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
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
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
Sodium Polystyrene Sulfonate (Kayexelate) (see Sodium Polystyrene Sulfonate): acts by releasing sodium and binding potassium
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
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)
Mechanism: genetic defect in ion transporter -> impairs sodium chloride reabsorption in the diluting segment of the distal tubule (mimics the action of thiazide diuretics)
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)
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
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
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
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)
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
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
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
Alkalemia Will Increase the Concentration of Unionized Nitrogen Compounds (Such as Ammonia), Which Enhances Penetration into the Central Nervous System and Therefore, Toxicity
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
Administration: 0.1 N solution via central venous catheter
Adverse Effects: hemolysis
References
The effect of prolonged administration of large doses of sodium bicarbonate in man. Clin Sci (Lond). 1954;13(3):383 [MEDLINE]
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]
