Abstract
Background
Toxic alcohol exposures are an ongoing concern in the United States. In the US, few studies characterize the local epidemiology of toxic alcohols over time.
Objectives
The objective was to examine the incidence of toxic alcohol ingestions and changes in management over time.
Methods
This retrospective cohort study evaluates toxic alcohol ingestion phone calls to a regional poison center in the United States covering four states. Data were queried for this poison center from the National Poison Data System (NPDS) using generic codes for each toxic alcohol. Inclusion criteria were ingestion of toxic alcohol, age ≥ 13 years, from January 1, 2000 to Dec 31, 2017. Exclusion criteria were unrelated effects coded in the medical outcome, duplicate data, or incomplete demographic data.
Results
Of 926 subjects (adults and teenagers), 71.5% were male, and the mean age was 34.5 years. Toxic alcohol ingestion was more common in individuals younger than 40 years, with a significant relationship between age and intentional abuse or misuse (p = 0.001). There was also a significant relationship between age and reason for ingestion, with younger patients more likely to be suicidal (p < 0.001). Ethyleneglycol was the most common toxic alcohol. There was no change in the incidence of toxic alcohol ingestions over the study period. The mortality rate was 1.7%, and 31.2%of patients were hospitalized in a critical care unit. Major effects and death were more common in younger patients (p < 0.001). There was a significant difference in medical outcomes based on the type of toxic alcohol(p = 0.03). Fomepizole was the most common treatment. A Poisson regression model found no change in fomepizole use during the study period (p = 0.1). Ethanol administration over the study period increased (p = 0.02), while hemodialysis decreased (p = 0.02).
Conclusion
Data obtained from a single regional United States poison center showed low mortality related to toxic alcohol ingestions. The most prevalent toxic alcohol was Ethylene glycol. In all cases, toxic alcohol ingestion was higher in the 20-29-year-old age group. Reasons for ingestion, in most cases, were suicidal. Fomepizole was the most common treatment, ethanol administration as an antidote is rising, and hemodialysis utilization is decreasing. Data may not be nationally representative.
Graphical abstract
Keywords: Toxic alcohol, Fomepizole, Ethylene glycol, Methanol, Ethanol, United States
Introduction
Toxic alcohols generally refer to methanol, ethylene glycol (EG), diethylene glycol, isopropyl alcohol, and some definitions include ethanol [1, 15]. This chemical class is responsible for accidental and intentional exposures [1]. Exposure to ethylene glycol is the most common, followed by methanol and diethylene glycol (as brake fluid) [16]. Methanol intoxication in the United States is approximately 1000 to 2000 cases per year (approximately 1% of all poisonings) [17, 18]. The United States National Poison Data System (NPDS) report in 2018 described 7242 cases of ethylene glycol and 1607 cases of methanol exposure [19]. The mortality of toxic alcohol poisoning varies greatly because of the differences in the amount of alcohol consumed and treatment [16–18].
Methanol producing toxicity ranges from 15 to 500 ml of a 40% solution to 60 to 600 ml pure methanol [18]. The toxic dose of diethylene glycol was expected at 0.14 mg/kg body weight, and the fatal dose at 1 to 1.63 g/kg body weight [18, 20]. A potentially fatal dose of ethylene glycol is also about 1-2 mL / kg of a concentrated solution of 95%, or about 1500 mg / kg [18, 21, 22]. Some researchers had suggested that isopropanol concentrations >150 mg / dl produce a coma and hypotension and levels >200 mg / dl are incompatible with life [18, 23].
Toxic alcohol poisoning is a serious toxicological concern in the United States (US) and worldwide. It can cause significant morbidity and mortality without timely diagnosis and treatment [2]. Mass methanol poisoning from contaminated beverages are still reported [3, 4]. Methanol is metabolized into formic acid, which causes acidosis, retinal and optic nerve damage. Ethylene glycol is metabolized to glycolic acid, the main acid metabolite, and then to oxalic acid. The latter combines with calcium to form insoluble calcium oxalate monohydrate (COM), deposited in the renal tubules and causes kidney damage. Diethylene glycol is metabolized into 2-hydroxyethoxyacetic acid (HEAA), which produces acidosis, and then diglycolic acid, which accumulates in the kidney and is the nephrotoxic metabolite [16].
Since 1965, management has involved [5] ethanol, a competitive substrate of alcohol dehydrogenase (ADH) that prevents the metabolism of parent toxic alcohols to toxic metabolites [6]. The Food and Drug Administration (FDA) approved fomepizole (4-methylpyrazole) for EG poisoning in 1997 and methanol poisoning in 2000 [7, 8]. Fomepizole changed the management of toxic alcohol poisonings and reduced the need for hemodialysis [9]. Trials are scarce directly comparing ethanol to fomepizole for toxic alcoholpoisoning [10]; advantages of fomepizole include ease of administration, predictable pharmacokinetics, fewer adverse effects, and stronger ADH inhibition [5]. The 2002 American Academy of Clinical Toxicology practice guideline recommended fomepizolerather than ethanol. However, intravenous ethanol continues to be used in many countries due to fomepizole’s cost [11–13]. Folate, pyridoxine, and thiamine are treatment adjuncts, shunting EG and methanol metabolism toward less toxic metabolites [11, 14]. For EG poisoning, patients with normal renal function and an absence of acidosis may be treated with fomepizole alone, without hemodialysis (HD), despite high serum EG concentrations [2]. Toxic alcohol poisoning is an ongoing concern in the U.S. Ghannoum et al. evaluated characteristics of US toxic alcohol toxicity from 2000 to 2013; however, exposure patterns may vary regionally within the US, and management may vary based on antidote availability, institutional protocols, and poison center guideline variation [2].
