Principles of Acid-Base Homeostasis

Introduction

• The pH of body fluids is maintained within a narrow physiological range to ensure normal cellular function.
• Arterial blood pH is normally maintained between 7.35 and 7.45.
• Acid-base balance depends on the continuous regulation of acid production, buffering, and elimination.
• Buffer systems, together with the lungs and kidneys, maintain stable hydrogen ion concentration.
• The lungs regulate carbon dioxide excretion, whereas the kidneys control hydrogen ion secretion and bicarbonate conservation.
• Disorders affecting pulmonary or renal function commonly produce acid-base disturbances, leading to impaired physiological function if not corrected.

General Concepts

Definitions

• pH is defined as the negative logarithm (base 10) of the hydrogen ion concentration in a solution.
• A lower pH indicates a higher hydrogen ion concentration and greater acidity.
• A higher pH indicates a lower hydrogen ion concentration and greater alkalinity.
• Ionization constant represents the tendency of an acid to dissociate into hydrogen ions and its conjugate base.
• pK is the negative logarithm of the ionization constant.
• For a buffer system, pK is the pH at which the concentrations of the weak acid and its conjugate base are equal.
• Acids with lower pK values dissociate more readily and are therefore stronger acids.
• An acid is a substance that donates hydrogen ions to body fluids.
• A base accepts hydrogen ions, thereby reducing the hydrogen ion concentration.
• A buffer consists of a weak acid and its conjugate base, or a weak base and its conjugate acid.
• Buffers minimize changes in pH when small amounts of acid or base are added to body fluids.

Concept of Acid-Base Balance

• Normal metabolism continuously produces both acids and bases.
• Acid–base homeostasis is maintained by balancing acid production with buffering and elimination.
• Chemical buffer systems provide the first line of defense against changes in pH.
• The lungs regulate carbon dioxide excretion, whereas the kidneys regulate hydrogen ion secretion and bicarbonate conservation.
• Coordinated actions of the respiratory and renal systems maintain normal acid–base balance.
• Metabolic processes continuously generate acids that must be effectively neutralized or removed.
• During intense anaerobic exercise, skeletal muscles produce lactic acid, causing a temporary increase in hydrogen ion concentration.
• Important acids formed in the body include carbonic acid, sulfuric acid, phosphoric acid, lactic acid, and ketoacids.

Volatile vs. Nonvolatile acids:

• Volatile acids are acids that can be converted to carbon dioxide and eliminated through the lungs.
• Carbon dioxide produced during cellular metabolism combines with water to form carbonic acid, the principal volatile acid.
• An adult produces approximately 15,000 to 20,000 millimoles of carbon dioxide each day, corresponding to a similar amount of volatile acid.
• Efficient pulmonary ventilation rapidly removes carbon dioxide, helping maintain normal blood pH.
• Nonvolatile acids cannot be excreted by the lungs and therefore require renal elimination.
• These acids are generated from the metabolism of sulfur-containing amino acids, phospholipids, and nucleic acids, as well as from incomplete oxidation of carbohydrates and fats.
• Lactic acid and ketoacids are important nonvolatile acids that increase during strenuous exercise, prolonged fasting, or uncontrolled diabetes mellitus.
• Healthy kidneys excrete approximately 50 to 100 milliequivalents of nonvolatile acid each day while regenerating bicarbonate.
• Diet influences the daily acid load.
• Diets rich in animal protein generally increase acid production, whereas fruits and vegetables provide alkali-producing precursors that reduce the net acid load.

