The use of lactate measurements in
critically ill patients has steadily increased to a level where in some cases
it may be considered lactate monitoring. In this brief review we discuss the
central metabolic role of lactate in animal metabolism, and address important
misconceptions as well as why lactate is mainly a marker of stress and how this
translates into its unique diagnostic utility in many acute conditions. Finally
several interesting future perspectives in lactate monitoring are discussed.
Elucidation of Lactate Metabolism and Misconceptions about Lactate
The history of lactate measurement
and lactate metabolism is a fascinating story (Kompanje et al. 2007), having
important relevance for current views on lactate, as some misunderstandings
persist. From the moment it was recognised that lactic acid is generated when
milk sours, some of the keenest investigators studied lactate metabolism.
Several Nobel prize winners, including Otto Meyerhof, Otto Warburg, Hans Krebs,
Carl Cori and Gerty Cori (Voet and Voet 2011) helped elucidate lactate
metabolism. Although often interchangeably used, lactic acid (HLa) and lactate
(La-) are of course
different entities, but for brevity we will not address this topic. Even at
extreme physiological conditions HLa is fully dissociated into H+ and La-. When cells produce and
export H+ and La-, the H+ will be partially
buffered in the extracellular space.
Early in the 20th century it was
recognised that glucose is a fuel used by virtually all living organisms. In
the middle of the 20th century it was discovered that in animals mitochondria
are able to fully oxidise carbohydrate and fat to CO2 and thereby generate far
more ATP (adenosine triphosphate) with so-called oxidative phosphorylation than
is possible by conversion of glucose to pyruvate (glycolysis) alone. In the
complete absence of oxygen, cells or tissues that are capable of both
glycolysis and oxidative phosphorylation can only use glycolysis. When
glycolysis produces pyruvate that cannot be further metabolised by
mitochondria, this pyruvate must be converted into lactate in order for
glycolysis to continue. This lactate must then be transported out of the cell,
and can then be converted back to pyruvate and metabolised by mitochondria
elsewhere in the body.
Although all oxygen-consuming
tissues possess the ability to consume lactate, the liver and kidneys also
possess the ability to convert this lactate back into glucose (gluconeogenesis)
and export this glucose into the circulation. The Cori cycle describes the
conversion of glucose to lactate by muscles, the subsequent transport of
lactate to the liver, regeneration of glucose by gluconeogenesis in the liver
and then transport of glucose back to the muscle. This cycle is an important
example of acute whole-body metabolic interaction between two organs. The Cori
cycle allows muscles to perform longer during strenuous exercise, since the
liver offloads the lactate-producing muscle. This cycle comes at a metabolic ‘cost’,
however. When glycolysis generates two ATP from a glucose molecule in the
muscle, the liver must spend six ATP to regenerate glucose from lactate. Thus
at the whole-body level the Cori cycle entails a loss of four ATP for each
recycled glucose. In contrast to the Cori cycle, the direct reuse of lactate by
the mitochondria of other cells carries no energy penalty (Voet and Voet 2011).
A persistent misconception about
lactate metabolism is that lactate production automatically implies “anaerobic
glycolysis”. However, in the majority of conditions lactate production occurs
in the presence of sufficient oxygen and fully functioning mitochondria. This
is both the case in physiology (e.g. during maximal exercise) and in
pathophysiology (e.g. sepsis). A related popular misconception is that muscle
ache is the result of accumulation of lactic acid. Thus lactate has long been
considered a detrimental waste product, in particular since regeneration of
glucose from it by the Cori cycle involves loss of ATP. But lactate is far from
a waste product. Just like glucose, lactate is a fuel with an ATP yield on par
with glucose upon complete oxidation. Given lactate’s central metabolic role,
the body can metabolise hundreds up to thousands of millimoles of lactate per
day (Cole 2003).The use of the term ‘clearance’ in the case of lactate is not
appropriate, since its concentration is the net result of the rapidly varying
production and consumption by many tissues (see Figure1).
Figure 1. three Metabolic states with Respect to Lactate Production and Consumption
source: Adapted from Bakker 2013
In most (patho)physiological conditions, acute energy requirements are a key driver of local or systemic lactate levels, irrespective of local oxygen tension. The left panel depicts non-stressed steady-state conditions where glucose is converted to pyruvate, which is subsequently fully oxidised to Co2, generating approximately 36 AtP (adenosine tri-phosphate) per glucose molecule.
