Ethylene glycol intoxication: mind your gap(s)!—a case report

Introduction

Toxic alcohols, including ethylene glycol, methanol and isopropanol, can cause severe toxicity, even relatively small ingestions (1). Ethylene glycol is a colorless and odorless liquid that can be found in antifreeze, hydraulic brake fluids, and other industrial products. Alcohol dehydrogenase (ADH) plays a key role in its metabolization, similar to ethanol, but it is the accumulation of its toxic metabolites, glycolic acid and oxalic acid, that leads to severe metabolic acidosis and organ damage (2). Clinical presentation varies but often includes neurological symptoms such as loss of consciousness, renal dysfunction, and abdominal pain. High anion-gap metabolic acidosis with an elevated osmol gap, attributed to unmeasured toxic alcohols, is considered characteristic. Calcium oxalate crystals in urine examination, although a late and nonspecific finding, can further support the diagnosis.

We present a case of ethylene glycol intoxication and highlight several challenges encountered in the diagnostic work-up and treatment process. We present this case in accordance with the CARE reporting checklist (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-27/rc).

Case presentation

A 57-year-old, suspected homeless male with no known medical history presented at the emergency department after being found unconscious in the water in a nearby park. At the time of the presentation, it was unclear whether it was a near-drowning incident. Vital signs on admission showed a blood pressure of 176/85 mmHg, a heart rate of 72 beats per minute, a full saturation of oxygen at 100% while breathing ambient air, a respiratory rate of 30 breaths per minute, and a temperature of 36.4 degrees Celsius. The Glasgow Coma Scale was 8; eye response opening to pain (E2), motor response localizing pain (M5), and verbal response absent (V1). Despite the impairment of consciousness, the patient retained the ability to independently keep his airway open. Further physical examination revealed lacerations of his right eyebrow and upper lip, but no other abnormalities.

Arterial blood gas analysis showed severe metabolic acidosis with a pH of 7.12 and bicarbonate of 11.5 mmol/L (Table 1). The kidney function was within the normal range for age and sex [creatinine 70 µmol/L (normal range, 59–104 µmol/L)]. Based on the above, we calculated an anion gap of 24.5 mmol/L and, given a plasma osmolality of 377 mOsm/kg, an osmol gap of 69 mOsm/kg. A computed tomography (CT) scan of the brain showed a fracture of the maxillary sinus, but no signs of intracranial pathology. The clinical presentation, characterized by loss of consciousness and elevated anion gap and osmol gap metabolic acidosis, raised suspicion of intoxication. The initial urine drug screening was positive for cocaine and opiates (Triage^® TOX Drug Screen, Quidel Corp., San Diego, CA, USA), and ethanol screening (determined by enzymatic method) in blood was below 0.1 mmol/L. The symptoms did not match the toxicology results and extensive toxicology screening was indicated. Blood screening for ethanol, isopropyl alcohol and methanol screening was conducted using gas chromatography with flame ionization detector (GC-FID). Ethylene glycol screening was performed in blood with liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Following the initial administration of 100 mL of sodium bicarbonate 8.4%, the pH level persisted at 7.14, accompanied by an increase in lactate level to 30 mmol/L in blood gas analysis. To assess whether this elevation in lactate levels was genuine or a result of a laboratory artifact, lactate measurements were repeated using different instruments, revealing a remarkable discrepancy. The lactate measured by blood gas analyzer was 30.0 mmol/L, however it was 12.0 mmol/L by clinical laboratory measurement. In the urine, calcium oxalate crystals were detected via microscopy. Pending the additional toxic alcohol screening (ethanol, isopropyl alcohol, methanol, and ethylene glycol), the patient was admitted to the intensive care unit and started on renal replacement therapy in the form of continuous veno-venous hemofiltration (CVVH). Given the combination of clinical presentation and lab abnormalities, ethylene glycol intoxication was suspected.