pH-Buffer Systems

• Buffer systems maintain the pH of body fluids within a narrow physiological range by minimizing changes in hydrogen ion concentration.
• A buffer resists large changes in pH when small amounts of acid or base are added.
• Most biological buffers consist of a weak acid and its conjugate base or a weak base and its conjugate acid.
• Buffer systems act immediately and represent the first line of defense against acid–base disturbances.
• The relationship between pH, buffer components, and acid dissociation is described by the Henderson–Hasselbalch equation.
• According to this equation, pH depends on the ratio of the conjugate base to the weak acid rather than their absolute concentrations.
• At equilibrium, the rate of acid dissociation equals the rate of reassociation of hydrogen ions with the conjugate base.
• The acid dissociation constant reflects the extent to which an acid ionizes in solution.
• Strong acids have a high dissociation constant and release hydrogen ions readily.
• Weak acids dissociate only partially and therefore function effectively as physiological buffers.
• Carbonic acid and lactic acid are examples of weak acids present in the body.
• Hydrochloric acid, nitric acid, and sulfuric acid are examples of strong acids that dissociate almost completely in aqueous solution.
• The effectiveness of a buffer is greatest when the solution pH is close to its pK value.
• A buffer provides optimal resistance to pH change within approximately one pH unit above or below its pK.
• Buffer capacity depends on both the concentration of the buffer components and the ratio between the weak acid and its conjugate base.
• Maximum buffering occurs when the concentrations of the weak acid and conjugate base are equal.
• Increasing the concentration of a buffer increases its capacity to neutralize added acids or bases.
• Buffer capacity is commonly expressed as buffer value, which represents the amount of strong acid or strong base required to change the pH of one liter of solution by one pH unit.
• The body contains several buffer systems that work together to preserve acid–base homeostasis.
• The bicarbonate–carbonic acid buffer system is the principal extracellular buffer and works closely with the lungs and kidneys.
• The plasma protein buffer system contributes to buffering through ionizable amino acid side chains, particularly histidine residues.
• The phosphate buffer system is especially important within cells and in the renal tubular fluid, where it facilitates hydrogen ion excretion.
• The hemoglobin buffer system is the major intracellular buffer in red blood cells and binds hydrogen ions generated during carbon dioxide transport.
• Bicarbonate, phosphate, and protein buffers also function within cells, although their relative importance varies among tissues.
• The coordinated action of these buffer systems, together with respiratory and renal regulation, maintains stable blood pH despite continuous acid production.

Bicarbonate-Carbonic Acid Buffer System

• The bicarbonate–carbonic acid buffer system is the principal extracellular buffer of the body.
• It is the most important buffer in plasma and also contributes significantly to buffering in red blood cells.
• The system consists of bicarbonate ions and carbonic acid in dynamic equilibrium.
• Although its pK is approximately 6.1, it functions effectively because bicarbonate is present in high concentration in extracellular fluid.
• Under normal physiological conditions, the bicarbonate-to-carbonic acid ratio is approximately 20:1, maintaining a blood pH close to 7.40.
• Carbon dioxide readily diffuses across cell membranes and is rapidly converted to carbonic acid by carbonic anhydrase.
• The lungs regulate the carbonic acid component by controlling carbon dioxide excretion through ventilation.
• Increased ventilation lowers carbon dioxide concentration and raises blood pH, whereas reduced ventilation has the opposite effect.
• The kidneys regulate the bicarbonate component by reabsorbing filtered bicarbonate and generating new bicarbonate ions.
• Bicarbonate also neutralizes nonvolatile acids produced during normal metabolism.
• Close coordination between the lungs and kidneys makes this the most effective physiological buffer system.

Plasma Protein Buffer System

• Plasma proteins are the major nonbicarbonate buffers in extracellular fluid.
• Albumin provides most of the buffering capacity because it is the most abundant plasma protein.
• Histidine residues within albumin contain ionizable groups that can accept or release hydrogen ions.
• This buffering action is particularly effective because the pK of histidine is close to physiological blood pH.
• Plasma proteins help stabilize blood pH during metabolic and respiratory acid–base disturbances.
• They also complement the bicarbonate buffer system by limiting rapid changes in hydrogen ion concentration.

Phosphate Buffer System

• The phosphate buffer system consists of both organic and inorganic phosphate compounds.
• Organic phosphates include adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, and 2,3-bisphosphoglycerate.
• Organic phosphate buffers are particularly important within cells and in red blood cells.
• The inorganic phosphate buffer consists of hydrogen phosphate and dihydrogen phosphate ions.
• Its pK of approximately 6.8 makes it an effective intracellular and renal tubular buffer.
• Although its contribution in plasma is limited, it plays a major role in buffering intracellular fluid.
• In the kidneys, phosphate buffers hydrogen ions in tubular fluid, facilitating acid excretion and urine acidification.

Hemoglobin Buffer System

• Hemoglobin is the principal nonbicarbonate buffer inside red blood cells.
• Histidine residues in hemoglobin readily bind or release hydrogen ions.
• Deoxygenated hemoglobin has a greater affinity for hydrogen ions than oxygenated hemoglobin.
• In systemic tissues, deoxygenated hemoglobin binds hydrogen ions generated during carbon dioxide transport, reducing changes in intracellular pH.
• In the lungs, oxygenation of hemoglobin releases hydrogen ions, which combine with bicarbonate to form carbon dioxide and water.
• This mechanism promotes efficient carbon dioxide elimination while maintaining acid–base homeostasis.
• Together, hemoglobin and phosphate buffers provide most of the intracellular buffering capacity of red blood cells.

