Normal plasma pH is maintained within the range of 7.35 to 7.45. Regulation of pH occurs by varying CO2 excretion from the lungs and by varying the rate of H+ excretion and HCO3− production in the kidney. In most clinical acid-base problems, the primary variables considered are pH, arterial Pco2, and [HCO3−]; the normal values are 7.40, 40 mm Hg, and 24 mmol/L, respectively.
Acids are molecules that release H+ in solution; bases are ions or molecules that can accept H+. Strong acids rapidly dissociate releasing large amounts of H+; weak acids partially dissociate releasing less H+. Strong bases react rapidly and strongly to neutralize H+; weak bases bind less H+. Most acids and bases encountered physiologically are “weak.” The [H+] in extracellular fluid is only 0.00004 mmol/L = 40 nmol/L. The logarithmic pH scale is used to express these very small values:
A 10-fold H+ concentration change represents a 1 unit pH change; a twofold H+ concentration change represents approximately a 0.3 unit pH change. The limits of extracellular fluid pH compatible with life are about 6.8 to 7.8.
Daily metabolism produces about 15,000 mmol of CO2 (volatile acid). Metabolism produces an additional 70 mmol of fixed acids (also called metabolic or nonvolatile acid), including organic acids and phosphoric and sulfuric acids. Defense against pH disturbance has three components:
Buffers provide limited but immediate limitations on pH change.
Changes in ventilation and CO2 excretion can occur over seconds to minutes to provide a rapid second line of defense against pH change.
Renal system H+ excretion and HCO3− synthesis is the final line of defense, acting over a period of hours to days to prevent sustained pH change.
A buffer is a substance that can reversibly bind H+. Buffering power expresses the effectiveness of a buffer system and is defined as “moles of strong acid added to 1 L of solution to reduce pH by 1 unit” or “moles of strong base added to 1 L of solution to increase pH by 1 unit.” The most important buffer in the extracellular fluid is the bicarbonate buffer system, created by the reaction between water and CO2 to form carbonic acid, which dissociates to H+ and HCO3−. The pH resulting from this reaction is calculated from the Henderson-Hasselbalch equation:
A healthy person in acid-base homeostasis has a plasma [HCO3−] of 24 mmol/L, an arterial Pco2 of 40 mm Hg, and a plasma pH of 7.4. Equation 6-9 correctly predicts this normal plasma pH:
The Henderson-Hasselbalch equation predicts that plasma pH is a simple function of the ratio of HCO3− to Paco2. If the pH increases, it could be due to an increase in HCO3− (metabolic alkalosis) or a decrease in arterial Pco2 (respiratory alkalosis). If the pH decreases, it could be due to a decrease in HCO3− (metabolic acidosis) or an increase in arterial Pco2 (respiratory acidosis).
Respiratory Contribution to Acid-base Balance
Normal pulmonary function balances CO2 excretion with metabolic CO2 production. Arterial Pco2 is monitored primarily by central chemoreceptors (see Chapter 5); alveolar ventilation increases to excrete more CO2 when the arterial Pco2 increases and decreases when the arterial Pco2 decreases. Pulmonary pathology may result in defects in respiratory performance or control that cause acid-base disturbances. Hypoventilation results in high arterial Pco2 (respiratory acidosis); hyperventilation results in low arterial Pco2 (respiratory alkalosis).
Changes in CO2 excretion can help to compensate for metabolic acid-base disturbances. Figure 6-37 shows that low plasma pH is a potent stimulus to increase alveolar ventilation, a response that is mediated through peripheral chemoreceptors (see Chapter 5). The resulting decrease in arterial Pco2 increases the plasma pH back toward normal. An increase in plasma pH causes a smaller change in alveolar ventilation than an equivalent decrease in plasma pH. This is necessary because correction for increased pH would require low ventilation rates, which compromise oxygenation of the blood.
Respiratory response to altered blood pH.
Renal Regulation of Acid-base Balance
The kidney has two major functions related to acid-base homeostasis:
Regulation of plasma [HCO3−] in the range of 22 mmol/L to 28 mmol/L. The kidney can excrete HCO3−, and it can generate new HCO3−. Under most circumstances, the renal venous blood contains more HCO3− than the renal arterial blood, reflecting continuous renal HCO3− production. The kidney generates just enough HCO3− to neutralize net acid production from metabolism.