In the US, few studies characterize the local epidemiology of toxic alcohols over time. As a result, granular epidemiologic data is scarce on toxic alcohol exposure and the management characteristics below the national level. Rocky Mountain Poison and Drug Safety (RMPDS) located in Denver, Colorado, is one of the largest poison centers in the United States, managing hundreds of thousands of calls each year.
The primary objective was to examine the incidence of toxic alcohol ingestions referred to as RMPDS in adults and teenagers over time. Secondary objectives were to characterize the most commonly reported toxic alcohol and investigate changes in managing toxic alcohol ingestions overtime in cases reported to one of the largest regional poison centers in the US.
Methods
This study was a retrospective cohort study, and all adults and teenagers’ ingestion calls were obtained due to toxic alcohol ingestion reported to the RMPDS which covers the four states of Colorado, Hawaii, Montana, and Nevada in the United States. Data were queried from the National Poison Data System (NPDS) using generic codes for methanol (excludes automotive and cleaning products) (031140), Automotive Products: Brake Fluid (201001), Automotive Products: Ethylene Glycol (includes antifreeze) (051221), Automotive Products: Glycol and Methanol Mixtures (051222), Automotive Products: Methanol (Windshield Washer, etc.) (031220), and Automotive Products: Other Glycols (051220). The following rarely used generic codes were not queried: Miscellaneous Cleaning Agents: Glycols (excludes automotive products), Miscellaneous Cleaning Agents: Methanol (excludes automotive products), Spot Removers/Dry Cleaning Agents: Glycols, Wall/Floor/Tile/All-Purpose Cleaning Agents: Glycols, and Wall/Floor/Tile/All-Purpose Cleaning Agents: Methanol.NPDS divided reported clinical effects in terms of relatedness to the exposure into 3 categories:1. Related to the exposure 2. Not related to the exposure 3. Unknown if related to the exposure.
Related to the exposure is coded when the timing of clinical effect is reasonable for reported exposure, the severity of the effect is consistent with reported exposure and effect is consistent with anticipated substance toxicity, and clinical assessment of relationship was made by a physician. However, it should be noted that an assessment of Related does not necessarily serve as confirmation of causality.
Not related to the exposure is when the effect was pre-existing or began prior to the exposure and was not augmented or worsened because of the exposure, or the effect can be attributed to a documented alternative etiology.
Unknown if related to the exposure is coded when the relationship between exposure and effect cannot be reasonably ascertained, the effect has never been ascribed to the substance, but an alternative etiology cannot be conclusively established, the effect is not expected based on reported exposure, Knowledge of patient’s history (e.g., concomitant illnesses, other medications) is not adequate to allow a determination of the relationship between the exposure and the effect.
Trained specialists systematically collect information in poison information centers, and cases are followed until outcomes can be determined. The American Association of Poison Control Centers (AAPCC) maintains the NPDS, which houses de-identified case records of self-reported information collected from callers during exposure management and poison information calls managed by the country’s poison control centers (PCCs). NPDS data does not reflect all exposures to a particular substance. Additional exposures may go unreported to PCCs; NPDS data should not be construed to represent the total incidence of US exposures to any substance. Exposures do not necessarily represent poisoning or overdose, and AAPCC cannot verify the accuracy of every report. Findings based on NPDS data do not reflect the opinions of AAPCC. Cases are reported to the poison center voluntarily by patients, caregivers, or healthcare professionals.
Inclusion criteria were cases of human exposure via ingestion to a toxic alcohol, age ≥ 13 years, from January 1, 2000, to Dec 31, 2017. Exclusion criteria were unrelated effects coded in the medical outcome, duplicate data, or incomplete demographic data. The year 2000 was chosen based on FDA approval of fomepizole for methanol.
Collected variables were sex, age, the reason for exposure, route, medical outcomes, level of healthcare, and treatments. NPDS categorized the reason of exposures to intentional, unintentional, other, and adverse reactions. Each of them has some subcategories. For example, intentional reasons have subcategories of suspected suicide, intentional abuse, misuse, and unknown. Intentional - Suspected suicidal: An exposure resulting from the inappropriate use of a substance for self-harm or self-destructive or manipulative reasons. Intentional - Misuse: An exposure resulting from the intentional improper or incorrect use of a substance for reasons other than pursuing a psychotropic effect. Intentional - Abuse: An exposure resulting from the intentional improper or incorrect use of a substance where the patient was likely attempting to gain a high, euphoric effect or some other psychotropic effect, including recreational use of a substance for any effect. Intentional- Unknown: An exposure that is determined to be intentional, but the specific motive is unknown.
Unintentional: any exposure with not a purpose of suicidal may consider unintentional and included: Unintentional-General, Unintentional-Misuse, Unintentional-Environmental (Any passive, non-occupational exposure that results from contamination of air, water, or soil.), Unintentional-Unknown (An exposure determined to be unintentional, but the exact reason is unknown.), and Unintentional-Occupational (Any exposure that occurs as a direct result of the person being on the job or in the workplace), respectively.
If the reason for exposure is neither unintentional and nor intentional, maybe categorize in the other category:
Other - Contaminant/tampering: The patient is an unintentional victim of a substance that has been adulterated (either maliciously or unintentionally) by introducing an undesirable substance. Other - Malicious: Patients who are victims of another person’s intent to harm them. Include cases where the individual thinks he has been poisoned by someone else, even with doubt about the patient’s psychological stability. Adverse Reaction: Unwanted effects due to an allergic, hypersensitivity, or idiosyncratic response to the active ingredient (s), inactive ingredient(s), or excipient of a drug, chemical, or other drug substance when the exposure involves the normal, prescribed, labeled or recommended use of the substance.
