Tales of the Anion Gap, Part II: Metabolic Acidosis

Normal acid-base balance in human beings is generally achieved by the pulmonary excretion of CO2 and the renal excretion of inorganic acids related to protein metabolism. This balance may be roughly summarized with the Henderson-Hasselbalch equation:

pH=pKa + log10 (A/HA) or:

pH=6.10 + log((HCO3-) / (0.03 X pCO2)) with a normal pH of 7.35-7.45

Acidemia refers to a metabolic condition in which, simply, the pH is low; this may be due to metabolic acidosis, respiratory acidosis, or a combination of both. Metabolic Acidosis refers to a pathologic condition in which a low pH is accompanied by a significant diminution of the serum HCO3- (versus what is normal for the patient)

Metabolic acidosis is caused by or associated with the following (these may occur in combination):

1. Increased acid production: eg. various poisonings, ketoacidosis, lactic acidosis
2. Bicarbonate loss eg. diarrhea, Type II (proximal) renal tubular acidosis, urinary diversion
3. Reduced renal excretion of inorganic acids eg. chronic renal failure, Type I (distal renal tubular acidosis)
4. Hyperchloremic acidosis related to dilution of serum bicarbonate by receiving large amounts of non-balanced IV fluids (eg, normal saline)

How should a patient with suspected metabolic acidosis be evaluated?

The patient’s blood electrolytes, pH and pCO2 should be measured. A venous blood gas (rather than arterial) is generally adequate for determination of the pCO2 and pH.

Most patients with a metabolic acidosis will attempt to neutralize their pH by hyperventilation, that is, by reducing their pCO2. This adaptation may occur within a few minutes and be essentially complete within hours. A variety of charts and normograms are used to evaluate the adequacy of this compensation, but the experienced clinician can generally identify the degree of compensation by sight or with a few mnemonics (eg, generally, pCO2 = 1.5 (Actual [HCO3] ) + 8 mmHg).

As an example, a patient with venous blood gas measurements of pH 7.32, HCO3-15, and pCO2 30 would demonstrate appropriate respiratory compensation for a metabolic acidosis, whereas a set of blood gases measuring pH 7.21, HCO3 15, and pCO2 39 would demonstrate both metabolic and respiratory acidosis.

When the patient is diagnosed with a metabolic acidosis, the measurement of the anion gap is of great usefulness. Recall, that the anion gap may be generally defined as: AG=unmeasured anions minus unmeasured cations. Because the unmeasured cations are usually stable in health and disease, attention may be primarily paid toward the nature and amount of the unmeasured anions.

An elevated anion gap implies the presence of an additional acid, generally dropping the serum HCO3 in a 1:1 fashion. Occasionally, this 1:1 ratio does not hold; this is called the delta gap. As remembered from Part I, the unmeasured anions are: serum proteins (albumin), organic acids, and inorganic acids. Examples of elevated anion gap metabolic acidosis include lactic acidosis, ketoacidosis, renal failure, and toxic alcohol and salicylate poisonings. Since normal anion gap metabolic acidosis implies loss of bicarbonate in most cases, examples of a normal anion gap metabolic acidosis include diarrhea, urinary diversion, proximal renal tubular acidosis, and use of carbonic anhydrase inhibitors.

In addition, most patients recovering from diabetic ketoacidosis with an elevated anion gap will in fact develop a normal anion (hyperchloremic) acidosis upon recovery.

It is critically important in defining normal versus high anion gap acidosis to be aware that:

1. The normal anion gap in most clinical laboratories is about 6 with a standard deviation of 1.5; therefore a patient with an anion gap of 9, previously considered normal would have an anion gap 2 standard deviations above the norm and would therefore be correctly classified as a high anion gap metabolic acidosis
2. Each one gram/dl lowering of the serum albumin will lower the anion gap by about 2.5. Therefore an acidotic, poorly nourished patient with an albumin of 2.0 and a calculated (normal) anion gap of 6 would have a similar acidotic picture as a patient with an anion gap of 11 and would be more accurately classified as an elevated anion gap metabolic acidosis even with a normal anion gap.
3. Unmeasured anions can be classified as serum proteins, organic acids and inorganic acids, so that one or more of these must be responsible for an increased anion gap metabolic acidosis.

To summarize, the evaluation of a patient with suspected metabolic acidosis should generally follow the following algorithm:

1. Is the patient acidotic?
2. Is the respiratory compensation appropriate?
3. Does the patient have an elevated or a normal anion gap acidosis?
4. If the anion gap is elevated, what is the unmeasured anion responsible?

Examples demonstrating the utility of these approaches will be provided with the next entry in this series.