Netherlands Journal of Critical Care

Copyright 2011, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. 

Received April 2010; accepted October 2010

Review

Lactate revisited: is lactate monitoring 

beneficial for ICU patients?
TC Jansen
Department of Intensive Care and department of Internal Medicine, Erasmus Medical Center University Medical Center, Rotterdam, 
The Netherlands

Abstract - Blood lactate levels are frequently measured in critically ill patients. Whilst these measurements are known to be accurate,
for the correct interpretation of hyperlactataemia, it is essential to have sufficient understanding of anaerobic and aerobic mechanisms of
production and clearance. The consistency of the prognostic value emphasizes the place of lactate measurement in the risk-stratification
of critically ill patients. However, until recently the clinical benefit of lactate-guided resuscitation in critically ill patients was unknown. By
referring to two recent multi-centre randomized controlled trials, this review provides an update on this important topic. The first study
showed that lactate clearance was non-inferior to central venous oxygen saturation (ScvO2) as a goal of early resuscitation in patients
with severe sepsis or septic shock who presented to the Emergency Department (ED). The second study showed that in patients with
hyperlactataemia on ICU admission, lactate monitoring significantly reduced hospital mortality when adjusting for predefined risk factors, a finding that was consistent with important secondary endpoints. This suggests that lactate monitoring has clinical benefit and
that lactate measurement should be incorporated in goal-directed therapy.
Keywords - lactate, lactic acidosis, monitoring, goal-directed therapy

Introduction
Blood lactate was first measured in human blood by the German
physician-chemist Johann Joseph Scherer in 1843, when he described a lethal case of fulminant septic shock due to puerperal
fever in a young woman [1]. Nowadays, lactate is frequently measured in critically ill patients, usually with the aim of detecting
tissue hypoxia [2]. However, other processes not related to tissue hypoxia can also result in increased lactate levels [3], which
complicates its clinical interpretation and therapy. Until recently,
the clinical benefit of lactate monitoring in critically ill patients
had not been subjected to rigorous clinical evaluation. Therefore,
the question remains: should we routinely monitor lactate in the
critically ill and if so, when should we measure it, what would
be the therapeutic consequences and would this improve patient
outcome?

within 15 minutes, storage <4C or use of fluoride oxalate tubes

are suggested. Infusion of Ringers lactate does not hamper the
accuracy of lactate measurement [11]. Finally, renal replacement therapy eliminates only negligible amounts of lactate [12],
although lactate-containing buffer solutions are able to induce
transient hyperlactataemia [13,14].
The level of lactate should not be estimated from other acid
base variables, as there is no clinically important relationship with
pH, base excess or anion gap [15,16]. Lactate is only responsible
for a minor percentage of metabolic acidosis in critically ill patients [17] and lactate or non-lactate etiologies of metabolic acidosis are associated with different mortality rates [18]. Therefore,
although hyperlactataemia has often been associated with the
presence of a metabolic acidosis, this relationship does not appear to be at all straightforward.

Accuracy of lactate measurement

Blood lactate levels can be measured using the hospitals central laboratory, point-of-care blood gas analyzers or hand-held
devices. Generally, all have reported small biases with clinically
acceptable limits of agreement [4,5]. Most investigators found
satisfactory agreement comparing capillary, venous or central/
mixed venous levels with arterial levels [6-8]. Ongoing in-vitro
glycolysis might occur after blood sampling, resulting in erroneous elevation of lactate levels [9], particularly in cases of leucocytosis or high hematocrit [10]. To avoid this problem, analysis

Causes of hyperlactataemia
Traditionally, hyperlactataemia has been associated with tissue
hypoxia. This causal relationship has been confirmed by experimental [19] and clinical [2] studies. Furthermore, even when systemic oxygen delivery is sufficient for metabolic demand, microcirculatory processes hampering oxygen utilization at the tissue
level may also raise lactate levels.
In addition to these anaerobic causes, the following aerobic
mechanisms can also contribute to hyperlactataemia:
- Catecholamine-stimulated increased Na-K-pump activity,
which increases aerobic glycolysis [3]
- Cytokine-mediated enhanced glycolysis [20,21]
- Mitochondrial dysfunction [22,23]
- Impaired activity of pyruvate dehydrogenase (PDH) in sepsis
[24]

