Introduction

Ethylene glycol (EG) and diethylene glycol (DEG) intoxication are defined as > 20 mg/dL EG/DEG in plasma, which may cause severe morbidity and mortality. The intoxication of both alcohols results from the metabolism of EG/DEG via alcohol dehydrogenase (ADH) enzymes and their conversion to their active toxic metabolites. Treatment modalities include blocking the formation and removal of toxic metabolites, which can be achieved through antidote administration and renal replacement therapy [1]. Individuals at risk of EG and DEG intoxication include patients with alcohol abuse, suicidal tendencies, and children who accidentally ingest antifreeze [2]. In August 2022, Indonesia experienced a sudden increase in acute kidney injury cases in children, initially attributed to multisystem inflammatory syndrome in children (MIS-C), which has been widely reported in post-COVID-19 children. All admitted patients fulfilled WHO criteria for MIS-C and consequently received intravenous immunoglobulin, methylprednisolone, and anticoagulants, with three patients (18.7%) also undergoing therapeutic plasma exchange due to unresponsiveness to standard care.

It was not until mid-October, after the World Health Organization noted EG/DEG intoxication in Gambia, that we began to suspect intoxication of EG/DEG from syrup-based medications. This WHO alert played a crucial role in guiding our investigation, as it highlighted the global nature of healthcare and the importance of sharing information and experiences. The resemblance of reports in history and patients’ clinical information further strengthened our suspicion [3,4,5]. Toxicology screening was subsequently performed on 19 patients, in which EG/DEG levels were measured in either blood or urine samples. Notably, EG/DEG has a sweet taste and was used as a dilutive agent to increase drug solubility, and only up to 0.2% of the sum of EG and DEG in polyethylene glycols was allowed by the United States Pharmacopoeia [6]. However, the EG/DEG of these medications exceeds the accepted limits.

Methods

This is a retrospective descriptive case series of children admitted to Dr. Cipto Mangunkusumo Hospital between January 2022 and July 2023 with acute kidney injury (AKI) of unknown origin. The inclusion criteria were: (1) children < 18 years old, (2) normal kidney and urinary tract anatomy, (3) no hypovolemia or severe infection, (4) no known renal-related comorbidities, and (5) received fomepizole therapy based on clinical suspicion of EG/DEG poisoning, with or without toxicology confirmation. We collected secondary data from the pediatric admission registry and electronic health records of children with acute kidney injury of unknown origin from January 2022 to July 2023 at Dr. Cipto Mangunkusumo Hospital, Jakarta, a national referral, and teaching hospital. Comprehensive information on patient data, including demographic indicators, past medical history of anuria, laboratory investigation results, intubation period, and treatment modalities, was analysed. This study did not involve patients or the public in the initial stages or during the research due to the retrospective nature of the study, which focused on evaluating the effectiveness of fomepizole as an antidote for EG/DEG poisoning. The initial design or conduct of the study analysed existing data from patients who had already received fomepizole; therefore, no active recruitment process was needed, and patients were not directly involved in choosing the outcome measures; rather, they were selected on the basis of their clinical relevance and literature on the efficacy of fomepizole as an antidote.

The diagnosis of EG/DEG intoxication was made on the basis of the following diagnostic criteria: plasma EG levels > 20 mg/dL (3 mmol/L), a known history of EG/DEG ingestion in large quantities, and an osmolar gap > 10 mOsm/kg or suspected EG/DEG intoxication with at least two or more of these laboratory findings; an arterial pH < 7.3, a serum bicarbonate concentration < 20 mEq/L (20 mmol/L), an osmolar gap > 10 mOsm/kg or oxalate crystals present in the urine. To determine the anion gap, the following formula was used: (Na + − Cl− − HCO3), which was corrected via the following equation: anion gap + 2.5 × [4.4 – observed serum albumin (g/dL)]. Acute kidney injury was defined and staged on the basis of the latest Kidney Disease Improving Global Outcomes (KDIGO) criteria. The data were analysed via IBM SPSS Statistics 26 (SPSS Inc., Chicago, IL). The results of continuous variables are presented as the means with standard deviations or medians with ranges, whereas categorical variables are presented as numbers with percentages. The Institutional Ethics Committee of Dr. Cipto Mangunkusumo National Referral Hospital approved the study.

