Management of poisoning with ethylene glycol and methanol in the UK: a prospective study conducted by the National Poisons Information Service (NPIS)

Background: Poisoning with methanol and ethylene glycol can cause serious morbidity and mortality. Specific treatment involves the use of antidotes (fomepizole or ethanol) with or without extracorporeal elimination techniques. Methods: A prospective audit of patients with methanol or ethylene glycol poisoning reported by telephone to the National Poisons Information Service (NPIS) in the UK was conducted during the 2010 calendar year and repeated during the 2012 calendar year. The study was conducted to determine the frequency of clinically significant systemic toxicity and requirement for antidote use and to compare outcomes and rates of adverse reaction and other problems in use between ethanol and fomepizole. Results: The NPIS received 1315 enquiries involving methanol or ethylene glycol, relating to 1070 individual exposures over the 2-year period. Of the 548 enquiries originating from hospitals, 329 involved systemic exposures (enteral or parenteral as opposed to topical exposure), of which 216 (66%) received an antidote (204 for ethylene glycol and 12 for methanol), and 90 (27%) extracorporeal treatment (86 for ethylene glycol and 4 for methanol). Comparing ethanol with fomepizole, adverse reactions (16/131 vs. 2/125, p?<?0.001) and administration errors, lack of monitoring, or inappropriate use (45/131 vs. 6/125, p?<?0.0001) were reported more commonly, whereas non-availability and inadequate stocks were reported less commonly (6/125 vs. 33/131, p?<?0.0001). Eight fatalities and complications or sequelae occurred in 21 patients. Poor outcome (death, complications, or sequelae) was significantly associated with older age, higher poisoning severity scores, and lower pH on admission (p?<?0.001). Conclusions: Systemic poisoning with ethylene glycol or methanol results in hospitalisation at least 2–3 times per week on average in the UK. No difference in outcome was detected between ethanol and fomepizole-treated patients, but ethanol was associated with more frequent adverse reactions.     

Delayed neurological sequelae from ethylene glycol,diethylene glycol and methanol poisonings

Introduction.?Ethylene glycol, diethylene glycol and methanol are widely available chemicals and are found in a variety of common household products including antifreeze, windshield washer fluid, brake fluid and lubricants. Following ingestion of these glycols and methanol, patients frequently develop an early neurological syndrome consisting of inebriation, ataxia, and if severe, seizures and coma. Though uncommon, a neurological syndrome may also develop as a delayed complication. Methods.?Using Pub Med 438 references were identified of which 45 were relevant. Features.?Ethylene glycol poisoning has produced cranial nerve deficits (usually VII nerve dysfunction) after a delay of 5–20 days, Parkinsonism and cerebral edema. Diethylene glycol ingestion has been associated with the development of optic nerve injury, cranial nerve deficits, quadraparesis and peripheral neuropathy. Methanol poisoning has led to Parkinsonism and polyneuropathy. Mechanisms of toxicity.?Oxalate crystal deposition likely causes the cranial neuropathies related to ethylene glycol and 2-hydroxyethoxyacetic acid is thought to be the causal moiety in cranial neuropathies resulting from diethylene glycol toxicity. Formic acid is implicated in the optic nerve damage associated with methanol. Conclusions.?Uncommonly, delayed neurological syndromes may develop as complications of poisoning due to ethylene glycol, diethylene glycol and methanol; the onset of such neurological damage is often days or even weeks post-ingestion. Further research is required to explain why the facial nerve is the cranial nerve most commonly involved and why the basal ganglia are predisposed to injury.     

Validation of a pre-existing formula to calculate the contribution of ethanol to the osmolar gap

Purpose. The aim of this study was to validate the formula derived by Purssell et al. that relates blood ethanol concentration to the osmolar gap and determine the best coefficient for use in the formula. The osmolar gap is often used to help diagnose toxic alcohol poisoning when direct measurements are not available. Methodology. Part I of the study consisted of a retrospective review of 603 emergency department patients who had a concurrent ethanol, basic metabolic panel and a serum osmolality results available. Estimated osmolarity (excluding ethanol) was calculated using a standard formula. The osmolar gap was determined by subtracting estimated osmolarity from the actual osmolality measured by freezing point depression. The relationship between the osmolar gap and the measured ethanol concentration was assessed by linear regression analysis. In Part II of this study, predetermined amounts of ethanol were added to aliquots of plasma and the estimated and calculated osmolarities were subjected to linear regression analysis. Results. In the cases of 603 patients included in Part I of the study, the median ethanol concentration in these patients was 166 mg/dL (Q1: 90, Q3: 254) and the range ethanol concentrations was 10–644 mg/dL. The mean serum osmolality was 338 mOsm/kg (SD: 30) and a range of 244–450 mOsm/kg. The mean osmolar gap was 47 (SD: 29) and a range of ? 15 to 55. There was a significant proportional relationship between ethanol concentration and osmolar gap (r² =?0.9882). The slope of the linear regression line was 0.2498 (95% CI: 0.2472–0.2524). The slope of the linear regression line derived from the data in Part II of the study was 0.2445 (95% CI: 0.2410–0.2480). Conclusions. The results of our study are in fairly close agreement with previous studies that used smaller samples and suggest that an accurate conversion factor for estimating the contribution of ethanol to the osmolar gap is [Ethanol (mg/dL)]/4.0.     

