Ethanol Intoxication-Related Metabolic and Biochemical Disturbances in Adolescents: A Matched Case- Control Study

doi:10.21203/rs.3.rs-1623833/v1

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Ethanol Intoxication-Related Metabolic and Biochemical Disturbances in Adolescents: A Matched Case- Control Study

https://doi.org/10.21203/rs.3.rs-1623833/v1

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Background: Alcohol is the most widely consumed substance by adolescents. However, only a few studies investigated metabolic and biochemical changes related with acute ethanol intoxication (AEI) with conflicting results. In this case-matched study, we aimed to investigate clinical and laboratory characteristics of the adolescents with AEI presented to pediatric emergency department (ED) at a tertiary referral center.

Methods: All consecutive adolescents with AEI (serum ethanol level >50 mg/dL) (n=335) and their sex- and age-matched control subjects with undetectable ethanol levels who presented to the pediatric ED between 2006-2019 were included in this case-matched study (a total of 670 patients). Demographic, clinical and laboratory data was collected through electronic health records retrospectively.

Results: Mean age was 16.0±1.5 years and M/F ratio was 1.5. Mean serum ethanol level was 156.4±58.4 mg/dl (range 50.8-341.2 mg/dl) in the AEI group. Glasgow coma scores were lower in the AEI group (14 [14-15] vs. 15 [15-15], p<0.001). Laboratory investigations revealed that acidosis (16.3%), hyperlactatemia (60.9%), hypoglycemia (1.7%), hypernatremia (2.2%), hypokalemia (12.3%), hyperchloremia (20.4%), hypocalcemia (13.9%), hypermagnesemia (9.7%), hyperalbuminemia (10.4%) were significantly more common in the AEI group as compared to the control group. Blood pH, lactate, Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺, albumin, BUN and uric acid levels were correlated with serum ethanol levels.

Conclusion: Being one of the largest case-matched study of AEI among adolescents published in the literature, this study shows that acute ethanol intoxication frequently leads to mild to moderate metabolic/biochemical derangements in adolescents. Clinicians should be aware of these findings in the management of AEI.

acute ethanol intoxication

adolescent

alcohol

biochemical

laboratory

metabolic

Alcohol is the most widely consumed substance by adolescents. A long-term study of substance use and related factors among US adolescents and adults revealed that by the end of high school, 59% have consumed alcohol at some time in their lives while 25% have done so by 8th grade(1). According to the Youth Profile of Turkey study, 15% of adolescents aged between 15–19 years in Turkey reported that they consumed alcohol at some point in their lifetime(2). Heavy episodic drinking prevalence among those aged between 15 to 19 in Turkey(3) was 0.9% which is lower than most European countries and the US(1,4).

Although minimum legal drinking age across Turkey is 18 years, acute ethanol intoxication (AEI) related emergency department (ED) visits occupy a considerable proportion of pediatric ED visits. As adolescents tend to use large volumes of alcohol, vulnerability to alcohol-related harm might be higher in adolescents than other age groups. In the emergency setting, AEI is mostly diagnosed in patients who present with its well-documented consequences including but not limited to alterations in mental status, need for urgent medical care, self-harm, use of illicit drugs, motor vehicle collisions, unintentional injuries, risky sexual behaviors, violence etc.(4–8).

In spite of the existing literature regarding different aspects of acute ethanol intoxication in children and adolescents, only a few studies investigated metabolic and biochemical changes related with AEI with conflicting results(9–13). Being one of the largest pediatric series of AEI in the literature, this study aimed to investigate and compare the clinical and biochemical characteristics of adolescent AEI cases with sex- and age-matched control subjects presenting to the pediatric ED at a single tertiary referral center.

2.1 Study design and setting:

This study was approved by the Institutional Ethics Committee (GO 17/468) and complies with the Helsinki Declaration. We conducted a retrospective, age and sex matched, case-control study to compare two cohorts of patients with or without acute ethanol intoxication who were evaluated at the pediatric ED between January 2006 and January 2019. Our institution is a high volume, academic tertiary referral center receiving around 80.000 pediatric emergency cases per year. In our pediatric ED, basic blood chemistry (including glucose, electrolytes, blood urea nitrogen (BUN), creatinine, uric acid, ALT, AST), blood gas analysis, serum ethanol levels are ordered for every patient presenting with altered mental status, new onset of psychiatric symptoms (i.e., psychosis and depression), attempted suicide, or alcohol and/or substance abuse suspicion. In selected patients, urine toxicological screen (including illicit and prescription drugs) is also performed.