The full definitions for different exposure reasons can further be found in the NPDS coding manual version 3.1 [24].
In addition, signs and symptoms of alcohol poisoning were collected at the time of the initial call as part of the routine provision of poison center guidance. Only symptoms classified as “related to the exposure” were included for analysis.
Toxic alcohol ingestions were divided into three groups (methanol, EG, or multiple toxic alcohols). Treatments included fomepizole, intravenous fluid, hemodialysis, alkalization, intubation, pyridoxine (Vitamin B6), ethanol, or folate. Medical outcomes were classified as none, minor, moderate, or major effect, or death, based on standardized national classifications by NPDS at the time of the initial call [25]. In accordance with the guidelines and procedures of the Colorado Multiple Institutional Review Board for the Protection of Human Subjects, the principal investigator found that the analysis of NPDS data for this study does not meet the criteria for the research of human subjects pursuant to 45 CFR 46.102 (f) (2) and that no approval of the institutional review board was required.
Ethics approval
This study complies with national guidelines. It was done on a subset of data from the National Poisoning Data System (NPDS) database. The data obtained from NPDS were de-identified. According to the described guidelines and policies of the Colorado Multiple Institutional Review Board regarding Human Research protection policies and plans, the lead investigator realized that the NPDS data’s analysis for this research study does not fulfill the criteria for human subjects pursuant’s research to 45 Code of Federal Regulations (CFR) 46.102 (f) (2). Similarly, we found that no institutional review board’s approval was required.
Statistical analysis
Descriptive statistics included frequency, percentage, mean, and standard deviation. Chi-squared and two independent sample t-test were used to compare frequencies between categories. Poisson regression models were used to assess the effect of time (period of 18 years). Incidence of toxic alcohol ingestion was tended as proportions of each ingested toxic alcohol relative to total cases of toxic alcohol ingestion per year reported to the poison center. P values were based on Poisson regression. Estimation was based on the number of ingested toxic alcohol cases per 100 cases reported to the poison center. Analysis was performed using Microsoft Excel 2013 (Microsoft Corp, Redmond, Washington) and SPSS version 21 (IBM, Armonk, NY). All reported P values are two-sided, and P < 0.05 was considered statistically significant.
Results
Demographic characteristics
A total of 1278 toxic alcohol exposure cases were identified, of which 1009 were exposed via ingestion, and 926 cases were analyzed. Figure 1 depicts a flow diagram of subject inclusion.52.2% of cases were reported from Colorado, and the majority were male (71.5%). The mean age was 34.5 ± 14.4 years, and the two age groups with the most subjects were 20-29 years (31.2%) and 30-39 years (20.9%). In all cases, toxic alcohol ingestion was higher in the 20-29-year-old age group. Table 1 lists demographic characteristics.
Fig. 1.
Flow diagram of subject inclusion
Table 1.
Demographic characteristics of toxic alcohol ingestion reported to a regional poison center in the United States over 18 years (2000-2017)
| Total (100%) n = 926 |
Ethylene glycol (74.6%) n = 691 |
Methanol (22.7%) n = 210 |
Multiple toxic alcohols (2.7%) n = 25 |
P value | ||
|---|---|---|---|---|---|---|
| Sex | Male | 662 (71.5) | 504 (72.9) | 138 (65.7) | 20 (80.0) | 0.08 |
| Female | 264 (28.5) | 187 (27.1) | 72 (34.3) | 5 (20.0) | ||
| Age (years) | 13-19 | 48 (5.2) | 22 (3.2) | 20 (9.6) | 6 (24.0) | <0.001 |
| 20-29 | 288 (31.2) | 228 (33.0) | 48 (23.0) | 12 (48.0) | ||
| 30-39 | 193 (20.9) | 155 (22.5) | 34 (16.3) | 4 (16.0) | ||
| 40-49 | 177 (19.2) | 155 (22.5) | 22 (10.5) | 0 (0.0) | ||
| 50-59 | 151 (16.3) | 90 (13.0) | 60 (28.7) | 1 (4.0) | ||
| ≥60 | 67 (7.3) | 40 (5.8) | 25 (12.0) | 2 (8.0) | ||
| Reason of exposure | Intentional - Suspected suicidal | 304 (32.8) | 226 (32.7) | 69 (32.9) | 9 (36.0) | 0.8 |
| Intentional Abuse/Misuse | 103 (11.1) | 79 (11.4) | 23 (11.0) | 1 (4.0) | ||
| Unintentional/Other | 519 (56.0) | 386 (55.9) | 118 (56.2) | 15 (60.0) | ||
| Medical Outcome | Death | 16 (1.7) | 10 (1.4) | 6 (2.9) | 0 (0.0) | 0.03 |
| Major effect | 68 (7.4) | 47 (6.8) | 16 (7.7) | 5 (20.0) | ||
| Moderate effect | 298 (32.2) | 228 (33.0) | 58 (27.8) | 12 (48.0) | ||
| Minor effect | 543 (58.7) | 406 (58.8) | 129 (61.7) | 8 (32.0) | ||
| Level of healthcare | Treated and released | 338 (37.0) | 257 (37.7) | 74 (35.7) | 7 (28.0) | 0.28 |
| Admitted: critical care unit | 285 (31.2) | 215 (31.6) | 59 (28.5) | 11 (44.0) | ||
| Admitted: noncritical unit | 156 (17.1) | 112 (16.4) | 40 (19.3) | 4 (16.0) | ||
| Admitted: psychiatry facility | 24 (2.6) | 13 (1.9) | 9 (4.3) | 2 (8.0) | ||
| Lost to follow-up | 72 (7.9) | 53 (7.8) | 18 (8.7) | 1 (4.0) | ||
| Refused referral or did not arrive at facility | 38 (4.2) | 31 (4.6) | 7 (3.4) | 0 (0.0) | ||
Outcomes
Medical outcomes overall had 58.7% (n = 543) of patients with only minor effects. The mortality rate of toxic alcohol ingestions was 1.7% (n = 16) overall, comprising 1.4% (n = 10) for EG and 2.9% (n = 6) for methanol. Thirty seven percent (n = 338) of patients were treated and discharged, while 31.2% (n = 285) were hospitalized in a critical care unit. Patients who developed major effects or death (n = 84) were younger (mean 28.8 ± 15.7 years, versus 38.9 ± 14for patients with minor or moderate effects, p < 0.001).
