Explain metabolic alkalosis, including its etiology, pathophysiology, clinical manifestations, and treatment.

Metabolic Alkalosis

Metabolic alkalosis is a primary acid-base disorder characterized by elevated serum bicarbonate (>26 mmol/L) and arterial pH (>7.45), resulting from either net gain of bicarbonate, loss of hydrogen ions, or volume contraction concentrating existing bicarbonate. 1, 2

Etiology and Pathophysiology

Generation Mechanisms

Metabolic alkalosis requires both generation (the initial event creating alkalosis) and maintenance (factors preventing renal bicarbonate excretion). 2, 3

Generation occurs through three primary mechanisms:

• Hydrogen ion loss via the gastrointestinal tract (vomiting, nasogastric suction) removes gastric hydrochloric acid, leaving bicarbonate behind 2, 3
• Renal hydrogen ion loss from diuretics (loop and thiazide), which increase distal sodium delivery and aldosterone-mediated hydrogen secretion 1, 2
• Exogenous alkali administration through oral or parenteral bicarbonate, citrate, lactate, or acetate 2, 4

Maintenance Factors

The kidney normally prevents metabolic alkalosis by excreting excess bicarbonate, but several factors impair this protective mechanism:

• Volume contraction stimulates proximal tubular sodium and bicarbonate reabsorption, preventing bicarbonate excretion (contraction alkalosis) 1, 2
• Hypochloremia limits bicarbonate excretion because chloride is required for bicarbonate secretion in exchange 5, 2
• Hypokalemia (<3.5 mEq/L) promotes intracellular hydrogen shift and increases renal hydrogen secretion 1, 2
• Aldosterone excess (primary or secondary) enhances distal hydrogen secretion via increased sodium reabsorption 1, 2
• Reduced GFR decreases filtered bicarbonate load, limiting renal bicarbonate excretion 2, 4

Specific Clinical Syndromes

Diuretic-induced alkalosis is the most common cause in hospitalized patients, with loop and thiazide diuretics causing chloride, sodium, and volume losses that trigger compensatory aldosterone activation. 1, 2

Bartter and Gitelman syndromes are genetic salt-wasting tubulopathies presenting with hypokalemic metabolic alkalosis, hypochloremia, elevated urinary chloride (>20 mEq/L), and normal-to-low blood pressure despite secondary hyperaldosteronism. 1, 2 Urinary calcium differentiates them: high in Bartter syndrome, low in Gitelman syndrome. 1

Mineralocorticoid excess states (primary hyperaldosteronism, Cushing syndrome, licorice ingestion) cause chloride-resistant alkalosis with hypertension and hypokalemia. 2, 4

Clinical Manifestations

Severe metabolic alkalosis (pH ≥7.55) significantly increases mortality in critically ill patients. 2

Clinical effects include:

• Central nervous system: Altered mental status, confusion, lethargy, seizures from decreased cerebral blood flow 4
• Cardiovascular: Arrhythmias (especially with concurrent hypokalemia), decreased myocardial contractility, coronary vasoconstriction 4
• Respiratory: Compensatory hypoventilation raising PaCO₂ by approximately 0.7 mmHg for each 1 mEq/L rise in bicarbonate, potentially causing hypoxemia 2
• Neuromuscular: Muscle weakness, tetany, paresthesias from decreased ionized calcium 4
• Metabolic: Hypokalemia, hypophosphatemia, hypomagnesemia 2

Paradoxical Aciduria

Patients with volume depletion and hypokalemia may excrete acidic urine (pH <6.0) despite systemic alkalosis—termed "paradoxical aciduria." 5 This occurs because aldosterone-driven distal sodium reabsorption requires hydrogen secretion for electroneutrality, overriding the systemic alkalosis. 5

Diagnostic Approach

Initial Laboratory Assessment

Obtain arterial blood gas showing pH >7.45, elevated bicarbonate (>26 mmol/L), and compensatory elevated PaCO₂. 1, 2

Measure serum electrolytes revealing:

• Hypochloremia (typically 85-95 mEq/L) 1
• Hypokalemia (<3.5 mEq/L), though potassium may be normal initially 1
• Calculate anion gap: Na⁺ − (HCO₃⁻ + Cl⁻), normal 10-12 mEq/L 6

Classification by Urinary Chloride

Urinary chloride concentration is the critical test distinguishing chloride-responsive from chloride-resistant alkalosis:

• Urinary Cl⁻ <20 mEq/L: Chloride-responsive (volume-depleted) alkalosis from vomiting, nasogastric suction, remote diuretic use, or post-hypercapnic state 1, 2
• Urinary Cl⁻ >20 mEq/L: Chloride-resistant alkalosis from ongoing diuretic use, mineralocorticoid excess, Bartter/Gitelman syndrome, or severe hypokalemia 1, 2