Methanol ingestion: prevention of toxic sequelae after massive ingestion

Methanol ingestion, a rare but potentially fatal poisoning, is often difficult to diagnose in the Emergency Department (ED) and historically has been difficult to treat. In this article, we report a methanol ingestion with a blood concentration of 692 mg/dL, which was treated with 4-methylpyrazole (Fomepizole) and dialysis, without sequelae. To our knowledge, such a massive ingestion has never been treated with this modality without development of long-term disability. Another unusual feature of this case is the significantly elevated serum osmolal gap at presentation without elevation in anion gap, demonstrating the effects of co-ingestion of ethanol. Additionally, there was a marked disparity between the patient’s breath alcohol analyzer level and the blood ethanol concentration, illustrating the inability of the breath alcohol analyzer to differentiate between volatile alcohols. Treatment of the methanol-poisoned patient with Fomepizole is discussed.     

Osmol gap method for the detection of diethylene glycol in human serum

BACKGROUND:

Measurement of the osmol gap (OG) is a technique that is used frequently in toxic alcohol poisonings (ethylene glycol (EG) and methanol) as a rapid means to estimate exposure, and can be performed in virtually all hospital laboratories. The value of the OG has not been previously evaluated for diethylene glycol (DEG) exposures. The primary objective of this study was to evaluate the utility of the OG in estimating DEG serum concentrations using the most common formula that is currently used for estimating methanol, ethanol, and ethylene glycol concentrations.

METHODS:

This was a controlled laboratory investigation using serum samples individually spiked with a known quantity of toxic alcohol compared to no toxic alcohol. Test samples were spiked with ethanol, DEG, EG, and methanol. Serum chemistries and osmolality and osmolarity were determined, and the OG was determined for each specimen.

RESULTS:

The percent error of estimating DEG concentrations of 26.3% was similar to the mean percent error for estimating other alcohol concentrations, 30.5%±5.6% (P>0.05, 95% confidence interval 16.7%-44.3%).

CONCLUSIONS:

The severity of metabolic effects associated with DEG and the need to appropriately determine rescue treatments mandate early detection of significant exposures for effective triage and patient management. Our results indicate that the percent error of the osmol gap method for estimating DEG concentration is similar to that of other toxic alcohols; this simple technique could be a valuable clinical tool, since quantitative DEG analysis is rarely available.KEY WORDS: Diethylene glycol, Osmol gap, Metabolic acidosis     

Survival following massive arsenic ingestion

A case of a 30-year-old man who ingested a massive quantity of arsenic (approximately 2,150 mg) in an apparent suicide attempt is presented. Aggressive initial therapy, including fluid resuscitation, chelation therapy, and hemodialysis, resulted in the patient's survival. The successful management of arsenic intoxication requires both prompt recognition and the initiation of specific and aggressive therapeutic modalities.     

二甘醇不同给药模式对大鼠肾功能的影响

目的：探讨二甘醇（DEG）不同给药模式对大鼠肾功能的影响。方法：61只大鼠随机分成4组,对照组单次腹腔注射生理盐水8mL/kg,A、B、C组分别腹腔注射DEG8mL/kg,1次;4mL/kg,12h/次,2次;4mL/kg,24h/次,2次。首次注射前和后1、4、8d以及15d测定大鼠血尿素氮（BUN）、肌酐（Cr）、CO2结合力（CO2CP）,第15天处死所有大鼠。每次采血前收集24h尿液待测,收集死亡大鼠及第15天处死大鼠的肾组织进行病理检查。结果：A组死亡3只,注射DEG后第1天血BUN、Cr、CO2CP比处理前都有明显改变（P〈0.05,P〈0.05,P 〈0.01）。B、C组分别死亡2、1只,定量和定性分析均显示BUN、Cr和CO2CP改变较晚,且比A组轻。病理提示死亡大鼠均有显著的肾小管变性、坏死。肾功能异常的总发生率在A、B、C组间依次下降。结论：单次剂量越大或重复间隔时间越密,DEG中毒发生机会越大,有利于估计DEG中毒的病情和预后,指导治疗。[著者文摘]     

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.     

