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Drug screens and toxic alcohols

16 min

Skills you'll build2 skills
  • Tell a presumptive immunoassay drug screen from GC-MS or LC-MS/MS identification
  • Predict how osmolal and anion gaps change as a toxic alcohol is metabolized

Try first

Try first

An emergency department patient who takes bupropion has a urine amphetamine immunoassay above its cutoff. The physician asks whether the patient used methamphetamine. What does the screen show?

Keep going to see the reasoning.

Keep going to see the reasoning.

Right. Keep going to follow the reasoning.

Keep going to see the reasoning.

Keep going to see the reasoning.

Get the idea

Use the explanation to check your first decision.

Presumptive screens and confirmation

A drug screen is an immunoassay. It reports that something in the urine bound a class-directed antibody above a cutoff, and it does not identify the compound. Identification needs gas chromatography with mass spectrometry (GC-MS) or liquid chromatography with tandem mass spectrometry (LC-MS/MS). A second immunoassay cannot identify the compound, because it also depends on antibody cross-reactivity. Report a presumptive result with its method and cutoff.1

A cutoff classifies a result for the test's purpose. A urine with a negative screen can contain drug below the cutoff. A panel detects only the compounds it is designed to detect. The opiate immunoassay, calibrated to morphine and codeine, does not detect fentanyl, methadone or buprenorphine.2

Osmolal and anion gaps over time

The parent alcohols are small, uncharged solutes. They raise measured osmolality above the calculated value:3

Calculated osmolality (mOsm/kg) = 2 × sodium (mmol/L) + glucose (mg/dL) ÷ 18 + BUN (mg/dL) ÷ 2.8

Osmolal gap = measured − calculated osmolality

Osmolality for this purpose is measured by freezing point depression. Vapor pressure osmometry does not detect the volatile alcohols.4 Ethanol also widens the gap, so a measured ethanol is added to the calculation when present.3

Methanol is metabolized to formate and ethylene glycol to glycolate. As this happens, the two gaps change in opposite directions:5

Time after ingestionOsmolal gapAnion gapBicarbonate
EarlyHigh, from the parent alcoholNear normalNear normal
LateFalling toward normalHigh, from the acid metabolitesLow

A normal osmolal gap at one point in time cannot exclude a toxic alcohol.5 Glycolate is also measured as lactate by lactate oxidase electrodes. A blood gas lactate far above the laboratory lactate, a lactate gap, points to ethylene glycol.6 Gas chromatography identifies the alcohol itself.3

Follow the bench demonstration

Sources for this step
References
  1. Clinical and Laboratory Standards Institute. Toxicology and Drug Testing in the Medical Laboratory. 3rd ed. CLSI guideline C52. Clinical and Laboratory Standards Institute; 2017. Accessed September 27, 2026. https://clsi.org/shop/standards/c52/
  2. Snozek CLH, Krasowski MD, Colby JM, et al. ADLM guidance document on laboratory testing for drugs of misuse to support the emergency department. J Appl Lab Med. 2026;11(1):155-180. doi:10.1093/jalm/jfaf172
  3. Rifai N, Chiu RWK, Young I, Burnham CAD, Wittwer CT, eds. Tietz Textbook of Laboratory Medicine. 7th ed. Elsevier; 2023.
  4. Walker JA, Schwartzbard A, Krauss EA, Sherman RA, Eisinger RP. The missing gap: a pitfall in the diagnosis of alcohol intoxication by osmometry. Arch Intern Med. 1986;146(9):1843-1844. doi:10.1001/archinte.146.9.1843
  5. 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
  6. Woo MY, Greenway DC, Nadler SP, Cardinal P. Artifactual elevation of lactate in ethylene glycol poisoning. J Emerg Med. 2003;25(3):289-293. doi:10.1016/S0736-4679(03)00203-8

Watch one

Read each decision and its explanation.

A man arrived at 02:00 with suspected toxic alcohol ingestion. Serum ethanol was not detected on either specimen. Osmolality is measured by freezing point depression. His second specimen is drawn at 10:00, and the first is shown as the previous result.

How do the two gaps change, and what do they show?

