Metabolic Alkalosis

Overview

Definition

Metabolic alkalosis is the process that results in the loss of hydrogen ions (H⁺) or the gain of HCO₃^–. In primary metabolic alkalosis, arterial blood gas will show:

• pH > 7.4 
• Partial pressure of CO₂ (PCO₂) > 40 mm Hg 
• HCO₃^– > 28 mEq/L

Epidemiology

• The most common acid-base disturbance in hospitalized patients
• Incidence: varies, depending on etiology
• Mortality: 
  • 45% when pH > 7.55
  • 80% when pH > 7.65

Etiology

• Vomiting and/or nasogastric suctioning
• Ingestion of non-absorbable antacids
• Mineralocorticoid excess:
  • Primary hyperaldosteronism
  • Cushing’s syndrome
• Loop or thiazide diuretics
• Bartter and Gitelman syndromes
• ↓ Effective arterial blood volume (prerenal states):
  • Renal artery stenosis
  • Congestive heart failure
  • Cirrhosis

Acid-base Review

Acid-base disorders are classified according to the primary disturbance (respiratory or metabolic) and the presence or absence of compensation.

Identifying the primary disturbance

Consider pH, PCO₂, and HCO₃^– to determine the primary disturbance. 

• Normal values:
  • pH: 7.35–7.45
  • PCO₂: 35–45 mm Hg
  • HCO₃^–: 22–28 mEq/L
• Difference between “-emia” and “-osis”:
  • The suffix “-emia” refers to “in the blood”:
    • Acidemia: more H⁺ in the blood = pH < 7.35
    • Alkalemia: more hydroxide ions (OH^–) in the blood = pH > 7.45 
  • The suffix “-osis” refers to a process:
    • Acidosis and alkalosis refer to the processes that cause acidemia and alkalemia, respectively. 
    • Blood pH may be normal in acidosis and alkalosis.
• Primary (uncompensated) respiratory disorders: 
  • Disorders caused by abnormalities in PCO₂
  • Both pH and PCO₂ are abnormal, in opposite directions 
  • Primary respiratory acidosis: pH < 7.35 and PCO₂ > 45
  • Primary respiratory alkalosis: pH > 7.45 and PCO₂ < 35
• Primary (uncompensated) metabolic disorders: 
  • Disorders caused by abnormalities in HCO₃^– 
  • Both pH and PCO₂ are abnormal, in the same direction. 
  • Primary uncompensated metabolic acidosis:
    • pH < 7.35 and PCO₂ < 40 
    • Think: “So the acidosis is not due to ↑ CO₂; it must be due to ↓ serum HCO₃^–”→ metabolic acidosis
    • Confirm by looking at HCO₃^–: will be low (< 22 mEq/L)
  • Primary uncompensated metabolic alkalosis: 
    • pH > 7.45 and PCO₂ > 40
    • Think: “So the alkalosis is not due to ↓ CO₂; it must be due to ↑ serum HCO₃^–” → metabolic alkalosis
    • Confirm by looking at HCO₃^–: will be high (> 28 mEq/L)
• Simple disorders:
  • The presence of any 1 of the above disorders with appropriate compensation
  • Respiratory disorders are compensated by renal mechanisms.
  • Metabolic disorders are compensated by respiratory mechanisms.
• Mixed disorders: presence of 2 primary disorders

Compensation

When a patient develops acidosis or alkalosis, the body will try to compensate. Oftentimes, compensation will result in normal pH.

• In primary metabolic acid-base disorders, the lungs may try to compensate in an attempt to normalize the pH.
  • Lungs respond to metabolic acidosis by ↑ ventilation
  • Lungs respond to metabolic alkalosis by ↓ ventilation
• Interpreting serum HCO₃^– levels:
  • Normal range: 22–28 mEq/L
  • ↑ HCO₃^– is due to either:
    • Metabolic alkalosis, or
    • Compensated chronic respiratory acidosis
  • ↓ HCO₃^– is due to either:
    • Metabolic acidosis, or
    • Compensated chronic respiratory alkalosis