The ethylene glycol level was 2,550 mg/L, surpassing the toxic threshold of 200 mg/L—with severe intoxication recognized at levels exceeding 500 mg/L. Ethanol was administered as an antidote. Ethanol inhibits the enzyme ADH, preventing the metabolization of ethylene glycol to toxic metabolites. In the first hour, the patient received a loading dose of 100 mL of 96% ethanol in a 2-L glucose 5% solution, followed by a continuous infusion of 50 mL of 96% ethanol in 1-L glucose 5% solution at a rate of 200 mL/h. To evaluate treatment, ethanol levels were assessed every 3 hours, aiming for a target ethanol level of 1,000 to 1,500 mg/L. In cases of severe ethylene glycol intoxication (ethylene glycol level >500 mg/L), hemodialysis is indicated. Despite the initiation of CVVH, a switch to a 3-hour high-efficiency hemodialysis session was executed once the ethylene glycol levels was known. During hemodialysis, the ethanol infusion rate was increased from 200 to 300 mL/h. Despite the increased rate, ethanol levels during the hemodialysis session remained below target (670 mg/L). An additional bolus of ethanol was administered and the infusion rate was further increased. Approximately 4 hours after admission to the intensive care unit, the patient’s consciousness recovered. After multidisciplinary consultation, it was decided to conduct another 3-hour hemodialysis session the next day and ethanol infusion was continued until normalization of metabolic changes. The patient recovered well and was discharged home the following day.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). The patient provided oral informed consent for this case report. He was discharged from the hospital after completing treatment. Unfortunately, we have not been able to contact him since and are therefore unable to share the patient perspective on the treatment, nor have we been able to obtain written consent.

Discussion

Ethylene glycol intoxication is rare and its clinical presentation is characterized by three phases. The initial phase, occurring 1 to 12 hours post-ingestion, is marked by symptoms such as metabolic acidosis, reduced consciousness, nausea, and vomiting. The second phase (12 to 24 hours after ingestion) may involve cardiopulmonary symptoms, including tachycardia and congestive heart failure in severe intoxication. The third and final phase (24 to 72 hours after ingestion) primarily presents with renal symptoms (3). Our patient presented with impaired consciousness and metabolic acidosis.

There are several pitfalls in diagnosing ethylene glycol intoxication. Firstly, there must be suspicion of intoxication with a toxic alcohol. In our case, the combination of clinical presentation with reduced level of consciousness and laboratory tests with a high anion gap and high osmol gap made an intoxication more likely. However, a serum ethylene glycol measurement is essential for diagnosis. This measurement is preferably executed with a LC-MS/MS, a technique that is complex and not widely available. An alternative method to perform this measurement is by GC-FID, but this is less accurate due to potential misinterpretation of interfering peaks (4). Secondly, microscopic urine examination is frequently performed and may show presence of calcium oxalate crystals in case of ethylene glycol intoxication. However, this finding is not specific and is also a late sign of ethylene glycol intoxication (5). Finally, the measured lactate levels can be falsely elevated: the metabolites glycolate and glyoxylate that give metabolic acidosis are misinterpreted as lactate by many point-of-care blood gas analyzers (6). We were able to verify this in our patient by performing a simultaneous lactate measurement in the central clinical laboratory and blood gas analyzer; the lactate measured by blood gas analyzer was 30.0 mmol/L, whereas it was 12.0 mmol/L by clinical laboratory measurement. The falsely high lactate values can lead to misdiagnosis, inappropriate laparotomies, and delayed antidote therapy. As laboratory analyzers measure plasma lactate only, the difference or the “lactate gap” may aid in early diagnosis (7).

The toxicity of ethylene glycol intoxication is mainly determined by its metabolites such as oxalic acid, which is formed by ADH. Ethanol and fomepizole are both competitive inhibitors of ADH with a higher affinity compared to ethylene glycol. Fomepizole has the strongest affinity for ADH, but is more expensive and less readily available. Ethanol requires dosing based on blood levels, posing practical challenges, as observed in our case (Figure 1). During hemodialysis the infusion rate was increased from 200 to 300 mL/h. However, ethanol levels remained below target and required further increase and an additional bolus of ethanol. Dosing ethanol, especially during renal replacement therapy, proves challenging (8). Another patient-related relevant factor might be chronic alcohol abuse, something which is not always known, and information that might be difficult to retrieve from the intoxicated patient with reduced consciousness. Chronic alcohol abuse can induce ADH and therefore increase clearance.

Figure 1 Ethanol concentration during treatment of ethylene glycol intoxication. The red dots represent the initiation of the 3-hour hemodialysis sessions.

CVVH was initiated for treatment of severe metabolic acidosis. The initial ethylene glycol level appeared to be 2,550 mg/L. Once ADH is blocked by ethanol, endogenous ethylene glycol clearance is at best 30 mL/min, it can be increased by high-efficiency hemodialysis (median clearance of 163 mL/min) and CVVH (median clearance of 72 mL/min) (9). Hemodialysis is recommended for ethylene glycol levels exceeding 500 mg/L. High-efficiency hemodialysis is not a sine cure in a patient without renal failure and requires both potassium and phosphate suppletion as well as adjustment of ethanol dose to keep ADH blocked. Unfortunately, we could not tailor treatment to our patient’s need since ethylene glycol assay results were not available in a clinical useful timeframe. Hemodialysis duration was estimated using a simple formula and nomogram to achieve a safe ethylene glycol concentration, based on the single ethylene glycol concentration at admission (10).