2.2 Study groups and patient selection:

The patients were identified through screening of the institutional laboratory database. We reviewed all consecutive patients for whom blood ethanol (ETOH) level was ordered at the pediatric ED between January 2006 and January 2019. Patients aged between 10–18 years who were diagnosed with AEI (confirmed with a blood ETOH level > 50 mg/dL at initial evaluation(14)) were included in the AEI (case) group. This limit was chosen because it is legal limit of alcohol intoxication in most countries including Turkey. Also, it is well known that levels below 50 mg/dL is rarely associated with clinical intoxication symptoms in adolescents(14). Sex- and age-matched control subjects were sampled from those who had undetectable serum ethanol levels, using 1:1 matching (control group). Patients were excluded if (1) ETOH levels were between 10–50 mg/dL, (2) severe trauma, coma, cardiopulmonary arrest, illicit drug intoxication were present, (3) a known history of chronic medical conditions which may alter laboratory parameters, (4) medical records were insufficient (e.g., no blood gases and/or biochemistry results available). Study flow chart is presented in Figure I.

2.3 Data source and variables:

Data were extracted from patient charts and electronic health records. Collected data included age, sex, presentation date and day of the week, presentation type (via emergency medical services or other), presenting symptoms and findings, source of alcohol, past medical history, and laboratory results, which comprised serum ETOH levels, blood gas analyses (pH, pCO₂, lactate, bicarbonate), glucose, electrolytes (sodium, potassium, chloride, phosphate, calcium, magnesium), renal function tests (blood urea nitrogen (BUN), uric acid, creatinine), and liver transaminase levels, amylase and lipase levels if applicable. In addition, treatment during hospital course and discharge status was noted. Among presentation symptoms, behavioral change was used as an umbrella term for inappropriate behavior (i.e., aggressive, or combative behavior), unstable mood and impaired judgment.

The following reference values derived from the previous literature were used:(15,16)

Blood gas parameters (venous): pH: 7.31–7.41, partial pressure of carbon dioxide (pCO₂): 38–51 mmHg, lactate: 0.5–2.2 mmol/L, standard bicarbonate (HCO₃^-): 20–28 mmol/L.
Electrolytes: sodium (Na⁺): 135–145 mmol/L, potassium (K⁺) 3.4–4.7 mmol/L, chloride (Cl^-) 97–107 mmol/L, phosphate: 2.4–5.4 mg/dL, ionized calcium (Ca^+ 2) 1.12–1.32, total calcium (Ca^+ 2): 8.8–10.8 mg/dL for < 12 years, 8.4–10.2 mg/dL for > 12 years (corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL])), magnesium (Mg²⁺): 1.6–2.4 mg/dL.
Basic chemistry: glucose: 60–100 mg/dL, albumin 3.6–5.2 mg/dL, creatinine: 0.5-1.0 mg/dL, blood urea nitrogen (BUN) 5–18 mg/dL, uric acid 3.0-7.7 mg/dl for males, 2.7–5.7 for females, amylase: 25–101 U/L, lipase: 3–32 U/L. Reference values used for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) according to age and sex were taken from the previous literature(15,17).

2.4 Statistical analysis:

Statistical analyses were performed with IBM SPSS v23.0 program. Data were presented as mean ± standard deviation, median [IQR] or count (percentages), whenever appropriate. Students’ t-test, Mann-Whitney U and Chi-square tests were performed to detect the differences between two independent groups for parametric, nonparametric, and categorical variables, respectively. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated. A Pearson’s correlation was used to determine whether two continuous variables correlate with each other. A p-value below 0.05 was considered statistically significant.

3.1 Demographic and clinical characteristics:

A total of 1097 patients had serum ethanol levels studied within the study period. Eighty-four patients were excluded because of insufficient laboratory work-up. Among the remaining 1013 subjects, 51 patients had serum ethanol levels between 10–50 mg/dL and were excluded. There were 344 patients, who had serum ethanol levels higher than 50 mg/dL. Among these, four patients were excluded because of severe trauma, three due to confirmed narcotic intoxication and two due to diabetic ketoacidosis. A total of 335 patients were included in the AEI group. Control group consisted of age and sex matched 335 patients, whose serum ethanol levels were undetectable (< 10 mg/dL) on the initial presentation to the ED (Fig. 1).