Management of lead foreign body ingestion

Abstract

Previous reports of lead foreign body (PbFB) ingestion by children include two cases of lead intoxication and two cases that resulted in death. It is generally accepted, however, that PbFB ingestion does not pose a risk of lead toxicity, provided that the PbFB is not retained in the gastrointestinal (GI) tract. Recent experience with two cases substantiates this belief. On separate occasions, two 9-year old girls ingested a PbFB. The first patient developed only mild, vague GI complaints. The highest reported blood lead level (BLL) was 15 mcg/dl. The second patient did not develop symptoms, and the highest reported BLL was 22 mcg/dl. Both patients passed the PbFB in the stool within two weeks. These cases suggest that PbFB ingestions can be treated in a manner similar to other uncomplicated foreign body ingestions.     

Diethylene glycol: widely used solvent presents serious poisoning potential

Objective: To describe the serious toxicity of a readily available solvent, diethylene glycol (DEG). We describe a case of intentional ingestion of a wallpaper stripper containing DEG resulting in severe multi-system organ failure. Case Report: A 27-year-old male presented to the Emergency Department (ED) one day after ingesting wallpaper stripper containing DEG. He developed acidosis, renal cortical necrosis, hepatocellular injury, and severe neurologic sequelae, including cranial neuropathies and peripheral demyelinating sensori-motor polyneuropathy. His neurologic function improved over 5 months. Discussion: Our case demonstrates the severe toxicity of DEG. DEG is present in numerous formulations, often without proper protective packaging. DEG has been associated with severe epidemic poisonings in the past and with the availability of safer alternatives, DEG in consumer products should be eliminated. Conclusion: DEG is found in numerous products. Delays in treatment can have devastating results, resulting in death or permanent disability. The pervasive use of this compound makes further human exposures likely.     

Transient non-cardiogenic pulmonary edema following massive ingestion of ethylene glycol butyl ether

A case of acute poisoning with ethylene glycol butyl ether (EGBE) is reported in a chronic alcohol abuser. On admission the 53-year-old patient was comatose with metabolic acidosis, shock, and noncardiogenic pulmonary edema confirmed by haemodynamic study. Following supportive treatment and haemodialysis the outcome was favorable. The relationship between respiratory failure and EGBE is examined.     

Medication errors associated with the use of ethanol and fomepizole as antidotes for methanol and ethylene glycol poisoning

Introduction. Little is known about medication errors which occur with the antidotes ethanol and fomepizole, used for treatment of methanol and ethylene glycol poisoning. Study objectives were to describe and compare the frequency, type, outcome and underlying causes of medication errors associated with ethanol and fomepizole. Methods. Patients aged ≥13 years were included if they were hospitalized in 1996–2005 for methanol or ethylene glycol poisoning and treated with ethanol or fomepizole. Charts from 10 hospitals were separately reviewed by two abstracters who recorded case details. A consensus panel of clinicians used the abstracted data to identify medication errors and classify error outcome. Fisher's exact test determined significant differences in the proportion of ethanol and fomepizole-treated cases with medication error and univariate logistic regression identified risk factors associated with harmful dosage errors. Results. There were 145 ethanol- and 44 fomepizole-treated cases. There was ≥1 medication error in 113/145 (78%) ethanol- and 20/44 (45%) fomepizole-treated cases (p = 0.0001) with more ethanol-related errors involving excessive dose, inadequate monitoring and inappropriate antidote duration. Harmful errors occurred in 19% of ethanol- and 7% of fomepizole-treated cases (p = 0.06) and were largely due to excessive antidote dose or delayed antidote initiation. Occurrence of harmful dosage error was reduced in cases with Poison Control Centre consultation, odds ratio (95% confidence interval) 0.39 (0.17, 0.91), hemodialysis 0.37 (0.16, 0.88), or fomepizole versus ethanol 0.24 (0.06, 1.04). Conclusion. Fomepizole was less prone to medication error than ethanol. Error-related harm was most commonly due to excessive antidote dose or delayed antidote initiation.     

Diglycolic acid,the toxic metabolite of diethylene glycol,chelates calcium and produces renal mitochondrial dysfunction in vitro

