At a Glance
Ethanol intoxication should be considered in any patient in whom there is unexplained loss of consciousness, altered sensorium, or onset of seizures. A toxic dose is 5g/kg in an adult and 3 g/kg in a child.
Ingestion of ethanol is common and is estimated to be responsible for some 600,000 emergency department visits annually in the United States. Household and personal hygiene products may contain significant amounts of ethanol (up to 95%) and may be accidentally ingested by small children. Ethanolic beverages have widespread social acceptance and so are often coingested with other medications in suicide attempts in which it may mask or enhance their effects. Binge drinking and ethanol coingestion with illicit or nonprescription drugs is more common in teens and young adults, as well as in some socioeconomic settings.
Ethanol intoxication ranges from disinhibited behavior to coma, hypotension, hypothermia, and respiratory depression. It may complicate or confound the clinical presentation of psychoses and traumatic injuries and is especially important to rule out head trauma. Pharmacokinetic interactions of ethanol may competitively delay or inductively increase the clearance or elimination of other drugs. The clinical picture produced by coingested hypnotics, benzodiazepines, barbiturates, opioids, and GHB markedly increases the risk of deep coma with respiratory failure after ethanol ingestion.
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Chronic ethanol use carries significant morbidity and mortality.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
Rapid point of care tests for ethanol on body fluids (i.e., blood, urine, or oral fluid) or by breath analysis (if the patient is able to cooperate) are sufficiently reliable to confirm diagnosis in most circumstances. Laboratory-based tests have better precision, and their results are more easily documented. Gas chromatography is the gold standard, but availability is confined to specialist toxicology laboratories. When the test is performed in the laboratory, attention to use of appropriate specimen preservatives can reliably prevent in-vitro production of ethanol during transport, except in exceptional circumstances.
Establishment of the presence of ethanol in the blood establishes the diagnosis of ethanol exposure, and this documentation is invaluable if there are medico-legal or forensic sequelae. However, blood concentrations do not correlate well with clinical effects in adults, although they can be used in older children to estimate the degree of lethargy anticipated. Children younger than 2 years of age are particularly sensitive to ethanol in terms of hypothermia and hypoglycemia. Children younger than 5 years of age are more likely to ingest nonbeverage ethanol than older children, and it is, therefore, important in this group to establish that ethanol is the compound ingested, rather than another toxic alcohol, such as methanol or isopropanol, as there are specific treatments for these that should be instigated.
Alcoholic aroma with history and signs/symptoms of intoxication may be helpful but are not sufficient to establish the diagnosis beyond doubt. Fruity aroma on the breath may be present in diabetic ketoacidosis, which can be ruled out if blood or urine glucose is not grossly elevated or ketones are not present in the urine. Blood glucose is normal to low in ethanol intoxication, even with ketosis, unless the patient has concomitant diabetes. Ketosis may occur later in the course of ethanol intoxication if glycogen supplies have been eliminated and hypoglycemia is present.
If ethanol analysis is not available, measure the serum osmolality by Freezing Point Depression (Vapor Dew Point Pressure methods are not reliable with volatile osmolytes). Osmolality will be elevated, and there will be a larger than normal osmolal gap. For calculation of the osmolal gap, a simultaneous measurement of serum sodium, glucose, and blood urea nitrogen (BUN) are required. This information can be used to calculate the amount of ethanol produced by the observed gap as follows:
Calculated osmol mOsm/kg = 2 [Na mmol/L] + [glucose mg/dL /18] + [BUN mg/dL / 2.8]
Osmolal Gap = Measured osmolality – Calculated osmolality which is normally <10 mOsmol/kg
Serum Ethanol (mg/dL) = 4.6 (10 – Osmolal Gap)
Urine osmolality will also be elevated in ethanol intoxication but is not as useful in making the diagnosis as it is naturally more variable than serum, and ethanol additionally induces a profound diuresis by inhibition of vasopressin release.
