DISEASEOF THE MONTH

Metabolic

BIFF F. PALMER and ROBERT J. ALPERN Department of Internal , University of Texas Southwestern Medical Center, Dallas, Texas.

In this article, we review , one of the most reabsorption, H4 secreted by the distal can titrate common fluid and disorders. An understanding of NH4 and phosphate and thus increase renal net acid excretion. the diagnosis and treatment of entities that cause metabolic A simple increase in distal delivery of Na salts without alkalosis requires a knowledge of the processes responsible for sustained or increased mineralocorticoid activity, as occurs in this disorder. volume expansion, does not increase net acid excretion. Sim- ilarly, increased mineralocorticoid activity in the absence of Generation and Maintenance of Metabolic distal Na delivery, as occurs in , fails to Alkalosis increase net acid excretion. To augment net acid excretion and The pathogenesis of metabolic alkalosis involves both the thus generate a metabolic alkabosis through renal mechanisms, generation and maintenance of this disorder ( 1 ). The genera- delivery of Na salts to the distal nephron must occur with tion of metabolic alkabosis refers to the addition of new HCO sustained or increased mineralocorticoid activity. to the blood as a result of either loss of acid or gain of alkali. directly stimulates electrogenic Na reabsorption in the corti- New HCO1 may be generated by either renal or extrarenal cal collecting duct by stimulating both apical membrane Na mechanisms. Because the kidneys have an enormous capacity permeability and the Na/K-ATPase. This leads to an in- to excrete HCO, even vigorous HCO generation may not be creased negative voltage of the tubule lumen that secondarily sufficient to produce sustained metabolic alkabosis. To main- increases the rates of K and H4 secretion. For every H tam a metabolic alkabosis, the capacity of the kidney to correct secreted into the lumen, a HCO is returned to the blood. In the the alkabosis must be impaired, or, equivalently, the capacity to absence of distal Na delivery, aldosterone cannot stimulate reclaim HCO must be enhanced. On the other hand, increased Na reabsorption and cannot alter the voltage, resulting in no capacity for HCO reclamation in the absence of generation is change in secretion of H and K (2). Although aldosterone also insufficient to cause metabolic alkalosis. Thus, the two has been shown to have a direct stimulatory effect on H ingredients required for the pathogenesis of metabolic alkalosis secretion in the distal nephron, the observation that mineralo- are the generation of new HCO combined with an augmen- corticoids do not stimulate renal K or H excretion in sub- tation in the capacity of the kidney to reclaim the filtered jects on a low-salt diet suggests that this direct effect is HCO. quantitatively of lesser importance than the indirect voltage effect. Renal Generation of Metabolic Alkalosis Relatively high distal Na delivery and high mineralocorti- may be generated from renal or extrarenal coid levels are seen in patients with primary increases in distal sources (Table I ). In most cases, the renal generation of HCO Na delivery and in patients with primary increases in miner- involves three features that function synergistically to increase alocorticoid levels. The word “primary” here refers to the fact H secretion in the distal nephron and cause renal net acid that the changes are not occurring secondary to changes in excretion to exceed metabolic acid production: (1) high distal volume. Thus, a primary increase in distal Na delivery occurs delivery of Na salts; (2) mineralocorticoid excess; and (3) K with that work proximal to the cortical collecting deficiency. In general, metabolic alkalosis, which is generated duct, such as osmotic diuretics, carbonic anhydrase inhibitors, by renal mechanisms, is maintained by similar processes in the loop diuretics, and . These result in increased distal distal nephron. In addition, enhanced HCO reclamation in Na delivery and increased Na excretion. The latter leads to more proximal portions of the nephron may contribute to volume contraction, which increases mineralocorticoid levels. maintenance by allowing longer segments of the distal tubule The result is increased distal Na delivery and increased mm- to be exposed to a bicarbonate-free urine. Instead of expending eralocorticoid levels. Bartter’s syndrome and Mg2 deficiency its comparatively limited H secretory capacity on HCO are in many respects similar to ingestion in that distal delivery of Na is high in these disorders as a result