The mid panel depicts a stressed situation where tissue immediately requires more AtP. Glycolysis generates only 2 AtP but can very rapidly increase by a two or three orders of magnitude. Even with optimal mitochondrial oxygenation and function, this rate of pyruvate production will saturate the much more complex but much less flexible process of oxidative phosphorylation. thus for glycolysis to continue, pyruvate must be converted to lactate.
The right panel depicts the post stress situation when lactate is converted back to pyruvate and fully oxidised. since lactate can be transported both at micro and at macro scales, lactate shuttles exist that allow the simultaneous production and consumption of lactate by different cells or tissues.
Hyperlactataemia and Stress
Although severe hypoxia or anoxia
induce lactic acidosis, the relation cannot be used in reverse, because in the
majority of cases in the ICU hyperlactataemia is not caused by hypoxia but by
stress. The three main conditions regarding lactate production and consumption
are depicted in Figure 1. During resting steady state conditions glycolysis and
oxidative phosphorylation are balanced, with no production of lactate. During
stress, when increased ATP production is required, glycolysis can increase
manifold. In these conditions excessive lactate production is not an indicator
of tissue hypoxia, but simply reflects the ability of glycolysis to vastly
outrun mitochondrial oxidative phosphorylation (Gladden 2004). The poor
relation of increased [La-] with oxygen delivery parameters underscores that stress, not
hypoxia, is the common driver of hyperlactataemia (Bakker 1991).
It is well known that adrenergic β2-activation can directly induce production of lactate (Levy 2008) and glucose. In addition, a recent study showed that hyperlactataemia and hyperglycaemia are closely associated and related to mortality in a large patient cohort (Kaukonen 2014). The well-established univariate relation of hyperglycaemia with mortality disappeared when hyperlactataemia was included. The investigators concluded that stress is the common denominator of both hyperlactataemia and hyperglycaemia (Kaukonen 2014).
In animal studies, treatment of
healthy dogs with prednisone dose dependently increased blood lactate levels
(Boysen et al. 2009). Furthermore a prospective controlled trial in cardiac
surgery patients (Ottens 2015) showed that the synthetic glucocorticoid
dexamethasone both induces hyperglyacemia and hyperlactataemia, underscoring
the deep connection between both the adrenergic and the corticoid stress
response and subsequent elevations of both lactate and glucose.
Timescales on which Changes in [La-] can Occur
In many institutions [La-] is
measured on ED admission and upon ICU admission and thereafter daily or only on
indication. In other institutions all glucose measurements performed for ICU
glucose-control are combined with lactate and blood gas analysis, resulting in
many [La-] values per day.
Theoretically even a far higher
frequency of measurement of circulating [La-] might be informative. The known
relevant biological variation of a specific signal in relation to the accuracy
of measurement determines the minimal timescales of scientific or clinical
interest. In the case of [La-] an interval of one minute makes sense, since
modern detectors achieve 0.1 mmol/L accuracy and [La-] can
decrease by >0.1 mmol/L/min during recovery and increase by >1 mmol/L/min
during severe stress. The rate of recovery of hyperlactataemia differs per
condition. A decrease of 20% per hour suggests successful sepsis treatment
(Jansen 2010), but after cardiopulmonary resuscitation or generalised seizures
faster recovery rates are the rule (Vincent et al. 1983).
Monitoring of Lactate and its Clinical Utility as a Strong Marker of Outcome
It is now well-established that of
all available laboratory measurements circulating lactate has the strongest
univariate relation with outcome. It is quite unlikely that another routine
laboratory measure will emerge that will outperform lactate in this respect. It
should be noted that obviously no single laboratory value, including lactate,
should serve as the sole value to interpret the condition of a patient. As
transpires from its function during stress, a high [La-] is
not harmful by itself, but represents a compensatory response to a variety of
severe underlying conditions (Kraut 2014). Thus [La-] may
be considered the ultimate example of a biochemical marker and not a mediator
of poor outcome. The considerable clinical utility (Jansen 2009) of [La-] rests
particularly on its specificity and less on its sensitivity, as illustrated by
the traffic light cartoon (see Figure 2).
Figure 2. The Practical importance of Lactate Monitoring
A large amount of information must be integrated (sub) consciously by intensivists when assessing iCU patients. some parameters serve as a generic alert that something is wrong, although it may not immediately be clear what is wrong. An abnormally high [La-] or Δ[La-] serves as such a warning to critically assess the condition of the patient and consider alternative diagnoses and additional interventions. the red colour signifies the most alarming condition since [La-] is elevated and still rising. obviously, a normal [La-] (green sign) makes severe conditions less likely, but can never exclude them.