Correspondence
T Jansen
E-mail: t.c.jansen@erasmusmc.nl

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TC Jansen

- Thiamin deficiency (beri-beris disease) [25]

- Liver dysfunction [26-28]
- Pulmonary lactate production [29,30], reflecting metabolic adaptations in response to inflammatory mediators
- Alkalosis; H+-linked carrier transport mechanism across the
cell membrane [31]
- Epinephrine [32, 33], metformin, nucleosidic reverse transcriptase inhibitors [34], methanol, cyanide [35] or ethyleneglycol [36].
Prognosis of hyperlactataemia
In a recent systematic Health Technology Assessment, all available studies that addressed the prognostic value of lactate
in the ED or the ICU were searched [37]. In the ED setting, the

area under the receiver operating characteristic curve (AUROC)

for mortality varied from 0.67 [38] to 0.98 [39], which indicates
moderate to excellent capability of discriminating non-survivors
from survivors. In the ICU setting, AUROC varied from 0.53 [40]
and 0.58 [41] to 0.86 [42]. To answer the question whether or
not a hyperlactataemic patient will die, which is what clinicians
want to know when individually assessing patients, the positive
predictive value or post-test probability is important. In some of
the studies included in the Health Technology Assessment, this
value was very low (4-15% [38,43,44]). However, comparison of
the pre-test probability (population mortality rate) with the posttest probability determines the value that lactate can add in risk-

Figure 1B. Additional treatment algorithm lactate group

Figure 1A. Early lactate-guided therapy in ICU patients study.
Treatment algorithm of control and lactate group.

Jansen et al. [54]. If lactate became 2,0 mmol/l, a further decrease was no longer
required. Fluid responsiveness was assessed by a fluid challenge of 200 mL crystalloids or colloids. The goal was an increase in MAP, ScvO2 or stroke volume, or a
Jansen et al. [54]. The goal for CVP was 12-15 mmHg in mechanically
ventilated patients. Besides the static CVP goals, CVP was used as a
dynamic safety limit during fluid challenges. Both crystalloids and colloids could be used at the discretion of the clinician. Albumin was not
a standard resuscitation fluid in the participating centers. The goal for
hemoglobin was 10 g/dl in patients with cardiac ischemia. (Hemoglobin
7.0 g/dL = 4.3 mmol/L, 10 g/dL = 6.2 mmol/L)

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decrease in heart rate. CVP was used as a dynamic safety limit: if CVP increased
2 mmHg, fluid administration was continued, if CVP increased > 2 and 5 mmHg,
fluid challenge was repeated after 10 minutes, if CVP increased 5 mmHg, fluid
administration was stopped. Before administration of vasodilators, fluid responsiveness was assessed and fluids were infused if necessary. The recommended
dose for nitroglycerin was 2 mg in hour followed by 2 mg per hour. Hemoglobin
7.0 g/dL = 4.3 mmol/L , 10 g/dl = 6.2 mmol/L, NTG=nitroglycerine, RBCs= red
blood cell transfusions

Netherlands Journal of Critical Care

Lactate revisited: is lactate monitoring beneficial for ICU patients?

