On the metabolic acidosis of ethylene glycol intoxication.

Methylene chloride was administered to rats by vaporization in a closed rebreathing system. Doses ranged from 80 to 800 μmol/kg. The rate of CO production was measured and the total amount of CO formed in excess of the endogenous amount was calculated. Addition of CH₂Cl₂ to the gas phase caused an initial increase in CO production to about 35 times the endogenous rate at all doses given. The total amount of CO formed when all CH₂Cl₂ was metabolized depended on the dose given, amounting to about 0.48 mol of CO/mol of CH₂Cl₂ administered. All dihalogenated methanes caused an increase in CO production and a decrease in methane production. At 100 μmol/kg the order of decreasing effect on both the initial production rate and the final amount of CO accumulated was CH₂Br₂ > CH₂Cl₂ > CH₂BrCl > CH₂I₂. Methane production by the intestinal bacteria was inhibited in the order CH₂BrCl > CH₂Br₂ > CH₂Cl₂ > CH₂I₂. The CO production of germ-free rats is increased by CH₂Cl₂ to the same extent as with controls. The data suggest that a low dose of dihalogenated methane causes substrate saturation of the enzyme system involved in CO production. Large doses of methylene chloride cause a progressive increase in the rate of CO production over several hours. Such results suggest that substrate-induced enzyme formation occurs when the concentration of methylene chloride is maintained.     

Leukemoid response in ethylene glycol intoxication

A 33-y-old male developed severe acidosis, renal failure, and profound neutrophilia after ingesting ethylene glycol. Workup for his neutrophilia excluded infectious and malignant causes. An elevated leukocyte alkaline phosphatase (LAP) level confirmed a leukemoid response, and the neutrophila resolved. Although several leukemoid reactions have been published due to therapeutic agents these reports are often incomplete or inaccurate; this is the first case of leukemoid response to a toxin. Leukemoid response is distinguishable from leukemia by the absence of clonally derived cells, although this is not easily apparent in extreme neutrophilia. Elevated LAP is useful in identifying leukemoid reaction from leukemia in cases of extreme neutrophila. If a patient develops extreme neutrophila in association with drug or toxin exposure, a leukemoid reaction should be considered and an LAP obtained.     

An approach to dialysis for ethylene glycol intoxication

Eleven cases of ethylene glycol ingestion were retrospectively analyzed for presentation, treatment, and outcome. Patients were grouped according to the time it took to receive medical attention, and whether or not they received I continuous hemodialysis (CHD) versus intermittent hemodialysis (IHD). Six patients presented within 12 h of exposure (Group 1), whereas 5 patients presented later (Group 2; range 48-120 h). Comparisons were made for age, ethylene glycol level, anion gap, osmolar gap, pH, admission creatinine level, time from ingestion to presentation, total time spent on hemodialysis, number of dialysis treatments, recovery time, recovery creatinine, hospital length of stay, and status. Significant differences were observed for ethylene glycol level, osmolar gap, and presentation time. Ten of the 11 patients received single pass hemodialysis, and 5 of these received I CHD. Of the 5 patients who received CHD versus the 5 patients who received IHD, none developed complications (p=0.004). Patients who presented within 10 h of exposure had fewer complications than those who presented > 12 h after exposure Timely CHD is superior to IHD in treating ethylene glycol intoxication. An adeQuate time course of hemodialysis can be approximated using the ethylene gycol index, and may eliminate reliance on ethylene glycol levels in determining adequate endpoints of dialysis in treating poisoned patients.     

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.     

A fatal intoxication involving carbamazepine, desipramine, and ethylene glycol

A fatal intoxication involving multiple substances including carbamazepine (CBZ), desipramine (DI), and ethylene glycol (EG), in which the blood CBZ concentration was higher than any previously reported in the literature is presented. Each compound, as well as the 10,11-epoxide metabolite of carbamazepine (CBZ-EP), was quantified in blood (CBZ, 79 mg/L; CBZ-EP, 11 mg/L; DI, 4.2 mg/L; EG, 3.6 g/L), bile (CBZ, 69 mg/L; CBZ-EP, 13 mg/L; DI, 23 mg/L; EG, 4.8 g/L), urine (CBZ, 6.5 mg/L; CBZ-EP, 5.7 mg/L; DI, 30 mg/L; EG, 3.3 g/L), stomach contents (CBZ, 280 mg; DI, 49 mg; EG, 2.8 g), liver (CBZ, 75 mg/kg; CBZ-EP, 11 mg/kg; DI, 49 mg/kg; EG, 2.0 g/kg), and kidney (CBZ, 41 mg/kg; CBZ-EP, 11 mg/kg; DI, 23 mg/kg; EG, 1.9 g/kg) using the following analytical techniques: high performance liquid chromatography with ultraviolet detection for CBZ and CBZ-EP, gas-liquid chromatography with mass selective detection for DI and gas-liquid chromatography with flame ionization detection for EG.     

