Chapter 3 Hydrogen ion homoeostasis and blood gases

Introduction

The normal processes of metabolism result in the net formation of 40–80 mmol of hydrogen ions per 24 h, principally from the oxidation of sulphur-containing amino acids. This burden of hydrogen ions is excreted by the kidneys, in the urine. In addition, there is a considerable endogenous turnover of hydrogen ions as a result of normal metabolic processes. Incomplete oxidation of energy substrates generates acid (e.g. lactic acid by glycolysis, oxoacids (ketoacids) from triacylglycerols (triglycerides)), while further metabolism of these intermediates consumes it (e.g. gluconeogenesis from lactate, oxidation of ketones). Temporary imbalances between the rates of production and consumption may arise in health (e.g. the accumulation of lactic acid during anaerobic exercise), but overall they are in balance and so make no contribution to net hydrogen ion excretion.

Potentially far more acid is generated as carbon dioxide during energy-yielding oxidative metabolism. In excess of 15 000 mmol/24 h of carbon dioxide is produced in this way, and is normally excreted by the lungs. Although carbon dioxide itself is not an acid, in the presence of water it can undergo hydration to form a weak acid, carbonic acid:

(3.1)

Carbon dioxide is removed from the body in expired air. As hydrogen ions can be generated stoichiometrically from carbon dioxide, the normal daily production of carbon dioxide is potentially equivalent to at least 15 mol of hydrogen ions. In health, pulmonary ventilation is controlled so that carbon dioxide excretion exactly matches the rate of formation.

The homoeostatic mechanisms for hydrogen ions and carbon dioxide are very efficient. Temporary imbalances can be absorbed by buffering and, as a result, the hydrogen ion concentration of the body is maintained within narrow limits (35–45 nmol/L (pH 7.35–7.46) in extracellular fluid (ECF)). The intracellular hydrogen ion concentration is slightly higher, but is also rigorously controlled. In disease, however, imbalances between the rates of acid formation and excretion can develop and may persist, resulting in acidosis or alkalosis.

Buffering of hydrogen ions

As hydrogen ions are generated they are buffered, thus limiting the rise in hydrogen ion concentration that would otherwise occur. A buffer system consists of a weak acid, that is, one that is incompletely dissociated, and its conjugate base. If hydrogen ions are added to a buffer, some will combine with the conjugate base and convert it to the undissociated acid. Thus, the addition of hydrogen ions to the bicarbonate–carbonic acid system (Equation 3.2) drives the reaction to the right, increasing the amount of carbonic acid and consuming bicarbonate ions:

(3.2)

Conversely, if the hydrogen ion concentration falls, carbonic acid dissociates, thereby generating hydrogen ions.

The efficacy of any buffer is limited by its concentration and by the position of the equilibrium. A buffer operates most efficiently at hydrogen ion concentrations that result in approximately equal concentrations of undissociated acid and conjugate base. The bicarbonate buffer system is the most important in the ECF, yet at normal ECF hydrogen ion concentrations, the concentration of carbonic acid is about 1.2 mmol/L, while that of bicarbonate is 20 times greater. However, the capacity of the bicarbonate system is greatly enhanced in the body because carbonic acid can readily be formed from carbon dioxide or disposed of by conversion into carbon dioxide and water (see Equation 3.1).

For every hydrogen ion buffered by bicarbonate, a bicarbonate ion is consumed (see Equation 3.2). To maintain the capacity of the buffer system, the bicarbonate must be regenerated. Yet, when bicarbonate is formed from carbonic acid (indirectly from carbon dioxide and water), equimolar amounts of hydrogen ions are formed simultaneously (see Equation 3.2). Bicarbonate formation can only continue if these hydrogen ions are removed. This process occurs in the cells of the renal tubules, where hydrogen ions are secreted into the urine, and where bicarbonate is generated and retained in the body.

Proteins, including intracellular proteins, are also involved in buffering. The proteinaceous matrix of bone is an important buffer in chronic acidosis. Phosphate is a minor buffer in the ECF but is of fundamental importance in the urine. The special role of haemoglobin is considered on p. 43.

