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+].
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.
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+.
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.
Table 77–2. Causes of an Increased Ag (Na+-Cl−-Hco3−) ||Download (.pdf)
Table 77–2. Causes of an Increased Ag (Na+-Cl−-Hco3−)
| Change in AG (usually small AG)|
| Ethylene glycol|
|Sodium with weak anions|
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.