Chapter 77. Acid-Base Balance

• The blood [H+] and pH are determined by the strong ion difference (SID), the PCO2, and the total concentration of weak acids, mostly consisting of phosphate and albumin.
• Both acidemia and alkalemia have potentially harmful physiologic effects, and the presence of either is related to mortality.
• Most acid-base derangements do not benefit from specific correction of the abnormal pH; instead, the intensivist should focus on detecting and treating the underlying condition.
• Acid-base disorders are easily characterized using a stepwise approach.
• Lactic acidosis is the most important acid-base abnormality in ICU patients. Inadequate tissue oxygenation underlies the lactic acidosis in some patients (acute hemorrhage, critical hypoxemia, cardiogenic shock) but probably does not in others (such as the resuscitated septic patient).

Acid-base balance and acid-base disorders are imperfect terms for the determining factors and disease processes that lead to a particular hydrogen ion concentration [H+] in the blood. The methodology used routinely to determine an acid-base disorder is accurate in defining the disturbance. This methodology does not, however, reveal the mechanisms that have led to a particular [H+] in blood. The components of blood that contribute to acid-base balance are

1. Water

2. Strong cations (Na+, Mg2 +, Ca2 +, K+) and strong anions (Cl−, lactate−)

3. Bicarbonate ion (HCO3−)

4. Weak acids and their conjugate bases (HA + A− = Atot) (Atot is the total independent variable, and HA + A− are dependent variables.)

5. Partial pressure of carbon dioxide (PCO2)

6. Carbonate ion (CO32−)

7. Hydroxyl ion (OH−)

8. Hydrogen ion (H+)

The difference between the strong cations and strong anions (the strong ion difference [SID]), PCO2, and the total amount of weak acids and their conjugate bases (Atot) are the only independent variables.1 All the other components are, by definition, dependent, including HCO3−, HA, A−, CO32−, OH−, and H+. Because the concentrations of each of these six variables are dependent on one or more of the independent variables, we must solve separate equilibrium equations for each. Water itself is minimally dissociated despite the importance of [H+] and can be considered a constant. The six equations are as follows:

Water dissociation:

Weak acid dissociation:

Weak acid conservation:

HCO3− formation:

CO32− formation:

Electrical neutrality:

K1 through K4 represent constants for the individual reactions. Now that we have six equations and six unknowns, we can arrange any unknown as a fourth-order polynomial and solve the equation. In acid-base balance, the dependent variable in question is [H+]. Stated less elegantly, there is a unique value for each of the six dependent variables once SID, PCO2, and Atot are known so that all the equations can be solved simultaneously.

The formula for bicarbonate formation in its most robust form is the familiar Henderson-Hasselbalch equation:

Since this equation is no more or less correct than any of the other five equations that must be solved simultaneously, there is nothing wrong with using it to determine an acid-base disorder. Indeed, the fact that all three values are readily available from a standard arterial blood gas determination explains the popularity of this equation.

By examining Eq. (77-7) it is possible to determine whether an acid-base disturbance is present and whether it is due to respiratory (PCO2) or metabolic derangements. One might assume, therefore, that pH is determined by the relationship between PCO2 and [HCO3−]. This presumption is false. Likewise, solving Eq. (77-2) for [H+] does not mean that [H+] is determined by the HA and A–. In truth, [H+] and thus pH are determined by PCO2, SID, and Atot. Since we define respiratory disorders by alterations in PCO2, metabolic disturbances are brought about by changes in SID and Atot. They are not caused by changes in [HCO3−], but rather, changes in [HCO3−] occur as a result of the disturbance.

As SID becomes less positive, more [H+] is released into the solution, and acidemia develops. As SID becomes more positive, more [H+] associates with [OH–], forming water, and alkalemia develops. By contrast, Atot, composed of weak acids, is acidifying. As Atot increases, the pH falls, and as Atot decreases, such as with hemodilution, the pH increases.

By definition, abnormalities in PCO2 are classified as respiratory disorders. SID (and possibly Atot) is manipulated by the human body to compensate for chronic respiratory disorders, thus maintaining pH within the normal range (7.35–7.45). SID decreases to compensate for a chronic respiratory alkalosis, and SID increases to compensate for a chronic respiratory acidosis. The physiologic determinants of PCO2 are straightforward:

where VCO2 is CO2 production and Va is alveolar ventilation. A change in PCO2 must be explained by one of these factors. Hypercarbia and hypocarbia usually can be explained easily at the bedside.

