Page 1398 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 100: Acid-Base Balance 971

have hypoalbuminemia or hypophosphatemia, and it has been recom- they do suggest that the conventional wisdom regarding lactate as evi-
mended to correct the normal AG for these abnormalities. 10,13 The dence of tissue dysoxia is an oversimplification at best. Indeed, many
following formula can be used to estimate the expected “normal” AG investigators have begun to offer alternative interpretations of hyperlac-
for a given patient: tatemia in this setting, 25-29 including metabolic dysfunction from mito-
chondrial to enzymatic derangements, which can and do lead to lactic
AGc = corrected AG = 2 (albuming/dL) acidosis. In particular, pyruvate dehydrogenase (PDH), the enzyme
+ 0.5 (phosphate mg /dL) (100-8)
responsible for moving pyruvate into the Krebs cycle, is inhibited by endo-
30
Thus, for a patient with half the normal albumin and phosphate, toxin. Catecholamine use, especially epinephrine, also results in lactic
the AGc should be approximately 5 mEq/dL. If the measured AG is acidosis, presumably by stimulating cellular metabolism (eg, increased
10 mEq/dL, then there would be 5 mEq/dL of negative charge still unac- hepatic glycolysis), and may be a common source of lactic acidosis in the
counted for—perhaps attributable to lactate, ketoacid anions, or others. ICU. 31,32 Interestingly, this phenomenon does not appear to occur with
32
An alternative to using the traditional AG is to focus on SID. By either dobutamine or norepinephrine and does not appear to be related
definition, SID must be equal to and opposite of the negative charges to decreased tissue perfusion.
contributed by all the anions, including total CO . Normally, the plasma Although controversy exists as to the source and interpretation of lactic
2
SID is strongly positive (between 40 and 42 mEq/L in healthy humans). acidosis in critically ill patients, there is no question about the ability of
Since charge must be balanced in any solution (the principle of electri- lactate accumulation to produce acidemia. Lactate is a strong ion by virtue
cal neutrality), there must be negative charges to balance this positive of the fact that at a pH within the physiologic range it is almost completely
charge. Total CO and the weak acids (mainly albumin and phosphate) dissociated (the pK of lactate is 3.9; at a pH of 7.4, 3162 ions are dissociated
a
2
account for the vast majority of this negative charge. These charges are for every one that is not). Because the body can produce and dispose of
equal to the “buffer base” first mentioned by Singer and Hastings over lactate rapidly, it functions as one of the most dynamic components of the
half a century ago. Thus, under normal circumstances, SID should SID. Lactic acid therefore can produce significant acidemia. Virtually any-
14
equal buffer base. Although hydroxyl ion concentration [OH ] is where in the body, pH is above 6.0, and lactate behaves as a strong anion.
−
+
another negative charge, its value is small enough to ignore. Thus total Its generation decreases the SID and results in increased [H ].
the effective SID (SIDe). Alternatively, the apparent SID (SIDa) can be ■ KETOACIDOSIS
CO + AG = SID.
15,16
This estimate of SID, or buffer base, is termed
2
estimated by the equation: Another common cause of a metabolic acidosis with a positive AG or SIG
is ketoacidosis. Ketones are formed by β-oxidation of fatty acids, a pro-
SIDa = ([Na ] + [K ] + [Ca ] cess inhibited by insulin. In insulin-deficient states (eg, diabetes), ketone
2+
+
+
+ [Mg ]) − ([Cl ] + [lactate ]) (100-9) formation may increase rapidly. This is so because severely elevated
−
2+
−
blood glucose concentrations produce an osmotic diuresis, and this may
Normally, SIDa = SIDe = SID = buffer base. However, if there are lead to volume contraction. This state is associated with elevated cortisol
unmeasured strong ions (eg, sulfates or ketoacid anions), then SIDa will levels and catecholamine secretion, which further stimulate free fatty acid
be an inaccurate estimate of true SID, and if there are abnormal weak production. In addition, increased glucagon, relative to insulin, leads
33
ions (eg, proteins), then SIDe will be an inaccurate measure of true SID. to decreased malonyl coenzyme A and increased carnitine palmityl acyl
When SIDa and SIDe are not equal, their difference (SIDa − SIDe) is transferase, the combination of which increases ketogenesis.