Regulation of Acid-Base Balance

• Acid–base balance is maintained primarily by coordinated respiratory and renal mechanisms.
• Chemical buffer systems provide immediate protection, whereas the lungs and kidneys provide long-term regulation.
• The respiratory system regulates carbon dioxide concentration, while the kidneys regulate hydrogen ion and bicarbonate balance.
• Together, these mechanisms maintain arterial blood pH within the normal range of 7.35–7.45.

Respiratory Mechanism

• The respiratory mechanism acts rapidly, usually within minutes, to correct disturbances in acid–base balance.
• It regulates blood pH by altering the rate and depth of ventilation.
• Peripheral chemoreceptors in the carotid and aortic bodies detect changes in arterial pH, carbon dioxide, and oxygen levels.
• Central chemoreceptors in the medulla respond primarily to changes in the pH of cerebrospinal fluid caused by alterations in carbon dioxide.
• An increase in carbon dioxide raises hydrogen ion concentration and lowers blood pH.
• During acidosis, elevated hydrogen ion concentration and increased carbon dioxide stimulate the chemoreceptors.
• The respiratory center responds by increasing the rate and depth of breathing.
• Hyperventilation enhances carbon dioxide elimination through the lungs.
• Reduction in carbon dioxide shifts the carbonic acid reaction toward decreased hydrogen ion formation, thereby increasing blood pH.
• Carbon dioxide diffuses rapidly across the blood–brain barrier, allowing cerebrospinal fluid pH to gradually return to normal.
• Ventilation returns to its resting level once normal carbon dioxide concentration and cerebrospinal fluid pH are restored.
• During alkalosis, respiratory rate decreases, causing carbon dioxide retention and restoration of hydrogen ion concentration.
• Respiratory compensation is rapid but cannot completely correct primary metabolic acid–base disorders without renal participation.

Renal Mechanism

• The kidneys provide the most effective long-term regulation of acid–base balance.
• Renal compensation develops over several hours and reaches maximum effectiveness within two to five days.
• The kidneys maintain acid–base homeostasis by reabsorbing filtered bicarbonate, secreting hydrogen ions, and generating new bicarbonate.
• They eliminate nonvolatile acids produced during normal metabolism.
• Net renal acid excretion normally equals the daily production of nonvolatile acids.
• Glomerular filtrate initially has a pH similar to plasma, but urine becomes acidic because of tubular hydrogen ion secretion.
• Normal urine pH ranges from approximately 4.5 to 8.0, with an average near 6.0.
• The kidneys do not excrete large amounts of free hydrogen ions because extremely acidic urine would damage renal tissues.
• Instead, hydrogen ions are excreted after combining with urinary buffer systems.

Exchange of H+ with Na+

• Hydrogen ions are secreted into the tubular lumen through sodium–hydrogen exchangers and hydrogen ion pumps.
• Sodium reabsorption is closely linked to hydrogen ion secretion, particularly in the proximal tubule.
• Intracellular carbonic anhydrase generates hydrogen ions and bicarbonate from carbon dioxide and water.
• Filtered bicarbonate combines with secreted hydrogen ions in the tubular fluid and is effectively reclaimed, preventing bicarbonate loss in urine.
• Nearly all filtered bicarbonate is reabsorbed under normal physiological conditions.

Excretion of Ammonium

• Renal tubular cells metabolize glutamine to produce ammonia and bicarbonate.
• Ammonia diffuses into the tubular lumen and binds secreted hydrogen ions to form ammonium.
• Ammonium becomes trapped in the tubular fluid and is excreted in urine.
• Increased ammonium production is the major adaptive response to chronic metabolic acidosis.
• This process also generates new bicarbonate that enters the circulation.

Excretion of H2PO4−

• Filtered hydrogen phosphate acts as an important urinary buffer.
• Secreted hydrogen ions combine with hydrogen phosphate to form dihydrogen phosphate, which is excreted in urine.
• This process contributes to titratable acidity and permits continued hydrogen ion secretion without excessive reduction in urine pH.
• Phosphate buffering is especially important in the distal tubule and collecting duct.
• Respiratory and renal mechanisms work together to maintain stable hydrogen ion concentration.
• Rapid respiratory adjustments and slower renal adaptations ensure effective maintenance of acid–base homeostasis during health and disease.