Causes of ingestion
Regarding reasons for ingestion, 32.8% of cases overall were suicidal (n = 304). There were 103 international cases, including 71 cases of intentional abuse and 32 cases of intentional misuse. The Unintentional causes including 177, 141, 83, 10, and 3 cases of Unintentional-General, Unintentional-Misuse, Unintentional-Environmental, Unintentional-Unknown, and Unintentional-Occupational, respectively. The Adverse reaction - Other were 25 cases. Other – Malicious and Other - Contamination/tampering were 18 and 9 cases, respectively. There was a significant relationship between age and reason for ingestion, with younger patients more likely to be suicidal (p < 0.001). In addition, there was a significant difference between sex and reason for ingestion(p = 0.001); intentional abuse/misuse and unintentional/other reasons were more common in males, while suicidal intent was more common in females. There was also a significant relationship between intentional abuse/misuse and age (p = 0.001); intentional abuse/misuse was more common in 30-39 years, while patients ≥60 years had the lowest rate.
Toxic alcohols
Among the possible toxic alcohols, 691 cases (74.6%) involved EG, 210 (22.7%) involved methanol, and 25 (2.7%) involved multiple toxic alcohols. Figure 2 shows the overall trend in the incidence of ingestion of these categories of toxic alcohols during the study period. EG was most common, and Poisson regression did not show a significant trend in the incidence of toxic alcohol ingestion. There was no difference between males and females for concurrent ethanol plus EG ingestion (p = 0.09), but there was a difference for ethanol plus methanol ingestion (p = 0.03). There was also a significant difference in clinical effects between the types of toxic alcohols (p = 0.03); moderate effects were more common from ingesting multiple toxic alcohols, while minor effects were more common from methanol or EG alone.
Fig. 2.
Trended incidence of proportions of each ingested toxic alcohol relative to total cases of toxic alcohol ingestions per year reported to a regional poison center in the United States over 18 years (2000-2017). P-values are based on Poisson regression
Clinical manifestations
Table 2 presents the clinical manifestations of toxic alcohol poisoning; the most frequent signs and symptoms were gastrointestinal symptoms (n = 342, 36.9%), Central Nervous System symptoms (n = 241, 26%), and acidosis (n = 208, 22.5%).
Table 2.
Clinical effects in toxic alcohol poisonings reported to a regional poison center in the United States over 18 years (2000-2017)
| Clinical effect | Total (%) n = 926 |
Ethylene glycol (%) n = 691 |
Methanol (%) n = 210 |
Multiple toxic alcohols (%) n = 25 |
|---|---|---|---|---|
| Gastrointestinal symptoms | 342 (36.9) | 255 (36.9) | 79 (37.6) | 8 (32.0) |
| CNS symptoms | 241 (26.0) | 170 (24.6) | 62 (29.5) | 11 (36.0) |
| Acidosis | 208 (22.5) | 157 (22.7) | 42 (20.0) | 9 (36.0) |
| Local effects | 77 (8.3) | 62 (9.0) | 15 (7.1) | 0 (0.0) |
| Anion gap increased | 84 (9.1) | 64 (9.3) | 14 (6.7) | 6 (24.0) |
| Creatinine increased | 78 (8.4) | 68 (9.8) | 8 (3.8) | 2 (8.0) |
| Electrolyte abnormality | 66 (7.1) | 39 (5.6) | 20 (9.5) | 7 (28.0) |
| Visual defect | 54 (5.8) | 26 (3.8) | 26 (12.4) | 2 (8.0) |
| Osmole gap increased | 28 (3.0) | 17 (2.5) | 9 (4.3) | 2 (8.0) |
| Seizure | 17 (1.8) | 11 (1.6) | 6 (2.9) | 0 (0.0) |
CNS is central nervous system
Clinical effects were determined at the time of the call by the Specialist in Poison Information, based on National Poison Data System (NPDS) convention
Managements
Table 3 shows treatments provided by toxic alcohol. The most common treatment was fomepizole (38.9%, n = 360), with a utilization rate of 39.9%and 33.8% for EG and methanol poisoning, respectively. Table 4 displays the use of fomepizole, ethanol, and HD. Overall, 57.3% (n = 531) of patients received none of these treatments, while 1.7% received all three. Figure 3 shows the number of cases per 100 people treated with fomepizole, ethanol, or HD while controlling for the number of cases per year. Fomepizole was the most common of these three treatments. Based on a Poisson regression model, there was no change in administration rates (p = 0.1). Ethanol administration over the study period increased (p = 0.02), while hemodialysis decreased (p = 0.02). There was a significant difference in mortality rate of patients receiving different antidote (fomepizole, ethanol, HD) (p < 0.01). Most of the deaths happened in the group of fomepizole + ethanol + HD (Table 4).
Table 3.
