# Acid-Base Questions on USMLE: 9-Step ABG Method

> How do you approach acid-base questions on USMLE Step 1?

A nine-step ABG method for USMLE Step 1, with every compensation rule, the albumin-corrected anion gap, GOLD MARK, toxic alcohols and three worked cases.

Work every acid-base question in one order: pH, then the primary disorder from PaCO2 and bicarbonate, then expected compensation (Winter's formula or another compensation rule), then the albumin-corrected anion gap and, if it is high, the delta ratio. Compensation outside the predicted range means a second disorder; osmolal gap, urine anion gap and urine chloride settle the cause.

## How do you approach acid-base questions on USMLE Step 1?

Acid-base items reward a fixed reading order, since each step can expose a disorder the previous one hid. The USMLE content outline names all four primary disorders, "mixed acid-base disturbances," and ethylene glycol and methanol as toxins. Since 14 May 2026 the exam runs as fourteen 30-minute blocks of up to 20 questions, about 90 seconds per item.

The on-screen USMLE laboratory values table (April 2026) lists pH 7.35-7.45, PCO2 33-45 mm Hg, bicarbonate 22-28 mEq/L, albumin 3.5-5.5 g/dL and osmolality 275-295 mOsmol/kg, but no anion gap, so bring that value yourself.

Compensation moves the second variable in the same direction as the primary change, and, in the Merck Manual's words, it cannot return pH completely to normal and never overshoots. A normal pH with a clearly abnormal PaCO2 and bicarbonate is therefore two primary disorders (more on the [Nephrology](/topics/nephrology) hub).

## The acid-base algorithm in nine steps

Ask nine questions in the same order every time; steps 7 to 9 apply only on their branch.

| Step | Question | Rule or formula | What the answer means |
| --- | --- | --- | --- |
| 1 | Acidemia or alkalemia? | pH below 7.35 or above 7.45 | Normal pH with abnormal PaCO2 and HCO3: mixed disorder |
| 2 | Which change explains the pH? | Acidemia: low HCO3 or high PaCO2; alkalemia: the reverse | The primary disorder |
| 3 | Is compensation appropriate? | Winter's formula, the metabolic alkalosis rule or the respiratory rules | Outside the range: a second primary disorder |
| 4 | Is the anion gap high? | Na − (Cl + HCO3); anchor on 12, range lab-dependent | An unmeasured acid was added |
| 5 | Is albumin low? | Add 2.5 per 1 g/dL of albumin below 4.0 | Unmasks a hidden gap |
| 6 | Is a second metabolic process hidden? | Delta ratio = (AG − 12) / (24 − HCO3) | Below 1: added normal-gap acidosis; above 2: added metabolic alkalosis |
| 7 | High gap, unknown ingestion? | Osmolal gap = measured − (2 x Na + glucose/18 + BUN/2.8); above 10 | Methanol or ethylene glycol |
| 8 | Normal gap: gut or kidney? | Urine anion gap = urine Na + urine K − urine Cl | Negative: diarrhea; positive: renal tubular acidosis |
| 9 | Metabolic alkalosis: which kind? | Urine chloride below or above 20 mEq/L (Merck) | Chloride-responsive or chloride-unresponsive |

## Expected compensation: formulas and limits

Each primary disorder has its own predictable compensation rule.

| Primary disorder | Compensating change | Rule of thumb | Merck Manual range |
| --- | --- | --- | --- |
| Metabolic acidosis | PaCO2 falls | Winter's formula: PaCO2 = 1.5 x HCO3 + 8 ± 2 | 1.2 mm Hg per 1 mEq/L fall in HCO3 |
| Metabolic alkalosis | PaCO2 rises | About 0.7 mm Hg per 1 mEq/L rise in HCO3 above 24 | 0.6-0.75 mm Hg per 1 mEq/L |
| Acute respiratory acidosis | HCO3 rises | 1 mEq/L per 10 mm Hg rise in PaCO2 | 1-2 per 10 mm Hg |
| Chronic respiratory acidosis | HCO3 rises | 4 mEq/L per 10 mm Hg | 3-4 per 10 mm Hg |
| Acute respiratory alkalosis | HCO3 falls | 2 mEq/L per 10 mm Hg fall in PaCO2 | 1-2 per 10 mm Hg |
| Chronic respiratory alkalosis | HCO3 falls | 5 mEq/L per 10 mm Hg | 4-5 per 10 mm Hg |