Pathophysiology

Generation of metabolic alkalosis

• ↑ Upper GI losses of H⁺:
  • Vomiting
  • Nasogastric suction
• ↑ Renal losses of H⁺:
  • Mineralocorticoid excess: aldosterone stimulates reabsorption of Na⁺ and excretion of H⁺ and K⁺
    • Cushing’s syndrome (hypercortisolism)
    • Conn syndrome (primary hyperaldosteronism)
    • Licorice ingestion (glycyrrhizic acid)
    • Liddle syndrome: ↑ activity of epithelial Na⁺ channels (ENaC channels) (reabsorb Na⁺) → mimics the activity of mineralocorticoid excess
  • Loop and thiazide diuretics: ↑ distal tubular delivery of Na⁺ → ↑ distal secretion of H⁺ and K⁺
  • Bartter syndrome: genetic impairment of NaCl reabsorption in the loop of Henle (mimics the action of loop diuretics)
  • Gitelman syndrome: genetic impairment of NaCl reabsorption in the distal tubule (mimics the action of thiazide diuretics)
• Hypokalemia leading to an intracellular shift of H⁺:
  • K⁺/H⁺ antiporter: K⁺ moves out of the cell and H+ moves into the cell.
  • HCO₃^– is left behind in the extracellular space.
  • Within the kidney, this intracellular shift of H⁺ causes:
    • ↑ Renal loss of H⁺
    • ↑ Renal reabsorption/regeneration of HCO₃^– 
• ↑ HCO₃^– intake:
  • Excessive antacids (e.g., calcium carbonate) or sodium bicarbonate pills
  • Calcium-alkali syndrome (previously known as milk-alkali syndrome)
• Contraction alkalosis:
  • Decreased extracellular volume + stable HCO₃^– = ↑ HCO₃^– concentration
  • Caused by any loss of fluid with a low HCO₃^– content (e.g., loop diuretics)

Maintaining metabolic alkalosis

The kidneys have an extensive ability to upregulate HCO₃^– elimination; therefore, a pathological process needs to be present for metabolic alkalosis to be maintained. Alkalosis is maintained via decreased HCO₃^– excretion or increased HCO₃^– reabsorption.

• ↓ HCO₃^– excretion can be caused by:
  • ↓ Effective arterial blood volume (prerenal states):
    • Na⁺ or K⁺ are required to secrete HCO₃^– (to maintain electroneutrality).
    • ↓ Renal blood flow → stimulates Na⁺reabsorption → ↓ Na⁺ in the tubules → limits the ability of HCO₃^– to remain in the tubules
    • ↓ Renal blood flow → ↓ glomerular filtration of HCO₃^– → ↓ HCO₃^– in the tubules for excretion
    • Causes: hypovolemia, heart failure, cirrhosis, nephrotic syndrome
  • Hypochloremia (e.g., laxative abuse):
    • Cl^– is exchanged for HCO₃^– in the collecting ducts.
    • ↓ Distal Cl^– → limits the ability for HCO₃^– secretion
• ↑ H⁺ secretion/HCO₃^– reabsorption/regeneration in the collecting ducts:
  • Stimulated by hypokalemia (H⁺/K⁺-ATPase)
  • Stimulated by ↑ distal tubular Na⁺ delivery in the setting of high aldosterone:
    • In prerenal states, aldosterone is ↑ in an attempt to ↑ blood delivery to the kidneys
    • Aldosterone ↑ H⁺ and K⁺ secretion in exchange for Na⁺ when it senses ↑ Na⁺ in the collecting ducts
    • Examples: loop/thiazide diuretics, Bartter/Gitelman syndromes

Repiratory compensation

Compensatory respiratory acidosis occurs in response to metabolic alkalosis.

• Hypoventilation → ↓ alveolar ventilation→ ↑ PaCO₂ → ↓ pH
• Total process is relatively fast:
  • Occurs within minutes 
  • Full effect is seen within 24 hours.
  • Due to the speed of compensation, the degree of compensation is not used to differentiate acute versus chronic metabolic acidosis.
• Change in PaCO₂ can be estimated by the following:
  • 1 mEq/L ↑ HCO₃^– causes 0.7 mm Hg ↑ PaCO₂
  • PaCO₂ = HCO₃^– + 10
  • The highest possible PaCO₂ from respiratory compensation alone is approximately 55 mm Hg.

