Metabolic Alkalosis

6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Arterial blood pH

FIGURE 6-30

Ninety-five percent confidence intervals for metabolic alkalosis. Metabolic alkalosis is the acid-base disturbance initiated by an increase in plasma bicarbonate concentration ([HCO3]). The resultant alkalemia dampens alveolar ventilation and leads to the secondary hypercapnia characteristic of the disorder. Available observations in humans suggest a roughly linear relationship between the steady-state increase in bicarbonate concentration and the associated increment in the arterial carbon dioxide tension (PaCO2). Although data are limited, the slope of the steady-state APaCO2 versus A[HCO^] relationship has been estimated as about a 0.7 mm Hg per mEq/L increase in plasma bicarbonate concentration. The value of this slope is virtually identical to that in dogs that has been derived from rigorously controlled observations [21]. Empiric observations in humans have been used for construction of 95% confidence intervals for graded degrees of metabolic alkalosis represented by the area in color in the acid-base template. The black ellipse near the center of the figure indicates the normal range for the acid-base parameters [3]. Assuming a steady state is present, values falling within the area in color are consistent with but not diagnostic of simple metabolic alkalosis. Acid-base values falling outside the area in color denote the presence of a mixed acid-base disturbance [4]. [H+]—hydrogen ion concentration.

Excess alkali

Alkali gain

Source?

Enteral

— Milk alkali syndrome

— Calcium supplements

— Absorbable alkali

— Nonabsorbable alkali plus K+ exchange resins

Parenteral

— Ringer's solution

— Bicarbonate

— Blood products Nutrition

H+ loss

Gastric

Intestinal Q

Suction

Villous adenoma Congenital chloridorrhea

Renal

H+ shift

Chloruretic diuretics Inherited transport defects Mineralocorticoid excess Posthypercapnia

K+ depletion

Reduced GFR

Mode of perpetuation?

Increased renal acidification t

Cl responsive defect Cl- resistant defect

FIGURE 6-31

Pathogenesis of metabolic alkalosis. Two crucial questions must be answered when evaluating the pathogenesis of a case of metabolic alkalosis. 1) What is the source of the excess alkali? Answering this question addresses the primary event responsible for generating the hyperbicarbonatemia. 2) What factors perpetuate the hyperbicarbon-atemia? Answering this question addresses the pathophysiologic events that maintain the metabolic alkalosis.

Days

FIGURE 6-32

Changes in plasma anionic pattern and body electrolyte balance during development, maintenance, and correction of metabolic alkalosis induced by vomiting. Loss of hydrochloric acid from the stomach as a result of vomiting (or gastric drainage) generates the hypochloremic hyperbicarbonatemia characteristic of this disorder. During the generation phase, renal sodium and potassium excretion increases, yielding the deficits depicted here. Renal potassium losses continue in the early days of the maintenance phase. Subsequently, and as long as the low-chloride diet is continued, a new steady state is achieved in which plasma bicarbonate concentration ([HCO3]) stabilizes at an elevated level, and renal excretion of electrolytes matches intake. Addition of sodium chloride (NaCl) and potassium chloride (KCl) in the correction phase repairs the electrolyte deficits incurred and normalizes the plasma bicarbonate and chloride concentration ([Cl-]) levels [22,23].

Days

FIGURE 6-33

Days

FIGURE 6-33

Changes in urine acid-base composition during development, maintenance, and correction of vomiting-induced metabolic alkalosis. During acid removal from the stomach as well as early in the phase after vomiting (maintenance), an alkaline urine is excreted as acid excretion is suppressed, and bicarbonate excretion (in the company of sodium and, especially potassium; see Fig. 6-32) is increased, with the net acid excretion being negative (net alkali excretion). This acid-base profile moderates the steady-state level of the resulting alkalosis. In the steady state (late maintenance phase), as all filtered bicarbonate is reclaimed the pH of urine becomes acidic, and the net acid excretion returns to baseline. Provision of sodium chloride (NaCl) and potassium chloride (KCl) in the correction phase alkalinizes the urine and suppresses the net acid excretion, as bicarbonaturia in the company of exogenous cations (sodium and potassium) supervenes [22,23]. HCO3—bicarbonate ion.

