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.     

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.     

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 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.     

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.     

4-Methylpyrazole may be an alternative to ethanol therapy for ethylene glycol intoxication in man

4-Methylpyrazole (4 MP) is a strong inhibitor of alcohol dehydrogenase. Its use in acute ethylene glycol (EG) or methanol intoxication has been suggested in experimental studies about its efficacy and safety. We report three cases of accidental intoxication with ethylene glycol in man treated orally with 20 mg/kg/day of 4 MP. The treatment was maintained until plasma EG concentrations became unmeasurable. The patients were admitted early during the course of the poisoning. Their neurological status was good. A slight metabolic acidosis observed in two cases was easily corrected and did not recur. Renal function remained normal in all cases. No patient underwent hemodialysis. On admission plasma EG concentrations were 24.2 mmol/l, 13 mmol/l and 9.7 mmol/l respectively. Plasma EG half-lives were 14.5, 11.5 and 14.75 hours respectively. Plasma oxalate concentrations and the rate of urine oxalate elimination, determined in two patients, were high on admission but quickly returned to normal. Concerning possible side effects of 4 MP, a skin rash was observed in one patient and a possible eosinophilia in the others. These three cases suggest that 4 MP may decrease the metabolic consequences of EG poisoning in man and may be of therapeutic value when administered early during the course of the intoxication before coma, seizures and organic renal failure have occurred.     

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.     

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.     

Ethylene glycol poisoning: experiences from an epidemic in Sweden.

In 1987 two lethal adult cases of accidental ethylene glycol poisoning were given spectacular attention in the Swedish mass media. This resulted in an epidemic of intentional ethylene glycol poisonings. In addition to six cases related to alcohol abuse, another 30 severe suicidal poisonings were reported to the Swedish Poison Information Centre in five months. The clinical course and outcome in these 36 severe cases are reviewed. The primary clinical manifestations were metabolic acidosis, CNS disturbances and kidney damage with circulatory failure in the most severe cases. Mortality was 17%. Fragmentation of the normal striation in heart cells was found in two of the fatal cases and severe brain damage in all fatal poisonings. The degree of acidosis but not the serum ethylene glycol level correlated with both kidney damage and outcome. Treatment included ethanol, correction of the metabolic acidosis and dialysis. Four patients with serum ethylene glycol concentrations of 10-20 mmol/L (620-1240 mg/L) but with no or minimal metabolic acidosis were treated with ethanol alone; none of these patients developed renal damage.     

Role of fomepizole in the management of ethylene glycol toxicity

OBJECTIVE: To systematically review English-language articles on fomepizole administration in patients with ethylene glycol poisoning. DATA SOURCES: MEDLINE, EMBASE, Current Contents, and PubMed. Search terms were fomepizole, 4-methylpyrazole, and ethylene glycol. The search was supplemented with a bibliographic review of all relevant articles. STUDY SELECTION: All published reports of fomepizole administration in patients with ethylene glycol poisoning were reviewed, irrespective of study design. We identified one clinical trial and subsequent pharmacokinetic study, one case series, and 13 case reports. RESULTS: Fomepizole has been investigated in 70 patients in open, unblinded studies. Most patients received an intravenous loading dose, with subsequent variable maintenance doses every 12 hours until plasma ethylene glycol levels became undetectable. Additional hemodialysis treatment generally was administered when patients had renal insufficiency or ethylene glycol levels above 50 mg/dl. Many patients had detectable ethanol levels either because of coadministration or as a result of adjunctive treatment at a referring center. Poorer patient outcomes, such as death and renal insufficiency, were associated with later clinical presentation time after ingestion. At therapeutic fomepizole levels (> 8.6 mg/ml), the half-life of ethylene glycol was prolonged to over 19 hours. Fomepizole appeared to be well tolerated by most patients. CONCLUSION: Fomepizole is an effective alcohol dehydrogenase inhibitor that decreases production of ethylene glycol metabolites. Reduced mortality and morbidity are undetermined because of the small number of patients evaluated to date. Data on comparative efficacy of fomepizole versus ethanol and data on administration of fomepizole in children are limited.     

Survival after ethylene glycol poisoning in a patient with an arterial pH of 6.58

This ethylene glycol poisoning case had a blood pH of 6.58 and severe hypothermia (30.9 C). The patient received supportive care with dialysis and ethanol therapy. He survived in his premorbid state after 23 days in the hospital. A similar case survived ethylene glycol poisoning neurologicaly intact with an initial pH of 6.46. Although severe acidosis in the presence of serious illness is usually associated with a poor prognosis, our case emphasized the importance of aggressive supportive care and antidotal therapy for ethylene glycol poisoning even when there is a low pH.     

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.     

"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.     

American Academy of Clinical Toxicology Practice Guidelines on the Treatment of Ethylene Glycol Poisoning. Ad Hoc Committee.

Fomepizole (4-methylpyrazole, 4-MP, Antizol) is a potent inhibitor of alcohol dehydrogenase that was approved recently by the US Food and Drug Administration (FDA) for the treatment of ethylene glycol poisoning. Although ethanol is the traditional antidote for ethylene glycol poisoning, it has not been studied prospectively. Furthermore, the FDA has not approved the use of ethanol for this purpose. Case reports and a prospective case series indicate that the intravenous (i.v.) administration of fomepizole every 12 hours prevents renal damage and metabolic abnormalities associated with the conversion of ethylene glycol to toxic metabolites. Currently, there are insufficient data to define the relative role of fomepizole and ethanol in the treatment of ethylene glycol poisoning. Fomepizole has clear advantages over ethanol in terms of validated efficacy, predictable pharmacokinetics, ease of administration, and lack of adverse effects, whereas ethanol has clear advantages over fomepizole in terms of long-term clinical experience and acquisition cost. The overall comparative cost of medical treatment using each antidote requires further study.     