Context: Diethylene glycol (DEG) has caused many cases of acute kidney injury and deaths worldwide. Diglycolic acid (DGA) is the metabolite responsible for the renal toxicity, but its toxic mechanism remains unclear. Objective: To characterize the mitochondrial dysfunction produced from DGA by examining several mitochondrial processes potentially contributing to renal cell toxicity. Materials and methods: The effect of DGA on mitochondrial membrane potential was examined in normal human proximal tubule (HPT) cells. Isolated rat kidney mitochondria were used to assess the effects of DGA on mitochondrial function, including respiratory parameters (States 3 and 4), electron transport chain complex activities and calcium-induced opening of the mitochondrial permeability transition pore. DGA was compared with ethylene glycol tetraacetic acid (EGTA) to determine calcium chelating ability. DGA cytotoxicity was assessed using lactate dehydrogenase leakage from cultured proximal tubule cells. Results: DGA decreased the mitochondrial membrane potential in HPT cells. In rat kidney mitochondria, DGA decreased State 3 respiration, but did not affect State 4 respiration or the ADP/O ratio. DGA reduced glutamate/malate respiration at lower DGA concentrations (0.5?mmol/L) than succinate respiration (100?mmol/L). DGA inhibited Complex II activity without altering Complex I, III or IV activities. DGA blocked calcium-induced mitochondrial swelling, indicating inhibition of the calcium-dependent mitochondrial permeability transition. DGA and EGTA reduced the free calcium concentration in solution in an equimolar manner. DGA toxicity and mitochondrial dysfunction occurred as similar concentrations. Discussion: DGA inhibited mitochondrial respiration, but without uncoupling oxidative phosphorylation. The more potent effect of DGA on glutamate/malate respiration and the inhibition of mitochondrial swelling was likely due to its chelation of calcium. Conclusion: These results indicate that DGA produces mitochondrial dysfunction by chelating calcium to decrease the availability of substrates and of reducing equivalents to access Complex I and by inhibiting Complex II activity at higher concentrations.     

In-vivo evidence of nephrotoxicity and altered hepatic function in rats following administration of diglycolic acid,a metabolite of diethylene glycol

Context: Diglycolic acid (DGA) is one of the two primary metabolites of diethylene glycol (DEG). DEG is an industrial solvent that has been implicated in mass poisonings resulting from product misuse in the United States and worldwide, with the hallmark toxicity being acute kidney injury, hepatotoxicity, encephalopathy and peripheral neuropathy. Our laboratory has generated in-vitro evidence suggesting that DGA is the metabolite responsible for the proximal tubule necrosis and decreased kidney function observed following DEG ingestion. Furthermore, we have shown that DGA specifically accumulates in kidney tissues (100× higher than peak blood concentrations) following DEG administration.

Objective: To examine renal and hepatic accumulation and dysfunction following direct administration of DGA in-vivo. We hypothesize that administration of DGA will result in renal and hepatic DGA accumulation, as well as proximal tubular necrosis and liver injury.

Materials and methods: Adult male Wistar rats were divided into three groups dosed with 0, 100 or 300?mg/kg DGA via single oral gavage. Urine was collected every 6–12?h and blood, kidneys and liver were removed upon sacrifice at 48?h post-dosing for analysis.

Results: DGA accumulated significantly in both kidney and liver tissue only at 300?mg DGA/kg. DGA concentrations in the kidneys and liver correlated with renal and hepatic injury, respectively. Histopathological and clinical chemistry analysis revealed that DGA-treated animals exhibited moderate liver fatty accumulation and marked renal injury, again only at 300?mg/kg.

Discussion: DGA-induced kidney injury demonstrated a steep dose response threshold, where severe damage occurred only in animals given 300?mg/kg DGA, while no toxicity was observed at 100?mg/kg.

Conclusion: These results provide evidence for in-vivo toxicity following direct administration of DGA, a metabolite of DEG. The steep dose–response threshold for toxicity suggests mechanistically that there is likely a saturable step that results in DGA accumulation in target organs.     

Two cases of rapid onset Parkinson's syndrome following toxic ingestion of ethylene glycol and methanol

Ethylene glycol and methanol are toxic alcohols commonly found in a variety of commercial products. We report two cases, one associated with ethylene glycol and one with methanol poisoning, which both led to acute hemorrhagic necrosis of the basal ganglia and resulted in acute Parkinson's syndrome. It is unlikely that oxalate crystal deposition is the only mechanism for such basal ganglia necrosis, because similar findings were seen following methanol intoxication. We discuss other possible mechanisms that may contribute towards this unusual neurotoxicity. Both of our patients survived their toxic ingestions, but then developed acute Parkinson's syndrome within 10 days of the ingestion. However, the patient who ingested methanol developed respiratory muscle stiffness/weakness, which responded poorly to anti-Parkinsonian drug therapy. Treatment with carbidopa/levodopa improved cogwheel rigidity and bradykinesia in both patients. We conclude that acute Parkinsonism is one of the lesser-recognized devastating complications of both ethylene glycol and methanol poisoning.     

Acute renal failure, neuropathy, and myopathy after ingestion of dipropylene glycol fog solution

Dipropylene glycol is used in several industrial products including cosmetics, emulsifiers, solvents, and as a fog solution for dance club special effects. Animal studies have suggested that dipropylene glycol has minimal toxicity. We report a case of a 32-year-old man who ingested more than 500 mL of dipropylene glycol-containing Fantasia fog solution (High Energy Lighting, Houston, TX) and subsequently developed acute renal failure, polyneuropathy, and myopathy.