Regulation of Hydrogen Ion Concentration (Acid–Base Balance)

Acids are produced in the course of metabolism

Metabolism generates carbon dioxide within cells. Carbon dioxide dissolves in water, forming carbonic acid, which in turn dissociates releasing hydrogen ion. The acids derived from sources other than CO₂ are known as nonvolatile; by definition, they cannot be removed through the lungs, and must be excreted via the kidney. The net production of nonvolatile acids is in the order of 50 mmol/24 h.

Lactic acid is produced during anaerobic glycolysis and its concentration in plasma is the hallmark of hypoxia. Ketoacids (acetoacetic and β-hydroxybutyric acid) are important in diabetes (Chapter 21). The metabolism of sulfur-containing amino acids and phosphorus-containing compounds also generates inorganic acids.

In spite of the amount of hydrogen ion produced, its blood concentration (or its negative logarithm, the pH), is remarkably constant: it remains between 35 and 45 nmol/L (pH 7.35–7.45). Maintenance of stable pH is essential because it affects the ionization of proteins (Chapter 2) and, consequently, the activity of many enzymes and other biologically active molecules such as ion channels. Changes in pH together with the partial pressure of carbon dioxide (pCO₂) affect the shape of the hemoglobin saturation curve, and thus tissue oxygenation (Chapter 5). Also, a decrease in pH increases sympathetic tone and may lead to cardiac dysrhythmias.

Maintaining the acid–base balance involves lungs, erythrocytes and kidneys

The acid–base balance involves the lungs, the erythrocytes, and the kidneys (Fig. 25.1). The lungs control the exchange of carbon dioxide and oxygen between the blood and the atmosphere; the erythrocytes transport gases between lungs and tissues; and the kidneys control plasma bicarbonate synthesis and the excretion of the hydrogen ion.

Clinical relevance

Clinically, understanding of the acid–base balance is important in many sub-specialties of medicine and surgery, and particularly in anesthesiology and critical care medicine.

Blood and tissues contain buffer systems that minimize changes in hydrogen ion concentration

The main buffer that neutralizes hydrogen ions released from cells is the bicarbonate buffer. Another important buffer is hemoglobin, which contributes to buffering of hydrogen ion generated from the carbonic anhydrase reaction. Within cells, the hydrogen ion is neutralized by intracellular buffers, mainly proteins and phosphates (Table 25.1 and Chapter 2).

Bicarbonate buffer is an open system which remains at equilibrium with atmospheric air

Buffering capacity of the bicarbonate buffer exceeds all the ‘closed’ buffer systems. The metabolically produced CO₂ diffuses through cell membranes and dissolves in plasma. The plasma solubility coefficient of CO₂ is 0.23 if pCO₂ is measured in kPa (0.03 if pCO₂ is measured in mmHg; 1 kPa = 7.5 mmHg or 1 mmHg = 0.133 kPa)). Thus, at the normal pCO₂ of 5.3 kPa (40 mmHg), the concentration of dissolved CO₂ (dCO₂) is:

CO₂ equilibrates with H₂CO₃ in plasma in the course of a slow, nonenzymatic reaction. Normally plasma H₂CO₃ concentration is very low, about 0.0017 mmol/L. However, because of the equilibrium between H₂CO₃ and dissolved CO₂ (theoretically all dissolved CO₂ could eventually convert into H₂CO₃), this component of the bicarbonate buffer can be taken as equal to the sum of the H₂CO₃ and the dissolved CO₂. The key equation describing the behavior of the bicarbonate buffer is the Henderson–Hasselbalch equation (Chapter 2). It expresses the relationship between pH and the components of the buffer:

The equation demonstrates that blood pH is determined by the ratio between the concentration of plasma bicarbonate (the ‘base’ component of the buffer) and the concentration of dissolved CO₂ (the ‘acid’ component). Normally, at pCO₂ of 5.3 kPa and dCO₂ concentration 1.2 mmol/L (see above) the plasma bicarbonate concentration is about 24 mmol/L. The pK of the bicarbonate buffer is 6.1. Let's insert the actual concentrations of buffer components into the preceding equation:

Thus the normal concentration of bicarbonate and normal partial pressure of CO₂ correspond to pH 7.40 (hydrogen ion concentration 40 nmol/L). The bicarbonate buffer minimizes changes in hydrogen ion concentration when acid is added to blood.

When the H⁺ concentration in the system increases, the bicarbonate component of the buffer accepts (H⁺), forming carbonic acid, which is subsequently converted into CO₂ and H₂O in the reaction catalyzed by carbonic anhydrase:

The CO₂ is eliminated through the lungs. The excess hydrogen ion has been neutralized and the [bicarbonate]/pCO₂ ratio brought back towards normal.

