Simple and mixed acid-base disordersAuthorBurton D Rose, MDSection EditorRichard H Sterns, MDDeputy EditorTheodore W Post, MDLast literature review version 18.2: May 2010 | This topic last updated: May 10, 2010 (More)

INTRODUCTION — Each day approximately 15,000 mmol of carbon dioxide (which can generate carbonic acid as it combines with water) and 50 to 100 meq of nonvolatile acid (mostly sulfuric acid derived from the metabolism of sulfur-containing amino acids) are produced. Acid-base balance is maintained by normal pulmonary and renal excretion of carbon dioxide and acid, respectively.

Renal excretion of acid involves the combination of hydrogen ions with urinary titratable acids, particularly phosphate (HPO42- + H+ —> H2PO4-) or with ammonia to form ammonium [1]. (See "Chapter 11A: Renal hydrogen excretion".) The latter is the primary adaptive response, since ammonia production from the metabolism of glutamine can be appropriately increased in the presence of an acid load.

Acid-base balance is usually assessed in terms of the bicarbonate-carbon dioxide buffer system:

Dissolved CO2 + H2O <—> H2CO3 <—> HCO3- + H+

The concentration of H2CO3 (carbonic acid) is normally so low that its role can be ignored and the ratio between the reactants can be expressed by the Henderson-Hasselbalch equation:

pH = 6.10 + log ([HCO3-] ÷ [0.03 x PCO2])

where the pH is equal to (-log [H+]), 6.10 is the pKa (equal to -log Ka), Ka is the dissociation constant for the reaction, 0.03 is equal to the solubility constant for CO2 in the extracellular fluid, and PCO2 is equal to the partial pressure of carbon dioxide in the extracellular fluid [2]. (See "Chapter 10B: Buffers".)

DEFINITIONS — With these principles in mind, the following definitions can be made:

Acidosis — A process that tends to lower the extracellular fluid pH (which is equivalent to raising the hydrogen concentration). From the Henderson-Hasselbalch equation, this can be induced by a fall in the extracellular (or plasma ) bicarbonate concentration or by an elevation in the PCO2.

Alkalosis — A process that tends to raise the extracellular fluid pH (which is equivalent to lowering the hydrogen concentration). From the Henderson-

Hasselbalch equation, this can be induced by an elevation in the extracellular (or plasma ) bicarbonate concentration or by a fall in the PCO2.

Metabolic acidosis — A disorder associated with a low pH and low bicarbonate concentration. (See "Approach to the adult with metabolic acidosis".)

Metabolic alkalosis — A disorder associated with a high pH and high bicarbonate concentration. (See "Pathogenesis of metabolic alkalosis".)

Respiratory acidosis — A disorder associated with a low pH and high PCO2. Respiratory alkalosis — A disorder associated with a high pH and low PCO2.

Compensatory responses — Each of the simple acid-base disorders is also associated with a compensatory response. The Henderson-Hasselbalch equation shows that the pH is determined by the ratio between the HCO3 concentration and PCO2, not by the value of either one alone.

The body responds to an acid-base disorder by making compensatory respiratory or renal responses in an attempt to normalize the pH. These responses are probably mediated at least in part by parallel alterations in regulatory cell (renal tubular or respiratory center) pH [3]. In metabolic acidosis, for example, ventilation is increased, resulting in a fall in PCO2, which tends to raise the pH toward normal. Note that protection of the HCO3/PCO2 ratio and therefore the pH requires a compensatory response that varies in the same direction as the primary disorder (low bicarbonate leads to low PCO2).

MIXED ACID-BASE DISORDERS — Some patients have two or more acid-base disorders. An understanding of the approach to this problem requires knowledge of the renal and respiratory compensations that have been empirically observed in patients with simple acid-base disorders. Values substantially different from those that are expected indicates the presence of a mixed disturbance [3].

