Acid-Base Balance I: Classic Approach (Henderson-Hasselbalch)

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The Henderson-Hasselbalch Equation and the Bicarbonate Buffer System

The main chemical buffer system of the extracellular space is composed of the conjugate acid-base pair of carbonic acid (H₂CO₃) and bicarbonate (HCO₃^-). The hydration of carbon dioxide and subsequent dissociation to bicarbonate is catalyzed by the enzyme carbonic anhydrase:

CO₂ + H₂O Carbonic Anhydrase H₂CO₃ H⁺ + HCO₃^-

The relationship between these chemical species and the negative logarithm of the hydrogen ion concentration (pH) is classically expressed by the Henderson-Hasselbalch equation:

pH = pK_a + ₁₀ (([HCO₃^-])/(α · pCO₂) )

Where:

• pK_a is the dissociation constant for the bicarbonate/carbonic acid buffer at body temperature (6.1).
• [HCO₃^-] is the serum bicarbonate concentration in milliequivalents per liter.
• pCO₂ is the partial pressure of carbon dioxide in arterial blood expressed in mmHg.
• α is the physical solubility coefficient of carbon dioxide in plasma water at a temperature of 37C (α = 0.0301 mmol/L/mmHg).

This buffer system is ideal in mammals since both components of the dissociation fraction are physiologically open variables, independently regulated by the respiratory system (which modulates the pulmonary elimination or retention of CO₂) and by the renal system (which dynamically controls the reabsorption and tubular excretion of HCO₃^-).

The Anion Gap

Plasma behaves for all physical purposes as an electrically neutral solution. The principle of electrical neutrality establishes that the sum of all the cations in the system must be mathematically equivalent to the total of the anions present. Conventional clinical laboratory measurement quantifies only a fraction of these ions:

Na⁺ + Unmeasured Cations = (Cl^- + HCO₃^-) + Unmeasured Anions

The rearrangement of these terms defines the classical Anion Gap equation:

Anion Gap = Na⁺ - (Cl^- + HCO₃^-)

The reference value considered normal for the Anion Gap ranges between 12 ± 2 mEq/L (or between 8 and 12 mEq/L depending on the ion selective electrode methodology used in each laboratory). It represents the gap of anions that usually circulate freely but are not routinely measured in the laboratory (composed mainly of plasma proteins with a net negative charge, inorganic phosphates and sulfates).

Mandatory Anion Gap Correction due to Hypoalbuminemia

Because serum albumin represents the largest contribution to the negative charge of unmeasured anions in plasma, any persistent decrease in albumin concentration decreases the baseline calculated Anion Gap value, critically masking the presence of elevated anion gap metabolic acidosis.

The calculated value must be corrected using the following correction formula:

Anion Gap_corrected = Anion Gap_calculated + 2.5 · ( 4.0 - [Albumin] (g/dL) )

The Gap Ratio (Delta/Delta)

The Delta/Delta ratio is an indispensable quantitative tool for the early detection of mixed acid-base balance disorders in patients who initially present with a high anion gap metabolic acidosis. Its mathematical calculation is expressed by the equation:

Delta Ratio (Δ/Δ) = Anion Gap_calculated - 1224 - [HCO₃^-]_measured

Physiological Interpretation of Results:

• Value < 0.4: Indicates a pure Normal Anion Gap Metabolic Acidosis (Hyperchloremic).
• Value between 0.4 and 0.8: Reflects a mixed metabolic acidosis: concurrent combination of acidosis with elevated Anion Gap and hyperchloremic acidosis.
• Value between 1.0 and 2.0: Suggests the presence of a pure and compensated high Anion Gap metabolic acidosis (classic pattern in diabetic ketoacidosis or early lactic acidosis).
• Value > 2.0: Reveals a Concurrent Metabolic Alkalosis concomitant with primary high Anion Gap acidosis, or reflects a previous state of compensation for a chronic respiratory acidosis.