++
The mystique that envelopes the subject of acid–base balance makes it necessary to point out that the core of the problem is not “buffer base” or “fixed cation” or the like, but simply the maintenance of the H+ concentration of the ECF. The mechanisms regulating the composition of the ECF are particularly important as far as this specific ion is concerned, because the machinery of the cells is very sensitive to changes in H+ concentration. Intracellular H+ concentration, which can be measured by using microelectrodes, pH-sensitive fluorescent dyes, and phosphorus magnetic resonance, is distinct from extracellular pH and appears to be regulated by a variety of intracellular processes. However, it is sensitive to changes in ECF H+ concentration.
++
The pH notation is a useful means of expressing H+ concentrations in the body, because the H+ concentrations are very low relative to those of other cations. Thus, the normal Na+ concentration of arterial plasma that has been equilibrated with red blood cells is about 140 mEq/L, whereas the H+ concentration is 0.00004 mEq/L (Table 39–1). The pH, the negative logarithm of 0.00004, is therefore 7.4. Of course, a decrease in pH of 1 unit, for example, from 7.0 to 6.0, represents a 10-fold increase in H+ concentration. It is important to remember that the pH of blood is the pH of true plasma—plasma that has been in equilibrium with red cells—because the red cells contain hemoglobin, which is quantitatively one of the most important blood buffers (seeChapter 36).
++
++
The pH of the arterial plasma is normally 7.40 and that of venous plasma slightly lower. Technically, acidosis is present whenever the arterial pH is below 7.40, and alkalosis is present whenever it is above 7.40, although variations of up to 0.05 pH unit occur without untoward effects. The H+ concentrations in the ECF that are compatible with life cover an approximately 5-fold range, from 0.00002 mEq/L (pH 7.70) to0.0001 mEq/L (pH 7.00).
++
Amino acids are utilized in the liver for gluconeogenesis, leaving NH4+ and HCO3– as products from their amino and carboxyl groups (Figure 39–5). The NH4+ is incorporated into urea (see Chapter 28) and the protons that are formed are buffered intracellularly by HCO3–, so little NH4+ and HCO3– escape into the circulation. However, metabolism of sulfur-containing amino acids produces H2SO4, and metabolism of phosphorylated amino acids such as phosphoserine produces H3PO4. These strong acids enter the circulation and present a major H+ load to the buffers in the ECF. The H+ load from amino acid metabolism is normally about 50 mEq/d. The CO2 formed by metabolism in the tissues is in large part hydrated to H2CO3 (see Chapter 36), and the total H+ load from this source is over 12,500 mEq/d. However, most of the CO2 is excreted in the lungs, and only small quantities of the H+ remain to be excreted by the kidneys. Common sources of extra acid loads are strenuous exercise (lactic acid), diabetic ketosis (acetoacetic acid and β-hydroxybutyric acid), and ingestion of acidifying salts such as NH4Cl and CaCl2, which in effect add HCl to the body. A failure of diseased kidneys to excrete normal amounts of acid is also a cause of acidosis. Fruits are the main dietary source of alkali. They contain Na+ and K+ salts of weak organic acids, and the anions of these salts are metabolized to CO2, leaving NaHCO3 and KHCO3 in the body. NaHCO3 and other alkalinizing salts are sometimes ingested in large amounts, but a more common cause of alkalosis is loss of acid from the body as a result of vomiting of gastric juice rich in HCl. This is, of course, equivalent to adding alkali to the body.
++
++
Buffering is of key importance in maintaining H+ homeostasis. It is defined in Chapter 1 and discussed in Chapter 36 in the context of gas transport, with an emphasis on roles for proteins, hemoglobin, and the carbonic anhydrase system in the blood. Carbonic anhydrase is also found in high concentration in gastric acid–secreting cells (see Chapter 25) and in renal tubular cells (see Chapter 37). Carbonic anhydrase is a protein with a molecular weight of 30,000 that contains an atom of zinc in each molecule. It is inhibited by cyanide, azide, and sulfide. In vivo, buffering is, of course, not limited to the blood. The principal buffers in the blood, interstitial fluid, and intracellular fluid are listed in Table 39–2. The principal buffers in cerebrospinal fluid and urine are the bicarbonate and phosphate systems. In metabolic acidosis, only 15–20% of the acid load is buffered by the H2CO3–HCO3– system in the ECF, and most of the remainder is buffered in cells. In metabolic alkalosis, about 30–35% of the OH– load is buffered in cells, whereas in respiratory acidosis and alkalosis, almost all of the buffering is intracellular.
++
++
In animal cells, the principal regulators of intracellular pH are HCO3– transporters. Those characterized to date include the Cl–HCO3– exchanger AE1, three Na+–HCO3– cotransporters, and a K+–HCO3– cotransporter.