Metabolic acidosis — The respiratory compensation results in an approximately 1.2 mmHg fall in PCO2 for every 1 meq/L reduction in the plasma bicarbonate concentration [4]. This response begins within 30 minutes [5], and is complete by 12 to 24 hours [6].

The respiratory compensation with acute metabolic acidosis is discussed separately. (See "Approach to the adult with metabolic acidosis".)

Metabolic alkalosis — The respiratory compensation tends to raise the PCO2 by 0.7 mmHg for every 1 meq/L elevation in the plasma bicarbonate concentration [7,8]. This response may not be seen in all patients because of concurrent problems. As an example, diuretics tend to induce metabolic alkalosis in heart failure or cirrhosis. However, both of these disorders, are associated with hyperventilation and a low PCO2. Thus, the expected rise in PCO2 with metabolic alkalosis may not be seen due to the underlying respiratory alkalosis.

Respiratory acidosis — The compensatory response to respiratory acid-base disorders occurs in two stages: cell buffering that acts within minutes to hours and the renal compensation that is not complete for 3 to 5 days. As a result, different responses are

seen with acute and chronic disorders. In acute respiratory acidosis, the plasma bicarbonate concentration rises 1 meq/L for every 10 mmHg elevation in the PCO2 (figure 1); this ratio increases to 3.5 meq/L per 10 mmHg in chronic respiratory acidosis (with better protection of the pH) due to increased renal acid excretion as ammonium (figure 2) [9,10]. The renal response is carefully regulated, so that administering extra bicarbonate results in the urinary excretion of the excess alkali without elevation in the plasma bicarbonate concentration [9].

Respiratory alkalosis — In acute respiratory alkalosis, the plasma bicarbonate concentration falls by 2 meq/L for every 10 mmHg decline in the PCO2 (figure 1). This ratio increases to 4 meq/L per 10 mmHg in chronic respiratory alkalosis, resulting in almost complete normalization of the pH (figure 3) [11,12]. Reductions in both bicarbonate reabsorption and in ammonium excretion contribute to the compensatory reduction in the plasma bicarbonate concentration [13].

Diagnosis — Evaluation of an acid-base disorder begins with measurement of the extracellular pH, not merely the plasma bicarbonate concentration. As an example, a low plasma bicarbonate concentration can be seen as the primary change in metabolic acidosis and as the compensatory response in respiratory alkalosis. Once the primary change is determined, the degree of compensation should then be assessed.

Clinical examples — The following examples show how these relationships can be used to diagnose simple or mixed metabolic and respiratory acid-base disorders [3,14]. Some patients also have both a metabolic acidosis and metabolic alkalosis (as with vomiting in diabetic ketoacidosis). Establishing this diagnosis requires a careful history and comparison of the fall in plasma bicarbonate concentration to the rise in the anion gap (the delta/delta). (See "The Δanion gap/ΔHCO3 ratio in patients with metabolic acidosis".)

Case 1 — A patient with diarrhea has an arterial pH of 7.23, bicarbonate concentration of 10 meq/L, and PCO2 of 23 mmHg. The low pH indicates acidemia, and the low plasma bicarbonate concentration indicates metabolic acidosis. The plasma bicarbonate concentration is 14 meq/L below normal, which should lead to a 17 mmHg fall in the PCO2 (14 x 1.2 = 17) from 40 to 23 mmHg. Thus, this patient has a simple metabolic acidosis. A PCO2 significantly higher than this level would indicate a concurrent respiratory acidosis. If, on the other hand, the PCO2 were lower than 20 mmHg, then a concurrent respiratory alkalosis would be present, as might be seen with salicylate intoxication.

