[NaJ tfHCOj [CI AG

The difference between the serum sodium (the contribution of potassium, largely an intracellular ion, is usually neglected) and the sum of serum chloride and bicarbonate, then, equals the concentration of the unmeasured anions. Correction of serum sodium for hyperglycemia is unnecessary because this condition similarly reduces chloride concentrations.4

The unmeasured anion concentration is commonly called the anion gap (AG), and in the past its normal value had been considered to be 12 ± 4 meq/L. Recent reports have suggested that a normal anion gap value of 7 ± 4 meq/L may be more appropriate to electrolyte measurements made with ion-specific electrodes. 5 However, the value used by the clinician should reflect institutional practice. 6 As with other acid-base concepts, the accepted "normal" range for the AG is less important than whether it has changed in relation to the patient's steady-state (baseline) value. Thus, a relative change in AG is more important than the actual value. However, virtually all values above 15 meq/L can be considered abnormal even when there is no previous comparison value available.

The anion gap may change even in the absence of acid-base disturbances. It may rise when (unmeasured) cations are decreased, as in severe states of hypomagnesemia, hypokalemia, and hypocalcemia. A reduced or even negative anion gap may result from an increase in unmeasured cations, such as lithium and unmeasured positively charged proteins resulting from myeloma and polyclonal gammopathies, or a decrease in unmeasured anions such as albumin and gamma globulin. A narrow or negative anion gap may also be the result of confounders of chloride measurement. Bromide is measured as chloride on an equimolar basis by chloride-specific electrodes. Other techniques of chloride measurement may produce even more inaccurate results in the presence of bromide. 7 Triglyceride levels greater than 600 mg/dL produce overestimation of chloride levels measured by colorimetric techniques and may also result in underestimation of serum sodium, resulting in an apparently negative anion gap. 4

While increases in the AG are traditionally considered in the context of metabolic acidosis, elevation of the anion gap may be seen with any acid-base disturbance. Metabolic and respiratory alkalosis, for example, may elevate the AG by 2 to 3 meq/L because of elevations in lactate produced by enhancement of glycolysis. Penicillin and carbenicillin, as anions, produce elevations in the AG. Their charges must be balanced by sodium, which is retained by renal tubules at the cost of enhancing secretion of potassium and hydrogen ion. This effect is enhanced by the presence of the poorly reabsorbed penicillin and carbenicillin ions in the tubule lumen, the negative charges of which serve as an electrical gradient for hydrogen and potassium ion secretion. The result is an elevated AG with a hypokalemic alkalosis, illustrating the principle that anions principally cleared by the kidney may elevate the AG, particularly when aldosterone activity is high.

However, elevation of the AG is most commonly associated with metabolic acidosis. The unmeasured anions associated with an elevated AG and metabolic acidosis are listed in Ta.bie,2..1.,-2. Traditional mnemonics for the differential diagnosis of an elevated AG acidosis unfortunately suggest that iron, theophylline, cyanide, biguanides, and other compounds are unmeasured anions. These substances actually elevate the anion gap by producing lactic acidosis, discussed later in this chapter. The result of using traditional mnemonics in evaluating elevated AG acidosis may be a satisfaction-of-search error, where the discovery of lactic acidosis provides a ready explanation for the elevated AG and thereby inhibits pursuit of the causes of lactic acidosis. We suggest that the differential diagnosis of metabolic acidosis with an elevated AG should emphasize distinctions between endogenous and exogenous unmeasured anion sources and avoid mixing the differential diagnosis of lactic acidosis with that of increased unmeasured anions.

TABLE 21-2 Unmeasured Anions Associated with an Elevated Anion Gap and Metabolic Acidosis

Clinical use of the AG requires an appreciation of its limitations. While an AG greater than 30 meq/L is usually caused by lactic acidosis or ketoacidosis, these conditions may exist even when the AG is normal. An AG value less than 25 meq/L has been found to be an insensitive indicator of elevated lactate levels in critically ill patients,8 and in trauma patients the postresuscitation AG does not predict lactate levels.9 Thus, the "normal" AG does not exclude the presence of increased concentrations of unmeasured anions. As noted previously, an AG increased from baseline but still within the "normal" range may be a clue. Direct measurements of lactate, formate, ketoacids, methanol (parent of formic acid), ethylene glycol (parent of oxalic acid and numerous other organic acids), and salicylate should be ordered when the AG is "normal" but the presence of any these substances is suspected.

A common clinical problem is the diagnosis of mixed acid-base disturbances in the presence of an elevated AG. Simple acid-base disturbances that produce elevated AGs are referred to as wide-AG metabolic acidoses. If a wide-AG metabolic acidosis is the only disturbance, then the change (elevation from baseline) in value of the AG (sometimes referred to as the delta gap)10 should exactly equal the change (decrease) in the [HCO3-]. This is a one-to-one relationship. This concept is represented mathematically in Eq (5).

This simple relationship can be used to great advantage in determining the presence of other metabolic acid-base disturbances. If the [HCO 3-] is even lower than predicted by the delta AG, then there must be a concomitant hyperchloremic (i.e., non-AG type) metabolic acidosis ( Fig.iii21-2^.). Similarly, if the decrease in [HCO3-] is less than expected based on the delta AG, there must be a concomitant metabolic alkalosis present. Note that acute respiratory conditions (respiratory acidosis or alkalosis) do not affect these determinations. Potential acid-base disturbances related to respiratory status must be further determined, as discussed below ( Fig.

FIG. 21-2A. Algorithm for determination of type of acidosis and mixed acid-base disturbances when pH indicates acidemia.

FIG. 21-2B. Algorithm for determination of type of alkalosis and mixed acid-base disturbances when pH indicates alkalemia.

FIG. 21-2C. Algorithm to check for acid-base disturbances when pH is in "normal" range.

Parameters Required for Clinical Acid-Base Evaluation

Clinical evaluation of acid-base disorders is an art requiring the synthesis of information gleaned from the clinical encounter and the laboratory. The history should emphasize events that may result in the gain or loss of acid or base, such as vomiting, diarrhea, or ingestion of acids or bases. There may also be evidence of diseases of the organs of acid-base homeostasis: the liver, kidneys, and lungs.

Laboratory evaluation requires blood samples for determination of electrolyte concentrations (potassium, sodium, chloride, and bicarbonate) and blood gases (pH, Pco2 and bicarbonate concentration). Most clinical laboratories measure two of the parameters reported in blood gas results, most commonly the pH and P co2, and use the Henderson-Hasselbalch equation to calculate the third.

Blood samples for acid-base evaluation are traditionally obtained by arterial puncture, but there is some evidence that venous blood may be used instead. Arterial and capillary values of pH and CO2 content in normal patients and those with diabetic ketoacidosis correlate well (correlation coefficient 0.9 and 0.98, respectively). Recent work has demonstrated high correlations between arterial and venous pH (r = 0.9689) and arterial and venous bicarbonate concentrations (r = 0.9543) in emergency department (ED) patients with diabetic ketoacidosis.11 The correlation between venous and arterial blood gas values in patients with severe shock remains uncertain, but in other circumstances, the use of venous values seems reasonable. Inexperienced clinicians frequently resort to arterial blood gas (ABG) determination as a means to "know" the pH. However, the pH per se is often the least important value for diagnosis and management. When respiratory status is not compromised, the pH can be calculated from knowing the venous [HCO3-] alone, as described below.

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