Main demographic and clinical parameters are presented in Table 1. Mean age and sex distribution were similar in both groups. Five percent of patients (n = 17) were aged between 10–14 years while 95% (n = 318) was 14–18 years (for two groups combined). Almost half of the patients (45.1%) were transported to the ED by emergency medical services (i.e., ambulance), whereas family or friends accompanied the others. Proportion of patients transported to the ED by ambulance was similar among groups (48.4% vs. 41.8%, p = 0.088). Majority of the visits in the AEI group (58.2%) were encountered on weekends (Friday to Sunday) whereas in the control group the visits were distributed across days of the week more evenly (44.2% on weekends) (p = 0.006). Alcohol source was documented for 191 patients (57%). Vodka and beer were the most frequently consumed beverages (50% and 41.4%, respectively). Consumption of energy drinks together with alcohol was not frequent (only in 5 cases).

Table 1

Demographic and clinical parameters in two groups.
	AEI (n = 335)	Control (n = 335)	Total (n = 670)	p value
Age	16.1 ± 1.5	16.0 ± 1.5	16.0 ± 1.5	0.206
Sex, male	200 (59.7)	207 (61.8)	407 (60.7)	0.635
Brought by ambulance	162 (48.4)	140 (41.8)	302 (45.1)	0.088
Triage level (CTAS)				0.012
Level 1	3 (0.9)	5 (1.5)	8 (1.2)
Level 2	9 (2.7)	11 (3.3)	20 (3)
Level 3	190 (56.7)	226 (67.5)	416 (62.1)
Level 4–5	133 (39.7)	93 (27.8)	226 (33.7)
Glasgow Coma Score	14 [14–15]	15 [15–15]	15 [15–15]	< 0.001
Decreased level of consciousness	104 (31)	58 (17.3)	162 (2.4)	< 0.001
Nausea/vomiting/dizziness	99 (29.6)	31 (9.3)	130 (19.4)	< 0.001
Hypothermia	13 (3.9)	1 (0.3)	14 (2.1)	0.001
Trauma	68 (20.3)	115 (34.3)	183 (27.3)	< 0.001
Suicide attempt	28 (8.4)	50 (14.9)	78 (11.6)	< 0.001
Behavioral change	21 (6.3)	13 (3.9)	34 (5)	0.159
Prescription drug use (declared by patient)	8 (2.4)	47 (14)	55 (8.2)	< 0.001
*Drug screen (positive/all tested)**	6/59 (10.2)	37/92 (40.2)	43/151 (28.5)	< 0.001

Data are presented as mean ± SD for parametric, median [IQR] for nonparametric or n (%) for categoric variables.

* Indicates positive results for prescription drugs only.

In the AEI group three patients were triaged as needing to be seen immediately by medical staff (T1), nine as needing to be seen in 15 minutes (T2) and 125 as needing to be seen in 30 minutes (T3) whereas in the control group five patients were triaged as needing to be seen immediately by medical staff (T1), 11 as needing to be seen in 15 minutes (T2) and 226 as needing to be seen in 30 minutes (T3). Difference across triage levels was significant between two groups; control group included more Level 1–3 than AEI group (p = 0.012). Conversely, median Glasgow Coma Scale score was significantly lower in the AEI group compared to the control group (14 [14–15] vs. 15 [15–15], respectively, p < 0.001). Hypothermia (tympanic temperature < 35^o C) was evident in 13 (3.9%) patients with AEI and only one (0.3%) in the control group (p = 0.001).

The leading symptoms at presentation were the decreased level of consciousness (n = 104, 31%) and nausea/vomiting/dizziness (n = 99, 29.6%) in the AEI group and were more frequent than in the control group. However, trauma and suicidal attempt were more common in the control group (p < 0.001). Details of presentation characteristics are presented in Table 1. All patients were seen and treated by pediatric ED medical staff. However, 96 patients (AEI: n = 67, (20%), control: n = 29, (8.7%), p < 0.001) were additionally consulted with either a pediatric mental health specialist or adolescent health specialist or both in the ED.

3.2 Laboratory characteristics:

3.2.1 Ethanol levels:

In the AEI group, mean serum ethanol level was 156.4 ± 58.4 mg/dl (median 151, range: 50.8-341.2 mg/dl). Twenty-one subjects (6.3%) had extremely high ethanol levels (above 250 mg/dl).

