THE LANCET Vol 354 August 7, 1999 505

Increased blood lactate concentration (hyperlactacidaemia)

in injury or sepsis is traditionally attributed to anaerobic
glycolysis due to inadequate oxygen delivery. According to
received wisdom, increased blood lactate signals hypoxia
and hypoperfusion. Tissue hypoxia is thought to contribute
to the development of multiple organ failure or death, and
prompt restoration of cellular oxygen delivery is a
fundamental goal of therapy. The usual indicators of
adequate tissue perfusion have been normalisation of blood
pressure, cardiac output, and urine output. However, these
clinical variables are believed to be misleading when they
have returned to normal yet circulating lactate remains
high. The degree and duration of hyperlactacidaemia have
been correlated with the subsequent development of organ
f a i l u r e .
1 , 2
If high blood lactate concentration reveals local
oxygen delivery failure that is masked by normalisation of
traditional indicators, the monitoring of a physiological
endpoint such as lactate might be a better guide to
r e s u s c i t a t i o n .
3
Clinical observations have challenged the accepted
notion of equating increased blood lactate with
h y p o p e r f u s i o n .
4
Nonetheless, current thinking continues to
interpret hyperlactacidaemia as hypoxia and to support
stimulation of cardiac output and enhancement of oxygen
delivery as therapy.
5
It is accepted that blood lactate
concentration may increase (albeit modestly) through ill-
defined mechanisms unrelated to tissue-oxygen debt. Such
mechanisms have been described vaguely as involving
disparity between peripheral glycolytic rate and
mitochondrial oxidative capacity, either in the liver or
e l s e w h e r e .
5
Concepts of such ambiguity are difficult to
evaluate experimentally or to apply clinically.
Although hypoxic tissues have high rates of anaerobic
glycolysis and lactate production, well-oxygenated tissues
Lancet 1999; 354: 50508
Depart ment of Surgery, Uni versi t y of Ci nci nnat i Medi cal Cent er,
231 Bet hesda Avenue, Ci nci nnat i , OH, USA (J H J ames PhD,
F A Luchette MD, F D McCarter MD, J E Fischer MD)
Correspondence t o: Dr J H J ames
(e-mail: jamesjh@ucmail.uc.edu)
can also generate lactate through aerobic glycolysisie,
glycolysis not attributable to oxygen deficiency. In some
situations, ATP production by aerobic glycolysis has been
associated with the activity of membrane ion pumps such
as the Na
+
, K
+
-ATPase. We propose that the epinephrine
surge after injury and in sepsis stimulates the sarcolemmal
N a
+
, K
+
-ATPase and greatly accelerates aerobic glycolysis
and lactate production that is coupled to Na
+
, K
+
- A T P a s e
activity in skeletal muscle. Consequently, a major
proportion of the increase in blood lactate that occurs in
injury or sepsis would be unrelated to poor tissue perfusion
and unlikely to respond to supranormal oxygen delivery.
Persistent hyperlactacidaemia in injured or septic patients
who are haemodynamically stable may result more from
epinephrine-stimulated aerobic glycolysis than from tissue
hypoxia. If our hypothesis is correct, there are profound
implications for the usefulness of lactate clearance as an
endpoint of resuscitation.
Previ ous evidence li nki ng hyperl act acidaemi a
and epinephrine in shock
Nearly 30 years ago, several studies made the existence of
an unqualified link between hyperlactacidaemia and tissue
hypoxia doubtful. These studies showed that
hyperlactacidaemia accompanying haemorrhage could be
largely prevented by pretreatment with combined and -
adrenergic-receptor blockade.
6
Similarly, adrenergic
blockade abolished lactic acidosis induced by infusion of
e p i n e p h r i n e .
7
In dogs with haemorrhagic shock, plasma
lactate correlated well with plasma catecholamines.
Surprisingly, combined and -adrenergic blockade
seemed to lessen hyperlactacidaemia not only by opposing
catecholamine action on tissues but also by reducing the
increase in plasma catecholamines.
