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

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
      • Aluminum Hydroxide (Alternagel, Alu-Cap, Dialume, Amphojel, Alu-Tab, Aloh-Gel) (see Aluminum Hydroxide)
      • Calcium Carbonate (Calcichew, Titralac) (see Calcium Carbonate)
      • Magnesium Hydroxide (Milk of Magnesia) (see Magnesium Hydroxide)
  • 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

• Hypokalemia (see Hypokalemia)
• Normotension
• Secondary Hyperreninemic Hyperaldosteronism (see Hyperaldosteronism)

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
    • Carbenicillin (see Carbenicillin)
    • Penicillin (see Penicillin)
• 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
    • Hypochloremia
    • Hyponatremia (see Hyponatremia)

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)

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

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)

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