Excretion of fixed metabolic acids. Acid in the urine is mainly in the form of ammonium ions (NH4+) and phosphoric acid (H2PO4−).
Recovery of filtered HCO3− and net acid excretion is usually required to maintain acid-base balance—almost all the filtered HCO3− must be recovered. Most HCO3− reabsorption occurs in the early proximal tubule via the mechanism shown in Figure 6-38. H+ is secreted into the lumen via the Na/H exchange, where it combines with filtered HCO3− to form carbonic acid. The enzyme carbonic anhydrase is anchored to the brush-border membrane of the proximal tubular cells, where it generates CO2 from carbonic acid. CO2 diffuses into the proximal tubule cells, where cytoplasmic carbonic anhydrase facilitates carbonic acid formation again. H+ and HCO3− are produced inside the cell from dissociation of carbonic acid. H+ is recycled for secretion into the lumen, and HCO3− enters extracellular fluid via a Na/HCO3− cotransporter in the basolateral membrane.
Mechanism of the proximal tubule HCO3− recovery. The pathway taken by filtered HCO3− is highlighted in yellow. The enzyme carbonic anhydrase (CA) catalyzes conversions of HCO3− to CO2 via carbonic acid. Inhibition of CA by the diuretic acetazolamide causes bicarbonaturia.
Bicarbonaturia (increased urinary HCO3− loss) is caused by carbonic anhydrase inhibitors such as acetazolamide, which disrupt tubular HCO3− reabsorption. Renal tubular acidosis type 2 (or proximal renal tubular acidosis) is a condition in which HCO3− resorption in the proximal tubules is impaired, resulting in urinary HCO3− loss in the setting of systemic acidosis.
Renal ammonia production accounts for approximately 75% of H+ excretion and occurs in the form of ammonium ions (NH4+). The proximal and distal tubules produce ammonia (NH3) from glutamate in the mitochondria. NH3 consumes free H+ and is converted to NH4+. Figure 6-39A shows that NH4+ is secreted as an alternate substrate to H+ via the Na/H exchangers in the luminal membrane. Deamination of glutamate also produces 2HCO3−, which are transported into the extracellular fluid across the basolateral membrane. The net effect of this process is excretion of acid in urine, plus generation of new HCO3− to replenish that consumed by buffering of metabolic acids in the extracellular fluid.
Mechanisms of H+ excretion and HCO3− generation. A. Renal ammoniagenesis results in the formation of NH4+ within cells because NH3 readily combines with H+ at physiologic pH. NH4+ is secreted via the Na/H exchangers. B. Titratable acid excretion as H2PO4− occurs when secreted H+ combines with filtered HPO42-. CA, carbonic anhydrase.
Titratable acid excretion is approximately 25% of H+ excretion and is in the form of phosphate ions. When H+ is secreted into the tubule lumen, it may be buffered by HPO42- to produce H2PO4−. Figure 6-39B shows that H+ secreted by the proximal tubule is derived from carbonic acid; HCO3− is generated concurrently and enters the extracellular fluid by cotransport with Na+ across the basolateral membrane. The net effect of this process is urinary excretion of acid, plus generation of new HCO3− for the extracellular fluid. Acid-excreted phosphate ions are measured as “titratable acids,” because titration of urine to the plasma pH of 7.4 does not include H+ associated with NH4+.
Acidification of urine occurs along the entire renal tubule. The proximal tubule secretes the most H+, but the proximal tubular fluid pH usually does not decrease below 6.8 due to the large amount of HCO3− and phosphate buffers present in the glomerular filtrate. The cells in the loop of Henle and the distal tubule and the principal cells in the cortical collecting duct all secrete H+ via the Na/H exchange. The α-intercalated cells in the collecting duct use primary active H+ secretion via the H+-ATPase and H/K-ATPase.
Na/H exchange in the distal tubule and the principal cells of the cortical collecting duct is stimulated by aldosterone. Hyperaldosteronism can be associated with metabolic alkalosis as a result of excessive H+ secretion into the urine.
