I. Problem/Condition.

Metabolic alkalosis refers to conditions that result in an elevation in the serum bicarbonate (HCO3-), to levels greater than 28 mmol/L, and an alkaline serum pH, greater than 7.40. The accumulation of base due to the addition of alkali, either in the form of bicarbonate or a precursor, such as lactate, citrate or acetate, rarely leads to metabolic alkalosis due to the tremendous capacity of the kidneys to increase HCO3- excretion. Thus, renal insufficiency or other factors, such as potassium or chloride depletion, has to be present in order for increased alkali ingestion to lead to metabolic alkalosis. Sustained metabolic alkalosis also occurs in situations of profound potassium or chloride depletion, in the absence of exogenous bicarbonate intake.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

In the setting of an elevated serum HCO3- level, several possibilities besides metabolic alkalosis have to be considered:

  • Chronic respiratory acidosis

– The compensatory response to chronic respiratory acidosis involves increased renal reabsorption of HCO3- to mitigate the decrease in serum pH resulting from long-standing CO2 retention. To be certain, check an arterial blood gas (ABG): the pH is alkalemic (greater than 7.40) in metabolic alkalosis and acidemic (less than 7.40) in chronic respiratory acidosis.

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  • Mixed acid-base disorders
  • -These scenarios are particularly common in hospitalized patients, such as those who have suffered cardiorespiratory arrest, septic shock, drug intoxication, diabetes mellitus and renal failure. Characterization of these disorders can be challenging but is necessary in order for the corrective action to be taken. In order to tease out the different components of the complex acid-base disorder, it is essential to be aware of the expected quantitative adaptive responses to each of the four simple acid-base disturbances.
  • -Concomitant primary respiratory alkalosis: In response to a chronic elevation in serum pH, hypoventilation occurs and the subsequent rise in PaCO2 minimizes the rise in serum pH. One can expect a rise in the PaCO2 of about 5 -7 mm Hg for every 10 mEq/L rise in the serum HCO3-. If the PaCO2 is below 40 mm Hg, however, this would suggest a concomitant primary respiratory alkalosis.
  • -Concomitant primary respiratory acidosis: Although the PaCO2 will be elevated in both conditions, the presence of respiratory acidosis will be signaled by a normal to slightly acidic serum pH.
  • -Concomitant anion-gap metabolic acidosis: Metabolic alkalosis may be present alongside metabolic acidoses. In this setting, the serum HCO3-may be normal or low, but calculation of the anion gap [ Na+ -(Cl-+ HCO3-) ] reveals an elevated gap. For instance, a diabetic patient may present with nausea and vomiting (leading to metabolic alkalosis), and the ensuing failure to administer insulin may prompt the development of ketoacidosis; hence, a concurrent anion gap metabolic acidosis.

B. Describe a diagnostic approach/method to the patient with this problem.

Once metabolic alkalosis has been established, the diagnostic approach is aimed at first ruling out exogenous sources of alkali. Thereafter, the etiologies of alkalosis may be broadly categorized into saline-responsive causes and saline-resistant forms. Although causes of saline-responsive alkaloses tend to also lead to volume depletion and low blood pressure, not all forms of saline-resistant metabolic alkaloses are characterized by high blood pressure; hence, blood pressure is not necessarily the discriminatory factor in delineating the different etiologies. The urine chloride concentration helps distinguish between saline-responsive (urine Cl < 10 mEq/L) and saline-resistant (urine Cl > 10 mEq/L) forms of metabolic alkalosis.

1. Historical information important in the diagnosis of this problem.

In general, metabolic alkalosis is well-tolerated and only when the serum HCO3-exceeds 50 mmol/L do patients develop neurologic symptoms, such as delirium, stupor, or seizures, or tetany due to resulting hypokalemia and hypocalcemia.

Exogenous alkali

When kidney function is normal, excess intake of bicarbonate or other forms of alkali is well-tolerated, unless renal failure ensues or there is concomitant chloride or potassium depletion. In the hospitalized patient, precursors of bicarbonate include lactate, which may be present in Lactated Ringer’s solution or peritoneal dialysis solutions, acetate, which may be present in total parenteral nutrition formulations, and citrate, a component of blood products and some potassium supplements. Hence, investigation of the types of fluid intake and the possibility of surreptitious sources of alkali should be entertained.

In the beginning of the 20th century, excessive intake of milk or cream was a component of a cocktail (Sippy diet) prescribed as treatment for peptic ulcer disease. This resulted in the milk-alkali syndrome characterized by renal failure and hypercalcemia. In the modern era, excess intake of calcium-containing supplements (mostly for osteoporosis prevention or treatment) has led to what has been termed calcium-alkali syndrome, in which metabolic alkalosis develops due to hypercalcemic acute renal failure. Hence, history should also be focused on the intake of calcium supplements and products like Alka Seltzer, aimed at relieving dyspepsia.

Saline-responsive metabolic alkalosis

History should be obtained regarding episodes of vomiting or nasogastric suctioning in the hospitalized patient. Surreptitious vomiting, as in patients with eating disorders, should be investigated carefully. Symptoms of intravascular volume depletion, such as lightheadedness, dizziness, decreased oral intake, syncope or palpitations should be elicited. Diuretic use should be queried as part of the medication history. In rare circumstances, chloride-depleting forms of diarrhea may lead to metabolic alkalosis and should be considered.

