Lactate and lactic acidosis

October 2007

Chris Higgins
Little Acre, Main Road
Shurdington
Nr Cheltenham
Gloucester
GL51 4XF, UK
E-mail: [email protected]

The integrity and function of all cells depend on an possible by the development of electrode-based lactate
adequate supply of oxygen. Severe acute illness is biosensors around a decade ago.
frequently associated with inadequate tissue perfusion
and/or reduced amount of oxygen in blood (hypoxemia) These biosensors are now incorporated into modern
leading to tissue hypoxia. blood gas analyzers and other point-of-care analytical
instruments, allowing lactate measurement by non-
If not reversed, tissue hypoxia can rapidly progress to laboratory staff on a drop (100 µL) of blood within a
multiorgan failure and death. For this reason a major minute or two. Whilst blood lactate concentration is
imperative of critical care is to monitor tissue oxygenation invariably raised in those with significant tissue hypoxia,
so that timely intervention directed at restoring an it can also be raised in a number of conditions not
adequate supply of oxygen can be implemented. associated with tissue hypoxia.

Measurement of blood lactate concentration has Very often patients with raised blood lactate
traditionally been used to monitor tissue oxygenation, concentration (hyperlactatemia) also have a reduced
a utility based on the wisdom gleaned over 50 years blood pH (acidosis). The combination of hyperlactatemia
ago that cells deprived of adequate oxygen produce and acidosis is called lactic acidosis. This is the most
excessive quantities of lactate. common cause of metabolic acidosis.

The real-time monitoring of blood lactate concentration The focus of this article is the causes and clinical
necessary in a critical care setting was only made significance of hyperlactatemia and lactic acidosis. The

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 article begins with a brief overview of normal lactate GLUCOSE
NAD+ ADP
metabolism.

Normal lactate production and metabolism [1] NADH ATP

Lactate, the anion that results from dissociation of lactic Pyruvate

LACTATE PYRUVATE
acid, is a product of glucose metabolism; specifically it DEHYDROGENASE DEHYDROGENASE
NADH
is the end product of anaerobic glycolysis. The glycolytic LACTATE NAD+ Acetyl CoA
pathway (Fig. 1), which can proceed anaerobically in
the cytoplasm of all cells, is a sequence of 13 enzymic
CO2, H2O
reactions in which glucose is converted to pyruvate.
CITRIC ACID
CYCLE
During this conversion, energy-rich adenosine triphosphate ATP Oxidative NADH
phosphorylation FADH
(ATP) is generated from adenosine diphosphate (ADP) ATP
and reduced nicotinamide adenine dinucleotide (NADH)
Anaerobic glycolysis Aerobic glycolysis
is generated from oxidized NAD (NAD+). (cytosolic only) (cytosolic and mitochondrial)

FIG 1: Lactate - a product of anaerobic glycolysis

The final step of anaerobic glycolysis is conversion
of pyruvate to lactate by the enzyme lactate
dehydrogenase. This last reaction provides a source Although lactate is freely filtered at the glomerulus, it is
of NAD+ essential for anaerobic glycolysis to proceed. almost all reabsorbed and normally <2 % of lactate is
Production of lactate is the only means for glucose removed from the body in urine [3]. The principal route
utilization and ATP production in erythrocytes (which of disposal begins with cytosolic conversion to pyruvate
have no mitochondrion) and in exercising muscle cells by the enzyme lactate dehydrogenase.
(which have an oxygen debt).
This pyruvate has two principal fates. The first is
In well-oxygenated tissue cells that contain oxidation to acetyl CoA by the enzyme pyruvate
mitochondrion, pyruvate is not preferentially converted dehydrogenase for ultimate metabolism to carbon
to lactate but rather metabolized to carbon dioxide dioxide and water via the citric acid cycle and oxidative
and water in mitochondria via two integrated phosphorylation. The second is conversion to glucose, a
metabolic pathways: the citric acid cycle and oxidative process called gluconeogenesis. Oxidation of pyruvate
phosphorylation. via the citric acid cycle can potentially occur in all cells
with mitochondrion, but gluconeogenesis is confined to
Conversion of a molecule of glucose to lactate liver and kidney cortex cells.
(anaerobic glycolysis) yields just two molecules of
ATP, whereas conversion to carbon dioxide and water For this reason liver and kidneys are the most significant
(aerobic glycolysis) has a much higher energy yield of 38 organs for lactate elimination, the liver accounting for
ATP molecules. disposal of around 60 % of circulating lactate [4] and
the kidneys for disposal of 25-30 % [5]. Overall, the
Although lactate can be produced in all tissues, skeletal body has immense capacity for lactate disposal, which
muscle, erythrocytes, brain and renal medulla tissues can, if necessary (e.g. following extreme exercise), rise
are the principal production sites in health. Normal as high as 500 mmol/hour, considerably higher than the
daily lactate production is of the order of 1500 mmol basal rate of production.
[1]. There are two main routes of lactate disposal:
conversion to pyruvate or elimination in urine (Fig. 2).

