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The clinical presentation of ethylene glycol poisoning is classically described in three stages. Neurological manifestations are apparent within 0. Cardiopulmonary manifestations may be observed 12—24 h after ingestion and may include tachypnea, tachycardia, hypertension, pulmonary edema, and congestive heart failure.
Renal complications are generally a late feature, occurring 24—72 h after ingestion, and consist of flank pain, costovertebral angle tenderness, oliguria, and renal failure. The severity of each stage and the progression from one stage to the next depend on the amount of ethylene glycol ingested as well as the timing of medical intervention. The most serious clinical features observed in ethylene glycol poisoning are due not to the parent compound but to the metabolites.
Ethylene glycol per se causes only minimal inebriation, which resembles ethanol intoxication 1 2. Because metabolism of the parent compound is required for toxicity, the latent period reflects the time required for the toxic metabolites to accumulate. In cases 1 and 2, the only apparent manifestation of ethylene glycol poisoning was mild neurological depression, because the patients were evaluated within hours of the ingestion.
In striking contrast, substantial renal insufficiency caused by the metabolites of ethylene glycol was manifest in case 3, because the poisoning was not detected until late in the clinical course, most likely several days after ingestion. Although these stages provide a useful theoretical framework for the clinical description of ethylene glycol poisoning, the onset and progression of this condition are not always straightforward or predictable. These stages may be confluent, one stage may predominate, or one or more of the stages may not be clinically apparent. Often, a patient is discovered comatose, experiencing both respiratory distress and acute renal insufficiency 7.
Variable symptom profiles are found in the literature of case reports 8 9 10 Renal failure is the most frequently reported manifestation of ethylene glycol ingestion; however, as in cases 1 and 2, prompt treatment may prevent crystalluria and renal insufficiency 12 13 Although the symptoms usually completely resolve soon after appropriate treatment for the acute episode, sequelae of ethylene glycol poisoning have included prolonged renal failure requiring dialysis for months, residual kidney damage, and cranial nerve deficits manifesting late in the clinical course and lasting as long as several months 15 16 17 Complete recovery from ethylene glycol poisoning with aggressive treatment, however, has been reported even after severe encephalopathy 19 or profound acidemia with a serum pH of 6.
Ethylene glycol is rapidly absorbed from the gastrointestinal tract, and symptoms of poisoning may be experienced within 30 min of ingestion. Percutaneous absorption of ethylene glycol has not been reported, but topical burn preparations containing propylene glycol or diethylene glycol have produced considerable toxicity in burn patients 20 Ethylene glycol is rapidly metabolized by alcohol dehydrogenase and other hepatic enzymes to glycoaldehyde and organic acids Fig.
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The elimination half-life of ethylene glycol is increased at least fivefold in the presence of ethanol because both compounds compete for the active site of alcohol dehydrogenase. Hemodialysis rapidly removes both ethylene glycol and its toxic metabolites, particularly glycolate and oxalate 24 25 26 Hemodialysis clearance is greater than renal clearance, but functioning kidneys contribute to the removal of ethylene glycol from the blood ADH, alcohol dehydrogenase.
Source: Toxicokinetic evaluation of ethylene glycol elimination during hemodialysis and ethanol infusion was performed in case 2 Fig. Utilizing the noncompartmental pharmacokinetic model with extravascular administration of the historical dose Winnonlin software package; Scientific Consulting Inc. During the two short intervals when ethanol infusion was maintained but hemodialysis was not performed Fig.
The duration of therapy with intravenous ethanol and the two intervals of hemodialysis HD are indicated by the bars above the graphs. The evolving laboratory profile in cases of ethylene glycol poisoning reflects the metabolism of ethylene glycol, the accumulation of organic acids, and the timing of medical intervention. Death, however, has been reported in patients with virtually undetectable serum ethylene glycol concentrations This discrepancy underscores the importance of prompt diagnosis and treatment of intoxication.
The poor correlation between serum ethylene glycol concentration and clinical outcome is the result of the rapid clearance of the parent drug and conversion to the severely toxic metabolites. In case 3, this time had elapsed, and the only evidence of ethylene glycol poisoning was the deposition of calcium oxalate crystals in the kidney. At a given time after ingestion, the concentrations of the remaining ethylene glycol and the accumulated acidic metabolites affect the magnitude of the osmolal gap and anion gap, respectively.