In many situations, there is a reciprocal relationship between the secretion of H+ and K+ in the collecting duct. This contributes to a general relationship in which acidosis is associated with hyperkalemia and alkalosis is associated with hypokalemia. For example, if the collecting duct is secreting a large amount of H+ to combat a primary acidosis, then less K+ is excreted and hyperkalemia may develop. Renal defense against alkalosis includes reducing H+ secretion, which increases K+ excretion and may cause hypokalemia. There are exceptions to this general relationship; for example, increasing Na+ delivery to the collecting duct during treatment with loop or thiazide diuretics drives more secretion of both H+ and K+ and can result in both alkalosis and hypokalemia.
Figure 6-40 is an algorithm that is used to describe acid-base disturbances. Respiratory disorders are defined based on arterial Pco2:
Algorithm used to describe acid-base disorders. Paco2 defines the presence of respiratory disorders; plasma [HCO3−] defines the presence of metabolic disorders.
Metabolic disorders can be defined based on plasma HCO3− concentration:
Base excess is another way of defining metabolic acid-base disturbances. Base excess is a calculated value that estimates the size of a metabolic disturbance independent of Pco2. It is defined as the amount of strong acid (or base), in mmol/L, needed to titrate the pH of 100% oxygenated blood to 7.4 at 37°C and at a Pco2 of 40 mm Hg:
The most common clinical presentation is two opposing acid-base disorders in which a primary disorder is compensated by a secondary disorder. Compensation refers to responses that normalize plasma pH. Table 6-4 summarizes the four primary acid-base disorders and the expected pattern of physiologic compensation.
Metabolic acidosis can be caused by excess production or ingestion of fixed acids. Common examples include accumulation of ketoacids in diabetic patients or accumulation of lactic acid during hypoxia. Another common example is failure of the kidney to excrete metabolic acid in patients with chronic renal failure. Ingestion of poisons such as methanol and ethylene glycol or excessive ingestion of aspirin also results in the generation of excess fixed acids. Excess H+ is buffered by plasma HCO3−, causing a decrease in plasma [HCO3−], which defines metabolic acidosis. Elevated plasma H+ stimulates ventilation via peripheral chemoreceptors. Compensatory respiratory alkalosis is usually present, which reduces the arterial Pco2 and increases the pH toward normal. The resolution of metabolic acidosis without treatment requires increased renal generation of new HCO3− and increased H+ excretion via NH3 production and titratable acid excretion.
Metabolic acidosis can also be caused by the loss of HCO3−. The most common example is gastrointestinal fluid loss due to diarrhea; however, renal HCO3− losses are also possible and may occur, for example, in patients with renal tubular acidosis. Calculation of the serum anion gap is used to help differentiate between metabolic acidosis caused by the addition of acid or the loss of HCO3−. Anion gap is calculated by subtracting the sum of serum Cl− and HCO3− concentrations from serum Na+ concentration:
Extracellular fluid is an electroneutral solution in which the total number of anions and cations must be equal. Anion gap is normally in the range of 8–16 mEq/L, and indicates the concentration of unmeasured anions such as protein, phosphate, sulfate, and citrate. The addition of a metabolic acid consumes HCO3− and replaces it with a conjugate base anion (e.g., lactate ions in the case of lactic acid). This adds to the unmeasured anions, which increases the calculated anion gap. When metabolic acidosis is caused by a loss of HCO3−, there is an increase in Cl− ( hyperchloremic metabolic acidosis) rather than the addition of other unmeasured anions, and the anion gap is normal.
Calculating the anion gap is helpful in approaching the differential diagnosis of metabolic acidosis.
The most common causes of metabolic acidosis with an increased anion gap are listed below. (Note: MULEPAK can be a helpful mnemonic for remembering the causes of an anion gap metabolic acidosis.)