Even relative extremes of [H+] are remarkably well tolerated (e.g., pH 7.1–7.7), at least for the short term, in otherwise healthy individuals. However, some authors have even suggested that acidemia itself may be beneficial to critically ill patients.2 For example, since acidemia shifts the oxyhemoglobin curve to the right, there is better oxygen delivery under acidemic conditions. Unfortunately, this “benefit” is dubious because acidosis also reduces synthesis of 2,3-diphosphoglycerate (2,3-DPG), and thus chronically, acidosis does not appear to improve oxygen delivery. Acidosis may produce other salutary effects on the circulation that could result in benefit in certain clinical scenarios,2 but acidosis also produces numerous undesirable effects on various systems (Table 77-1), and we caution against “permissive acidosis.”

This is not to say that we believe that correcting an acid-base disorder is always appropriate. Indeed, the existing evidence does not support the use of sodium bicarbonate for the purpose of correcting the pH in most conditions of acute acidosis,3 and some animal experiments even suggest harm.4 However, supporting respiratory compensation when feasible and avoiding acidosis when possible seems a prudent course of action in most clinical scenarios. Frequently, when treating critically ill patients, it is easy to blur the lines between supportive measures and therapeutic interventions. Common forms of acidemia may be associated with significant mortality because of the disease processes that underlie them, not necessarily because of the actual [H+]. For instance, bowel infarction is lethal, and only surgical resection is curative. Treating the lactic acidosis without addressing the underlying cause of the lactic acidosis in this scenario is certain to fail. Dissecting out the effects of acidosis itself from the causes that underlie it is difficult in patients. However, acidosis itself has been shown to produce harm in animal models5–8—especially in models of sepsis, where decreased survival time and hypotension appear to be attributable to exogenous acid loading.7,8 Nonetheless, it has yet to be demonstrated that treating acidosis improves outcome.

To diagnose a disorder leading to a change in SID, an actual accounting of strong ions occurs. A decrease in SID may be brought about by the generation of organic strong anions (e.g., lactate and ketones) or the loss of strong cations paired with weak anions to balance charge. If the patient has diarrhea, he or she is losing [Na+] and [HCO3−]; therefore, the [Cl−] will increase relative to the [Na+], leading to a decrease in SID and, ultimately, acidosis.

The organs of the gastrointestinal tract are underappreciated regulators of acid-base balance. Their ability to manipulate SID complexly is a direct result of the fact that strong ions are handled differently in different portions of the gastrointestinal tract. Cl− is pumped into the stomach, reducing SID in the stomach and increasing the [H+] (decreasing the pH) and, at the same time, causing the alkaline tide in the blood (increasing SID) that occurs at the beginning of a meal when gastric acid secretion is maximal. The alkaline tide refers to the Cl−-depleted plasma that leaves the stomach. The elevated SID leads to a decrease in [H+] (increase in pH). Cl− is reabsorbed in the duodenum, and plasma [H+] or pH is restored. Given the combination of Cl− secretion into the stomach and Cl− reabsorption in the duodenum, a net balance occurs, and plasma [H+] or pH is not affected. However, if gastric secretions are removed from the patient by nasogastric (NG) suction or by vomiting, Cl− cannot be reabsorbed, and SID will increase. Increased SID will lead to a metabolic alkalosis.

The pancreas secretes fluid into the small intestine, which has a SID that is much higher than plasma and very low in [Cl−]. The Cl−-rich plasma leaving the pancreas counteracts the alkaline tide along with Cl− reabsorption in the duodenum. Large amounts of pancreatic fluid loss will lead to a decrease in plasma SID and an associated acidosis. At the other end of the gastrointestinal (GI) tract, in the large intestine, most of the Cl− already has been removed in the small intestine, so the only strong ions present are Na+ and K+. If large amounts of these strong ions are lost with diarrhea fluid, then the plasma SID will decrease, and acidosis will result. During ischemia to the intestinal tract, significant amounts of lactate can be produced. At physiologic pH, lactate acts as a strong anion and decreases SID, leading to a metabolic acidosis. There is some evidence that the gut may modulate systemic acidosis in experimental endotoxemia by removing anions from the plasma.9 However, the full capacity of the GI tract to effect acid-base balance is not known. The treatment of metabolic acidosis requires treatment of an underlying disease process and not, strictly speaking, of the acid-base disorder. If the patient developed a lactate acidosis following a seizure, this lactic acidosis would resolve rapidly once the liver metabolized the lactate. Indeed, treatment of acid-base disturbances can lead to severe overshoot alkalosis or acidosis.

