Role of enzymatic measurement of ethylene glycol in the management of patients with unexplained metabolic acidosis
Ingestion of a variety of alcohols can result in toxic effects, which may include metabolic acidosis due to their metabolism. Common alcohols/glycols often implicated are ethylene glycol, methanol and isopropanol. Isopropanol ingestion usually does not cause major toxicity unless a large amount is ingested, when CNS depression, haemorrhagic gastritis and tracheobronchitis may be seen. It does not usually result in a metabolic acidosis, the isopropanol being metabolized to acetone (“ketosis without acidosis”).
Traditionally, where ingestion of ethylene glycol is suspected, specific measurement has required a gas-chromatographic method. This has restricted the potential use of the method due to the need for specialised techniques and equipment that may only be available in specialist referral laboratories. This often precludes the recommended turnaround time of 2-4 hours[1]
It is therefore not surprising that alternative strategies are utilized to manage patients suspected of ingestion of such alcohols or to exclude ethylene glycol as a potential cause of an unexplained metabolic acidosis. Early and accurate diagnosis is important in the management of patients presenting with potential ethylene glycol toxicity to determine the need to start timely treatment with antidotes such as fomepizole or ethanol. The most commonly applied strategy in excluding toxic alcohols as a cause of an unexplained metabolic acidosis involves the determination of the osmolar gap, i.e. the difference observed between a measured and calculated osmolality on a sample of serum/plasma. A number of studies[2],[3],[4]have looked at the effectiveness of osmolar gap (and the different formulae which may be utilized), and a number of common “truths” are apparent.
Traditionally, where ingestion of ethylene glycol is suspected, specific measurement has required a gas-chromatographic method. This has restricted the potential use of the method due to the need for specialised techniques and equipment that may only be available in specialist referral laboratories. This often precludes the recommended turnaround time of 2-4 hours[1]
It is therefore not surprising that alternative strategies are utilized to manage patients suspected of ingestion of such alcohols or to exclude ethylene glycol as a potential cause of an unexplained metabolic acidosis. Early and accurate diagnosis is important in the management of patients presenting with potential ethylene glycol toxicity to determine the need to start timely treatment with antidotes such as fomepizole or ethanol. The most commonly applied strategy in excluding toxic alcohols as a cause of an unexplained metabolic acidosis involves the determination of the osmolar gap, i.e. the difference observed between a measured and calculated osmolality on a sample of serum/plasma. A number of studies[2],[3],[4]have looked at the effectiveness of osmolar gap (and the different formulae which may be utilized), and a number of common “truths” are apparent.
- The greater the osmolar gap, the greater the likelihood that a toxic alcohol has been ingested
- The increased specificity seen with a large osmolar gap comes at the expense of sensitivity.
- The sensitivity and specificity of the osmolar gap can depend on both the formula and the cut-off used.
Complicating this, there are issues around the reference interval for osmolar gap, which has been noted to range from -5 to 9 mOsmol/kg in normal volunteers[5]. In patients admitted to emergency departments, the range seen is much greater, potentially from -10 to 20mOsmol/kg5,[6] which may impact on the sensitivity and specificity of the technique where lower concentrations of the alcohol may be present.
Another factor which may limit the usefulness of osmolar gap is the fact that as time progresses after ingestion of the alcohol, more of the alcohol will have been metabolised. This will reduce any potential osmolar gap, and its sensitivity will therefore likewise be reduced, resulting in the anion gap increasing as the osmolar gap decreases.[7]
Reliance on indirect methods may therefore result in delayed or missed treatment opportunities in patients with potentially life-threatening conditions. The lack of readily accessible chromatographic services within every laboratory serving an emergency department should not be a reason to delay specific measurement of the most common toxic alcohol when an accurate enzymatic method is available. This method now allows the measurement Ethylene Glycol using the routine clinical chemistry analysers found in all hospital laboratories or in the case of the Fastox product, a semi quantitative result using a spectrophotometer.
The use of enzymatic techniques for the measurement of ethylene glycol enables rapid (within 1 hour) measurement within the laboratories serving Emergency Departments, without the need to maintain specialised analytical services, or transport samples to distant laboratories with inevitable delays in result turnaround.
Assay limitations:
Catachem Ethylene Glycol Method (C504-0A, Quantitative Method)
The method if performed according to the manufacturer’s specifications has been shown to be specific, accurate and precise, demonstrating good correlation between itself and conventional gas-chromatographic techniques.
Glycerol, propylene glycol, formic acid, n-propanol, isopropanol, acetone, methanol, ethanol, glycolic acid, polyethylene glycol, oxalic acid, glyoxal solution, glyoxylic acid, 1,2-butanediol, 1,4-butanediol, 1,3-propanediol, 1-butanol, 1,3-butanediol,1-octanol, as well as the antidote drug Fomepizole[8] have all been shown to not interfere with the assay.
An incorrect result for ethylene glycol was produced at concentrations in excess of 1000mg/l for propylene glycol, 2,3-butanediol, diethylene, triethylene, and tetraethylene glycols, but all results were notably associated with a rate error and were hence easily distinguishable. [8]
[1] Wu AH, McKay C, Broussard LA, Hoffman RS, Kwong TC, Moyer TP, Otten EM, Welch SL, Wax P: National academy of clinical biochemistry laboratory medicine practice guidelines: recommendations for the use of laboratory tests to support poisoned patients who present to the emergency department. Clin Chem 2003; 49:357-379.