An osmolal gap may not be apparent late in the course of poisoning, whereas an anion gap may not be evident early in the clinical course 18 29 These observations reflect the relative amounts of the compounds that are the source of the gaps. The production of unmeasured organic acids will increase the anion gap. The osmolal gap is also an estimate of unmeasured constituents in the serum.
The difference between measured and calculated osmolality, the osmolal gap, results from the presence of other solutes in serum, which are not considered in the above formula. Consequently, osmolality should be measured by freezing point depression, because the vapor pressure method will underestimate volatile alcohols As ethylene glycol is being metabolized or removed by dialysis, its contribution to the osmolal gap diminishes because the accumulating acidic, negatively charged metabolites do not contribute to the osmolal gap These anions are counterbalanced by sodium and are taken into consideration in the formula for calculating the serum osmolality Nonionic metabolites of ethylene glycol may contribute to the osmolal gap; however, the concentration of the parent compound accounts for most of the osmolal gap in cases of ethylene glycol poisoning The corrected osmolal gap, or the residual osmolality, can be used to monitor patients who have simultaneously ingested ethylene glycol and ethanol or patients who are receiving ethanol infusion for ethylene glycol poisoning Although metabolism of ethylene glycol diminishes the osmolal gap, the generation of unmeasured acidic metabolites of ethylene glycol augments the anion gap 18 In case 3, the increased anion gap most probably reflected the delay in diagnosis and the accumulation of acidic metabolites.
In case 1, however, the anion gap was within the reference range, most probably because the intoxication was detected and treated promptly; acidic metabolites had not reached appreciable concentration. Aside from the temporal dependence of the increased anion gap on the metabolism of the parent compound, an anion gap may not be present in cases of ethylene glycol poisoning for other reasons.
Simultaneous ingestion of ethanol will competitively inhibit the metabolism of ethylene glycol and delay the appearance of an anion gap Simultaneous ingestion of bromide masks the anion gap because bromide is not distinguished from chloride in some assays Finally, simultaneous ingestion of lithium carbonate may conceal the anion gap by providing additional bicarbonate For these reasons, neither osmolal nor anion gaps are universally present in cases of ethylene glycol poisoning, and their absence cannot be used to rule out toxic alcohol or ethylene glycol ingestion 29 Conversely, the simultaneous presence of metabolic acidosis with an increased anion and osmolal gap, although highly suggestive of ethylene glycol or methanol poisoning, is not specific for these intoxications 40 Anion and osmolal gaps may be present in other clinical settings such as diabetic ketoacidosis, alcoholic ketoacidosis, chronic renal failure, multiple organ failure, and critical illness 40 42 43 44 45 46 47 In case 4, both metabolic acidosis with an increased anion gap and an increased osmolal gap were present.
Ethylene glycol poisoning was initially considered but later discounted after gas chromatography failed to confirm the results of the screening test for ethylene glycol. The increased anion and osmolal gaps in this case were probably the result of multiple organ failure. Calcium oxalate crystalluria and deposition of these crystals in the kidney, brain, or other organs are distinctive laboratory features in ethylene glycol poisoning.
In case 3, the findings of renal tubular necrosis and deposition of calcium oxalate crystals by renal biopsy Fig.
Ethylene glycol poisoning: toxicokinetic and analytical factors affecting laboratory diagnosis
Chelation of calcium by the oxalate deposited in the kidneys and other organs may explain the hypocalcemia that is often observed in cases of ethylene glycol poisoning. Another clinical setting characterized by calcium oxalate nephrolithiasis is primary hyperoxaluria, a rare inherited metabolic disorder associated with early-onset renal failure and death. Healthy individuals, especially those with dietary excesses of foods rich in oxalate such as tomatoes, garlic, spinach, rhubarb, cocoa, and tea, may also exhibit calcium oxalate crystalluria without associated renal insufficiency.
