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Relative hyperlactatemia and hospital mortality in critically ill patients: A retrospective multi-centre study

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Higher lactate concentrations within the normal reference range (relative hyperlactatemia) are not considered clinically significant. We tested the hypothesis that relative hyperlactatemia is independently associated with an increased risk of hospital death. This observational study examined a prospectively obtained intensive care database of 7,155 consecutive critically ill patients admitted to the Intensive Care Units (ICUs) of four Australian university hospitals. We assessed the relationship between ICU admission lactate, maximal lactate and time-weighted lactate levels and hospital outcome in all patients and also in those patients whose lactate concentrations (admission n = 3,964, maximal n = 2,511, and time-weighted n = 4,584) were under 2 mmol.L-1 (i.e. relative hyperlactatemia). We obtained 172,723 lactate measurements. Higher admission and time-weightedlactate concentration within the reference range was independently associated with increased hospital mortality (admission odds ratio (OR) 2.1, 95% confidence interval (CI) 1.3 to 3.5, P = 0.01; time-weighted OR 3.7, 95% CI 1.9 to 7.00, P < 0.0001). This significant association was first detectable at lactate concentrations > 0.75 mmol.L-1. Furthermore, in patients whose lactate ever exceeded 2 mmol.L-1, higher time-weighted lactate remained strongly associated with higher hospital mortality (OR 4.8, 95% CI 1.8 to 12.4, P < 0.001). In critically ill patients, relative hyperlactataemia is independently associated with increased hospital mortality. Blood lactate concentrations > 0.75 mmol.L-1 can be used by clinicians to identify patients at higher risk of death. The current reference range for lactate in the critically ill may need to be re-assessed.
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Nichol et al. Critical Care 2010, 14:R25
http://ccforum.com/content/14/1/R25
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RESEARCH
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Research
Relative hyperlactatemia and hospital mortality in
critically ill patients: a retrospective multi-centre
study
Alistair D Nichol*
1,3
, Moritoki Egi
2
, Ville Pettila
1
, Rinaldo Bellomo
1,4
, Craig French
5
, Graeme Hart
4
, Andrew Davies
3
,
Edward Stachowski
6
, Michael C Reade
4
, Michael Bailey
1,3
and David James Cooper
1,3
Abstract
Introduction: Higher lactate concentrations within the normal reference range (relative hyperlactatemia) are not
considered clinically significant. We tested the hypothesis that relative hyperlactatemia is independently associated
with an increased risk of hospital death.
Methods: This observational study examined a prospectively obtained intensive care database of 7,155 consecutive
critically ill patients admitted to the Intensive Care Units (ICUs) of four Australian university hospitals. We assessed the
relationship between ICU admission lactate, maximal lactate and time-weighted lactate levels and hospital outcome in
all patients and also in those patients whose lactate concentrations (admission n = 3,964, maximal n = 2,511, and time-
weighted n = 4,584) were under 2 mmol.L
-1
(i.e. relative hyperlactatemia).
Results: We obtained 172,723 lactate measurements. Higher admission and time-weightedlactate concentration
within the reference range was independently associated with increased hospital mortality (admission odds ratio (OR)
2.1, 95% confidence interval (CI) 1.3 to 3.5, P = 0.01; time-weighted OR 3.7, 95% CI 1.9 to 7.00, P < 0.0001). This significant
association was first detectable at lactate concentrations > 0.75 mmol.L
-1
. Furthermore, in patients whose lactate ever
exceeded 2 mmol.L
-1
, higher time-weighted lactate remained strongly associated with higher hospital mortality (OR
4.8, 95% CI 1.8 to 12.4, P < 0.001).
Conclusions: In critically ill patients, relative hyperlactataemia is independently associated with increased hospital
mortality. Blood lactate concentrations > 0.75 mmol.L
-1
can be used by clinicians to identify patients at higher risk of
death. The current reference range for lactate in the critically ill may need to be re-assessed.
Introduction
In healthy individuals there is a continuous cycle of lactate
production and metabolism, which ensures that blood lac-
tate concentrations are normally low [1,2]. Higher blood
lactate concentrations occur when lactate production
exceeds clearance, when clearance capacity is decreased or
more frequently when both occur simultaneously [3,4]. Ele-
vated blood lactate concentrations above the accepted nor-
mal reference range (absolute hyperlactataemia) are
common and associated with increased hospital mortality in
the critically ill [5-12]. Their usefulness in identifying criti-
cally ill patients at higher risk of death has led to the adop-
tion of lactate measurement in most blood gas analyzers
and the frequent measurement of lactate in the critically ill.