of impaired reabsorption of NaCI in the loop of Henle. Similarly, a primary increase in mineralocorticoid levels, as Correspondence to Dr. Biff F. Palmer, Department of , occurs with an aldosterone-secreting adenoma, directly in- University of Texas Southwestern Medical Center, 5323 Harry Hines Boule- creases distal Na reabsorption, resulting in volume expan- yard, Dallas, TX 75235. sion, which suppresses proximal Na reabsorption and in- 1046-6673/0809- 1462$03.0()/0 Journal of the American Society of creases distal Na delivery. The result again is increased distal Copyright 0 1997 by the American Society of Nephrology Na delivery and increased minerabocorticoid levels. In both Metabolic Alkalosis 1463

Table 1. Generation of metabolic alkalosis anions such as citrate and lactate are rapidly metabolized to HCO and thus will not contribute to vol- Extrarenal ume. Nonreabsorbable anions such as sulfate and phosphate excessive loss of acid are rapidly excreted by the kidney, and again will not contrib- loss of acid into gastric juice: , nasogastric ute to extracellular fluid volume. The only remaining anions suction are C1 and HCO1. Thus, ifone is trying to correct a metabolic intestinal acid loss: vilbous adenoma, congenital alkalosis maintained by volume contraction, the only anion that chboridorrhea may be added to the extracellular fluid that will be retained and translocation of acid into cells: sodium deficiency not converted to HCO is C1. excessive gain of bicarbonate The mechanisms by which volume contraction maintains oral or parenteral intake of bicarbonate metabolic alkalosis have been recently reviewed and will only of lactate, ketones, or other organic anions be summarized briefly (4). In some settings, volume contrac- to bicarbonate tion is associated with a decrease in GFR, which would de- Renal crease the filtered load of HCO, decreasing the quantity of coupling of high minerabocorticoid activity and high distal HCO that must be reabsorbed to maintain metabolic alkabo- sodium delivery sis. In addition, volume contraction increases the capacity of persistent minerabocorticoid excess the proximal tubule to reabsorb HCO by two mechanisms. potassium deficiency First, volume contraction beads to a decreased permeability of the paracellular pathway to HCO and thus inhibits the back- leak of HCO from the blood into the tubule lumen. Second, decreases in extracellular fluid volume lead to changes in cases, there is also increased K excretion, which results in K circulating and local levels of hormones, which stimulate prox- depletion, which further enhances distal W secretion and net imal tubule transcellular H secretion, such as angiotensin II, acid excretion. The mechanisms responsible for this are dis- norepinephrine, and dopamine. Finally, volume contraction cussed below. decreases C1 delivery to the cortical collecting tubule. Be- Posthypercapnic alkalosis is also generated in the kidney. cause HCO secretion in the collecting tubule requires luminab Posthypercapnic alkalosis refers to patients who are hypercap- Cl to exchange for HCO, the rate of HCO secretion will be nic and develop a compensatory metabolic alkabosis due to decreased. renal HCO retention. After the Pco, is corrected, the high K depletion affects renal function in many ways that can blood I HCO] now represents a primary metabolic alkalosis, affect the kidney’s ability to maintain metabolic alkalosis. K which may be maintained by the kidney (see below). depletion causes a decrease in GFR, which would lower the filtered load of HCO and secondarily contribute to mainte- Extrarenal Generation of Metabolic Alkalosis nance of metabolic alkabosis. In addition, K depletion has Extrarenal factors may also be responsible for the generation been demonstrated to stimulate rates of proximal and distal of metabolic alkalosis. Acid loss, as in vomiting or nasogastric tubule H secretion (5-7). Finally, K depletion leads to suction, leads to addition of new HCO to the blood. Alkali gain, as in the milk-alkali syndrome or with the use of inject- adaptive increases in the enzymes that synthesize NH4, caus- able NaHCO3 during cardiopulmonary , may also ing increased rates of ammoniagenesis in the proximal tubule generate metabolic alkabosis. Acid may also be transbocated (8). Although all of these effects contribute to the generation within the body, producing in one compartment and and maintenance of metabolic alkalosis, K deficiency also alkalosis in the other. This may occur with severe potassium inhibits aldosterone secretion, an effect that inhibits acidifica- deficiency. Finally, relative