A marker that highlights situations
that entails increased risk can help physicians and nurses to focus their
diagnostic and therapeutic resources on those who stand to benefit most. In our
experience it is possible in most patients with marked hyperlactataemia to
correctly identify the underlying cause. When the cause is not immediately
evident, it may trigger appropriate additional investigations. The prospective
randomised LACTATE trial was the first to demonstrate the benefit of [La-]
guidance during early sepsis treatment (Jansen 2010).
Future Perspectives – Decision Support
We anticipate several developments concerning lactate monitoring. Continuous lactate monitoring holds great promise as suggested by first clinical studies in cardiac surgery patients with a continuous intravascular microdialysis system that allows ex vivo detection of circulating lactate and glucose levels (Schierenbeck 2014). Measuring [La-] on timescales of minutes will likely uncover important hitherto undetected phenomena.
Continuous combined lactate and glucose
monitoring may provide a powerful tool to monitor liver function, something
currently not possible. When serial measurements show that [La-] rises whilst [Glu] is ‘normal’
or decreases, gluconeogenesis may be impaired, indicating partial (de Felice
2014) or complete liver failure (Oldenbeuving 2014). Likewise the time course
of [La-] after an IV lactate bolus
can be used to quantify the liver’s metabolic ability in real time and
repeatedly (Tapia et al. 2015).
Eventual incorporation of [La-] into scoring systems that
predict mortality such as APACHE or SAPS seems inevitable, since [La-] univariately outperforms
all known biochemical markers for predicting mortality. Inclusion of [La-] is long overdue, because
these scoring systems already incorporate many less powerful but equally
available predictors such as potassium, leukocyte count or glucose.
An important conceptual challenge is to
translate the predictive power of [La-] and Δ[La-]/Δt for specific conditions to sufficient
pathophysiological understanding, so that an increased [La-] can be optimally
interpreted in individual cases. Because many different acute conditions can
lead to hyperlactataemia, we believe structured decision support to best
interpret increased [La-] may be of use. Building on
the principles set out in the LACTATE study (Jansen 2010), we are currently
developing such a decision support system. Optimal interpretation of a rise in
[La-] within a specific clinical
context may also prevent incorrect reflexes of caregivers. Unfortunately, even
in our ICUs we frequently discover that a fluid bolus is administered when [La-] rises, even if
hyperlactataemia does not result from hypovolaemia, but for example from anxiety
(ter Avest 2011). Designing lactate computer support will be inherently more
complex than computerised glucose or potassium control, since in glucose or
potassium control measurement and therapeutic corrections can to a large extent
be fully ‘outsourced’ to the computer and the ICU nurse (Vogelzang 2008;
Hoekstra 2010). The first goal for computerised lactate support should be to
improve understanding of [La-]
dynamics and leave the specific diagnostic and therapeutic actions to the
Lactate sensors employ technology very similar
to glucose sensors. Thus many measurement techniques developed for glucose can
be ported to lactate. Although [La-] is currently mostly determined in critically ill patients, this
measurement may also be employed in patients on general wards or even in
outpatients. A potentially very important example of the latter group may be
type II diabetics who usually use metformin. Metformin is a key oral
antidiabetic drug used by maybe 100 million patients worldwide. A small but
important minority of these patients can develop metformin associated lactic
acidosis (MALA). Hand-held combined lactate and glucose measurements would be
very useful for timely detection of emerging MALA in this very large population
of chronic patients.
Lactate is a central intermediate metabolite that allows the flexible integration of the two ATP generating systems that animals possess. Increases in lactate may usually reflect metabolic stress rather than tissue hypoxia. Increased lactate levels have a stronger relation to mortality than observed for any other biochemical marker.
The scientific and clinical rationale for more
frequent measurements of [La-] is
supported by a growing body of evidence and facilitated by advanced analysers.
The emerging technology of continuous lactate measurements also holds large
scientific and clinical promise for critically ill patients. We will study the impact of continuous lactate
monitoring on outcome in future trials.
- Lactate is a central intermediate metabolite that is usually increased because of stress.
- Of all laboratory parameters, in the spectrum of critically ill patients, lactate has the strongest relation with outcome.
- The rate of change of circulating lactate is also of prognostic importance.
- Monitoring of lactate on short timescales is both
scientifically and clinically useful.
- Future trials may establish whether continuous lactate monitoring improves outcome.