Bicarbonate reabsorption and hydrogen ion excretion

The glomerular filtrate contains the same concentration of bicarbonate ions as the plasma. At normal rates of glomerular filtration, approximately 4300 mmol/24 h of bicarbonate is filtered by the renal glomeruli. If this bicarbonate were not reabsorbed, copious amounts would be excreted in the urine, depleting the body’s buffering capacity and causing an acidosis. In health, at normal plasma bicarbonate concentrations, virtually all the filtered bicarbonate is reabsorbed.

The luminal surface of renal tubular cells is impermeable to bicarbonate and, therefore, direct reabsorption cannot occur. Within the renal tubular cells, carbonic acid is formed from carbon dioxide and water (Fig. 3.1). This otherwise rather slow reaction (see Equation 3.1) is catalysed in the kidneys by the enzyme carbonate dehydratase (carbonic anhydrase). The carbonic acid thus formed dissociates into hydrogen and bicarbonate ions. The bicarbonate ions pass across the basolateral borders of the cells into the interstitial fluid. The hydrogen ions are secreted across the luminal membrane in exchange for sodium ions, which accompany bicarbonate into the interstitial fluid (see Fig. 3.1). The formation of bicarbonate and hydrogen ions is promoted by their continuous removal and by the presence of carbonate dehydratase.

Figure 3.1 Reabsorption of filtered bicarbonate by renal tubular cells. Bicarbonate cannot be reabsorbed directly. Hydrogen and bicarbonate ions are generated in renal tubular cells and the hydrogen ions are secreted in exchange for sodium into the tubular lumen where they combine with filtered bicarbonate to form carbon dioxide and water. Bicarbonate ions diffuse with sodium from the tubular cells into the interstitial fluid and thence into the plasma.

In the tubular fluid, hydrogen ions combine with bicarbonate to form carbonic acid, most of which dissociates into carbon dioxide and water. Some of the carbon dioxide diffuses back into the renal tubular cells (and is converted via carbonic acid into bicarbonate and hydrogen ions), while the remainder is excreted in the urine. This whole process, which takes place primarily in the proximal convoluted tubules, effectively results in the reabsorption of filtered bicarbonate.

Although hydrogen ions are secreted into the tubular fluid during bicarbonate reabsorption, this does not represent net acid excretion. The formation of these hydrogen ions merely provides the means for the reabsorption of bicarbonate. Net acid excretion depends on the same reactions occurring in the renal tubular cells but, in addition, requires the presence of a suitable buffer system in the urine. This is because the minimum urinary pH that can be generated, 4.6, is equivalent to a hydrogen ion concentration of approximately 25 µmol/L. Given a normal urine volume of 1.5 L/24 h, free hydrogen ion excretion can account for less than a thousandth of the total amount that has to be excreted. The principal urinary buffer is phosphate. This is present in the glomerular filtrate, approximately 80% being in the form of the divalent anion, . This combines with hydrogen ions and is converted to :

(3.3)

At the minimum urinary pH, virtually all the phosphate is in the form. About 30–40 mmol of hydrogen ions are normally excreted in this way every 24 h.

Ammonia, produced by the deamination of glutamine in renal tubular cells, is also an important urinary buffer. The enzyme that catalyses this reaction, glutaminase, is induced in states of chronic acidosis, allowing increased ammonia production and hence increased hydrogen ion excretion via ammonium ions. Ammonia can readily diffuse across cell membranes, but ammonium ions, formed when ammonia buffers hydrogen ions (Equation 3.4), cannot. Passive reabsorption of ammonium ions is therefore prevented.