Case 2 — Establishing the correct diagnosis is more difficult with respiratory acid-base disorders, because of the difference between the acute and chronic responses. Consider the following arterial blood values: pH equals 7.27; PCO2 equals 70 mmHg; and bicarbonate concentration equals 31 meq/L. The low pH and hypercapnia indicate that the patient has some form of respiratory acidosis. In view of the 30 mmHg rise in the PCO2, the plasma bicarbonate concentration should be elevated by 3 meq/L (to 27 meq/L) with acute hypercapnia, and by 11 meq/L (to 35 meq/L) with chronic

hypercapnia. The observed value of 31 meq/L is between these expected levels and could be explained by one of three disorders:

Chronic respiratory acidosis with superimposed metabolic acidosis to lower the plasma bicarbonate concentration, as might occur in a patient with chronic obstructive pulmonary disease who develops diarrhea due to viral gastroenteritis.

Acute respiratory acidosis with superimposed metabolic alkalosis to elevate the plasma bicarbonate concentration, as might occur in a patient with vomiting due to theophylline toxicity who then develops an acute asthmatic attack.

Acute, superimposed on mild chronic respiratory acidosis, as can be induced by pneumonia in a patient with chronic hypercapnia.

Thus, the correct diagnosis in a primary respiratory acid-base disorder can be established only when correlated with the clinical history. This is true even when the arterial blood values appear to represent a simple disorder. If, for example, the plasma bicarbonate concentration had been 35 meq/L in Case 2, then the results would have been compatible with an uncomplicated chronic respiratory acidosis. However, similar findings could have been induced by the combination of acute hypercapnia and metabolic alkalosis. The history should allow these possibilities to be distinguished.

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REFERENCES1. Rose, BD, Post, TW, Clinical Physiology of Acid-Base and Electrolyte Disorders,

5th ed, McGraw-Hill, New York, 2001, pp. 328-347.2. Rose, BD, Post, TW, Clinical Physiology of Acid-Base and Electrolyte Disorders,

5th ed, McGraw-Hill, New York, 2001, pp. 307-312.3. Rose, BD, Post, TW, Clinical Physiology of Acid-Base and Electrolyte Disorders,

5th ed, McGraw-Hill, New York, 2001, pp. 542-545.4. Bushinsky, DA, Coe, FL, Katzenberg, C, et al. Arterial PCO2 in chronic

metabolic acidosis. Kidney Int 1982; 22:311.5. Wiederseiner, JM, Muser, J, Lutz, T, et al. Acute metabolic acidosis:

Characterization and diagnosis of the disorder and the plasma potassium response. J Am Soc Nephrol 2004; 15:1589.

6. Pierce, NF, Fedson, DS, Brigham, KL, et al. The ventilatory response to acute base deficit in humans. Time course during development and correction of metabolic acidosis. Ann Intern Med 1970; 72:633.

7. Javaheri, S, Shore, NS, Rose, BD, Kazemi, H. Compensatory hypoventilation in metabolic alkalosis. Chest 1982; 81:296.

8. Javaheri, S, Kazemi, H. Metabolic alkalosis and hypoventilation in humans. Am Rev Respir Dis 1987; 136:1011.

9. Polak, A, Haynie, GD, Hays, RM, Schwartz, WB. Effects of chronic hypercapnia on electrolyte and acid-base equilibrium. I. Adaptation. J Clin Invest 1961; 40:1223.

10. van Ypersele de Striho, C, Brasseur, L, de Coninck, J. The "carbon dioxide response curve" for chronic hypercapnia in man. N Engl J Med 1966; 275:117.

11. Arbus, GS, Hebert, LA, Levesque, PR, et al. Characterization and clinical application of "the significance band" for acute respiratory alkalosis. N Engl J Med 1969; 280:117.

12. Krapf, R, Beeler, I, Hertner, D, Hulter, HN. Chronic respiratory alkalosis — The effect of sustained hyperventilation on renal regulation of acid-base equilibrium. N Engl J Med 1991; 324:1394.

13. Gennari, FJ, Goldstein, MB, Schwartz, WB. The nature of the renal adaptation to chronic hypocapnia. J Clin Invest 1972; 51:1722.

14. Rose, BD, Post, TW, Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York, 2001, pp. 615-619.