Metabolic Alkalosis

Acid-Base Physiology



  • Alkalemia is Defined as an Increase in the Arterial pH (>7.40)
  • Note that a Patient Have an Alkalemic pH without Having a Metabolic Alkalosis
    • Example: respiratory alkalosis can produce alkalemia without the presence of a metabolic alkalosis

Metabolic Alkalosis

  • Metabolic Alkalosis is Defined as Disorder Which Results in a Primary Increase in Serum Bicarbonate (i.e. Not as a Compensatory Response to Hypercapnia)
  • Note that a Patient Can Have a Metabolic Alkalosis without Being Alkalemic
    • Example: a metabolic alkalosis may induce respiratory compensation (with bradypnea and increased pCO2) without significant alkalemia


Exogenous Bicarbonate/Alkali/Bicarbonate Precursor

  • General Comments
    • Alkali Administration Typically Only Results in Metabolic Alkalosis in the Setting of Hemodynamic Disturbances Which Impair the Bicarbonate Excretory Ability of the Kidneys
  • Acetate
    • Mechanism
      • Acetate is Converted to the Bicarbonate in the Liver
    • Clinical Scenarios
      • Acetate is Commonly Used in Total Parenteral Nutrition (TPN) Formulations
  • Citrate (see Sodium Citrate)
    • Mechanism
      • Exogenous Citrate is Normally Converted to Bicarbonate in the Mitochondria of Liver, Skeletal Muscle, and Kidney (Na-Citrate + H2CO3 -> Citric Acid + NaHCO3 -> H2O + CO2)
    • Clinical Scenarios: citrate is commonly used to chelate calcium and prevent coagulation
      • Citrate Use During Continuous Veno-Venous Hemodialysis (CVVHD)
      • Citrate Use in Blood Products (Packed Red Blood Cells, Fresh Frozen Plasma, etc)
        • Citrate-Related Metabolic Alkalosis is Likely to Occur When >8 Units of Packed Red Blood Cells are Transfused
        • Large Quantities of Fresh Frozen Plasma May Be Used During Plasmapheresis
  • Co-Administration of Sodium Polystyrene Sulfonate (Kayexelate) and Poorly Absorbed Oral Antacid in Advanced Chronic Kidney Disease
    • Agents
    • Mechanism of Poorly Absorbed Oral Antacid Action in the Normal Physiologic State
      • Hydroxide/Carbonate Component Combines with Gastric Hydrogen Ions to Generate Carbon Dioxide and Water
      • Cation Component (Magnesium, Aluminum, or Calcium) Combines with Bicarbonate in the More Distal Gastrointestinal Lumen, Resulting in Excretion in the Stool
    • Mechanism of Poorly Absorbed Oral Antacid Action Combined with Sodium Polystyrene Sulfonate (Kayexelate) in Advanced Chronic Kidney Disease
      • Sodium Released from Sodium Polystyrene Sulfonate (Kayexelate) is Systemically Reabsorbed
      • Sodium Polystyrene Sulfonate (Kayexelate) Resin Binds Potassium (Normally Present in the Gastrointestinal Tract) and Magnesium/Aluminum/Calcium (from the Antacid)
        • All are Then Excreted in the Stool
      • Hydroxide/Carbonate from the Antacid are Systemically Reabsorbed
        • In the Setting of a Low Glomerular Filtration Rate, the Absorbed Bicarbonate Cannot Be Rapidly Renally Excreted, Resulting in Metabolic Alkalosis
  • Freebase/Crack Cocaine Abuse (see Cocaine): metabolic alkalosis may occur when large quantities are abused (particularly with renal insufficiency)
    • Mechanism
      • Frequently Synthesized Using Household Drain Cleaner (a Strong Base)
  • Gluconate
    • Mechanism
      • Gluconate is Converted to Bicarbonate in the Liver
  • Intentional Induction of Metabolic Alkalosis in Athletes: has been used to enhance exercise performance
    • Mechanism
      • Enhanced Hydrogen Ion Efflux from Muscle and Decreased Interstitial Potassium Accumulation in Muscle -> Improved ATP Resynthesis and Anaerobic Glycolysis
  • Lactated Ringers (see Lactated Ringers)
    • Mechanism
      • Lactate is Converted to Bicarbonate in the Liver (1L of Lactated Ringers is Equivalent to 25 mmol of Bicarbonate Precursor)
  • Milk-Alkali Syndrome (Calcium Alkali Syndrome) (see Milk Alkali Syndrome)
    • Epidemiology
      • Most Cases are Associated with the Ingestion of Calcium Supplements (with or without Vitamin D)
    • Mechanisms
      • Hypercalcemia Enhances Renal Hydrogen Ion Secretion
      • Hypovolemia Results in Decreased Glomerular Filtration Rate, Impairing Renal Bicarbonate Excretion
      • Alkalosis Further Enhances Renal Calcium Reabsorption, Exacerbating the Hypercalcemia
  • Pyruvate
    • Mechanism
      • Pyruvate is Converted to Bicarbonate in the Liver
  • Sodium Bicarbonate (see Sodium Bicarbonate)
    • Mechanism
      • Administration of Bicarbonate