(3.4)

At normal intracellular hydrogen ion concentrations, most ammonia is present as ammonium ions. Diffusion of ammonia out of the cell disturbs the equilibrium, causing more ammonia to be formed. The simultaneous production of hydrogen ions would seem to negate the process. However, these ions are used up in gluconeogenesis, when they combine with glutamate formed by the deamination of glutamine. There may also be some shift of hepatic urea synthesis (a process that generates hydrogen ions) to glutamine synthesis (which consumes them). Urinary hydrogen ion excretion is summarized in Figure 3.2. Acidification of the urine takes place primarily in the distal parts of the distal convoluted tubules and in the collecting ducts, where an ATP-dependent H⁺-pump in the α-intercalated cells secretes hydrogen ions in exchange for potassium ions. In addition, sodium reabsorption by the principal cells creates an electrochemical gradient that engenders the secretion of potassium and hydrogen ions. Aldosterone facilitates hydrogen ion secretion directly by stimulating the H⁺-pump and indirectly through enhancing sodium reabsorption.

Figure 3.2 Renal hydrogen ion excretion. Hydrogen and bicarbonate ions are generated in renal tubular cells from carbon dioxide and water by the reversal of the buffering reaction. The hydrogen ions are excreted in the urine buffered by phosphate and ammonia, while the bicarbonate enters the ECF, replacing that which was consumed in buffering.

It will be apparent that hydrogen and bicarbonate ions are generated in equimolar amounts in renal tubular cells. This is essential for the reabsorption of filtered bicarbonate but also means that, when a hydrogen ion is excreted in the urine, a bicarbonate ion is produced and retained. This process effectively regenerates the bicarbonate ions consumed when hydrogen ions are buffered.

There is considerable secretion of both acid (by the stomach) and bicarbonate (by the pancreas and small intestine) into the gut, but these processes are normally in balance and in health do not contribute to net hydrogen ion excretion.

Transport of carbon dioxide

Carbon dioxide, produced by aerobic metabolism, diffuses out of cells and into the ECF. A small amount combines with water to form carbonic acid, thereby increasing the hydrogen ion concentration of the ECF.

In red blood cells, metabolism is anaerobic and little carbon dioxide is produced. Carbon dioxide thus diffuses into red cells down a concentration gradient and carbonic acid is formed, facilitated by carbonate dehydratase (Fig. 3.3). Haemoglobin buffers the hydrogen ions formed when the carbonic acid dissociates. Haemoglobin is a more powerful buffer when in the deoxygenated state and the proportion in this state increases during the passage of blood through capillary beds, as oxygen is lost to the tissues.

Figure 3.3 Transport of carbon dioxide in the blood. In capillary beds, carbon dioxide diffuses into red blood cells and combines with water to form carbonic acid; the reaction is catalysed by carbonate dehydratase. The carbonic acid dissociates to form hydrogen ions, which are buffered by haemoglobin, and bicarbonate, which diffuses out of the cell; chloride diffuses in to maintain electrochemical neutrality. In the alveoli, the process reverses; carbon dioxide is produced from bicarbonate and is excreted in the expired air.

The overall effect of this process is that carbon dioxide is converted to bicarbonate in red blood cells. This bicarbonate diffuses out of the red cells because a concentration gradient develops: electrochemical neutrality is maintained by inward diffusion of chloride ions (the chloride shift). In the lungs, the reverse process occurs: the oxygenation of haemoglobin reduces its buffering capacity, liberating hydrogen ions; these combine with bicarbonate to form carbon dioxide, which diffuses into the alveoli to be excreted in the expired air while bicarbonate diffuses into the cells from the plasma.

Most of the carbon dioxide in the blood is present in the form of bicarbonate. Dissolved carbon dioxide, carbonic acid and carbamino compounds (compounds of carbon dioxide and protein) account for less than 2.0 mmol/L in a total carbon dioxide concentration of approximately 26 mmol/L. The terms ‘bicarbonate’ and ‘total carbon dioxide’ are frequently used synonymously. They are not strictly the same but may be considered to be so for most practical clinical purposes. It is technically difficult to measure bicarbonate concentration alone: most analytical techniques for bicarbonate actually measure total carbon dioxide.