8
These early reports
called for further studies into shock that would direct
greater attention to the metabolic effects of epinephrine
than to those of reduced tissue perfusion.
6
S u b s e q u e n t
studies in dogs confirmed that elevated arterial lactate in
shock was due not to lack of oxygen but to increased
lactate production that could be mimicked by epinephrine
i n f u s i o n .
9
Lact at e is an unreli able i ndicat or of t issue hypoxia i n injur y or
s e p s i s
J Howard James, Fred A Luchett e, Freda D McCart er, Josef E Fischer
Hypothesis
Hi gh bl ood l act at e concent rat i on (hyperl act aci daemi a) i n t rauma or sepsi s i s t hought t o i ndi cat e t i ssue hypoxi a and
anaerobi c gl ycol ysi s even when bl ood pressure, cardi ac out put , and uri ne out put are wi t hi n cl i ni cal l y accept abl e
ranges. However, mechani sms of l act at e generat i on by wel l -oxygenat ed t i ssues have recei ved l i t t l e at t ent i on. Wi t hi n
cel l s, oxi dat i ve and gl ycol yt i c energy product i on can proceed i n separat e, i ndependent compart ment s. In skel et al
muscl e and ot her t i ssues, aerobi c gl ycol ysi s i s l i nked t o ATP provi si on for t he Na
+
-K
+
pump, t he act i vi t y of whi ch i s
st i mul at ed by epi nephri ne. In i nj ured pat i ent s, hypokal aemi a may refl ect i ncreased Na
+
, K
+
-ATPase act i vi t y. We
propose t hat i ncreased bl ood l act at e oft en refl ect s i ncreased aerobi c gl ycol ysi s i n skel et al muscl e secondary t o
epi nephri ne-st i mul at ed Na
+
, K
+
-ATPase act i vi t y and not anaerobi c gl ycol ysi s due t o hypoperfusi on. The hypot hesi s
expl ai ns why hyperl act aci daemi a oft en nei t her correl at es wi t h t radi t i onal i ndi cat ors of perfusi on nor di mi ni shes wi t h
i ncreased oxygen del i very. When ot her vari abl es have ret urned t o normal , cont i nued at t empt s at resusci t at i on based
on el evat ed bl ood l act at e may l ead t o unnecessary use of bl ood t ransfusi on and i not ropi c agent s i n an effort t o
i ncrease oxygen del i very and l act at e cl earance.
Skelet al muscl e as primary source of lact at e in
s h o c k
I n shocked dogs, the primary source of lactate was
identified as skeletal muscle, in which lactate
concentrations exceeded those in other tissues.
1 0
W h e n
radiolabelled glucose was infused, the specific activity of
lactate in arterial blood was similar to that in organs other
than skeletal muscle, but lower in skeletal muscle itself.
1 0
This result indicates that, in shock, skeletal muscle
generates lactate more readily from its glycogen stores than
from circulating glucose. Because skeletal muscle
constitutes about 40% of the body-cell mass, changes in its
metabolism in response to injury or infection allow it to
become the main producer of lactate, perturbing overall
carbohydrate metabolism.
Epinephrine and hyperl act acidaemi a
I n healthy individuals at rest, the plasma epinephrine
threshold for producing an increase in circulating lactate is
between 150 and 300 pg/mL, or about three to six times
the normal concentration.
1 1 , 1 2
In exercising individuals,
increases in plasma lactate can be detected when the
epinephrine concentration reaches about 200 pg/mL.
1 3
A s
we shall discuss, epinephrine concentrations in sepsis or
after injury frequently exceed these thresholds.
During exercise of increasing intensity, plasma lactate
concentration increases gradually at low work levels, but
then increases rapidly as exercise increases to higher work
intensity. The intensity at which lactate begins abruptly to
increase is often called the lactate threshold or anaerobic
t h r e s h o l d ,
1 4
suggesting that, at some work level, oxygen
delivery becomes inadequate to meet metabolic demand.