The single numbers are shorthand inside Merck's ranges (StatPearls uses 1 and 4 for respiratory acidosis); every rule is an approximation, so call a second disorder only when the value clearly misses the range. More cases: this [Winter's formula question breakdown](/blog/2026-06-03-q-bank-breakdown-winter-s-formula-why-every-answer-choice-matters).

Renal compensation takes days (Merck: 3 to 5 for respiratory acidosis, 2 to 3 for respiratory alkalosis), so the history decides acute versus chronic. Merck caps compensatory PaCO2 in metabolic alkalosis near 55 mm Hg; anything higher adds a respiratory acidosis.

## Anion gap: normal range, albumin correction and the low gap

The anion gap, Na − (Cl + HCO3), estimates unmeasured anions, and its normal range varies by laboratory method and person (Kraut and Madias): StatPearls gives 4 to 12 mmol/L, a 2020 CDC report 3 to 10. StatPearls and Merck use 12 as the typical value, so anchor on 12 unless the stem gives a range.

Albumin is an unmeasured anion, so hypoalbuminemia lowers the gap and can mask a high-gap acidosis. StatPearls puts the effect at 0.25 mmol/L per 1 g/L; with normal albumin taken as 4.0 g/dL, corrected gap = measured gap + 2.5 x (4.0 − albumin in g/dL): a gap of 11 at an albumin of 2.0 g/dL corrects to 16. Correct routinely in critical illness and in any [nephrotic syndrome](/blog/nephrotic-vs-nephritic-syndrome-usmle) stem. A low gap is itself a clue: IgG myeloma, lithium toxicity, hypercalcemia and hypermagnesemia lower it.

## The delta ratio: finding a hidden second metabolic disorder

The delta ratio asks whether bicarbonate fell as far as the anion gap rose; in a pure high-gap acidosis each added proton consumes one bicarbonate and leaves one anion, so the changes roughly match.

| Delta ratio | Reading |
| --- | --- |
| Below 1 | Added normal-gap (hyperchloremic) acidosis |
| 1-2 | Uncomplicated high-gap acidosis; usually near 1, higher in lactic acidosis than in ketoacidosis |
| Above 2 | Added metabolic alkalosis, or a bicarbonate that started high (compensated chronic respiratory acidosis) |

StatPearls uses the difference, (AG − 12) − (24 − HCO3): above 6 means a metabolic alkalosis, below −6 a normal-gap acidosis. Treat cut-offs as soft: the ratio assumes a baseline gap of 12 and bicarbonate of 24, and Kraut and Madias warn it varies too much between patients to diagnose a mixed disorder alone. Practice: [mixed acid-base disorders question breakdown](/blog/2026-06-03-q-bank-breakdown-mixed-acid-base-disorders-why-every-answer-choice-matters).

## High anion gap acidosis: GOLD MARK replaces MUDPILES

GOLD MARK is a high anion gap mnemonic proposed in a 2008 Lancet letter by Mehta, Emmett and Emmett.

| Letter | Cause | Clue in the stem |
| --- | --- | --- |
| G | Glycols: ethylene and propylene glycol | Antifreeze with oxalate crystals and kidney injury; propylene glycol from lorazepam or phenobarbital infusions |
| O | Oxoproline (pyroglutamic acid) | Chronic acetaminophen use, often by malnourished women |
| L | L-lactate | Shock or sepsis (type A); metformin or NRTIs (type B) |
| D | D-lactate | Short bowel syndrome; routine lactate assays miss it |
| M | Methanol | Blurred vision or vision loss from formate |
| A | Aspirin | Tinnitus, hyperventilation and a primary respiratory alkalosis |
| R | Renal failure | Rising creatinine and BUN |
| K | Ketoacidosis | Diabetes, alcohol use disorder, fasting or undernutrition |

MUDPILES (methanol, uremia, diabetes, paraldehyde, iron and isoniazid, lactate, ethylene glycol, salicylates) is fading for the letter's reasons: paraldehyde acidosis is now exceedingly rare, iron and isoniazid are two of many toxins that act through lactic acidosis, and the list misses D-lactate, 5-oxoproline and propylene glycol. StatPearls still teaches CAT MUDPILES, so recognize both.