Calcium oxalate crystals in urine are pleomorphic, variegated, and birefringent when viewed through polarized light. In cases of ethylene glycol poisoning, calcium oxalate may be excreted not only as dihydrate crystals, which are envelope-shaped dipyramidal, octahedral , but also as monohydrate crystals, which are needle-shaped spindle or prism shaped Fig. Other forms of calcium oxalate include dumbbell, ovoid, and elliptical crystals. If the results of more-definitive laboratory tests are not available, the detection of calcium oxalate crystalluria, particularly the monohydrate form, provides supportive evidence for the diagnosis of ethylene glycol poisoning 30 49 50 Because the monohydrate form may be the only form seen early or at any time during the course of the episode, familiarity with the microscopic features of calcium oxalate monohydrate crystals is important.
The monohydrate form is very strongly birefringent and may be distinguished from uric acid by its solubility in dilute hydrochloric acid. In the early s, identification of the pleomorphic nature of calcium oxalate crystalluria prompted the recommendation that physicians recognize the monohydrate calcium oxalate crystals to facilitate rapid diagnosis of ethylene glycol ingestion The medical literature has been confused by morphological descriptions of crystals that resemble those of hippuric acid as well as by theoretical arguments supporting their formation 25 X-ray diffraction, however, definitively identifies the needle-shaped crystals as calcium oxalate monohydrate and not hippuric acid 30 50 Renewed emphasis has recently been placed on the need to increase proficiency during microscopic analysis of urine to recognize calcium oxalate monohydrate as well as dihydrate crystals in cases of suspected ethylene glycol poisoning Because urinalysis is rapid and easy, repeated urine microscopy is a potentially useful adjunct in the differential diagnosis of an anion gap metabolic acidosis of unknown origin 18 Other frequently reported findings on urinalysis in cases of ethylene glycol poisoning include low specific gravity, proteinuria, and microscopic hematuria.
Examination of urine for calcium oxalate crystals is the most widely accessible laboratory technique for detecting a metabolite of ethylene glycol. Because the toxicity of ethylene glycol depends on its oxidation to organic acids, several other methods have been utilized to measure these products. Glycolic acid, the predominant metabolite, has been measured by HPLC and gas chromatography, by a colorimetric method, and by isotachophoresis 27 52 53 The colorimetric method utilizes sulfuric acid and chromotropic acid and is relatively specific for glycolic acid In contrast, isotachophoresis can measure the four major acidic metabolites of ethylene glycol simultaneously Isotachophoresis is an electrophoretic technique that orders and concentrates substances of intermediate effective mobilities between an ion of high effective mobility and one of much lower effective mobility.
Sample components ultimately separate into adjacent zones that migrate at the same velocity.
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Although a laboratory test for glycolic acid would have been a useful diagnostic adjunct in case 3, none is currently available at most medical centers or reference laboratories. The method of choice for measuring ethylene glycol is gas chromatography, with flame ionization detection of ethylene glycol itself or of a derivative. Commonly, ethylene glycol is analyzed as the boronic ester derivative by using packed or capillary columns. Underivatized ethylene glycol is difficult to analyze because of poor chromatographic behavior and the poor detection limit of flame ionization detectors.
However, direct injection of ethylene glycol on a wide-bore capillary column has been described 55 56 Advantages of these methods include elimination of the derivatization step, resolution of diethylene glycol and other diols as well as other polar drugs, and extended analytical life of the Nukol column.
An appropriate internal standard, such as 1,3-propanediol or 1,2-butanediol, must be used with gas-chromatographic analysis. Recently, the use of propylene glycol as an internal standard has been discouraged 57 58 The inclusion of propylene glycol in some intravenous pharmaceutical preparations contributes to the concentration of the internal standard, thus resulting in underestimation of the ethylene glycol concentration in the serum sample.
Moreover, propylene glycol itself may be responsible for clinical toxicity, and its presence in a serum sample may be masked when this compound is used as an internal standard. In one notorious case, propionic acid was mistakenly identified as ethylene glycol by gas chromatography Consequently, a mother was falsely accused of poisoning her infant son who, in fact, had an inherited metabolic disease, methylmalonic acidemia.
