Unintentional ethylene glycol ingestions in children

ABSTRACT Background: Toxic alcohol poisoning may result in severe acidemia and death. Previous work from our regional poison center (RPC) revealed that most pediatric unintentional methanol exposures are benign and do not require alcohol dehydrogenase (ADH) blockade or hemodialysis. Methods: We retrospectively reviewed all ethylene glycol (EG) cases in patients less than 6 years of age reported to our RPC over a 19 year period. We included unintentional ingestions with measured EG concentrations. Results: Twenty-nine cases met inclusion criteria. EG concentrations were undetectable in 25 cases (86%). No patient became symptomatic or acidemic. No EG concentration warranted treatment with ADH inhibition or hemodialysis. However, 21 patients (72%) received fomepizole or ethanol. Fifteen patients (52%) transferred from a community hospital to a pediatric specialty hospital. All 27 children admitted to the hospital went to a pediatric intensive care unit (PICU) while awaiting EG results. Conclusions: No child during the 19-year period required either antidote or hemodialysis. Unintentional EG exposures in typical pediatric patients may warrant nothing more than repeat laboratory testing (electrolytes, pH) to exclude evolving toxicity. Timely availability of EG laboratory test results would likely reduce unnecessary and expensive use of antidote, transport, and PICU resources.


Background
Ingestion of ethylene glycol (EG) can result in severe acidemia, end-organ dysfunction and death. The most common sources of household exposures are automotive products such as antifreeze, de-icers, and brake fluids, but it is also present in some solvents, detergents, inks, and fire extinguishers. Exposures are relatively rare. In 2018, there were 6,411 EG exposures reported to U.S. poison control centers, of which the majority were unintentional (4,990 or 78%) and 469 exposures occurred in children ≤ 5 years old [1].
Given the high morbidity which can occur in significant ingestions, pediatric exposures naturally generate a high degree of concern. However, in the population of very young children, exposures are almost exclusively exploratory or accidental, in which ingestion of only small volumes is expected.
Our center previously investigated unintentional methanol ingestions in pediatric patients and found that most exposures were benign and did not require alcohol dehydrogenase (ADH) blockade or hemodialysis [2]. The aim of the present study was to investigate the frequency and severity of unintentional EG ingestions in young children less than 6 years of age and to characterize the management of these patients. Several case reports of EG exposures in children [3][4][5][6][7][8][9] and retrospective studies [10,11] demonstrate the clinical features of EG poisoning in children and the safety of fomepizole therapy in children. However, to date, there are no retrospective studies that evaluate EG concentrations and outcomes in this age group.

Methods
We performed a retrospective analysis of unintentional ethylene glycol exposures reported to the Illinois Poison Center (IPC) between January 1, 2002 and December 31, 2020. The IPC covers the entire state of Illinois. We extracted all reported unintentional ethylene glycol exposures in patients < 6 years of age during the study period. We excluded cases in which no ethylene glycol concentration was obtained. We recorded the clinical characteristics of the exposures, including any symptoms present, available laboratory values, the frequency of treatment with ADH blockade and/or hemodialysis, frequency of inter-hospital transfer, and frequency of pediatric intensive care unit (PICU) admission. We analyzed data using descriptive statistics. The Cook County Health IRB deemed the study exempt from informed consent.

Results
There were 29 unintentional EG exposures in children ≤ 5 years old during the study period that met inclusion criteria. Only 4 patients (14%) had detectable EG concentrations, ranging from 2.5 to 14.9 mg/dL ( Figure 1). No patient met criteria for antidotal therapy or hemodialysis. However, 21 patients (72%) received ADH blockade while awaiting EG concentrations ( Figure 2). Nineteen patients received fomepizole, and two received ethanol infusions.
No patients in the study were symptomatic at any time. None of the patients developed acidemia. All documented basic metabolic panel (electrolytes, BUN, creatinine, glucose) and blood gas values were within the normal ranges. Fifteen patients (52%) were transferred to a facility capable of administering fomepizole and/or hemodialysis. The majority of patients were admitted (27 or 93%), and all of these went to a PICU ( Figure 2).