stratification. From the evaluated studies, it is clear that lactate

generally increased the ability to predict non-survival, both in the
ED and the ICU settings. The consistency of this finding means
that lactate certainly has a place in the risk-stratification of critically ill patients.
As early identification of critical illness is widely acknowledged
as a vital step towards improving survival [45-47], recent studies
have transferred the prognostic ability of lactate monitoring from
the hospital to the pre-hospital setting, with promising results
[48,49]. These recent data indicate a new avenue of research into
the earliest possible treatment of hemodynamic shock. Further
studies are required to evaluate whether the use of lactate measurement in Emergency Medical Services has potential for triage
decisions, earlier detection of occult shock and earlier start of
goal-directed therapy in order to, ultimately, influence patient
outcome.
Why do patients with hyperlactataemia die?
Lactate itself is not harmful. It is regularly administered to patients without harmful effect when using Ringers lactate or lactate-containing buffer solutions for renal replacement therapy.
In addition, just reducing lactate levels by the administration of
dichloroacetate was not associated with a clinical benefit [50].
These observations show that lactate itself does not cause bad
outcome, remembering that increased lactate is just associated
with adverse outcome. This is also reflected by the association
between lactate levels and multiple organ failure. For example,
both the duration of and level of hyperlactataemia are related to
the Sequential Organ Failure Assessment (SOFA) score [51]. The
relationship between hyperlactataemia and organ failure or mortality brings us to the most important question: can early lactateguided resuscitation actually prevent organ dysfunction and, ultimately, improve patient survival?
Does lactate monitoring benefit critically ill patients?
Lactate monitoring has the potential to improve outcome when
hyperlactataemia triggers goal-directed DO2 therapy. Until re-

cently, the only known single-centre clinical trial advocating such

lactate-directed therapy was performed in post cardiac surgery
patients [52]. It showed a reduction in length of stay but the findings could not easily be extrapolated to other critical care populations.
In 2010, two multi-centre clinical trials were published on the
clinical value of lactate-directed therapy [53,54].
Lactate-guided therapy: The USA
Jones et al. tested the hypothesis of non-inferiority between lactate clearance and central venous oxygen saturation (ScvO2) as
goals of early resuscitation in patients presenting to the ED with
severe sepsis or septic shock [53]. In their three-centre, open-label, randomized controlled study, 300 patients were randomized
to either a goal of ScvO2 of at least 70% or a decrease in lactate
of at least 10%, both in combination with normalization of central
venous pressure (CVP) and mean arterial pressure (MAP). The intervention lasted until all goals were achieved or for up to 6 hours.
There were no differences found in treatments administered during the initial 72 hours of hospitalization. In-hospital mortality in
the lactate group was non-inferior to the ScvO2 group (17% vs.
23%, 95% CI for the 6% difference -3% to 15%).
Early goal-directed therapy is resource intensive, and the
relative contributions of the individual components to the overall
treatment effect are not well characterized. This has become particularly relevant since controversy has been generated [55,56]
regarding the results of the reference trial of Rivers [57]. The study
of Jones et al. provides the first step in identifying the key components responsible for the efficacy of this strategy, with the goal
of reducing the burden of implementation without loss of benefit
[58].
Time, expertise, and specialized equipment required to continuously measure ScvO2 might pose a barrier to the implementation of ScvO2-driven resuscitation programmes in the ED [59,60].
However, although the study of Jones et al. possibly eliminates
the need for a specialized catheter and its associated electronic
instrumentation, it does not prevent the need for a central venous

Table 1. Mortality

Variable

Control group (n=177)

Lactate group (n=171)

Relative risk (95%CI)

P Value

In-hospital mortality

43.5% (77/177)

33.9% (58/171)

0.78 (0.60-1.02)

0.067

28-day mortality

35.6% (63/177)

30.4% (52/171)

0.85 (0.63-1.16)

0.30

ICU-mortality

34.5% (61/177)

28.7% (49/171)

0.83 (0.61-1.14)

0.24

Unadjusted analysis - % (n)*

Adjusted analysis - hazard ratio (95% CI)

In-hospital mortality

0.61 (0.43-0.87)

0.006

28-day mortality

0.75 (0.52-1.09)

0.134

ICU-mortality

0.66 (0.45-0.98)

0.037

Jansen et al. [54] *Chi-square test. Cox proportional hazard analysis with adjustment for age, sex, APACHE II (modified; at baseline) and SOFA (modified;
at baseline), and stratified for centre and sepsis group, as predefined in the study protocol.