Saline-resistant metabolic alkalosis

Several potential causes of saline-resistant forms of metabolic alkalosis lead to hypertension; hence, symptoms of new onset or long-standing, frequently difficult-to-control hypertension, should be elicited. Additionally, a number of these diseases have a genetic basis; hence, any family history of hypokalemia or hypertension should be obtained. Mineralocorticoid excess may arise from licorice intake and should be ruled out in the history. Finally, symptoms of hypokalemia should be elicited, including muscle cramps, weakness or polyuria. Long-standing hypokalemia may be associated with chronic renal failure.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

The focus of the physical exam is on assessing the patient’s volume status and ensuring hemodynamic stability. Additionally, physical findings of bulimia nervosa, including Russell sign, calluses, or abrasions on the dorsum of the hand overlying the metacarpophalangeal and interphalangeal joints, caused by repeated contact with the incisors during self-induced vomiting, should be noted. Altered mental status may be present in some patients due to electrolyte disturbances or concomitant acute renal failure.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Exogenous alkali

No additional testing in patients for whom a clear source of additional alkali is identified. In patients with milk-alkali or calcium-alkali syndrome, the presence of hypercalcemia may prompt additional testing to ensure that alternative etiologies of hypercalcemia are ruled out.

Saline-responsive alkalosis (urine Cl < 10)

Usually no further testing or radiologic studies is necessary, except as needed to identify the reason(s) for vomiting, or diarrhea.

Saline-resistant alkalosis (urine Cl > 10 mEq/L)

Further laboratory and radiographic testing depends upon the potential etiologies being entertained. In patients with suspected primary hyperaldosteronism, measurement of the aldosterone to plasma renin activity ratio is warranted; followed by radiographic imaging of the adrenals. Several etiologies, particularly Bartter and Gitelman syndromes may require additional confirmation of potassium wasting, through 24-hour measurements of urinary potassium. Additional testing for urinary magnesium wasting may also be necessary. Genetic tests are available for Bartter, Gitelman, Liddle syndromes and glucocorticoid remediable aldosteronism.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

As noted above, saline-responsive metabolic alkaloses are characterized by urinary chloride concentration less than 10 mEq/L. Potential etiologies include:

  • Acid loss from stomach
  • -Vomiting
  • -Nasogastric suction
  • Diuretic therapy
  • Chloride-depleting diarrhea
  • -Congenital chloride diarrhea
  • -Villous adenoma of the colon

In saline-resistant forms of metabolic alkalosis, the urinary chloride concentration is greater than 10 mEq/L. Potential etiologies include:

  • Mineralocorticoid excess
  • -Primary hyperaldosteronism
  • -Cushing syndrome
  • -ACTH-secreting tumor
  • -Reninoma
  • -Glucocorticoid-remediable aldosteronism
  • -Fludrocortisone therapy
  • Apparent mineralocorticoid excess
  • -Licorice
  • -Liddle’s syndrome
  • -11-beta-hydroxysteroid dehydrogenase deficiency
  • Potassium losing nephropathies
  • -Bartter syndrome
  • -Gitelman syndrome

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Besides the urinary chloride concentration, measurement of other urine electrolytes may not be useful in evaluating metabolic alkalosis. In particular, the urine Na concentration (or calculation of the fractional excretion of Na, FENa), may not truly reflect the patient’s volume status. When renal function is intact, an increased renal excretion of HCO3-will also lead to urinary Na loss, in order to maintain electroneutrality. As a consequence, despite intravascular volume depletion in saline-responsive causes of metabolic alkalosis, the urinary Na concentration will be elevated, i.e. greater than 20 mEq/L.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Metabolic Alkalosis.

Exogenous alkali

Recognition of the exogenous source of alkali and prompt discontinuation or dose adjustment should alleviate the alkalosis. In patients on chronic total parenteral nutrition, adjustment of acetate levels is necessary. In patients with milk-alkali or calcium-alkali syndrome, therapy is aimed at reversing the renal failure with aggressive fluid resuscitation and treating hypercalcemia. Furosemide may be used to enhance calciuresis.

Saline-responsive metabolic alkalosis

Therapy is aimed at restoring intravascular volume depletion through the administration of intravenous sodium chloride until hemodynamic stability is achieved. Concomitant hypokalemia may be treated with intravenous or oral potassium supplementation. In patients with metabolic alkalosis in the setting of diuretic therapy, repletion with potassium chloride aids in resolving the alkalosis. Alternatively, in patients with significant edema, consider the use of the carbonic anhydrase inhibitor acetazolamide to effect enhanced renal bicarbonate wasting. Proton pump inhibitors or H2blockers may mitigate the loss of acidic gastric contents in patients requiring long-term nasogastric suctioning.

Saline-resistant metabolic alkalosis

Management will depend upon the underlying cause. Patients with primary hyperaldosteronism may be treated with surgical resection of the adrenal adenoma, or medical therapy with aldosterone antagonists, such as spironolactone or eplerenone. Glucocorticoid-remediable aldosteronism responds to oral steroid therapy. Inhibition of the constitutively active epithelial sodium channel (ENaC) with amiloride in patients with Liddle syndrome is the most effective treatment. In Bartter and Gitelman syndromes, repletion of potassium loss, and magnesium (in Gitelman syndrome) ameliorates the metabolic alkalosis. Nonsteroidal antiinflamatory drugs may be helpful in Gitelman syndrome.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.


IV. What’s the evidence?