Metabolic Alkalosis

March

Etiology and Pathogenesis

Most cases are caused by excessive renal tubular reabsorption of bicarbonate (HCO₃^-) due to factors such as reduced blood volume, loss of chloride (Cl^-), or potassium (K⁺) depletion.

Increased Maximum Reabsorption Threshold for Bicarbonate in Proximal Renal Tubules

Volume-Depletion Alkalosis

Conditions such as emesis, pyloric obstruction, or gastric drainage lead to significant loss of hydrochloric acid (HCl). This results in an increased absorption of HCO₃^- from intestinal fluid that has not been neutralized by gastric acid, causing alkalemia. Reduced blood volume increases renal reabsorption of sodium (Na⁺) and HCO₃^-, leading to paradoxical acidic urine and elevated serum HCO₃^- and pH, ultimately resulting in volume-depletion alkalosis.

Hypokalemic Alkalosis

Potassium depletion induces H⁺ ions to shift into cells, increasing renal tubular secretion of H⁺ while augmenting Na⁺ and HCO₃^- reabsorption. This leads to hypokalemic metabolic alkalosis, often accompanied by Cl^- deficiencies.

Hypochloremic Alkalosis

Transient alkalemia occurs due to gastric fluid loss, as reduced Cl^- in renal tubular cells leads to enhanced reabsorption of Na⁺, K⁺, and HCO₃^-.

Potassium-wasting diuretics promote greater loss of Cl^- compared to Na⁺.

Primary hyperaldosteronism also contributes to hypochloremic alkalosis.

These conditions can be corrected through chloride supplementation, hence the term "chloride-responsive alkalosis."

Hypercapnic Alkalosis

Chronic respiratory acidosis (e.g., when rapid correction of hypoventilation leads to a sudden decrease in arterial carbon dioxide pressure, PaCO₂) can result in alkalosis due to increased renal reabsorption of HCO₃^-.

Increased Renal Production of Bicarbonate

Elevated Na⁺ levels in the distal nephrons facilitate renal acid secretion and enhance bicarbonate generation (resulting in increased net acid excretion), contributing to renal metabolic alkalosis.

Potassium-Sparing and Sodium-Retaining Diuretics

These agents increase sodium salt concentrations in distal renal tubules. Additionally, they can reduce blood volume and lead to hypokalemia and hypochloremia.

Excess Mineralocorticoids

Overproduction of mineralocorticoids promotes renal tubular reabsorption of Na⁺ while enhancing H⁺ and K⁺ secretion, which can result in metabolic alkalosis.

Liddle Syndrome

This condition leads to sodium retention and potassium excretion, causing metabolic alkalosis of renal origin.

Slow Metabolic Conversion of Organic Acids

This is an important cause of transient metabolic alkalosis, frequently observed after insulin treatment for diabetic ketoacidosis or due to large amounts of acetate from hemodialysis.

Compensatory Mechanisms

The increase in alkaline substances in the body activates buffering systems that convert strong bases into weaker bases, consuming HCO₃^- and increasing carbonic acid (H₂CO₃) levels. This inhibits the respiratory center, reducing lung ventilation and causing CO₂ retention, along with a compensatory increase in HCO₃^-. Reduced renal carbonic anhydrase activity decreases H⁺ formation and excretion, while also reducing reabsorption of sodium bicarbonate (NaHCO₃). This compensates by maintaining the [HCO₃^-]/[H₂CO₃] ratio at 20:1, restoring normal pH levels.

Clinical Manifestations

Mild cases may be masked by the symptoms of the primary disease. Severe cases are characterized by slow, shallow respiration. Increased protein-bound calcium and reduced free calcium levels, along with elevated acetylcholine release, exacerbate neuromuscular excitability due to alkalosis. Symptoms often include facial and limb muscle twitching, carpopedal spasms, and numbness around the mouth and extremities. Increased hemoglobin-oxygen affinity reduces oxygen availability to tissues, causing dizziness, restlessness, delirium, or even coma. In cases of concurrent hypokalemia, symptoms such as flaccid paralysis may also occur.

Diagnosis and Differential Diagnosis

Efforts to identify and distinguish the underlying causes of H⁺ loss or bicarbonate retention are important, with laboratory tests serving as the basis for diagnosis. In metabolic alkalosis, laboratory findings include increased levels of HCO₃^-, actual bicarbonate (AB), standard bicarbonate (SB), buffer base (BB), and base excess (BE). If the influence of respiratory factors can be excluded, elevated carbon dioxide combining power (CO₂CP) supports the diagnosis. Measurements of urinary electrolytes, urine pH, renin, angiotensin, aldosterone, adrenocorticotropic hormone (ACTH), and cortisol may assist in determining the underlying cause. During the uncompensated phase, blood pH >7.45 and H⁺ concentration <35 nmol/L are observed. In hypokalemic alkalosis, serum potassium is reduced, and urine is acidic. In hypochloremic alkalosis, serum chloride is lowered, while urinary chloride (Cl^-) is typically >10 mmol/L.

Prevention and Treatment

Mild to moderate cases primarily require management of the underlying disease. In cases of hypovolemia, isotonic saline is used for volume expansion. In the presence of hypokalemia, potassium supplementation is administered, and in hypochloremia, saline or other chloride-containing fluids are provided. Severe cases also prioritize the use of isotonic saline as the first-line treatment.

Excessive intake of alkaline substances should be avoided. Potassium supplementation is essential when using potassium-wasting diuretics or treating diseases associated with increased mineralocorticoids.

Other pharmacological options include:

Ammonium Chloride (NH₄Cl)

This provides chloride (Cl^-) and, through hepatic conversion of ammonium, releases H⁺. It is administered orally at a dose of 1–2 g three times daily, or intravenously when necessary. Intravenous supplementation is calculated based on the target correction, such as 0.2 mmol of NH₄Cl to increase extracellular Cl^- by 1 mmol or 2% NH₄Cl (1 ml/kg body weight) to reduce CO₂CP by 0.45 mmol/L. For IV use, a 5% glucose solution is diluted to prepare an isotonic 0.9% NH₄Cl solution for infusion in 2–3 doses. Ammonium chloride is contraindicated in patients with liver dysfunction, heart failure, or concomitant respiratory acidosis.

Dilute Hydrochloric Acid (HCl)

Hydrochloric acid provides Cl^- and H⁺ directly. Twenty milliliters of 10% HCl is equivalent to 3 g of ammonium chloride and is typically diluted 40-fold for oral use, dosed 4–6 times daily.

Arginine Hydrochloride

Twenty grams of arginine dissolved in 500–1,000 ml of intravenous fluid is infused slowly over more than 4 hours. Each gram of arginine provides 4.8 ml of both Cl^- and H⁺ and is suitable for metabolic alkalosis resulting from hepatic dysfunction.

Acetazolamide

As a carbonic anhydrase inhibitor, acetazolamide increases renal excretion of bicarbonate (HCO₃^-) and is appropriate for patients with fluid overload or hypervolemia. It is particularly useful in treating conditions like heart failure, cirrhosis, or metabolic alkalosis induced by thiazide diuretics. Acetazolamide is also effective in cases of respiratory acidosis combined with metabolic alkalosis. However, it is contraindicated in metabolic acidosis with hypokalemia, adrenal insufficiency, hepatic encephalopathy, renal insufficiency, or nephrolithiasis.