# Acid-Base Disorders: A Systematic Approach

## Overview

Acid-base analysis is a foundational clinical reasoning skill for internal medicine residents. A systematic stepwise approach prevents missed diagnoses, especially in mixed disorders. The analysis requires integration of arterial blood gas (ABG) data, serum electrolytes, and clinical context. The traditional Henderson-Hasselbalch approach remains the most widely taught and clinically practical method.

## Physiology Review

### Normal Values

Normal arterial pH ranges from 7.35 to 7.45, PaCO2 from 35 to 45 mmHg, bicarbonate from 22 to 26 mEq/L, PaO2 from 80 to 100 mmHg, and the anion gap from 8 to 12 mEq/L without albumin correction.

### Buffer Systems

The bicarbonate buffer system (CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3-) is the primary system. The kidneys regulate bicarbonate (the metabolic component) over hours to days, while the lungs regulate CO2 (the respiratory component) within minutes to hours. Additional buffers include hemoglobin, phosphate, and proteins.

## Stepwise Approach to ABG Interpretation

### Step 1: Assess the pH

A pH below 7.35 indicates acidemia, a pH above 7.45 indicates alkalemia, and a pH between 7.35 and 7.45 may be normal or may reflect a mixed disorder with offsetting processes.

### Step 2: Identify the Primary Disorder

Metabolic acidosis presents with low pH and low bicarbonate. Metabolic alkalosis presents with high pH and high bicarbonate. Respiratory acidosis presents with low pH and high PaCO2. Respiratory alkalosis presents with high pH and low PaCO2.

### Step 3: Assess Compensation

| Primary Disorder | Compensation Formula | Expected Change |
|-----------------|---------------------|----------------|
| Metabolic acidosis | Winter's: PaCO2 = (1.5 × HCO3) + 8 ± 2 | PaCO2 decreases |
| Metabolic alkalosis | PaCO2 = (0.7 × HCO3) + 21 ± 2 | PaCO2 increases |
| Acute respiratory acidosis | HCO3 rises 1 mEq/L per 10 mmHg ↑PaCO2 | Minimal compensation |
| Chronic respiratory acidosis | HCO3 rises 3.5 mEq/L per 10 mmHg ↑PaCO2 | Renal compensation |
| Acute respiratory alkalosis | HCO3 falls 2 mEq/L per 10 mmHg ↓PaCO2 | Minimal compensation |
| Chronic respiratory alkalosis | HCO3 falls 5 mEq/L per 10 mmHg ↓PaCO2 | Renal compensation |

For metabolic acidosis, the expected PaCO2 is calculated using Winter's formula: (1.5 x HCO3) + 8, with a range of plus or minus 2. For metabolic alkalosis, expected PaCO2 equals (0.7 x HCO3) + 21, plus or minus 2. In acute respiratory acidosis, bicarbonate rises 1 mEq/L per 10 mmHg rise in PaCO2. In chronic respiratory acidosis, bicarbonate rises 3.5 mEq/L per 10 mmHg rise in PaCO2. In acute respiratory alkalosis, bicarbonate falls 2 mEq/L per 10 mmHg fall in PaCO2. In chronic respiratory alkalosis, bicarbonate falls 5 mEq/L per 10 mmHg fall in PaCO2. If compensation is more or less than expected, a mixed disorder is present.

### Step 4: Calculate the Anion Gap

The anion gap equals sodium minus (chloride plus bicarbonate). It must be corrected for albumin: adjusted AG equals the calculated AG plus 2.5 multiplied by (4.0 minus measured albumin). An elevated anion gap (above 12) indicates an anion gap metabolic acidosis (AGMA).

### Step 5: Calculate the Delta-Delta Ratio (if AGMA present)

The delta-delta ratio equals (AG minus 12) divided by (24 minus bicarbonate). A ratio below 1 indicates a concurrent non-anion gap metabolic acidosis. A ratio between 1 and 2 indicates a pure AGMA. A ratio above 2 indicates a concurrent metabolic alkalosis.

<image>Stepwise algorithm for arterial blood gas interpretation showing assessment of pH, primary disorder identification, compensation analysis, anion gap calculation, and delta-delta ratio</image>

## Anion Gap Metabolic Acidosis (AGMA)

### Differential Diagnosis -- MUDPILES

The MUDPILES mnemonic captures the major causes: Methanol, Uremia, Diabetic ketoacidosis (and starvation/alcoholic ketoacidosis), Propylene glycol, Isoniazid/Iron, Lactic acidosis, Ethylene glycol, and Salicylates.

### Lactic Acidosis

Type A lactic acidosis results from tissue hypoperfusion, including shock, cardiac arrest, severe hypoxemia, and mesenteric ischemia. Type B occurs without tissue hypoperfusion and is caused by medications (metformin, linezolid, epinephrine), liver failure, malignancy, thiamine deficiency, or seizures. D-lactic acidosis occurs in short bowel syndrome and is not detected by standard lactate assays, which measure only L-lactate.

### Osmolar Gap

Calculated osmolality equals 2 times sodium plus glucose divided by 18 plus BUN divided by 2.8. The osmolar gap is the difference between measured and calculated osmolality. An elevated gap (above 10) suggests toxic alcohols such as methanol, ethylene glycol, or isopropanol.