(Table 1)
Table 1 Tests Results indicative of the Disorder
Table 1
| Ethanol Quantitation Serum, whole blood or breath | Ethanol Quantitation Urine | Serum Osmolal Gap |
|---|---|---|
| >10 mg/dL positive | ||
| 20-50 mg/dL diminished fine motor control, relaxation, increased talkativeness | ||
| 50-100 mg/dL impaired judgment and coordination | ||
| 100-150 mg/dL difficulty with gait and balance, slurred speech, personality and behavioral changes | ||
| 150-250 mg/dL lethargy, difficulty sitting upright | ||
| 250-400 mg/dL stupor, amnesia, diplopia/nystagmus, dysarthria, hypothermia, nausea and vomiting, | Positive >10 mg/dL | Positive > 20 mOsm/kg |
| 400 mg/dL respiratory depression, coma in the unhabituated user 500 mg/dL death | Generally 1.3 times blood ethanol concentration | See above for calculating serum ethanol from the osmolal gap. |
| Chronic excessive ingestion tones down response; chronic alcoholics often tolerate concentrations of 400 mg/dL. | ||
| Breath alcohol meters usually report in blood ethanol equivalents. |
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
A number of liquid drug formulations, in particular cough syrups and allergy medicines, contain 2-25% ethanol and are sometimes abused for this reason. Their ingestion does not invalidate the alcohol measurement but can shift the clinical picture, for example, toward an anticholinergic toxidrome due to the presence of the antihistamines.
Ethanol may have been administered as an antidote for methanol and ethylene glycol poisoning. Osmolality measurements will be affected by the presence of these other osmotically active alcohols, and extra care should be taken when interpreting the results. In contrast, enzymatic tests are only minimally affected by these.
If blood and urine ethanol are not concordant, consider contamination of the specimen(s). Blood ethanol can be significant if an ethanol swab is used for venipuncture site preparation and not adequately dried (could be as high as 100 mg/dL, depending on the amount of blood collected). When there is ethanol in the urine (>40 mg/dL in the absence of glucose or ketones) but none in the blood (<10 mg/dL), consider adulteration of the urine specimen in an attempt to invalidate or out-perform the drug screen testing process.
Confusion is possible, since laboratories report ethanol in a variety of units of measure. Conversion factors for these are as follows:
100 mg/dL = 100 mg% = 0.1% = 1 g/L
1 mmol/L = 4.6 mg/dL
Biological specimens for laboratory based tests should be collected with fluoride oxalate preservative to prevent conversion of substrates to ethanol by fermenting yeasts or bacteria, especially if testing is delayed more than a few hours. Stability is generally 2 weeks at room temperature with fluoride oxalate, 3 months at 4°C, 6 months at 20°C in tightly capped tubes.
Falsely low ethanol results can occur from:
Temperature dependent chemical oxidation to acetaldehyde
Prolonged storage in plastic containers, particularly if not adequately filled
Opening frozen samples, which can result in significant loss as the water matrix freezes but not the ethanol
Falsely elevated ethanol results can occur from:
Bacterial/yeast production of ethanol in unpreserved specimens is more likely with long delays before testing, particularly in urine if there is glucose present, which can be easily checked by dipstick).
Severe bacteremia rapidly overwhelms the added preservative; a blood glucose incompatible with life (<25 mg/dL) provides a clue that this has occurred.
Absorption of vapors while stored in laboratory refrigerators alongside ethanolic solutions can falsely elevate ethanol results.
Considerations with Breath Ethanol
Breath ethanol of 0.5 mg/L is equivalent to 100 mg/dL or 0.1% in blood. At least 15-20 minutes must elapse between ingestion and testing; vomitus will affect the result. Artificially low breath ethanol will be obtained in patients with anemia and hypothermia, as well as poor respiratory function, including the elderly, since alveolar air is not poorly exhaled and blood perfusion of the alveoli and gas diffusion across the alveolar membrane are suboptimal. False negatives are rare.