Results

Baseline characteristics of the 19 patients with confirmed or suspected ethylene glycol or diethylene glycol intoxication are summarized in Table 1. The cohort consisted of 10 males (52.6%) and 9 females (47.4%), with a median age of 21 months (IQR: 12–47.5). At the time of admission, patients had a median arterial pH of 7.489 (IQR: 7.376–7.516), consistent with the metabolic disturbances associated with toxic alcohol ingestion. Renal dysfunction was evident, with a median serum urea of 217.8 mg/dL (IQR: 115.5–252.5) and creatinine of 7.1 mg/dL (IQR: 5.05–9.5). Anuria had persisted for a median of 3 days (IQR: 1–4) prior to admission. Hepatic transaminases were elevated in most patients, with ALT and AST medians of 145 U/L (IQR: 76–170.5) and 135 U/L (IQR: 94.5–247), respectively. The median Glasgow Coma Scale (GCS) on admission was 13 (IQR: 11–15), and all patients had reduced or absent urine output before the first dose of fomepizole, with a median diuresis of 0 mL/kg/hour (IQR: 0–0.385).

Table 1 Baseline Demographic and Clinical Characteristics of 19 Patients who received Fomepizole (n=19)
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All patients who met the diagnostic criteria for EG/DEG intoxication were treated with fomepizole [7,8,9]. The dosage regimen for fomepizole followed the guidelines provided by the AATC. A loading dose of 15 mg/kg was administered, followed by four maintenance doses of 10 mg/kg over a period of 48 h. The administration of fomepizole was based on the patient’s clinical and laboratory conditions. After the initial five doses, the delivery of fomepizole was continued at a rate of 15 mg/kg every 12 h until the metabolic acidosis resolved. The dosage and administration schedule were adjusted on the basis of the AACT recommendations for hemodialysis patients [10].

The severity of illness and outcomes of the cohort are detailed in Table 2. KDIGO staging was applied to classify the degree of acute kidney injury, and critical care interventions including continuous renal replacement therapy (CRRT) and mechanical ventilation were recorded. Among the 19 patients, 94,7% were in KDIGO Stage 3, 84,2% required CRRT, and 68,4% were intubated. The overall mortality rate was 26.3%, with five deaths documented.

Table 2 Illness Severity and Critical Care Interventions in EG/DEG Exposed Patients
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Syrup medication was used prior to admission in all patients, typically administered for febrile illness or upper respiratory symptoms. All patients had documented use of syrup-based medications, including products that were subsequently confirmed by the Indonesian Ministry of Health to contain EG/DEG contaminants during the national toxic syrup investigation. Although exact ingestion timing could not be confirmed, the time from reported onset of anuria to hospital admission ranged from 0 to 8 days, with a median of 3 days (IQR 1–4), as summarized in Table 3. This finding suggests a consistent delay between toxic exposure and clinical presentation, highlighting the importance of early recognition in outbreak settings.

Table 3 Time Interval from Onset of Anuria to Hospital Admission
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A comparison of clinical and laboratory characteristics between deceased and surviving patients is presented in Table 4. Deceased patients tended to have lower GCS scores and more severe metabolic acidosis at admission, reflected by lower median pH values. Hepatic transaminases (AST and ALT) were markedly elevated in the deceased group, suggesting more profound hepatic injury. While urea and creatinine levels were elevated in both groups, deceased patients had slightly higher median values. Diuresis prior to fomepizole administration was lower in deceased patients, consistent with persistent anuria. Interestingly, although a greater proportion of survivors underwent CRRT, the duration from anuria onset to hospital admission was similar between groups, suggesting that factors beyond timing of presentation contributed to clinical outcomes.

Table 4 Comparison of Clinical Parameters between Deceased and Surviving Patients
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Temporal trends of clinical and laboratory parameters across treatment milestones were visualized using box-and-whisker plots (Figs. 1, 2, 3, 4, 5 and 6). These plots summarize patient values at key points during fomepizole administration and follow-up. The X-axis categories represent treatment phases, not continuous time intervals. At presentation, 5 out of 19 patients (26.3%) were lethargic in the ER, with a mean GCS of 12 ± 2.95 (Fig. 1). Two patients (12.5%) were already intubated upon admission. Mechanical ventilation was required in 13 patients, with a mean duration of 25 days (range: 2–51).

