Metabolic alkalosis is common–half of all acid-base disorders as described in one study  . This observation should not be surprising since vomiting, the use of chloruretic diuretics, and nasogastric suction are common among hospitalized patients. The mortality associated with severe metabolic alkalosis is substantial; a mortality rate of 45% in patients with an arterial blood pH of 7.55 and 80% when the pH was greater than 7.65 has been reported  . Although this relationship is not necessarily causal, severe alkalosis should be viewed with concern, and correction by the appropriate intervention should be undertaken with dispatch when the arterial blood pH exceeds 7.55.
Metabolic alkalosis occurs when a primary pathophysiologic process leads to the net accumulation of base within or the net loss of acid from the extracellular fluid (ECF); typically, the intracellular compartment becomes more acidic in potassium-depletion alkalosis  . Unopposed by other primary acid-base disorders, metabolic alkalosis is recognized by increases in both arterial blood pH–alkalemia–and plasma bicarbonate concentration. The increase in arterial blood pH promptly, normally, and predictably depresses ventilation resulting in increased PaCO2 and the buffering of the alkalemia. The PaCO2 increases about 0.5 to 0.7 mmHg for every 1.0 mM increase in plasma HCO3 concentration  . Although a PaCO2 greater than 55 mmHg is uncommon, compensatory increases to 60 mmHg have been documented in severe metabolic alkalosis. Failure of an appropriate compensatory increase in PaCO2 should be interpreted as a mixed acid-base disturbance in which a stimulus to hyperventilation–primary respiratory alkalosis–accompanies primary metabolic alkalosis.
Classification and Definitions
Metabolic alkalosis has been classified by the primary organ system involved, the response to therapy, or the underlying pathophysiology; the latter is presented in Table 1 . The most common group–those due to chloride depletion–can, by definition, be corrected without potassium repletion. The other major grouping is that due to potassium depletion, usually with mineralocorticoid excess. Metabolic alkalosis due to both potassium and chloride depletion also may occur and is not rare.
Bicarbonate or base loading, whether exogenous or endogenous (as in bone dissolution), is rarely a sole cause of significant persistent metabolic alkalosis because the normal kidney is so efficient at excreting bicarbonate. Such transient states may occur during and immediately after an oral or intravenous infusion of NaHCO3 or base equivalent, e.g., citrate in transfused blood or fresh frozen plasma  . They may also occur after the successful treatment of ketoacidosis or lactic acidosis, as these organic anions are metabolized to bicarbonate. Finally, after successful correction of hypercapnia in respiratory acidosis before the kidney can excrete the bicarbonate retained for compensation, metabolic alkalosis may occur transiently provided that chloride intake is adequate. In these transient states, the urinary pH should be relatively alkaline (>6.2).
The course of metabolic alkalosis can be divided into generation, maintenance, and correction phases  . Generation occurs by loss of protons from the ECF into the external environment or into the cells, or by gain of base by the oral or intravenous route or from the base stored in bone apatite. Disequilibrium occurs in the generation phase when the resultant elevation of plasma bicarbonate exceeds the capacity of the renal tubule to reabsorb bicarbonate. Transient bicarbonaturia (urinary pH >6.2) with resulting sodium loss ensues until a new steady state of chronic metabolic alkalosis is achieved and bicarbonate excretion ceases. At this point, the urine is relatively acidic–so-called paradoxical aciduria–and metabolic alkalosis is likely to be in the maintenance phase.
Pathophysiology of Chloride-Depletion Alkaloses
Chloride may be lost from the gut, kidney, or skin. The loss of gastric fluid, which contains 60 to 140 mM HCl and lesser variable concentrations of sodium and potassium  , results in alkalosis because bicarbonate generated during the production of gastric acid returns to the circulation. In the Zollinger-Ellison syndrome or pyloric stenosis, these losses may be massive. Although sodium and potassium loss in the gastric fluid varies in concentration, the obligate urinary loss of these cations is intensified by bicarbonaturia, which occurs during disequilibrium. Gastrocystoplasty, recently introduced for bladder augmentation, may also result in urinary HCl losses sufficient to produce alkalosis  .