[2]Krahn J and Khajuria A. Osmolality gaps: diagnostic accuracy and long-term variability. Clin Chem 2006; 52:737–739.
[3] Lynd LD, Richardson KJ, Purssell RA, et al. An evaluation of the osmole gap as a screening test for toxic alcohol poisoning. BMC Emerg Med 2008; 8: 5.
[4] Krasowski M, Wilcoxon R and Miron J. A retrospective analysis of glycol and toxic alcohol ingestion: utility of anion and osmolal gaps. BMC Clin Pathol 2012; 12: 1.
[5] Hoffman R, Smilkstein M, Howland M, et al. Osmol gaps revisited: normal values and limitations. J Toxicol Clin Toxicol 1993; 31: 81–93.
[6] Abakken L, Johansen KS, Ryeningen EB, et al. Osmolal and anion gaps in patients admitted to an emergency medicine department. Hum Exp Toxicol 1994; 13:131–134.
[7] Mycyk M and Aks S. A visual schematic for clarifying the temporal relationship between the anion and osmol gaps in toxic alcohol poisoning. Am J Emerg Med 2003;21: 333–335.
[8] Juenke JM, Hardy L, McMillin GA, et al. Rapid and specific quantification of ethylene glycol levels: adaptation of a commercial enzymatic assay to automated chemistry analyzers. Am J Clin Pathol 2011; 136:318–324.
Another factor which may limit the usefulness of osmolar gap is the fact that as time progresses after ingestion of the alcohol, more of the alcohol will have been metabolised. This will reduce any potential osmolar gap, and its sensitivity will therefore likewise be reduced, resulting in the anion gap increasing as the osmolar gap decreases.[7]
Reliance on indirect methods may therefore result in delayed or missed treatment opportunities in patients with potentially life-threatening conditions. The lack of readily accessible chromatographic services within every laboratory serving an emergency department should not be a reason to delay specific measurement of the most common toxic alcohol when an accurate enzymatic method is available. This method now allows the measurement Ethylene Glycol using the routine clinical chemistry analysers found in all hospital laboratories or in the case of the Fastox product, a semi quantitative result using a spectrophotometer.
The use of enzymatic techniques for the measurement of ethylene glycol enables rapid (within 1 hour) measurement within the laboratories serving Emergency Departments, without the need to maintain specialised analytical services, or transport samples to distant laboratories with inevitable delays in result turnaround.
Assay limitations:
Catachem Ethylene Glycol Method (C504-0A, Quantitative Method)
The method if performed according to the manufacturer’s specifications has been shown to be specific, accurate and precise, demonstrating good correlation between itself and conventional gas-chromatographic techniques.
Glycerol, propylene glycol, formic acid, n-propanol, isopropanol, acetone, methanol, ethanol, glycolic acid, polyethylene glycol, oxalic acid, glyoxal solution, glyoxylic acid, 1,2-butanediol, 1,4-butanediol, 1,3-propanediol, 1-butanol, 1,3-butanediol,1-octanol, as well as the antidote drug Fomepizole[8] have all been shown to not interfere with the assay.
An incorrect result for ethylene glycol was produced at concentrations in excess of 1000mg/l for propylene glycol, 2,3-butanediol, diethylene, triethylene, and tetraethylene glycols, but all results were notably associated with a rate error and were hence easily distinguishable. [8]
[1] Wu AH, McKay C, Broussard LA, Hoffman RS, Kwong TC, Moyer TP, Otten EM, Welch SL, Wax P: National academy of clinical biochemistry laboratory medicine practice guidelines: recommendations for the use of laboratory tests to support poisoned patients who present to the emergency department. Clin Chem 2003; 49:357-379.
[2]Krahn J and Khajuria A. Osmolality gaps: diagnostic accuracy and long-term variability. Clin Chem 2006; 52:737–739.
[3] Lynd LD, Richardson KJ, Purssell RA, et al. An evaluation of the osmole gap as a screening test for toxic alcohol poisoning. BMC Emerg Med 2008; 8: 5.
[4] Krasowski M, Wilcoxon R and Miron J. A retrospective analysis of glycol and toxic alcohol ingestion: utility of anion and osmolal gaps. BMC Clin Pathol 2012; 12: 1.
[5] Hoffman R, Smilkstein M, Howland M, et al. Osmol gaps revisited: normal values and limitations. J Toxicol Clin Toxicol 1993; 31: 81–93.
[6] Abakken L, Johansen KS, Ryeningen EB, et al. Osmolal and anion gaps in patients admitted to an emergency medicine department. Hum Exp Toxicol 1994; 13:131–134.
[7] Mycyk M and Aks S. A visual schematic for clarifying the temporal relationship between the anion and osmol gaps in toxic alcohol poisoning. Am J Emerg Med 2003;21: 333–335.
[8] Juenke JM, Hardy L, McMillin GA, et al. Rapid and specific quantification of ethylene glycol levels: adaptation of a commercial enzymatic assay to automated chemistry analyzers. Am J Clin Pathol 2011; 136:318–324.