Ethylene glycol developmental toxicity: unraveling the roles of glycolic acid and metabolic acidosis.

This study sought to determine the relative roles of glycolic acid (GA), a toxicologically important metabolite of ethylene glycol (EG), and metabolic acidosis in causing developmental toxicity in Sprague-Dawley rats. To tease apart these two interrelated factors, we developed an experimental approach in which high blood glycolate levels could be achieved, in either the presence or absence of metabolic acidosis. Initially, rats previously implanted with a carotid artery cannula were given, on gestation day (gd) 10, 40.3 mmol/kg (2500 mg/kg) of EG via gavage, 8.5 mmol/kg (650 mg/kg) of GA via gavage, 8.5 mmol/kg (833 mg/kg) of sodium glycolate (NaG; pH 7.4) via subcutaneous (sc) injection, or distilled water via gavage (control). Peak serum glycolate was nearly identical (8.4-8.8 mM) in the EG, GA, and NaG groups and, as expected, EG and GA caused a metabolic acidosis, but acid base balance was normal with NaG. Subsequently, these treatments were given on gd 6-15 to groups of 25 time-mated rats, followed by fetal evaluation on gd 21. EG and GA decreased fetal body weights and caused a similar spectrum of developmental effects, including numerous axial skeleton malformations. NaG treatment also caused slight decreases in fetal body weight, increases in skeletal variations, and totally malformed fetuses. These results indicate that glycolate, in the absence of metabolic acidosis, can cause the most sensitive of EG's developmental effects, whereas metabolic acidosis appears to interact with glycolate at very high doses to markedly enhance teratogenesis. These results support previous studies, which indicated that glycolate is the proximate developmental toxicant for EG, and that GA toxicokinetic parameters can be used to define a quantitative, physiologically based threshold for EG-induced developmental effects.     

Cholestyramine-induced hyperchloremic metabolic acidosis.

Cholestyramine is a nonabsorbable anion exchange resin that is used predominantly for the treatment of hypercholesterolemia in adults and the management of acute diarrhea in children. The authors report two cases of severe hyperchloremic nonanion gap metabolic acidosis associated with the use of cholestyramine therapy. The authors recommend that patients taking cholestyramine who have concomitant renal insufficiency or who are volume depleted or who are taking spironolactone be monitored carefully for the emergence of a hyperchloremic metabolic acidosis.     

Quetiapine-induced diabetes with metabolic acidosis

Medication adherence with antipsychotics is adversely impacted by the burden of untoward adverse effects. In particular, sexual side-effects may interfere with compliance, but are often underreported by patients. Sexual dysfunction related to hyperprolactinemia is commonly described, but ejaculatory disturbance due to potent alpha1 adrenergic antagonism may also occur, and has been reported frequently with certain typical antipsychotics such as thioridazine, but rarely with atypical antipsychotics. Presented here is the case of a 51 year old male with schizophrenia who developed retrograde ejaculation on high dose risperidone therapy (8 mg/day) with prompt resolution of symptoms upon dose reduction. The absence of decreased libido or erectile dysfunction indicates that alpha1 adrenergic antagonism and not low serum testosterone due to hyperprolactinemia is the etiology for this side-effect. This case illustrates another mechanism for sexual adverse effects, and the need for routine inquiry into sexual dysfunction during atypical antipsychotic therapy.     

Association of beta hydroxybutyric acidosis with isoniazid intoxication

Acute metabolic acidosis associated with accumulation of lactate has been previously reported in isoniazid (INH) intoxication. To our knowledge, association of INH toxicity with beta-hydroxybutyric acidosis has not been demonstrated previously. The present report documents the occurrence of beta-hydroxybutyric acidosis in patients with INH intoxication. The reason for the lack of previous reports of this association is not clear, although failure to measure plasma beta-hydroxybutyrate levels in previous studies is a likely possibility. Our patients received intravenous sodium bicarbonate, anticonvulsants and dialysis which resulted in complete reversal of metabolic acidosis and other manifestations of INH toxicity.     

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.     