Finally, the liver is perhaps the most important abdominal organ involved in the regulation of acid-base balance.10,11 Hepatic glutaminogenesis is important for systemic acid-base balance and is tightly controlled by mechanisms sensitive to plasma [H+] and is stimulated by acidosis.12 Nitrogen metabolism by the liver can produce urea, glutamine, or NH4+. Normally, the liver does not release more than a very small amount of NH4+ but incorporates this nitrogen into either urea or glutamine. However, the production of urea or glutamine has significantly different effects at the level of the kidney. This is so because glutamine is used by the kidney to generate NH4+ and facilitate the excretion of Cl−. Thus the production of glutamine can be seen as having an alkalinizing effect on plasma pH because of the way in which the kidney uses it. In humans, the liver is also the only organ than synthesizes albumin, the major component of Atot.

Manipulating [H+] in the blood is intellectually easy once one understands the importance of SID but certainly is not of proven benefit. When administered to patients, equimolar concentrations of Na+ and Cl− (such as in saline solutions) will increase the [Cl−] more rapidly than the [Na+] because [Na+] is normally much greater than [Cl−]. When this occurs, SID will decrease, and [H+] will increase. In a test tube, lactated Ringer's solution will behave just like saline because lactate is a strong ion. However, in humans, lactate metabolism is rapid even under conditions of relatively severe hepatic dysfunction. If the liver is functioning and can metabolize lactate, then the unbalanced Na+ will increase the SID and result in alkalemia. Conversely, if lactate-containing solutions are administered quickly (as in replacement fluid for hemofiltration) and hepatic function is impaired, acidosis will develop, just as in the case of saline loading, because SID is lowered.

Normal saline (0.9% NaCl) is often blamed for causing a “dilutional” acidosis, but all that is occurring is that [Na+] is relatively unchanged as the [Cl−] rises, leading to a decreased SID and hyperchloremic acidosis. Adding 75 mEq/L of [NaHCO3] to 0.45% saline (77 mEq/L Na+and 77 mEq/L Cl–) will create an isotonic solution that contains half the [Cl−] (a strong anion) with twice the [Na+] (strong cation). This solution has a higher SID than normal saline or lactated Ringer's solution and favors alkalemia. Mixing 150 mEq NaHCO3 in 1 L of sterile water increases the SID further and creates an even more potent alkalizing fluid. Again, it is worth emphasizing the need to treat the underlying disorder and not just “correct” the acid-basis disorder.

The anion gap (AG) was popularized over 30 years ago. Traditionally, it is calculated from the equation [(Na+) + (K+)] − [(Cl−) + (HCO3−)] K+ is often omitted because its plasma concentration is so tightly controlled that there is little variation. However, this is a mistake for two reasons. First, a 2- to 3-mEq difference in the AG may be clinically relevant in some scenarios, and second, techniques used to correct the AG for abnormalities in Atot require a full accounting of other ions. The difference in the gap is made up largely by albumin and, to a lesser extent, phosphate. Other anions, such as sulfate and lactate, normally contribute less than 2 mEq of negative charge, similar in fact to the amount of positive charge contributed by ionized calcium and ionized magnesium. Thus these ions tend to offset each other. Many medical textbooks still report a normal range for the AG of about 12 to 16 mEq (when K+ is considered). This value, however, is based on older assay methods that were less sensitive for Cl−; the expected AG using modern analyzers is closer to 8 to 10 mEq. However, many critically ill patients have hypoalbuminemia or hypophosphatemia, and it has been recommended to correct the normal AG for these abnormalities.10,13 The following formula can be used to estimate the expected “normal” AG for a given patient:

Thus, for a patient with half the normal albumin and phosphate, the AGc should be approximately 5 mEq/dL. If the measured AG is 10 mEq/dL, then there would be 5 mEq/dL of negative charge still unaccounted for—perhaps attributable to lactate, ketoacid anions, or others.

