Metabolic acidosis glycols

Chronic or large ingestions of propylene glycol have been associated with the development of hyperosmolar anion-gap metabolic acidosis, renal dysfunction, hemolysis, cardiac arrhythmias, and seizures. 

Many of these reactions are related to the quantity of excipient found in a dosage form. Benzyl alcohol benzalkonium chloride, propylene glycol, lactose, and polysorbates are all associated with dose-related toxic reactions [52-54], Large-volume parenterals containing 1.5% benzyl alcohol as a preservative have caused metabolic acidosis, cardiovascular collapse, and death in low birth weight premature neonates and infants. The cumulative dose of benzyl alcohol ranged from 99 to 234 mg/kg per day in these patients [55,56], Dose-related adverse effects to excipients are of particular concern in the preterm, low birth weight infant because... 

Refractory GCSE has also been treated with large-dose continuous infusion lorazepam or diazepam. Lorazepam contains propylene glycol, which can accumulate and cause marked osmolar gap, metabolic acidosis, and renal toxicity. 

Toxieology. Ethylene glycol aerosol causes irritation of the upper respiratory tract ingestion can cause central nervous system depression, severe metabolic acidosis, liver and kidney damage, and pulmonary edema. 

Methanol and ethylene glycol are contaminants of illicit ethanol, and can be taken as ethanol substitutes. Both agents cause severe metabolic acidosis with a high anion gap. 

Management of methanol and ethylene glycol poisoning is similar. Symptomatic support of respiration and circulation is augmented by correction of metabolic acidosis with intravenous bicarbonate infusion, and control of seizures with diazepam. Ethanol inhibits the metabolism of methanol and ethylene glycol to the toxic metabolites, and can give time for further treatment. The goal is to maintain blood ethanol concentrations between 100 and 150 mg per decilitre, sufficient to saturate alcohol... 

Inpatients with high ethyleneglycol levels (>50 mg/dl), significant metabolic acidosis or renal failure, consider hemodialysis to remove ethylene glycol and its toxic metabolites... 

Three stages of ethylene glycol overdose occur. Within the first few hours after ingestion, there is transient excitation followed by CNS depression. After a delay of 4-12 hours, severe metabolic acidosis develops from accumulation of acid metabolites and lactate. Finally, delayed renal insufficiency follows deposition of oxalate in renal tubules. The key to the diagnosis of ethylene glycol poisoning is recognition of anion gap acidosis, osmolar gap, and oxalate crystals in the urine in a patient without visual symptoms. 

Normally, the sum of the cations exceeds the sum of the anions by no more than 12-16 mEq/L (or 8-12 mEq/L if the formula used for estimating the anion gap omits the potassium level). A larger-than expected anion gap is caused by the presence of unmeasured anions (lactate, etc) accompanying metabolic acidosis. This may occur with numerous conditions, such as diabetic ketoacidosis, renal failure, or shock-induced lactic acidosis. Drugs that may induce an elevated anion gap metabolic acidosis (Table 58-1) include aspirin, metformin, methanol, ethylene glycol, isoniazid, and iron. 

A 34-year-old woman with a history of renal insufficiency induced by long-term use of cocaine developed respiratory failure and was intubated and sedated with intravenous lorazepam (65 mg, 313 mg, and 305 mg on 3 consecutive days). After 2 days she had a metabolic acidosis, with hyperlactatemia and hyperosmolality. Propylene glycol, a component of the lorazepam intravenous formulation, was considered as a potential source of the acidosis, as she had received more than 40 times the recommended amount over 72 hours. Withdrawal of lorazepam produced major improvements in lactic acid and serum osmolality. 

A 36-year-old long-distance truck driver took 200 ml of ethylene glycol in a suicide attempt (32). He vomited, lost consciousness, and had miosis and external ophthalmoplegia. There was a severe metabolic acidosis with a wide anion gap and many crystals in the urinary sediment. Acute oliguric renal failure required continuous hemodialysis for 6 days. A CT scan of the brain showed low-density areas in the bilateral basal ganglia, midbrain, and pons. A renal biopsy showed tubular oxalate deposits. He gradually recovered within 36 days. 