Additional Diagnostic Studies for Chloride-Resistant Alkalosis

When urinary chloride >20 mEq/L, measure:

• Plasma renin and aldosterone: Both markedly elevated in Bartter/Gitelman syndrome and secondary hyperaldosteronism; aldosterone high with suppressed renin in primary hyperaldosteronism 1
• Fractional excretion of chloride: >0.5% indicates renal salt-wasting (Bartter/Gitelman, diuretic abuse) 1
• Urinary calcium: High in Bartter syndrome, low in Gitelman syndrome 1
• Blood pressure: Hypertension suggests mineralocorticoid excess; normotension suggests Bartter/Gitelman or diuretic use 1

Treatment

Chloride-Responsive Alkalosis (Urinary Cl⁻ <20 mEq/L)

Volume repletion with isotonic saline (0.9% NaCl) is the cornerstone of treatment, restoring extracellular volume and providing chloride for bicarbonate excretion. 1, 5

• Administer 15-20 mL/kg/h during the first hour for significant volume depletion 5
• After initial resuscitation, continue at 4-14 mL/kg/h based on clinical response 5

Potassium chloride supplementation is essential when hypokalemia is present:

• Doses of 20-60 mEq/day are frequently required to maintain serum potassium 4.5-5.0 mEq/L 1
• Use potassium chloride exclusively; avoid potassium citrate or bicarbonate, which worsen alkalosis 1

Chloride-Resistant Alkalosis (Urinary Cl⁻ >20 mEq/L)

Potassium-sparing diuretics are first-line therapy for mineralocorticoid excess:

• Amiloride 2.5 mg daily, titrate to 5 mg daily (most effective for metabolic alkalosis) 1
• Spironolactone 25 mg daily, titrate to 50-100 mg daily 1
• Avoid combining with ACE inhibitors without close monitoring due to hyperkalemia risk 1

For diuretic-induced alkalosis:

• Reduce or temporarily discontinue diuretics if clinically feasible 1
• Add potassium-sparing diuretic (amiloride or spironolactone) 1
• Consider acetazolamide 500 mg IV single dose if adequate kidney function 1

Bartter and Gitelman Syndromes

Sodium chloride supplementation (5-10 mmol/kg/day) plus potassium chloride for potassium repletion are essential. 1

NSAIDs (indomethacin or ibuprofen) reduce prostaglandin-mediated salt wasting, especially in symptomatic patients. 1

Co-administer gastric acid inhibitors (proton-pump inhibitor) when prescribing NSAIDs to prevent gastrointestinal complications. 1

Severe Metabolic Alkalosis (pH >7.55)

Acetazolamide 500 mg IV as a single dose rapidly lowers serum bicarbonate when renal function is adequate (contraindicated if significant renal impairment). 1

In refractory cases with concurrent renal failure, hemodialysis with low-bicarbonate/high-chloride dialysate is the treatment of choice. 1

Special Considerations

In heart failure patients with diuretic-induced alkalosis:

• Continue necessary diuresis but add acetazolamide to promote bicarbonate excretion 1
• Add aldosterone antagonist (spironolactone) to the diuretic regimen 1
• Monitor closely for hypokalemia, which worsens with carbonic anhydrase inhibition 1

Avoid sodium bicarbonate or alkalinization strategies—these are contraindicated and worsen the alkalosis. 1

Monitoring Parameters

During acute treatment, check serum electrolytes (Na⁺, K⁺, Cl⁻, HCO₃⁻) every 2-4 hours. 6

Monitor blood pressure, serum potassium, and fluid status regularly after initiating treatment to ensure therapy doesn't cause hypertension, hyperkalemia, or volume overload. 1

Venous pH can be used for ongoing monitoring after initial diagnosis (typically ~0.03 units lower than arterial pH), eliminating the need for repeat arterial blood gases. 6

Common Pitfalls

Failing to measure urinary chloride leads to incorrect classification and inappropriate treatment. 1, 2

Attempting to correct compensatory elevated bicarbonate in chronic respiratory acidosis worsens the patient's acid-base status—the elevated bicarbonate is protective and maintains normal pH. 1, 6

Using potassium citrate or potassium bicarbonate for potassium repletion worsens metabolic alkalosis; always use potassium chloride. 1

Overlooking Bartter or Gitelman syndrome in euvolemic patients with unexplained hypokalemic metabolic alkalosis, especially with history of polyhydramnios and premature birth. 1

Administering large volumes of 0.9% saline can produce iatrogenic hyperchloremic metabolic acidosis by increasing serum chloride and decreasing the strong ion difference; switch to balanced crystalloids after initial resuscitation. 6