Treatments for toxic alcohol ingestion reported to a regional poison center in the United States over 18 years (2000-2017)
| Treatment | Total (%) n = 926 |
Ethylene glycol (%) n = 691 |
Methanol (%) n = 210 |
Multiple toxic alcohols (%) n = 25 |
|---|---|---|---|---|
| Fomepizole | 360 (38.9) | 276 (39.9) | 71 (33.8) | 13 (52.0) |
| Intravenous fluid | 270 (29.2) | 207 (30.0) | 37 (17.6) | 6 (24.0) |
| Hemodialysis | 154 (16.6) | 11 (16.1) | 43 (8.9) | 7 (10.8) |
| Alkalization | 76 (8.2) | 51 (7.4) | 20 (9.5) | 5 (20.0) |
| Intubation | 78 (8.4) | 52 (7.5) | 21 (10.0) | 5 (20.0) |
| Pyridoxine (Vitamin B6) | 35 (3.8) | 32 (4.6) | 2 (1.0) | 1 (4.0) |
| Ethanol | 53 (5.7) | 33 (4.8) | 16 (7.6) | 4 (16.0) |
| Dilute/irrigate/wash | 167 (18.0) | 132 (19.1) | 34 (16.2) | 1 (4.0) |
| Folate | 23 (2.5) | 11 (1.6) | 11 (5.2) | 1 (4.0) |
| Other | 216 (23.3) | 157 (22.7) | 53 (25.2) | 6 (24.0) |
| Notherapy | 241 (26.0) | 178 (25.8) | 58 (27.6) | 5 (20.0) |
Table 4.
Use of fomepizole, ethanol, and hemodialysis for toxic alcohol ingestions reported to a regional poison center in the United States over 18 years (2000-2017)
| Treatment | Total (%) n = 926 |
Ethylene glycol (%) n = 691 |
Methanol (%) n = 210 |
Multiple toxic alcohols (%) n = 25 |
Death* (%) |
|---|---|---|---|---|---|
| HD alone | 8 (0.9) | 4 (0.6) | 4 (1.9) | 0 (0.0) | 0 (0.0) |
| Fomepizole alone | 209 (22.6) | 167(24.2) | 36 (17.1) | 6 (24.0) | 1 (0.5) |
| Ethanol alone | 22 (2.4) | 14 (2.0) | 6 (2.9) | 2 (8.0) | 0 (0.0) |
| HD + ethanol | 5 (0.5) | 3 (0.4) | 2 (1.0) | 0 (0.0) | 0 (0.0) |
| Fomepizole + HD | 125 (13.5) | 93 (13.5) | 27 (12.9) | 5 (20.0) | 9 (7.2) |
| Fomepizole + ethanol | 10 (1.1) | 5 (0.7) | 4 (1.9) | 1 (4.0) | 0 (0.0) |
| Fomepizole + ethanol + HD | 16 (1.7) | 11 (1.6) | 4 (1.9) | 1 (4.0) | 2 (12.5) |
| None | 531 (57.3) | 394 (57.0) | 127 (60.5) | 10 (40.0) | 4 (0.75) |
HD is hemodialysis
*p value < 0.001
Fig. 3.
Trends in the use of fomepizole, ethanol, and hemodialysis for ingested toxic alcohol poisoning at a regional poison center in the United States over 18 years (2000-2017). P values are based on Poisson regression
Discussion
Admissions due to alcohol-related intoxications in the US during18 years were analyzed in this study. The current study results showed no significant differences in the incidence of toxic alcohol ingestions between 2000 (a year when fomepizole was available for both EG and methanol in the United States) until 2017 in the US. Pieces of evidence suggest that the incidence of toxic alcohol consumption increases over time from the past to the present [26–28]. Alcohol policy can influence alcohol poisoning rates and economic conditions, which confirm geographical differences in alcohol-related admission rates [28]. In this study, approximately half of the subjects were younger than 40 years old; most were male; toxic alcohol ingestion rates were significantly higher in 20-29 years old. EG ingestion was significantly more common than methanol, and patients who developed major effects or death tended to be younger. These findings are similar to other US and United Kingdom (UK)‘s studies [13, 29]. EG is a component of antifreeze, polishes, cleansers, and coolants. It is widely commercially accessible, especially in regions such as Colorado, with high use of antifreeze in winter. One study found thatEG poisoned patients are more likely to experience major effects or death if they are older andmale [30]. Unintentional ingestion accounted for the greatest proportion of toxic alcohol exposures. Other studies have demonstrated that age ≥ 18 years, female sex, and ingestion route are correlated with intentional EG exposure [30]. Several US states have laws requiring the addition of denatonium benzoate (a bittering agent) to EG in an attempt to decrease intentional ingestion; however, it has not been shown effective in reducing ingestions, so it is unlikely to account for differences between national and regional findings [31].
Mortality in this study was low (1.7% overall, 1.4% for EG, 2.9% for methanol). Mortality for EG exposure varies globally; Tanasescu et al. found a mortality rate of 27% in Romania, while Ghannoum et al. reported a mortality rate of 2.4% in the US [2, 32]. White (2020) examined patterns of alcohol-related deaths between 1999 and 2017 using death certificates and found the number of alcohol-related mortality doubled in the US Alcohol also accounted for 2.6% of roughly 2.8 million deaths in the United States in 2017 [33]. Jobson et al. evaluated 45,097 individuals who reported EG exposure in the US from 2006 through 2013. They found a mortality rate < 1%, and that mortality was higher in males [30]. Other studies have shown high mortality rates in methanol outbreaks; in a methanol poisoning outbreak in Libya mortality rate was 10% [34]. Mortality rates of 29% and 21% were reported in two outbreaks in Kenya. Two methanol poisoning outbreaks in Iran had mortality rates of 11% and 8% [4, 34, 35]. In the US, mortality from methanol is lower, which may be from improved supportive care and the availability of fomepizole. The mortality rate in the current study is low compared with other studies on toxic alcohols, which may relate to differences in patient population, regional product availability containing toxic alcohols, or institutional practices.
