When this calculation is carried through in a patient with metabolic acidosis, recognized as a fall in both pH and HCO₃ concentration, a comparison can be made between the calculated Pco₂ and the patient’s Pco₂. If the observed and calculated values for Pco₂ are similar, a primary metabolic acidosis causing the acidemia is suggested. However, as mentioned before, there could be a metabolic acidosis of greater magnitude and a simultaneous metabolic alkalosis such that the pH remains acid. The Winter equation reaches importance in establishing a mixed disturbance. If, for example, the Pco₂ observed was less than the Pco₂ calculated for a primary metabolic acidosis, a second condition lowering Pco₂ is suspected; and that would need to be a primary respiratory alkalosis. A simple approach to considering acid–base problems is depicted in box 59.1.

Box 59.1 GENERAL APPROACH TO AN ACID–BASE DISORDER

METABOLIC ACIDOSIS

Retention of acid consumes endogenous alkali stores, reflected by a fall in serum bicarbonate. However, serum bicarbonate, if at a stable level, is not in itself an indication of the achievement of external acid–base balance. For example, in some patients with chronic kidney disease or those with some form of renal-tubular acidosis, there is a daily retention of acid with a stable but low bicarbonate concentration. The acid is incorporated into bone mineral, liberating bicarbonate salts at the expense of bone disease. Metabolic acidosis may be the result of one or more of three processes: (1) the pathologic overproduction of endogenous acids, such as ketoacids and lactic acid, or the consumption of exogenous substances such as methanol with an acidic form (formic acid); (2) a failure of renal acid excretion and bicarbonate regeneration, as in kidney failure; and (3) loss of alkali stores, as in diarrhea or renal-tubular acidosis.

CLASSIFICATION OF METABOLIC ACIDOSES

The Anion Gap

Chemically, the classification to help arrive at a diagnosis is made by the use of the serum anion gap (AG). The anion gap, which only reports the usual, routinely measured electrolytes, will yield a gap because normally circulating ions are not being directly measured and entered into the equation. If they were, there would be electroneutrality and hence no gap. The equation for the serum anion gap is as follows:

    The usual normal contributor to the anion gap is circulating albumin, which accounts for about 10–12 mEq/L or 2.5 mEq/L per g/dL of albumin. When the actual number deviates from the normal anion gap, the presence of an unmeasured charged species is indicated. If the gap is higher than normal, there is an unmeasured anion such as lactate or salicylate. If the anion gap is lower than normal, either a low albumin state exists or there is the presence of an unmeasured cation, as in multiple myeloma.

    A comparison may be made between the change in the anion gap from normal (the anion gap observed minus 12) to the change in bicarbonate concentration from normal (25 minus the bicarbonate). This entity, known as the delta-delta, may help to determine a mixed disorder. Examples include a large increase in the anion gap without as large an increase in the change in the bicarbonate fall; such a finding might suggest the simultaneous presence of an anion-gap metabolic acidosis and a metabolic alkalosis. Alternatively, the gap acidosis could be associated with a chronic respiratory acidosis, which would also tend to raise the bicarbonate concentration. Another example would be the observation of a change in bicarbonate concentration greater than the change in anion gap, as would be found in the setting of simultaneous anion-gap metabolic acidosis and either a respiratory alkalosis or an additional hyperchloremic metabolic acidosis.

    Causes of an anion-gap metabolic acidosis are shown in table 59.3. In patients with chronic renal failure, sulfates, phosphates, and organic acid anions are poorly filtered and accumulate in the extracellular space. l-Lactic acidosis is another common cause, induced by either hypotensive shock, hypoxemia, or sepsis, but also by tumors, such as certain lymphomas, as well as drugs and toxic ingestions. Some drugs that can cause lactic acidosis include isoniazid and nucleoside reverse transcriptase inhibitors. Propylene glycol, used as the diluent for many drugs, including lorazepam, when given in high concentrations may metabolize to lactic acid. Metformin, used in treatment of diabetes, is more likely to cause lactic acidosis when used in the setting of poor renal function. In some patients with intestinal bacterial overgrowth, a condition known as d-lactic acidosis may develop as a result of the bacterial lactate dehydrogenase and the production of the nonphysiological isomer of lactic acid, d-lactic acid.

    Salicylates are among other ingestions that may result in anion-gap metabolic acidosis, particularly in overdose situations. Acetaminophen toxicity has increasingly been found to be a cause of acquired 5-oxoprolinuria. Methanol will cause a severe anion-gap acidosis with toxic acids including formic acid developing; and ethylene glycol, particularly ingested in antifreeze, will give organic acid anions. In some cases it is useful to compare an anion gap and osmolar gap to support the suspicion of a toxic overdose. The calculated osmolarity is 2 × [Na] + [glu]/18 + [BUN]/2.8 + [ethanol]/4.6, where glucose, blood urea nitrogen (BUN) and ethanol concentrations are given as milligrams per deciliter. The measured osmolality is performed by freezing point depression in the laboratory. The difference between measured and calculated values should be normally <10 mOsm/kg. If that value is exceeded, then the presence of a nonelectrolyte is suspected. If there is also an anion gap present, then the clinician should suspect substances such as methanol and ethylene glycol. The goal of therapy would be to prevent breakdown of the alcohols to the toxic acid anions. Treatments such as inhibitors of alcohol dehydrogenase and hemodialysis are frequently used.

    The “delta-delta,” which is the relationship between the change in anion gap from normal and the change in the serum bicarbonate from normal, is expressed:

For example, if a patient with a normal serum albumin and an acidemia had an anion gap of 32 mEq/L and a serum HCO₃^– of 11 mEq/L, the delta/delta would be 20/14. This value exceeds 1 and therefore suggests the presence of an additional metabolic alkalosis.

HYPERCHLOREMIC ACIDOSIS

In this group of disorders (table 59.4), the serum anion gap is normal because the fall in bicarbonate concentration is balanced by an increase in the chloride concentration instead of an unmeasured anion. The more common disorders are associated with hypokalemia, as in the following instances. In the case of watery diarrhea with large stool volumes, the loss of K⁺ and Na⁺ are accompanied either by HCO₃^– or by organic anions of bacterial origin. These losses may be excessive in small bowel disease or ileostomies—but also in the majority of colonic diarrhea cases. Several forms of renal tubular acidosis are also associated with losses of Na⁺, K⁺, and HCO₃^–, resulting in a relatively increased Cl^– concentration in the blood to compensate for the loss of HCO₃^–. These disorders are usually distinguished from each other by the medical history, but evaluation of urine electrolytes may be useful. Attention should be paid to the urinary anion gap:

    In the presence of a non–anion-gap metabolic acidosis, if the value is greater than zero, an additional unmeasured anion is suggested. Assuming that this value does not represent an excreted anion, such as a ketoacid anion, then this finding suggests the absence of large amounts of the cation NH₄⁺. NH₄⁺ should be very elevated in patients whose acidosis originates from a nonrenal source because the kidney’s capacity to generate NH₃ is preserved. Therefore, when the anion gap is positive and ammonium is low, a renal source is suggested. When the anion gap is negative (i.e., less than zero) it is assumed that the kidney is able to produce ammonia, and therefore a nonrenal source is suspected. In some situations a stool anion gap can be measured by measuring Na⁺, K⁺, and Cl^– in watery stool. If the stool anion gap is greater than the serum bicarbonate concentration, those losses will result in a hyperchloremic acidosis. In contrast, if the stool gap were less than the serum bicarbonate concentration, a metabolic alkalosis would be predicted.

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