The most common causes of metabolic acidosis without an increased anion gap are:
A 16-year-old girl with diabetes mellitus was found unconscious and unresponsive. The results of arterial blood gas analysis showed the following abnormalities:
The acid-base disorder described in the algorithm in Figure 6-40 is metabolic acidosis (low [HCO3−]) with no respiratory component (normal arterial Pco2), which is producing a severe acidemia (low plasma pH). The anion gap is calculated as follows:
The patient has diabetic ketoacidosis, which produces an increased anion gap. A metabolic acidosis is present with no respiratory compensation, resulting in a severe life-threatening acidemia.
Metabolic alkalosis most commonly results from a loss of gastric H+ due to vomiting, and results in excess HCO3− in the blood. A net gain of HCO3− by the renal system can also occur; an example is “contraction alkalosis”, when HCO3− retention occurs as a side-effect of responses to low effective circulating volume. HCO3− retention occurs with low effective circulating volume by a combination of a low GFR, which reduces filtered HCO3− load, and avid proximal tubular reabsorption. Aldosterone levels are also increased when the effective circulating volume is low, causing increased H+ secretion by the distal nephron. Other causes of hyperaldosteronism may also cause metabolic alkalosis, including Cushing's disease (see Chapter 8).
Increased arterial blood pH (alkalemia) usually results in a degree of compensatory respiratory acidosis. Arterial Pco2 increases as a result of reduced alveolar ventilation and decreases the pH toward normal. Physiologic correction of metabolic alkalosis requires increased renal excretion of HCO3−, with reduced rates of acid excretion and HCO3− retention.
Metabolic alkalosis may be either chloride sensitive or chloride resistant. The presence of high plasma [HCO3−] in metabolic alkalosis “displaces” Cl− from the plasma. Patients with metabolic alkalosis are given intravenous saline solution (NaCl); if Cl− is retained in the plasma, the [HCO3−] is reduced and the metabolic alkalosis is Cl− sensitive. Examples of Cl−-sensitive metabolic alkalosis include contraction alkalosis and vomiting or gastric suction. Cl−-resistant metabolic alkalosis occurs if urinary Cl− excretion is persistently large; this occurs, for example, during active use of loop or thiazide diuretics or in tubular NaCl reabsorption disorders such as Bartter's or Gitelman's syndromes.
A 2-year-old child who is lethargic and dehydrated has a 3-day history of vomiting. The results of arterial blood gas analysis show the following abnormalities:
The acid-base disorder described in the algorithm in Figure 6-40 is metabolic alkalosis (high [HCO3−]) with no respiratory component (normal arterial Pco2), which is producing an alkalemia (high plasma pH). Treatment of the patient with saline infusion and an antiemetic agent will restore acid-base homeostasis.
Metabolic alkalosis in this child was caused by a loss of HCl in gastric fluids. The alkalosis was Cl− sensitive because fluid loss was stopped and the renal system was able to retain Cl− and excrete HCO3−.
Respiratory acidosis is caused by inadequate alveolar ventilation that results in CO2 retention. Inadequate ventilation may result from neuromuscular disorders, airway obstruction, or ingestion of agents that suppress breathing (e.g., narcotics). An increase in arterial Pco2 defines respiratory acidosis, which increases plasma [HCO3−] and [H+] through the Henderson-Hasselbalch equilibrium reaction. If respiratory acidosis occurs acutely, there is inadequate time for renal compensation. In chronic respiratory acidosis, the renal system normalizes the pH by excreting more acid and producing more HCO3−, which is added to extracellular fluid.
A 24-year-old man who is a known heroin addict was found unresponsive with a hypodermic needle in his arm. The results of arterial blood gas analysis showed the following abnormalities:
Po2 = 50 mm Hg (normal = 80–100 mm Hg)
Pco2 = 80 mm Hg
[HCO3−] = 23 mEq/L (normal = 22–28 mEq/L)
pH = 7.08 (normal = 7.35–7.45)
The acid-base disorder described in the algorithm in Figure 6-40 is respiratory acidosis (high arterial Pco2) with no metabolic component (normal [HCO3−]), which is producing a severe acidemia (low plasma pH).
The patient overdosed on a narcotic that caused respiratory depression, alveolar hypoventilation, and respiratory acidosis.