While the normal lactate concentration in unstressed indi-
viduals is 1.0 ± 0.5 mmol.L
-1
[1,2], patients with critical ill-
ness are considered to have normal lactate levels at
concentrations of less than 2 mmol.L
-1
[13]. Furthermore,
this 2 mmol.L
-1
cut off may be considered to be a conserva-
tive threshold as some have suggested that a level of up to 4
mmol.L
-1
is within the normal limits [14].
However, it is unknown whether a higher blood lactate
concentration within the current reference range (relative
hyperlactataemia) might also be associated with increased
hospital mortality. This knowledge would be clinically
important because the currently used upper reference limit
* Correspondence: Alistair.Nichol@med.monash.edu.au
1
Australian and New Zealand Intensive Care-Research Centre, School of Public
Health and Preventive Medicine, Monash University, Alfred Hospital Campus,
75 Commercial Road, Prahran, VIC 31821, Australia
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for lactatemia may fail to identify many patients who are at
higher risk of death.
We hypothesized that higher blood lactate concentrations
within the reference range would be associated with an
increased risk of hospital death and investigated the rela-
tionship between ICU admission, maximal and time-
weighted blood lactate concentrations and hospital mortal-
ity in a large cohort of critically ill patients.
Materials and methods
The data collection and the data analysis for this study are
part of ongoing de-identified data auditing processes across
the participating hospitals, which have all waived the need
for informed consent. The Austin Hospital Ethics Commit-
tee approved the study.
Study population and data sources
We conducted this study as a four-centre retrospective
investigation of a prospectively gathered intensive care
database. Four Australian university teaching hospital
intensive care units enrolled patients in this study. We
included all patients admitted to these ICUs from January
2000 to October 2004.
The blood lactate concentration data used for this study
were stored and retrieved electronically. We obtained age,
sex, use of mechanical ventilation, reason for ICU admis-
sion, surgical and non-surgical divided into (trauma, car-
diac/vascular, gastrointestinal tract, neurological and
thoracic/respiratory diseases), and Acute Physiology and
Chronic Health Evaluation (APACHE) II score [15] from
the electronic data repositories of each ICU, using prospec-
tively collected data as part of a continuing data collection
by the Australian and New Zealand Intensive Care Society -
Centre for Outcome and Resources Evaluation (ANZICS-
CORE). We coded admission diagnosis by APACHE III
system used by the ANZICS-CORE - Adult Patient Data-
base [16].
All patients had initial arterial lactate and blood gas mea-
sured by blood gas analyser (Rapilab, Bayer Australia, Syd-
ney, NSW, Australia, upper normal limit 2.00 mmol.L
-1
) at
the time of admission to the ICU. The timing of repeat mea-
surements was at the discretion of the managing critical
care team. All subsequent blood lactate measurements were
performed using the same blood-gas analyzer in each hospi-
tal. A normal (within reference) lactate was defined as a
concentration between 0.00 and 2.00 mmol.L
-1
[13]. Labo-
ratories in the participating hospitals comply with standards
of the National Association of Testing Authorities [17] and
the Royal College of Pathologists of Australasia [18].
Statistical Analysis
We used the ICU admission (Lac
ADM
) and maximal (Lac-
MAX
) blood lactate concentrations to indicate the admission
and highest value recorded while in the ICU. We first
assessed blood lactate concentration in all patients and sec-
ond, in those patients whose ICU admission (Lac
ADM
), and
maximal (Lac
MAX
) blood lactate concentrations never
exceeded the normal reference range (that is, < 2 mmol.L
-
1
). In addition, to avoid the potential effect of surveillance
bias due to the increased blood lactate monitoring in more
severely ill patients, we calculated the time-weighted lac-
tate concentration (Lac
TW
). This time-weighted method is
more representative of the true lactate level during the ICU
stay than the arithmetic mean, as it assumes a linear trend
between each individual lactate measurement for each
patient during their ICU stay. This method was modified
from, and used in accordance with, an approach previously
used by Finney et al to describe hyperglycaemia [19].