Considerations for Enzymatic Tests
Depending on the precise kit formulation, alcohol dehydrogenase (ADH) methods can be subject to positive interference from lactate and/or lactate dehydrogenase (LDH). Positive ethanol results in patients with hepatic necrosis, megaloblastic anemia, muscular dystrophy, and/or metabolic acidosis that do not correlate with clinical symptoms and should, therefore, be remeasured by an alternative assay, preferably gas chromatography.
What Lab Results Are Absolutely Confirmatory?
Ethanol analysis by gas chromatography is the gold standard for both identification and quantitation of ethanol and allows for simultaneous detection (and frequently quantitation) of methanol, acetone, and isopropanol. The blood, plasma, or serum quantity can be related to the degree of intoxication. Urine concentration varies in relation to the blood with time course from ingestion: early on, plasma is greater than urine; in equilibrium urine is 1.3 times plasma; after cessation of exposure, urine is greater than plasma. This relationship may help determine the time course, or indicate possible degradation or contamination/adulteration of specimen.
Once the diagnosis is established, it is not usually necessary to perform repeat measurements, unless the intoxication does not resolve in the expected time frame. Serum ethanol should decline at 15-25 mg/dL/hour in nonhabituated patients and at 25-35 mg/dL/hour or more in alcoholics.
Rapid point of care alcohol tests and laboratory tests based on enzymatic principles are not able to indicate the presence of other volatiles, nor may they always give the correct quantitative ethanol value in the presence of alcohols other than ethanol. However, they are adequate for establishing the diagnosis in the majority of patients. When a patient does not recover in the time frame anticipated based on the expected decline of blood ethanol; appears more intoxicated than the blood alcohol suggests; or has uncharacteristic symptoms, such as a profound metabolic acidosis, then gas chromatography for volatile alcohols should be obtained to ensure a correct diagnosis. Since children younger than 5 years of age frequently ingest nonbeverage alcohol, it is wise to obtain a gas chromatography alcohol determination so the presence of other alcohols can be ruled out.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
Standard of care tests are needed for treatment. However, in large ingestions in which intoxication lasts longer than 8 hours, glucose monitoring is essential to avoid hypoglycemic seizures or altered mental status. Children younger than 2 years of age who have small glycogen stores and have a serum ethanol greater than 50 mg/dL require frequent glucose monitoring until glycemic control is reestablished. Metabolic acidosis is not common and is generally only mild in ethanol intoxication, unless the amount ingested is large, and does not usually require correction.
Urine pregnancy test should be performed in age-appropriate females. It should be remembered that this test may give false negatives when urine is very dilute, as the ßHCG is diluted out to below the sensitivity of the assay.
A urine drug screen should be requested if other agents are suspected of being involved. This can be a set of simple immunoassays for recreational drugs, which can be performed as a Point of Care or a laboratory-based test. Laboratory tests frequently also include acetaminophen and salicylate. This determines whether the clinical picture is due to ethanol alone or is confounded by coingestion of sedative-hypnotic agents, such as benzodiazepines, barbiturates, opioids, or gamma-hydroxybutyrate (GHB).
If specimens have already been discarded and the patient recovered by the time ethanol intoxication is suspected, it may still be possible to establish the diagnosis. Although the vast majority of ethanol is metabolized to acetaldehyde by ADH and a lesser amount by CYP2E1, a small fraction (<0.1%) is metabolized by UDP-Glucuronosyl transferase (UDPGT) to ethyl glucuronide. This minor metabolite is nonvolatile; water soluble; stable to storage; and can be detected in urine, serum, and hair. Urine becomes positive within 3 hours of ingestion and remains so for about 4 days.