On the other hand, when the H⁺ concentration decreases, the carbonic acid component of the buffer will dissociate to supply H⁺ for a reaction that will yield water and bicarbonate ion (at this stage the increase in plasma bicarbonate is minimal):

Subsequently, the ventilation rate will decrease, retaining CO₂ and attempting to normalize the [bicarbonate]/pCO₂ ratio:

Thus the denominator in the Henderson–Hasselbalch equation (pCO₂) is controlled by the lungs. For this reason it is called ‘the respiratory component of the acid–base balance’. On the other hand, plasma bicarbonate concentration is controlled by the kidneys and erythrocytes and, consequently, it is called ‘the metabolic component of the acid–base balance’ (Fig. 25.2).

Carbonic anhydrase converts the dissolved CO₂ into carbonic acid

Erythrocytes and renal tubular cells contain a zinc-containing enzyme, carbonic anhydrase (CA), which converts dissolved CO₂ into carbonic acid. Carbonic acid dissociates, yielding hydrogen and bicarbonate ions:

This is how renal tubular cells and erythrocytes produce bicarbonate. The kidneys regulate bicarbonate reabsorption and synthesis, and the erythrocytes adjust its concentration in response to changes in pCO₂.

Respiratory and metabolic components of the acid–base balance are interlinked

The respiratory and metabolic components of the acid–base balance are closely inter-dependent: one tends to compensate for the untoward changes in the other. When the primary disorder is respiratory (such as, for instance, a severe chronic obstructive airway disease, COAD) and causes accumulation of CO₂, a compensatory increase in bicarbonate reabsorption by the kidney takes place. Conversely, the decrease in pCO₂ (as happens during hyperventilation in an asthmatic attack) would cause a kidney response, leading to decreased bicarbonate reabsorption.

Conversely, when the primary problem is metabolic (for instance, diabetic ketoacidosis), a decrease in bicarbonate concentration and the resulting decrease in pH stimulate the respiratory center to increase the ventilation rate. The CO₂ is blown off and plasma pCO₂ decreases. This is why patients with metabolic acidosis hyperventilate. On the other hand, an increase in plasma bicarbonate (causing an increase in pH) leads to a decrease in the ventilation rate, and to CO₂ retention. Thus, the compensatory change always tends to normalize the [bicarbonate]/pCO₂ ratio, helping to bring the pH towards normal (Fig. 25.3).

Intracellular buffers are proteins and phosphates

The two main intracellular buffers are proteins and phosphates, and the buffering is governed by the HPO₄^2–/H₂PO₄^– and [protein]/protein-H } ratios. Hemoglobin is an important extracellular protein buffer.

Note that when the hydrogen ion is present in plasma in excess, it enters cells in exchange for potassium and this may result in an increase in plasma potassium concentration. Conversely, a decrease in plasma hydrogen ion, or bicarbonate excess, would be buffered by cell-derived hydrogen ion. Hydrogen ion would enter plasma in exchange for potassium, decreasing plasma potassium concentration. Thus acidemia, (low blood pH) may be associated with hyperkalemia, and alkalemia (high blood pH) is associated with hypokalemia (Fig. 25.4).

The lungs supply oxygen necessary for tissue metabolism and remove the generated CO₂

Approximately 10,000 L of air pass through the lungs of an average person each day. Lungs lie in the thoracic cavity surrounded with the pleural sac, a thin ‘bag’ of tissue that lines the thoracic cage at one end, and attaches to the external surface of the lungs at the other. When the thoracic cage expands during inspiration, negative pressure created in the expanding pleural sac inflates the lung.

The airways are ‘tubes’ of progressively decreasing diameter. They consist of the trachea, large and small bronchi, and even smaller bronchioles (Fig. 25.5). At the end of the bronchioles, there are pulmonary alveoli – structures lined with endothelium and covered with a film of surfactant – the main component of which is dipalmitoylphosphatidylcholine (Chapter 26). Surfactant decreases the surface tension of the alveoli. The gas exchange takes place in the alveoli.

Respiration rate is controlled by the respiratory center located in the brainstem

Both the partial pressures of oxygen (pO₂) and carbon dioxide (pCO₂) affect the ventilation rate: the respiratory center has chemoreceptors sensitive to pCO₂ and to pH. Under normal circumstances it is not the pO₂ that stimulates ventilation, but the increase in pCO₂ or the decrease in pH. However, when the pO₂ falls and hypoxia develops, it begins to control ventilation through a set of receptors located in the carotid bodies in the aortic arch. When arterial pO₂ decreases to less than 8 kPa (60 mmHg), this ‘hypoxic drive’ becomes the main controller of the ventilation rate. Persons who suffer from hypoxia due to chronic lung disease depend on hypoxic drive to maintain their ventilation rate (see Clinical Box on this page).