In this study, the most common signs and symptoms of toxic alcohol were gastrointestinal symptoms, CNS symptoms, and acidosis. Abdominal pain, nausea, vomiting, and altered mental state are the most common symptoms found in about 25 to 37% of alcohol-related admissions [18, 36]. Neurological abnormalities like confusion, stupor, and coma often occur in alcohol poisoning [18, 37]. Methanol, ethylene glycol, diethylene glycol, and propylene glycol intoxication can also cause hyperosmolality and metabolic acidosis [18]. The onset and severity of clinical and laboratory abnormalities largely depend on the production of formic acid [11, 18, 38]. It is even confirmed that metabolic acidosis correlates directly with blood formate concentrations [39, 40]. The severe neurologic dysfunction and visual abnormalities often occur in patients with severe metabolic acidosis [18, 38, 41, 42]. In this study, 42.7% of patients received fomepizole, ethanol, or hemodialysis. 22.6% of whom received fomepizole alone, 2.4% received ethanol alone, and 13.5% received a combination of hemodialysis and fomepizole. A national US study that also used NPDS data reported similar results of ethanol administration to 2.7% of methanol and EG exposure cases, whilefomepizolewas given in approximately 10% of cases, andhemodialysis was provided to 3.4% of methanol and 6.7% of EG cases [19]. Given the narrower sample, the use of fomepizole at our regional poison center was higher than national utilization (22.6 vs. 10%), which may relate to the difference in patient population or institutional practices. Fomepizole has clear advantages in terms of ease of administration, predictable pharmacokinetics, rarer side effects, reduced risk of medication errors, improved tolerability in use over a longer period, and stronger inhibition of ADH. Unfortunately, fomepizole costs significantly more than ethanol [2]. Due to fomepizole’s safety, effectiveness, and availability in the US, fomepizole administration was more common than ethanol and HD during the study period. In the UK, in 2012, ethanol administration was ten times more common than fomepizole [13, 29]. For toxic alcohol poisoning, particularly methanol, hemodialysis is an effective treatment. The decision for hemodialysis should balance the expense and complications of HD to ethanol or fomepizole [43]. Ghannoum et al. investigated US trends in toxic alcohol poisonings using NPDS data and found thatin early EG poisoning, particularly when fomepizole is administered, the use of hemodialysis has declined over time [2]. However, a similar trend for early methanol poisoning was not observed in that study. In the current study, there was no change in the use offomepizoleover the study period. Therapeutic ethanoluse for toxic alcohol ingestionsincreased at our regional poison center over this period,while hemodialysis use decreased.
The selection of ethanol or fomepizole to prevent metabolism by ADH of toxic alcohol largely depends on availability and cost, which may explain the use of ethanol in some hospitals. However, ethanol and fomepizole were similarly effective based on data from a methanol outbreak in the Czech Republic [44]. Notably, a Poisson regression model found that rates of fomepizole administration did not significantly change during the study period. Thus, although the trend in ethanol administration increased, ethanol use as an antidote is negligible in the US, with utilization much lower than fomepizole or HD. In our study, there was a significant difference in mortality rate of patients receiving different antidote (fomepizole, ethanol, HD). Most of the deaths happened in the group of fomepizole + ethanol + HD. However, considering that the interventions (i.e., hemodialysis, ethanol, fomepizole) were generally needed to treat the patients who experienced serious outcomes, any relationship between treatment and outcome should be interpreted cautiously.
This study has several limitations; the NPDS database does not generally include laboratory data, which hampers a more robust analysis of outcomes. Furthermore, although calls from home comprised many calls, training medical staff usually provides management information such as HD and antidote administration. In some cases, HD may have been used for reasons other than to treat toxic alcohol poisoning (e.g., kidney injury or elimination of a co-ingesting amenable to HD removal). Finally, the current study has a biased sample and is not necessarily nationally representative. Besides, due to a relatively low mortality rate, we could not evaluate an accurate comparison of the efficacy of different treatments.
Conclusion
Data from a single regional United States poison center that serves four states demonstrates low mortality from toxic alcohol ingestions. There were no significant differences in the incidence of toxic alcohol ingestions between 2000 (when fomepizole was available for both EG and methanol in the United States) until 2017. Intentional exposure to EG recreational use of methanol remained a significant issue. Fomepizole is the most common treatment in our region, while ethanol administration is increasing. Our study showed that toxic alcohol poisoning, especially ethylene glycol poisoning, should be considered a priority for health policy authorities. In addition, local medical toxicologists should provide educational plans regarding the proper treatment of toxic alcohol. This study analyzed admissions due to toxic alcohol-related poisoning in 18 years in the United States. The results of this study can help complete the picture of toxic alcohol-related intoxication worldwide. However, a larger dataset may be needed to generalize the data.