Unfortunately, immunoassays are not yet available, and testing is confined to specialized laboratories where GCMS is used. There are concerns regarding test reliability in patients with polymorphisms in UDPGT and the possibility of in-vitro bacterial hydrolysis of the glucuronide conjugate, especially in urine in which contamination is more likely. Ethanol in the serum combines nonenzymatically with a number of carboxylic acids, including circulating fatty acids, producing fatty acid ethyl esters (FAEEs). These can also be quantitated in serum by GCMS and have the capability to detect a single exposure to ethanol for about 24 hours. They are not yet sufficiently investigated to relate their quantity to the amount of ethanol exposure.
If the patient has already expired, vitreous humor is the most reliable fluid for post mortem ethanol analysis, since it is a sealed aseptic environment. (Table 2)
Some patients presenting with acute ethanol intoxication will be chronic imbibers. Traditional markers of chronic use are serum GGT and mean blood corpuscular volume (MCV). Newer markers are carbohydrate deficient transferrin (CDT), which typically requires more than 1000g ethanol consumption within 2 weeks to be elevated (>6% of transferrin with two or less sialic acid residues is indicative of alcohol use provided the patient does not have the genetically deficient C2D polymorphism, which naturally produces low sialylation).
Table 2
| Specimen | Ratio |
|---|---|
| Serum | 1.16 |
| Urine | 1.3 at equilibrium |
| Vitreous humor | 1.2 |
| Spinal Fluid | 1.1 |
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
Therapeutic Ethanol Administration
Intravenous or oral ethanol may have been administered as an antidote for methanol and ethylene glycol poisoning. Osmolality measurements will be affected by the presence of these other osmotically active alcohols, and extra care should be taken when interpreting the results. In contrast, ADH and AO enzymatic tests are only minimally affected, showing less than 1% cross reactivity with ethylene glycol and less than 1% for methanol and isopropanol. Similarly, there is little response with acetone or ketones. However, cross reactivity with higher alcohols, such as n-butanol, can be significant (>25% for n-butanol and >60% for n-propanol), but these are not commonly encountered, even in nonbeverage ethanol-containing products.
Considerations with Breath Ethanol
Breath ethanol of 0.5 mg/L is equivalent to 100 mg/dL or 0.1% in blood.
At least 15-20 minutes must elapse between ingestion and testing, since ethanol in the mouth and upper airway will invalidate the assumed relationship of breath to blood ethanol (2100 mL of alveolar air contains the same amount of ethanol as 1 mL of blood). Vomitus will affect the result.
Breath ethanol slightly underestimates the blood ethanol at high ethanol concentrations. Anemia artificially lowers the breath ethanol value because of the higher than allowed plasma water fraction in the blood. The amount of ethanol on the breath increases by 6.8% for each degree Celsius rise above normal body temperature. Artificially low results will be obtained in patients with poor respiratory function, including the elderly, since alveolar air is not poorly exhaled and blood perfusion of the alveoli and gas diffusion across the alveolar membrane are suboptimal. False negatives with this test are rare.
Considerations for Enzymatic Tests
Considerations for enzymatic tests are based on reaction of ethanol with either Alcohol Oxidase (AO) or Alcohol Dehydrogenase (ADH) with visualization or spectrophotometric measurement of a dye product or of nicotinamide adenine dinucleotide (NADH) or an analog. Depending on the precise kit formulation, ADH methods can be subject to positive interference from elevated lactate (> 2mg/dL) and/or LDH (>1000 U/L), producing serum ethanol concentrations as high as 150 mg/dL. Positive ethanol results in patients with hepatic necrosis, megaloblastic anemia, muscular dystrophy, and/or metabolic acidosis that do not correlate with clinical symptoms should be remeasured by an alternative assay, preferably gas chromatography.
Osmolality
If basing diagnosis on elevated osmolal gap, consider exclusion of other causes of elevated osmolal gap (i.e., methanol; isopropanolethylene glycol; propylene glycol; and diuretics, such as mannitol). Untreated methanol, isopropanol, and ethylene glycol will all progress to profound anion gap metabolic acidosis in contrast to ethanol intoxication.