As the relationship between Lac
ADM
, Lac
MAX
, Lac
TW
and
mortality was expected not to be linear in nature, categori-
cal variables were created. We divided lactate into four
bands: normal (0.00 to 2.00 mmol.L
-1
); mild hyperlactemia
(2.01 to 4.00 mmol.L
-1
); moderate hyperlactatemia (4.01 to
6.00 mmol.L
-1
) and severe hyperlactatemia (> 6.01
mmol.L
-1
) for comparison.
The normal range of lactate (0.00 to 2.00 mmol.L
-1
) was
subsequently divided into eight bands. However, due to the
small number of patients with values under < 0.75 mmol.L
-
1
we combined the three lower octiles to achieve adequate
size for statistical comparison. We therefore compared: the
lower limit of normal (LLN, 0.00-0.75 mmol.L
-1
); upper
limit of normal (ULN, 1.76 to 2.00 mmol.L
-1
) and four
intermediate categories (0.75 to 1.00 mmol.L
-1
); (1.01 to
1.25 mmol.L
-1
); (1.26 to 1.50 mmol.L
-1
); (1.51 to 1.75
mmol.L
-1
).
To confirm that any association between Lac
TW
levels
within the normal range and mortality was not being biased
by patients who had individual lactate concentrations above
2 mmol.L
-1
while in the ICU, we then examined the associ-
ation between Lac
TW
and mortality in the cohort of patients
whose lactate never exceeded 2 mmol.L
-1
.
The primary outcome for analysis was hospital mortality
and the secondary outcome was ICU mortality. We per-
formed crude univariate analysis with lactate as a catagorial
variable for comparison between groups according to hos-
pital survival status using chi-square test for proportions,
Student t-test for normally distributed outcomes and Wil-
coxon rank sum tests otherwise. In addition, we performed
multivariate analysis where we adjusted for all available
predictors of hospital mortality included in the models
(gender, age, APACHE II, mechanical ventilation, surgical
admission and diagnosis type) determined by backward
elimination of non-significant variables. Furthermore, to
determine if the lactate associations were consistent across
patient admission diagnosis subgroups and study hospitals,
we examined the interactions between measures of lactate
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and other variables in the model. We report results from the
multivariate models using odds ratios, OR (95% confidence
intervals, 95% CI).
All analyses were performed using SAS version 9.2 (SAS
Institute Inc, Cary, NC, USA). A two-sided P-value of 0.05
was considered to be statistically significant.
Results
We studied a heterogeneous cohort of 7,155 critically ill
patients with 172,723 blood lactate measurements (Table
1). The absolute blood lactate concentrations (admission
lactate Lac
ADM
, maximal lactate Lac
MAX
and time-weighted
lactate Lac
TW
), were significantly higher in non-survivors
compared to survivors (Table 1).
Overall assessment of hyperlactatemia (absolute
hyperlactatemia)
A higher crude Lac
ADM
, Lac
MAX
and Lac
TW
concentration
above the reference range (0.00 to 2.00 mmol.L
-1
) was
associated with a higher hospital and ICU mortality rate
(Figure 1, Panel a, b, c, respectively). Multivariate analysis
showed that compared to the current reference lactate con-
centration (0.00 to 2.00 mmol.L
-1
) a higher Lac
ADM
(> 8
mmol.L
-1
), Lac
MAX
(> 10 mmol.L
-1
) and Lac
TW
(> 6
mmol.L
-1
) blood lactate concentration was strongly associ-
ated with an increased adjusted hospital mortality (Lac
ADM
OR213.49 (95% CI 28.69 to 1588.71), P < 0.0001); Lac
MAX
OR8.44 (95% CI 5.99 to 11.91), P < 0.0001) Lac
TW
OR
37.78 (95% CI 18.72 to 76.25), P < 0.0001). This associa-
tion between lactate (Lac
ADM
, Lac
MAX
and Lac
TW
) and
adjusted mortality was independent of admission diagnosis,
admission hospital and APACHE II score.
Assessment of relative hyperlactatemia
We further identified the cohorts of patients with a Lac
ADM
(n = 3,964), Lac
MAX
, (n = 2,511) and with Lac
TW
(n =
4,584) within the current reference range (0.00 to 2.00
mmol.L
-1
). Table 2 shows the clinical characteristics of the
Lac
ADM
subgroup of patients divided into hospital survivors
and non-survivors. Patients with an admission or time
weighted lactate level just below 2 mmol.L
-1
had a crude
hospital mortality rate of approximately 20% (Figures 2a
and 3b). Lac
ADM
, Lac
MAX
and Lac
TW
were significantly
higher in hospital non-survivors compared to survivors
(Table 2).