Fig. 1
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Glasgow Coma Scale (GCS) Trends Across Fomepizole Treatment Milestones

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Fig. 2
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Diuresis (mL/kg/hour) Trends Across Fomepizole Treatment Milestones

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Fig. 3
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Creatinine (mg/dL) Trends Across Fomepizole Treatment Milestones

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Fig. 4
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Urea (mg/dL) Trends Across Fomepizole Treatment Milestones

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Fig. 5
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AST (U/L) Trends Across Fomepizole Treatment Milestones

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Fig. 6
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ALT (U/L) Trends Across Fomepizole Treatment Milestones

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Lactate levels were measured in 12 patients and were elevated in all, with a mean of 1.9 ± 0.96 mmol/L (range: 0.8–4.3). In EG/DEG intoxication, oxalate crystal deposition in the kidneys often leads to anuria; therefore, renal function was closely monitored.

All patients had abnormal urea (Fig. 2) and creatinine (Fig. 3) levels, with a mean urea of 194.59 ± 97.5 mg/dL (range: 12.8–372.4) and creatinine of 7.25 ± 5.03 mg/dL (range: 0.2–23.5). Following the first dose of fomepizole, renal function began to improve. However, 4 out of 19 patients (21%) experienced a recurrence of renal impairment during the treatment course, which eventually resolved. The most significant improvements occurred after the second and first maintenance doses for urea and creatinine, respectively. Fourteen patients were discharged with improved kidney function, and one required ongoing hemodialysis for complete resolution.

All patients demonstrated improvement in urine output (Fig. 4) following the loading dose of fomepizole. However, anuria persisted in deceased patients. Only one of them showed transient improvement before returning to oliguria (< 0.2 mL/kg/hour) until death.

AST (Fig. 5) and ALT (Fig. 6) were elevated in all patients at baseline, indicating hepatic involvement. Mean AST was 187.9 ± 140.79 U/L (range: 17–496), and ALT was 201.1 ± 214.31 U/L (range: 10–748). While fomepizole can cause transient hepatotoxicity, only two patients (10.5%) had persistently elevated AST and four (21%) had elevated ALT at discharge. These patients were discharged with regular hepatic function follow-up.

Distinguishing between chronic low-dose exposure and acute EG/DEG poisoning is critical. The former results from unintentional repeated ingestion of small doses, while the latter typically involves a single large exposure and is more common in intentional overdoses. The mortality rate in this cohort was 26.3%, with five deaths recorded.

Of the 19 patients, five (26.3%) died during hospitalization. Their GCS on admission ranged from 10 to 15, with two presenting as altered. Three of the five required CRRT and four required intubation and mechanical ventilation. Admission pH values were generally lower in this group, ranging from 7.100 to 7.516, indicating varying severity of metabolic acidosis. Liver enzyme levels were elevated in all five patients, with ALT ranging from 78 to 297 U/L and AST from 85 to 298 U/L. While not all deaths could be definitively attributed to a single organ failure, the findings suggest a correlation between multi-organ involvement (including hepatic injury and severe acidosis) and poor outcomes. Fourteen patients were discharged from the hospital with complete recovery within an average of 52 days of hospitalization. However, one patient still requires long-term hemodialysis to ensure proper recovery.

Discussion

Ethylene and diethylene glycol poisoning is a life-threatening condition that requires prompt and accurate diagnosis [7, 9, 11]. Early detection is crucial, given its high morbidity and mortality rates when left untreated [9, 11]. Ethylene glycol is a common antifreeze component, and accidental ingestion or intentional self-harm can lead to poisoning [2, 12]. The mortality rate varies between 1% and 22% and is highest in patients with severe metabolic acidosis (pH < 7.1), high blood ethylene glycol levels, and delayed initiation of treatment (> 10 h). The presence of a serum osmolar gap can aid in diagnosis. However, over time, serum osmolality decreases as ethylene glycol is metabolized, while the serum anion gap increases, leading to anion gap acidosis and hyperosmolality, which can occur singly or in combination [13]. – [14] Therefore, a thorough understanding of the clinical presentation and timely laboratory tests are essential in managing this medical emergency. However, diagnosing EG/DEG poisoning can be difficult, leading to underdiagnosis and highlighting the need for increased awareness and vigilance. Metabolic acidosis is present in 86% of patients, making it challenging to obtain a medication history because of their decreased consciousness at admission. Measurements of EG/DEG levels may prove helpful, but it is not a viable option in emergency situations, as it takes several days to analyse. Within 8 to 24 h of consuming a lethal dose, the occurrence of oxalic acid and calcium oxalate monohydrate crystals can lead to cerebral edema and kidney failure due to blockage and injury to the tubular system. If left untreated, the ingestion of glycol can lead to multiorgan failure and death within 24–36 h [15]. The recommended course of treatment for pediatric patients with EG/DEG-associated acute kidney injury involves the simultaneous administration of renal replacement therapy and fomepizole. Our study described the clinical and laboratory features of 19 patients who suffered from AKI caused by EG/DEG intoxication and were treated with fomepizole as the preferred antidote by AACT.