termed the strong ion gap (SIG). The SIG is positive when unmeasured Ketone bodies include acetone, acetoacetate, and β-hydroxybutyrate.
anions exceed unmeasured cations, and the SIG is negative when Both acetoacetate and β-hydroxybutyrate are strong anions at physiologic
unmeasured cations exceed unmeasured anions. pH (pK = 3.8 and 4.8, respectively). Thus, like lactate, their presence
a
decreases the SID and increases the [H ]. Ketoacidosis may result from
+
POSITIvE-ANION-GAP (SIG) ACIDOSES diabetes (DKA) or alcohol (AKA). The diagnosis is established by mea-
■ LACTIC ACIDOSIS suring serum ketones. However, it is important to understand that the
nitroprusside reaction used for this measurement only measures acetone
In many forms of critical illness, lactate is the most important cause of a and acetoacetate, not β-hydroxybutyrate. The state of measured ketosis
metabolic acidosis. Lactate has been shown to correlate with outcome depends on the ratio of acetoacetate to β-hydroxybutyrate. This ratio is low
17
in patients with hemorrhagic and septic shock. Lactic acid tradition- when lactic acidosis coexists with ketoacidosis because the reduced redox
18
19
ally is viewed as the predominant source of metabolic acidosis occur- state of lactic acidosis favors production of β-hydroxybutyrate. In such
ring in sepsis. In this view, lactic acid is released primarily from the circumstances, the apparent level of ketosis is small relative to the amount
20
musculature and the gut as a consequence of tissue hypoxia. Moreover, of acidosis and the elevation of the AG. There is also a risk of confusion
the amount of lactate produced is felt to correlate with the total oxygen during treatment of ketoacidosis because ketones, as measured by the
debt, the magnitude of the hypoperfusion, and the severity of shock. nitroprusside reaction, may increase despite resolving acidosis. This occurs
17
In recent years, this view has been challenged by the observations as a result of the rapid clearance of β-hydroxybutyrate with improvement
that during sepsis, even with profound shock, resting muscle does not in acid-base balance and without change in the measured level of ketosis.
produce lactate. Indeed, studies by various investigators have shown Furthermore, ketones may even appear to increase as β-hydroxybutyrate is
that the musculature actually may consume lactate during endotox- converted to acetoacetate. Hence it is better to monitor success of therapy
emia. 21-23 Data concerning the gut are less clear. There is little question by pH and AG or SIG than by the assay of serum ketones.
that underperfused gut can release lactate; however, it does not appear The acidosis seen in AKA is usually less severe. The treatment consists
that the gut releases lactate during sepsis if its perfusion is maintained. of fluids and glucose rather than insulin. Indeed, insulin is contraindi-
34
35
Under such conditions, the mesentery is either neutral to or even takes cated because it may cause precipitous hypoglycemia. Thiamine must
up lactate. 21,22 Perfusion is likely to be a major determinant of mesen- also be given to avoid precipitating Wernicke encephalopathy.
gut lactate production could not be shown when flow was maintained ■ RENAL FAILURE
teric lactate metabolism. In a canine model of sepsis using endotoxin,
with dopexamine hydrochloride. 23 Although renal failure may produce a hyperchloremic metabolic acidosis,
It is interesting to note that studies in animals as well as humans have especially when chronic, the increase in sulfate and other acids frequently
shown that the lung may be a prominent source of lactate in the setting increases the AG and SIG. However, the increase is usually not large.
of acute lung injury. 21,24-26 While studies such as these do not address the Similarly, uncomplicated renal failure rarely produces severe acidosis
underlying pathophysiologic mechanisms of hyperlactatemia in sepsis, except when it is accompanied by high rates of acid generation, such as
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