A higher admission lactate (Lac
ADM
) concentration
within the reference range was associated with higher crude
hospital mortality (Figure 2a), with a mortality rate of
18.5% in the higher risk cohort. There also was a significant
independent relationship between Lac
ADM
within the refer-
ence range and adjusted hospital mortality (Figure 2b).
Higher Lac
TW
within the reference range was independently
associated with higher adjusted hospital mortality (Figure
3b) with a crude mortality rate of 21.1% in the higher risk
cohort (Figure 3a). In addition, higher Lac
TW
(1.5 to 2.00
mmol.L
-1
vs 0.00 to 0.75 mmol.L
-1
) was also independently
associated with hospital mortality in the cohort of patients
whose lactate never exceeded 2 mmol.L
-1
(Lac
TW
OR4.8,
95% CI 1.8 to 12.4, P < 0.001, n = 2,254).
The association between adjusted hospital mortality and
Lac
ADM
and Lac
TW
lactate concentrations within the normal
range was first detected at lactate concentrations over 0.75
mmol.L
-1
and the strength of this association increased with
higher lactate concentrations within the reference range
(Figures 2b and 3b). The detected association between lac-
tate within the reference range and adjusted hospital mortal-
ity was independent of admission diagnosis, admission
hospital and APACHE II score. Interestingly, a higher crude
and adjusted maximal lactate (Lac
MAX
) concentration
within the normal reference range was not independently
associated with increased hospital mortality (data not
shown).
Discussion
Statement of key findings
We tested whether higher levels of lactatemia within the
current reference range (relative hyperlactemia) are inde-
pendently associated with an increased risk of hospital mor-
tality. We found that most patients admitted to ICU had an
admission or time weighted lactate level within the current
normal reference range and yet a crude hospital mortality
rate of approximately 20%. We also found that higher ICU
admission (Lac
ADM
) and time weighted (Lac
TW
) blood lac-
tate concentrations within the normal reference range were
strongly and independently associated with hospital mortal-
ity. In addition, this increased mortality risk was first
detected at lactate concentrations above 0.75 mmol.L
-1
.
Comparison with previous studies
Many studies have found that either Lac
ADM
or Lac
MAX
above the reference range are associated with higher mor-
tality following cardiothoracic surgery [12], trauma [7],
major abdominal surgery [5], high risk surgery, major vas-
cular trauma, sepsis [20], liver disease [21], in ventilated
neonates [22] and critically ill children [11]. Our observa-
tions that the extent of absolute hyperlactatemia is strongly
linked with mortality independent of admission diagnostic
group in a large mixed cohort of critically ill patients con-
firm that lactate is a useful marker in the intensive care set-
ting to identify patients at high risk of death. In addition,
these findings suggest that other observations related to lac-
tate obtained from our cohort might also be generalizable.
In addition, we found that time weighted lactate (Lac
TW
), a
representation of the lactate concentration throughout the
ICU stay, was strongly associated with increasing hospital
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mortality. The finding that the duration of this derangement
while in the ICU is associated with increased mortality
expands previous work demonstrating that periods of sus-
tained hyperlactataemia (that is, ongoing excess production
or decreased clearance of lactate) is associated with an
increased risk of death [3,5,23-28].
To our knowledge, this is the first study to assess the rela-
tionship of higher lactate concentrations within the current
reference range and mortality. We found a strong associa-
tion between an increased Lac
ADM
and Lac
TW
within the
current reference range and increased hospital mortality.
Furthermore, we demonstrated that higher Lac
TW
in the
cohort of patients whose lactate ever exceeded 2 mmol.L
-1
was also strongly associated with higher hospital mortality.
These results suggest that relative hyperlactaemia may be
useful in identifying critically ill patients at high risk of
death. Furthermore, we have demonstrated that the higher
mortality associated with higher lactate levels (Lac
ADM
and
Lac
TW
) within the normal reference range is detectable at
all concentrations > 0.75 mmol.L
-1
compared to 0.00 to
0.75 mmol.L
-1
. In their aggregate, these results suggest that
the transition from physiological to pathological lactatemia
occurs at a concentration well below 2.00 mmol.L
-1
and that
an elevated Lac
ADM
and/or Lac
TW
> 0.75 mmol.L
-1
identi-
fies critically ill patients at higher risk of death.