All patients included in this study had commonalities, including anuria and a history of fever that led to the consumption of antipyretic syrup. Certain pharmaceutical compounds, such as paracetamol, are hydrophobic and require appropriate solvents for dissolution. Glycerol and propylene glycol are the preferred solvents because of their high solubility, nontoxicity, and compatibility with the human body. These solvents not only serve as dissolving agents but also provide additional benefits, such as antimicrobial activity, viscosity enhancement, and taste masking, making them ideal for liquid drug formulations. Unfortunately, some manufacturers engage in the illegal practice of substituting glycerol and propylene glycol with EG/DEG, a toxic substance, or lower-quality versions of nontoxic solvents that are contaminated with EG/DEG, which has led to incidents of poisoning. The lethal dosage threshold of DEG has yet to be determined, but it is estimated to fall between 0.014 and 0.35 mg/kg. It was not possible to determine the exact amount of DEG ingested by the patients, as it was unintentional. All patients presented to the emergency room with anuria, indicating that ingestion had occurred at least 24 h prior. Fomepizole and ethanol are inhibitors of ADH, an enzyme that mediates the metabolism of EG. By blocking this enzyme, the formation of toxic metabolites is reduced, making these two compounds effective antidotes for EG poisoning. In the past, ethanol was the primary treatment for DEG intoxication, but its efficacy and impact on ethylene glycol metabolism remain largely unknown. As a result, fomepizole was chosen as the preferred treatment for DEG intoxication, and we administered it to our patients [16,17,18]. We monitored the effectiveness of fomepizole through laboratory tests, specifically by checking urea and creatinine levels and conducting blood gas analysis before and after administering loading and maintenance doses of fomepizole. Our findings revealed that renal function decreased in 15 patients during fomepizole treatment, as evidenced by increased urea and creatinine levels, particularly after the first and fourth maintenance doses. These results align with those of a previous study that demonstrated decreased renal function in patients with stage 3 acute kidney injury caused by DEG intoxication who were treated with fomepizole [5].

Retrospectively analysing the plasma results, we observed a trend toward increased levels of urea and creatinine, which were subsequently reduced after the administration of fomepizole. Although there was an initial increase in both renal indicators, their levels eventually decreased as the fomepizole regimen was completed and hemodialysis was performed. Hemodialysis was performed in patients with severe metabolic acidosis (pH < 7.25), electrolyte imbalances, renal failure, and visual disturbances caused by ethylene glycol levels greater than 50 mg/dL. A comparison between deceased (n = 5) and surviving patients (n = 14) showed that deceased patients tended to have lower pH on admission (median 7.451 vs. 7.512), lower GCS scores, and higher transaminase levels (ALT 154 vs. 98 U/L; AST 243 vs. 135 U/L). While CRRT and intubation were common in both groups, three of five deceased patients had received CRRT, and four were intubated. These findings suggest that more severe metabolic derangement and hepatic dysfunction may be associated with mortality, although the small sample size limits statistical comparison. All the surviving patients showed improvement in kidney function. The patients were discharged, with five patients requiring routine kidney function checkups due to nonnormalized urea and creatinine levels, which improved. One patient still required hemodialysis. In a group of four patients who did not undergo hemodialysis, the lack of metabolite production (indicated by an absence of acidosis) suggested that plasma concentrations of EG exceeding 50 mg per deciliter could be safely managed with fomepizole treatment, as long as the patients had acceptable renal function. All patients showed diuresis improvement after being given the first loading dose of fomepizole, with surviving patients showing continued improvement. However, anuria persisted in all deceased patients, with only one patient showing slight diuresis improvement but eventually returning to an output of less than 0.2 ml/kg/hour until death. Although some patients presented with near-normal GCS and pH, mortality occurred in those who later progressed to multiorgan failure. This highlights the unpredictability and severity of EG/DEG toxicity, even in children who initially appear stable.