Clinical Presentation, Diagnosis, and Management

Clinical presentation

The clinical presentation is dependent on the underlying etiology. Symptoms may include:

• Vomiting
• BP abnormalities:
  • Hypertension (primary mineralocorticoid excess)
  • Hypotension (↓ effective circulating volume)
• Hypokalemia
• Hypocalcemia:
  • Tetany
  • Chvostek sign: contraction of facial muscles when the facial nerve is tapped
  • Trousseau sign: carpopedal spasm with inflation of the BP cuff
  • Changes in mental status/seizures
• Findings consistent with a prerenal state: 
  • Congestive heart failure: 
    • Chest pain
    • Dyspnea on exertion
    • ↑ Jugular venous distension
    • Pulmonary edema (e.g., crackles on lung exam)
    • Peripheral edema
  • Cirrhosis:
    • Jaundice
    • Ascites
    • Hepatomegaly with/without splenomegaly
    • Telangiectasias

Diagnosis

The etiology of metabolic alkalosis is usually ascertainable from the history alone. Urine Cl^– can be helpful in cases in which the patient is reluctant to provide a full history (e.g., self-induced vomiting in eating disorders) or for less common etiologies (e.g., Conn, Bartter, and Gitelman syndromes).

Urine chloride:

• Urine Cl^– < 20 mEq/L: body Cl^– is also depleted, typically in volume depletion:
  • Vomiting
  • Nasogastric suction
• Urine Cl^– > 20 mEq/L: Body Cl^– level is normal, typically in patients with volume expansion:
  • Mineralocorticoid excess:
    • Cushing’s syndrome (hypercortisolism)
    • Conn syndrome (primary hyperaldosteronism)
    • Licorice ingestion (glycyrrhizic acid)
    • Liddle syndrome
    • Bartter and Gitelman syndromes
  • Severe hypokalemia (K⁺ < 2)

Other tests:

• Basic metabolic panel (BMP): 
  • Allows assessment of HCO₃^–
  • Important for managing electrolytes, especially K⁺
• Arterial blood gas
• Testing relevant to the suspected underlying etiology

Management

Treatment is aimed at the underlying etiology.

• Attempt to improve renal HCO₃^– excretion to resolve alkalosis:
  • In patients without edema (true volume depletion): volume repletion with isotonic saline
  • In patients with ↓ effective circulating volume (e.g., heart failure):
    • Potassium chloride
    • K⁺-sparing diuretics (e.g., amiloride)
    • Avoid isotonic saline as it will worsen symptoms without improving alkalosis.
• Correct electrolyte abnormalities, especially:
  • K⁺
  • Cl^–
  • Na⁺ (through fluid management)
• Consider dialysis in patients with CKD.

Clinical Relevance

• Primary hyperaldosteronism: an increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex. Classically, hyperaldosteronism presents with hypertension, hypokalemia, and metabolic alkalosis. Patients with hypertension who are either treatment resistant and/or associated with hyperkalemia should be screened for hyperaldosteronism by assessing plasma aldosterone concentration and plasma renin activity. The diagnosis of primary hyperaldosteronism requires confirmatory tests and an abdominal CT scan. Management involves the use of aldosterone receptor antagonists and surgical excision of any aldosterone-secreting tumors.
• Cushing’s syndrome: a disorder characterized by features resulting from chronic exposure to excess glucocorticoids. The condition may be exogenous due to chronic glucocorticoid intake, or endogenous due to the increased adrenal secretion of cortisol or increased production of adrenocorticotropic hormone (ACTH) from the pituitary gland or ectopic sources. Typical clinical features include central obesity, thin and bruisable skin, abdominal striae, secondary hypertension, hyperglycemia, and proximal muscle weakness. The initial diagnostic approach is to establish hypercortisolism via urinary and salivary cortisol tests along with a low-dose dexamethasone suppression test. 
• Calcium-alkali syndrome: previously known as milk-alkali syndrome. Calcium-alkali syndrome leads to hypercalcemia, metabolic alkalosis, and AKI due to the excessive ingestion of a source of calcium and alkali, which is usually calcium carbonate. Treatment involves stopping the supplements and giving loop diuretics to alleviate hypercalcemia.
• Congestive heart failure: the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. In congestive heart failure, the cardiac output is reduced, which decreases blood flow to the kidneys. In several patients, congestive heart failure can lead to metabolic alkalosis. Echocardiography can confirm the diagnosis and provide information about the EF. Treatment is directed at the removal of excess fluid and decreasing oxygen demand of the heart. Prognosis depends on the underlying cause, compliance with medical therapy, and the presence of comorbidities.