bicarbonate generation (increased tion. The net result is that K deficiency alone has only a small concentration) may be induced by extracellular volume con- variable effect on overall acid base balance (9,10). In humans, traction. In alb of these circumstances, for metabolic alkabosis K deficiency alone does not cause significant metabolic al- to be sustained, the capacity of the kidney to reclaim bicar- kalosis unless associated with volume contraction. However, a bonate must also be enhanced. few patients have been described in whom severe K depletion (serum [K] < 2 mEqIL) is the sole factor responsible for Maintenance of Metabolic Alkalosis generation and maintenance of metabolic alkalosis ( 1 1). Reduced effective arterial blood volume is the mechanism By contrast, if K depletion occurs in a setting in which responsible for the maintenance of metabolic alkalosis in the mineralocorticoid secretion is nonsuppressible. then the stim- majority of patients. In general, this form of alkabosis has been ulatory effects on renal acidification dominate, and metabolic referred to as hypochloremic metabolic alkalosis. However, alkalosis will develop. Thus, in the setting of primary miner- careful studies have demonstrated that the key to maintenance alocorticoid excess in which extracellular fluid volume is ex- of metabolic alkalosis is not the C1 concentration, but rather panded, K deficiency significantly enhances the generation the total body Cl (3). The key role played by total body C1 and maintenance of metabolic alkabosis. Indeed, in patients is understandable by considering the different types of anions with primary , patients with the most se- that may contribute to extracellular fluid volume. Organic vere K depletion have the most marked metabolic alkalosis 1464 Journal of the American Society of Nephrology

( 12, 13). Correction of the K deficit will return the plasma Table 2. Syndromes of metabolic alkalosis HCO concentration toward normal in this setting. Minerabocorticoids contribute to the maintenance of meta- Effective volume contraction, secondary increase in aldosterone, BP normal or low bobic alkalosis by stimulating W secretion in the distal nephron ( 14). As discussed earlier, mineralocorticoids are im- . gastrointestinal, dietary, or other nonrenal generation portant in the generation and maintenance of metabolic alka- vomiting or nasogastric suction losis only when high levels are associated with increased distal chloride wasting diarrhea villous adenoma delivery of Nat. This will occur with primary increases in mineralocorticoids i n which mineralocorticoid-induced vol- ume expansion ensures high distal delivery of Nat Diuretics . renal generation that act proximal to the cortical collecting duct, Bartter’s diuretics (mercurial, loop, or diuretics) syndrome, and Mg2 deficiency may also cause this scenario, volume depletion with increased distal delivery of with volume contraction leading to high aldosterone levels and poorly reabsorbable anions the defect in more proximal Na absorption maintaining distal Bartter’s syndrome Na delivery. In patients with extrarenal generation of alkalo- sis, filtered loads of HCO may exceed the capacity of the posthypercapnic state proximal tubule leading to distal delivery of Na and HCO Extracellular fluid volume expansion with minerabocorticoid and thus allow high mineralocorticoid levels to play a role by effect, increased BP increasing H secretion and decreasing the magnitude of bi- S increased renin, increased aldosterone carbonaturia. renal artery stenosis accelerated hypertension Clinical Syndromes Associated with Metabolic renin secreting tumor Alkalosis . decreased renin, increased aldosterone Metabolic alkabosis will be seen in clinical conditions that adrenal adenoma lead to the generation and maintenance of alkabosis (Table 2). bilateral adrenal hyperplasia From a clinical point of view, it is useful to divide these dexamethasone-responsive adrenal hyperplasia conditions into two groups based on whether they are associ- carcinoma ated with volume contraction or volume expansion. . decreased renin, decreased aldosterone Cushing’s syndrome Volume Contraction exogenous mineralocorticoid These conditions are those in which the clinical disorder congenital adrenal enzyme defect leads to generation of metabolic alkalosis and a contracted 1 1f3 hydroxylase deficiency or inhibitor effective arterial volume. The alkalosis may be generated re- Liddle’s syndrome nally or extrarenally. These conditions are characterized by Renal insufficiency contraction of the