Excretion of Other Acids

• The kidneys excrete several metabolic acids that cannot be eliminated through the lungs.
• During conditions such as prolonged fasting or uncontrolled diabetes mellitus, ketone bodies increase in plasma and are excreted in urine.
• These include acetoacetic acid and β-hydroxybutyric acid, while acetone is excreted mainly through the lungs, with only a small amount appearing in urine.
• Strong mineral acids derived from metabolism, such as sulfuric and phosphoric acids, dissociate into hydrogen ions before excretion.
• Secreted hydrogen ions combine with urinary buffers, allowing safe elimination without markedly lowering urine pH.

Reclamation of Bicarbonate

• Reabsorption of bicarbonate is essential for maintaining normal extracellular pH.
• Nearly all filtered bicarbonate is reclaimed under normal physiological conditions.
• Approximately 80–85% of filtered bicarbonate is reabsorbed in the proximal convoluted tubule.
• About 10–15% is reabsorbed in the thick ascending limb of the loop of Henle.
• The remaining small fraction is reabsorbed in the distal tubule and collecting duct.
• Bicarbonate reabsorption depends on hydrogen ion secretion into the tubular lumen.
• Secreted hydrogen ions combine with filtered bicarbonate, allowing its indirect reabsorption rather than direct transport.
• Reduced bicarbonate reabsorption decreases plasma bicarbonate concentration and contributes to metabolic acidosis.
• When plasma bicarbonate concentration exceeds the renal threshold, excess bicarbonate is excreted, making the urine more alkaline.
• Bicarbonate reabsorption is closely linked to sodium reabsorption in the renal tubules.

Formation of New Bicarbonate

• The kidneys generate new bicarbonate to replace bicarbonate consumed while buffering nonvolatile acids.
• New bicarbonate enters the circulation through two principal mechanisms.
• These mechanisms are the excretion of titratable acids and the excretion of ammonium ions.
• Generation of new bicarbonate is especially important during chronic acid loading.

Excretion of Titrable Acids

• Secreted hydrogen ions combine with urinary buffers to form titratable acids.
• Hydrogen phosphate is the major urinary buffer responsible for this process.
• Creatinine, urate, and other organic buffers also contribute to titratable acidity.
• Formation of dihydrogen phosphate permits continued hydrogen ion secretion without excessive reduction in urine pH.
• For every hydrogen ion excreted as a titratable acid, one new bicarbonate ion is added to the bloodstream.
• The amount of titratable acid excreted depends on the availability of urinary phosphate and other buffers.

Excretion of Ammonium Ion

• Renal tubular cells metabolize glutamine to produce ammonia and bicarbonate.
• Ammonia diffuses into the tubular lumen and binds hydrogen ions to form ammonium.
• Ammonium becomes trapped in the tubular fluid and is excreted in urine.
• Each ammonium ion excreted results in the addition of one new bicarbonate ion to the circulation.
• Ammonium excretion increases markedly during chronic metabolic acidosis and is the most important adaptive mechanism for increasing renal acid elimination.
• Impaired hydrogen ion secretion reduces ammonium formation, decreases net acid excretion, and limits bicarbonate regeneration.

Abnormalities of Acid-Base Balance

• Acid–base disorders develop when the production, buffering, or elimination of acids and bases becomes impaired.
• These disturbances alter the normal arterial blood pH of 7.35–7.45.
• Acidosis occurs when arterial blood pH falls below 7.35 because of excess acid accumulation or loss of bicarbonate.
• Alkalosis occurs when arterial blood pH rises above 7.45 because of excess bicarbonate or loss of hydrogen ions.
• The body responds through respiratory and renal compensatory mechanisms, but compensation does not completely correct the primary disorder.
• Acid–base disorders are classified into four major types:
  • Metabolic acidosis
  • Respiratory acidosis
  • Metabolic alkalosis
  • Respiratory alkalosis

Metabolic Acidosis

• Metabolic acidosis is characterized by a primary reduction in plasma bicarbonate concentration.
• It results from increased acid production, reduced acid excretion, or excessive bicarbonate loss.
• Increased production of organic acids occurs in conditions such as diabetic ketoacidosis, lactic acidosis, methanol poisoning, and severe salicylate toxicity.
• Reduced renal acid excretion occurs in chronic kidney disease and renal tubular acidosis, leading to retention of nonvolatile acids.
• Excessive bicarbonate loss may occur through the gastrointestinal tract during severe diarrhea, pancreatic or intestinal fistulas, or through impaired renal bicarbonate reabsorption.
• As bicarbonate is consumed while buffering excess hydrogen ions, plasma bicarbonate concentration decreases and blood pH falls.

