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
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
- 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]