effective arterial volume, a circumstance . exogenous bicarbonate load in setting of decreased GFR usually associated with reduced distal delivery of Na salts . milk-alkali syndrome and a volume-mediated stimulation of the renin-angiotensin- aldosterone system. Ordinarily, this would not be associated Miscellaneous with renal generation of alkabosis. However, if distal Na S potassium deficiency delivery is inappropriately increased, as with use of diuretics, Bartter’s syndrome, and Mg2 deficiency, or secondary to the presence of a poorly reabsorbable anion, then net acid excre- lead to volume contraction, which will halt the bicarbonaturia tion will be stimulated and alkalosis may result. Thus, in these and lead to maintenance of the metabolic alkalosis. When NaCl conditions the renal defect leads to generation of the abkalosis is provided, the kidney corrects the alkalosis. and volume contraction, which secondarily causes the kidney A number of extrarenal conditions lead to the generation of to maintain the abkabosis. metabolic alkalosis associated with volume contraction, which Posthypercapnic metabolic alkalosis refers to a condition in secondarily causes the kidney to maintain the alkalosis. These which chronic hypercapnia leads to a compensatory metabolic conditions include vomiting, nasogastric suction, villous ade- alkalosis. During this period of hypercapnia, renal retention of noma, congenital chboridorrhea, and severe volume contrac- HCO1 is associated with a chloruresis. This likely occurs tion. because NaHCO3 retention causes volume expansion, which In all of these conditions, alkalosis leads to renal K wast- causes the kidney to excrete NaC1. The net result is that ing, and the resultant K depletion contributes to the mainte- patients with hypercapnia have increased total body NaHCO3 nance of metabolic alkalosis. However, volume contraction and decreased total body NaC1. When hypercapnia is corrected, remains the major factor responsible for maintenance. If one the kidney will attempt to correct the alkalosis by excreting corrects the K deficit without correcting the volume deficit, HCO. However, if NaC1 is not provided, bicarbonaturia will metabolic alkabosis remains, whereas correction of the volume Metabolic Alkabosis 1465 deficit with persistent leads to correction of the be genetic or may be due to ingestion of an inhibitor, glycyr- metabolic alkalosis ( 1,16). rhizic acid, which is present in licorice and chewing tobacco. An additional genetic disorder that appears as a hypermin- eralocorticoid state with low renin and aldosterone levels is Volume Expansion with Mineralocorticoid Excess Liddle’s syndrome. This condition differs from the conditions These conditions are associated with a primary increase in above in that hypertension and hypokalemic alkabosis are not minerabocorticoid activity. Increased mineralocorticoid activity responsive to mineralocorticoid receptor antagonists. Thus, the is considered primary in that it persists in the face of expansion defect is actually downstream of the mineralocorticoid recep- of the effective extracellular fluid volume, which normally tor. Studies have now demonstrated that Liddle’s syndrome is would lead to its suppression. As long as dietary Na is due to a mutation in the luminal membrane Na channel of the normal, distal delivery of Na salts will be plentiful, and cortical collecting duct, which increases its activity (19). This urinary K and net acid excretion will be increased. This will leads to enhanced Na reabsorption and voltage changes sim- result in K deficiency and the generation and maintenance of ilar to those associated with hypermineralocorticoid states, metabolic alkalosis. As discussed earlier, the resulting hypo- resulting in hypertension, hypokalemia, and alkalosis. kalemia further increases net acid excretion in the presence of nonsuppressible minerabocorticoid activity. Renal Insufficiency From the clinical point of view, conditions with primary In the setting of significant renal disease, HCO clearance is increases in mineralocorticoid activity are most easily divided decreased, and severe metabolic alkalosis may occur after into three groups based on circulating levels of renin and exogenous HCO administration. Similarly, renal insuffi- aldosterone. First, patients may have increased levels of renin, ciency is a critical event in the pathogenesis of milk-alkali which cause increased levels of aldosterone. Increased renin syndrome. In this syndrome, consumption of large quantities of production may result from conditions such as renal artery milk and