3.2.2 Blood gases:

Mean blood pH and lactate levels were significantly different whereas pCO₂ and HCO₃ were similar between two groups (Table 2). Acidemia was significantly more common in the AEI group (16.3% vs. 2.5%, p < 0.001, OR: 7.467 (95% CI: 2.862–19.478)) whereas alkalemia prevalence was higher in the control group (15.8% vs. 32%, p < 0.001). Hypocapnia was a common finding in both groups (31% vs. 30.1%, p = 0.833). Hyperlactatemia (> 2.2 mmol/L) was significantly more prevalent in the AEI group (60.9% vs. 18.5%, p < 0.001, OR: 6.849 (95% CI: 4.545–10.309)). Lactic acidosis (lactate > 5 mmol/L and acidosis) was evident in 5.2% of AEI group while only 0.4% of the control group (p = 0.001) (Table 3).

Table 2

Mean values of laboratory parameters in two groups
	AEI (n = 335)	Control (n = 335)	Total (n = 670)	p value
Blood Gases
pH	7.37 ± 0.06	7.40 ± 0.05	7.38 ± 0.6	< 0.001
pCO₂	41.2 ± 7.5	40.4 ± 7.8	40.8 ± 7.7	0.329
Lactate	2.58 ± 1.66	1.39 ± 1.13	1.99 ± 1.54	< 0.001
HCO₃⁻	22.2 ± 2.0	21.5 ± 6.8	21.8 ± 4.9	0.140
Electrolytes
Na⁺	139.9 ± 2.6	138.0 ± 2.2	139.0 ± 2.6	< 0.001
K⁺	3.84 ± 0.42	3.95 ± 0.34	3.90 ± 0.38	< 0.001
Cl⁻	105.8 ± 2.7	104.2 ± 2.5	104.9 ± 2.7	< 0.001
Total Ca⁺⁺	9.4 ± 0.5	9.7 ± 0.5	9.6 ± 0.5	< 0.001
Corrected Ca⁺⁺	8.8 ± 0.8	9.1 ± 0.9	9.0 ± 0.9	< 0.001
Ionized Ca⁺⁺	1.13 ± 0.09	1.18 ± 0.8	1.15 ± 0.09	< 0.001
Phosphate	3.6 ± 0.9	3.7 ± 1.0	3.7 ± 1.0	0.360
Mg⁺⁺	2.2 ± 0.3	2.1 ± 0.2	2.1 ± 0.2	< 0.001
Biochemistry
Glucose	103.4 ± 22.1	104.1 ± 21.7	103.7 ± 21.9	0.713
Albumin	4.8 ± 0.4	4.6 ± 0.4	4.7 ± 0.4	< 0.001
Creatinine	0.69 ± 0.14	0.70 ± .014	0.70 ± 0.14	0.388
BUN	10.7 ± 3.2	12.6 ± 3.4	11.6 ± 3.4	< 0.001
Uric acid	5.7 ± 1.3	5.3 ± 1.6	5.5 ± 1.5	< 0.001
AST	26.4 ± 20.4	25.7 ± 17.3	26.0 ± 18.9	0.370
ALT	18.1 ± 16.7	17.1 ± 13.3	17.6 ± 15.0	0.631
AST/ALT ratio	1.65 ± 0.61	1.64 ± 0.55	1.65 ± 0.58	0.840