Early laboratory findings include a high serum osmolal gap from the ethylene glycol. An extreme metabolic acidosis with greatly elevated anion gap follows, principally from glycolic acid [100]. Hypocalcemia and hyperkalemia may be evident and urinalysis may reveal calcium oxalate crystalluria, hematuria, and proteinuria. 

Treatment should include correction of metabolic acidosis, inhibition of ethylene glycol metabolism and if necessary, extracorporeal elimination of the parent alcohol and metabolites. Acidemia likely increases tissue penetration of toxic metabolites and hinders renal clearance. Although evidence is lacking, bicarbonate administration should be given to correct acidemia. Although more expensive, fomepizole is preferred to ethanol for ADH inhibition due to proven efficacy, predictable pharmacokinetics, and lack of adverse effects [105]. Inhibition of ADH with fomepizole prevents formation of toxic metabolites and renal injury, and improves add-base status [106]. Elimination half-life of ethylene glycol with fomepizole in patients with preserved renal function is approximately 20 hours [107]. Pyridoxine and thiamine should be administered to promote glyoxyhc add conversion less toxic metabolites than oxalate [108]. 

Leon M, Graeber C. Absence of high anion gap metabolic acidosis in severe ethylene glycol poisoning A potential effect of simultaneous lithium carbonate ingestion. Am J Kidney Dis 1994 23 313-316. 

The most serious adverse effects associated with polyethylene glycols are hyperosmolarity, metabolic acidosis, and renal failure following the topical use of polyethylene glycols in burn patients.Topical preparations containing polyethylene glycols should therefore be used cautiously in patients with renal failure, extensive burns, or open wounds. 

Hypoventilation causes retention of C02 by the lungs, which can lead to a respiratory acidosis. Hyperventilation can cause a respiratory alkalosis. Metabolic acidosis can result from accumulation of metabolic acids (lactic acid or the ketone bodies p-hydroxybutyric acid and acetoacetic acid), or ingestion of acids or compounds that are metabolized to acids (methanol, ethylene glycol). Metabolic alkalosis is due to increased HC03, which is accompanied by an increased pH. Acid-base disturbances lead to compensatory responses that attempt to restore normal pH. For example, a metabolic acidosis causes hyperventilation and the release of C02, which tends to lower the pH. During metabolic acidosis, the kidneys excrete NH4+, which contains H+ buffered by ammonia. 

Ethylene glycol and glycoaldehyde have an intoxicating effect on the central nervous system that can lead to ataxia, sedation, coma, and respiratory arrest. The metabolic acidosis reported in toxicity is due to the acidic metabolites, especially glycolic acid. Ethylene glycol itself may result in a large osmolar gap. Oxalic acid may combine with calcium to form calcium oxylate crystals. The precipitation of these crystals in tissue may result in renal failure and hypocalcemia. 

These acid metabolites are responsible for much of the toxicity of ethylene glycol, the clinical manifestations of which include neurological abnormalities (CNS depression in severe cases, coma and convulsions), severe metabolic acidosis, acute renal failure, and cardiopulmonary failure. The serum concentration of glycolic acid correlates more closely with clinical symptoms and mortality than does the concentration of ethylene glycol. Secause of the rapid elimination of ethylene glycol (ti/2 3 hours), its serum concentration may be low or undetectable at a time when that for glycolic acid remains elevated. Thus the determi-... 

Ingested ethylene glycol is metabolized to glycolic and oxalic acids and other acidic metabolites. Its metabolism leads to an acidosis with high anion and osmolal gaps. Accumulation of toxic metabohtes may contribute to lactic acid production that further contributes to the acidosis. Precipitation of calcium oxalate and hippurate crystals in the urinary tract... 

An unusual and treatment-resistant form of symptomatic hypocalcemia is seen in patients treated with large amounts of burn cream that contains polyethylene glycols. The glycols are absorbed and metabolized to dicarboxylic adds that bind calcium. Patients develop markedly increased total calcium and decreased free calcium, along with a metabolic acidosis and increased serum osmolality from the glycols. 

---