ACID-BASE REGULATION AND DISORDERS

Hydrogen ion (H⁺) is especially reactive; it can attach to negatively charged proteins and, in high concentrations, alter their overall charge, configuration, and function Acid-base equilibrium is closely tied to fluid and electrolyte balance, and disturbances in one of these systems often affect another

Acid-Base Physiology

Most acid comes from carbohydrate and fat metabolism, which generates of CO₂ daily. CO₂ is not an acid itself but combines with water (H₂O) in the blood to create carbonic acid (H₂CO₃), which in the presence of the enzyme carbonic anhydrase dissociates into H+ and HCO₃^-. The H⁺ binds with hemoglobin in RBCs and is released with oxygenation in the alveoli, at which time the reaction is reversed, creating H₂O and CO₂, which is exhaled in each breath

Lesser amounts of organic acid derive from the following:

• Incomplete metabolism of glucose and fatty acids into lactic acid and keto-acids

• Metabolism of sulfur-containing amino acids (cysteine, methionine) into sulfuric acid

• Metabolism of cationic amino acids (arginine, lysine)

• Hydrolysis of dietary phosphate

This "fixed" or "metabolic" acid load cannot be exhaled and therefore must be neutralized or excreted (mostly in urine)

In the other hand, most base comes from metabolism of anionic amino acids (glutamate and aspartate) and from oxidation and consumption of organic anions such as lactate and citrate, which produce HCO₃^-

Acid-Base Balance Acid-base balance is maintained by chemical buffering and by pulmonary and renal elimination

Chemical buffering: Chemical buffers are solutions that resist changes in pH. Intracellular and extracellular buffers provide an immediate response to acid-base disturbances. Bone also plays an important buffering role. A buffer is made up of a weak acid and its conjugate base. The conjugate base can accept H⁺ and the weak acid can relinquish it thereby minimizing changes in free H⁺ concentration. The most important extracellular buffer is the HCO3-/CO2 system, described by the equation: H⁺ + HCO₃^- ⇔ H₂CO₃ ⇔ CO₂ + H₂O; an increase in H⁺ drives the equation to the right and generates CO₂. This important buffer system is highly regulated; CO₂ concentrations can be finely controlled by alveolar ventilation, and H⁺ and HCO₃^- concentrations can be finely regulated by renal excretion.

Derived from the Henderson-Hasselbalch equation: H⁺ = 24 × pCO₂/HCO₃^- . This equation illustrates that acid-base balance depends on the ratio of pCO₂ and HCO₃^-, not on the absolute value of either one alone. With this formula, any 2 values (usually H⁺ and pCO₂) can be used to calculate the other (usually HCO₃^-)

Other important physiologic buffers include intracellular organic and inorganic phosphates and proteins, including Hb in RBCs. Less important are extracellular phosphate and plasma proteins

Bone becomes an important buffer after consumption of extracellular HCO₃^-. Bone initially releases sodium carbonate (NaHCO₃) and potassium carbonate (KHCO₃) in exchange for H₊. With prolonged acid loads, bone releases calcium carbonate (CaCO₃) and calcium phosphate (CaPO₄). Long-standing acidemia therefore contributes to bone demineralization and osteoporosis.

Pulmonary regulation: CO₂ concentration is finely regulated by changes in tidal volume and respiratory rate (minute ventilation). A decrease in pH is sensed by arterial chemoreceptors and leads to increases in tidal volume or respiratory rate; CO₂ is exhaled and blood pH increases. In contrast to chemical buffering, which is immediate, pulmonary regulation occurs over minutes to hours. It is about 50 to 75% effective; it does not completely normalize pH

Renal regulation: The kidneys control pH by adjusting the amount of HCO­₃^- that is reabsorbed and the amount of H+ that is excreted; increase in HCO₃^- is equivalent to removing free H⁺. Changes in renal acid-base handling occur hours to days after changes in acid-base status. HCO₃^- reabsorption occurs mostly in the proximal tubule and, to a lesser degree, in the collecting tubule. H₂O within the tubular cell dissociates into H⁺ and hydroxide (OH^-); in the presence of carbonic-anhydrase, the OH^- combines with CO₂ to form HCO₃^-, which is transported back into the peritubular capillary, while the H⁺ is secreted into the tubular lumen and joins with freely filtered HCO₃^- to form CO₂ and H₂O, which are also reabsorbed. Decreases in effective circulating volume (such as occur with diuretic therapy) increase HCO₃^- reabsorption, while increases in parathyroid hormone in response to an acid load decrease HCO₃^- reabsorption. Also, increased pCO₂ leads to increased HCO₃ reabsorption, while Cl^- depletion (typically from volume depletion) leads to increased Na⁺ reabsorption and HCO₃^- generation by the proximal tubule