Ketoacidosis does not need a high glucose: the empagliflozin label (revised January 2026) warns glucose may be under 250 mg/dL, so ketones and a high gap on an SGLT2 inhibitor point to DKA, managed as in the [type 1 vs type 2 diabetes guide](/blog/diabetes-type-1-vs-type-2-usmle).

## Toxic alcohols and the osmolal gap

The osmolal gap is measured minus calculated serum osmolality; a large gap flags an unmeasured osmole such as methanol or ethylene glycol. Merck calculates 2 x Na + glucose/18 + BUN/2.8, plus blood ethanol/5 when present (a 2001 study found ethanol/3.7 fits better), and calls a difference above 10 abnormal. The osmolal gap peaks early and falls as alcohol dehydrogenase makes acids and the anion gap climbs, so a late presenter may have little osmolal gap left.

| Alcohol | Toxic product | Gap pattern | Distinguishing findings |
| --- | --- | --- | --- |
| Methanol | Formic acid (formate) | High anion gap and osmolal gap | Blurred vision or blindness from optic nerve injury; putamen necrosis |
| Ethylene glycol | Glycolic and oxalic acids | High anion gap and osmolal gap | Calcium oxalate crystals, acute kidney injury, hypocalcemia |
| Isopropyl alcohol | Acetone | Osmolal gap without anion gap acidosis | Ketosis without acidosis; hemorrhagic gastritis |

Fomepizole, a competitive alcohol dehydrogenase inhibitor, is labeled for ethylene glycol or methanol poisoning, alone or with hemodialysis (generic injections, no boxed warning, October 2026); ethanol blocks the same enzyme.

## Normal anion gap acidosis and the urine anion gap

A normal anion gap acidosis means bicarbonate was lost, the kidney failed to excrete acid, or chloride-rich fluid was added, so chloride rises as bicarbonate falls.

| Mechanism | Causes | Clue |
| --- | --- | --- |
| Gut bicarbonate loss | Diarrhea, enteric fistulas, ileostomy or colostomy | Negative urine anion gap |
| Kidney: acid excretion fails or bicarbonate leaks | Renal tubular acidosis types 1, 2 and 4; acetazolamide | Positive urine anion gap (type 2 varies) |
| Chloride-rich infusion | Rapid sodium chloride, ammonium chloride | Large-volume resuscitation |
| Urinary diversion | Ureterosigmoidostomy, ureteroileal conduit | Prior diversion surgery |
| Aldosterone deficiency (type 4 RTA) | Hypoaldosteronism | High potassium |

The urine anion gap, urine Na + urine K − urine Cl, indirectly measures urinary ammonium: negative when the kidney excretes acid normally and the loss was intestinal, positive with a renal loss. RTA types 1, 2 and 4 are separated in the [renal tubular acidosis guide](/blog/renal-tubular-acidosis-types-usmle).

## Metabolic alkalosis: urine chloride sorts the causes

Metabolic alkalosis needs a process that adds bicarbonate or removes acid and a kidney that keeps the excess, driven mainly by volume depletion and hypokalemia; in vomiting, hydrochloric acid leaves and aldosterone released by volume contraction holds bicarbonate in.