TestResultPreviousReference intervalFlag
Sodium138 mmol/L8 hours ago: 140 mmol/L140 mmol/L8 hours ago135–145 mmol/L135–145
Chloride102 mmol/L8 hours ago: 104 mmol/L104 mmol/L8 hours ago98–107 mmol/L98–107
Bicarbonate8 mmol/L Low8 hours ago: 24 mmol/L24 mmol/L8 hours ago22–29 mmol/L22–29Low
Glucose108 mg/dL High8 hours ago: 90 mg/dL90 mg/dL8 hours ago70–99 mg/dL70–99High
BUN14 mg/dL8 hours ago: 14 mg/dL14 mg/dL8 hours ago8–24 mg/dL8–24
Osmolality, measured293 mOsm/kg8 hours ago: 318 mOsm/kg318 mOsm/kg8 hours ago275–295 mOsm/kg275–295

Specimen: H 10, L 15, I 1. Serum drawn 10:00, previous specimen drawn at arrival at 02:00

  1. Confirm the method. Osmolality was measured by freezing point depression.

    Vapor pressure osmometry would miss a volatile alcohol.

  2. Calculate the first osmolal gap: 2 × 140 + 90 ÷ 18 + 14 ÷ 2.8 = 280 + 5 + 5 = 290 mOsm/kg, and 318 − 290 = 28 mOsm/kg.

    The gap on arrival shows how much unmeasured solute was present then.

  3. Calculate the first anion gap: 140 − (104 + 24) = 12 mmol/L, with a normal bicarbonate of 24 mmol/L.

    The anion gap shows whether acid metabolites had formed yet.

  4. Calculate the second pair: 2 × 138 + 108 ÷ 18 + 14 ÷ 2.8 = 276 + 6 + 5 = 287 mOsm/kg, so the osmolal gap is 293 − 287 = 6 mOsm/kg. The anion gap is 138 − (102 + 8) = 28 mmol/L.

    The same two calculations on the later specimen show the direction of change.

  5. Note the direction of change. The osmolal gap fell from 28 to 6 mOsm/kg as the anion gap rose from 12 to 28 mmol/L and bicarbonate fell to 8 mmol/L.

    As the parent alcohol is metabolized to acid anions, the two gaps change in opposite directions.

The osmolal gap fell from 28 to 6 mOsm/kg as the anion gap rose from 12 to 28 mmol/L. The pattern fits a toxic alcohol being metabolized to its acid, and the normal later osmolal gap does not exclude it.

Practice this skill

Your turn

Problem 1 of 3 · Hints available

A class-directed urine drug immunoassay is presumptively positive. Which approach can provide definitive identification of a covered compound?

Correct. Gas chromatography with mass spectrometry (GC-MS) or liquid chromatography with tandem mass spectrometry (LC-MS/MS) separates and identifies by structure or mass. The targeted method must include the compound in question.

Incorrect. A second immunoassay still depends on antibody cross-reactivity, so it cannot identify the compound that bound.

Incorrect. Creatinine, specific gravity, pH, and oxidant checks show whether the urine is dilute or adulterated. They do not identify a drug.

Hint
  1. Consider what each method depends on to produce its result.
  2. Identification needs a method that distinguishes compounds by structure or mass.

Review Screens, confirmation, and cutoffs

Problem 2 of 3 · Hints available

A late methanol presentation shows severe high-anion-gap acidosis and a normal osmolal gap. Osmolality was measured by freezing-point depression. Which explanation fits?

Incorrect. Freezing-point depression is the required method because it retains the volatile alcohols that vapor-pressure osmometry loses.

Correct. As the parent alcohol is metabolized, the osmolal gap falls and formate accumulates as an unmeasured anion, raising the anion gap. A normal osmolal gap at one time point cannot exclude toxic alcohol exposure.

Incorrect. Ethanol adds osmoles of its own and cannot remove the methanol contribution. Unless the calculated osmolality includes an ethanol term, co-ingestion widens the osmolal gap.

Hint
  1. Consider what happens to methanol in the body over the hours after ingestion.
  2. The osmolal gap reflects the parent alcohol, and the anion gap reflects its acid.

Review Alcohols and glycols

Problem 3 of 3 · On your own

A woman is brought in unresponsive with fentanyl patches on her skin. Her urine opiate immunoassay is below its cutoff, and the physician asks whether the negative screen rules out opioid exposure. What does the laboratory tell the physician?

