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CHAPTER 114
Pathophysiology of
Hyperlactatemia
Barry A. Mizock
OBJECTIVES
This chapter will:
1. Discuss the major factors that modulate lactate produc-
tion and utilization during critical illness.
2. Review acid-base aspects of lactic acidosis (LA).
Lactate has traditionally been viewed as a toxic metabolic
byproduct of excessive anaerobic glycolysis. This view
in turn has engendered therapeutic approaches to hyper-
lactatemia directed at enhancing lactate removal (e.g.,
dialysis, dichloroacetate). However, this view has been
challenged, and lactate is now recognized to play an
important role in maintaining cellular bioenergetics. The
pathogenesis of acidosis in hyperlactatemic states is also
controversial.
PATHOPHYSIOLOGY
An increase in blood lactate ultimately reflects an imbal-
ance between production and utilization. Lactate may be
viewed as a metabolic “dead end,” because its generation
and removal both require transition through pyruvate as
catalyzed by lactate dehydrogenase (LDH). Any condition
raising the concentration of pyruvate further enhances
lactate production by virtue of mass action1,2—that is,
greater availability of pyruvate augments lactate produc-
tion without altering the kinetic rates between substrates.
All tissues produce lactate, but skeletal muscle, because
of its large mass, has the greatest potential.2 The most
important determinant of pyruvate (and lactate) produc-
tion is glycolytic flux.1-3 Pyruvate production may also be
increased by transamination of alanine to pyruvate.4 This
mechanism plays a significant role in enhancing lactate
production during sepsis.5 The major factors that increase
glycolytic flux during critical illness are (1) a decrease in
the tissue phosphorylation state, (2) hormones (especially
epinephrine), (3) inflammatory cytokines (e.g., tumor
necrosis factor [TNF]), and (4) alkalemia (Fig. 114-1). The
phosphorylation state is expressed by the following
ratio:
ADP + ATP
AMP + ADP + ATP
where ADP is adenosine diphosphate. The phosphoryla-
tion state may be reduced by either a decrease in synthesis
of adenosine triphosphate (ATP) (e.g., secondary to tissue
hypoperfusion) or an increase in energy demand.
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Chapter 114 / Pathophysiology of Hyperlactatemia 597
It had previously been thought that LA during shock
resulted from increased “anaerobic” glycolysis consequent
to global oxygen delivery below the critical oxygen deliv-
ery threshold. Connett and associates6 proposed that the
term dysoxia be used to describe conditions in which
cytochrome turnover is limited by oxygen delivery.
However, the clinical significance of a dysoxic stimulus
for lactate production is questionable, given the results of
a study finding that the critical delivery threshold in septic
and nonseptic humans was approximately 4 mL/kg/min,
a value 50% lower than previously thought and that would
be very uncommon in patients who were actively treated.7
In this context, hyperlactatemia can be viewed as an unre-
liable indicator of dysoxia.
According to Connett and associates,6 the state of tissue
oxygenation in the majority of patients with shock is best
described by the term adapted cell hypoxia. In this physi-
ological state, tissue oxygenation is less than that in the
absence of stress but sufficient to maintain oxygen and
ATP flux because of adaptive changes in cellular metabo-
lism. These changes can be briefly summarized. A drop in
the phosphorylation state enhances aerobic glycolysis in
skeletal muscle by stimulating the rate-limiting enzyme
phosphofructokinase. This stimulus in turn raises the con-
centration of lactate in the cytosol. Lactate is then “shut-
tled” into the mitochondria, where it supports ATP
synthesis by (1) supplying reducing equivalents for the
respiratory chain and (2) converting to pyruvate by means
of mitochondrial LDH, with subsequent oxidation. Aerobic
formation of lactate is thus a mechanism by which the
cytosol and mitochondria interact to maintain adequate
oxidative synthesis of ATP in skeletal muscle.8 Evidence
supporting the presence of a lactate shuttle in cardiac
muscle and liver has also been reported.9 As stated by
Leverve,10 “hyperlactatemia in patients with circulatory
compromise may be best viewed as a sentinel that signals
the upper limit for metabolic adaptation that is not neces-
sarily linked to inadequate oxygen delivery.”
Lactate production in skeletal muscle may also be
enhanced by hormones (e.g., epinephrine, insulin). James
and colleagues11 observed that in septic or hemorrhagic
animal models, lactate production in muscle was mark-
edly increased by virtue of a β2 -adrenergic receptor–medi-
ated increase in activity of Na+-K+ membrane pumps.11 The
resultant activation of Na+,K+-ATPase generated ADP,
which in turn augmented aerobic glycolytic flux. This
mechanism has been confirmed in humans with septic
shock.12 Inflammatory cytokines (e.g., tumor necrosis
factor) promote an increase in lactate production by stimu-
lating glucose uptake and glycolytic flux in tissue macro-
phages.2,13 This mechanism is important in the pathogenesis
of hyperlactatemia accompanying systemic inflammatory
states. Alkalemia enhances glycolysis through stimulation
of phosphofructokinase; however, the resultant increase in
blood lactate is generally mild.