<image>Differential diagnosis framework for anion gap metabolic acidosis with MUDPILES mnemonic and associated osmolar gap patterns</image>

## Non-Anion Gap Metabolic Acidosis (NAGMA)

### Key Feature

NAGMA presents as a hyperchloremic metabolic acidosis with low bicarbonate accompanied by a proportional rise in chloride.

### Differential -- HARDUPS

The HARDUPS mnemonic covers the causes: Hyperalimentation (TPN), Acetazolamide/Addison disease, Renal tubular acidosis, Diarrhea (the most common cause), Ureteral diversions (ileal conduit), Pancreatic fistula, and Saline infusion (dilutional).

### Renal Tubular Acidosis (RTA)

| RTA Type | Defect | Urine pH | Potassium | Key Associations |
|----------|--------|----------|-----------|-----------------|
| Type 1 (Distal) | Cannot secrete H+ | >5.5 | Low | Nephrolithiasis, nephrocalcinosis, Sjogren's, SLE |
| Type 2 (Proximal) | Cannot reabsorb HCO3- | Variable | Low | Fanconi syndrome, myeloma, acetazolamide |
| Type 4 (Hypoaldo) | Low aldosterone/resistance | <5.5 | High | Diabetic nephropathy, ACEi/ARBs, spironolactone |

Type 1 (Distal RTA) results from inability to secrete hydrogen ions, producing a urine pH above 5.5, hypokalemia, and nephrolithiasis or nephrocalcinosis. Type 2 (Proximal RTA) involves inability to reabsorb bicarbonate, with variable urine pH, hypokalemia, and Fanconi syndrome. Type 4 (Hypoaldosteronism) is characterized by hyperkalemia and urine pH below 5.5, commonly resulting from diabetic nephropathy, ACE inhibitors/ARBs, or spironolactone.

### Urine Anion Gap

The urine anion gap equals urine sodium plus urine potassium minus urine chloride. A negative urine anion gap indicates GI loss with appropriate renal ammonium excretion. A positive urine anion gap indicates a renal cause (RTA with impaired ammonium excretion).

## Metabolic Alkalosis

### Etiologies

Chloride-responsive metabolic alkalosis (urine chloride below 20 mEq/L) is caused by vomiting, nasogastric suction, diuretics (after effect), and post-hypercapnia. Chloride-resistant metabolic alkalosis (urine chloride above 20 mEq/L) results from hyperaldosteronism, Cushing syndrome, Bartter/Gitelman syndromes, active diuretic use, and severe hypokalemia.

### Management

Chloride-responsive alkalosis is treated with normal saline resuscitation and KCl replacement. Chloride-resistant alkalosis requires treatment of the underlying cause, with acetazolamide useful in select cases such as volume-overloaded patients with metabolic alkalosis. Rarely, HCl infusion is needed for severe refractory metabolic alkalosis with pH above 7.65.

<image>Classification of metabolic alkalosis by urine chloride concentration distinguishing chloride-responsive from chloride-resistant etiologies</image>

## Respiratory Acid-Base Disorders

### Respiratory Acidosis

Acute causes include CNS depression (opioids, sedatives), neuromuscular disease (myasthenia gravis, Guillain-Barre syndrome), and upper airway obstruction. Chronic causes include COPD, obesity hypoventilation syndrome, and neuromuscular disease. Management focuses on treating the underlying cause, with non-invasive ventilation or mechanical ventilation as needed.

### Respiratory Alkalosis

Respiratory alkalosis is the most common acid-base disorder in hospitalized patients. Causes include pain, anxiety, fever, early sepsis, pulmonary embolism, pregnancy, hepatic encephalopathy, salicylate toxicity, and high altitude. It rarely requires specific treatment beyond addressing the underlying cause.

## The Stewart (Physicochemical) Approach

The Stewart approach is an alternative framework based on the strong ion difference (SID), total weak acids (Atot), and PaCO2. It may better explain complex acid-base disturbances in critically ill patients but is more complex to apply at the bedside, and the traditional approach remains standard for most clinical scenarios. It highlights the important role of chloride and albumin in acid-base balance.

## Clinical Pearls

The anion gap must always be corrected for albumin because hypoalbuminemia is common in hospitalized patients and masks a true AGMA. A normal pH does not mean normal acid-base status, and mixed disorders should always be sought. In DKA, a delta-delta ratio above 2 suggests pre-existing metabolic alkalosis (such as from vomiting) or pre-existing chronic respiratory acidosis. Compensation never overcorrects; if it appears to, a second primary disorder is present. Salicylate toxicity classically causes a mixed primary respiratory alkalosis and primary AGMA. In chronic respiratory acidosis with acute decompensation, the degree of bicarbonate elevation helps determine the chronic versus acute component.

## References

- Seifter JL. Integration of Acid-Base and Electrolyte Disorders. N Engl J Med. 2014;371:1821-1831.
- Berend K, et al. Physiological Approach to Assessment of Acid-Base Disturbances. N Engl J Med. 2014;371:1434-1445.
- Emmett M, Palmer BF. Simple and Mixed Acid-Base Disorders. UpToDate. 2024.
- Kraut JA, Madias NE. Lactic Acidosis. N Engl J Med. 2014;371:2309-2319.
- Adeva-Andany M, et al. Comprehensive Review on Lactate Metabolism. Mitochondrion. 2014;17:76-100.