Table 3

Prevalence (percentage), odds ratio and 95% confidence interval of abnormal laboratory parameters in the AEI vs. control groups.
	AEI (n = 335)	Control (n = 335)	Total (n = 670)	p value	OR (95%CI)
Blood Gases
pH				< 0.001
Acidemia	16.3	2.5	9.7	< 0.001	7.467 (2.862–19.478)
Alkalemia	15.8	32	23.5	< 0.001	0.400 (0.246–0.641)
pCO₂				0.223
Hypocapnia	31.0	30.1	30.5	0.838	1.045 (0.685–1.595)
Hypercapnia	8	5.2	6.7	0.320	1.587 (0.708–3.559)
Lactate				< 0.001
Hypolactatemia	17.3	22.6	20.0	0.144	0.719 (0.462–1.121)
Hyperlactatemia	60.9	18.5	39.7	< 0.001	6.849 (4.545–10.309)
HCO₃⁻				0.301
Hypobicarbonatemia	12.1	13.7	12.9	0.625	0.866 (0.486–1.542)
Hyperbicarbonatemia	0.5	2.0	1.2	0.147	0.225 (0.025–2.037)
Electrolytes
Na⁺				0.01
Hyponatremia	1.6	3.3	2.5	0.145	0.460 (0.158–1.340)
Hypernatremia	2.2	0	1.1	0.007	NA
K⁺				< 0.001
Hypokalemia	12.3	2.7	7.4	< 0.001	4.972 (2.367–10.447)
Hyperkalemia	2.5	2.4	2.5	0.945	1.035 (0.384–2.793)
Cl⁻				< 0.001
Hypochloremia	0	0.9	0.5	0.251	NA
Hyperchloremia	20.4	7.7	13.8	< 0.001	3.067 (1.866–5.051)
Total Ca⁺⁺				< 0.001
Hypocalcemia	1.9	0.6	1.2	0.145	3.115 (0.624–15.550)
Hypercalcemia	4.7	16.2	10.5	< 0.001	0.255 (0.141–0.463)
Corrected Ca⁺⁺				< 0.001
Hypocalcemia	13.9	2.8	8.2	< 0.001	5.677 (2.722–11.840)
Hypercalcemia	0.3	0.6	0.5	0.579	0. 513 (0.046–5.682)
Ionized Ca⁺⁺				< 0.001
Hypocalcemia	30.8	16.0	23.6	0.001	2.337 (1.440–3.791)
Hypercalcemia	1.0	0.5	0.7	0.604	1.873 (0.169–20.833)
Phosphate				0.276
Hypophosphatemia	10.1	7.9	9.0	0.336	1.304 (0.758–2.242)
Hyperphosphatemia	2.8	4.6	3.7	0.245	0.610 (0.263–1.414)
Mg⁺⁺				0.006
Hypomagnesemia	0.7	0	0.4	0.304	NA
Hypermagnesemia	9.7	1.4	5.5	0.003	7.467 (1.652–33.751)
Biochemistry
Glucose				0.095
Hypoglycemia (< 60 mg/dL)	1.7	0	0.9	0.031	NA
Mild hyperglycemia (100–200 mg/dL)	47.9	47.6	47.8	0.935	1.014 (0.727–1.414)
Hyperglycemia (> 200 mg/dL)	0.3	0.7	0.5	0.519	0.462 (0.042–5.128)
Albumin				0.015
Hypoalbuminemia	0.3	1.2	0.8	0.186	0.253 (0.028–2.278)
Hyperalbuminemia	10.4	4.9	7.6	0.009	2.237 (1.205–4.149)
Creatinine				0.778
Low creatinine	7.0	6.7	6.9	0.881	1.048 (0.568–1.933)
High creatinine	1.9	2.7	2.3	0.485	0.691 (0.243–1.965)
BUN				0.001
Low BUN	1.9	0.3	1.1	0.051	6.351 (0.760–53.025)
High BUN	1.3	6.4	3.9	0.001	0.188 (0.064–0.554)
Uric acid				0.124
Hypouricemia	1.0	2.8	1.9	0.098	0.345 (0.093–1.288)
Hyperuricemia	16.6	13.0	14.7	0.196	1.337 (0.860–2.083)
AST
High AST	6.1	7.7	6.9	0.425	0.778 (0.419–1.443)
ALT
High ALT	5.4	3.7	4.5	0.296	1.493 (0.701–3.175)
AST/ALT ratio
>1	90.7	89.3	90.0	0.545	1.173 (0.699–1.972)
>2	16.7	16.9	16.9	0.945	0.985 (0.650–1.493)

3.2.3 Electrolytes:

Significant differences were detected in sodium, potassium, chloride, calcium (total, corrected and ionized), magnesium levels between the two groups (Table 2). Hypernatremia (2.2% vs. 0%, p = 0.007), hypokalemia (12.3% vs. 2.7%, p < 0.001, OR: 4.972 (95% CI: 2.367–10.447)), hyperchloremia (20.4% vs. 7.7%, p < 0.001, OR: 3.067 (95% CI: 1.866–5.051)), hypocalcemia (corrected total: 13.9% vs. 2.8%, p < 0.001, OR: 5.677 (95% CI: 2.722–11.840); ionized: 30.8% vs. 16.0%, p = 0.001, OR: 2.337 (95% CI: 1.440–3.791)) and hypermagnesemia (9.7% vs. 1.4%, p = 0.003, OR: 7.467 (95% CI: 1.652–33.751)) were significantly more common in the AEI group (Table 3).