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 LACTATE Hyperlactatemia and lactic acidosis

Hyperlactatemia is a pathological state in which resting

Around 2 % excreted
blood lactate concentration is abnormally high (>1.5
unchanged in urine
mmol/L). Moderate to severe hyperlactatemia (>3.0 to
Most converted to pyruvate >5.0 mmol/L) is associated with abnormal accumulation
H NAD NADH O of hydrogen ions (H+) and a resulting tendency to
O O
CH3 C C - CH3 C C - acidosis.
O LACTATE DEHYDROGENASE O
OH
Lactate Pyruvate
These hydrogen ions are a product of ATP hydrolysis
to ADP [2]. In the presence of oxygen, hydrogen ions
produced during ATP hydrolysis are utilized in the
Pyruvate
mitochondrial process of oxidative phosphorylation, but
this is often not possible in the context of anaerobic
glycolysis associated with hyperlactate production.
Entry to mitochondria- Conversion to oxaloacetate
conversion to acetyl and ultimtately glucose
CoA and subsequent (gluconeogensis). Occurs Instead, hydrogen ions accumulate in blood, eventually
metabolism in citric acid cycle only in liver and kidneys.
overwhelming the bicarbonate and other buffering

FIG 2: Principal mechanisms of lactate disposal systems that maintain blood pH within normal limits
(7.35-7.45). The combination of hyperlactatemia and
acidosis is called lactic acidosis and although there is
no universal agreement for definition of lactic acidosis,
Normal blood lactate concentration the most widely used is blood lactate >5.0 mmol/L in
combination with pH <7.35 [7].
Lactate produced within erythrocytes cannot be
metabolized further and is released to the circulation. Lactic acidosis is the most common cause of metabolic
In some tissues (e.g. skeletal muscle) lactate may be acidosis [8].
produced at a faster rate than it can be metabolized and
in these circumstances lactate would also be released to Cause of hyperlactatemia and lactic
circulation. acidosis – general considerations

In health, blood lactate concentration is maintained Hyperlactatemia develops when the rate at which
within the approximate range of 0.5-1.5 mmol/L [6]. lactate is released from peripheral tissue cells to
This reflects a balance between the rate of lactate circulation exceeds the rate at which it is removed from
release to blood from erythrocytes and other tissue cells circulation by liver and kidneys. Both increased lactate
and rate of lactate clearance from blood, principally by production and decreased lactate removal/metabolism
the liver and kidney. can be causative.

