DISEASE OF THE MONTH J Am Soc Nephrol 11: 369–375, 2000 Metabolic Alkalosis JOHN H. GALLA Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio. Metabolic alkalosis is common—half of all acid-base disor- Bicarbonate or base loading, whether exogenous or endog- ders as described in one study (1). This observation should not enous (as in bone dissolution), is rarely a sole cause of signif- be surprising since vomiting, the use of chloruretic diuretics, icant persistent metabolic alkalosis because the normal kidney and nasogastric suction are common among hospitalized pa- is so efficient at excreting bicarbonate. Such transient states tients. The mortality associated with severe metabolic alkalosis may occur during and immediately after an oral or intravenous is substantial; a mortality rate of 45% in patients with an infusion of NaHCO3 or base equivalent, e.g., citrate in trans- arterial blood pH of 7.55 and 80% when the pH was greater fused blood or fresh frozen plasma (5). They may also occur than 7.65 has been reported (2). Although this relationship is after the successful treatment of ketoacidosis or lactic acidosis, not necessarily causal, severe alkalosis should be viewed with as these organic anions are metabolized to bicarbonate. Finally, concern, and correction by the appropriate intervention should after successful correction of hypercapnia in respiratory acido- be undertaken with dispatch when the arterial blood pH ex- sis before the kidney can excrete the bicarbonate retained for ceeds 7.55. compensation, metabolic alkalosis may occur transiently pro- Metabolic alkalosis occurs when a primary pathophysiologic vided that chloride intake is adequate. In these transient states, process leads to the net accumulation of base within or the net the urinary pH should be relatively alkaline (Ͼ6.2). loss of acid from the extracellular fluid (ECF); typically, the The course of metabolic alkalosis can be divided into gen- intracellular compartment becomes more acidic in potassium- eration, maintenance, and correction phases (6). Generation depletion alkalosis (3). Unopposed by other primary acid-base occurs by loss of protons from the ECF into the external disorders, metabolic alkalosis is recognized by increases in environment or into the cells, or by gain of base by the oral or both arterial blood pH—alkalemia—and plasma bicarbonate intravenous route or from the base stored in bone apatite. concentration. The increase in arterial blood pH promptly, Disequilibrium occurs in the generation phase when the result- normally, and predictably depresses ventilation resulting in ant elevation of plasma bicarbonate exceeds the capacity of the increased PaCO2 and the buffering of the alkalemia. The renal tubule to reabsorb bicarbonate. Transient bicarbonaturia Ͼ PaCO2 increases about 0.5 to 0.7 mmHg for every 1.0 mM (urinary pH 6.2) with resulting sodium loss ensues until a increase in plasma HCO3 concentration (4). Although a PaCO2 new steady state of chronic metabolic alkalosis is achieved and greater than 55 mmHg is uncommon, compensatory increases bicarbonate excretion ceases. At this point, the urine is rela- to 60 mmHg have been documented in severe metabolic alka- tively acidic—so-called paradoxical aciduria—and metabolic losis. Failure of an appropriate compensatory increase in alkalosis is likely to be in the maintenance phase. PaCO2 should be interpreted as a mixed acid-base disturbance in which a stimulus to hyperventilation—primary respiratory Pathophysiology of Chloride-Depletion alkalosis—accompanies primary metabolic alkalosis. Alkaloses Generation Classification and Definitions Chloride may be lost from the gut, kidney, or skin. The loss Metabolic alkalosis has been classified by the primary organ of gastric fluid, which contains 60 to 140 mM HCl and lesser system involved, the response to therapy, or the underlying variable concentrations of sodium and potassium (7), results in pathophysiology; the latter is presented in Table 1. The most alkalosis because bicarbonate generated during the production common group—those due to chloride depletion—can, by of gastric acid returns to the circulation. In the Zollinger- definition, be corrected without potassium repletion. The other Ellison syndrome or pyloric stenosis, these losses may be major grouping is that due to potassium depletion, usually with massive. Although sodium and potassium loss in the gastric mineralocorticoid excess. Metabolic alkalosis due to both po- fluid varies in concentration, the obligate urinary loss of these tassium and chloride depletion also may occur and is not rare. cations is intensified by bicarbonaturia, which occurs during disequilibrium. Gastrocystoplasty, recently introduced for bladder