598 Section 7 / Acid-Base Problems
Cytokines
(TNF, IL-1)
Alkalosis
+
Hormones
Glucose + (epinephrine,
+ insulin)
Glycolysis
+ Phosphorylation
Alanine Pyruvate Lactate
LDH
Gluconeogenesis Oxidation
Glucose
CO2 ⫹ H2O
The liver is the major organ of lactate clearance, metabo-
lizing approximately 40% to 50% of daily lactate produc-
tion. Uptake (and egress) of lactate in liver and other
organs occurs as the consequence of facilitated transport
by a family of monocarboxylate transporters.14 This process
is saturable and involves cotransport of H+.14 Lactate is
metabolized in liver through oxidation and gluconeogen-
esis; the relative importance of these processes varies
according to the underlying physiological state. Gluconeo-
genesis appears to predominate during health, whereas
oxidation assumes a more important role in the setting of
critical illness. The liver has substantial functional reserve,
and hepatic dysfunction per se does not generally result
in significant hyperlactatemia unless concomitant factors
increase lactate production. In addition, other organs also
participate in the metabolism of lactate. A human study
performed during the anhepatic phase of liver transplanta-
tion showed that the steady-state concentration of lactate
in blood increased by only 1 mm/L after the liver was
removed.15 The kidney metabolizes lactate through oxida-
tion and gluconeogenesis. An animal study indicated that
approximately 30% of infused lactate was removed by the
kidneys.16 The relative contributions of oxidation and
gluconeogenesis are influenced by physiological state and
pH. Acidosis decreases renal lactate oxidation but increases
its conversion to glucose. Hypoglycemia enhances renal
gluconeogenesis from lactate (presumably mediated by
epinephrine). Although lactate is freely filtered by the
glomerulus, more than 95% is reabsorbed. Urinary loss of
lactate may occur during severe hyperlactatemia, but the
total amount is relatively small (≥2% of total lactate
removal).17 The heart takes up lactate for oxidation, espe-
cially during hyperlactatemia. Oxidation of lactate may
satisfy up to 60% of myocardial energy needs and, because
it may be directly oxidized, is a more efficient energy
source than glucose.9 Lactate has a positive inotropic
effect, and removal of lactate via dichloroacetate has been
shown to reduce cardiac performance.18 Wounds have also
been shown to oxidize lactate in preference to glucose.19
In summary, critical illness is commonly accompanied
by enhanced glycolytic flux and lactate production. An
increase in blood lactate in this setting is best viewed as
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state
FIGURE 114-1. Production and utilization of
lactate. IL-1, interleukin-1; LDH, lactate dehy-
drogenase; TNF, tumor necrosis factor.
the manifestation of an adaptive stress response rather
than as a reflection of cellular dysoxia.
ACID-BASE ASPECTS OF
HYPERLACTATEMIA
The mechanism by which acidosis accompanies increased
glycolytic production of lactate is controversial. In 1978,
Zilva20 proposed that anaerobic glycolysis was not acidify-
ing20; that is, that glycolytic flux generates lactate, ATP,
and water but does not directly produce lactic acid. This
researcher postulated that the acidosis accompanying
hyperlactatemia occurred as the consequence of increased
H+ production resulting from unreversed cytoplasmic ATP
hydrolysis, as follows:
ATP → ADP + P + H +
In this view, a decrease in oxidative regeneration of ATP
consequent to tissue hypoperfusion results in an accumu-
lation of H+ and a fall in pH. Conversely, in the setting of
maintained oxidative metabolism, H+ is buffered when
ATP is reconstituted (providing a potential explanation for
the occurrence of hyperlactatemia in the absence of acido-
sis). However, Bellomo and Ronco21 questioned the concept
of unreversed ATP hydrolysis. In reality, ATP is converted
to ADP and orthophosphate (a very weak acid; pKa = 6.8).
If unreversed ATP hydrolysis were occurring, one would
also expect to see increased plasma phosphate, which is
not the case. In addition, severe septic shock would result
in profound ATP depletion, which has not been docu-
mented.22 Finally, the rise in acidity would be small
because the total amount of ATP in the body is less than
0.1 mol. A more likely explanation is provided by Stew-
art’s physicochemical theory of acid-base.23 In this view,
an increase in concentration of a strong anion such as
lactate results in a relative excess in anionic charge in the
blood. Electroneutrality is maintained by an increase in
[H+] consequent to enhanced dissociation of water, which
in turn promotes a fall in pH (see Chapter 111).