++
When a strong acid is added to the blood, the major buffer reactions are driven to the left. The blood levels of the three “buffer anions” Hb– (hemoglobin), Prot– (protein), and HCO3– consequently drop. The anions of the added acid are filtered into the renal tubules. They are accompanied (“covered”) by cations, particularly Na+, because electrochemical neutrality is maintained. By processes that have been discussed above, the tubules replace the Na+ with H+ and in so doing reabsorb equimolar amounts of Na+ and HCO3–, thus conserving the cations, eliminating the acid, and restoring the supply of buffer anions to normal. When CO2 is added to the blood, similar reactions occur, except that since it is H2CO3 that is formed, the plasma HCO3– rises rather than falls.
+++
RENAL COMPENSATION TORESPIRATORY ACIDOSIS &ALKALOSIS
++
As noted in Chapter 36, a rise in arterial PCO2 due to decreased ventilation causes respiratory acidosis and conversely, a decline in PCO2 causes respiratory alkalosis. The initial changes shown in Figure 35–7 are those that occur independently of any compensatory mechanism; that is, they are those of uncompensated respiratory acidosis or alkalosis. In either situation, changes are produced in the kidneys, which then tend to compensate for the acidosis or alkalosis, adjusting the pH toward normal.
++
HCO3– reabsorption in the renal tubules depends not only on the filtered load of HCO3–, which is the product of the glomerular filtration rate and the plasma HCO3– level, but also on the rate of H+ secretion by the renal tubular cells, since HCO3– is reabsorbed by exchange for H+. The rate of H+ secretion—and hence the rate of HCO3– reabsorption—is proportional to the arterial PCO2, probably because the more CO2 that is available to form H2CO3 in the tubular cells, the more H+ that can be secreted. Furthermore, when the PCO2 is high, the interior of most cells becomes more acidic. In respiratory acidosis, renal tubular H+ secretion is therefore increased, removing H+ from the body; and even though the plasma HCO3– is elevated, HCO3– reabsorption is increased, further raising the plasma HCO3–. This renal compensation for respiratory acidosis is shown graphically in the shift from acute to chronic respiratory acidosis in Figure 35–7. Cl– excretion is increased, and plasma Cl– falls as plasma HCO3– is increased. Conversely, in respiratory alkalosis, the low PCO2 hinders renal H+ secretion, HCO3– reabsorption is depressed, and HCO3– is excreted, further reducing the already low plasma HCO3– and lowering the pH toward normal.
++
When acids stronger than Hb and the other buffer acids are added to blood, metabolic acidosis is produced; and when the free H+ level falls as a result of addition of alkali or removal of acid, metabolic alkalosis results. Following the example from Chapter 35, if H2SO4 is added, the H+ is buffered and the Hb–, Prot–, and HCO3– levels in plasma drop. The H2CO3 formed is converted to H2O and CO2, and the CO2 is rapidly excreted via the lungs. This is the situation in uncompensated metabolic acidosis. Actually, the rise in plasma H+ stimulates respiration, so that the PCO2, instead of rising or remaining constant, is reduced. This respiratory compensation raises the pH even further. The renal compensatory mechanisms then bring about the excretion of the extra H+ and return the buffer systems to normal.
++
The anions that replace HCO3– in the plasma in metabolic acidosis are filtered, each with a cation (principally Na+), thus maintaining electrical neutrality. The renal tubular cells secrete H+ into the tubular fluid in exchange for Na+; and for each H+ secreted, one Na+ and one HCO3– are added to the blood. The limiting urinary pH of 4.5 would be reached rapidly and the total amount of H+ secreted would be small if no buffers were present in the urine to “tie up” H+. However, secreted H+ reacts with HCO3– to form CO2 and H2O (bicarbonate reabsorption); with HPO42– to form H2PO4–; and with NH3 to form NH4+. In this way, large amounts of H+ can be secreted, permitting correspondingly large amounts of HCO3– to be returned to (in the case of bicarbonate reabsorption) or added to the depleted body stores and large numbers of the cations to be reabsorbed. It is only when the acid load is very large that cations are lost with the anions, producing diuresis and depletion of body cation stores. In chronic acidosis, glutamine synthesis in the liver is increased, using some of the NH4+ that usually is converted to urea (Figure 39–5), and the glutamine provides the kidneys with an additional source of NH4+. NH3 secretion increases over a period of days (adaptation of NH3 secretion), further improving the renal compensation for acidosis. In addition, the metabolism of glutamine in the kidneys produces α-ketoglutarate, and this in turn is decarboxylated, producing HCO3–, which enters the bloodstream and helps buffer the acid load (Figure 39–5).
++
The overall reaction in blood when a strong acid such as H2SO4 is added is:
++
For each mole of H+ added, 1 mole of NaHCO3 is lost. The kidney in effect reverses the reaction:
++
and the H+ and SO42– are excreted. Of course, H2SO4 is not excreted as such, the H+ appearing in the urine as titratable acidity and NH4+.
++
In metabolic acidosis, the respiratory compensation tends to inhibit the renal response in the sense that the induced drop in Pco2 hinders acid secretion, but it also decreases the filtered load of HCO3– and so its net inhibitory effect is not great.