Implications for clinicians
These findings expand our understanding of lactate as a
clinical biomarker in the ICU. Relatively small changes in
lactate homeostasis as detected by higher blood concentra-
tions within the reference range may reflect important oth-
erwise undetected physiological changes, which may reflect
widespread metabolic stress [29] and increased use of lac-
tate as a fuel source [30].
A higher time weighted lactate (Lac
TW
) below 2 mmol.L
-
1
, the cohort of patients whose lactate ever exceeded 2
mmol.L
-1
, was also strongly associated with increased hos-
pital mortality. This finding extends our understanding of
the reference range by emphasizing the role of the duration
of lactate derangement in predicting increased risk of death
Table 1: Clinical characteristics of hospital survivors and non-survivors
nHospital
Non-survivors
nHospital
Survivors
P-value
Male Sex 1,561 57.3% (894) 5,590 60.2% (3,365) 0.035
APACHE II score 1,250 24.6 (8.1) 4,845 15.1 (6.6) < 0.0001
Age (yr) 1,428 65.8 (16.6) 5,181 59.7 (18.9) < 0.0001
Number on mechanical
ventilation
1,434 81.2% (1164) 5,515 55.6% (3,066) < 0.0001
Surgical patients 1,565 28.4% (444) 5,590 48.7% (2,722) < 0.0001
Diagnosis at admission
Cardiac and vascular 1,565 26% (407) 5,590 21.6% (1,207) 0.0003
Thoracic and respiratory 1,565 18.5% (290) 5,590 18.9% (1,057) 0.69
Trauma 1,565 2.2% (34) 5,590 7.9% (442) < 0.0001
Neurological 1,565 14.1% (221) 5,590 10.9% (609) 0.0004
Gastrointestinal tract
diseases
1,565 14.1% (221) 5,590 22.9% (1,280) < 0.0001
Other 1,565 25% (391) 5,590 17.7% (989) < 0.0001
ICU stay (days) 1,559 3.0 (1.5 to 6.6) 5,589 2.5 (1.6 to 4.9) < 0.0001
Hospital stay (days) 1,312 9 (3 to 24) 5,131 14 (8 to 29) < 0.0001
Admission blood lactate
(mmom.L-1)
1,395 2.3 (1.4 to 4.4) 5,037 1.5 (1.0 to 2.4) < 0.0001
Time-weighted blood lactate
(mmom.L-1)
1,411 2.0 (1.4 to 3.3) 4,977 1.3 (1.0 to 1.8 < 0.0001
Max blood lactate (mmom.L-1)
1,565 4.0 (2.2 to 7.5) 5,590 2.1 (1.4 to 3.3) < 0.0001
Data are expressed as, percentage (number), (standard deviation) or median (interquartile range).
APACHE II, Acute Physiology and Chronic Health Evaluation II.
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[3,5,23-25,28,31,32]. Furthermore, it highlights the clinical
importance of persistently higher lactate concentrations.
This notion may explain why Lac
TW
(which reflects the
extent and duration of the derangement) but not Lac
MAX
(which only reflects its momentary extent) predicted mor-
tality within the reference range.
Our results suggest that ICU clinicians confronted with a
patient with a Lac
ADM
or Lac
TW
(persistently higher lactate)
over 0.75 mmol.L
-1
should look for any remediable causes
of physiological stress and appreciate that these patients are
at increased risk of an adverse outcome.
Strengths and limitations of the study
The strengths of our study include the fact that it is the larg-
est investigation of lactatemia in a general multicenter
cohort of patients, thus carrying a higher degree of external
validity. It used data from > 170,000 measurements
obtained with state-of the-art technology, thus increasing
their accuracy and reproducibility. It used robust and clini-
cally relevant outcomes. It is the first to study the indepen-
dent relationship between relative hyperlactatemia and
outcome and identified clinically relevant findings. Limita-
tions of the study include the fact that it is retrospective in
design and thus potentially subject to systematic error and
bias. However, all the clinical and electronic data utilised
were collected prospectively in a large number of consecu-
tive critically ill patients in four ICUs. The data are numeri-
cal in nature and were measured independently; thus they
were not amenable to selection bias or unintended manipu-
lation. A number of common ICU therapeutic interventions
such as epinephrine [33], metformin [34], nucleoside ana-
logues in HIV [35], high-volume hemofiltration (HVHF)
with lactate-buffered replacement fluids [36] can all affect
lactate levels and we did not have information on their use.