Exercise represents a physiological process in which this From a biochemical viewpoint the central problem is
balance is temporarily upset due to the rapid increase in usually decreased utilization of pyruvate in oxidative or
lactate production by muscle cells in temporary oxygen gluconeogenic pathways. Under these circumstances
debt. In severe exercise, blood lactate may rise to levels pyruvate can only be converted to lactate. For example,
in excess of 20 mmol/L but due to the capacity for rapid since oxygen is essential for pyruvate oxidation, any
lactate disposal, in health this rise is only transitory. condition that deprives tissues of oxygen can lead to
increased production of lactate, which then accumulates

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 in blood at a faster rate than it can be removed by liver Perfusion is not the sole determinant of tissue
and kidneys. oxygenation, which also depends on an adequate
amount of oxygen in blood. Tissue hypoxia and
The problem is compounded by acidosis because consequent Type A lactic acidosis can thus occur despite
the capacity of the liver to remove lactate from the adequate perfusion if the oxygen content of blood or the
circulation is pH dependent and severely impaired oxygen-carrying capacity of blood is sufficiently reduced.
by reduced blood pH. In fact, experimental evidence
suggests that at blood pH of 7.0 or less, lactate uptake This is the mechanism of the Type A lactic acidosis that
is so impaired that the liver produces more lactate than can occur in patients with severe anemia [10], severe
it consumes [9]. hypoxemia (e.g. respiratory failure) [11] and carbon
monoxide poisoning [12]. In practice, anemia and
There is some renal compensation because acidosis hypoxemia are rarely the sole causes of Type A lactic
enhances kidney uptake of lactate [5]. However, this can acidosis. More commonly they are contributory factors in
only compensate for around 50 % of the hepatic loss and the development of Type A lactic acidosis among patients
acidosis, whatever its cause, can be a major contributory already predisposed because of inadequate perfusion.
factor in the pathogenesis of hyperlactatemia.
The massive increase in muscular activity that occurs
Specific causes of lactic acidosis during seizures can cause Type A lactic acidosis due to
local muscle tissue hypoxia consequent on a temporary
Traditionally, lactic acidosis has been divided into two mismatch between oxygen demand and oxygen supply
broad etiological categories; Type A and Type B. Type A is (very similar to the physiological lactic acidosis that
lactic acidosis resulting from tissue hypoxia (biochemical occurs during exercise). In common with exercise-
mechanism outlined above) and Type B is lactic acidosis induced lactic acidosis, seizure-induced lactic acidosis is
occurring in the context of normal tissue perfusion and self-limiting, spontaneously resolving within a few hours
adequate global tissue oxygenation. of seizure cessation [13].

Type A lactic acidosis Type B lactic acidosis

Tissue hypoxia and Type A lactic acidosis arise as a result If lactic acidosis occurs in the context of apparently
of inadequate perfusion of tissues in hemorrhagic, adequate tissue oxygenation and normal hemodynamics
cardiogenic and septic shock. These conditions (i.e. normal blood pressure, no volume depletion,
associated with volume depletion and/or severe normal blood oxygen and oxygen-carrying capacity), it
hypotension may be the result of major trauma/surgery is traditionally termed Type B lactic acidosis.
or acute medical conditions (e.g. myocardial infarction,
systemic infection) causing cardiovascular collapse. The vital role of the liver and kidneys for lactate uptake
from circulation and subsequent metabolism via the citric
Type A lactic acidosis then is a feature of acute, life- acid cycle and gluconeogenesis determines that hepatic
threatening (critical) illness. The conventionally held and renal disease, whatever its cause, predisposes to
view that lactic acidosis occurring in the context of sepsis mild hyperlactatemia and rarely Type B lactic acidosis.
and septic shock is the sole result of tissue hypoxia is Malignant disease may be associated with lactic
now challenged (see below) and for critically ill patients, acidosis, most cases of Type B lactic acidosis occurring
whose condition is caused or complicated by infection, in hematological malignancy (leukemia, lymphoma) [14].
the distinction between Type A and Type B lactic acidosis
is blurred and inappropriate. Type B lactic acidosis is a feature of several individually
very rare inherited disorders that are characterized