Circulating epinephrine concentration also rises with
increasing exercise intensity; at maximum exercise intensity
in trained athletes (runners or cyclists) epinephrine
concentrations may reach 15002500 pg/mL.
1 5
D u r i n g
exercise, oxygen saturation of muscle myoglobin remained
stable at high exercise intensity and correlated poorly with
circulating lactate concentration.
1 6
However, several
exercise studies have shown excellent correlation between
concentrations of plasma lactate and epinephrine.
1 3 , 1 5 1 7
These observations suggest that the lactate threshold
during exercise reflects increased aerobic glycolysis,
stimulated by the rising epinephrine concentration rather
than anaerobic glycolysis due to tissue hypoxia.
Pronounced hyperlactacidaemia has also been associated
with the high blood concentrations of epinephrine that
occur in phaeochromocytoma
1 8
or in patients treated with
epinephrine after cardiopulmonary bypass.
1 9
In acute
bronchospasm or asthmatic attacks,
2
-agonists can, rarely,
cause lactic acidosis that is associated with hypokalaemia.
2 0
Epinephrine secretion
2 1
and plasma lactate
2 2
can remain
elevated for many weeks after major thermal injury. In
burn-injured patients, there is little evidence for
impairment of oxygen use,
2 3
and lactate concentrations can
be lowered by blockade with propranolol.
2 2
In patients
with shock due to sepsis, trauma, or haemorrhage, plasma
epinephrine can be elevated for prolonged periods.
2 4
I n
patients with septic shock, a group with high mortality,
epinephrine was consistently high (>500 pg/mL) for 35
days preceding death. In most patients with traumatic or
haemorrhagic shock, epinephrine concentrations were
highest (>4000 pg/mL) immediately after injury or blood
loss, and then fell to within the normal range in 1 or 2
days. However, in some of these patients, plasma
epinephrine remained substantially elevated (5002000
pg/mL) for several days after injury.
2 4
In one study, the haemodynamic effects of epinephrine
were compared with those of dopamine in patients with
severe bacterial sepsis or malaria.
3 5
In 84% of these
patients, epinephrine infusion was terminated earlier than
planned because of pronounced lactic acidosis. Dopamine
infusion was well tolerated, however, and both agents
increased oxygen delivery and oxygen consumption.
These observations do not necessarily identify skeletal
muscle as the source of the lactate, although in some
situations this inference can be made.
1 6 , 2 6
Clearer evidence
comes from studies showing that epinephrine stimulates
lactate production by isolated skeletal muscle.
2 7
Historically, attempts to understand epinephrine-
stimulated lactate production in skeletal muscle have
focused on ATP supplyie, increased activity of
glycogen phosphorylase and phosphofructokinase, which
are enzymes thought to be the flux-controlling steps in
glycogenolysis and glycolysis.
2 8
Less attention has been
given to ATP demandie, changes in cellular processes
that may require increased ATP production. One such
process is likely to be increased ion transport by the
N a
+
, K
+
- A T P a s e .
Epi nephri ne st i mul at es Na
+
, K
+
-ATPase act i vit y
i n skel et al muscl e
Epinephrine has acute effects on muscle physiology.
Muscles ability to conduct an action potential and
contract depends on the membrane potential and
concentration gradients across the membrane for sodium
and potassium. These ion gradients are maintained by the
N a
+
, K
+
-ATPase, which consumes one molecule of ATP to
transport three sodium ions out of the cell and two
potassium ions into the cell. At rest, muscle uses less than
10% of its total Na
+
, K
+
-ATPase activity to maintain
sodium and potassium gradients. During muscle activity,
ion movements associated with action potentials dissipate
sodium and potassium gradients. If unopposed, this
dissipation of ion gradients will result in loss of muscle
membrane excitability. When muscle activity is high, the
large reserve of Na
+
, K
+
-ATPase activity in muscle
preserves membrane excitability and muscle contractility.