Days

FIGURE 6-34

Days

FIGURE 6-34

Changes in plasma anionic pattern, net acid excretion, and body electrolyte balance during development, maintenance, and correction of diuretic-induced metabolic alkalosis. Administration of a loop diuretic, such as furosemide, increases urine net acid excretion (largely in the form of ammonium) as well as the renal losses of chloride (Cl-), sodium (Na+), and potassium (K+). The resulting hyperbicarbonatemia reflects both loss of excess ammonium chloride in the urine and an element of contraction (consequent to diuretic-induced sodium chloride [NaCl] losses) that limits the space of distribution of bicarbonate. During the phase after diuresis (maintenance), and as long as the low-chloride diet is continued, a new steady state is attained in which the plasma bicarbonate concentration ([HCO3]) remains elevated, urine net acid excretion returns to baseline, and renal excretion of electrolytes matches intake. Addition of potassium chloride (KCl) in the correction phase repairs the chloride and potassium deficits, suppresses net acid excretion, and normalizes the plasma bicarbonate and chloride concentration ([Cl-]) levels [23,24]. If extracellular fluid volume has become subnormal folllowing diuresis, administration of NaCl is also required for repair of the metabolic alkalosis.

Maintenance of Cl -responsive metabolic alkalosis

Basic mechanisms Mediating factors

IGFR

ÎHCO3 reabsorption

Cl depletion ECF volume depletion K+ depletion Hypercapnia

Basic mechanisms Mediating factors

ÎHCO3 reabsorption

Cl depletion ECF volume depletion K+ depletion Hypercapnia

ÎNa+ reabsorption and consequent ÎH+ and K+ secretion

ÎH + secretion coupled to K+ reabsorption

Net acid excretion maintained at control

ÎNa+ reabsorption and consequent ÎH+ and K+ secretion

ÎH + secretion coupled to K+ reabsorption

Net acid excretion maintained at control

FIGURE 6-35

Maintenance of chloride-responsive metabolic alkalosis. Increased renal bicarbonate reabsorption frequently coupled with a reduced glomerular filtration rate are the basic mechanisms that maintain chloride-responsive metabolic alkalosis. These mechanisms have been ascribed to three mediating factors: chloride depletion itself, extracellular fluid (ECF) volume depletion, and potassium depletion. Assigning particular roles to each of these factors is a vexing task. Notwithstanding, here depicted is our current understanding of the participation of each of these factors in the nephronal processes that maintain chloride-responsive metabolic alkalosis [22-24]. In addition to these factors, the secondary hypercapnia of metabolic alkalosis contributes importantly to the maintenance of the prevailing hyperbicarbonatemia [25].

Maintenance of Cl -resistant metabolic alkalosis

Maintenance of Cl -resistant metabolic alkalosis

FIGURE 6-36

Maintenance of chloride-resistant metabolic alkalosis. Increased renal bicarbonate reabsorption is the sole basic mechanism that maintains chloride-resistant metabolic alkalosis. As its name implies, factors independent of chloride intake mediate the height ened bicarbonate reabsorption and include mineralocorticoid excess and potassium depletion. The participation of these factors in the nephronal processes that maintain chloride-resistant metabolic alkalosis is depicted [22-24, 26].