 Chapter 115 / Impact of Acid-Base Disorders on Different Organ Systems
Although severe hyperlactatemia (e.g., serum lactate
> 10 mM/L) is generally accompanied by acidemia, the
correlation between lactate and pH may not be tight with
less severe hyperlactatemia. Critically ill patients with
hypermetabolic stress (e.g., sepsis, burn, trauma) com-
monly display a modest elevation in lactate (e.g., serum
lactate 2-5 mM/L), which can occur in the absence of aci-
demia. The term stress hyperlactatemia has been proposed
to describe this state.24 As described previously, it was
postulated that greater lactate production is not necessar-
ily acidifying provided that oxidative metabolism is main-
tained, because H+ ions are consumed when ATP is regen-
erated. However, it is more plausible that a normal pH is
preserved because of intracellular buffering of H+ or, more
likely, as the consequence of an intracellular shift of chlo-
ride, thereby maintaining the strong ion difference.25 In
addition, increased production of unmeasured cations has
been described during critical illness and could also serve
to counterbalance excess anionic charge.26 It is therefore
unlikely that the lack of acidosis during hyperlactatemic
stress reflects a distinct pathogenesis.27
CONCLUSION
All tissues produce lactate, but skeletal muscle has the
greatest capacity to increase lactate in the blood. Hyper-
lactatemia results from enhanced aerobic glycolytic flux as
the consequence of a decrease in the phosphorylation state
and/or a β2-adrenergic receptor–mediated increase in
membrane pump activity. Lactate is an important meta-
bolic intermediate that helps maintain mitochondrial ATP
production during critical illness. Significant disturbances
in the bioenergetic state are signaled by an increase in
lactate in the blood. Lactate can therefore be viewed as a
sentinel that monitors cellular energy charge in muscle.
The presence of hyperlactatemia is an important indicator
of a potentially serious disorder and should prompt further
evaluation by the clinician.
CHAPTER 115
Impact of Acid-Base Disorders on
Different Organ Systems
Kyle J. Gunnerson
OBJECTIVES
This chapter will:
1. Describe the unique organ system effects of different
acid-base disorders.
2. Discuss the effects of hypercapnia with potential use of
CO2 as a therapeutic strategy in acute respiratory dis-
tress syndrome and ischemic reperfusion injury.
3. Emphasize that metabolic acidosis affects virtually all
organ systems and different etiologies of metabolic
acidosis have different effects.
4. Explain that intracellular pH appears to be the major
force affecting cellular and organ function.
5. Explain that the role of extracellular pH on organ func-
tion usually depends on how it affects intracellular
pH.
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599
Key Points
1. An increase in blood lactate level has poor speci-
ficity as an indicator of tissue dysoxia.
2. Increased lactate production during circulatory
shock results from enhanced aerobic glycolysis in
skeletal muscle secondary to a β2-adrenergic
receptor–mediated stimulation of membrane Na+-
K+ pumps.
3. Lactate production by tissue macrophages also
plays a significant role in the pathogenesis of
hyperlactatemia in patients with a systemic in-
flammatory response (e.g., sepsis, burn, trauma).
4. Acidosis accompanying hyperlactatemia is not
the result of unreversed hydrolysis of adenosine
triphosphate. It is best explained by the physico-
chemical theory of acid-base balance.
Key References
6. Connett RJ, Honig CR, Gayeski TEJ, Brooks GA: Defining
hypoxia: A systems view of VO2, glycolysis, energetics, and
intracellular PO2. J Appl Physiol 1990;68:833-842.
9. Brooks GA, Dubouchaud H, Brown M, et al: Role of mito-
chondrial lactate dehydrogenase and lactate oxidation in
the intracellular lactate shuttle. Proc Nat Acad Sci U S A
1999;96:1129-1134.
10. Leverve XM: Lactic acidosis: A new insight? Minerva Anes-
tesiol 1999;65:205-209.
11. James JH, Luchette FA, McCarter FD, Fischer JE: Lactate is an
unreliable indicator of tissue hypoxia in injury or sepsis.
Lancet 1999;354:505-508.
12. Levy B, Gibot S, Franck P, et al: Relation between muscle
Na+K+ ATPase activity and raised lactate concentrations in
septic shock: A prospective study. Lancet 2005;365:871-875.
See the companion Expert Consult website for the complete
reference list.
It is not uncommon for critically ill patients to have dis-
turbances in acid-base equilibrium. Extracellular acid-base
disorders have been recognized for many years and form
the historical base of the understanding of the body’s regu-
lation of pH. New findings have led to an appreciation of
the complexity and tight regulation of intracellular pH
(pHi). It is becoming apparent that pHi may be more impor-
tant in cellular function. Observations of the effects that
extracellular pH has on organ systems may be a representa-
tion of their effect on pHi. The etiology (respiratory vs.
metabolic) and duration of acid-base alterations also deter-
mine how they affect organ function.
Conventional thought holds that acid-base imbalance is
more a result, or marker, of organ dysfunction than a
cause. The association of organ dysfunction with worsen-
ing metabolic acidosis has been known for some time
in a variety of states—burns,1 trauma,2,3 advanced age,4