An alternative to using the traditional AG is to focus on SID. By definition, SID must be equal to and opposite of the negative charges contributed by all the anions, including total CO2. Normally, the plasma SID is strongly positive (between 40 and 42 mEq/L in healthy humans). Since charge must be balanced in any solution (the principle of electrical neutrality), there must be negative charges to balance this positive charge. Total CO2 and the weak acids (mainly albumin and phosphate) account for the vast majority of this negative charge. These charges are equal to the “buffer base” first mentioned by Singer and Hastings over half a century ago.14 Thus, under normal circumstances, SID should equal buffer base. Although hydroxyl ion concentration [OH−] is another negative charge, its value is small enough to ignore. Thus total CO2 + AG = SID.15,16 This estimate of SID, or buffer base, is termed the effective SID (SIDe). Alternatively, the apparent SID (SIDa) can be estimated by the equation

Normally, SIDa = SIDe = SID = buffer base. However, if there are unmeasured strong ions (e.g., sulfates or ketoacid anions), then SIDa will be an inaccurate estimate of true SID, and if there are abnormal weak ions (e.g., proteins), then SIDe will be an inaccurate measure of true SID. When SIDa and SIDe are not equal, their difference (SIDa – SIDe) is termed the strong ion gap (SIG). The SIG is positive when unmeasured anions exceed unmeasured cations, and the SIG is negative when unmeasured cations exceed unmeasured anions.

Lactic Acidosis

In many forms of critical illness, lactate is the most important cause of a metabolic acidosis.17 Lactate has been shown to correlate with outcome in patients with hemorrhagic18 and septic shock.19 Lactic acid traditionally is viewed as the predominant source of metabolic acidosis occurring in sepsis.20 In this view, lactic acid is released primarily from the musculature and the gut as a consequence of tissue hypoxia. Moreover, the amount of lactate produced is felt to correlate with the total oxygen debt, the magnitude of the hypoperfusion, and the severity of shock.17 In recent years this view has been challenged by the observations that during sepsis, even with profound shock, resting muscle does not produce lactate. Indeed, studies by various investigators have shown that the musculature actually may consume lactate during endotoxemia.21–23 Data concerning the gut are less clear. There is little question that underperfused gut can release lactate; however, it does not appear that the gut releases lactate during sepsis if its perfusion is maintained. Under such conditions, the mesentery is either neutral to or even takes up lactate.21,22 Perfusion is likely to be a major determinant of mesenteric lactate metabolism. In a canine model of sepsis using endotoxin, gut lactate production could not be shown when flow was maintained with dopexamine hydrochloride.23

It is interesting to note that studies in animals as well as humans have shown that the lung may be a prominent source of lactate in the setting of acute lung injury.21,24–26 While studies such as these do not address the underlying pathophysiologic mechanisms of hyperlactatemia in sepsis, they do suggest that the conventional wisdom regarding lactate as evidence of tissue dysoxia is an oversimplification at best. Indeed, many investigators have begun to offer alternative interpretations of hyperlactatemia in this setting,25–29 including metabolic dysfunction from mitochondrial to enzymatic derangements, which can and do lead to lactic acidosis. In particular, pyruvate dehydrogenase (PDH), the enzyme responsible for moving pyruvate into the Krebs cycle, is inhibited by endotoxin.30 Catecholamine use, especially epinephrine, also results in lactic acidosis, presumably by stimulating cellular metabolism (e.g., increased hepatic glycolysis), and may be a common source of lactic acidosis in the ICU.31,32 Interestingly, this phenomenon does not appear to occur with either dobutamine or norepinephrine32 and does not appear to be related to decreased tissue perfusion.

Although controversy exists as to the source and interpretation of lactic acidosis in critically ill patients, there is no question about the ability of lactate accumulation to produce acidemia. Lactate is a strong ion by virtue of the fact that at a pH within the physiologic range it is almost completely dissociated (i.e., the pKa of lactate is 3.9; at a pH of 7.4, 3162 ions are dissociated for every one that is not). Because the body can produce and dispose of lactate rapidly, it functions as one of the most dynamic components of the SID. Lactic acid therefore can produce significant acidemia. Virtually anywhere in the body, pH is above 6.0, and lactate behaves as a strong anion. Its generation decreases the SID and results in increased [H+].