Villous adenomas of the colon usually produce a hyperchloremic metabolic acidosis because of the loss of large volumes of colonic fluid, rich in potassium and bicarbonate. However, 10 to 20% of these tumors will secrete chloride rather than
Etiologies of metabolic alkalosis Chloride depletion
Gastric losses: vomiting, mechanical drainage, bulimia chloruretic diuretics: bumetanide, chlorothiazide, metolazone, etc.
diarrheal states: villous adenoma, congenital chloridorrhea posthypercapneic state dietary chloride deprivation with base loading: chloride-deficient infant formulas gastrocystoplasty cystic fibrosis (high sweat chloride)
Potassium depletion/mineralocorticoid excess
primary aldosteronism: adenoma, idiopathic, hyperplasia, renin-responsive, glucocorticoid-suppressible, carcinoma apparent mineralocorticoid excess primary deoxycorticosterone excess: 11beta- and 17alpha-hydroxylase deficiencies
drugs: licorice (glycyrrhizic acid) as a confection or flavoring, carbenoxolone
Liddle syndrome secondary aldosteronism adrenal corticosteroid excess: primary, secondary, exogenous severe hypertension: malignant, accelerated, renovascular hemangiopericytoma, nephroblastoma, renal cell carcinoma
Bartter and Gitelman syndromes and their variants laxative abuse, clay ingestion
hypercalcemia of malignancy acute or chronic milk-alkali syndrome
carbenicillin, ampicillin, penicillin bicarbonate ingestion: massive or with renal insufficiency recovery from starvation hypoalbuminemia bicarbonate with potassium, and thus result in metabolic alkalosis  .
Congenital chloridorrhea, an autosomal recessive disease, is caused by defective apical chloride/bicarbonate exchange in the colon and perhaps the ileum because of a mutation of the Down-Regulated in Adenoma (DRA) gene  . This defect results in copious diarrhea with major chloride losses  . Gastric and jejunal functions are normal. Although fecal sodium and potassium concentrations are normal, the unremitting watery stool results also in sodium, potassium, and volume losses. The renal response mediated by aldosterone is intense sodium and water reabsorption at the expense of proton and potassium secretion, thereby further promoting alkalosis.
Chloruretic agents such as chlorothiazide, furosemide, and their congeners all directly produce the loss of chloride, sodium, and fluid in the urine  . These losses, in turn, promote metabolic alkalosis by several possible mechanisms. ( 1) Diuretic-induced increases in sodium delivery to the distal nephron accelerate potassium and proton secretion  . ( 2) ECF volume contraction stimulates renin and aldosterone secretion, which blunts sodium loss but accelerates the secretion of potassium and protons. ( 3) Potassium depletion will independently augment bicarbonate reabsorption in the proximal tubule  and ( 4) stimulate ammonia production, which, in turn, will increase urinary net acid excretion. Urinary losses of chloride exceed those for sodium and are associated with alkalosis even when potassium depletion is prevented  .
Respiratory acidosis is compensated by accelerated renal bicarbonate reabsorption in various nephron segments and increased urinary chloride excretion   . The patient with chronic respiratory acidosis is chloride-depleted, and the kidney will maintain this deficit until the hypercapnia is corrected. When respiratory acidosis is corrected, accelerated bicarbonate reabsorption, which is no longer appropriate, persists if sufficient chloride is not available and “post-hypercapneic” metabolic alkalosis remains.
Skin losses of chloride may generate alkalosis in cystic fibrosis. Alkalosis may even be the presenting feature in adolescence with a few of the several hundred mutations in the cystic fibrosis transmembrane regulator (CFTR) gene  .
The cessation of events that generate alkalosis is not necessarily accompanied by resolution of the alkalosis. To account for maintained metabolic alkalosis in these instances, the kidney must retain bicarbonate by either a decrease in GFR with an accompanying decrease in filtered bicarbonate, or by an increase in bicarbonate reabsorption, or by both mechanisms. Because chloride-depletion alkaloses are usually characterized by concurrent deficits of sodium, potassium, and fluid, as well as chloride, controversy has arisen regarding which of these deficits is responsible for the maintenance of the alkalosis.
Kassirer and Schwartz showed that experimental chloride-depletion alkalosis effected by gastric suction could be completely 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  . Based on this and other studies, they concluded that chloride repletion was pivotal in the correction  , but a role for volume repletion per se was not excluded. Subsequently, Cohen provided evidence of a primary role for volume expansion  .