calcium-containing antacids results in hypercalcemia stenosis, accelerated hypertension, or a renin-secreting tumor. and metabolic abkalosis. Hypersecretion of aldosterone also may be primary, in which case it will be associated with suppressed renin levels. Condi- tions that may give rise to primary hyperaldosteronism include Approach to the Patient with Metabolic adrenal adenomas, bilateral adrenal hyperplasia, dexametha- Alkalosis sone-responsive adrenal hyperplasia, and adrenal carcinoma. The approach to the patient suspected of metabolic alkalosis Dexamethasone-responsive adrenal hyperplasia has been begins with analysis of the arterial blood gas, ensuring that one shown to be due to a translocation, which causes the promoter is dealing with a primary metabolic alkabosis rather than a of the 1 113 hydroxylase gene, an ACTH responsive gene, to compensation for a (Figure 1 ). After doc- move to the 1 8 hydroxylase gene, a rate-limiting gene in umenting that the patient has a metabolic alkalosis, further aldosterone synthesis (17). The net result is that ACTH causes evaluation is based on consideration of the factors responsible increased expression of aldosterone synthase, increasing aldo- for maintenance. As shown in Table 2, the causes of metabolic sterone synthesis, and secretion. Provision of glucocorticoids alkalosis may be conveniently divided between those in which to the patients suppresses ACTH, thus inhibiting aldosterone alkalosis is maintained by a decreased effective arterial vol- synthesis. ume, those in which it is maintained by the combination of A third group of patients displays evidence of excessive high aldosterone and high distal Na delivery, and those in mineralocorticoid activity attributable to a mineralocorticoid which it is maintained by renal failure. In general, it is obvious agent other than aldosterone. Measured levels of renin and when patients have renal failure, and these entities will not be aldosterone are low. Examples of these syndromes include discussed further. adrenogenitab syndromes in which there is oversecretion of The first key step in the approach, therefore, is the assess- nonaldosterone mineralocorticoids such as deoxycorticoste- ment of the effective arterial volume. As in most patients, rone, and the various causes of Cushing’s syndrome, in which effective arterial volume may be assessed by the physical secretion of hydrocortisone is increased. Whether patients with examination, emphasizing the presence or absence of postural Cushing’s syndrome develop hypokalemic alkalosis likely de- changes in pulse and BP. The serum uric acid and the blood pends on their relative levels of cortisol and 1 13 hydroxylase. urea nitrogen:creatinine ratio are also helpful. Finally, urinary The enzyme 1 1f3 hydroxybase is expressed in minerabocorti- are helpful. Patients with a low effective arterial coid-responsive cells and is responsible for inactivating corti- volume should have low urinary Na and Cl concentrations. sol in these cells (1 8). This reaction, which converts the active In these patients, bicarbonaturia or excretion of other nonre- cortisol to the inactive cortisone, is responsible for the limited absorbable anions may lead to inappropriately high urinary mineralocorticoid activity of cortisol. When cortisol levels Na concentrations even in the presence of volume contrac- exceed the capacity of 1 1 3 hydroxylase to inactivate it, it binds tion. Thus, the urinary Cl is frequently more useful in these to the mineralocorticoid receptor and elicits mineralocorticoid patients. effects. In addition to its relevance to Cushing’s syndrome, When urinary C1 is low, this usually points to a contracted decreases in the activity of 1 l hydroxylase may result in effective arterial volume. If this is associated with a high urine hypermineralocorticoid states. Such decreases in activity may Nat, the patient likely is excreting a nonreabsorbable anion or 1466 Journal of the American Society of Nephrology

Approach To The Patient With Metabolic Alkalosis 1. Check Arterial Blood Gas To Exclude Compensation For Respiratory Acidosis 1 Assess Volume Status / N I Normal or t EABV Conditions associated with t _/ N_ minerabocorticoid effect Unne[Cl] t Urine [Cl] 1 Measure renin and aldosterone / 1 . Active diuretic use 2. Mgi-i deficiency thnne[Na] t Unne[Na] 3. Bartter’s syndrome

1 . Posthypercapneic 1 . Voniting (active) 2. Remote use of diuretics 2. Excretion of non-reabsorbable anion 3. Vonting (not active)

Figure 1. Approach to the patient with metabolic alkalosis. EABV, effective arterial blood volume.