Respiratory alkalosis is caused by excessive alveolar ventilation, resulting in greater CO2 loss than production. Increased ventilation is most commonly a response to hypoxemia (e.g., ascent to high altitude; pulmonary embolism); another common cause is psychogenic hyperventilation. A low arterial Pco2 decreases the plasma [HCO3−] and [H+]. If respiratory alkalosis occurs acutely, there is no time for renal compensation. In chronic respiratory alkalosis, the renal system normalizes the pH by excreting less acid and producing less “new” bicarbonate.
A 56-year-old man suffered a panic attack while awaiting surgery. The results of arterial blood gas analysis showed the following abnormalities:
Po2 = 112 mm Hg (normal 80–100 mm Hg)
Pco2 = 24 mm Hg
[HCO3−] = 23 mEq/L (normal = 22–28 mEq/L)
pH = 7.60 (normal = 7.35–7.45)
The acid-base disorder described in the algorithm in Figure 6-40 is respiratory alkalosis (low arterial Pco2) with no metabolic component (normal plasma [HCO3−]), which is producing an alkalemia (high plasma pH).
The patient's panic attack resulted in acute hyperventilation and respiratory alkalosis. The acid-base abnormality will be readily corrected when breathing returns to normal.
Compensation of Primary Acid-Base Disorders
Compensation refers to responses that normalize plasma pH. Figure 6-41 illustrates compensatory responses and includes the expected size of changes in [HCO3−] or arterial Pco2. Compensation usually is not complete, which allows the primary acid-base disorder to be recognized as the disorder that is consistent with plasma pH. For example, if both alkalosis and acidosis are present and the pH is acidic, the acidosis must be considered the primary disorder, partially compensated by the alkalosis.
Compensatory acid-base changes. Primary acid-base disorders are usually consistent with plasma pH unless there is complete compensation. The expected degree of compensation for each primary disorder is shown.
Figure 6-41 also indicates expected changes in the arterial Pco2 and [HCO3−] during acute and chronic compensation. When [H+], [HCO3−], and arterial Pco2 differ from the expected compensatory range, the patient has a complex acid-base disorder. This can arise if more than one acid-base disturbance is present with independent causes such as a trauma patient in shock, and respiratory failure can then result in primary lactic acidosis and a primary respiratory acidosis, or it can occur from prior clinical interventions such as intravenous infusion with fluids containing buffers.
Excessive aspirin ingestion causes a mixed acid-base disorder. Aspirin uncouples oxidative phosphorylation, resulting in a primary metabolic lactic acidosis. Additionally, the direct effects of aspirin on the respiratory centers in the medulla cause the central chemoreceptors to be more sensitive to arterial Pco2 levels, which results in a primary respiratory alkalosis.
A 42-year-old man in chronic renal failure is being treated with hemodialysis. The results of arterial blood gas analysis showed the following abnormalities:
The acid-base disorder described in the algorithm in Figure 6-40 is metabolic acidosis (low [HCO3−]) with a respiratory alkalosis (decreased arterial Pco2) and a normal pH.
The primary acid-base disorder is a chronic metabolic acidosis produced by renal failure and loss of urinary H+ excretion. The expected respiratory compensation, as described in Figure 6-41, is approximately a 1.3-mm Hg decrease in arterial Pco2 for every 1 mEq/L decrease in [HCO3−]. In this case, [HCO3−] is 24–15 = 9 mEq/L below normal. The expected decrease in arterial Pco2 is 9 × 1.3 = 11.7, which corresponds with the observed data (28 mm Hg is 12 mm Hg less than a normal average arterial Pco2 of 40). The respiratory compensation is complete because pH is in the normal range. Note: this is not a primary chronic respiratory alkalosis compensated by metabolic acidosis because the plasma pH is 7.35 and compensation never overshoots the normal pH of 7.40. The same conclusion is indicated by the observation that the decrease in plasma [HCO3−] in this patient differs significantly from that expected for compensation of a chronic respiratory alkalosis. An arterial Pco2 of 28 mm Hg is 40–28 = 12 mm Hg less than normal, giving an expected decrease in [HCO3−] of only 4–5 mEq/L (Figure 6-41), whereas the actual decrease in [HCO3−] is 9 mEq/L.