| Group | Urine chloride | Causes | Clue and fix |
| --- | --- | --- | --- |
| Chloride-responsive | Below 20 mEq/L | Vomiting or nasogastric suction, laxative abuse, diuretics after they wear off, posthypercapnia, cystic fibrosis sweat loss | Volume depletion; corrects with 0.9% saline |
| Chloride-unresponsive, hypertensive | Above 20 mEq/L | Primary aldosteronism (low renin, high aldosterone); licorice, Cushing or Liddle syndrome (both low); renovascular disease (both high) | Renin and aldosterone sort it |
| Chloride-unresponsive, normal or low blood pressure | Above 20 mEq/L | Diuretic still acting, Bartter or Gitelman syndrome, severe hypokalemia or hypomagnesemia | Replace potassium and magnesium |
| Alkali load | -- | Milk-alkali syndrome from calcium carbonate, bicarbonate loading | Antacid or supplement history |

| Feature | Bartter syndrome | Gitelman syndrome |
| --- | --- | --- |
| Defect and look-alike | Thick ascending limb; mimics a loop diuretic | Distal tubule NaCl cotransporter (SLC12A3); mimics a thiazide |
| Urine calcium | Normal or high; nephrocalcinosis common | Low |
| Serum magnesium | Normal or low | Low, sometimes very low |
| Usual presentation | Before birth to early childhood; antenatal form causes polyhydramnios | Late childhood to adulthood |

Both give hypokalemic metabolic alkalosis with high renin and aldosterone and low or low-normal blood pressure; surreptitious vomiting leaves urine chloride usually below 20 mmol/L, and a urine diuretic screen exposes diuretic misuse. More: this [metabolic alkalosis question breakdown](/blog/2026-06-03-q-bank-breakdown-metabolic-alkalosis-why-every-answer-choice-matters).

## Respiratory acidosis and alkalosis: causes to recognize

Respiratory disorders start with ventilation, so the history usually names the cause before the gas does.

| Disorder | Causes |
| --- | --- |
| Respiratory acidosis, central | Opioids, sedatives, anesthetics, alcohol, brainstem stroke |
| Respiratory acidosis, pump or lung | Neuromuscular weakness, chest wall defects, airway obstruction, COPD, inadequate ventilator settings |
| Respiratory alkalosis, central | Anxiety, pain, head injury, stroke, salicylates, progesterone in pregnancy, sepsis, chronic liver disease |
| Respiratory alkalosis, hypoxemia or lung | High altitude, pulmonary embolism, pneumonia, asthma, pulmonary edema |

Acute respiratory alkalosis brings perioral paresthesias, cramps and, as ionized calcium falls, carpopedal spasm. Pulmonary embolism often presents without hypoxia, so consider it in any hyperventilating patient. Lowering a chronic retainer's PaCO2 too fast unmasks the compensatory bicarbonate as a posthypercapnic alkalosis.

## Classic mixed disorders

Step 1 mixed disorders recur as a few clinical stories, each with a signature on the gas.

| Story | Disorders | Signature on the gas |
| --- | --- | --- |
| Salicylate poisoning | Respiratory alkalosis plus high-gap acidosis | PaCO2 below the Winter range; pH near normal or high early, low late |
| DKA after days of vomiting | High-gap acidosis plus metabolic alkalosis | Delta ratio above 2 |
| DKA after heavy saline, or with diarrhea | High-gap plus normal-gap acidosis | Delta ratio below 1 |
| COPD on a loop or thiazide diuretic | Chronic respiratory acidosis plus metabolic alkalosis | Bicarbonate above the chronic-compensation range |
| Sepsis | Lactic acidosis plus respiratory alkalosis | PaCO2 below the Winter range |

Salicylates stimulate the medullary respiratory center and uncouple oxidative phosphorylation; in young children the alkalosis often goes unrecognized. Treatment alkalinizes the urine to pH 7.5-8.5 with sodium bicarbonate, adding hemodialysis when severe.

> **10-second strategy:** pH -> primary disorder -> compensation -> albumin-corrected gap -> delta ratio if the gap is high; then osmolal gap for an unknown ingestion, urine anion gap for a normal gap, urine chloride for metabolic alkalosis.

## How USMLE tests acid-base: traps that cost points

Most acid-base items hide one number that changes the answer, and the wrong choices reward skipping a step.