Head CT in patient with metabolic acidosis

An unresponsive 30-year-old female with a history of anxiety and chronic alcohol abuse presented to an emergency department with altered mental status and a severe metabolic acidosis. The patient was intubated for airway protection, and she empirically received folic acid, bicarbonate, and 5% ethanol continuous infusion for suspected ingestion of toxic alcohol. Following transfer to our institution, the patient was minimally responsive to noxious stimuli. She received fomepizole at dosing corrected for hemodialysis (HD), and bicarbonate via multiple boluses and continuous infusion. The ethanol drip was stopped. The nephrology service had been alerted to this patient’s arrival and condition; hemodialysis via a standard heparinized circuit was initiated immediately after her arrival, which produced a marked improvement in the patient’s acid-base status. Her serum methanol concentration subsequently returned at > 200 mg/dL. After 12 hours and 2 sessions of hemodialysis, the patient remained unresponsive despite minimal sedation. Anisocoria was noted on exam. Computed tomography of the brain demonstrated a large hematoma in the left basal ganglia that extended into the left frontal and parietal white matter accompanied by intraventricular extension, midline shift, loss of grey-white differentiation throughout, suggesting tonsillar herniation (Figure 1). Forty-eight hours after presentation, radionuclide imaging of the brain revealed no intracranial blood flow; heart, lungs, liver, kidneys, and pancreas were subsequently harvested for transplantation.     

Chronic acidosis with metabolic bone disease

The case is reported of a woman in whom a chronic hyperchloraemic acidosis and osteomalacia developed follow implantation of her ureters into the rectum. For 14 years she took regular sodium bicarbonate, but a little over four years after discontinuing it she developed clinical, biochemical, radiological and radionuclide evidence of osteomalacia. The latter improved rapidly when sodium bicarbonate was recommenced. This clinical situation is one of the few instances in man where a chronic metabolic acidosis in the context of normal or only mildly impaired renal function can result in osteomalacia.     

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.     

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.     

Bialaphos poisoning with apnea and metabolic acidosis

A 64-year-old man with ethanol intoxication, ingested a bottle of Herbiace (100 ml, 32 w/v% of bialaphos, CAS #35597-43-4, Meiji Seika Kaisha, Tokyo, Japan). He had severe metabolic acidosis and was treated with infusions of sodium bicarbonate and furosemide, plus gastric lavage and enema. The metabolic acidosis improved 15 hours after treatment but nystagmus, apnea and convulsions were progressive. Although his sensorium was clear, spontaneous respirations were not observed for 64 hours. The electroencephalographic findings of atypical triphasic waves and slow waves suggest a unique response to bialaphos poisoning. His clinical course indicates that the management of apnea is critically important to recovery from bialaphos poisoning.     

Alkyldiol antidotes to ethylene glycol toxicity in mice.

A series of alkyldiols were compared to ethanol or pyrazole as antidotes in ethylene glycol toxicity. Mouse liver alcohol dehydrogenase oxidized ethanol and a series of alkyldiols. The K_m values in millimoles per liter determined from the assays were 0.4 with ethanol, 53 with ethylene glycol, 14 with propylene glycol, 5.4 with 1,3-propanediol, 3.8 with 1,2-butanediol, 1.5 with 1,3-butanediol, 0.5 with 1,4-butanediol, 56 with 2,3-butanediol, 0.23 with 1,5-pentanediol, and 0.031 with 1,6-hexanediol. These data indicated that ethanol and the alkyldiols, with the exception of 2,3-butanediol, had higher affinities for mouse liver alcohol dehydrogenase than ethylene glycol. Propylene glycol (27.2 mmol/kg), 1,2-butanediol (11.2 mmol/kg), and 1,3-butanediol (22.3 mmol/kg) were the only alkyldiols found to protect mice. Acute and delayed toxicity and hexobarbital sleeping time studies indicated that the alkyldiols which protected the mice were, in general, the least toxic and least hypnotic of the alkyldiols. Therapeutic ratios found by dividing the 144 hr LD50 of an antidote by the dose which produced the maximum antidotal effect were 3.17 for ethanol, 2.56 for pyrazole, 6.16 for propylene glycol, 4.15 for 1.2-butanediol, and 5.11 for 1,3-butanediol. These data suggest that the alkyldiol antidotes are effective and may be safter than either ethanol or pyrazole.     

Severe metabolic acidosis and "muti" (traditional herbal medicine) ingestion in young children

Twenty infants and young children admitted with severe metabolic acidosis and a positive history of 'muti' ingestion were investigated. All had accompanying gastroenteritis and significant dehydration. Biochemical data was diagnostic of high anion/gap metabolic acidosis in the majority (70 per cent). Further biochemical data indicated that lactic acidosis and pre-renal azotaemia resulting from severe hypovolaemia were likely causes of the high anion GAP metabolic acidosis. There was no evidence to suggest that the ingested muti per se was associated directly with the acidosis or acute renal failure seen in these children.