++
In metabolic alkalosis, the plasma HCO3– level and pH rise (Figure 39–6). The respiratory compensation is a decrease in ventilation produced by the decline in H+ concentration, and this elevates the Pco2. This brings the pH back toward normal while elevating the plasma HCO3– level still further. The magnitude of this compensation is limited by the carotid and aortic chemoreceptor mechanisms, which drive the respiratory center if any appreciable fall occurs in the arterial PO2. In metabolic alkalosis, more renal H+ secretion is expended in reabsorbing the increased filtered load of HCO3–; and if the HCO3– level in plasma exceeds 26–28 mEq/L, HCO3– appears in the urine. The rise in PCO2 inhibits the renal compensation by facilitating acid secretion, but its effect is relatively slight.
++
+++
THE SIGGAARD–ANDERSEN CURVE NOMOGRAM
++
Use of the Siggaard–Andersen curve nomogram (Figure 39–6) to plot the acid–base characteristics of arterial blood is helpful in clinical situations. This nomogram has Pco2 plotted on a log scale on the vertical axis and pH on the horizontal axis. Thus, any point to the left of a vertical line through pH 7.40 indicates acidosis, and any point to the right indicates alkalosis. The position of the point above or below the horizontal line through a Pco2 of 40 mm Hg defines the effective degree of hypoventilation or hyperventilation.
++
If a solution containing NaHCO3 and no buffers were equilibrated with gas mixtures containing various amounts of CO2, the pH and Pco2 values at equilibrium would fall along the dashed line on the left in Figure 39–6 or a line parallel to it. If buffers were present, the slope of the line would be greater; and the greater the buffering capacity of the solution, the steeper the line. For normal blood containing 15 g of hemoglobin/dL, the CO2 titration line passes through the 15-g/dL mark on the hemoglobin scale (on the underside of the upper curved scale) and the point where the Pco2 = 40 mm Hg and pH = 7.40 lines intersect, as shown in Figure 39–6. When the hemoglobin content of the blood is low, there is significant loss of buffering capacity, and the slope of the CO2 titration line diminishes. However, blood of course contains buffers in addition to hemoglobin, so that even the line drawn from the zero point on the hemoglobin scale through the normal Pco2–pH intercept is steeper than the curve for a solution containing no buffers.
++
For clinical use, arterial blood or arterialized capillary blood is drawn anaerobically and its pH measured. The pHs of the same blood after equilibration with each of two gas mixtures containing different known amounts of CO2 are also determined. The pH values at the known Pco2 levels are plotted and connected to provide the CO2 titration line for the blood sample. The pH of the blood sample before equilibration is plotted on this line, and the Pco2 of the sample is read off the vertical scale. The standard bicarbonate content of the sample is indicated by the point at which the CO2 titration line intersects the bicarbonate scale on the Pco2 = 40 mm Hg line. The standard bicarbonate is not the actual bicarbonate concentration of the sample but, rather, what the bicarbonate concentration would be after elimination of any respiratory component. It is a measure of the alkali reserve of the blood, except that it is measured by determining the pH rather than the total CO2 content of the sample after equilibration. Like the alkali reserve, it is an index of the degree of metabolic acidosis or alkalosis present.
++
Additional graduations on the upper curved scale of the nomogram (Figure 39–6) are provided for measuring buffer base content; the point where the CO2 calibration line of the arterial blood sample intersects this scale shows the mEq/L of buffer base in the sample. The buffer base is equal to the total number of buffer anions (principally Prot–, HCO3–, and Hb–) that can accept hydrogen ions in the blood. The normal value in an individual with 15 g of hemoglobin per deciliter of blood is 48 mEq/L.
++
The point at which the CO2 calibration line intersects the lower curved scale on the nomogram indicates the base excess. This value, which is positive in alkalosis and negative in acidosis, is the amount of acid or base that would restore 1 L of blood to normal acid–base composition at a Pco2 of 40 mm Hg. It should be noted that a base deficiency cannot be completely corrected simply by calculating the difference between the normal standard bicarbonate (24 mEq/L) and the actual standard bicarbonate and administering this amount of NaHCO3 per liter of blood; some of the added HCO3– is converted to CO2 and H2O, and the CO2 is lost in the lungs. The actual amount that must be added is roughly 1.2 times the standard bicarbonate deficit, but the lower curved scale on the nomogram, which has been developed empirically by analyzing many blood samples, is more accurate.
++
In treating acid–base disturbances, one must, of course, consider not only the blood but also all the body fluid compartments. The other fluid compartments have markedly different concentrations of buffers. It has been determined empirically that administration of an amount of acid (in alkalosis) or base (in acidosis) equal to 50% of the body weight in kilograms times the blood base excess per liter will correct the acid–base disturbance in the whole body. At least when the abnormality is severe, however, it is unwise to attempt such a large correction in a single step; instead, about half the indicated amount should be given and the arterial blood acid–base values determined again. The amount required for final correction can then be calculated and administered. It is also worth noting that, at least in lactic acidosis, NaHCO3 decreases cardiac output and lowers blood pressure, so it should be used with caution.