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The anion gap and lactate

17 min

Skills you'll build4 skills
  • Calculate an anion gap using the stated potassium convention
  • Correct an anion gap for albumin under the stated convention
  • Calculate a delta ratio using compatible gap and bicarbonate baselines
  • Check a raised lactate for processing delay, glycolate interference, and nonhypoxic causes

At the bench: Assess specimen interference before reporting a chemistry result · Review electrolyte results and related calculations for consistency

Try first

Try first

Your laboratory calculates the anion gap without potassium and reports it against 7 to 16 mmol/L. A panel gives sodium 138, potassium 4.5, chloride 100 and bicarbonate 22 mmol/L. A colleague reports a gap of 20.5 mmol/L and flags it high. What went wrong?

Right. Keep going to follow the reasoning.

Keep going to see 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.

Anion gap conventions

The anion gap is the excess of unmeasured anions over unmeasured cations. Without potassium: AG = sodium − (chloride + bicarbonate), all in mmol/L. The potassium-inclusive convention adds potassium (mmol/L). Interpret with the interval for the selected convention.1

The potassium-inclusive gap is higher by the measured potassium, about 4 mmol/L. A gap is interpreted only against the interval for its own convention. The examples here leave potassium out, with an interval of about 7 to 16 mmol/L.1

Correct the gap for albumin

Albumin is the largest normal unmeasured anion. Each 1 g/dL fall in albumin lowers the expected gap by about 2.5 mmol/L, so a low albumin can mask a raised gap. Albumin-corrected anion gap (AG, mmol/L) = measured AG (mmol/L) + 2.5 × [4.0 − albumin (g/dL)]. The correction is approximate, and the selected gap convention and laboratory interval still apply.2

The delta ratio

After the albumin correction, compare the rise in the gap with the fall in bicarbonate:1

Delta ratio = (measured gap − normal gap) ÷ (normal bicarbonate − measured bicarbonate)

The normal values match the gap convention in use, for example a gap of 12 mmol/L and bicarbonate of 24 mmol/L. A ratio of about 1 to 2 fits a single high-gap acidosis. A ratio below 1 suggests an added normal-gap acidosis. A ratio above 2 suggests an added metabolic alkalosis or a high starting bicarbonate.1

Causes of a raised lactate

Lactate is the most common unmeasured anion in acute illness. It rises when production outpaces clearance.1 Tissue hypoxia is one cause. Adrenergic drive, liver failure, some drugs and some cancers raise it too.1 Two causes are preanalytical or analytical:

  • Processing delay. Cells continue to produce lactate in the tube. A specimen left unspun at room temperature reads falsely high. The tube, temperature and time to separation follow the assay's instructions.3
  • Glycolate. This ethylene glycol metabolite reads as lactate on some lactate oxidase methods. Disagreement with a second method reveals the interference.4

When the gap and the lactate disagree, confirm the specimens, the convention and the handling before release.1

Follow the bench demonstration

Sources for this step
References
  1. Rifai N, Chiu RWK, Young I, Burnham CAD, Wittwer CT, eds. Tietz Textbook of Laboratory Medicine. 7th ed. Elsevier; 2023.
  2. Haber LA, Dhaliwal G, Lo L, Rizzuto G. Evaluating a low anion gap: a practical approach. Cleve Clin J Med. 2023;90(10):619-623. doi:10.3949/ccjm.90a.23035
  3. Hashim IA, Mohamed M, Cox A, Fernandez F, Kutscher P. Plasma lactate measurement as an example of encountered gaps between routine clinical laboratory processes and manufacturers' sample-handling instructions. Pract Lab Med. 2018;12:e00109. doi:10.1016/j.plabm.2018.e00109
  4. Brindley PG, Butler MS, Cembrowski G, Brindley DN. Falsely elevated point-of-care lactate measurement after ingestion of ethylene glycol. CMAJ. 2007;176(8):1097-1099. doi:10.1503/cmaj.061288

Watch one

Read each decision and its explanation.

A patient with liver disease has sodium 140, potassium 4.0, chloride 106 and bicarbonate 20 mmol/L, with albumin 1.9 g/dL. Your laboratory uses the no-potassium convention with an interval of 7 to 16 mmol/L. Is the anion gap raised?

  1. Choose the convention: no potassium, read against 7 to 16 mmol/L.

    The laboratory's convention determines which ions enter the calculation.

  2. Calculate the gap: 140 − (106 + 20) = 14 mmol/L, which is within the interval.

    The gap is sodium minus the two measured anions.

  3. Find the albumin deficit: 4.0 − 1.9 = 2.1 g/dL.

    Albumin is the largest normal unmeasured anion, and this albumin is low.

  4. Correct the gap: 14 + 2.5 × 2.1 = 14 + 5.25 = 19.3 mmol/L.

    Each 1 g/dL of missing albumin lowers the expected gap by about 2.5 mmol/L.

  5. Compare: 19.3 mmol/L is above 16 mmol/L.

    The corrected gap is read against the same convention's interval.

The albumin-corrected gap is 19.3 mmol/L, which is raised. The low albumin masked the excess unmeasured anions in the uncorrected gap of 14 mmol/L.

Practice this skill

Your turn

Problem 1 of 3 · Hints available

Using corrected anion gap (AG) = AG + 2.5 × (4.0 − albumin), what is the corrected gap for AG 10 mmol/L and albumin 2.0 g/dL?

Correct. 10 + 2.5 × (4.0 − 2.0) = 10 + 5 = 15 mmol/L, which is then compared with the interval for the selected convention.