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 by deficiency of specific enzymes involved in lactate acidosis due to the inhibitory effect that salicylate has
metabolism (either gluconeogenesis or pyruvate on oxidative phosphorylation.
oxidation). These include pyruvate carboxylase deficiency
[15], glucose-6-phosphate dehydrogenase (G6PD) A similar mitochondrial effect accounts for the lactic
deficiency, fructose-1,6-diphosphatase deficiency [16] acidosis that occurs in cyanide poisoning. Most HIV
and pyruvate dehydrogenase deficiency, the most patients prescribed anti-retroviral drugs develop mild
common [17]. These conditions are collectively referred chronic hyperlactatemia (serum lactate 1.5-3.5 mmol/L)
to as congenital lactic acidosis. [19], and in a small unpredictable minority this evolves
to severe lactic acidosis [20].
A long list of drugs and toxins can cause lactic acidosis
(Table I), and taken together these represent by far Lactic acidosis and sepsis
the most common cause of Type B lactic acidosis.
Biguanides are a class of blood glucose-lowering drugs The notion that lactic acidosis occurring in the context
used in the treatment of diabetes; metformin, the most of critical illness is Type A and therefore always indicates
widely prescribed, has been linked to lactic acidosis tissue hypoxia is clearly over-simplistic. Critically ill
[18]. However, in most cases of metformin-associated patients are as likely as any other to be suffering Type B
lactic acidosis, there is some evidence of liver or renal lactic acidosis and due consideration must be given to
impairment that predisposes to hyperlactatemia. the causes of Type B lactic acidosis outlined above when
assessing any patient (including those who are critically
ill) presenting with raised blood lactate.
Biguanides (e.g. metformin)
Ethanol Sepsis is an additional and far more significant
Methanol complicating issue that warrants special attention, not
Antiretroviral drugs least because it is such a common feature of critical illness.
Cyanide Sepsis is a condition in which the distinction between
Theophylline Type A and Type B lactic acidosis is inappropriate because
Cocaine in some patients with sepsis, lactate accumulates despite
Simvastatin adequate tissue oxygenation [21].
Salicylates
Paracetamol (acetaminophen) A number of mechanisms have been proposed for lactate
Lactulose accumulation in the absence of tissue hypoxia among
Propylene glycol Epinephrine, norepinephrine patients with sepsis. These include reduced clearance
of lactate from circulation by liver and kidneys [22]; a
TABLE I: Some drugs and toxins that can cause lactic acidosis.
specific defect induced by sepsis in the enzyme pyruvate
dehydrogenase that impairs pyruvate utilization in the citric
Metabolism of ethanol is associated with increased acid cycle [23]; and increased pyruvate production [24].
NADH/NAD+ ratio favoring conversion of pyruvate to
lactate [2]. Gluconeogenesis is also inhibited so that Sepsis and septic shock are associated with a stress
the combination of moderate hyperlactatemia and response that includes increased release of epinephrine
hypoglycemia is a not infrequent finding in patients (adrenalin). This hormone stimulates the membrane-
suffering acute effects of alcohol abuse. bound enzyme Na+/K+-ATPase, which utilizes ATP
generated by aerobic glycolysis to provide the energy
Pre-existing alcoholic liver disease exacerbates the acute necessary to “pump” ions into and out of cells. Na+/
hyperlactatemia-precipitating Type B lactic acidosis. K+-ATPase stimulation increases aerobic glycolysis and
Salicylate overdose can be associated with lactic thereby lactate production.

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 It has been hypothesized that the hyperlactatemia a compensatory response to any form of metabolic
associated with sepsis may be at least in part the result acidosis, may be evident.
of this epinephrine-stimulated aerobic glycolysis [21].
Prognostic value of lactate measurement in critical
Whatever the mechanism it is clear that in many whose care
critical illness is either caused by or complicated by
infection, lactic acidosis is not necessarily entirely the The traditional use of lactate measurement as a marker
result of tissue hypoxia. In these circumstances measures of inadequate tissue perfusion and tissue hypoxia in
taken to enhance tissue perfusion would be less effective critical care is somewhat limited by the increasing
in reducing blood lactate and resolving acidosis. realization over the past decade that trauma victims and
others suffering potential critical illness may have raised
D-lactic acidosis lactate despite adequate tissue perfusion.