The opiate immunoassay is calibrated to morphine and codeine and does not detect fentanyl. A negative result gives no evidence about fentanyl.

Treated a screen result as identification of a specific drug

A class-directed immunoassay reports that something bound its antibody above a cutoff, and cross-reacting compounds can do that. Reporting the screen as a named drug skips identification by gas or liquid chromatography with mass spectrometry (GC-MS or LC-MS/MS) that the two-tier design requires.

A panel reports only on the compounds it covers. Fentanyl needs its own immunoassay or a targeted method that measures it.

A lower cutoff still leaves an antibody that does not recognize fentanyl. The limitation is in which compounds the antibody detects.

Validity testing shows whether the urine is dilute or adulterated. It cannot make the opiate assay detect fentanyl.

Review Screens, confirmation, and cutoffs

Use it

Read the case evidence, then make each decision. The step is complete without it.

  • A man is found confused at home, and no history is available.
  • Ethanol is not detected.
  • Osmolality is measured by freezing point depression, and the calculated osmolality is 291 mOsm/kg, giving an osmolal gap of 12 mOsm/kg.
  • The blood gas analyzer, which uses a lactate oxidase electrode, reads lactate at 12.8 mmol/L.
  • The chemistry analyzer measures lactate on the same draw by a method that does not react with glycolate.
TestResultReference intervalFlag
Sodium139 mmol/L135–145 mmol/L135–145
Chloride101 mmol/L98–107 mmol/L98–107
Bicarbonate9 mmol/L Low22–29 mmol/L22–29Low
Osmolality, measured303 mOsm/kg High275–295 mOsm/kg275–295High
Lactate, chemistry analyzer2.9 mmol/L High0.5–2.2 mmol/L0.5–2.2High

Specimen: H 12, L 10, I 2. Serum and arterial blood drawn together on arrival

Decision 1 of 3

The anion gap is 139 − (101 + 9) = 29 mmol/L. Does the osmolal gap of 12 mOsm/kg exclude a toxic alcohol?

A late specimen can show a small osmolal gap because most of the parent alcohol is already metabolized. The high anion gap shows its acid is present.

Ruled out toxic alcohol on a normal osmolal gap

As methanol or ethylene glycol is metabolized, the osmolal gap falls as the acid metabolites raise the anion gap, so a late specimen can show a normal osmolal gap with severe acidosis. Reading the normal gap as exclusion misses the exposure.

As the alcohol is metabolized, its osmoles disappear and its acid anions accumulate. A modest osmolal gap with an anion gap of 29 mmol/L fits that later stage.

Freezing point depression retains the volatile alcohols. Vapor pressure osmometry is the method that loses them.

Review Alcohols and glycols

Decision 2 of 3

What explains a blood gas lactate of 12.8 mmol/L with a chemistry analyzer lactate of 2.9 mmol/L?

An analyzer fault would show in its QC and in other patients. A lactate gap on one patient's specimen points to something in that specimen.

The chemistry lactate comes from a separate tube, so lactate made in the syringe would raise only the blood gas result. A short transport also adds far less than 10 mmol/L. A gap this large between a method that reads glycolate and one that does not points to glycolate.

Glycolate, the acid metabolite of ethylene glycol, cross-reacts on lactate oxidase electrodes. A lactate gap this large points to ethylene glycol.

Review Lactate

Decision 3 of 3

The team asks the laboratory to identify the alcohol. Which test does that?

The osmolal gap counts unmeasured solute of any kind. It cannot identify the alcohol, and it keeps falling as the alcohol is metabolized.

Gas chromatography separates and identifies methanol, ethylene glycol and the other alcohols by their retention and detection.

Enzymatic ethanol assays are largely specific for ethanol. They do not measure methanol or ethylene glycol.

Drug screens are class-directed immunoassays for drugs of misuse. They do not detect toxic alcohols.

Review Screens, confirmation, and cutoffs

The high anion gap with a small osmolal gap fits a toxic alcohol that is already largely metabolized, and the lactate gap points to ethylene glycol:

  • anion gap 29 mmol/L
  • osmolal gap 12 mOsm/kg
  • blood gas lactate 12.8 mmol/L with a chemistry lactate of 2.9 mmol/L

Most of the parent alcohol has been metabolized, its acid is present, and gas chromatography identifies the alcohol.

For reference

Sources checked