Virtually absent

• Vomiting, gastric suction

• Postdiuretic phase of loop and distal agents

• Posthypercapnic state

• Villous adenoma of the colon

• Congenital chloridorrhea

• Post alkali loading

• Laxative abuse

• Other causes of profound K+ depletion

• Diuretic phase of loop and distal agents

• Bartter's and Gitelman's syndromes

• Primary aldosteronism

• Cushing's syndrome

• Exogenous mineralocorticoid agents

• Secondary aldosteronism malignant hypertension renovascular hypertension primary reninism

• Liddle's syndrome

FIGURE 6-37

Urinary composition in the diagnostic evaluation of metabolic alka-losis. Assessing the urinary composition can be an important aid in the diagnostic evaluation of metabolic alkalosis. Measurement of urinary chloride ion concentration ([Cl-]) can help distinguish between chloride-responsive and chloride-resistant metabolic alkalosis. The virtual absence of chloride (urine [Cl-] < 10 mEq/L) indicates significant chloride depletion. Note, however, that this test loses its diagnostic significance if performed within several hours of administration of chloruretic diuretics, because these agents promote urinary chloride excretion. Measurement of urinary potassium ion concentration ([K+]) provides further diagnostic differentiation. With the exception of the diuretic phase of chloruretic agents, abundance of both urinary chloride and potassium signifies a state of mineralocor-ticoid excess [22].

SIGNS AND SYMPTOMS OF METABOLIC ALKALOSIS

Central

Nervous System

Cardiovascular System

Respiratory System

Neuromuscular System

Metabolic Effects

Renal (Associated Potassium Depletion)

Headache

Lethargy

Stupor

Delirium

Tetany

Seizures

Potentiation of hepatic encephalopathy

Supraventricular and ventricular arrhythmias Potentiation of digitalis toxicity Positive inotropic ventricular effect

Hypoventilation with attendant hypercapnia and hypoxemia

Chvostek's sign Trousseau's sign Weakness (severity depends on degree of potassium depletion)

Increased organic acid and ammonia production Hypokalemia Hypocalcemia Hypomagnesemia Hypophosphatemia

Polyuria Polydipsia

Urinary concentration defect Cortical and medullary renal cysts

FIGURE 6-38

Signs and symptoms of metabolic alkalosis. Mild to moderate metabolic alkalosis usually is accompanied by few if any symptoms, unless potassium depletion is substantial. In contrast, severe metabolic alkalosis ([HCO3] > 40 mEq/L) is usually a symptomatic disorder. Alkalemia, hypokalemia, hypoxemia, hypercapnia, and decreased plasma ionized calcium concentration all contribute to these clinical manifestations. The arrhythmogenic potential of alka-lemia is more pronounced in patients with underlying heart disease and is heightened by the almost constant presence of hypokalemia, especially in those patients taking digitalis. Even mild alkalemia can frustrate efforts to wean patients from mechanical ventilation [23,24].

FIGURE 6-39

Pathophysiology of the milk-alkali syndrome. The milk-alkali syndrome comprises the triad of hypercalcemia, renal insufficiency, and metabolic alkalosis and is caused by the ingestion of large amounts of calcium and absorbable alkali. Although large amounts of milk and absorbable alkali were the culprits in the classic form of the syndrome, its modern version is usually the result of large doses of calcium carbonate alone. Because of recent emphasis on prevention and treatment of osteoporosis with calcium carbonate and the availability of this preparation over the counter, milk-alkali syndrome is currently the third leading cause of hypercalcemia after primary hyper-parathyroidism and malignancy. Another common presentation of the syndrome originates from the current use of calcium carbonate in preference to aluminum as a phosphate binder in patients with chronic renal insufficiency. The critical element in the pathogenesis of the syndrome is the development of hypercalcemia that, in turn, results in renal dysfunction. Generation and maintenance of metabolic alkalosis reflect the combined effects of the large bicarbonate load, renal insufficiency, and hypercal-cemia. Metabolic alkalosis contributes to the maintenance of hypercalcemia by increasing tubular calcium reabsorption. Superimposition of an element of volume contraction caused by vomiting, diuretics, or hypercalcemia-induced natriuresis can worsen each one of the three main components of the syndrome. Discontinuation of calcium carbonate coupled with a diet high in sodium chloride or the use of normal saline and furosemide therapy (depending on the severity of the syndrome) results in rapid resolution of hypercalcemia and metabolic alkalo-sis. Although renal function also improves, in a considerable fraction of patients with the chronic form of the syndrome serum creatinine fails to return to baseline as a result of irreversible structural changes in the kidneys [27].

