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Drug levels and overdose timing

16 min

  • Confirm dose and draw time before comparing a drug level with its trough or peak target
  • Recognize when binding changes make a total drug level understate the free drug
  • Decide whether an acetaminophen level can be plotted on the nomogram

Read the full reference

Try first

Try first

A gentamicin specimen labeled "trough" arrives with no collection time, and the requisition does not give the time of the last dose. What does the laboratory do?

The next section explains it.

The next section explains it.

Right. The next section explains why.

The next section explains it.

The next section explains it.

Get the idea

The time makes the number

A drug concentration is read against a target only at the right time after a dose. Every request carries the drug, the dose and route, the time of the last dose or the end of the infusion, and the draw time.1

  • A trough is drawn immediately before the next dose.
  • A peak's time is set by the drug's monitoring protocol.
  • A specimen with no collection time is reported with that gap stated, or recollected.1

A specimen drawn from a line used to infuse the same drug carries drug left in the catheter. It can read many times the true concentration.2

Total drug can hide the free drug

Routine assays measure total drug, bound plus unbound. Phenytoin is about 90% bound to albumin, and the free 10% carries its activity. Hypoalbuminemia, uremia, pregnancy and displacing drugs such as valproate raise the free fraction. A patient can then show toxicity with the total inside its target range.2 Free phenytoin is measured by ultrafiltration or equilibrium dialysis at 37 °C. Albumin correction equations perform poorly in uremia and critical illness.2

The acetaminophen nomogram needs a clock

The Rumack-Matthew nomogram applies from 4 to 24 hours after a single acute ingestion at a known time. The US treatment line passes through 150 µg/mL at 4 hours and halves every 4 hours:3

Treatment line (µg/mL) = 150 × 0.5(hours since ingestion − 4) ÷ 4

Hours after ingestion481216
Treatment line (µg/mL)1507537.518.8

Three results cannot be plotted:3

  • a concentration drawn before 4 hours, when absorption is still under way and the result can understate what is coming
  • an ingestion at an unknown time
  • repeated doses over hours or days

The laboratory reports the concentration with the ingestion and draw times. The poison service or treating team decides on the antidote.3

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. Rifai N, Chiu RWK, Young I, Burnham CAD, Wittwer CT, eds. Tietz Textbook of Laboratory Medicine. 7th ed. Elsevier; 2023.
  3. Dart RC, Mullins ME, Matoushek T, et al. Management of acetaminophen poisoning in the US and Canada: a consensus statement. JAMA Netw Open. 2023;6(8):e2327739. doi:10.1001/jamanetworkopen.2023.27739

Watch one

A roommate saw a woman swallow a bottle of acetaminophen tablets at 21:00, all at once. Her acetaminophen concentration, drawn at 03:00, is 118 µg/mL. Can the result be plotted on the nomogram, and where does it fall?

  1. Check the ingestion: a single acute ingestion, with the time known from a witness.

    The nomogram describes the fall in concentration after one dose taken at one time.

  2. Count the hours: 21:00 to 03:00 is 6 hours, which is inside the window.

    The line applies only from 4 to 24 hours after ingestion.

  3. Find the line at 6 hours: 150 × 0.5(6 − 4) ÷ 4 = 150 × 0.50.5 = 150 × 0.707 = 106 µg/mL.

    The line falls by half every 4 hours from 150 µg/mL at 4 hours.

  4. Compare: 118 µg/mL is above 106 µg/mL.

    A result above the line is what the treating team acts on.

  5. Report the concentration with the 21:00 ingestion and 03:00 draw times.

    The team needs both times to read the result.

The result can be plotted. At 6 hours the treatment line is 106 µg/mL, and the concentration of 118 µg/mL lies above it.

Your turn

Problem 1 of 3

A vancomycin trough was ordered before a 12:00 dose. The specimen labeled trough was drawn from the opposite arm at 12:45, after the 12:00 infusion had started. What should the laboratory do?

Incorrect. The label cannot stand in for the recorded collection time. A specimen drawn during the infusion reads above a true trough.

Incorrect. Post-dose sampling times are protocol-specific, and a specimen drawn mid-infusion is neither a trough nor a protocol-defined peak.

Correct. A trough is drawn immediately before the next dose. This specimen was drawn during the infusion, so no trough target applies to it. Under the monitoring protocol, report it with both times stated, or recollect it.

Hint
  1. Compare the draw time with the time the infusion started.
  2. A trough target applies to a specimen drawn immediately before the dose.

Review Specimen timing and documentation

Problem 2 of 3

Total phenytoin is within the usual target range, but marked hypoalbuminemia raises concern about the active fraction. Which measurement best addresses that question?

Correct. Phenytoin is about 90% bound to albumin, and hypoalbuminemia raises the free fraction that carries the activity. Ultrafiltration or equilibrium dialysis at 37 °C measures that fraction directly.