Clinical and Laboratory Assessment of Hydrogen Ion Status

As will be seen, many conditions are associated with abnormalities of blood hydrogen ion concentration and partial pressure of carbon dioxide (Pco₂). The clinical features associated with both these abnormalities and with an altered partial pressure of oxygen (Po₂) are shown in Figure 3.4.

Figure 3.4 Effects of increased or decreased values of Pco₂, Po₂ and [H⁺] in the blood. Paraesthesiae, dizziness, muscle cramps and tetany are related to a decrease in ionized calcium.

It is usual to measure hydrogen ion concentration [H⁺] in arterial blood anticoagulated with heparin. The arteriovenous difference for [H⁺] is small (<2 nmol/L), but the difference is significant for Pco₂ (approximately 1.1 kPa (8 mm Hg) higher in venous blood) and Po₂ (approximately 7.5 kPa (56 mm Hg) lower in venous blood).

It is vital that air is excluded from the syringe, both before and after drawing blood, and that, if possible, analysis is performed immediately. (In practice, the analysers are usually situated close to the patient, e.g. in intensive therapy units, rather than in a remote laboratory (see p. 5).) If the blood sample has to be transported, the syringe, capped with a blind hub and enclosed in a plastic bag, should be chilled in ice water. The analysers measure [H⁺] (strictly, activity), Pco₂ and Po₂ using specific electrodes; these measurements are together known colloquially as ‘blood gases’; they frequently measure other analytes in addition, for example, lactate, haemoglobin, sodium and potassium.

By the law of mass action, it follows from the equations describing the dissociation of carbonic acid (Equations 3.1 and 3.2) that [H⁺] is directly proportional to Pco₂ and inversely proportional to bicarbonate concentration; that is, it is determined by the ratio of Pco₂ to bicarbonate:

(3.5)

The constant, K, embraces the dissociation constants for Equations 3.1 and 3.2 and the solubility coefficient of carbon dioxide, which governs the concentration of the gas in solution at a given partial pressure. When [H⁺] is measured in nmol/L, bicarbonate in mmol/L and Pco₂ in kilopascals (kPa), the value of K is approximately 180 at 37°C; if Pco₂ is measured in mm Hg, the value of K is 24.

It follows that it is possible to calculate the bicarbonate concentration from the [H⁺] and Pco₂ alone. In blood gas analysers, the bicarbonate concentration is derived by calculation and not measured. It is not the same as the bicarbonate (strictly, total carbon dioxide) measured by most laboratory analysers. There has been considerable argument over whether it is valid to derive a bicarbonate concentration in this way, given that the values of the constants involved are based on observations in supposedly ideal solutions, which biological fluids are not. However, for most practical purposes the derivation is an acceptable one.

An appreciation of the relationship between [H⁺], bicarbonate concentration and Pco₂ is of fundamental importance to an understanding of the pathophysiology of hydrogen ion homoeostasis. It will be apparent from Equation 3.5 that the relationships between [H⁺] and Pco₂ and between bicarbonate concentration and Pco₂ are linear. These relationships have been quantified by measurements made in vivo, and it is therefore possible to predict the effect of a change in one variable on another, for example the effect of an acute rise in Pco₂ on [H⁺]. This information is an important aid in the interpretation of acid–base data.

The relationships between [H⁺], Pco₂ and bicarbonate concentration are plotted in Figure 3.5. This diagram may be useful as an aide-mémoire to the interpretation of acid–base data but should not be used as a substitute for a full understanding of the underlying principles.

Figure 3.5 The relationship between Pco₂, hydrogen ion concentration and bicarbonate concentration. The shaded areas represent the ranges of values found in simple disturbances of acid–base homoeostasis. Data falling outside these areas indicate mixed disturbances.

Many instruments for blood gas analysis generate other data such as standard bicarbonate and base excess. The definitions, uses and misuses of these terms are described later.

Disorders of Hydrogen Ion Homoeostasis

Four components can be identified in the pathophysiology of hydrogen ion disorders (acid–base disorders):

It is helpful to consider these separately, although in reality they may occur concurrently, albeit with different time courses.