We were therefore unable to include these in our multivari-
ate analyses. However, the size of our study and the
strength of the association between Lac
ADM
and Lac
TW
and
mortality within the reference range independent of admis-
sion diagnosis and hospital suggest that these factors are not
likely to have confounded the signal in this study. Despite
this, clinicians should be aware of the potential of these iat-
rogenic causes of relative or absolute hyperlactataemia.
Due to the smaller numbers of patients in the cohort with
Lac
ADM
and Lac
TW
in the lowest three octiles, we com-
Figure 1 Relationship among the admission, maximal and time weighted blood lactate concentration and mortality. Relationship among the
admission blood lactate concentration (Lac
ADM
) Panel (a); maximal blood lactate concentration (Lac
MAX;
) Panel (b); and time weighted blood lactate
concentration (Lac
TW
) Panel (c); and hospital and ICU mortality. The number of patients in each group is expressed as (n).
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Figure 2 Relationship between the admission blood lactate concentration within the normal range and mortality rate. Relationship between
the admission blood lactate (Lac
ADM
) concentration within the normal range and ICU and hospital mortality rate (Panel (a)). The number of patients
in each group is expressed as (n). Panel (b) displays the result (adjusted odds ratios (OR) with 95% Confidence Interval (CI)) of a multivariate analysis
assessing the association between admission blood lactate (Lac
ADM
) within the normal range and hospital mortality. (All ORs in the multivariate anal-
ysis are compared to the 0.00 to 0.75mmol.L
-1
group with the horizontal line representing an OR of 1.0.).
pressed these octiles into a single group (0.00 to 0.75
mmol.L
-1
) to provide sufficient numbers for statistical anal-
yses. This compression limited our ability to determine if
higher blood lactate concentrations below 0.75 mmol.L
-1
may also be associated with increasing mortality.
Future research
Our findings are novel and need to be confirmed by similar
studies in other countries or patient populations before they
can be considered to reflect a general biological principle.
Such studies should ideally be performed prospectively
with a simultaneous collection of information on interven-
tions, which may affect lactate by dilution (intravenous flu-
ids) or by changing its metabolism (drugs) and these studies
should ideally also include non-ICU cohorts of patients
(that is, Emergency Department patients). If these studies
confirm the value of relative hyperlactatemia, the reference
value for lactate in critically ill patients may require adjust-
ment.
Conclusions
In conclusion, higher Lac
ADM
and Lac
TW
blood lactate con-
centrations within the current reference range are associated
with greater hospital mortality. These results suggest that
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Figure 3 Relationship between time-weighted blood lactate concentration within the normal range and mortality rate. Relationship be-
tween time-weighted blood lactate (Lac
TW
) concentration within the reference range and ICU and hospital mortality rate (Panel (a)). The number of
patients in each group is expressed as (n). Panel (b) displays the result (adjusted odds ratios (OR) with 95% Confidence Interval (CI)) of a multivariate
analysis assessing the association between time-weighted blood lactate concentration (Lac
TW
) within the normal range and hospital mortality. Abbre-
viations: OR U95; odds ratio upper 95% CI; OR L95, odds ratios lower 95% CI. (All ORs in the multivariate analysis are compared to 0.00 to 0.75 mmol.L
-
1
group with the horizontal line representing an OR of 1.0.).
even relative hyperlactaemia is a useful biomarker in criti-
cal illness. They also suggest that the upper level of the ref-
erence value for lactate in critically ill patients may require
readjustment. Finally, they imply that clinicians should be
especially alert in all patients with admission and/or persis-
tent blood lactate concentrations within the current upper
limit of the reference range.
Key messages
• Blood lactate concentration is increasingly being mea-
sured in the critically ill.
• Higher intensive care unit blood lactate concentrations
above the current normal range (absolute hyperlac-
tatemia) are associated with increased hospital mortal-
ity.