bicarbonate. These may be distinguished using the urine pH. A hypokalemic alkalosis is due to a primary increase in miner- urine pH of 7 or 8 indicates significant bicarbonaturia. A urine alocorticoids or whether it is merely due to the thiazide. Here pH of less than 6.5 suggests that another nonreabsorbable the serum Na can be very helpful. In general, patients on anion is responsible. such as ketoanions or an antibiotic. Once thiazides all tend to have low serum Na concentrations, the question of a nonreabsorbable anion is raised, the specific whereas patients with minerabocorticoid excess syndromes one responsible is usually clear. If a patient has significant tend to have high serum Na concentrations. The presence of bicarbonaturia, it suggests that the patient has generated a a [Nat] of 144 to 146 mEqfL in a patient on thiazides suggests metabolic alkalosis of greater magnitude than the kidney is a primary increase in mineralocorticoids. being driven to maintain. Because the kidney cannot generate and correct an alkabosis at the same time, this suggests extra- Clinical Consequences of Metabolic Alkalosis renal generation. Whether this is due to vomiting, nasogastric Metabolic alkalosis is generally considered a benign condi- suction, or a Cl wasting, diarrhea is usually obvious. tion by most . However, there is evidence that sug- A high urinary C1 in a patient with volume contraction gests that under certain circumstances metabolic alkalosis may suggests diuretics. Bartter’s syndrome. or Mg2 depletion. If contribute significantly to mortality. In fact, a direct relation- urine Na and C1 are low, the cause of the alkalosis may ship has been shown between increasing blood pH and hospital be posthypercapnic. diuretics (without a diuretic effect at the mortality in patients with a pH of greater than 7.48 (20,21). time of measurement), or vomiting (likely not actively vomit- The demonstration that high arterial blood pH correlates with ing). mortality does not establish a cause/effect relationship. It is If the patient has hypertension and appears euvolemic/vol- certainly plausible that conditions associated with high mor- ume expanded, one is likely dealing with a primary increase in tality cause metabolic and , making alka- mineralocorticoids. Workup of these patients is extremely im- losis merely a marker of a poor prognosis. However, there are portant because these disorders represent a common cause of a number of reasons to believe that high blood pH may con- treatable hypertension. Here the measurement of renin and tribute to the poor prognosis. This is based on some of the aldosterone represents the next step. If measured renin and known pathophysiologic effects of a high blood pH. aldosterone are both elevated, it is important to be certain that First, increases in blood pH (alkalemia) cause respiratory the patient was not volume-contracted at the time of measure- depression. This effect of metabolic pH changes on respiration ment. This can frequently be accomplished by a saline sup- is mediated via both central and peripheral chemoreceptors. pression test. This is not a problem if renin levels are sup- Although the effects of metabolic alkabosis on respiration are pressed. Table 2 lists the various disease entities that should be well appreciated, the effects of alkalosis to decrease tissue considered based on the results of the renin and aldosterone oxygen delivery are less well appreciated. Alkalosis can de- measurements. crease oxygen delivery by two possible mechanisms. First, by One difficult scenario is a patient with hypertension who is the Bohr effect, alkalosis leads to a shift in the oxygen disso- taking a thiazide diuretic. In this case, it is not clear whether the ciation curve of hemoglobin, which decreases the ability of Metabolic Alkalosis 1467 hemoglobin to release oxygen in peripheral tissues. Thus, even tamed by volume contraction, administration of NaC1 should in the absence of changes in blood flow, alkalosis may lead to correct the alkalosis. Although it is not necessary to give K to marked decreases in oxygen delivery to tissues. these patients to correct the alkalosis, one frequently adminis- In addition to the Bohr effect, alkalosis is a potent vasocon- ters KCI to correct the hypokalemia. Other treatment ap- strictor. Numerous studies have shown that increases in pH proaches that may be used are Mg2 replacement in Mg2 associated with decreases in Pco2 (respiratory alkalosis) lead to deficiency, K replacement in severe K deficiency, removal vasoconstriction and decreased perfusion of the brain, heart, of the source of excess minerabocorticoid in appropriate pa- and peripheral circulation. Respiratory alkalosis is used clini- tients, cessation of diuretic , or cessation of nasogastric cally to decrease cerebral blood flow in patients with cerebral suction. In patients in whom nasogastric suction is necessary, edema. Although it is unclear from studies in man and whole addition of H2 receptor blockade may decrease the tendency to animals whether pH changes due to metabolic alkalosis have generate the metabolic alkalosis. the same effect, in vitro studies show that pH is the critical In certain patients, it may be difficult to correct the factors determinant of vascular