Ethanol elimination kinetics following massive ingestion in an ethanol naive child

Abstract

Objective:

At low-to-moderate concentrations, ethanol elimination follows zero-order kinetics. It is unknown whether renal, pulmonary or other first-order processes become significant in patients with very high serum ethanol concentrations. Additionally, it is unclear whether ethanol naive subjects induce their metabolism during acute intoxication. We present the toxicokinetic analysis in a child with a massive ingestion of ethanol.

Case report:

A 15-year-old girl without significant medical history presented to the Emergency Department after drinking 24 ounces of tequila. She was found unresponsive at home with a Glasgow Coma Score of 3. Her presenting vitals were as follows: 118/69 mmHg blood pressure; pulse rate was 88 beats per minute; respiratory rate of 20 breaths per minute; pulse-oximetry is 96% on room air. Other than obtundation, her physical examination was normal. She was intubated for airway protection and admitted to the ICU. Her initial serum ethanol concentration was 543 mg/dL. A repeat level 3 h later was 722 mg/dL. Post-absorptive ethanol concentrations decreased from 693 mg/dL to 291 mg/dL over the following 15.5 h. The patient had spontaneous eye opening 24 h after presentation. Her projected serum ethanol concentration at that time was 215 mg/dL. She was extubated 2 h later and had an uneventful recovery.

Results:

The elimination of ethanol in the post-absorptive phase remained zero-order at a rate of 26.3 mg/dL/h (5.7 mmol/L/h) with a Pearson’s correlation coefficient (R ²) of 0.9968 (p < 0.01). There was no evidence of acute induction in metabolism although pharmacodynamic tolerance likely occurred.

Conclusion:

Even at very high ethanol concentrations in ethanol naive subjects, elimination of ethanol follows a zero-order toxicokinetic model.

Introduction

Reactions involving an enzyme and a single substrate can be described by Michaelis–Menten kinetics. As concentrations of substrate rise, the enzyme becomes saturated and the reaction velocity approaches V _MAX, becoming constant and independent of further increases in substrate concentration. This phase describes zero-order kinetics. Alcohol dehydrogenase becomes saturated at very low concentrations of ethanol (the K _M is low), ¹ and the kinetics of its elimination at clinically relevant concentrations has traditionally been described by zero-order kinetics. ^{2 –5} However, in some case reports, there is a suggestion that apparent first-order elimination may predominate at extremely high concentratrions. ^{6 –10} All these cases except one involved chronic drinkers with significant tolerance. In this study, we report the case of an ethanol naive adolescent girl exposed to extremely high ethanol concentrations and present an analysis of her elimination kinetics.

Case report

A 15-year-old girl without significant past medical history or history of chronic ethanol use skipped school with a friend and drank 24 ounces of tequila in one afternoon. This dose would contain 229–257 g of ethanol (using a specific gravity of 0.7939, depending on whether it was 80 or 90 proof). Since the girl’s mass was 53 kg, this ingestion would be expected to result in a serum concentration of 720–808 mg/dL (corresponding to 80 or 90 proof) assuming a volume of distribution of 0.6 L/kg and a bioavailability of 100%. The girl became increasingly unresponsive, and her friend called 911. She was brought to the Emergency Department (ED) by ambulance. On arrival to the ED, her blood pressure was 118/69 mmHg; pulse rate was 88 beats per minute; respiratory rate of 20 breaths per minute; pulse-oximetry is 96% on room air. She had a Glasgow Coma Score (GCS) of 3, with no response to painful stimuli. Her physical examination was otherwise unremarkable, and she had no focal neurologic deficits. The patient was intubated for airway protection and admitted to the intensive care unit (ICU). Gastric emptying was not performed.

Serum ethanol concentrations were determined by an enzymatic rate method assay using a Beckman Coulter Unicel^® DxC 800. The patient’s initial serum ethanol concentration was 543 mg/dL. Other laboratory values were within the normal range and the electrocardiogram was also normal. A repeat ethanol concentration 3 h later was 722 mg/dL, which likely reflected continued absorption. Serial ethanol concentrations were determined while she was managed in the ICU. A linear regression model of her post-absorptive concentration was constructed using the least-squares method, and the square of a Pearson’s correlation coefficient (R²) was determined.

Results

Serial ethanol concentrations are recorded in Table 1. The first two concentrations were not included in the elimination kinetic analysis because of continued absorption. The last concentration was not included because it approached the error limits of the assay. Post-absorptive phase ethanol concentrations were plotted on linear coordinates (Figure 1). Elimination followed apparent zero-order kinetics closely at a rate of 26.3 mg/dL/h (5.7 mmol/L/h), with an R² of 0.9968. The girl regained consciousness at 24 h post-presentation. Her serum ethanol concentration at that time would have been 215 mg/dL, as extrapolated from the elimination curve.

Table 1.

Serum ethanol concentrations at times post-ingestion^a

Time (h)	0	3	6	10	15	21.5	39
Ethanol concentrations (mg/dL)	543	722	693	594	441	291	1.6

^aConcentrations initially rise, most likely due to continued gastrointestinal absorption.

Figure 1.

Post-absorptive phase serum ethanol concentrations (mg/dL) plotted against time (h) from emergency department presentation.

Discussion

At low-to-moderate concentrations, ethanol elimination follows zero-order kinetics, typically between 15 and 23 mg/dL/h (95% confidence interval: approximately 2–7 mmol/L/h). ^{2 –5} However, other first-order pathways, including renal, pulmonary, or enzymatic rates (such as the microsomal ethanol oxidizing system, the 2E1 isozyme of cytochrome P450, or the pi-isozyme of alcohol dehydrogenase), may become significant in patients with very high serum ethanol concentrations. Additionally, it is unclear if and when ethanol naive subjects are able to abruptly induce their metabolism during an acute intoxication. Although there are several reports of apparent first-order elimination kinetics after large alcohol ingestions in adults with a history of chronic ethanol intake, ^{6 –9} there is only one prior report of these kinetics following similarly high concentrations in children or non-ethanol-dependent patients. ¹⁰ A previous report of first-order ethanol kinetics in a 30 month-old pediatric patient involved a much lower serum concentration. In our ethanol-naive 15-year-old girl, apparent zero-order elimination at a rate of 26.3 mg/dL/h with an R² of 0.9968 (p < 0.01) was maintained throughout the post-absorptive phase after a peak serum concentration of 722 mg/dL was achieved. However, low rates of first-order elimination may be masked by higher rates of zero order elimination. It is also possible that in a 30-month-old, these rates may become more significant.

Although there was no evidence of pharmacologic induction, the fact that the girl regained consciousness at a predicted ethanol concentration of 215 mg/dL suggests a possible role for acute physiologic tolerance (the Mellanby effect ¹¹ ). This is consistent with the idea that physiologic tolerance results from mechanisms other than induction of elimination pathways.

This conclusion is limited by the absence of concentrations near the end of the curve, and it is possible that the induction occurred in the last 18 h of the patient’s clinical course (after she regained consciousness). As in any case report, the conclusions are also limited by the fact that this was a single patient, and results might differ if this natural experiment were to be repeated in other patients.