This is a rare and very specific form of lactic acidosis Notwithstanding this limitation, lactate measurement
confined to those with short-bowel syndrome and those has value in the emergency room and intensive
who have undergone jejunoileal bypass surgery [25], a care unit because, irrespective of the mechanism of
treatment for severe obesity. Lactic acid exists naturally hyperlactatemia, blood lactate concentration predicts
in two isomeric forms: L-lactic acid and D-lactic acid. morbidity and mortality.

In humans lactate is derived from the L-form, but The prognostic value of lactate measurement has been
some bacterial species can produce the D-form. In confirmed in many patient groups.
the aforementioned patient group, carbohydrate
malabsorption can lead to abnormal increase in the gut of For example, in a prospective study of 76 major trauma
D-lactate-producing bacterial species. The D-lactic acid is victims serial lactate measurements were made over
released to the gut, absorbed and accumulates in blood. the first 48 hours after admission [26]. All 27 patients
whose lactate normalized within 24 hours survived but
Susceptible patients suffer episodes of D-lactic acidosis only three of 22 patients whose lactate remained raised
usually following ingestion of a high-carbohydrate meal. at 48 hours survived.
Since routine methods of lactate measurement detect
only the L-isomer, blood lactate is falsely normal and the In a study of 1278 patients with infection, mortality
only biochemical clue to the condition is unexplained was 4.9 % among those whose lactate was less than
high anion gap acidosis. 2.5 mmol/L on admission compared with 36 % among
those whose lactate was >4mmol/L [27]. Finally, an early
Clinical significance of hyperlactatemia study of 233 critically ill patients suffering various forms
of shock revealed a mortality rate of 67 % among those
Clinical signs whose lactate was >3.82 mmol/L compared with only
25 % for those whose lactate was <3.82 mmol/L [28].
Mild to moderate hyperlactatemia (blood lactate <5
mmol/L) causes no specific signs and symptoms. As These and many other studies have demonstrated that
lactate levels rise above 5 mmol/L, there is an increasing raised lactate in the context of trauma, sepsis and critical
risk of the clinical manifestations of lactic acidosis, illness generally is a poor prognostic sign indicating
which are tachycardia (increased heart rate) tachypnea the need for immediate and intensive resuscitative
(increased respiratory rate) and alteration in mental measures. If these are effective in reducing blood lactate
status that can range from mild confusion to coma [1]. within 24-48 hours, the chances of survival can be
The deep sighing respiration (Kussmaul’s respiration), greatly increased [29].

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 A recent expert committee concluded that there is
good evidence that point-of-care lactate testing leads
to improved outcomes for patients in a variety of critical
care settings [30].

Sampling requirements for lactate measurement

Although some authorities recommend arterial blood

for lactate measurement, venous blood is a suitable
alternative; results are not clinically significantly different
[31]. Use of a tourniquet during blood collection should
be avoided because it can cause falsely increased lactate.
Heparin is a suitable anticoagulant.

In vitro glycolysis and therefore lactate production

continues after sampling so that lactate concentration
increases by 30 % in just 30 minutes if kept at room
temperature. For this reason blood must be analyzed
immediately it is sampled. If there is to be any delay,
the sample must be stored on ice to inhibit ongoing
glycolysis. Preanalytical errors associated with lactate
measurement are the subject of a recent review [32].

Summary

Lactate is a normal product of anaerobic glycolysis. The

principal clinical significance of lactate is that in severe
acute illness anaerobic glycolysis is often increased – a
result of tissue hypoxia. As a consequence blood lactate
concentration increases.

The clinical value of lactate as an indicator of tissue

hypoxia is diminished by the fact that hyperlactatemia
can occur despite normal tissue perfusion and adequate
oxygen delivery if, for example, mechanisms of lactate
metabolism/disposal are compromised. Irrespective
of the cause, hyperlactatemia is often associated with
reduction in blood pH and the resulting condition lactic
acidosis.

Despite the lack of specificity for tissue hypoxia, lactate

is a valuable prognostic marker in all forms of critical
illness and a useful diagnostic tool in the investigation
of patients presenting with unexplained metabolic
acidosis.

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Data subject to change without notice.

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