smooth muscle tone, regardless of responsible for maintenance of metabolic alkalosis. This oc- whether pH is altered by changes in Pco2 or HCO concen- curs most frequently in patients whose metabolic alkalosis is tration (22,23). Studies in humans and intact animals are com- maintained by decreased effective arterial volume but whose plicated by expansion of the circulating blood volume with a cardiovascular system cannot tolerate administration of NaCl. NaHCO3 infusion and by other possible secondary effects such In these situations, one must ask how important it is to correct as rapid renal potassium wasting in acute metabolic alkalosis. the metabolic alkalosis. On the basis of the above discussion, It seems most likely that blood pH is a determinant of vascular patients in whom one would want to aggressively correct resistance such that organ perfusion may be compromised in metabolic alkalosis would include: (1) patients with chronic metabolic, as well as respiratory, alkalosis. This may be a more lung disease in whom intubation is imminent or extubation is severe problem in patients with chronic metabolic alkalosis, difficult and in whom metabolic alkalosis needs to be corrected which is frequently associated with contraction of the circulat- to improve the drive to respiration; (2) patients with myocar- ing blood volume (see below). dial ischemia with evolving myocardial infarction, patients Alkalosis-induced vasoconstriction, together with the Bohr who are having chest pain postinfarction, or patients with effect, may cause clinical tissue hypoxia in certain settings. For unstable angina; and (3) ill patients with cerebral dysfunction example, has been shown to precipitate chest in whom cerebral hypoperfusion is a possible contributing pain, ST segment elevation, and spasm on coronary angiogra- factor. phy in patients with Prinzmetal’s angina (24). Similarly, hy- If metabolic alkalosis needs to be treated aggressively and perventilation has been shown to cause angina in the presence cannot be treated by correcting the cause of the generation or or absence of coronary artery disease (25,26). Alkalosis has maintenance, a number of options remain. First, ammonium also been reported to induce cardiac , which are chloride may be given (27). This is generally a safe way to unresponsive to antiarrhythmics and respond only to correction administer acid if given orally. However, if given intrave- of the alkalosis. Unfortunately, this is only substantiated by a nously, especially in patients with liver disease, ammonium number of case reports, and it is difficult to prove an increased chloride may cause ammonia toxicity. Arginine hydrochloride incidence. has been used in the past to lower the plasma [HCO] but has In summary, evidence suggests that alkalemia can decrease since been taken off the market because of life-threatening oxygen delivery to tissues, and this may become a key factor in hyperkalemia. certain critically ill patients. Alkalemia constricts vascular The most commonly used approach to correct alkalosis in smooth muscle in vitro and appears to decrease tissue perfusion these difficult patients is administration of carbonic anhydrase in vivo. This, along with inhibition of oxygen release from inhibitors such as acetazolamide. Carbonic anhydrase catalyzes hemoglobin, leads to decreased tissue oxygen delivery, which the of luminal carbonic acid (produced when fib- is demonstrable clinically with regard to the heart where cor- tered HCO reacts with secreted H ) to water and CO2 and the onary artery spasm, angina, arrhythmias, and congestive heart hydration of cellular CO2 to carbonic acid, allowing the for- failure may be precipitated. Most likely, oxygen delivery to the mation of H for secretion into the luminal fluid. The uncata- brain is also compromised in ill patients with alkalosis, but it is lyzed dehydration of carbonic acid occurs very slowly. By frequently clinically difficult to distinguish brain hypoxia from inhibiting the activity of this enzyme, carbonic anhydrase other causes of encephalopathy. As will be referred to later, inhibitors inhibit renal acidification and thus cause the kidney critically ill patients, in whom perfusion of the heart and brain to at least partially correct the metabolic alkabosis (28). The is essential, should likely have their alkalosis aggressively magnitude of the bicarbonaturia induced is directly related to corrected. the serum HCO concentration. As the HCO concentration falls, the clinical effectiveness of the drug declines in a parallel Treatment of Metabolic Alkalosis manner. As a result, only rarely does the plasma HCO con- The treatment of metabolic alkalosis is best achieved by centration return to normal. correcting the factor responsible for maintenance. In addition, Acetazolamide is frequently used in patients with chronic it is frequently helpful to correct the factor that generated the respiratory acidosis who develop a metabolic alkalosis. Nor- alkalosis. If patients have a metabolic alkalosis that is main- mally, in patients with chronic respiratory acidosis the capacity 1468 Journal of the American Society of Nephrology