- **Calling expected compensation a second disorder.** A PaCO2 inside the Winter range is physiology.
- **Trusting a normal pH.** A pH of 7.37 with a bicarbonate of 14 and a PaCO2 of 25 is two disorders: Winter's predicts 27 to 31, so a respiratory alkalosis rides on the acidosis.
- **Choosing paraldehyde or iron for short bowel syndrome or chronic acetaminophen use.** Think D-lactate and 5-oxoproline.

## Two worked ABG examples

Both gases follow the nine steps; every number checks by hand.

**Example 1: vomiting plus DKA.** A 19-year-old with type 1 diabetes has vomited for three days: sodium 135, chloride 88, bicarbonate 15 mEq/L, albumin 4.0 g/dL, serum ketones positive, pH 7.32, PaCO2 30 mm Hg.

1. **pH 7.32** with a low bicarbonate: metabolic acidosis.
2. **Winter's formula:** 1.5 x 15 + 8 = 30.5, range 28.5 to 32.5; the PaCO2 of 30 fits.
3. **Anion gap:** 135 − (88 + 15) = 32, high, with normal albumin.
4. **Delta ratio:** (32 − 12) / (24 − 15) = 2.2, above 2; the delta gap, 20 − 9 = 11, is also above 6.

Answer: compensated high anion gap ketoacidosis plus a metabolic alkalosis from vomiting.

**Example 2: COPD on a loop diuretic.** A 68-year-old with COPD started furosemide two weeks ago: pH 7.47, PaCO2 60 mm Hg, bicarbonate 42 mEq/L.

1. **pH 7.47** with a high bicarbonate: metabolic alkalosis.
2. **Expected PaCO2:** 40 + (0.6 to 0.75) x (42 − 24) is about 51 to 54 mm Hg, so the measured 60 adds a respiratory acidosis.
3. **Cross-check:** chronic respiratory acidosis at a PaCO2 of 60 predicts a bicarbonate of only about 30 to 32.

Answer: chronic respiratory acidosis plus a diuretic-induced metabolic alkalosis; urine chloride stays high while furosemide acts.

## Worked vignette: an unknown ingestion

A 34-year-old man arrives 10 hours after drinking an unlabeled liquid from his garage. He is drowsy, with normal vision. Serum sodium is 140 mEq/L, chloride 102 mEq/L, bicarbonate 10 mEq/L, BUN 14 mg/dL, creatinine 2.1 mg/dL, glucose 90 mg/dL, albumin 4.0 g/dL and measured osmolality 320 mOsmol/kg; ethanol is undetectable. Arterial pH is 7.26 and PaCO2 23 mm Hg. Urine microscopy shows calcium oxalate crystals. Which substance did he most likely drink?

- A. Ethanol
- B. Ethylene glycol
- C. Isopropyl alcohol
- D. Methanol
- E. Salicylates

**Answer: B.** A bicarbonate of 10 at pH 7.26 is a metabolic acidosis, and Winter's formula (1.5 x 10 + 8 = 23, range 21 to 25) fits the PaCO2. The gap is 140 − (102 + 10) = 28 with normal albumin, and the delta ratio, (28 − 12) / (24 − 10) = 1.1, hides no second process. Calculated osmolality is 2 x 140 + 90/18 + 14/2.8 = 290, an osmolal gap of 30. Both gaps mean a toxic alcohol, and oxalate crystals with kidney injury name ethylene glycol. Ethanol (A) is undetectable. Isopropyl alcohol (C) becomes acetone: ketosis without acidosis. Methanol (D) raises both gaps, but its formate targets the optic nerve and forms no oxalate. Salicylates (E) add a respiratory alkalosis that would pull PaCO2 below the Winter range.

**Next step:** fomepizole to block alcohol dehydrogenase, plus hemodialysis, which EXTRIP (2023) recommends for an anion gap above 27 mmol/L or kidney injury.