Respiratory Compensation

• A fall in blood pH stimulates peripheral and central chemoreceptors.
• The respiratory center responds by increasing the rate and depth of breathing.
• Hyperventilation increases carbon dioxide elimination from the lungs.
• Reduction in arterial carbon dioxide decreases carbonic acid concentration and partially restores blood pH.
• Respiratory compensation begins within minutes and reaches near-maximal effectiveness within several hours.
• Compensation reduces the severity of acidosis but does not eliminate the underlying metabolic disturbance.

Renal Compensation

• When kidney function is preserved, renal compensation enhances the correction of metabolic acidosis.
• The kidneys increase hydrogen ion secretion into the tubular fluid.
• Ammonium production and excretion increase, promoting removal of excess acid.
• Excretion of titratable acids also increases through phosphate buffering.
• The kidneys reabsorb virtually all filtered bicarbonate and generate new bicarbonate ions.
• These adaptations gradually restore plasma bicarbonate concentration and improve acid–base homeostasis over several days.

Respiratory Acidosis

Respiratory acidosis results from inadequate carbon dioxide elimination, causing increased arterial carbon dioxide, elevated carbonic acid, and decreased blood pH.

Table 158.1: Differences in primary and compensatory changes in various types of acid base disorders.

Acid–Base Disorder	Primary Disturbance	Expected Compensatory Response
Metabolic acidosis	Decreased plasma bicarbonate	Decreased arterial carbon dioxide due to hyperventilation
Metabolic alkalosis	Increased plasma bicarbonate	Increased arterial carbon dioxide due to hypoventilation
Respiratory acidosis (acute)	Increased arterial carbon dioxide	Plasma bicarbonate increases by ~1 mmol/L for every 10 mm Hg rise in carbon dioxide
Respiratory acidosis (chronic)	Persistent increased arterial carbon dioxide	Plasma bicarbonate increases by ~3.5–4 mmol/L for every 10 mm Hg rise in carbon dioxide
Respiratory alkalosis (acute)	Decreased arterial carbon dioxide	Plasma bicarbonate decreases by ~2 mmol/L for every 10 mm Hg fall in carbon dioxide
Respiratory alkalosis (chronic)	Persistent decreased arterial carbon dioxide	Plasma bicarbonate decreases by ~4–5 mmol/L for every 10 mm Hg fall in carbon dioxide

Etiopathogenesis

• Respiratory acidosis develops when inadequate alveolar ventilation causes retention of carbon dioxide.
• Increased arterial carbon dioxide raises carbonic acid concentration, resulting in a fall in blood pH.
• Disorders that depress the respiratory center include opioid overdose, sedative medications, encephalitis, meningitis, traumatic brain injury, and cerebrovascular disease.
• Diseases affecting the respiratory apparatus include chronic obstructive pulmonary disease, severe asthma, acute respiratory distress syndrome, neuromuscular disorders, and chest wall deformities.
• Other contributing conditions include severe obesity with hypoventilation, obstructive sleep apnea, and marked abdominal distension, such as massive ascites.
• Immediately after carbon dioxide retention, chemical buffer systems reduce the rise in hydrogen ion concentration.
• Hemoglobin and intracellular protein buffers provide most of the initial buffering capacity.
• Buffering increases plasma bicarbonate concentration, but this response does not fully correct the acidosis.
• The transient rise in bicarbonate reflects buffering rather than a true metabolic alkalosis.

Renal Compensation

• The kidneys provide the major long-term compensation for respiratory acidosis.
• Renal compensation begins within 6–12 hours and reaches maximum effectiveness after 2–5 days.
• The kidneys increase hydrogen ion secretion into the tubular fluid.
• Ammonium excretion and titratable acid excretion increase, while filtered bicarbonate is almost completely reabsorbed.
• New bicarbonate is generated and returned to the circulation, partially restoring blood pH.

Respiratory Compensation

• Respiratory compensation is possible only when hypoventilation is caused by a reversible or partial defect.
• Increased arterial carbon dioxide stimulates peripheral and central chemoreceptors, promoting deeper and faster breathing.
• If the underlying respiratory disorder severely limits ventilation, this compensatory response is inadequate.
• Definitive correction requires treatment of the underlying cause and restoration of effective alveolar ventilation.