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TC Jansen

catheter. Furthermore, measuring lactate without venous oxygen

saturations might put some patients at risk as S(c)vO2 can be a
valuable tool to differentiate anaerobic from aerobic hyperlactataemia, which often requires different treatment [61]. In addition,
it seems questionable whether the target of a 10% reduction in
lactate in 6 hours is sufficient to guarantee adequate resuscitation; e.g., has a patient been treated well enough when the lactate level has decreased from 6.7 to 6.0 mmol/l after 6 hours of
resuscitation?
Another important limitation is that only 10% of the patients
received either dobutamine or red blood cell transfusion. Because
fluids and vasopressor administration were guided by CVP and
MAP in both groups, this means that the potential difference in
protocol actions directly attributable to either lactate clearance
or ScvO2 was very small. This complicates the interpretation of
the study of Jones and colleagues because in retrospect, it might
seem implausible that a change in this resuscitation target could
increase mortality by 10%, the non-inferiority margin selected for
the trial [58].

Lactate-guided therapy: The Netherlands
In a two-year, multi-centre, open-label, randomized controlled
trial conducted in four centres in the region of Rotterdam [54],
348 patients were randomly allocated to either lactate-guided
monitoring (lactate group) or non-lactate guided monitoring (control group) during the first eight hours of ICU stay (figure 1A). In
the lactate group, treatment was guided by lactate levels with
the objective to decrease lactate by 20% or more per two hours
(figure 1B); in the control group the treatment team had no knowledge of lactate levels (except for the admission value) during the
first eight hours. This resulted in administration of more fluids and
vasodilators in the lactate group. A non-significant 9.6% absolute
mortality reduction was found in the unadjusted primary outcome
analysis (p=0.067)(table 1), which was consistent with a highly
significant mortality reduction in the pre-defined multivariable
analysis (p=0.006) and with a decrease in important secondary
outcome measures such as organ failure, duration of mechanical
ventilation and length of ICU-stay.
Two results of this study need further attention. First, there
was a discrepancy in the significance between the unadjusted
and adjusted primary outcome analysis. The statistical method
of predefined covariate adjustment increased the power of the
study without requiring increased sample size [62]. This tech-

nique made treatment effect estimation more individualized, reduced noise in the analysis and thereby improved the statistical
power, i.e. the ability to identify a smaller treatment effect when it
really exists. The second study finding that needs attention is the
similar course of lactate levels in the two groups. This suggests
no causal relationship between the administered therapy (i.e. additional fluid resuscitation and vasodilator therapy) and hyperlactataemia. Instead, lactate might be an epiphenomenon of severity
of disease. By acting as a warning signal, clinicians might have
interpreted hyperlactataemia as a warning that their patients did
not clinically improve or even deteriorate in the presence of stable
hemodynamic parameters. This could have triggered intensified
resuscitation or attention to other causes than inadequate tissue
perfusion of impaired lactate reduction (e.g. non-controlled septic
focus). Additionally, ScvO2 monitoring, which was mandatory in
the lactate group and facultative in the control group, might have
had an impact on the observed outcome as well. Unfortunately,
the design of the study does not allow definite conclusions on the
mechanism behind the outcome benefit to be drawn.
The strengths of the study include the immediate start of the
study treatment following ICU admission, the use of hospital mortality as the primary endpoint and its multi-centre design, particularly as growing concerns have been raised regarding adoption of
single-centre studies in clinical guidelines [63]. Finally, the results
extend the concept of Rivers early-goal-directed therapy from
the ED to the ICU and to other patient groups besides severe
sepsis or septic shock.
Conclusion
Lactate measurement is accurate and clinicians at the bedside
can trust the numerical value they collect. However, sufficient
understanding of anaerobic and aerobic mechanisms of production and clearance is essential for the correct interpretation of
hyperlactataemia. Although the prognostic value of lactate can
vary considerably depending on the patient population, lactate
generally increases the ability to predict non-survival, both in the
ED and ICU. Until recently, there was a lack of clinical trials investigating the value of lactate-guided resuscitation therapy. Two
recent multi-centre trials have confirmed that the use of lactate
levels in goal-directed therapy improves clinical outcome [53,54].
These findings suggest that lactate monitoring is beneficial for
ICU patients and that it should be incorporated in early resuscitation strategies for critically ill patients.

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