Author contributions
OM, CH, JS, AH contributed to the manuscript’s conceptualization, design, and preparation. OM, CH, JS, AH conducted the data collection and contributed to acquisition and interpretation. JS, SN, SB, AH, and OM made substantial contributions to drafting the manuscript and revising it critically for important intellectual content. All authors have read and approved the final version of the manuscript.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Ng PC, Long BJ, Davis WT, et al. Toxic alcohol diagnosis and management: an emergency medicine review. Intern Emerg Med. 2018;13(3):375–383. doi: 10.1007/s11739-018-1799-9. [DOI] [PubMed] [Google Scholar]
- 2.Ghannoum M, Hoffman RS, Mowry JB, et al. Trends in toxic alcohol exposures in the United States from 2000 to 2013: a focus on the use of antidotes and extracorporeal treatments. Semin Dial. 2014;27(4):395–401. doi: 10.1111/sdi.12237. [DOI] [PubMed] [Google Scholar]
- 3.Hekmat R, Samini F, Dadpour B, et al. Should guidelines for conventional hemodialysis initiation in acute methanol poisoning, be revised, when no fomepizloe is used? Iran Red Crescent Med J. 2012;14(11):743. doi: 10.5812/ircmj.3467. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Hassanian-Moghaddam H, Nikfarjam A, Mirafzal A, et al. Methanol mass poisoning in Iran: role of case finding in outbreak management. J Public Health. 2015;37(2):354–359. doi: 10.1093/pubmed/fdu038. [DOI] [PubMed] [Google Scholar]
- 5.Lepik KJ, Levy AR, Sobolev BG, et al. Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole. Annals of emergency medicine. 2009;53(4):439-450. e10. [DOI] [PubMed]
- 6.Wacker WE, Haynes H, Druyan R, et al. Treatment of ethylene glycol poisoning with ethyl alcohol. JAMA. 1965;194(11):1231–1233. doi: 10.1001/jama.1965.03090240065018. [DOI] [PubMed] [Google Scholar]
- 7.Brent J, McMartin K, Phillips S, et al. Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med. 1999;340(11):832–838. doi: 10.1056/NEJM199903183401102. [DOI] [PubMed] [Google Scholar]
- 8.Brent J, McMartin K, Phillips S, et al. Methylpyrazole for toxic alcohols study group Fomepizole for the treatment of ethylene glycol poisoning. New Eng J Med. 1999;340:832–838. doi: 10.1056/NEJM199903183401102. [DOI] [PubMed] [Google Scholar]
- 9.Hovda K, Jacobsen D. Expert opinion: fomepizole may ameliorate the need for hemodialysis in methanol poisoning. Human & Experimental Toxicology. 2008;27(7):539–546. doi: 10.1177/0960327108095992. [DOI] [PubMed] [Google Scholar]
- 10.Beatty L, Zed P, Magee K, Kanji S, Green R. Fomepizole versus ethanol in the treatment of toxic alcohol intoxication: a systematic review. CJEM. 2010;12(3):269. [Google Scholar]
- 11.Barceloux DG, Randall Bond G, Krenzelok EP, et al. American Academy of clinical toxicology practice guidelines on the treatment of methanol poisoning. J Toxicol Clin Toxicol. 2002;40(4):415–446. doi: 10.1081/CLT-120006745. [DOI] [PubMed] [Google Scholar]
- 12.Sturkenboom M, Van Rieke H, Uges D. Treatment of ethylene glycol and methanol poisoning: why ethanol? Netherlands Journal of Critical Care. 2009;13(6):297–302. [Google Scholar]
- 13.Thanacoody RH, Aldridge G, Laing W, et al. National audit of antidote stocking in acute hospitals in the UK. Emerg Med J. 2013;30(5):393–396. doi: 10.1136/emermed-2012-201224. [DOI] [PubMed] [Google Scholar]
- 14.Barceloux D, Krenzelok E, Olson K, et al. American Academy of clinical toxicology practice guidelines on the treatment of ethylene glycol poisoning. Ad hoc committee. J Toxicol Clin Toxicol. 1999;37(5):537–560. doi: 10.1081/CLT-100102445. [DOI] [PubMed] [Google Scholar]
- 15.Hassanian-Moghaddam H, Zamani N. A brief review on toxic alcohols: management strategies. Iranian Journal of Kidney Diseases. 2016;10(6):344. [PubMed] [Google Scholar]
- 16.McMartin K, Jacobsen D, Hovda KE. Antidotes for poisoning by alcohols that form toxic metabolites. Br J Clin Pharmacol. 2016;81(3):505–515. doi: 10.1111/bcp.12824. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Gallagher N, Edwards FJ. The diagnosis and management of toxic alcohol poisoning in the emergency department: a review article. Adv J Emerg Med. 2019;3(3). [DOI] [PMC free article] [PubMed]
- 18.Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol. 2008;3(1):208–225. doi: 10.2215/CJN.03220807. [DOI] [PubMed] [Google Scholar]
- 19.Gummin DD, Mowry JB, Beuhler MC, et al. 2019 annual report of the American association of poison control centers’ National Poison Data System (NPDS): 37th annual report. Clin Toxicol. 2020;58(12):1360–1541. doi: 10.1080/15563650.2020.1834219. [DOI] [PubMed] [Google Scholar]
- 20.Ferrari LA, Giannuzzi L. Clinical parameters, postmortem analysis and estimation of lethal dose in victims of a massive intoxication with diethylene glycol. Forensic Sci Int. 2005;153(1):45–51. doi: 10.1016/j.forsciint.2005.04.038. [DOI] [PubMed] [Google Scholar]
- 21.Iqbal A, Glagola JJ, Nappe TM. Ethylene Glycol Toxicity. [Updated 2020 Aug 14]. 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537009/. [PubMed]
- 22.Eder AF, McGrath CM, Dowdy YG, et al. Ethylene glycol poisoning: toxicokinetic and analytical factors affecting laboratory diagnosis. Clin Chem. 1998;44(1):168–177. doi: 10.1093/clinchem/44.1.168. [DOI] [PubMed] [Google Scholar]
- 23.Zaman F, Pervez A, Abreo K. Isopropyl alcohol intoxication: a diagnostic challenge. American Journal of Kidney Diseases. 2002;40(3):e12. 1-e12. 4. [DOI] [PubMed]
- 24.American Association of Poison Control Centers. National poison data system (NPDS): NPDS coding users’ manual version 3.1 [Online]. Alexandria (VA): American Association of Poison Control Centers; 2014. [cited 2018 Oct 23]. Available from: https://prod-knowledge-repository.s3-us-gov-west-1.amazonaws.com/references/NPDS%20Coding%20Users%20Manual%20%28May%202014%29.pdf.
