaneous measurements of the serum-osmolal gap (corrected for ethanol) and anion gap were correlated with these data. Mean renal clearance of ethylene glycol was 27.5 +/- 4.1 ml/min, with a fractional ethylene glycol excretion of 19.8 +/- 1.5%. This was lower than the mean urea clearance of 89.4 +/- 11.0 ml/min and fractional urea excretion of 66.0 +/- 7.8%. Hemodialyzer clearance of ethylene glycol was 156 ml/min. There was a nearly exact correlation between the serum ethylene glycol level and the corrected osmolal gap (r = 0.998, p less than 0.01). The calculated renal elimination half-life of ethylene glycol was 18 hr. We conclude that with a moderate diuresis, the normal human kidney contributes significantly to the removal of ethylene glycol from the blood. Corrected serum osmolal gap provides a nearly exact approximation of the serum ethylene glycol level and is a useful therapeutic guide.     

"Bicarbonate resistant" metabolic acidosis in association with ethylene glycol intoxication.

A case of massive ingestion of ethylene glycol is described. The clinical characteristics of this disorder such as persistent metabolic acidosis and oxaluria as well as changes in serum osmolality that may accompany ingestion of certain toxins are emphasized. The rapid clearance of ethylene glycol from the blood during hemodialysis is noted and the use of ethyl alcohol to block metabolic conversion of ethylene glycol to oxalic acid, which is also a toxin, is described. The importance of early diagnosis and therapy is stressed.     

Survival and complete recovery after severe acute ethylen glycol poisoning — a case report

Early signs of acute ethylene glycol (EG) poisoning are similar to ethanol intoxication. However, such signs of EG poisoning are followed by severe metabolic acidosis, increased anion gap, neurological and renal dysfunction, and, without adequate therapy, up to 40% mortality. Early recognition and treatment with intravenous ethanol or fomepizole and bicarbonate, renal replacement therapy, and supportive measures are the key elements of survival.     

Triethylene glycol poisoning treated with intravenous ethanol infusion

INTRODUCTION: Poisoning with triethylene glycol has been rarely reported in humans. Triethylene glycol is thought to be metabolized by alcohol dehydrogenase to acidic products resulting in the production of a metabolic acidemia. Triethylene glycol metabolism has previously been shown to be inhibited by fomepizole (4-methyl pyrazole) administration. We report a case of triethylene glycol ingestion, presenting with a metabolic acidemia, treated with intravenous ethanol administration. CASE REPORT: A 23-year-old female presented to the emergency department approximately 1-1.5 hours following ingestion of a gulp of triethylene glycol (99%) brake fluid with coma (GCS-3) and metabolic acidemia (pH 7.03, PCO2 44 mm Hg, Bicarbonate 11 mmol/L, anion gap 30 mmol/L, serum creatinine 90 mumol/L). She was intubated and given 100 mmol of intravenous sodium bicarbonate. An ethanol loading dose was administered followed by an infusion to maintain serum ethanol at 100 mg/dL. Acidemia gradually resolved over the next 8 hours and she was extubated 12 hours later. The ethanol infusion was continued for a total of 22 hours. There was no recurrence of acidemia. Serum ethanol, ethylene glycol, and methanol levels were nondetectable on presentation, as was serum salicylate. Urine drug of abuse screen and thin-layer chromatography revealed no other coingested substances. The patient was discharged to a psychiatric ward 36 hours postingestion. CONCLUSION: Pure triethylene glycol poisoning results in coma and metabolic acidemia and may be treated with alcohol dehydrogenase inhibitors such as ethanol.     

Ethylene glycol intoxication: case report and pharmacokinetic perspectives

A 42-year-old man was brought to the emergency department with ethylene glycol intoxication. He was hemodynamically stable and had normal renal function. His serum ethylene glycol concentration was 284 mg/dl approximately 1 hour after ethylene glycol consumption. The patient was treated with fomepizole and forced diuresis. Elimination of ethylene glycol in this patient followed first-order pharmacokinetics. Elimination pharmacokinetics in this patient were compared with that in a patient who received fomepizole and hemodialysis. Fomepizole monotherapy can be given in patients without renal failure or metabolic acidosis even with serum ethylene glycol concentrations greater than 50 mg/dl. However, cost estimates based on this case suggest that if the patient is treated adequately with a single hemodialysis session and 24-hour hospitalization, then fomepizole monotherapy may be more expensive than the combination regimen of fomepizole and hemodialysis.     

Butoxyethanol ingestion with prolonged hyperchloremic metabolic acidosis treated with ethanol therapy

BACKGROUND: Severe toxic ingestions of butoxyethanol (CAS No. 111-76-2) are rare despite the prevalence of this glycol ether in products such as glass and surface cleaners. Manifestations of acute butoxyethanol toxicity include metabolic acidosis, hemolysis, hepatorenal dysfunction, and coma, but vary widely in reported cases. Furthermore, the optimal therapeutic approach is not yet established. Much of the toxicity of butoxyethanol has been ascribed to its aldehyde and acid metabolites which are similar to those produced by oxidative metabolism of methanol and ethylene glycol. Although the roles of alcohol dehydrogenase inhibition with ethanol or fomepizole and hemodialysis are clear in the case of toxic ingestions of methanol and ethylene glycol, they remain poorly defined for butoxyethanol poisoning. CASE REPORT: We report the case of a 51-year-old female who ingested up to 8 ounces of Sanford Expo White Board Cleaner (butoxyethanol and isopropanol). She developed prolonged hyperchloremic metabolic acidosis and mental status depression and was treated with ethanol therapy but not hemodialysis. This patient recovered without apparent sequelae. The kinetics of butoxyethanol metabolism in this case are described and the potential therapeutic options are discussed.     

Oral administration of oxalate-enriched spinach extract as an improved methodology for the induction of dietary hyperoxaluric nephrocalcinosis in experimental rats

Experimental induction of hyperoxaluria by ethylene glycol (EG) administration is disapproved as it causes metabolic acidosis while the oral administration of chemically synthesized potassium oxalate (KOx) diet does not mimic our natural system. Since existing models comprise limitations, this study is aimed to develop an improved model for the induction of dietary hyperoxaluria, and nephrocalcinosis in experimental rats by administration of naturally available oxalate rich diet. Male albino Wistar rats were divided into five groups. Group I, control; group II rats received 0.75% EG, group III rats fed with 5% KOx diet and group IV and V rats were administered with spinach extract of 250 and 500?mg soluble oxalate/day respectively, for 28 d. Urine and serum biochemistry were analyzed. After the experimental period, rats were sacrificed, liver and kidney tissue homogenates were used for antioxidant and lipid peroxidation assay. Relative change in expression of kidney injury molecule-1 (KIM-1) and crystal modulators genes in kidney tissues were evaluated. Tissue damage was assessed by histology studies of liver and kidney. Experimental group rats developed hyperoxaluria and crystalluria. Urine parameters, serum biochemistry, antioxidant profile, lipid peroxidation levels and gene expression analysis of experimental group II and III rats reflected acute kidney damage compared to group V rats. Histopathology results showed moderate hyperplasia in liver and severe interstitial inflammation in kidneys of group II and III than group V rats. Ingestion of naturally available oxalate enriched spinach extract successfully induced dietary hyperoxaluria and nephrocalcinosis in rats with minimal kidney damage.