Clinical syndrome Affected gene Affected chromosome Localization of tubular defect

Bartter's syndrome

Bartter's syndrome

Type 1

NKCC2 0 15q15-q21

Type 2

ROMK ♦ 11q24

Gitelman's syndrome

Gitelman's syndrome

Tubular Perit lumen I Cel J sp

i Peritubular Tubular

16q13

Peritubular Tubular

Peritubular space

-2K Pase

Car"

Thiazides

Thick ascending limb (TAL) Distal convoluted tuble (DCT) Cortical collecting duct (CCD)

FIGURE 6-40

Clinical features and molecular basis of tubular defects of Bartter's and Gitelman's syndromes. These rare disorders are characterized by chloride-resistant metabolic alkalosis, renal potassium wasting and hypokalemia, hyperreninemia and hyperplasia of the juxtaglomerular apparatus, hyperaldosteronism, and normotension. Regarding differentiating features, Bartter's syndrome presents early in life, frequently in association with growth and mental retardation. In this syndrome, urinary concentrating ability is usually decreased, polyuria and polydipsia are present, the serum magnesium level is normal, and hypercalciuria and nephrocalcinosis are present. In contrast, Gitelman's syndrome is a milder disease presenting later in life. Patients often are asymptomatic, or they might have intermittent muscle spasms, cramps, or tetany. Urinary concentrating ability is maintained; hypocal-ciuria, renal magnesium wasting, and hypomagnesemia are almost constant features. On the basis of certain of these clinical features, it had been hypothesized that the primary tubular defects in Bartter's and Gitelman's syndromes reflect impairment in sodium reabsorption in the thick ascending limb (TAL) of the loop of Henle and the distal tubule, respectively. This hypothesis has been validated by recent genetic studies [28-31]. As illustrated here, Bartter's syndrome now has been shown to be caused by loss-of-function mutations in the loop diuretic-sensitive sodium-potassium-2chloride cotransporter (NKCC2) of the TAL (type 1 Bartter's syndrome) [28] or the apical potassium channel ROMK of the TAL (where it recycles reabsorbed potassium into the lumen for continued operation of the NKCC2 cotransporter) and the cortical collecting duct (where it mediates secretion of potassium by the principal cell) (type 2 Bartter's syndrome) [29,30]. On the other hand, Gitelman's syndrome is caused by mutations in the thiazide-sensitive Na-Cl cotransporter (TSC) of the distal tubule [31]. Note that the distal tubule is the major site of active calcium reabsorption. Stimulation of calcium reabsorption at this site is responsible for the hypocalci-uric effect of thiazide diuretics.

For alkali gain

Eliminate source of excess alkali

Discontinue administrationof bicarbonate or its precursors.

via gastric route

For H+ loss via renal route

For H+ shift

For decreased GFR

Interrupt perpetuating mechanisms

Administer antiemetics; discontinue gastric suction; administer H2 blockers or H+-K+ ATPase inhibitors. Discontinue or decrease loop and distal diuretics; substitute with amiloride, triamterene, or spironolactone; discontinue or limit drugs with mineralo-corticoid activity.

For Cl responsive acidification defect

Potassium repletion

ECF volume repletion; renal replacement therapy

Administer NaCl and KCl

For Cl resistant acidification defect

• Adrenalectomy or other surgery, potassiuim repletion, administration of amiloride, triamterene, or spironolactone.

FIGURE 6-41

Metabolic alkalosis management. Effective management of metabolic alkalosis requires sound understanding of the underlying pathophysiology. Therapeutic efforts should focus on eliminating or moderating the processes that generate the alkali excess and on interrupting the mechanisms that perpetuate the hyperbicarbonatemia. Rarely, when the pace of correction of metabolic alkalo-sis must be accelerated, acetazolamide or an infusion of hydrochloric acid can be used. Treatment of severe metabolic alkalosis can be particularly challenging in patients with advanced cardiac or renal dysfunction. In such patients, hemodialysis or continuous hemofiltration might be required [1].

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