2 9
The activity of the Na
+
, K
+
-ATPase in muscle is stimulated
acutely by insulin, epinephrine, increased intracellular
506 THE LANCET Vol 354 August 7, 1999
St i mulat i on by epinephrine of compart ment al i sed glycolysi s
coupled t o Na
+
, K
+
-ATPase act i vi t y
sodium concentration, and contractile activity itself, among
other factors.
3 0
Thus skeletal muscle has a large latent
capacity to transport sodium and potassium, thereby
consuming ATP, in response to various stimuli. However,
maximum stimulation of the Na
+
, K
+
pump in skeletal
muscle by epinephrine is greater than that by insulin.
Epinephrine stimulates Na
+
, K
+
-ATPase activity in
isolated skeletal muscles, thereby increasing potassium
uptake and sodium excretion and hyperpolarising the
membrane potential. This effect is mimicked by other
-adrenergic agonists, and by analogues of cyclic AMP,
and is blocked by propranolol or ouabain. These
observations suggest that epinephrine stimulates the Na
+
,
K
+
-ATPase (figure) by binding to adrenergic
2
- r e c e p t o r s
and raising cyclic AMP production.
3 1
The reduction of
circulating potassium concentration after administration of
insulin or of -adrenergic agonists is probably due, at least
partly, to stimulation of the Na
+
, K
+
-ATPase in skeletal
m u s c l e .
3 2
Aerobic gl ycolysi s and t he Na
+
, K
+
- A T P a s e
Increased activity of the Na
+
, K
+
-ATPase leads to increased
lactate production under well-oxygenated conditions in
various cells, including erythrocytes, vascular smooth
muscle, neurons, glia, and skeletal muscle.
3 3 3 6
C o n v e r s e l y ,
inhibition of the Na
+
, K
+
pump with ouabain reduces
lactate production. To explain this feature, it has been
proposed that clusters of enzymes consisting of the
complete glycolytic cascade may be associated with
membranes in proximity to ion transporters.
3 3 , 3 7
F u r t h e r
research is necessary to clarify whether, among other
possibilities, only a distinct subgroup of membrane Na
+
, K
+
pumps preferentially receives glycolytically derived ATP or
whether hormones, energy demand, and nutritional state
influence the ratio of oxidatively derived to glycolytically
derived ATP supplied to membrane ion pumps. It is
nonetheless clear that glycolysis provides ATP to sustain
N a
+
, K
+
-ATPase activity in cells with intact oxidative
capacity, including skeletal muscle.
In a subcellular compartment to which access by
diffusion from the bulk cytoplasm was limited, local ADP
availability would regulate local ATP production (figure).
In this compartment, ATP consumption by the Na
+
, K
+
-
ATPase would be the main influence on ADP availability.
Close association between ATP-consuming membrane ion
pumps and ATP-producing glycolytic enzymes would
tightly couple the use and synthesis of ATP such that the
rate of ATP utilisation regulated the rate of ATP
production. Furthermore, the flux-controlling enzyme in
glycolysis, phosphofructokinase, is activated by ADP and
inhibited by ATP. Stimulation of the Na
+
, K
+
- A T P a s e
would generate ADP, thereby raising phosphofructokinase
activity and accelerating aerobic glycolysis. In keeping with
this proposed mechanism, either -receptor blockade by
p r o p r a n o l o l
3 8
or inhibition of the Na
+
, K
+
-ATPase by
ouabain inhibits epinephrine-stimulated lactate production
by skeletal muscle in vitro.
2 7
Hypokalaemi a af t er injury i ndi cat es i ncreased
N a
+
, K
+
-ATPase act i vit y
Muscle potassium uptake is stimulated by epinephrine or
other
2
agonists, and that stimulation is inhibited by
ouabain, indicating involvement of the Na
+
- K
+
p u m p .
3 1 , 3 9
Administration of
2
agonists results in a prompt decrease
in circulating potassium.
3 2 , 4 0
More than half of randomly
selected trauma patients present with hypokalaemia, the
degree of which is associated with the severity of trauma
and with subsequent mortality.