A widely accepted hypothesis for the pathophysiology of the maintenance and correction of chloride-depletion alkalosis based on volume proposed the following  : Volume contraction accompanying alkalosis augments fluid reabsorption in the proximal tubule, and, because bicarbonate is preferentially reabsorbed compared with chloride in this segment, alkalosis is maintained. With ECF volume expansion, fluid reabsorption in the proximal tubule is depressed, delivering more bicarbonate and chloride to the distal nephron, which possesses a substantial capacity to reabsorb chloride but a limited one for bicarbonate. As a result, chloride is retained, bicarbonate excreted, and alkalosis corrected. In this construct, chloride administration has only a permissive role for volume expansion, which itself is regarded as the extrarenal impetus for correction.
This “classical” hypothesis based on volume has been reappraised in a series of studies of both acute and chronic chloride-depletion alkalosis in human and rat  . In these studies, chloride-depletion alkalosis has been completely corrected by the administration of any of several non-sodium chloride salts despite persistently low GFR, decreased plasma volume, negative sodium balance, decreasing body weight, continuing urinary potassium loss, persistently high plasma aldosterone concentration, and continued bicarbonate loading–all of which would, if anything, maintain or generate alkalosis. During either expansion or contraction of ECF volume, alkalosis was not corrected without chloride replacement  . Even during sustained volume contraction, chloride promptly induced bicarbonaturia and progressively corrected the alkalosis. In humans with diuretic-induced alkalosis maintained for 5 d by chloride restriction, alkalosis was corrected as chloride was repleted quantitatively despite decreased GFR, renal blood flow, and the decreased plasma volume that persisted throughout the correction  . In contrast, men given equal amounts of neutral sodium phosphate became volume-expanded with worsening of their alkalosis. Thus, we would extend the earlier conclusion of Schwartz and coworkers to state that chloride is necessary and sufficient for the correction of chloride-depletion alkalosis  . Volume depletion is a commonly associated but not a causative or essential factor for the maintenance of alkalosis.
We have proposed that intrarenal mechanisms responsive to chloride depletion can plausibly account for the maintenance of alkalosis regardless of the status of the ECF volume. In the absence of volume depletion, chloride depletion appears to decrease GFR by tubuloglomerular feedback  by an alteration in the signal perceived by the macula densa–tubule fluid chloride concentration or osmolality. Such a protective response by the kidney would blunt fluid and sodium losses, which are likely to attend the bicarbonaturia frequently encountered during disequilibrium alkalosis. Chloride depletion also increases renin secretion by a macula densa mechanism, resulting in increased aldosterone secretion that may be disproportionate to the magnitude of an accompanying hypokalemia and thereby augment potassium wasting.
Although normal functioning of the proximal tubule is essential to permit appropriate bicarbonate reabsorption, the collecting duct appears to be the major nephron site for altered electrolyte and proton transport in both maintenance of and recovery from metabolic alkalosis. The collecting duct is heterogeneous anatomically and functionally throughout its length with regard to both cells and segments, but the major cell stimulated by chloride-depletion alkalosis is the type B intercalated cell in the cortical segment   . During maintenance, bicarbonate secretion does not occur because insufficient chloride is available for bicarbonate exchange and bicarbonate reabsorption is maintained distally in the medullary segments. When chloride is administered and luminal or cellular chloride concentration or amount increases, bicarbonate is promptly excreted and alkalosis is corrected. When a defect in renal transport itself is the proximate cause of alkalosis, i.e., Bartter syndrome, other alterations in renal electrolyte transport likely occur.
Pathophysiology: Potassium Depletion/Mineralocorticoid Excess Alkalosis Generation
Dietary potassium depletion is associated with modest metabolic alkalosis and with an increase in intracellular sodium and proton concentrations and suppression of aldosterone   . Metabolic alkalosis is generated primarily by an intracellular shift of protons. However, potassium depletion is also associated with enhanced renal ammonia production, and a contribution of increased net acid excretion has not been excluded in humans   . Similarly, administration of aldosterone causes only a slight degree of metabolic alkalosis if potassium depletion is prevented  . While escape from the sodium-retaining effect of mineralocorticoids occurs at the expense of persistent intravascular and ECF volume expansion and resulting hypertension, escape does not occur from their potassium-wasting effect. When potassium depletion and mineralocorticoid excess occur together, prominent metabolic alkalosis is common.
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