augmentation, may also result in urinary HCl losses Correspondence to Dr. John H. Galla, University of Cincinnati Medical Center, sufficient to produce alkalosis (8). P. O. Box 670585, Cincinnati, OH 45267-0585. Phone: 513-558-5471; Fax: 513-558-4309; E-mail: [email protected] Villous adenomas of the colon usually produce a hyperchlo- 1046-6673/1102-0369 remic metabolic acidosis because of the loss of large volumes Journal of the American Society of Nephrology of colonic fluid, rich in potassium and bicarbonate. However, Copyright © 2000 by the American Society of Nephrology 10 to 20% of these tumors will secrete chloride rather than 370 Journal of the American Society of Nephrology J Am Soc Nephrol 11: 369–375, 2000 Table 1. Etiologies of metabolic alkalosis metabolic alkalosis by several possible mechanisms. (1) Di- uretic-induced increases in sodium delivery to the distal Chloride depletion nephron accelerate potassium and proton secretion (13). (2) gastric losses: vomiting, mechanical drainage, bulimia ECF volume contraction stimulates renin and aldosterone se- chloruretic diuretics: bumetanide, chlorothiazide, cretion, which blunts sodium loss but accelerates the secretion metolazone, etc. of potassium and protons. (3) Potassium depletion will inde- diarrheal states: villous adenoma, congenital chloridorrhea pendently augment bicarbonate reabsorption in the proximal posthypercapneic state tubule (14) and (4) stimulate ammonia production, which, in dietary chloride deprivation with base loading: chloride- turn, will increase urinary net acid excretion. Urinary losses of deficient infant formulas chloride exceed those for sodium and are associated with gastrocystoplasty alkalosis even when potassium depletion is prevented (15). cystic fibrosis (high sweat chloride) Respiratory acidosis is compensated by accelerated renal Potassium depletion/mineralocorticoid excess bicarbonate reabsorption in various nephron segments and primary aldosteronism: adenoma, idiopathic, hyperplasia, increased urinary chloride excretion (16,17). The patient with renin-responsive, glucocorticoid-suppressible, chronic respiratory acidosis is chloride-depleted, and the kid- carcinoma ney will maintain this deficit until the hypercapnia is corrected. apparent mineralocorticoid excess When respiratory acidosis is corrected, accelerated bicarbonate ␤ ␣ primary deoxycorticosterone excess: 11 - and 17 - reabsorption, which is no longer appropriate, persists if suffi- hydroxylase deficiencies cient chloride is not available and “post-hypercapneic” meta- drugs: licorice (glycyrrhizic acid) as a confection or bolic alkalosis remains. flavoring, carbenoxolone Skin losses of chloride may generate alkalosis in cystic Liddle syndrome fibrosis. Alkalosis may even be the presenting feature in ado- secondary aldosteronism lescence with a few of the several hundred mutations in the adrenal corticosteroid excess: primary, secondary, cystic fibrosis transmembrane regulator (CFTR) gene (18). exogenous severe hypertension: malignant, accelerated, Maintenance renovascular The cessation of events that generate alkalosis is not neces- hemangiopericytoma, nephroblastoma, renal cell sarily accompanied by resolution of the alkalosis. To account carcinoma for maintained metabolic alkalosis in these instances, the kid- Bartter and Gitelman syndromes and their variants ney must retain bicarbonate by either a decrease in GFR with laxative abuse, clay ingestion an accompanying decrease in filtered bicarbonate, or by an Hypercalcemic states increase in bicarbonate reabsorption, or by both mechanisms. hypercalcemia of malignancy Because chloride-depletion alkaloses are usually characterized acute or chronic milk-alkali syndrome by concurrent deficits of sodium, potassium, and fluid, as well Other as chloride, controversy has arisen regarding which of these carbenicillin, ampicillin, penicillin deficits is responsible for the maintenance of the alkalosis. bicarbonate ingestion: massive or with renal insufficiency Kassirer and Schwartz showed that experimental chloride-de- recovery from starvation pletion alkalosis effected by gastric suction could be completely hypoalbuminemia corrected by chloride repletion with either KCl or NaCl, thus eliminating deficits of sodium or potassium per se as specific causes of maintenance in these circumstances (19). Based on this bicarbonate with potassium, and thus result in metabolic alka- and other studies, they concluded that chloride repletion was losis (9). pivotal in the correction (20), but a role for volume repletion per Congenital chloridorrhea, an autosomal recessive disease, is se was not excluded. Subsequently, Cohen provided evidence of caused by defective apical chloride/bicarbonate