Discussion
Nineteen years of retrospective data from the IPC revealed 29 patients < 6 years of age who had negligible EG concentrations and did not warrant targeted management with ADH blockade or hemodialysis.
These findings highlight the discrepancy between the aggressive care that is often prescribed in these cases with the overwhelmingly benign presentations and outcomes that were seen in our study. In retrospect, all patients could have safely stayed in the ED or general pediatrics floor at their original facility with observation and serial laboratory monitoring. Limited resources such as PICU beds and expensive antidotes such as fomepizole can likely be spared in these patients who present asymptomatic with a straightforward history of an unintentional ingestion. The wholesale price of fomepizole from Mylan Institutional, a typical US supplier, is $1408 per 1.5 g vial [12].
However, a logistical challenge in these situations is obtaining an ethylene glycol concentration within a timely manner. These are typically specialty send-out specimens with a minimum turnaround time of approximately 6 h, not including transport time to an outside laboratory. This delay often creates angst among providers even when there is a low suspicion for a significant ingestion and frequently leads to conservative management (empiric antidotal therapy, monitoring in a PICU) until EG toxicity can be definitively ruled out. In spite of the laboratory delay, however, a logical approach in the asymptomatic patient with initially normal laboratory values would be observation with serial testing of electrolytes, pH, and lactate. At our institution, we repeat these tests over the course of 8-12 h and consider the patient medically clear if the pH and bicarbonate concentration remain stable. While there is no evidence to support use of this specific timeline, and institutional practice may vary, it does provide ample time for acidemia to develop. In our opinion, this effectively rules out ethylene glycol toxicity when the laboratory values are stable or improving.
While this study illustrates that unintentional EG ingestions in the youngest children are generally benign, cases involving an uncertain history or suspicion of abuse or neglect require caution. Unfortunately, intentional EG poisoning by caregivers may occur [7], and such cases may well be described to hospital staff as "accidental. " Additional case reports (generally all from outside of the US) describe EG products stored or decanted into beverage containers with resulting ingestion and severe toxicity in young children [8,9].
Finally, one question which comes up regarding unintentional EG ingestions in children is whether the addition of the bittering agent denatonium benzoate (DB, Bitrex®, Johnson Matthey, Edinburgh, Scotland) to commercial products has changed the incidence and outcomes of these exposures. Oregon was the first state to require the addition of DB to automotive products containing at least 10% ethylene glycol in 1991, and 17 states now require DB [13]. Illinois mandated it in 2011 [14]. Additionally, in 2012, the Consumer Specialty Products Association and the Humane Society Legislative Fund promised the voluntary addition of DB to all antifreeze products in the US. Multiple studies have found no change in the incidence or severity of pediatric exposures in the US after adding DB [13,15,16]. It is therefore unlikely that the presumed increasing use of DB over our study period was a factor in the benign outcomes. However, we do not know what proportion of the exposures involved EG containing DB.

Limitations
A strength of this study is that it examines the rare event of ethylene glycol ingestion with documented concentrations in the young pediatric patient over almost two decades. However, it has the inherent limitations common to all poison center studies. Case records in this database are from self-reported calls reflecting only the information provided when the public or healthcare professionals report an actual or potential exposure to EG. Some pediatric EG exposures may not be reported to poison centers, and potentially consequential events may have escaped our series. Additionally, our search may have missed cases due to incomplete product information or other documentation errors.

Conclusions
In this case series of 29 unintentional EG ingestions, few patients had detectable EG concentrations, and none required antidotal therapy or hemodialysis. However, most patients received ADH blockade (72%) and inter-hospital transfer (52%) to institutions with pediatric ICU units or dialysis capabilities. The above measures were unnecessary in all of these cases. Unintentional EG ingestions in young children may warrant nothing more than serial laboratory values and observation to ascertain the development of any signs of toxicity. More timely EG test results could reduce unnecessary antidote use, inter-hospital transfers, and PICU admissions.

Disclosure statement
No potential conflict of interest was reported by the authors.

Funding
The author(s) reported there is no funding associated with the work featured in this article.