Ketoacidosis

Another common cause of a metabolic acidosis with a positive AG or SIG is ketoacidosis. Ketones are formed by beta-oxidation of fatty acids, a process inhibited by insulin. In insulin-deficient states (e.g., diabetes), ketone formation may increase rapidly. This is so because severely elevated blood glucose concentrations produce an osmotic diuresis, and this may lead to volume contraction. This state is associated with elevated cortisol levels and catecholamine secretion, which further stimulate free fatty acid production.33 In addition, increased glucagon, relative to insulin, leads to decreased malonyl coenzyme A and increased carnitine palmityl acyl transferase, the combination of which increases ketogenesis.

Ketone bodies include acetone, acetoacetate, and β-hydroxybutyrate. Both acetoacetate and β-hydroxybutyrate are strong anions at physiologic pH (pKa = 3.8 and 4.8, respectively). Thus, like lactate, their presence decreases the SID and increases the [H+]. Ketoacidosis may result from diabetes (DKA) or alcohol (AKA). The diagnosis is established by measuring serum ketones. However, it is important to understand that the nitroprusside reaction used for this measurement only measures acetone and acetoacetate, not β-hydroxybutyrate. The state of measured ketosis depends on the ratio of acetoacetate to β-hydroxybutyrate. This ratio is low when lactic acidosis coexists with ketoacidosis because the reduced redox state of lactic acidosis favors production of β-hydroxybutyrate. In such circumstances, the apparent level of ketosis is small relative to the amount of acidosis and the elevation of the AG. There is also a risk of confusion during treatment of ketoacidosis because ketones, as measured by the nitroprusside reaction, may increase despite resolving acidosis. This occurs as a result of the rapid clearance of β-hydroxybutyrate with improvement in acid-base balance and without change in the measured level of ketosis. Furthermore, ketones may even appear to increase as β-hydroxybutyrate is converted to acetoacetate. Hence it is better to monitor success of therapy by pH and AG or SIG than by the assay of serum ketones.

The acidosis seen in AKA is usually less severe. The treatment consists of fluids and glucose rather than insulin.34 Indeed, insulin is contraindicated because it may cause precipitous hypoglycemia.35Thiamine also must be given to avoid precipitating Wernicke's encephalopathy.

Renal Failure

Although renal failure may produce a hyperchloremic metabolic acidosis, especially when chronic, the increase in sulfate and other acids frequently increases the AG and SIG. However, the increase is usually not large. Similarly, uncomplicated renal failure rarely produces severe acidosis except when it is accompanied by high rates of acid generation, such as from hypermetabolism.36 In all cases, the SID is decreased and is expected to remain so unless some therapy is provided. Hemodialysis will permit the removal of sulfate and other ions and allow normal Na+ and Cl− balance to be restored, thus returning the SID to normal (or near normal). However, patients not yet requiring dialysis and those who are between treatments are often given other therapies to increase the SID. NaHCO3 is used as long as the plasma [Na+] is not already elevated. Other options include Ca2+, which usually requires replacement anyway. Ca2+ replacement cannot increase the SID much given the rather narrow range of ionized Ca2+ (0.975 − 1.125 mmol/L). Even though Ca2+ is a divalent cation, it is unreasonable to expect much effect on the SID by administering Ca2+.

Poisons

Metabolic acidosis with an increased AG and SIG is a major feature of various types of drug and substance intoxications (Table 77-2; see also Chap. 102). Again, it is generally more important to recognize these disorders so that specific therapy can be provided than to treat the acid-base disorder itself.

Miscellaneous and Unknown

Table 77-2 lists several commonly and not so commonly recognized causes of positive AG metabolic acidosis. It is important to recognize that unexplained anions have been found commonly in the plasma of critically ill and injured patients. The etiology or even identity of these anions has not been established, nor has the clinical significance.

Hyperchloremic metabolic acidosis occurs as a result of either the increase in Cl− relative to strong cations, especially Na+, or the loss of cations with retention of Cl−. As seen in Fig. 77-1, these disorders can be separated by history and by examination of the urine [Cl−]. When acidosis occurs, the normal response by the kidney is to increase Cl− excretion. Failure to do so identifies the kidney as the source of acidosis. Extrarenal hyperchloremic acidoses occur as a result of exogenous Cl− loads (iatrogenic acidosis) or because strong cations (Na+ or K+) are lost from the lower gastrointestinal tract disproportionally to the loss of strong anions (Cl−).