• Higher intensive care unit admission blood lactate
concentrations within the current normal range (relative
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Table 2: Clinical characteristics for hospital survivors and non-survivors in patients with admission blood lactate
concentration within the reference range
nHospital
Non-survivors
nHospital
Survivors
P-value
Male Sex 607 58.2% (353) 3,357 59% (1,981) 0.71
APACHE II score 485 22.1 (7.3) 2,891 14.2 (6.2) < 0.0001
Age (yr) 556 66.0 (16.5) 3,090 60.7 (18.7) < 0.0001
Number on mechanical ventilation 551 77.3% (426) 3,313 48.7% (1,613) < 0.0001
Surgical patients 607 31% (188) 3,357 50.9% (1,709) < 0.0001
Diagnosis at admission
Cardiac and vascular 607 15.2% (92) 3,357 20.4% (685) 0.003
Thoracic and respiratory 607 24.2% (147) 3,357 20% (671) 0.017
Trauma 607 3.6% (22) 3,357 8.8% (295) < 0.0001
Neurological 607 18.1% (110) 3,357 10.9% (366) < 0.0001
Gastrointestinal tract diseases 607 15.3% (93) 3,357 23.7% (796) < 0.0001
Other 607 23.6% (143) 3,357 16.2% (544) < 0.0001
ICU stay (days) 606 3.0 (2.0 to 8.0) 3,357 2.0 (1.3 to 4.0) < 0.0001
Hospital stay (days) 501 12.9 (5.2 to 30.2) 3,064 13.0 (7.9 to 26.7) 0.041
Admission blood lactate (mmom.L-1)
607 1.3 (1 to 1.6) 3,357 1.2 (0.9 to 1.5) < 0.0001
Time-weighted blood lactate
(mmom.L-1)
599 1.4 (1.1 to 1.9) 3,212 1.20 (1.0 to 1.5) < 0.0001
Max blood lactate (mmom.L-1)
607 2.4 (1.6 to 4.1) 3,357 1.7 (1.3 to 2.4) < 0.0001
Data are expressed as, percentage (number), (standard deviation) or median (interquartile range) APACHE II, Acute Physiology and Chronic
Health Evaluation II.
hyperlactatemia) are associated with increased hospital
mortality.
• Higher time weighted intensive care unit blood lactate
concentrations within the current normal range (relative
hyperlactatemia) are associated with increased hospital
mortality.
• Higher blood lactate concentrations within the current
normal range can be used to identify patients at high
risk of death; possibly suggesting that we need to revise
the current definition of normal blood lactate concentra-
tion in the critically ill.
Abbreviations
ANZICS-APD: Australian and New Zealand Intensive Care Society - Adult
Patient Database; ANZICS-CORE: Australian and New Zealand Intensive Care
Society - Centre for Outcome and Resources Evaluation; APACHE: Acute Physio-
logical and Chronic Health Evaluation; LLN: lower limit of normal; Lac
ADM
:
admission lactate; Lac
MAX
: maximal lactate; Lac
TW
: time-weighted lactate; OR:
odds ratio; ULN: upper limit of normal.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
AN, RB, VP, GH, D JC, MB and ES carried out the database searches, participated
in the data collation and drafted the manuscript with AD, CF, ES, MR. AN, RB, VP,
DJC, MB conceived of the study, and participated in its design and coordina-
tion and helped to draft the manuscript. All authors read and approved the
final manuscript.
Acknowledgements
No financial support was received for the collation of this article.
Author Details
1
Australian and New Zealand Intensive Care-Research Centre, School of Public
Health and Preventive Medicine, Monash University, Alfred Hospital Campus,
75 Commercial Road, Prahran, VIC 31821, Australia,
2
Department of
Anaesthesiology and Resuscitology, 2-5-1 Shikata-cho, Okayama, 700-8558,
Japan,
3
Department of Intensive Care, The Alfred Hospital, 75 Commercial
Road, Prahran, VIC 31821, Australia,
4
Department of Intensive Care, The Austin
Hospital, 145 Studley Road, Heidelberg, VIC 3084, Australia,
5
Department of
Intensive Care, The Western Hospital, 148 Gordon Street, Footscray, VIC 3011,
Australia and
6
Department of Intensive Care, Westmead Hospital, Darcy Road &
Hawksebury Road, Westmead, Sydney, NSW 2145, Australia
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doi: 10.1186/cc8888
Cite this article as: Nichol et al., Relative hyperlactatemia and hospital mor-
tality in critically ill patients: a retrospective multi-centre study Critical Care
2010, 14:R25
... Further complications include a septic state [14,15] by presence of a confirmed or suspected infection, possibly aggravated by a severe or shock state with additional occurrence of multiple organ damage (MOF), and hypotension [14,15]. Several studies assessed the prognostic value of lactate in septic patients for adverse events (AE) and mortality [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Specifically, a value greater than 4.0 [mmol/L] was markedly associated with a substantial rate of subsequent death [18,20,28], although the general association seems to be linear [18,[25][26][27] and critically dependent on injury severity [29,30]. ...