Effective Extracellular Fluid Volume Contraction

General Features

Gastrointestinal Hydrogen Ion Loss

  • Congenital Chloride Diarrhea (Chloridorrhea)
    • Mechanism: genetic mutation in intestinal chloride-bicarbonate exchanger -> diarrheal stool contains high chloride concentration (in contrast to other forms of diarrhea, where stool chloride concentration is usually low)
  • High-Volume Ileostomy Output
    • Clinical: may result in either metabolic acidosis or metabolic alkalosis (depending on the nature and duration of the losses)
  • Laxative Abuse
    • Mechanism: unclear
    • Clinical: hypokalemia (see Hypokalemia) is common
  • Nasogastric Suction
    • Mechanism: loss of gastric acid
  • Villous Adenoma (see Colonic Polyps)
    • Mechanism: unclear
    • Clinical: hypokalemia (see Hypokalemia) is common
  • Vomiting (see Nausea and Vomiting)
    • Mechanism: loss of gastric acid

Renal Hydrogen Ion Loss

  • Bartter Syndrome (see Bartter Syndrome)
    • Mechanism: genetic defect in ion transporter -> impairs sodium chloride reabsorption in the loop of Henle (mimics the action of loop diuretics)
  • Gitelman Syndrome (see Gitelman Syndrome)
    • Mechanism: genetic defect in ion transporter -> impairs sodium chloride reabsorption in the diluting segment of the distal tubule (mimics the action of thiazide diuretics)
  • Diuretics/Hypovolemia (see Hypovolemic Shock)
    • Mechanisms
      • Loss of bicarbonate-free fluid from extracellular space (extracellular fluid space contraction), resulting in increased bicarbonate concentration (contraction alkalosis)
      • Hypovolemia results in stimulation of angiotensin and aldosterone release -> increased bicarbonate absorption with increased hydrogen ion and potassium secretion (hypokalemia exacerbates the metabolic alkalosis, see below)
  • Hypercalcemia (see Hypercalcemia)
    • Mechanism
      • Hypercalcemia enhances renal hydrogen ion secretion
  • Hypokalemia (see Hypokalemia)
    • Mechanisms
      • Hypokalemia causes potassium to shift from cells to the extracellular fluid space -> hydrogen ions move into cells to maintain electroneutrality (increasing plasma bicarbonate and lowering the intracellular pH)
      • In renal tubular cells, the intracellular acidosis enhances hydrogen ion secretion into the tubular lumen with absorption of bicarbonate into the blood
      • Hypokalemia also increases renal ammoniagenesis and ammonium excretion -> results in metabolic alkalosis
    • Clinical: since many etiologies of metabolic alkalosis may also result in potassium loss (via vomiting, diuretics, or mineralocorticoid excess), the resulting hypokalemia exacerbates the underlying metabolic alkalosis
  • Hypomagnesemia (see Hypomagnesemia)
    • Mechanism: stimulation of renin and aldosterone secretion -> enhancement of distal acidification
  • Non-Absorbable Anions: administered in large quantities
    • Mechanism
      • Increased transepithelial potential difference -> enhanced distal acidification and potassium secretion
    • Agents
  • Pendred Syndrome (see Pendred Syndrome)
    • Mechanism: decreased activity of pendrin (which normally functions as a sodium-independent chloride-bicarbonate exchanger on the apical membrane of type B intercalated cells in the distal nephron, working in conjunction with the neutral sodium-chloride cotransporter, to maintain normal sodium chloride balance)
  • Post-Hypercapnic Metabolic Alkalosis
    • Mechanism: hypercapnia present prior to mechanical ventilation results in expected compensatory renal hydrogen excretion (in the form of ammonium chloride) and bicarbonate absorption (resulting in elevated bicarbonate and associated hypochloremia)
      • During inadvertent mechanical ventilation to a normal pCO2, a residual metabolic alkalosis is observed (this may persist for a period to time, especially if the patient has decreased effective arterial blood volume, decreased glomerular filtration rate, and/or is chloride deficient)
    • Treatment
      • Maintain pCO2 Near Patient’s Baseline (or Gradually Decrease the pCO2): although an abrupt decrease in the pCO2 may theoretically increase the cerebral intracellular pH and result in neurologic injury (with seizures or coma) [MEDLINE], it is likely that the rapid change in pCO2 is responsible rather than the alkalosis itself
        • Note: if the patient is a chronic CO2 retainer, a decrease in the serum bicarbonate may undesirably result in the loss of compensatory bicarbonate which will be required for subsequent ventilator weaning
      • Chloride Administration: enhances renal bicarbonate excretion
  • Refeeding Syndrome (see Refeeding Syndrome)
    • Mechanism: enhanced metabolism of ketoacids back to bicarbonate
  • Recovery from Lactic Acidosis/Ketoacidosis
    • Epidemiology
    • Mechanism
      • Rapid Correction of the Underlying Pathology Results in Metabolism of Lactic Acid/Ketones to Yield an Equivalent Amount of Bicarbonate
      • Enhanced Renal Acid Excretion During the Pre-Existing Period of Acidosis and Alkali Therapy During the Treatment Phase of Acidosis May Result in New Generation of Bicarbonate
      • Acidosis-Induced Extracellular Fluid Volume Contraction and Potassium Deficiency May Also Act to Sustain the Metabolic Alkalosis