Ventilation and lung perfusion together determine gas exchange

Blood supply to the pulmonary alveoli is provided by the pulmonary arteries that carry deoxygenated blood from the periphery and through the right ventricle. After its oxygenation in the lungs, the blood flows through pulmonary veins to the left atrium. In the alveolar capillaries of the lungs, it accepts oxygen, which diffuses through the alveolar wall from the inspired air; at the same time the CO₂ diffuses from the blood into the alveoli (Fig. 25.5) and is removed with the expired air.

The rate of diffusion of gases in and out of the blood is determined by the difference in partial pressures between alveolar air and blood. Table 25.3 shows the pO₂ and pCO₂ in the lungs. Compared with the atmospheric air, pCO₂ in the alveolar air is slightly higher and pO₂ slightly lower (this is due to the water vapor pressure). Carbon dioxide is much more soluble in water than oxygen, and equilibrates with blood more rapidly. Therefore, when problems develop, one first notices a decrease in blood pO₂ (hypoxia). An increase in pCO₂ (hypercapnia) occurs later and usually indicates a more severe disease. The other major factor determining gas exchange is the rate at which the blood flows through the lungs (the perfusion rate). Normally the alveolar ventilation rate is approximately 4 L/min and the perfusion 5 L/min (the ratio of ventilation to perfusion (Va/Q) is 0.8).

Different combinations of disturbed ventilation and perfusion may occur

In pathologic conditions, some parts of the lung may be well-perfused, but poorly ventilated. This occurs when some alveoli collapse and are unable to exchange gases. As a result, the blood pO₂ decreases, because there is no diffusion of oxygen from the alveolar air. The presence of oxygen-poor blood in the arterial circulation is known as the ‘shunt’ condition. On the other hand, when ventilation is adequate but perfusion poor, gas exchange cannot take place: in such cases, part of the lung behaves as if it had no alveoli at all, forming the ‘physiologic dead space’. Examples of conditions related to poor ventilation, poor perfusion, or the combination of both, are given below:

Table 25.4 lists pathologic conditions related to gas exchange.

Erythrocytes transport CO₂ to the lungs in a ‘fixed’ form – as bicarbonate

Human metabolism produces CO₂ at a rate of 200–800 mL/min. The CO₂ dissolves in water and generates carbonic acid, which in turn dissociates into hydrogen and bicarbonate ions. Thus, CO₂ generates large numbers of hydrogen ions:

In plasma, the above reaction is nonenzymatic and proceeds slowly, generating only minute amounts of carbonic acid, which remains in equilibrium with a large amount of dissolved CO₂. However, the same reaction in the erythrocytes is catalyzed by carbonic anhydrase, which ‘fixes’ CO₂ as bicarbonate. The generated hydrogen ion is buffered by hemoglobin.

The bicarbonate ion produced by erythrocyte carbonic anhydrase reaction moves to plasma in exchange for chloride ion (the ‘chloride shift’) (Fig. 25.6). As much as 70% of all CO₂ produced in tissues becomes bicarbonate; approximately 20% is carried ‘fixed’ to hemoglobin as carbamino groups, and only 10% remains dissolved in plasma.

In the lungs, higher pO₂ facilitates dissociation of CO₂ from hemoglobin. This is known as the Haldane effect. The hemoglobin releases its hydrogen ion, which reacts with bicarbonate, and forms carbonic acid, which, in turn, releases CO₂.

Proximal tubules reabsorb bicarbonate in the process aided by carbonic anhydrase

Normally, bicarbonate is reabsorbed in the proximal tubule and the urine is almost bicarbonate-free. The surfaces of the renal tubular cells facing the lumen are impermeable to bicarbonate. The filtered bicarbonate combines with hydrogen ion secreted by the cells, and forms carbonic acid, which is converted into CO₂ by carbonic anhydrase located on the luminal membrane. The CO₂ diffuses into cells, where intracellular carbonic anhydrase converts it back into carbonic acid, dissociating into hydrogen and bicarbonate ions. Bicarbonate is returned to the plasma, and the hydrogen ion is secreted into the lumen of the tubule to trap more filtered bicarbonate. Note that, in this process, hydrogen ion is used exclusively to aid bicarbonate reabsorption, and there is no net excretion (Fig. 25.7).

Distal tubules generate new bicarbonate and excrete hydrogen

The situation is different in the distal tubule where bicarbonate is generated. The mechanism is identical to that of bicarbonate reabsorption, but this time there is both a net loss of hydrogen ions from the body and a net gain of bicarbonate. The CO₂ diffuses into cells. The distal tubule carbonic anhydrase converts it into carbonic acid, which dissociates into hydrogen ion and bicarbonate. Bicarbonate is transported to the plasma, and hydrogen ion is secreted into the tubule lumen. However, no bicarbonate is present in the lumen of the distal tubule (all has been reabsorbed earlier) and the hydrogen ion is buffered (trapped) by phosphate ions present in the filtrate, and by ammonia synthesized by the proximal tubules. It is subsequently excreted in the urine (Fig. 25.8).