Criteria for discontinuation of hemodialysis for ethylene glycol intoxication consist of an anion gap <18 mmol/L, ethylene glycol concentration <250 mg/L and correction of acid-base abnormalities (9). In our patient, the anion gap after the first dialysis session was 12.5 mmol/L and acid-base abnormalities had been resolved. However, a new ethylene glycol level was not immediately available. The ethylene glycol level had to be estimated using the osmol gap and factoring in the contribution of ethanol to the osmol gap during treatment. The approximate contribution of ethylene glycol to the osmol gap was crudely estimated at 14 mOsm/kg, corresponding to an estimated ethylene glycol level of 868 mg/L. We decided to perform a second hemodialysis session the following day, taking into account a rebound increase in ethylene glycol concentration, which has been reported to be of a median magnitude of 30% of the immediate post dialysis concentration (9). When neither renal failure nor acidemia is present the advantages of intermittent hemodialysis added to ADH inhibition are mainly to reduce the length of hospitalization and limit risks of ethanol therapy, rather than reducing the occurrence of major adverse outcomes from ethylene glycol (9). Notably, the measured ethylene glycol level before the second session of hemodialysis turned out to be 362 mg/dL, so our calculation overestimated the true ethylene glycol level. This higher-than-expected endogenous clearance suggests our patient to be a chronic alcohol abuser.

Conclusions

Ethylene glycol intoxication depresses the central nervous system significantly and its metabolites induce metabolic acidosis characterized by high anion gap and high osmol gap. Falsely elevated lactate levels (lactate gap, i.e., difference in values obtained from two different analyzer methods) and the presence of urine calcium oxalate crystals aid in early diagnosis of ethylene glycol intoxication. The primary treatment involves inhibiting ADH with fomepizole or ethanol, the latter requiring careful dosing based on serum levels. Hemodialysis can accelerate elimination. Estimating the ethylene glycol plasma concentration based on the osmol gap, as a measure of toxicity, is challenging. A running ethylene glycol assay enables patient-tailored (dialysis) treatment, avoiding unnecessary costs.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-27/rc

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-27/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-27/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). The patient provided oral informed consent for this case report. He was discharged from the hospital after completing treatment. Unfortunately, we have not been able to contact him since and are therefore unable to share the patient perspective on the treatment, nor have we been able to obtain written consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. McQuade DJ, Dargan PI, Wood DM. Challenges in the diagnosis of ethylene glycol poisoning. Ann Clin Biochem 2014;51:167-78. [Crossref] [PubMed]
2. Scalley RD, Ferguson DR, Piccaro JC, et al. Treatment of ethylene glycol poisoning. Am Fam Physician 2002;66:807-12. [PubMed]
3. Zwaveling JH, Sangster B, van Dijk A. Ethylene glycol poisoning. Ned Tijdschr Geneeskd 1988;132:485-9. [PubMed]
4. Dziadosz M. Direct analysis of ethylene glycol in human serum on the basis of analyte adduct formation and liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2018;1072:100-4. [Crossref] [PubMed]
5. Sheta HM, Al-Najami I, Christensen HD, et al. Rapid Diagnosis of Ethylene Glycol Poisoning by Urine Microscopy. Am J Case Rep 2018;19:689-93. [Crossref] [PubMed]
6. Tintu A, Rouwet E, Russcher H. Interference of ethylene glycol with (L)-lactate measurement is assay-dependent. Ann Clin Biochem 2013;50:70-2. [Crossref] [PubMed]
7. Hauvik LE, Varghese M, Nielsen EW. Lactate Gap: A Diagnostic Support in Severe Metabolic Acidosis of Unknown Origin. Case Rep Med 2018;2018:5238240. [Crossref] [PubMed]
8. Levine M, Curry SC, Ruha AM, et al. Ethylene glycol elimination kinetics and outcomes in patients managed without hemodialysis. Ann Emerg Med 2012;59:527-31. [Crossref] [PubMed]
9. Ghannoum M, Gosselin S, Hoffman RS, et al. Extracorporeal treatment for ethylene glycol poisoning: systematic review and recommendations from the EXTRIP workgroup. Crit Care 2023;27:56. [Crossref] [PubMed]
10. Iliuta IA, Lachance P, Ghannoum M, et al. Prediction and validation of the duration of hemodialysis sessions for the treatment of acute ethylene glycol poisoning. Kidney Int 2017;92:453-60. [Crossref] [PubMed]