Metabolic Alkalosis

Mineralocorticoid excess either primary or secondary can occur for a myriad of causes (Table 1) . Acting at its receptor in the principal cell of the collecting duct, mineralocorticoid stimulates the apical sodium channel and basolateral Na,K-ATPase, and increased sodium reabsorption promotes potassium secretion through the apical potassium channel. Associated sodium retention usually leads to hypertension, as in primary aldosteronism, or often to edema, as in secondary aldosteronism, e.g., in cardiac failure.

Low plasma renin and high circulating aldosterone characterize the primary disorders, whereas high plasma renin and aldosterone characterize the secondary causes. Most all of the primary disorders are due to adrenal neoplasia or hyperplasia except the glucocorticoid-suppressible variety. This autosomal dominant disease is caused by a chimeric gene formed by the overlap of the gene for 11 beta-hydroxylase with that for aldosterone synthase [32] . The former is regulated by adrenocorticotropin hormone (ACTH), whereas the latter normally is not. As a consequence of this chimera, aldosterone secretion becomes responsive to ACTH and aldosterone excess results.

Apparent mineralocorticoid excess syndromes have more complex pathophysiologies and are associated with low circulating aldosterone and low plasma renin. Several of these involve genetic alterations in the enzymatic pathway for adrenosteroid biosynthesis; others are drug-induced [33] . Licorice, found in confections, chewing tobacco, some soft drinks, and herbal preparations, and carbenoxolone, a drug used for the treatment of peptic ulcer, contain glycyrrhetinic acid or its derivative, either of which potently inhibit the renal isoform of 11 beta-hydroxysteroid dehydrogenase present only in the principal cell. This enzyme normally shunts cortisol, which exceeds the concentration of aldosterone by a ratio of 100:1, to the inactive cortisone. Thus, with these inhibitors, cortisol acts at the promiscuous mineralocorticoid receptor. In contrast, Liddle syndrome, an autosomal dominant disorder with variable clinical expression, is characterized by a structural defect in a subunit of the apical sodium channel in the principal cell of the collecting duct that leads to unregulated sodium reabsorption with the cascade of events as above [34] .

Several consequences of potassium depletion likely contribute to the renal maintenance of metabolic alkalosis. Potassium secretion is stimulated by enhanced luminal sodium delivery, increased aldosterone concentrations, increased cellular potassium activity, or diminished availability of luminal chloride. Proximal tubule bicarbonate reabsorption is enhanced and may be secondary to intracellular acidosis, which facilitates proton secretion. In the cortical collecting tubule, aldosterone stimulates proton secretion and bicarbonate reabsorption either directly or indirectly by an increased lumen-negative potential [35] . Type A intercalated cells in the outer medullary segment increase in size and number in potassium depletion and maybe engaged in potassium conservation at the expense of continued bicarbonate reabsorption probably through both H-ATPase and H,K-ATPase. The important role of intracellular acidosis in potassium-depletion alkalosis is supported by correction of the alkalosis by infusion of potassium without any suppression of renal net acid excretion [36] ; correction is assumed to occur by the movement of potassium into and of protons out of the cell, which titrates ECF bicarbonate.

Some disorders may be characterized by both chloride and potassium depletion, which serve to intensify the alkalosis. They are usually associated with sodium losses and normotension or hypotension. Downregulation of chloride transporters occurs in potassium depletion [37] , and thus severe potassium depletion, in particular, is accompanied by renal chloride wasting.

Alkalosis in Bartter (BS) and Gitelman (GS) syndromes and their variants are likely dependent on both potassium and chloride depletion. Most patients with BS are usually detected in infancy with failure to thrive. A primary hereditary defect in coupled Na,K,2Cl reabsorption in the thick ascending limb of Henle’s loop explains renal sodium, potassium, and chloride wasting, macula densa and volume depletion-stimulated activation of the renin-aldosterone system, and high renal production of prostaglandin E2 [38] . Both prostaglandin E2 excess and severe potassium depletion can further impair Na,K,2Cl reabsorption in the ascending limb. Hypercalciuria is prominent while serum magnesium concentration is usually normal. Hypokalemia is less severe in “variant” BS likely because the mutation is in the luminal ROMK channel, which facilitates potassium recycling from the thick ascending limb of Henle’s loop into the lumen–a step essential for the normal functioning of the Na,K,2Cl cotransporter.