Ethylene and propylene glycol are nephrotoxins and will cause elevations in serum creatinine and BUN, and ethylene glycol additionally produces calcium oxalate crystaluria and profound hypocalcemia. Hyperosmolar hyperglycemic coma presents with markedly elevated glucose concentration (often >900 mg/dL glucose without ketosis or fruity odor), which adds 50 mOsmol/kg to the measured osmolality, but the gap will not be elevated, since glucose is included in the osmolality calculation.
Ethanol Metabolism
Ethanol is metabolized predominantly by ADH and CYP2E1 to acetaldehyde, and then by Aldehyde Dehydrogenase (ALDH) to acetate. Peak blood ethanol concentrations are achieved about 30-90 minutes after ingestion, and longer when ingested with food. Hepatic metabolism proceeds at zero order, because ADH is substrate saturated when blood ethanol is above 20 mg/dL.
Women metabolize ethanol less well than men, because they have lower concentrations of ADH in their gastrointestinal (GI) tract and, therefore, absorb relatively more of each dose. Their smaller size and higher percentage of body fat also produces higher blood concentrations for the dose consumed relative to men. Gastric ADH is also inhibited by cimetidine and ranitidine, leading to greater bioavailability of ethanol.
Chronic ethanol use results in faster metabolic elimination of ethanol by ADH enzyme induction (25-35 mg/dL/hour or even faster).
Dose Calculations
Back calculation of blood ethanol concentration based on average values for pharmacokinetic parameters is sometimes performed, and roughly each hour elapsed reduces blood ethanol by 20 mg/dL (range 13-25). Knowledge of the dose of ethanol ingested can be helpful in determining the validity of the history or suicidal intention. As an approximation, the amount of alcohol consumed can be estimated, since one drink produces 25 mg/dL blood ethanol in an adult. This can be derived more accurately using the following formula, where the blood alcohol concentration is BAC, the % ethanol content of the beverage is half its stated degree proof, the distribution volume is Vd, and the specific gravity of ethanol is SG (0.8 g/mL):
where Vd = 0.68 L/kg in males and 0.55 L/kg in females.
The dose ingested can also be expressed in terms of g/kg, calculated from the known ingestion using the formula:
The dose ingested can also be expressed in terms of g/kg, which is calculated from the BAC using the formula:
where Vd = 0.68 L/kg in males and 0.55 L/kg in females.
1 unit of ethanol “drink” = 1/2 oz = 15 mL ethanol, which is contained in approximately 12 oz of beer, 1.5 oz of hard liquor, or 5 oz of wine.
Antabuse (disulfiram) inhibits ALDH and causes acetaldehyde to accumulate sufficiently to exceed the km for the reverse reaction and ethanol is produced. Ethanol elimination does not, therefore, follow the expected rate. The inherited polymorphism ALDH 2*2 results in enzyme with markedly decreased activity and produces a similar effect and occurs in Southeast Asian populations and some American Indians. Bacteria in the GI tract produce small amounts of ethanol by fermentation of food. This is normally completely eliminated by ADH in the GI tract or by first pass metabolism. Intestinal overgrowth by Candida or yeasts may produce ethanol at a rate exceeding the capacity of this system, especially when it occurs simultaneously with ingestion of high carbohydrate meals and a decreased ADH capacity to eliminate it. This phenomenon has never been convincingly demonstrated outside Japanese and other Southeast Asian populations.
If ethanol is coingested with acetaminophen, competition for metabolism by CYP3A4 results in inhibition of ethanol metabolism, prolonging the clinical effects. Ethanol simultaneously induces the expression of CYP3A4, which subsequently increases the toxicity of acetaminophen by increasing the production of the toxic metabolite NAPQI (N-acetyl-p-benzoquinone imine). When administering the acetaminophen antidote N-acetyl cysteine (NAC), it is necessary to drop the treatment level by about 50% (100 mcg/mL acetaminophen at 4 hours postingestion, rather than 200 mcg/mL).
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