Renal Tubular Acidosis

Examination of the urine and plasma electrolytes and pH and calculation of the urine SIDa allow one to correctly diagnose most cases of renal tubular acidosis (RTA)37 (see Fig. 77-1). However, caution must be exercised when the plasma pH is greater than 7.35 because this may turn off urine Cl− excretion. In such circumstances it may be necessary to infuse sodium sulfate or furosemide. These agents stimulate Cl− and K+ excretion and may be used to unmask the defect and to probe K+ secretory capacity.

The mechanisms of RTA are not well established. It is likely that much of the confusion has occurred as a result of attempting to understand the physiology from the point of view of regulating [H+] and [HCO3−]. However, as we have discussed, this is simply inconsistent with the principles of physical chemistry. The kidney does not excrete H+ any more as NH4+ than it does as H2O. The purpose of renal ammoniagenesis is to allow the excretion of Cl−, which balances the charge of NH4+. The defect in all types of RTA is the inability to excrete Cl− in proportion to Na+, although the reasons vary by type. Treatment is largely dependent on whether the kidney will respond to mineralocorticoid replacement or there is loss of Na+ that can be replaced as NaHCO3.

Classic distal (type I) RTA responds to NaHCO3 replacement, and generally 50 to 100 mEq/d is required. K+ defects are also common in this type of RTA, and K+ replacement is also required. A variant of the classic distal RTA is a hyperkalemic form, which is actually more common than the classic type. The central defect here appears to be impaired Na+ transport in the cortical collecting duct. These patients also respond to NaHCO3 replacement. Proximal (type II) RTA is characterized by both Na+ and K+ reabsorption defects. The disorder is uncommon and usually part of the Fanconi syndrome, where reabsorption of glucose, phosphate, urate, and amino acids is also impaired. Treatment of this disorder with NaHCO3 is ineffective because increased ion delivery merely results in increased excretion. Thiazide diuretics have been used to treat this disorder with varying success.

Type IV RTA is caused by aldosterone deficiency or resistance. This disorder is diagnosed by the high serum K+ and low urine pH (<5.5). Treatment is usually most effective if the cause can be removed. The most common causes are drugs such as nonsteroidal anti-inflammatory agents, heparin, or potassium-sparing diuretics. Occasionally, mineralocorticoid replacement is required.

Gastrointestinal Acidosis

Fluid secreted into the gut lumen contains higher amounts of Na+ than Cl−, similar to the differences in plasma. Extremely large losses of these fluids, particularly if volume is replaced with fluids containing equal amounts of Na+ and Cl−, will result in a decrease in the plasma [Na+] relative to [Cl−] and a decrease in the SID.

Iatrogenic Acidosis

Two of the most common causes of a hyperchloremic metabolic acidosis are iatrogenic, and both are due to administration of chloride. Modern parenteral nutrition formulas contain weak anions such as acetate in addition to Cl−, and the balance of each anion can be adjusted depending on the acid-base status of the patient. If sufficient amounts of weak anions are not provided, the plasma [Cl−] will increase, decreasing the SID and resulting in acidosis. As already discussed, administration of normal saline can cause a decrease in the SID and, subsequently, an acidosis.

Metabolic Alkalosis

Metabolic alkalosis occurs as a result of an increased SID. This may occur secondary to losses of anions (e.g., Cl− from the stomach) or increases in cations (rare). Metabolic alkaloses can be divided into those in which Cl− losses are temporary and can be effectively replaced (chloride-responsive) and those in which hormonal mechanisms produce ongoing losses that can, at best, be offset temporarily by Cl− administration (chloride-resistant) (Fig. 77-2). Similar to hyperchloremic acidosis, these disorders can be distinguished by examination of the urine [Cl−]. Although much more investigation has focused on acidosis, alkalosis appears to be associated with poor prognosis as well. In a prospective study, Anderson and Henrich38 looked at 409 patients with an arterial pH of greater than 7.48. Of these patients, 213 were medical and 196 were surgical. Overall, hospital mortality was 27.9% and increased as pH values rose, reaching 48.5% when the pH was greater than 7.60. While only 2% had pure metabolic alkalosis, patients at greatest risk were those with a mixed respiratory and metabolic alkalosis, having a mortality of 44.2%.