Acid is actively excreted into the proximal and distal tubules where it combines with urinary buffers—primarily freely filtered HPO₄^-2, creatinine, uric acid, and ammonia—to be transported outside the body. The ammonia buffering system is especially important because other buffers are filtered in fixed concentrations and can be depleted by high acid loads; by contrast, tubular cells actively regulate ammonia production in response to changes in acid load. Arterial pH is the main determinant of acid secretion, but excretion is also influenced by K⁺, Cl^-, and aldosterone levels. Intracellular K⁺ concentration and H⁺ secretion are reciprocally related; K⁺ depletion causes increased H⁺ secretion and hence metabolic alkalosis

Acid-Base Disorders

Acid-base disorders are changes in arterial pCO₂, serum HCO₃^-, and serum pH
Acidemia is serum pH < 7.35
Alkalemia is serum pH > 7.45

Classification

Primary acid-base disturbances are defined as metabolic or respiratory based on clinical context and whether the primary change in pH is due to an alteration in serum HCO3- or in pCO2.
Metabolic acidosis is serum HCO3- < 24 mEq/L. Causes are

• Increased acid production
• Acid ingestion
• Decreased renal acid excretion
• GI or renal HCO3- loss

Metabolic alkalosis is serum HCO3- > 24 mEq/L. Causes are

• Acid loss
  HCO3- retention

Respiratory acidosis is pCO2 > 40 mm Hg (hypercapnia). Cause is

• Decrease in minute ventilation (hypoventilation)

Respiratory alkalosis is pCO2 < 40 mm Hg (hypocapnia). Cause is

• Increase in minute ventilation (hyperventilation)
  
  Mixed acid-base disorders comprise 2 or more primary disturbances

Symptoms and Signs

Compensated or mild acid-base disorders cause few symptoms or signs. Severe, uncompensated disorders have multiple cardiovascular, respiratory, neurologic, and metabolic consequences

SYSTEM	SYSTEM	ALKALEMIA
Cardiovascular	Impaired cardiac contractility Arteriolar dilation Venoconstriction Centralization of blood volume Increased pulmonary vascular resistance Decreased cardiac output Decreased systemic BP Decreased hepatorenal blood flow Decreased threshold for cardiac arrhythmias Attenuation of responsiveness to catecholamines	Arteriolar constriction Reduced coronary blood flow Reduced anginal threshold Decreased threshold for cardiac arrhythmias
Metabolic	Insulin resistance Inhibition of anaerobic glycolysis Reduction in ATP synthesis Hyperkalemia Protein degradation Bone demineralization (chronic)	Stimulation of anaerobic glycolysis Formation of organic acids Decreased oxyhemoglobin dissociation Decreased ionized Ca Hypokalemia Hypomagnesemia Hypophosphatemia
Neurologic	Inhibition of metabolism and cell-volume regulation Obtundation and coma	Tetany Seizures Lethargy Delirium Stupor
Respiratory	Compensatory hyperventilation with possible respiratory muscle fatigue	Compensatory hypoventilation with hypercapnia and hypoxemia

Diagnosis

• ABG
• Serum electrolytes
• Anion gap calculated
• If metabolic acidosis is present, delta gap calculated and Winter's formula applied
• Search for compensatory changes

Evaluation is with ABG and serum electrolytes. Acid-base balance is generally most accurately assessed with measurement of pH and pCO2 on arterial blood. In cases of circulatory failure or during cardiopulmonary resuscitation, measurements on venous blood may more accurately reflect conditions at the tissue level and may be a more useful guide to bicarbonate administration and adequacy of ventilation.
Changes in pCO2 reflect the respiratory component, and changes in HCO3- reflect the metabolic component. However, several calculations may be required to determine whether changes in pCO2 and HCO3- are primary or compensatory and whether a mixed disorder is present; in mixed disorders, values may be deceptively normal. Interpretation must also consider clinical conditions (eg, chronic lung disease, renal failure, drug overdose)