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Drug levels and overdose timing

16 min

Skills you'll build3 skills
  • 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

At the bench: Check collection timing before interpreting a therapeutic drug result

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?

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.

Specimen timing for drug monitoring

A drug concentration can be compared with a target only when it is drawn at the right time after a dose. Every request includes 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 contains drug left in the catheter. The result can be many times the true concentration.2

Total and free drug

Routine assays measure total drug, bound plus unbound. Phenytoin is about 90% bound to albumin, and the free 10% is the active drug. 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

Timing for the acetaminophen nomogram

The Rumack-Matthew nomogram applies to specimens drawn 4 to 24 hours after an acute ingestion began. The start time must be reliable. The 2023 US and Canada consensus defines acute ingestion as all doses taken within less than 24 hours, as one dose or several. Count from the first dose. 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

The nomogram does not apply to:3

  • a concentration drawn before 4 hours, when absorption is still under way and the result can understate what is coming
  • a concentration drawn more than 24 hours after ingestion began
  • an ingestion with an unknown or unreliable start time
  • repeated supratherapeutic ingestion extending over more than 24 hours

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

Read each decision and its explanation.

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. It was a single acute ingestion, and a witness gives the time.

    The nomogram applies to an acute ingestion with a known time.

  2. Count the hours. From 21:00 to 03:00 is 6 hours, which is within 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 the result with the line. 118 µg/mL is above 106 µg/mL.

    The treating team acts on a result above the line.

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

    The team needs both times to interpret 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.

Practice this skill

Your turn

Problem 1 of 3 · Hints available

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 does not replace 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 · Hints available

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, which is pharmacologically active. 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 measures bound plus unbound drug.

Hint
  1. Consider which fraction of phenytoin is active.
  2. Low albumin changes how much of the total is unbound.

Review Total and free drug

Problem 3 of 3 · On your own

Four acetaminophen concentrations arrive overnight. Your laboratory follows the 2023 US and Canada consensus. Which one can be plotted on the nomogram?

The specimen was drawn 2 hours after ingestion. Absorption can still be under way, so this early concentration cannot be plotted.

Without a start time, there is no point on the time axis. Report the concentration and note the unknown start time for separate assessment.

The doses span 4 hours, so this is an acute ingestion. The specimen was drawn 9 hours after the first dose at 18:00, so it can be plotted. The treatment line at 9 hours is about 63 µg/mL. Report the concentration with the dose times and the draw time.

The doses span 52 hours, so this is repeated supratherapeutic ingestion. The nomogram does not apply, even with the last dose 5 hours before the draw. Report the concentration with the full dose history for the treating team or poison service.

Review Acetaminophen and salicylate overdose

Use it

Read the case evidence, then make each decision. The step is complete without 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/mL Delta1 day ago: 15.6 µg/mL15.6 µg/mL1 day ago10.0–20.0 µg/mL10.0–20.0Delta
Phenytoin, total12 µg/mL1 day ago: 13 µg/mL13 µg/mL1 day ago10–20 µg/mL10–20
Albumin2.0 g/dL Low1 day ago: 2.1 g/dL2.1 g/dL1 day ago3.5–5.0 g/dL3.5–5.0Low
Creatinine3.4 mg/dL High1 day ago: 3.3 mg/dL3.3 mg/dL1 day ago0.74–1.35 mg/dL0.74–1.35High

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 identifies that lumen.

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

Review Specimen integrity and interference

Decision 2 of 3

What do you do with the vancomycin?

With a comment, a result four times yesterday's trough stays in the record and may be compared with the trough target.

A repeat measures the same catheter drug again.

The draw time fits a trough, but drug left in the catheter makes the result reflect the lumen contents.

A specimen from a vein or lumen free of vancomycin, drawn before the dose, gives a trough that reflects the patient's drug concentration.

Review Specimen integrity and interference

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 warns that the total can understate the active drug, and a free phenytoin measures that drug directly.

Review Total and free drug

The draw site explains the high vancomycin:

  • 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.

For reference

Sources checked