3.2.4 Basic Biochemistry:

Mean serum glucose levels, mild hyperglycemia and hyperglycemia rates were not different between two groups. However, hypoglycemia was observed in 1.7% of the AEI group whereas no patient in the control group was hypoglycemic (p = 0.031). Mean serum albumin levels were slightly higher in the AEI group (4.8 ± 0.4 vs. 4.6 ± 0.4, p < 0.001). Similarly, hyperalbuminemia was more common in the AEI group (10.4% vs. 4.9%, p = 0.009). Creatinine levels were similar between two groups, whereas blood urea nitrogen levels were lower; uric acid levels were slightly higher in the AEI than control group. When abnormal levels were examined, only hyperuricemia was found to be more common in the control group (1.3% vs. 6.4%, p = 0.001). Liver transaminase (AST, ALT) levels were similar between the groups. High AST/ALT ratio (> 1) was very common finding in this study cohort with no difference between two groups. Amylase was studied in 90 patients (23 in AEI, 67 in control group). The groups did not differ in terms of high amylase levels (17.4% vs. 13.4%, p = 0.733). Lipase was studied in 41 patients (13 in AEI, 28 in control group) with no difference seen in the rates of high lipase levels between two groups (30.8% vs. 14.3%, p = 0.237).

3.2.5 Correlation of ethanol levels with other parameters:

Serum ethanol levels were negatively correlated with GCS, pH, K⁺, Ca²⁺, and BUN; but positively correlated with lactate, Na⁺, Cl⁻, Mg²⁺, albumin and uric acid levels (Table 4).

Table 4

Clinical and laboratory parameters significantly correlated with ethanol levels (r: correlation coefficient)
	Pearson’s r	p value
GCS	-0.340	< 0.001
pH	-0.286	< 0.001
Lactate	0.395	< 0.001
Na⁺	0.317	< 0.001
K⁺	-0.156	< 0.001
Cl⁻	0.278	< 0.001
Corrected Ca⁺⁺	-0.328	< 0.001
Ionized Ca⁺⁺	-0.279	< 0.001
Mg⁺⁺	0.230	< 0.001
Albumin	0.114	0.004
BUN	-0.228	< 0.001
Uric acid	0.170	< 0.001

3.3 Management of the patients with AEI:

In the AEI group 260 patients (77.6%) received intravenous hydration while 35 (10.4%) were treated with additional medications (antiemetics, proton-pump inhibitors). Majority of patients (n = 275, 82%) were followed up in the ED until resolution of the symptoms (median 6 hours). Sixty patients (18%) required either observation over 24 hours or hospitalization due to trauma, suicidal attempt or metabolic/biochemical consequences of AEI (i.e., severe acidosis).

This study summarized 13-year experience on acute ethanol intoxication of adolescent patients in a tertiary reference center in Turkey and adds a very large series of AEI investigating laboratory results of AEI in comparison to age and sex-matched controls. Here, we demonstrated metabolic and biochemical derangements associated with AEI in adolescents and their correlations with serum ethanol levels.

In the recent years, the frequencies of pediatric ED visits for acute ethanol intoxication have increased worldwide(18). We also observed a similar trend of increase throughout years. Most ED visits due to AEI were encountered during weekend period as expected. Males slightly dominated the study population, and the mean age of our patients was like that in other studies, but it is worrisome that there were 17 (5%) patients under the age of 14 years.

In the present study, decreased level of consciousness was more frequent in AEI group than control group. In addition, hypothermia and nausea/vomiting were more frequent in the AEI group. These findings were in line with the previous literature(10,19). However, associated trauma and suicide attempt were less frequent in the AEI group in our study. The inclusion of other intoxications (except for illicit drugs) and non-AEI associated trauma in the control group could underlie this difference and may represent a selection bias (i.e., cases with suicide attempt and trauma were routinely tested for ethanol levels as part of forensic medicine examination).

A well-described feature of AEI is the hyperlactatemia and mild acidosis(10). In the present study, AEI patients demonstrated lower blood pH levels, and higher lactate levels as compared to the control group. Indeed, odds of acidemia and lactatemia were nearly 7 times greater in the AEI group. On the other hand, pCO₂ and bicarbonate levels were in normal range and similar between two groups. Therefore our study confirms the findings of Bouthoorn et al. (19,20) who found more metabolic acidosis versus respiratory acidosis in contrast to Lamminpaa et al. (10,21) whose study involved predominantly respiratory acidosis in the AEI cases. Elevated lactic acid levels and/or lactic acidosis were frequently seen in our patients, a common finding also reported previously by others(12,22). Lactate levels > 5 mmol/L, which was previously shown to be associated with increased mortality in patients with AEI, was also more common (5.2% vs. 0.4%, p = 0.001) in our study group(23). However, there was no mortality or serious morbidity associated with critical lactate levels in our series. We showed a significant negative correlation of serum ethanol concentration with blood pH (Pearson’s r=-0.286, p < 0.001) and positive correlation with lactate levels (Pearson’s r = 0.395, p < 0.001) (Table 4). Other studies also demonstrated similar results previously(10–12,20,23,24). As a result of ethanol metabolism, oxidation of acetaldehyde to acetate increases intramitochondrial NADH/NAD + ratio, which account for both ketoacidosis and lactic acidosis in AEI(25). Furthermore, hypoperfusion and tissue hypoxia due to altered blood vessel tone secondary to ethanol-induced central nervous system depression together with hypothermia can lead to lactic acidosis(24,26). Besides, consequences of poisoning with other drugs like acetaminophen, carbon monoxide, methanol, or ethylene glycol, which can also lead to lactic acidosis are more severe in childhood. Nevertheless, although other toxicology was more common in the control group, lactic acid levels were higher in the AEI group suggesting that hyperlactatemia was more likely linked to ethanol-intoxication.

