Metabolic Alkalosis

Acid-Base Physiology


Definitions

Alkalemia

  • Definition: increase in arterial pH
  • Note: patient can be alkalemic without having a metabolic alkalosis
    • Example: respiratory alkalosis can produce alkalemia without the presence of a metabolic alkalosis

Metabolic Alkalosis

  • Definition: disorder that results in an increase in serum bicarbonate
  • Note: 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

Etiology

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 Used in Total Parenteral Nutrition (TPN) Formulation
  • Citrate (see Sodium Citrate)
    • Mechanism: exogenous citrate is normally converted to bicarbonate in 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 Kayexelate and Poorly Absorbed Oral Antacid in Advanced Chronic Kidney Disease
    • Agents
      • Kayexelate (see Kayexelate): acts by releasing sodium and binding potassium
      • Poorly Absorbed Oral Antacids
    • 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 -> excretion in the stool
    • Mechanism of Poorly Absorbed Oral Antacid Action Combined with Kayexelate in Advanced Chronic Kidney Disease
      • Sodium released from kayexelate is systemically reabsorbed
      • Kayexelate resin binds potassium (normally present in the gastrointestinal tract) and magnesium/aluminum/calcium (from the antacid) -> all are 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): 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’s Syndrome (see Bartter’s 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
    • Mechanism: rapid correction of the underlying pathology leads to lactic acid/ketones being metabolized to yield an equivalent amount of bicarbonate
      • In addition, new generation of bicarbonate may result from enhanced renal acid excretion during the pre-existing period of acidosis and alkali therapy during the treatment phase of acidosis
      • Acidosis-induced extracellular fluid volume contraction and potassium deficiency may also act to sustain the metabolic alkalosis

Other Losses

  • 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 -> this generates an electronegative charge in the tubular lumen, decreasing back-diffusion of hydrogen ions back into the tubular cells -> increasing hydrogen 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)

Hyperreninemic

  • Accelerated Hypertension (see Hypertension)
    • Mechanism: xxx
  • Estrogen (see Estrogen)
    • Mechanism: xxx
  • Renal Artery Stenosis (see Renal Artery Stenosis)
    • Mechanism: xxx
  • Renin-Secreting Tumor
    • Mechanism: renin secretion by tumor

Hyporeninemic

  • Adrenal Enzyme Defects
    • 11β-Hydroxylase Deficiency
    • 17α-Hydroxylase Deficiency
  • Cushing Syndrome (see Cushing Syndrome)
  • Primary Hyperaldosteronism (see Hyperaldosteronism)
    • Adrenal Adenoma
    • Adrenal Carcinoma
    • Adrenal Hyperplasia
  • Secondary Hyperaldosteronism with Loop/Thiazide Diuretic Administration (see Hyperaldosteronism): associated with disorders of decreased effective arterial blood volume
    • Mechanisms
      • Secondary hyperaldosteronism (in the absence of diuretic use) usually has avid proximal tubule 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 use): the diuretics increase distal sodium delivery and tubular flow, which allows high aldosterone levels to generate marked metabolic alkalosis and hypokalemia
    • Cirrhosis (see End-Stage Liver Disease)
    • Congestive Heart Failure (CHF) (see Congestive Heart Failure)
    • Hypovolemia (see Hypovolemic Shock)
  • Glycyrrhizinates: glycyrrhizinates inhibit 11β-hydroxysteroid dehydrogenase (type 2), the enzyme which inactivates cortisol
    • 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

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

  • Liddle’s Syndrome (see Liddle’s Syndrome)
    • Mechanism: increased activity of the collecting duct sodium channel (ENaC)

Diagnostic Work-Up of Metabolic Alkalosis

Serum Bicarbonate

  • Increased

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

  • pH: required
  • pCO2: required

Urinary Sodium, Chloride, and Potassium

  • Alkaline Urine with Increased Urine Sodium + Increased Urine Potassium + Decreased Urine Chloride: suggests vomiting or alkali ingestion
  • Acidic Urine with Decreased Urine Sodium + Decreased Urine Potassium + Decreased Urine Chloride: suggests prior vomiting, post-hypercapnic metabolic alkalosis, or prior diuretic use
  • Normal Urine Sodium + Normal Urine Potassium + Normal Urine Chloride: suggests magnesium deficiency, Bartter’s syndrome, Gitelman’s syndrome, or current diuretic use

Serum Renin and Aldosterone

  • Serum Aldosterone: xxx
  • Serum Renin: xxx

Clinical Features of Metabolic Alkalosis

General Comments

  • Clinical Manifestations Attributable to Metabolic Alkalosis are Less Common Than in Acute Respiratory Alkalosis: 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)

Treatment

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

References

  • CNS Disorder During Mechanical Ventilation in Chronic Pulmonary Disease. JAMA. 1964;189:993 [MEDLINE]
  • Effects of chronic hypercapnia on electrolyte and acid-base equilibrium. II. Recovery, with special reference to the influence of chloride intake. J Clin Invest. 1961;40:1238 [MEDLINE]
  • Metabolic alkalosis due to absorption of “nonabsorbable” antacids. Am J Med. 1983;74(1):155 [MEDLINE]
  • Acid-base disturbances in gastrointestinal disease. Dig Dis Sci. 1987;32(9):1033 [MEDLINE]
  • Acute Electrolyte and Acid-Base Disorders in Patients With Ileostomies: A Case Series. Am J Kidney Dis. 2008 Sep;52(3):494-500. doi: 10.1053/j.ajkd.2008.04.015. Epub 2008 Jun 17 [MEDLINE]