American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning

EPIDEMIOLOGY: Almost all cases of acute methanol toxicity result from ingestion, though rarely cases of poisoning have followed inhalation or dermal absorption. The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes. MECHANISMS OF TOXICITY: Methanol has a relatively low toxicity and metabolism is responsible for the transformation of methanol to its toxic metabolites. Methanol is oxidized by alcohol dehydrogenase to formaldehyde. The oxidation of formaldehyde to formic acid is facilitated by formaldehyde dehydrogenase. Formic acid is converted by 10-formyl tetrahydrofolate synthetase to carbon dioxide and water. In cases of methanol poisoning, formic acid accumulates and there is a direct correlation between the formic acid concentration and increased morbidity and mortality. The acidosis observed in methanol poisoning appears to be caused directly or indirectly by formic acid production. Formic acid has also been shown to inhibit cytochrome oxidase and is the prime cause of ocular toxicity, though acidosis can increase toxicity further by enabling greater diffusion of formic acid into cells. FEATURES: Methanol poisoning typically induces nausea, vomiting, abdominal pain, and mild central nervous system depression. There is then a latent period lasting approximately 12-24 hours, depending, in part, on the methanol dose ingested, following which an uncompensated metabolic acidosis develops and visualfunction becomes impaired, ranging from blurred vision and altered visual fields to complete blindness. MANAGEMENT: For the patient presenting with ophthalmologic abnormalities or significant acidosis, the acidosis should be corrected with intravenous sodium bicarbonate, the further generation of toxic metabolite should be blocked by the administration of fomepizole or ethanol and formic acid metabolism should be enhanced by the administration of intravenous folinic acid. Hemodialysis may also be required to correct severe metabolic abnormalities and to enhance methanol and formate elimination. For the methanol poisoned patient without evidence of clinical toxicity, the first priority is to inhibit methanol metabolism with intravenous ethanol orfomepizole. Although there are no clinical outcome data confirming the superiority of either of these antidotes over the other, there are significant disadvantages associated with ethanol. These include complex dosing, difficulties with maintaining therapeutic concentrations, the need for more comprehensive clinical and laboratory monitoring, and more adverse effects. Thus fomepizole is very attractive, however, it has a relatively high acquisition cost. CONCLUSION: The management of methanol poisoning includes standard supportive care, the correction of metabolic acidosis, the administration of folinic acid, the provision of an antidote to inhibit the metabolism of methanol to formate, and selective hemodialysis to correct severe metabolic abnormalities and to enhance methanol and formate elimination. Although both ethanol and fomepizole are effective, fomepizole is the preferred antidote for methanol poisoning.     

Incorporation of therapeutic interventions in physiologically based pharmacokinetic modeling of human clinical case reports of accidental or intentional overdosing with ethylene glycol.

Although occupational uses of the high production volume (HPV) chemical ethylene glycol (EG) have not been associated with adverse effects, there are case reports where humans have either intentionally or accidentally ingested large quantities of EG, primarily from antifreeze. The acute toxicity of EG can proceed through three stages, each associated with a different metabolite: central nervous system depression (ethylene glycol), cardiopulmonary effects associated with metabolic acidosis (glycolic acid), and ultimately renal toxicity (oxalic acid), depending on the total amounts consumed and the effectiveness of therapeutic interventions. A physiologically based pharmacokinetic (PBPK) model developed in a companion paper (Corley et al., 2005). Development of a physiologically based pharmacokinetic model for ethylene glycol and its metabolite, glycolic acid, in rats and humans. Toxicol. Sci., in press 2005) was refined in this study to include clinically relevant treatment regimens for EG poisoning such as hemodialysis or metabolic inhibition with either ethanol or fomepizole. Such modifications enabled the model to describe data from several human case reports, confirming the ability of the previous model to describe the pharmacokinetics of EG and its metabolite, glycolic acid, in humans across a broad range of doses and multiple exposure routes. By integrating the case report data sets with controlled studies in this PBPK model, it was demonstrated that fomepizole, if administered early enough in a clinical situation, can be more effective than ethanol or hemodialysis in preventing the metabolism of EG to more toxic metabolites. Hemodialysis remains an important option, however, if treatment is instituted after a significant amount of EG is metabolized or if renal toxicity has occurred.     

Acute renal failure and metabolic acidosis due to oxalic acid intoxication: a case report

Most of the reports of oxalic acid intoxication are in cases of ethylene glycol intoxication. These symptoms are known to be central nerve system manifestations, cardiopulmonary manifestations and acute renal failure. There have been only a few reports of direct oxalic acid intoxication. However, there have been a few recent reports of oxalic acid intoxication due to the ingestion of star fruit and ascorbic acid. We herein report the case of a patient with acute renal failure and metabolic acidosis caused directly by consumption of oxalic acid. During the initial examination by the physician at our hospital, the patient presented with tachypnea, a precordinal burning sensation, nausea and metabolic acidosis. After admission, the patient developed renal failure and anion gap high metabolic acidosis, but did not develop any CNS or cardio-pulmonary manifestations in the clinical course. The patient benefitted symptomatically from hemodialysis.