In our study population, neither hyperglycemia, nor hypoglycemia, was frequent. Hypoglycemia, albeit rare, was more common in the AEI group. Some older studies reported mild hypoglycemia in children, arguably due to low glycogen stores of younger children, preceding fasting period, as well as the inhibition of glycogenolysis and gluconeogenesis by alcohol(10,27). On the other hand, ethanol may exert differential effects on glycogenolysis and gluconeogenesis between fasted and fed states(28). However, other studies did not show a high rate of hypoglycemia. Indeed, recent studies found that mild hyperglycemia may be more common in the AEI(12,20,29). In our study, mild and overt hyperglycemia rates were similar between the AEI and control groups. Nevertheless, we found that almost half of the patients in both groups had slight elevations in blood glucose levels, which might represent stress-associated response with increased adrenaline, and cortisol levels(12,20,29).

The most common electrolyte disturbances in the AEI group were hyperchloremia (20.4%), hypocalcemia (corrected total 13.9%, ionized 30.8%), and hypokalemia (12.3%). Although less frequent, hypermagnesemia (9.7%) and hypernatremia (2.2%) were more frequent in the AEI vs. control group. The greatest odds ratios were found for hypokalemia (OR: 4.97), hyperchloremia (OR: 3.07), hypocalcemia (OR: 5.68) and hypermagnesemia (OR: 7.47). Bouthorn et al. found hyperchloremia in 31.1% and described this as the most frequent electrolyte disturbance. Our results confirm their findings. Hypokalemia was the most common electrolyte imbalance in some other studies(21). Hyperchloremia, hypernatremia, and hypokalemia were all attributed to volume depletion associated with AEI due to water deficit through diuresis and vomiting and activation of compensatory pathways. Slightly higher levels of albumin and higher rates of hyperalbuminemia (10.4% vs. 4.9%) in the AEI vs. control group may indicate mild dehydration associated with ethanol intoxication, but it is less likely that these alterations result in clinically significant effect. Interestingly, we found significantly more hypocalcemic (both total and ionized Ca²⁺ levels) patients in the AEI group, even after correction for albumin levels. This finding was not demonstrated in the pediatric AEI literature before. This might be due to transient hypoparathyroidism during the AEI as demonstrated by Laitinen et al.(30). They showed hypocalcemia, hypercalcuria, hypermagnesemia and hypermagnesuria along with decreased levels of parathyroid hormone during the acute phase of AEI in adults. This mechanism may explain both calcium and magnesium disturbances found in our patients with AEI.

Serum creatinine and uric acid levels were similar between groups, mostly within normal ranges. However, mean blood urea nitrogen levels were significantly lower in the AEI group compared to the controls, although abnormal levels were not so common. To the best of our knowledge, no significant changes in creatinine, uric acid and BUN has been reported to date in the pediatric AEI literature. However, in one study, researchers showed that low-dose infusion of alcohol acutely down-regulated urea synthesis in healthy individuals(31). This mechanism may explain slightly lower BUN levels in our study group as compared to the controls. Overall, our findings confirm that renal function parameters are largely unaffected by AEI in the pediatric population.