Acid–base disorders are classified as either respiratory or non-respiratory (or metabolic) according to whether or not there is a primary (causative) change in Pco₂. The term acidosis signifies a tendency for the [H⁺] to be above normal, and alkalosis for it to be below normal.

Primary mixed acid–base disorders, that is, disorders of combined respiratory and non-respiratory origin, are common. However, the secondary, or compensatory, responses to a primary disorder of hydrogen ion homoeostasis may produce changes in the measured indices indistinguishable from those seen in primary mixed disorders.

Non-respiratory (metabolic) acidosis

The primary abnormality in non-respiratory acidosis is either increased production or decreased excretion of hydrogen ions other than from carbon dioxide. In some cases, both may contribute. Loss of bicarbonate from the body can also, indirectly, cause an acidosis. Causes of non-respiratory acidosis are given in Figure 3.6. Excess hydrogen ions are buffered by bicarbonate (Equation 3.2) and other buffers. The carbonic acid thus formed dissociates (Equation 3.1) and the carbon dioxide is lost in the expired air. This buffering limits the potential rise in hydrogen ion concentration, but at the expense of a reduction in bicarbonate concentration, which is a constant feature of non-respiratory acidosis.

Figure 3.6 Principal causes of non-respiratory (metabolic) acidosis. ^aAcidosis with normal anion gap.

Compensation is effected by hyperventilation, which increases the removal of carbon dioxide and lowers the Pco₂. The Pco₂/[HCO₃⁻] ratio falls, thus tending to reduce the [H⁺] (Equation 3.5). Hyperventilation is a direct result of the increased [H⁺] stimulating the respiratory centre. Respiratory compensation cannot completely normalize the [H⁺], as it is the high concentration itself that stimulates the compensatory hyperventilation. Furthermore, the increased work of the respiratory muscles produces carbon dioxide, thereby limiting the extent to which the Pco₂ can be lowered.

If the cause of the acidosis is not corrected, a new steady state may be attained, with a raised [H⁺], low bicarbonate and low Pco₂. In the steady state, the decrease in Pco₂ attributable to respiratory compensation is approximately 0.17 kPa (1.3 mm Hg) for each 1 mmol/L decrement in bicarbonate concentration. The extent to which compensation can take place will be limited if respiratory function is compromised. Even with normal respiratory function, it is exceptional for a Pco₂ of <1.5 kPa (11.3 mm Hg) to be recorded, however severe the non-respiratory acidosis.

In a healthy person, hyperventilation would produce a respiratory alkalosis. In general, the compensatory mechanism for any acid–base disturbance involves the generation of a second, opposing disturbance. In the case of a metabolic acidosis, compensation is through the generation of a respiratory alkalosis (although this only limits the severity of the acidosis: the patient does not become alkalotic). In a respiratory acidosis, compensation is through the generation of a metabolic alkalosis (see below).

If renal function is normal in a patient with non-respiratory acidosis, excess hydrogen ions can be excreted by the kidneys. However, in many cases there is impairment of renal function, although this may not be the primary cause of the acidosis.

The complete correction of a non-respiratory acidosis requires reversal of the underlying cause, for example rehydration and insulin for diabetic ketoacidosis (see Case history 11.2) and removal of salicylate in salicylate overdose. It is important to maintain adequate renal perfusion to maximize renal hydrogen ion excretion. The use of exogenous bicarbonate to buffer hydrogen ions is discussed below and on p. 193.

Increased production of hydrogen ions

This is the cause of the acidosis in ketoacidosis (diabetic, alcoholic), lactic acidosis and acidosis seen in poisoning, for example with salicylate and ethylene glycol.

Decreased excretion of hydrogen ions

Acidosis occurs in renal glomerular failure (see Case history 4.2), when the decreased glomerular filtration causes a reduction in the amount of sodium that is filtered and, therefore, available for exchange with hydrogen ions. The amount of phosphate filtered and available for buffering also decreases. Renal tubular acidoses are discussed in Chapter 4.