Other Hydrogen Ion Loss

  • Cystic Fibrosis (CF) (see Cystic Fibrosis)
    • Epidemiology: metabolic alkalosis may occur in young children (rare in older children and adults)
    • Mechanism: excessive sweating with loss of sodium chloride (but not bicarbonate)
    • Clinical

Extracellular Fluid Volume Expansion

General Features

  • Hypertension (see Hypertension)
  • Hypokalemia (see Hypokalemia)
  • Mineralocorticoid Excess (see Hyperaldosteronism)
    • Mechanisms by Which Mineralocorticoids Enhanced Distal Renal Tubular Hydrogen Ion Secretion: these mechanisms enhance the movement of sodium from the distal tubule into the extracellular fluid, generating an electronegative charge in the tubular lumen, resulting in decreased back-diffusion of hydrogen ions back into the tubular cells and increased hydrogen ion and potassium secretion (resulting in hypokalemia)
      • Direct Stimulation of Secretory Hydrogen Ion-ATPase Pump
      • Increase in Activity of Na-K-ATPase
      • Increase in Number of Open Epithelial Sodium Channels (ENaC)


  • Adrenal Enzyme Defects
    • 11β-Hydroxylase Deficiency
    • 17α-Hydroxylase Deficiency
  • Cushing Syndrome (see Cushing Syndrome)
  • Glycyrrhizinates
    • Etiology
      • Carbenoxolone (see Carbenoxolone): glycyrrhetinic acid derivative (with a steroid-like structure), similar to compounds found in the root of the licorice plant
      • Chewing Tobacco: may contain glycyrrhizin
      • Herbal Teas: may contain glycyrrhizin
      • Natural Licorice: derived from Glycyrrhiza Gabra plant, contains glycyrrhizic acid (which has mineralocorticoid and glucocorticoid properties)
      • However, most licorice sold in the US does not contain natural licorice
      • Root Beer: may contain glycyrrhizin
    • Mechanism
      • Glycyrrhizinates Inhibit 11β-Hydroxysteroid Dehydrogenase (Type 2), the Enzyme Which Inactivates Cortisol
  • Primary Hyperaldosteronism (see Hyperaldosteronism)
    • Adrenal Adenoma
    • Adrenal Carcinoma
    • Adrenal Hyperplasia
  • Secondary Hyperaldosteronism with Loop/Thiazide Diuretic Administration (see Hyperaldosteronism
    • Etiology (Disorders of Decreased Effective Arterial Blood Volume)
    • Mechanisms
      • Secondary Hyperaldosteronism in the Absence of Diuretic Use
        • Usually Has Avid Proximal Tubular Sodium Reabsorption Which Markedly Decreases Distal Sodium Delivery and Tubular Flow Rates
        • Consequently, Even High Aldosterone Levels Cannot Generate a Large Amount of Distal Sodium Reabsorption or Potassium and Hydrogen Ion Secretion
      • Secondary Hyperaldosteronism with Loop/Thiazide Diuretic Administration
        • Diuretics Increase Distal Sodium Delivery and Tubular Flow, Which Allows High Aldosterone Levels to Generate Marked Metabolic Alkalosis and Hypokalemia