- 25.Gummin DD, Mowry JB, Spyker DA, et al. 2017 annual report of the American Association of Poison control centers’ National Poison Data System (NPDS): 35th annual report. Clin Toxicol. 2018;56(12):1213–1415. doi: 10.1080/15563650.2018.1533727. [DOI] [PubMed] [Google Scholar]
- 26.Khadem Rezayian M, Afshari R. Alcohol intoxication: an emerging public health problem. Asia Pacific Journal of Medical Toxicology. 2017;6(1):1–5. [Google Scholar]
- 27.Brusin KM, Nekhoroshkov RO. A 13-year retrospective study on toxic alcohol poisoning in middle Urals, Russia. Asia Pacific Journal of Medical Toxicology. 2015;4(1):43–46. [Google Scholar]
- 28.World Health Organization . Global status report on alcohol and health 2018. Geneva, Switzerland: WHO Press; 2019. [Google Scholar]
- 29.Perera N, Eddleston M. Hill S, et al. Characteristics and management of poisoning with ethylene glycol and methanol in the United Kingdom Clinical Toxicology. 2010;48(3):290–290. [Google Scholar]
- 30.Jobson MA, Hogan SL, Maxwell CS, et al. Clinical features of reported ethylene glycol exposures in the United States. PLoS One. 2015;10(11):e0143044. doi: 10.1371/journal.pone.0143044. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.White NC, Litovitz T, White MK, et al. The impact of bittering agents on suicidal ingestions of antifreeze. Clin Toxicol. 2008;46(6):507–514. doi: 10.1080/15563650802119700. [DOI] [PubMed] [Google Scholar]
- 32.Tanasescu A, Macovei R, Tudosie M. Outcome of patients in acute poisoning with ethylene glycol-factors which may have influence on evolution. J Med Life. 2014;7(Spec Iss 3):81. [PMC free article] [PubMed]
- 33.White AM, Castle IJP, Hingson RW, et al. Using death certificates to explore changes in alcohol-related mortality in the United States, 1999 to 2017. Alcohol Clin Exp Res. 2020;44(1):178–187. doi: 10.1111/acer.14239. [DOI] [PubMed] [Google Scholar]
- 34.Rostrup M, Edwards JK, Abukalish M, et al. Correction: the methanol poisoning outbreaks in Libya 2013 and Kenya 2014. PLoS One. 2016;11(6):e0157256. doi: 10.1371/journal.pone.0157256. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Massoumi G, Saberi K, Eizadi-Mood N, et al. Methanol poisoning in Iran, from 2000 to 2009. Drug Chem Toxicol. 2012;35(3):330–333. doi: 10.3109/01480545.2011.619193. [DOI] [PubMed] [Google Scholar]
- 36.Wrenn KD, Slovis CM, Minion GE, et al. The syndrome of alcoholic ketoacidosis. Am J Med. 1991;91(2):119–128. doi: 10.1016/0002-9343(91)90003-G. [DOI] [PubMed] [Google Scholar]
- 37.Bennett IL, Jr, Cary FH, Mitchell GL, Jr, et al. Acute methyl alcohol poisoning: a review based on experiences in an outbreak of 323 cases. Medicine. 1953;32(4):431–463. doi: 10.1097/00005792-195312000-00002. [DOI] [PubMed] [Google Scholar]
- 38.Jacobsen D, McMartin KE. Methanol and ethylene glycol poisonings. Medical Toxicology. 1986;1(5):309–334. doi: 10.1007/BF03259846. [DOI] [PubMed] [Google Scholar]
- 39.Kerns W, Tomaszewski C, McMartin K, et al. Formate kinetics in methanol poisoning. J Toxicol Clin Toxicol. 2002;40(2):137–143. doi: 10.1081/CLT-120004401. [DOI] [PubMed] [Google Scholar]
- 40.McMartin KE, Ambre JJ, Tephly TR. Methanol poisoning in human subjects: role for formic acid accumulation in the metabolic acidosis. Am J Med. 1980;68(3):414–418. doi: 10.1016/0002-9343(80)90113-8. [DOI] [PubMed] [Google Scholar]
- 41.Hovda KE, Hunderi OH, TAFJORD AB, et al. Methanol outbreak in Norway 2002–2004: epidemiology, clinical features and prognostic signs. J Intern Med. 2005;258(2):181–190. doi: 10.1111/j.1365-2796.2005.01521.x. [DOI] [PubMed] [Google Scholar]
- 42.Paasma R, Hovda KE, Tikkerberi A, et al. Methanol mass poisoning in Estonia: outbreak in 154 patients. Clin Toxicol. 2007;45(2):152–157. doi: 10.1080/15563650600956329. [DOI] [PubMed] [Google Scholar]
- 43.Roberts DM, Yates C, Megarbane B, et al. Recommendations for the role of extracorporeal treatments in the management of acute methanol poisoning: a systematic review and consensus statement. Crit Care Med. 2015;43(2):461–472. doi: 10.1097/CCM.0000000000000708. [DOI] [PubMed] [Google Scholar]
- 44.Zakharov S, Rulisek J, Nurieva O, et al. Intermittent versus continuous renal replacement therapy in acute methanol poisoning: comparison of clinical effectiveness in mass poisoning outbreaks. Ann Intensive Care. 2017;7(1):1–11. doi: 10.1186/s13613-017-0300-7. [DOI] [PMC free article] [PubMed] [Google Scholar]