of the kidney to reabsorb bicarbonate increases, resulting in an secretion into the tubule lumen. Spironolactone can further increase in plasma HCO concentration. Use of loop diuretics limit distal H secretion because this drug not only inhibits in such patients. as in the treatment of cor pulmonale, may aldosterone-stimulated Na reabsorption, but also blocks the result in further increases in the serumHCO concentration. In direct stimulatory effect of aldosterone on the H secretory this setting, the induction of a metabolic alkalosis can depress pump. ventilation, aggravating both the hypoxemia and hypercapnia. Na channel blockers such as amiloride and triamterene are Normally. the metabolic alkalosis can be treated by discontinu- also effective in these patients. These drugs directly inhibit the ing the diuretic and administering NaC1. In the patient who is luminal membrane Na channel, decreasing the luminal elec- significantly edematous, however, this approach may not be tronegativity of the collecting duct and secondarily impairing practical. In this circumstance, acetazolamide can be used to renal K and H losses. The net effect is inhibition of renal inhibit HCO reabsorption and thus lower serum HCO con- Na retention, K loss, and increases in renal net acid excre- centration. tion, resulting in prevention of hypertension and hypokalemic A potential problem that is associated with use of carbonic alkabosis. anhydrase inhibitors in patients with lung disease is a worsen- As discussed earlier, Liddle’s syndrome is characterized by ing of hypercapnia. Carbonic anhydrase is normally present hypokalemic metabolic alkalosis and volume expansion, but is within red blood cells and is involved in CO7 movement into not due to minerabocorticoid excess. Rather, this disorder re- red cells in peripheral tissues and movement from red cells into suits from overactivity of the Na channel in the distal the alveoli in the lungs. Thus, carbonic anhydrase inhibition nephron. Predictably, use of spironolactone to block the mm- can prevent red cell uptake of CO, in peripheral tissues and can eralocorticoid receptor is without effect in this disorder. By prevent CO2 release in the lung. The latter may lead to an contrast, the electrolyte abnormalities and hypertension are increase in the Pco, of the arterial blood, whereas the former normalized by use of the sodium channel blockers triamterene may bead to an additional increase in Pco, in peripheral tissues. and amiboride. Generally, patients with normal lungs respond to this by in- creasing respiration and preventing the increase in the Pco2 of the arterial blood. However, patients with lung disease cannot Summary respond adequately, and further increases in arterial Pco2, as In summary, the kidney possesses numerous mechanisms well as even greater increases in unmeasured tissue Pco2, may that help to prevent metabolic alkalosis. Maintenance of met- be dangerous to the patient. abolic alkalosis for any length of time means that renal ho- A safe approach to the aggressive treatment of metabolic meostatic mechanisms for HCO excretion have been dis- alkalosis that has gained support is the use of hydrochloric acid rupted. Understanding the mechanisms that may perturb the infusions (29,30). In general, hydrochloric acid may be safely kidney’s ability to correct alkalosis will lead to improved administered as a 0. 1S to 0.25 Normal solution in normal saline clinical approaches to differential diagnosis and treatment of or D5W given through a central line. It is imperative that the the patient. Although metabolic alkabosis is frequently not position of the central line in the superior vena cava be verified dangerous, in certain settings metabolic alkalosis may contrib- by chest x-ray before initiating infusion. There are a large ute to mortality and should be treated aggressively. number of reports published showing that such an infusion is safe (29,30). If the wishes, the HC1 may be added to an amino acid solution in total parenteral nutrition and given References centrally (31). In addition, there is also a report in which HC1 1 . Seldin DW, Rector FC Jr: The generation and maintenance of was given in an amino acid solution with intralipid through a metabolic alkabosis. Kidney mt 1: 306-321, 1972 peripheral vein (32). 2. Seldin DW, Welt LG, Cort JH: The role of sodium salts and The preferred treatment of metabolic alkalosis in patients adrenal steroids in the production of hypokalemic alkalosis. Yale with volume expansion and primary mineralocorticoid excess J Biol Med 29: 229-247, 1956 is to remove the underlying cause of the persistent mineralo- 3. Cohen JJ: Correction of metabolic alkalosis by the kidney after corticoid activity. When this is not possible, therapy is directed isometric expansion of extracellular fluid. Am J Med 47: 1 181- at blocking the actions of the mineralocorticoid at the level of 1192, 1968 the kidney. The potassium-sparing diuretics are effective 4. Alpern Ri, Emmett M, Seldin DW: Metabolic alkabosis. In: The agents in blocking the actions of minerabocorticoids in the Kidney: Physiology and Pathophysiology, 2nd Ed., edited by kidney and are commonly used in the treatment of these Seldin DW, Giebisch G, New York, Raven Press, 1992, pp 2733-2758 disorders. Mineralocorticoid receptor blockers such as spirono- 5. 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