Metabolic Alkalosis

• Metabolic alkalosis is an acid–base disorder characterized by a primary increase in plasma bicarbonate concentration.
• It results in an increased bicarbonate-to-carbon dioxide ratio and an arterial blood pH above 7.45.
• Elevated blood pH increases the binding of ionized calcium to plasma proteins.
• The resulting reduction in ionized calcium increases neuromuscular excitability.
• Severe alkalemia, particularly when blood pH exceeds 7.55, may produce muscle cramps, carpopedal spasm, or tetany despite normal total serum calcium.

Etiopathogenesis

• Metabolic alkalosis is broadly classified into saline-responsive, saline-resistant, and exogenous base-load alkalosis.
• Classification is based on the underlying mechanism and urinary chloride concentration.

Saline Responsive Alkalosis

• This form is usually associated with urinary chloride concentration below 10–20 millimoles per liter.
• It commonly results from extracellular fluid volume depletion and chloride loss.
• Patients may have either normal or elevated blood pressure depending on the underlying cause.

Normotensive Saline Responsive Alkalosis

• Common causes include persistent vomiting, gastric suction, pyloric or duodenal obstruction, recovery from chronic respiratory acidosis, cystic fibrosis, and previous diuretic therapy.
• Vomiting causes loss of hydrogen ions, chloride, sodium, and water from gastric secretions.
• Extracellular fluid volume contraction activates the renin–angiotensin–aldosterone system.
• Increased aldosterone promotes sodium reabsorption and enhances hydrogen ion and potassium secretion.
• Reduced glomerular filtration and increased bicarbonate reabsorption maintain the alkalosis.
• Administration of isotonic saline corrects volume depletion, restores chloride stores, and reverses most cases.

Hypertensive Saline Responsive Alkalosis

• Liddle syndrome is a rare inherited disorder caused by excessive activity of epithelial sodium channels in the distal nephron.
• Persistent sodium reabsorption produces hypertension, hypokalemia, metabolic alkalosis, and suppression of renin and aldosterone secretion.

Saline Unresponsive (Resistant) Alkalosis

• This type is usually associated with urinary chloride concentration greater than 20 millimoles per liter.
• Correction requires treatment of the underlying disorder rather than saline administration.
• Normotensive causes include potassium deficiency, magnesium deficiency, ongoing diuretic use, and Bartter syndrome.
• Hypertensive causes include primary aldosteronism, Cushing syndrome, and renal artery stenosis.
• Potassium replacement is essential when hypokalemia contributes to the alkalosis.

Exogenous Base-Load Alkalosis

• Excessive intake or administration of alkali can produce metabolic alkalosis, especially when renal bicarbonate excretion is impaired.
• Milk-alkali syndrome results from excessive consumption of calcium-containing antacids and absorbable alkali.
• Patients with chronic kidney disease are particularly susceptible because of reduced bicarbonate excretion.

Respiratory Alkalosis

• Respiratory alkalosis results from excessive alveolar ventilation, leading to excessive elimination of carbon dioxide.
• Decreased arterial carbon dioxide lowers carbonic acid concentration and increases blood pH.
• The rise in the bicarbonate-to-carbon dioxide ratio characterizes this disorder.
• Common pulmonary causes include asthma, pneumonia, pulmonary embolism, and early stages of congestive heart failure associated with hyperventilation.
• Nonpulmonary causes include hypoxemia at high altitude, severe anemia, hyperthyroidism, fever, sepsis, meningitis, encephalitis, anxiety-related hyperventilation, and certain drugs such as salicylates during the early phase of toxicity.
• Excessive mechanical ventilation is an important iatrogenic cause of respiratory alkalosis.

Compensation

• Immediate compensation is provided by intracellular buffers, including hemoglobin and tissue proteins, which release hydrogen ions and reduce plasma bicarbonate concentration.
• During persistent respiratory alkalosis, the kidneys decrease bicarbonate reabsorption and increase bicarbonate excretion in urine.
• Renal compensation also decreases hydrogen ion secretion, ammonium production, and titratable acid excretion.
• Chloride reabsorption increases to maintain electrical neutrality.
• Renal compensation begins within several hours and becomes maximal after 2–5 days.
• Severe or prolonged respiratory alkalosis may reduce cerebral blood flow and produce dizziness, paresthesia, muscle cramps, and, in extreme cases, tetany due to reduced ionized calcium concentration.