This error occurred in two independent laboratories. Accurate interpretation of the retention times of the compounds identified in the serum sample might have prevented the tragic consequences of this inaccurate diagnosis. Identification based on retention time alone has led to confusion of 2,3-butanediol as well as propionic acid with ethylene glycol 60 61 ; thus, if the presence of ethylene glycol is suspected in a sample, confirmation by mass spectrometry is recommended. Moreover, methanol-like products generated by the oxidation—reduction derivatization procedure in sera from ketoacidotic diabetic patients may be misinterpreted as evidence of ethylene glycol poisoning The screening assay utilizes glycerol dehydrogenase purified from E.
This enzyme catalyzes the oxidation of ethylene glycol, producing NADH, which is measured spectrophotometrically. No cross-reaction is observed with ethanol, methanol, n -propanol, isopropanol, acetaldehyde, lactate, glyoxal, glycolic acid, glyoxylic acid, or oxalic acid. Interfering substances include glycoaldehyde and glycerol, which compete with ethylene glycol for the active site of the enzyme. Although glycoaldehyde is one of the ethylene glycol metabolites, its short half-life makes it unlikely to interfere with the assay.
However, critically ill patients may have an increased serum concentration of free glycerol, most frequently related to intravenous infusion of glycerol-containing medications Conceivably, glycerol could reach a concentration in serum sufficient to interfere in the enzymatic assay for ethylene glycol in this clinical setting. Another interference in the screening test for ethylene glycol was delineated in case 4 4. Ethylene glycol poisoning was considered in this patient because the toxicology screen detected ethylene glycol and several of the key diagnostic features were present: cardiorespiratory compromise, increased anion gap metabolic acidosis, increased osmolal gap, renal insufficiency, and crystalluria.
The positive result obtained in the enzymatic screening test, however, was not confirmed by gas chromatography. The source of the interference in the enzymatic assay for ethylene glycol in this case was markedly increased concentrations of serum l -lactate dehydrogenase LD and lactic acid. In patients with increased serum lactate and LD, extraneous production of NADH from the oxidation of lactate to pyruvate catalyzed by LD may interfere with the assay, resulting in falsely positive values for ethylene glycol.
This interference has also been reported in the enzymatic assay for ethanol, which likewise measures NADH as its endpoint Goals of treatment in cases of ethylene glycol intoxication include reducing the load of ingested ethylene glycol, correcting the metabolic acidosis of early toxicity, preventing additional metabolism of ethylene glycol, and removing the parent compound as well as toxic metabolites from the circulation. If ingestion is recognized early, ethylene glycol may be removed from the gastrointestinal tract by inducing emesis, administering activated charcoal, or performing gastric lavage.
Ethanol is administered as a preferential substrate for alcohol dehydrogenase, thereby competitively inhibiting metabolism of ethylene glycol to its toxic metabolites and allowing excretion of the unmetabolized parent compound. As in case 1, ethanol therapy may be sufficient to prevent renal failure and effect complete clinical recovery 12 14 Additional measures, however, are often initiated simultaneously before renal failure supervenes. Hemodialysis removes both ethylene glycol and its toxic metabolites, particularly glycolate and oxalate, as well as ethanol 23 24 Consequently, ethanol administration should be maintained during hemodialysis.
Ethanol therapy is associated with additional neurological depression, and frequent monitoring during hemodialysis is necessary to maintain ethanol serum concentrations at appropriate values. As an alternative to ethanol therapy for ethylene glycol poisoning, other potent and specific inhibitors of alcohol dehydrogenase, e. In conclusion, early diagnosis and treatment of ethylene glycol poisoning can prevent substantial morbidity and mortality. The diagnosis may be straightforward, as in cases 1 and 2, if the patient or a third party relates a clear history of ethylene glycol poisoning.
If the poisoning is not detected until late in the clinical course, as in case 3, toxicokinetic variables affecting measurement of serum ethylene glycol and other variables such as the anion gap and osmolal gap may obscure the laboratory diagnosis of suspected ethylene glycol poisoning. Finally, as in case 4, analytical variables may affect the results of laboratory assays for ethylene glycol. Accusations of impropriety feature in escalating dispute.
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