In contrast, GS often presents in adults, is less severe, is often heterozygotic, and, at least in the United States, is more common than BS. The genetic defect in this syndrome is in the thiazide-sensitive NaCl cotransporter in the distal convoluted tubule [38] . It is associated with hypocalciuria and hypomagnesemia but not increased urinary prostaglandins.

Gut potassium losses such as in laxative abuse or geophagia are rarely associated with severe alkalosis. Urinary potassium is low in laxative abuse, and plasma bicarbonate is rarely above 30 to 34 mEq/L [39] .

Pathophysiology: Miscellaneous
Milk-alkali syndrome in which both bicarbonate and calcium are ingested produces alkalosis by several mechanisms, including vomiting, hypercalcemia (which increases bicarbonate reabsorption), and a reduced GFR. Cationic antibiotics in high doses can cause alkalosis by obligating bicarbonate to the urine. Hypoalbuminemia causes mild metabolic alkalosis because of the diminution of the negative charge that albumin normally contributes to the anion gap and the shift in the buffering curve for plasma.

Clinical and Diagnostic Aspects
The symptoms of metabolic alkalosis per se are difficult to separate from those of chloride, volume, or potassium depletion. Apathy, confusion, cardiac arrhythmias, and neuromuscular irritability (related in part, perhaps, to a low ionized plasma calcium) are common when alkalosis is severe [40] . Compensatory hypoventilation may cause hypoxia or contribute to pulmonary infection in very ill or immunocompromised patients.

The cause of chronic metabolic alkalosis is often evident on the initial assessment of the patient with a careful history and physical examination (Table 1) . In the absence of blood gas measurements, an increase in the anion gap–due primarily to lactate–and hypokalemia favor the diagnosis of metabolic alkalosis over respiratory acidosis when plasma chloride is low and bicarbonate high.

Urinary chloride and potassium measurements before therapy are useful diagnostically. Low urinary chloride (<10 mEq/L) characterizes alkalosis in which chloride depletion predominates unless a chloruretic diuretic is present; it remains low until chloride repletion is nearly complete. A urinary potassium concentration of >30 mEq/L in the presence of hypokalemia establishes renal potassium wasting, which is indicative of an intrinsic renal defect, diuretics, or high circulating aldosterone. Conversely, a urinary potassium concentration of <20 mEq/L suggests extrarenal potassium loss. When metabolic alkalosis due primarily to potassium depletion is suggested, the presence of a severe alkalosis should prompt a search for additional causative factors, such as chloride depletion or base ingestion. If the cause of the alkalosis is not readily apparent, the urine should be screened for diuretics.

Surreptitious induction of alkalosis as with diuretics or vomiting (bulimia) can be difficult to detect, but certain clues may help to establish the diagnosis: The patients are more often female; an underlying psychiatric abnormality may be present; the severity of alkalosis may fluctuate; the patient can easily obtain diuretics; intermittently alkaline urine can occur with acute-on-chronic vomiting; patients with surreptitious vomiting may have blackened teeth enamel and scarred knuckles. Diuretic abuse usually leads to more severe potassium depletion than vomiting.

Treatment is directed in two general areas: ( 1) correction of existing deficits and ( 2) prevention of continuing losses. With regard to the latter, drugs, agents, or other interventions that generate alkalosis should be discontinued whenever possible.

Chloride-Responsive Alkaloses
Although replacement of the chloride deficit is essential, selection of the accompanying cation–sodium, potassium, or proton–is dependent on assessment of ECF volume status, the presence and degree of associated potassium depletion, and the degree and reversibility of any depression of GFR. If kidney function is normal, bicarbonate and base equivalents will be excreted with sodium or potassium and metabolic alkalosis will be rapidly corrected as chloride is made available.

If depletion of chloride and ECF volume coexist, as is most common, isotonic NaCl is the appropriate therapy and simultaneously corrects both deficits. In patients with overt signs of volume contraction, the administration of a minimum of 3 to 5 L of 150 mEq/L NaCl is usually necessary to correct volume deficits and metabolic alkalosis. When the ECF volume is assessed as normal, total body chloride deficit can be estimated by the formula: 0.2 ? Body weight (kg) ? Desired increment in plasma chloride (mEq/L). The replacement of continuing losses of fluid and electrolytes must be added to this regimen. As the chloride deficit is corrected, a brisk alkaline diuresis will occur with a decrease in plasma bicarbonate toward normal.