Gain of Function Mutation of Sodium Channel with Extracellular Fluid Volume Expansion

  • Liddle Syndrome (see Liddle Syndrome)
    • Mechanism
      • Increased Activity of the Collecting Duct Sodium Channel (ENaC)

Diagnostic Work-Up of Metabolic Alkalosis

Serum Bicarbonate (see Serum Bicarbonate)

  • Increased

Arterial Blood Gas (ABG) (see Arterial Blood Gas)

  • pH: required to assess for the presence of alkalemia
  • pCO2: required to rule out hypercapnia as the driver for bicarbonate retention

Urine Sodium, Chloride, and Potassium

  • Patterns (with Suggested Clinical Etiologies)
    • Alkaline Urine with Increased Urine Sodium + Decreased Urine Chloride + Increased Urine Potassium
      • Alkali Ingestion
      • Vomiting
    • Acidic Urine with Decreased Urine Sodium + Decreased Urine Chloride + Decreased Urine Potassium
      • Post-Hypercapnic Metabolic Alkalosis
      • Prior Diuretic Use
      • Vomiting
    • Normal Urine Sodium + Normal Urine Chloride + Normal Urine Potassium
      • Current Diuretic Use
      • Bartter’s Syndrome
      • Gitelman’s syndrome
      • Magnesium Deficiency

Serum Renin and Aldosterone (see Serum Renin and Serum Aldosterone)

  • Serum Aldosterone
  • Serum Renin

Clinical Features of Metabolic Alkalosis

General Comments

  • Clinical Manifestations Attributable to Metabolic Alkalosis are Less Common Than in Acute Respiratory Alkalosis (Since Metabolic Alkalosis Probably Causes a Smaller Change in Intracellular and Brain pH than Acute Respiratory Alkalosis)
    • Acute Respiratory Alkalosis: rapid shift in arterial pCO2 is almost immediately transmitted throughout the total body water (including the intracellular fluid compartment, the brain, and the cerebrospinal fluid) -> this accounts for the characteristic symptoms of paresthesias, carpopedal spasm, and lightheadedness observed in acute respiratory alkalosis
    • Metabolic Alkalosis: alterations in blood bicarbonate cause slower and less marked pH changes within the intracellular fluid compartment and across the blood brain barrier

Neurologic Manifestations

  • General Comments
    • Typically Only Occur in the Setting of Severe Metabolic Alkalosis with Associated Hypocalcemia/Hypomagnesemia
  • Agitation
  • Delirium (see Delirium)
  • Increased Risk of Hepatic Encephalopathy (see Hepatic Encephalopathy)
    • Mechanism
      • Alkalemia Will Increase the Concentration of Unionized Nitrogen Compounds (Such as Ammonia), Which Enhances Penetration into the Central Nervous System and Therefore, Toxicity
  • Muscle Spasms/Tetany (see Tetany)
  • Obtundation/Coma (see Obtundation-Coma)
  • Parasthesias (see Parasthesias)
  • Seizures (see Seizures)


Metabolic Alkalosis Associated with Vomiting/Nasogastric Suction/Gastrointestinal Hydrogen Ion Loss

  • Normal Saline (see Normal Saline): chloride repletion restores the ability of the kidney to excrete the excess bicarbonate
  • Treatment of Hypokalemia: as required
  • Proton Pump Inhibitors (PPI) (see Proton Pump Inhibitors): decrease gastric hydrogen ion concentration and therefore, will decrease hydrogen ion loss during nasogastric suction

Metabolic Alkalosis Associated with Diuretics

  • Normal Saline (see Normal Saline): chloride repletion restores the ability of the kidney to excrete the excess bicarbonate
  • Treatment of Hypokalemia: as required
  • Acetazolamide (Diamox) (see Acetazolamide): carbonic anhydrase inhibitor diuretic that enhances renal bicarbonate excretion
    • Avoid use in the setting of hypokalemia

Metabolic Alkalosis Associated with Hypokalemia

  • Resistant to Sodium Chloride Replacement Until Hypokalemia is Corrected
  • Treatment of Hypokalemia: critical

Metabolic Alkalosis Associated with Primary Hyperaldosteronism/Cushing Syndrome/Renal Artery Stenosis

  • Treat Underlying Disorder

Other Potential Treatments

  • Hydrochloric Acid (HCl) Drip (see Hydrochloric Acid)
    • Administration: 0.1 N solution via central venous catheter
    • Adverse Effects: hemolysis