These disorders usually occur as a result of Cl− losses from the stomach, such as from vomiting or gastric drainage. The treatment involves lowering the SID, by giving NaCl (since serum [Cl−] will rise greater than serum [Na+]), KCl, or even HCl (which is most potent because it contains only strong anions). Saline plus KCl is usually the treatment of choice because volume depletion usually coexists with these disorders. Volume depletion, in turn, stimulates aldosterone secretion, which results in Na+ reabsorption and the loss of K+ and Cl−.

Diuretics and other forms of volume contraction produce metabolic alkalosis predominantly by stimulating aldosterone, as discussed earlier. However, diuretics also induce K+ and Cl− excretion directly, further complicating the problem and inducing metabolic alkalosis more rapidly.

These disorders (see Fig. 77-2) are characterized by an increased urine [Cl−] (>20 mmol/L) and are said to be chloride-resistant because of ongoing Cl− losses. Most commonly, this occurs as a result of increased mineralocorticoid activity. Treatment requires that the underlying disorder be addressed.

Rarely, an increased SID (and therefore metabolic alkalosis) occurs secondary to cation administration rather than anion depletion. Examples of these disorders include milk-alkali syndrome and intravenous administration of strong cations without strong anions. The latter occurs with massive blood transfusion or plasma exchange because Na+ is given with citrate (a weak anion) instead of Cl−. Similar results occur when parenteral nutrition formulations contain too much acetate and not enough Cl− to balance the Na+ load.

Pathophysiology of Respiratory Acid-Base Disorders

CO2 production by the body (at 220 mL/min) is equal to 15,000 mM/day of carbonic acid.39 This compares with less than 500 mM/day (depending on diet) for all nonrespiratory acids, which are managed by the kidney and gut. Pulmonary ventilation is adjusted by the respiratory center in response to signals from PCO2, pH and PO2, as well as some from exercise, anxiety, and wakefulness. The normal PCO2 of 40 mm Hg is attained by a precise match of alveolar ventilation to metabolic CO2 production. PCO2 changes in a “compensatory” ventilatory response to altered arterial pH produced by metabolic acidosis or alkalosis in predictable ways.

Diseases of Ventilatory Impairment

As for virtually all acid-base disorders, treatment begins with addressing the underlying disorder. Acute respiratory acidosis can be caused by CNS suppression, neuromuscular disease or impairment (e.g., myasthenia gravis, hypophosphatemia/ hypokalemia), severe mechanical derangements of the chest wall, or airway and parenchymal lung disease (e.g., asthma, acute respiratory distress syndrome [ARDS], etc.). This last category of conditions also produces primary hypoxia, not just alveolar hypoventilation. The two can be distinguished by the alveolar gas equation:

where R is the respiratory exchange coefficient (generally taken as 0.8), PiO2 is the inspired oxygen tension (room air is approximately 150 mm Hg), and PaO2 is the alveolar PO2. Thus, as PCO2 increases the PaO2 will decrease in a predictable fashion. If the PaO2 is significantly lower than the calculated PaO2, there is a defect in gas exchange.

Chronic respiratory acidosis is caused most often by chronic lung disease (e.g., chronic obstructive pulmonary disease [COPD]) or chest wall disease (e.g., kyphoscoliosis). Rarely, its cause is central hypoventilation or chronic neuromuscular disease.

Respiratory Alkalosis

Respiratory alkalosis may be the most frequently encountered acid-base disorder. It occurs in residents at high altitude and in a number of pathologic conditions, the most important of which include salicylate intoxication, early sepsis, hepatic failure, and hypoxic respiratory disorders. Respiratory alkalosis also occurs with pregnancy and with pain or anxiety. Hypocapnia appears to be a particularly bad prognostic indicator in patients with critical illness.40 As in acute respiratory acidosis, acute respiratory alkalosis results in a small change in [HCO3−], as dictated by the Henderson-Hasselbalch equation. If hypocapnia persists, the SID will begin to decrease as a result of renal Cl− reabsorption. After 2 to 3 days, the SID will assume a new, lower steady state.41 Severe alkalemia is unusual in respiratory alkalosis, and management therefore is directed to the underlying cause of the acid-base disorder. Typically, these mild acid-base changes are more important clinically as an alarm than as any threat they pose to the patient.