Plasma potassium concentration should be followed serially. Concomitant potassium repletion is clinically indicated to avoid other potentially harmful effects of potassium depletion. Potassium can be provided conveniently by adding KCl 10 to 20 mEq/L to the regimen.

In the clinical setting of volume overload such as in congestive heart failure, administration of NaCl is clearly inadvisable. Chloride should be repleted with KCl as above unless hyperkalemia is present or if the ability to excrete a potassium load is a concern.

Intravenous HCl is indicated if NaCl or KCl is contraindicated and correction should be immediate, i.e., when the arterial pH is greater than 7.55, and in the presence of hepatic encephalopathy, cardiac arrhythmia, digitalis cardiotoxicity, or altered mental status. The amount of HCl, given as 0.1 or 0.2 M solutions, needed to correct alkalosis is calculated by the formula: 0.5 ? Body weight (kg) ? Desired decrement in plasma bicarbonate (mEq/L); continuing losses must also be replaced. The use of 50% of body weight as the volume of distribution of infused protons relates mainly to the prior buffering of alkali including those in intracellular sites; infused protons must restore these buffers as well as titrating extracellular bicarbonate. Because the goal of such therapy is to rescue the patient from severe alkalosis, it is usually prudent to plan to initially restore the plasma bicarbonate concentration halfway toward normal. HCl must be given through a catheter placed in the vena cava or a large tributary vein. The proper placement of the catheter should be confirmed radiographically because leakage of HCl can lead to sloughing of perivascular tissue; in the mediastinum, this could be a catastrophe. Rates of infusion up to 25 mEq/h have been reported. These patients are best managed in an intensive care unit with frequent measurement of arterial blood gases and electrolytes.

NH4 Cl is an alternative, which may be given into a peripheral vein; its rate of infusion should not exceed 300 mEq/24 h. NH4 Cl is contraindicated by the presence of renal or hepatic insufficiency. In concurrent renal failure, azotemia would be worsened and, in hepatic failure, acute ammonia intoxication with coma could result. Lysine or arginine HCl should be avoided because they have been associated with dangerous hyperkalemia.

If GFR is adequate (serum creatinine <4 mg/dl), the use of acetazolamide 250 to 500 mg daily, which produces a diuresis of primarily NaHCO3 by inhibition of carbonic anhydrase, can be considered. When high sodium excretion must be maintained or if a high serum potassium is present, acetazolamide is particularly useful. Natriuresis can be sustained while progressive metabolic alkalosis is avoided. If hyperkalemia is absent, KCl should be concurrently administered because of the high likelihood of developing hypokalemia during the ensuing alkaline diuresis.

When the kidney is incapable of responding to chloride repletion or dialysis is necessary for the control of renal failure, exchange of bicarbonate for chloride by hemodialysis or peritoneal dialysis will effectively correct metabolic alkalosis. The usual dialysates for both peritoneal dialysis and hemodialysis, which contain high concentrations of bicarbonate or its metabolic precursors, must be modified in these circumstances. In an emergency, peritoneal dialysis can be performed against sterile solutions of 150 mEq/L NaCl with appropriate maintenance of plasma potassium, calcium, and magnesium concentrations by intravenous infusion.

Additional therapeutic approaches are needed in certain specific clinical situations associated with chloride-depletion metabolic alkalosis. In the presence of pernicious vomiting or the need for the continual removal of gastric secretions, metabolic alkalosis will continue to be generated and replacement of preexisting deficits will be impeded by these losses. In such circumstances, the administration of a proton pump inhibitor, such as omeprazole, will blunt gastric acid production. Antiemetics may also be helpful. Proton pump inhibitors have also been used effectively to blunt the acid loss that occurs with gastrocystoplasty.

Congenital chloridorrhea is responsive to continued repletion of fluid, chloride, and potassium losses by supplementation of the dietary intake, whereas antidiarrheal agents are largely ineffective. Reduction in gastric HCl production by proton pump inhibition has been shown to aid in the maintenance of chloride balance [41] . Villous adenomas require surgical removal.

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