4 1
An acute, transient
reduction in plasma potassium also occurs immediately
after severe head trauma and has been attributed to
massive catecholamine discharge.
4 2
These observations suggest that stimulation by
epinephrine of muscle Na
+
, K
+
-ATPase activity in injured
patients has been detected many times in the guise of
h y p o k a l a e m i a .
H y p o t h e s i s
After injury and/or haemorrhage and during sepsis,
neuroendocrine and cardiovascular stimuli combine to
trigger and sustain release of epinephrine. High
epinephrine concentrations stimulate adrenergic receptors
in skeletal-muscle cell membranes and, among other
effects, increase cyclic AMP production. This increase
leads to the coordinated stimulation both of Na
+
, K
+
-
ATPase activity and of glycogenolysis. Increased Na
+
- K
+
pump activity results in accelerated aerobic glycolysis that
is sustained mainly by glycogen-derived glucose-6-
phosphate. Rapid ATP production fuelled by glycogen
causes hyperlactacidaemia and muscle glycogen depletion,
and intracellular accumulation of potassium in muscle
results in hypokalaemia. Therapeutic measures to hasten
lactate clearance by raising perfusion and oxygen delivery
to supranormal levels would be expected to have little
direct effect on these metabolic processes. However, such
measures may reduce glycolysis indirectly, by reducing the
stimuli for epinephrine release. Unnecessary use of blood
products (red-cell transfusion) subjects the patient to
increased risk of infectious viral agent transmission.
Inappropriate use of inotropic agents in an effort to raise
tissue oxygen delivery at the expense of increased
myocardial oxygen consumption may have little benefit for
the patient. However, if resuscitation is inadequate and if
hypotension, hypovolaemia, or hypoxia persist and
continue to stimulate epinephrine release,
4 3
t r e a t m e n t s
aimed at improving tissue perfusion may reduce blood
lactate by slowing epinephrine secretion. If epinephrine
secretion persists for reasons unrelated to inadequate
resuscitation, aerobic glycolysis would be expected to
persist. Although hypotension, hypovolaemia, or hypoxia
can stimulate epinephrine secretion and thus raise lactate
concentration, continued efforts at resuscitation in the
presence of normal blood pressure, PO
2
, pulse, and urine
ouput may be indefensible and possibly harmful.
Test ing t he hypot hesi s
The hypothesis predicts that epinephrine is a primary
stimulus to lactate production through stimulation of Na
+
,
K
+
pump activity in skeletal muscle. These predictions can
be tested in healthy individuals by an assessment of the net
flux of lactate and potassium across a limb. If this
hypothesis is correct, we would expect to find the following
associations over a range of epinephrine concentrations: (i)
lactate flux should be positively correlated with epinephrine
concentration; (ii) potassium flux should be negatively
correlated with epinephrine concentration; and (iii) lactate
flux should be proportional to potassium flux. Moreover,
-blockade would be expected to dissociate epinephrine
concentrations from lactate and potassium fluxes. We are
unaware of any study that has examined all of these
r e l a t i o n s .
THE LANCET Vol 354 August 7, 1999 507
Patients with severe head trauma, but with relatively
minor systemic injuries, have increased metabolic
expenditure, a hyperdynamic cardiovascular state,
4 4
a n d
increased circulating epinephrine
4 5
and lactic acid
c o n c e n t r a t i o n s .
4 6
In these patients, propranolol reduces
blood pressure, heart rate, cardiac work, and epinephrine
c o n c e n t r a t i o n s .
4 7
Limb flux studies like those described
above could be done in these patients. Studies in which
plasma concentrations of potassium, lactate, and
epinephrine were to be measured concurrently should
show positive correlations between epinephrine and lactate
and negative correlations between potassium and lactate as
well as between potassium and epinephrine. In these
patients without major systemic injury, -blockade might
be of use in dissociating plasma lactic acid from
epinephrine concentrations.
Supported by grants from Shriners Hospitals for Children and theUS
Public Health Service.
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