Regulation of Acid-Base Balance in the Fetus and Neonate

Introduction

The majority of the existing information on the regulation of acid-base homeostasis in mammals and humans was obtained from studies in adult subjects. Revolution in micromethodology and advances in developmental physiology and molecular biology provided additional insights and improved our understanding of the key mechanisms of fetal and neonatal regulation of acid-base balance.

In general, acid-base homeostasis is tightly regulated by extracellular and intracellular buffer systems and respiratory and renal compensatory mechanisms of the organism. Under physiologic circumstances, volatile and fixed acids generated by normal metabolism are excreted and the pH remains stable. The normal range of H ⁺ ion concentration in the extracellular fluid is 35 to 45 nEq/L (nanoequivalents per liter) corresponding to a pH of 7.45 and 7.35, respectively. Volatile carbonic acid is produced in the largest amounts and is readily excreted by the lungs in the form of carbon dioxide. Fixed acids, which include lactic acid, ketoacids, phosphoric acid, and sulfuric acid, are buffered principally by extracellular bicarbonate. The bicarbonate used in this process is then regenerated by the kidneys in a series of transmembrane transport processes resulting in the excretion of H ⁺ ions in the form of titratable acids and ammonium.

Extracellular Buffer System

Using various acid-base pairs, the extracellular buffer system responds immediately to alterations in pH in a fashion represented by the Henderson-Hasselbalch equation. The carbonic acid–bicarbonate system is the most important component of this buffer system. Based on the isohydric principle, changes in the concentrations of a single acid-base pair can be used as an indicator of acid-base homeostasis for the entire system. Therefore serial measurements of the carbonic acid–bicarbonate buffer system have been used to describe accurately the changes in both the experimental and the clinical settings.

Intracellular Buffer System

The most important components of the intracellular buffer system are the hemoglobin and intracellular proteins and phosphates acting as an intracellular H ⁺ sink and reservoir attached to the extracellular buffers. This system provides buffering at a slower rate compared with extracellular buffers and requires several hours to reach maximum capacity.

Respiratory Compensatory Mechanism

Because of the open nature of the carbonic acid–bicarbonate system, normal gas exchange in the lungs serves as an immediate regulator of acid-base homeostasis by maintaining a normal Pa co ₂ , thus eliminating the excess carbon dioxide generated by an acid load. However, activation of the respiratory compensatory mechanism is necessary to return pH further toward normal.

Changes in pH and Pa co ₂ activate both central and peripheral chemoreceptors, with predominance of central activation. Because low steady-state bicarbonate values in the cerebrospinal fluid (CSF), but not the plasma, are thought to affect central respiratory drive, in metabolic acidosis, full activation of the respiratory compensation is delayed by a few hours. In contrast, carbon dioxide moves freely across the blood-brain barrier. As a consequence, in respiratory acidosis, hypercarbia alters H ⁺ ion concentrations in CSF and cerebral interstitial fluid rapidly, leading to immediate activation of the respiratory compensatory mechanism.

Earlier reports suggested active transport of bicarbonate across the blood-brain barrier. However, a substantial body of evidence in animal models has demonstrated that generation of bicarbonate via hydroxylation of dissolved CO ₂ during CSF formation comprises the primary mechanism of bicarbonate production in the CSF. Almost two-thirds of bicarbonate synthesis is catalyzed by carbonic anhydrase, predominantly in the choroid plexus and glial cells. Plasma bicarbonate appears to affect CSF levels only when significant changes in serum bicarbonate levels take place. A number of ion transporters (Na ⁺ , HCO ₃ ⁻ cotransporters, Cl ⁻ /HCO ₃ ⁻ exchanger) have been suggested as molecular mechanisms for such transport across the blood-brain barrier.

Renal Compensatory Mechanism

By altering renal H ⁺ excretion in response to changes in extracellular pH, renal compensation is the ultimate mechanism to adjust H ⁺ content in the body. Although full activation of this system usually requires 2 to 3 days, alterations in renal acidification may be seen as early as a few hours after the development of the acid-base disturbance.

Urine acidification and bicarbonate reabsorption take place in several segments of the nephron: proximal tubule, loop of Henle, distal tubule, and collecting ducts where most acidification occurs. Active secretion of H ⁺ ions into the tubular lumen is the primary mechanism responsible for urinary acidification. Filtered bicarbonate combines with secreted H ⁺ , forming carbonic acid that then dissociates into CO ₂ and H ₂ O. Catalyzed by the luminal carbonic anhydrase IV enzyme, this reaction allows bicarbonate to enter tubular epithelial cells in the form of CO ₂ . In the cytoplasm, CO ₂ undergoes reverse transformation by the cytosolic carbonic anhydrase II enzyme forming bicarbonate and H ⁺ . The regenerated bicarbonate then enters the bloodstream via transmembrane transporters in the basolateral membrane.

Net H ⁺ ion secretion in the distal nephron continues even after the reabsorption of virtually all bicarbonate. Based on data from animal experiments, it appears that the type A intercalated cells in the distal and collecting tubules are responsible for the active H ⁺ secretion via apical H ⁺ -ATPase. The secreted H ⁺ ions are excreted in the urine in the form of titratable acids (phosphate and sulfate salts) and as ammonium salts. In addition to the excretion of H ⁺ ions, renal ammoniagenesis also results in the generation of bicarbonate.

In alkalosis, type B and non-A, non-B intercalated cells increase HCO ₃ ⁻ excretion via Na ⁺ -independent, electroneutral Cl ⁻ /HCO ₃ ⁻ exchanger, also known as pendrin , in their apical membrane.

Regulation of Acid-Base Balance in the Fetus