Incorrect. Correction equations assume otherwise normal binding and perform poorly in uremia and critical illness. They estimate the total at normal albumin without measuring the active fraction.

Incorrect. A plain tube avoids the gel adsorption that lowers total phenytoin, but the result still counts bound plus unbound drug.

Hint
  1. Ask which fraction of phenytoin acts on the brain.
  2. Low albumin changes how much of the total is unbound.

Review Total and free drug

Problem 3 of 3

Four acetaminophen concentrations arrive on one evening. Which one can be plotted on the nomogram?

Absorption is incomplete at 2 hours, and the concentration can still rise. A result drawn before 4 hours cannot be placed on the nomogram.

Plotted an early, unknown-time, or repeated-ingestion result

The nomogram applies only from 4 to 24 hours after a single acute ingestion at a known time. An earlier level can understate the peak, and an unknown or repeated exposure has no valid time point, so plotting either gives false reassurance.

Without a known ingestion time there is no point on the time axis. The result needs separate assessment.

Plotted an early, unknown-time, or repeated-ingestion result

The nomogram applies only from 4 to 24 hours after a single acute ingestion at a known time. An earlier level can understate the peak, and an unknown or repeated exposure has no valid time point, so plotting either gives false reassurance.

A single acute ingestion at a known time, drawn between 4 and 24 hours after it, fits the nomogram. At 9 hours the line sits at about 63 µg/mL.

Repeated doses over days have no single time of ingestion. The nomogram cannot be applied, and these exposures have their own assessment.

Plotted an early, unknown-time, or repeated-ingestion result

The nomogram applies only from 4 to 24 hours after a single acute ingestion at a known time. An earlier level can understate the peak, and an unknown or repeated exposure has no valid time point, so plotting either gives false reassurance.

Review Acetaminophen and salicylate overdose

Use it

  • A man in the intensive care unit receives vancomycin every 12 hours through a peripherally inserted central catheter.
  • The last infusion ended at 06:00, and the next dose is due at 18:00.
  • A trough was drawn at 17:30. The collector notes it was drawn through the catheter lumen used for vancomycin.
  • He also takes phenytoin.
TestResultPreviousReference intervalFlag
Vancomycin, trough62.4 µg/mL15.6 µg/mL1 day ago10.0–20.0 µg/mLDelta
Phenytoin, total12 µg/mL13 µg/mL1 day ago10–20 µg/mL
Albumin2.0 g/dL2.1 g/dL1 day ago3.5–5.0 g/dLLow
Creatinine3.4 mg/dL3.3 mg/dL1 day ago0.74–1.35 mg/dLHigh

Specimen: H 12, L 18, I 3. Drawn 17:30 through the catheter lumen used for vancomycin

Decision 1 of 3

What best explains the vancomycin of 62.4 µg/mL?

His creatinine is unchanged from yesterday, when the trough was 15.6 µg/mL. Accumulation would not quadruple the trough in one day at a steady creatinine.

Residual vancomycin in the lumen mixes into the specimen and can raise the result many times over. The collector's note names that lumen.

The draw at 17:30 came before the 18:00 dose, and the last infusion ended at 06:00.

Review Specimen timing and documentation

Decision 2 of 3

What do you do with the vancomycin?

A comment leaves a number four times yesterday's trough in the record, and it may be read against the trough target.

A repeat measures the same catheter drug again.

The draw time fits a trough. Drug left in the catheter makes the result describe the lumen.

A specimen from a vein or lumen free of vancomycin, drawn before the dose, gives a trough that describes the patient.

Review Specimen timing and documentation

Decision 3 of 3

What do you do with the total phenytoin of 12 µg/mL?

An albumin of 2.0 g/dL and a creatinine of 3.4 mg/dL both raise the free fraction. The free phenytoin can be toxic with this total.

Assumed unchanged total drug means unchanged free drug

Phenytoin is about 90% bound to albumin, and hypoalbuminemia, uremia, pregnancy, or displacing drugs raise the free fraction. A total concentration within the therapeutic range can then accompany a toxic free concentration, and albumin-correction equations perform poorly in uremia and critical illness.

Correction equations perform poorly in uremia and critical illness, and he has both. A corrected total still does not measure the free drug.

The specimen is suitable, so the total is reportable. The comment tells the reader that the total can understate the active drug, and a free phenytoin answers that.

Review Total and free drug

The clue that settles it is the draw site:

  • The vancomycin trough rose from 15.6 to 62.4 µg/mL in one day at a steady creatinine.
  • The collector drew it through the lumen used for vancomycin.

The vancomycin is redrawn from a clean site before the dose. The phenytoin tube has no such problem, and its total is released with a comment about the free fraction.

Keep

Sources checked