We sought to analyze whether liver enzymes were elevated in the setting of acute ethanol intoxication in pediatric population. It seems that only a few patients had mild increase (less than 5 times the upper limits) in AST and ALT. Interestingly, Binder et al.(32) showed that not individual liver enzymes but AST/ALT ratio is quite sensitive in detecting acute ethanol intoxication. They reported that 92.6% of 249 children and adolescents with AEI showed elevated AST/ALT ratio (> 1). Our results echo their findings with strikingly similar proportions (90.7%) of high AST/ALT ratio despite very few patients with elevated liver enzymes. However, age- and sex-matched control group presented to the pediatric ED in our study also showed similar rates of elevated AST/ALT ratio (89.3%). This indifference did not change when AST/ALT ratio > 2 (instead of > 1) was considered. Taken together, these results call into question the conclusions of Binder et al. (32) that this ratio may represent acute effects of alcohol-related injury to hepatocytes and can be clinically used as a marker for early reversible liver injury due to acute ethanol intoxication in addition to well-known alcoholic liver disease. On the contrary, elevation of AST/ALT ratio seems not specific to the AEI and may be linked to acute stress response or other mechanisms common to both groups. We think that selection of outpatient pediatric cases as controls may have masked to reveal this fact in the study of Binder et al.(32).

This is a single center retrospective case-control study spanning thirteen years. To our knowledge, this study is one of the largest of the published series of pediatric AEI investigating a wide range of biochemical results in comparison to matched controls. We included all consecutive patients with AEI. Their data was compared with that of sex- and age-matched control subjects with undetectable serum ethanol levels, who presented to the pediatric ED within the same study period. In addition to demographic and clinical characteristics, a wide array of blood tests including blood gases, electrolytes, renal and hepatic markers were collected and analyzed. Data completeness was satisfactorily high for both study groups. Limitations of this study are largely pertaining to its retrospective nature. Possible differences (reported and unreported) in some baseline characteristics of the two groups can be a limitation of this study, although we attempted to mitigate this by selecting 1:1 age- and sex-matched control group from among the pediatric ED patients with suspicion of AEI. Although sex- and age-matching was performed, it should be noted that control subjects were chosen from among those with undetectable ethanol levels; therefore, they represent only a small portion of pediatric emergency visits in which serum ethanol levels were studied. We excluded those with medical conditions that might affect biochemical results, which in turn, may have introduced a selection bias. Most statistical differences found in this study seems subtle and possibly clinically insignificant. This fact limits its generalizability and clinical applicability. However, given the strong correlation between ETOH levels and certain biochemical parameters it is evident that this study sheds further light on pathophysiology of AEI, and therefore these findings may be more valuable in more severe AEI cases.

This study shows that the laboratory alterations are common in adolescent AEI. Although they mostly seem subtle and possibly clinically insignificant for milder cases, the strong correlation between ETOH levels and certain biochemical parameters suggests that AEI is associated with a variety of biochemical derangements in a dose-dependent manner, and thus these findings may be more valuable for clinicians in managing more severe AEI cases.

AEI: acute ethanol intoxication

ALT: alanine aminotransferase

AST: aspartate aminotransferase

BUN: blood urea level

Ca⁺²: calcium

CI: confidence interval

Cl^-: chloride

CO₂: carbon dioxide

ED: emergency department

ETOH: ethanol

GCS: Glasgow Coma Score

HCO₃^-: bicarbonate

K⁺: potassium

Mg⁺²: magnesium

Na⁺: sodium

OR: odds ratio

pCO₂: partial carbon dioxide pressure

Ethics approval and consent to participate: Hacettepe University Faculty of Medicine Institutional Ethics Committee (GO 17/468) approved this study. Consent to participate was exempted due to the type of research (Hacettepe University Faculty of Medicine Institutional Ethics Committee (GO 17/468)). This study complies with the Helsinki Declaration.

Consent for publication: Not applicable

Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests: None

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors contributions:

DH: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Roles/Writing - original draft; CO: Data curation, Investigation; ECO: Data curation, Investigation; ZGD: Investigation, Supervision, Writing - review & editing; AP: Investigation, Supervision, Writing - review & editing; OT Conceptualization, Investigation, Methodology, Supervision, Visualization, Writing - review & editing.

Acknowledgements: The authors would like to thank Dr. Sahin Hanalioglu for statistical analyses.

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No competing interests reported.

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Ethanol Intoxication-Related Metabolic and Biochemical Disturbances in Adolescents: A Matched Case- Control Study

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Abstract

Figures

1. Background:

2. Materials And Methods:

2.1 Study design and setting:

2.2 Study groups and patient selection:

2.3 Data source and variables:

2.4 Statistical analysis:

3. Results:

3.1 Demographic and clinical characteristics:

3.2 Laboratory characteristics:

3.2.1 Ethanol levels:

3.2.2 Blood gases:

3.2.3 Electrolytes:

3.2.4 Basic Biochemistry:

3.2.5 Correlation of ethanol levels with other parameters:

3.3 Management of the patients with AEI:

4. Discussion:

5. Limitations:

6. Conclusion:

Abbreviations

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