Incorrect. 10 − 5 = 5 mmol/L subtracts the albumin term. Low albumin lowers the expected gap, so the correction adds to it.

Incorrect. This adds 2.5 only once. The albumin deficit is 2.0 g/dL, so the added term is 2.5 × 2.0 = 5 mmol/L.

Hint
  1. Find how far the albumin is below 4.0 g/dL.
  2. Multiply that deficit by 2.5, then decide whether it adds to or subtracts from the gap.

Review Interpreting the gap

Problem 2 of 3 · Hints available

After any needed albumin correction, the anion gap (AG) is 28 mmol/L and bicarbonate is 16 mmol/L. Using normal AG 12 and bicarbonate 24 mmol/L, what is the delta ratio?

Incorrect. 8 ÷ 16 = 0.5 inverts the ratio. The rise in the gap is divided by the fall in bicarbonate.

Incorrect. 28 ÷ 16 = 1.75 divides the measured values and skips both baseline differences.

Correct. (28 − 12) ÷ (24 − 16) = 16 ÷ 8 = 2.0, at the upper end of the 1.0 to 2.0 range typical of a relatively pure high-anion-gap metabolic acidosis.

Hint
  1. The top of the ratio is the rise in the gap above its normal value.
  2. The bottom is the fall in bicarbonate below its normal value.

Review Delta gap and delta ratio

Problem 3 of 3 · On your own

Sodium is 136, chloride 104 and bicarbonate 18 mmol/L, with albumin 2.4 g/dL. Using the no-potassium convention and corrected gap = gap + 2.5 × (4.0 − albumin), what is the albumin-corrected anion gap?

Show the answer

18 mmol/L

Gap = 136 − (104 + 18) = 14 mmol/L. Corrected gap = 14 + 2.5 × (4.0 − 2.4) = 14 + 4 = 18 mmol/L.

Review Interpreting the gap

Use it

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

  • Ines Blank, 58, MRN 7815024, is a stable outpatient at a routine visit.
  • Plasma lactate is ordered. The procedure requires a heparin tube on ice, separated within 15 minutes.
  • The lactate tube sat unspun at room temperature for 3 hours before processing.
  • The chemistry panel came from a separate tube, handled on time.
  • She has no history of toxic ingestion.
  • QC for both runs is acceptable.
TestResultReference intervalFlag
Lactate5.4 mmol/L High0.5–2.2 mmol/L0.5–2.2High
Sodium139 mmol/L135–145 mmol/L135–145
Potassium4.2 mmol/L3.5–5.1 mmol/L3.5–5.1
Chloride103 mmol/L98–107 mmol/L98–107
Total CO225 mmol/L22–29 mmol/L22–29
Albumin4.1 g/dL3.5–5.0 g/dL3.5–5.0

Specimen: H 8, L 12, I 1. Lactate: heparin tube unspun at room temperature for 3 hours. Panel: separate tube, handled on time.

Decision 1 of 3

Using the no-potassium convention, what is her anion gap?

(139 + 4.2) − (103 + 25) = 15.2 mmol/L includes potassium. The no-potassium gap is 139 − (103 + 25) = 11 mmol/L.

Read a potassium-inclusive gap on a no-potassium interval

The potassium-inclusive gap is higher than the no-potassium gap by the measured potassium, about 4 mmol/L. Read against a no-potassium interval, a specimen with a normal gap can look high.

139 − 103 = 36 mmol/L leaves out bicarbonate. Both chloride and bicarbonate are subtracted from sodium.

139 − (103 + 25) = 11 mmol/L, inside the 7 to 16 mmol/L interval. With albumin at 4.1 g/dL, no correction is needed.

Review The anion gap

Decision 2 of 3

What best explains the lactate of 5.4 mmol/L?

A stable outpatient with a normal gap and bicarbonate shows nothing that points to poor oxygen delivery. The lactate tube sat unspun for 3 hours, and its cells continued to produce lactate.

Read a raised lactate as tissue hypoxia

Lactate rises with adrenergic drive, impaired clearance, delayed processing, and glycolate interference as well as with hypoxia. Reading every elevation as tissue hypoxia misses the specimen and method causes, such as a falsely high lactate from delayed processing.

Red and white cells continue glycolysis until the plasma is separated. Three hours at room temperature is far outside the procedure, and the normal gap and bicarbonate fit a patient without lactic acidosis.

Glycolate comes from ethylene glycol, and she has no history of it. The handling error is enough to explain the result.

Review Lactate

Decision 3 of 3

What do you do with the lactate?

The tube was handled outside the procedure, and the value includes lactate made after collection. If released, it would be interpreted as a raised patient lactate.

Read a raised lactate as tissue hypoxia

Lactate rises with adrenergic drive, impaired clearance, delayed processing, and glycolate interference as well as with hypoxia. Reading every elevation as tissue hypoxia misses the specimen and method causes, such as a falsely high lactate from delayed processing.

A comment cannot say how much of the 5.4 mmol/L came from the tube. The falsely high result would still be reported.

The handling error happened after collection, so a correctly handled redraw gives a lactate that reflects her true value. Record the reason on the order.

A repeat measures the same plasma and the same lactate made during the delay.

Review Lactate

The handling record and the anion gap explain this lactate. The tube sat unspun for 3 hours, and her gap of 11 mmol/L and bicarbonate of 25 mmol/L show no acid load. The raised lactate came from glycolysis in the tube, so the specimen is redrawn.

For reference

Sources checked