## Sources

- StatPearls (NCBI Bookshelf): [Metabolic acidosis](https://www.ncbi.nlm.nih.gov/books/NBK482146/), [Biochemistry, anion gap](https://www.ncbi.nlm.nih.gov/books/NBK539757/), [Respiratory acidosis](https://www.ncbi.nlm.nih.gov/books/NBK482430/)
- PubMed: [Mehta 2008, GOLD MARK](https://pubmed.ncbi.nlm.nih.gov/18790311/), [Reddy 2009, delta ratio](https://pubmed.ncbi.nlm.nih.gov/19769708/), [Kraut 2007, anion gap](https://pubmed.ncbi.nlm.nih.gov/17699401/), [Kraut 2013, gap by acid](https://pubmed.ncbi.nlm.nih.gov/23833313/), [Purssell 2001, ethanol](https://pubmed.ncbi.nlm.nih.gov/11719745/), [EXTRIP 2023, ethylene glycol](https://pubmed.ncbi.nlm.nih.gov/36765419/)
- CDC MMWR: [Methanol hand sanitizer poisonings, 2020](https://www.cdc.gov/mmwr/volumes/69/wr/mm6932e1.htm)
- USMLE: [Step 1 format](https://www.usmle.org/step-exams/step-1), [content outline (PDF)](https://www.usmle.org/sites/default/files/2022-01/USMLE_Content_Outline_0.pdf), [sample items and laboratory values (PDF)](https://www.usmle.org/sites/default/files/2021-10/Step_1_Sample_Items.pdf)

Turn the nine steps into a reflex on timed vignettes: [Practice acid-base questions on StepGenie](https://dashboard.stepgenie.app/sign-up).

## Frequently asked questions

### What is Winter's formula and when do you use it?

Winter's formula predicts the respiratory compensation for a metabolic acidosis: expected PaCO2 equals 1.5 times the bicarbonate plus 8, give or take 2. Use it on every metabolic acidosis. At a bicarbonate of 12, the expected PaCO2 is 24 to 28 mm Hg. A measured PaCO2 inside that range means compensation is appropriate; a higher value adds a respiratory acidosis, and a lower one adds a respiratory alkalosis, as in salicylate poisoning or sepsis.

### What is a normal anion gap, and how do you correct it for albumin?

The anion gap is sodium minus the sum of chloride and bicarbonate, and its normal range depends on the laboratory method: StatPearls gives 4 to 12 mmol/L, and a 2020 CDC report used 3 to 10. StatPearls and the Merck Manual use 12 as the typical value, and the USMLE laboratory table lists no anion gap range. Because albumin is an unmeasured anion, add 2.5 mEq/L to the measured gap for every 1 g/dL that albumin falls below 4.0 g/dL.

### Is MUDPILES still used, or should you learn GOLD MARK?

Learn GOLD MARK and recognize MUDPILES. GOLD MARK, from a 2008 Lancet letter, stands for glycols (ethylene and propylene), oxoproline, L-lactate, D-lactate, methanol, aspirin, renal failure and ketoacidosis. Its authors noted that paraldehyde acidosis has become exceedingly rare, that iron and isoniazid are only two of many toxins acting through lactic acidosis, and that MUDPILES misses D-lactate, 5-oxoproline and propylene glycol. Both cover the classic causes, but only GOLD MARK names the newer acids.

### How does urine chloride classify metabolic alkalosis?

Urine chloride below 20 mEq/L means the kidney is reabsorbing chloride avidly: a chloride-responsive alkalosis from vomiting, nasogastric suction, laxative abuse or diuretics that have worn off, which corrects with 0.9% saline. Urine chloride above 20 points to a chloride-unresponsive cause, either mineralocorticoid excess with hypertension or, with normal or low blood pressure, Bartter syndrome, Gitelman syndrome, severe hypokalemia or a diuretic that is still acting. Diuretics raise urine chloride only while they act.

### What acid-base disorder does salicylate toxicity cause?

Salicylate toxicity causes two primary disorders at once. Salicylates stimulate the medullary respiratory center, producing a respiratory alkalosis, and uncouple oxidative phosphorylation, so lactic and keto acids build a high anion gap metabolic acidosis. Respiratory alkalosis dominates early and metabolic acidosis later, and in young children the alkalosis often goes unrecognized. Expect tinnitus, nausea, vomiting and hyperventilation with a PaCO2 below the Winter range. Treatment alkalinizes the urine with sodium bicarbonate, adding hemodialysis for severe poisoning.

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