In patients who continued to experience metabolic acidosis and hypocalcemia despite receiving the complete fomepizole regimen, fomepizole administration was continued until both indicators were resolved. Multiple doses of fomepizole can result in a temporary increase in transaminase levels [19]. We closely monitored the hepatic function of our patients and discovered that only one patient had normal AST and ALT levels on admission. Despite some patients showing elevated AST and ALT levels after the fourth maintenance dose, all patients demonstrated an overall improvement in their AST and ALT levels following fomepizole treatment. The elevated levels eventually returned to normal levels. Although two patients still had high AST and ALT levels, they were eligible for discharge and advised to undergo routine follow-up for further hepatic function evaluation.

Our findings differed from those of previous studies that reported only slight increases in AST and normal ALT levels after six days of fomepizole administration. In our study, one patient had a 5-fold increase in ALT levels but normal AST levels. These results suggest that fomepizole treatment may cause a temporary increase in transaminase levels in some patients. However, close monitoring of hepatic function and routine follow-ups can help detect and manage any potential adverse effects of treatment. Further investigation is necessary, as the mechanism of the increase in transaminase levels needs to be elucidated. Although formal statistical testing was not feasible due to sample size, a descriptive comparison between survivors and non-survivors suggested that lower admission pH, higher liver transaminases, and lower GCS scores may be associated with increased mortality. This supports previous findings that early severe acidosis and hepatic dysfunction are predictors of poor outcome in toxic alcohol ingestion. Further study with a larger cohort would be necessary to clarify these associations.

Nonetheless, an increase in the ALT level is a conventional sign of minor liver injury. Repeated administration of certain drugs can cause mild and reversible increases in transaminase levels [19]. – [20] Although fomepizole is considered a safe and effective antidote for treating EG/DEG poisoning, some adverse effects have been reported in patients receiving fomepizole therapy. These effects include bradycardia, seizures, and headaches, but our clinical findings suggest that they are not directly related to fomepizole administration [11]. Notably, these side effects have not been previously reported in studies involving patients with DEG poisoning, where the most common adverse events were rash, high serum aminotransferase concentrations, and eosinophilia [11, 16]. Our study aligns with these previous findings, as we observed high serum aminotransferase concentrations in two patients who received fomepizole therapy [11]. Upon admission, lactate levels were measured in 11 patients, 7 of whom had abnormal results. However, elevated lactate levels may not always indicate a correct diagnosis because of the presence of glycolate, a metabolite that some chemical analyzers may misread, particularly blood gas analyzers. It is crucial to consider the possibility of false positives when interpreting lactate levels [21,22,23,24]. Thus, it is likely that a significant number of children were unknowingly exposed to EG/DEG poisoning during the initial phase of the outbreak.

This study has several limitations. First, its retrospective design limited our ability to control for confounding variables or collect prospective data such as precise ingestion history. Second, toxicology testing was not available for all patients, and in some cases, results were delayed, complicating correlation with clinical progression. Third, medication-specific data including dosage and exact concentrations of EG/DEG in syrups were not always accessible. Lastly, the small sample size and lack of a comparison group reduce the generalizability of our findings.

Conclusion

The findings of this study indicate that fomepizole is an effective antidote for treating EG/DEG intoxication, even if the patient ingests it periodically in consistent amounts. The clinical presentation of acute EG/DEG intoxication may vary depending on the time elapsed since ingestion, and the phases of intoxication may not occur in a sequence as previously thought. However, clinicians can establish a working diagnosis of EG/DEG intoxication by taking a patient’s history, including clinical course, history of syrup-based medication consumption, and laboratory findings, without waiting for blood toxicology test results. To improve the chances of survival, early diagnosis and treatment of EG/DEG poisoning are crucial. Therefore, we recommend administering fomepizole as soon as possible after diagnosis, as our studies have shown a significant reduction in mortality rates with earlier treatment.