Ammonia generated by glutaminase reaction participates in the excretion of hydrogen ion

Ammonia is generated during the transformation of glutamine into glutamic acid catalyzed by glutaminase. Ammonia diffuses across the luminal membrane, allowing hydrogen ion to be trapped inside the tubule as the ammonium ion (NH₄⁺), to which the membrane is impermeable.

There are four main disorders of acid–base balance

The key to further classification is the ‘location’ of the primary cause within the respiratory and metabolic components of the system. If the primary cause is the change in pCO₂, the acidosis or alkalosis is called respiratory, and if it is bicarbonate, the acidosis or alkalosis is called metabolic. Thus there are four main disorders of acid–base balance: respiratory acidosis, metabolic acidosis, respiratory alkalosis, and metabolic alkalosis (Fig. 25.3). However, mixed disorders can also develop; we consider them later.

Lung and the kidney work in a concerted way to minimize changes in plasma pH: this is known as the compensation of acid–base disorders

Acidosis is accompanied by a decreased ratio of plasma bicarbonate to pCO₂, and alkalosis by an increased ratio. Whenever a problem occurs, the compensating mechanisms are triggered to bring the hydrogen ion concentration back towards normal. This translates into normalizing the [bicarbonate]/pCO₂ ratio in the Henderson–Hasselbalch equation.

Consequently, when the respiratory acidosis causes an increase in pCO₂, the kidney will increase the generation of bicarbonate, increasing its plasma concentration and normalizing the ratio. Conversely, when diabetic ketoacidosis causes depletion of plasma bicarbonate, ventilation rate increases, pCO₂ decreases and the ratio of bicarbonate/pCO₂ changes towards normal. While respiratory compensation can occur within minutes, metabolic compensation takes hours to days to develop fully (Table 25.5).

Respiratory acidosis occurs most often in lung disease and results from decreased ventilation

The most common cause is the chronic obstructive airways disease (COAD). Severe asthmatic attack can result in respiratory acidosis because of bronchial constriction. Respiratory acidosis often accompanies hypoxia (respiratory failure); in such a case, an increase in pCO₂ often parallels the decrease in pO₂ (Table 25.6, see Clinical Box on page 336).

Metabolic acidosis results from excessive production, or inefficient metabolism or excretion, of nonvolatile acids

A classic example of metabolic acidosis is the diabetic ketoacidosis, when ketoacids, acetoacetic acid, and β-hydroxybutyric acid accumulate in the plasma (Chapter 21). Acidosis may also occur during extreme physical exertion, when there is accumulation of lactic acid generated from muscle metabolism; in normal circumstances, lactate would be quickly metabolized on cessation of exercise. However, when large amounts of lactate are generated as a consequence of hypoxia, lactic acidosis may become life-threatening, as happens, for instance, in shock (Table 25.6).

Excretion of nonvolatile acids is also impaired in renal failure, and this also leads to metabolic acidosis. Renal failure develops when the perfusion of the kidneys is inadequate (e.g. in trauma, shock, or dehydration) or if there is an intrinsic kidney disease such as glomerulonephritis (inflammatory reaction in the renal tubular tissue).

Excessive loss of bicarbonate can also be a cause of metabolic acidosis. This is common when bicarbonate present in the intestinal fluid is lost as a result of severe diarrhea or surgical drainage after bowel surgery.

Impaired bicarbonate reabsorption and hydrogen ion secretion causes rare renal tubular acidoses

Defects in renal handling of bicarbonate and hydrogen ion lead to a group of relatively rare disorders known as renal tubular acidoses (RTA). The proximal RTA is caused by impaired reabsorption of bicarbonate, and the distal RTA by impaired hydrogen ion excretion. Proximal RTA is usually accompanied by other defects in proximal transport mechanisms (this is known as the Fanconi syndrome).

Generally, acidosis is a much more common condition than alkalosis.

Alkalosis is rarer than acidosis

A mild respiratory alkalosis may be a consequence of hyperventilation during exercise, anxiety attack, or fever. It also occurs in pregnancy. Metabolic alkalosis is often associated with abnormally low serum potassium concentration, as a result of cellular buffering. Cellular entry or exit of potassium ion is associated with the movement of hydrogen ion in an opposite direction. Thus, alkalosis can cause hypokalemia, and hypokalemia (Chapter 22) may lead to alkalosis. Severe metabolic alkalosis may also occur as a result of the massive loss of hydrogen ion from the stomach during vomiting (see Clinical Box on this page), or as a result of nasogastric suction after surgery. Lastly, it may occur when too much bicarbonate is given intravenously: for instance, during resuscitation from cardiac arrest (Table 25.6).