... Several studies assessed the prognostic value of lactate in septic patients for adverse events (AE) and mortality [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Specifically, a value greater than 4.0 [mmol/L] was markedly associated with a substantial rate of subsequent death [18,20,28], although the general association seems to be linear [18,[25][26][27] and critically dependent on injury severity [29,30]. As a result, already cases with intermediately elevated lactate levels (2.0 -3.9 [mmol/L]) based on the actual threshold for hyperlactatemia as > 2 [mmol/L] [19,31] may be at-risk for developing a critical health state or death [17,[20][21][22][23][24]. ...
... Changes in treatment recommendations since the starting point of data acquisition were not considered. Investigation regarding the known association between lactate levels and mortality [17,18,25,27,28] was not performed. The high rate of early death in non-septic patients could result from airway or breathing impairment in the absence of head injury, complete loss of consciousness or severy bleeding, but specific cause attribution is not possible based on our data analysis. ...
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... In the subgroup analysis of 3 lactate levels, even the patients with normal lactate levels � 1.5mmol/L showed a significant OR for hospital mortality (Fig 3). A normal lactate level in unstressed individuals is 1.0±0.5 mmol/L [33]. However, Nicol et al. [33] documented significantly higher ORs for hospital mortality at lactate levels of 0.75-1.0,1.01-1.25, and 1.26-1.50 ...
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Hyperlactatemia is frequent in critically ill patients and is often used as a marker of adverse outcome. However, studies to date have focused on selected intensive care unit (ICU) populations. We sought to determine the occurrence and relation of hyperlactatemia with ICU mortality in all patients admitted to four ICUs in a large regional critical care system. All adults ([greater than or equal to] 18 years) admitted to ICUs in the Calgary Health Region (population 1.2 million) during 2003 to 2006 were included retrospectively. Lactate determinations were at the discretion of the attending service and hyperlactatemia was defined by a lactate level > 2 mmol/L. A total of 13,932 ICU admissions occurred among 11,581 patients. The median age was 63 years (37% female), the mean APACHE II score was 25 +/- 9 (n = 13,922). At presentation (within first day of admission), 12,246 patients had at least one lactate determination and the median peak lactate was 1.8 (IQR 1.2 to 2.9) mmol/L. The cumulative incidence of at least one documented episode of hyperlactatemia was 5578/13,932 (40%); 5058 (36%) patients had hyperlactatemia at presentation, and a further 520 (4%) developed hyperlactatemia subsequently. The incidence of hyperlactatemia varied significantly by major admitting diagnostic category (P < 0.001) and was highest among neuro/trauma patients 1053/2328 (45%), followed by medical 2047/4935 (41%), other surgical 900/2274 (40%), and cardiac surgical 1578/4395 (36%). Among a cohort of 9107 first admissions with ICU stay of at least one day, both hyperlactatemia at presentation (712/3634 (20%) vs. 289/5473 (5%); P < 0.001) and its later development (101/379 (27%) vs. 188/5094 (4%); P < 0.001) were associated with significantly increased case fatality rates as compared with patients without elevated lactate. After controlling for confounding effects in multivariable logistic regression analysis, hyperlactatemia was an independent risk factor for death. Hyperlactatemia is common among the critically ill and predicts risk for death.
Conference Paper
Objective: Hyperglycemia is common in critically ill patients, even in those without diabetes mellitus. Aggressiveglycemic control may reduce mortality in this population. However, the relationship between mortality, the control of hyperglycemia, and the administration of exogenous insulin is unclear. The objective was to determine whether blood glucose level or quantity of insulin administered is associated with reduced mortality in critically ill patients. Methods: This was a single-center, prospective, observational study of 531 patients (median age, 64 years) newly admitted over the first 6 months of 2002 to an adult intensive care unit (ICU) in a UK national referral center for cardiorespiratory surgery and medicine. The primary end point was intensive care unit (ICU) mortality. Secondary end points were hospital mortality, ICU and hospital length of stay, and predicted threshold glucose level associated with risk of death. Results: Of 531 patients admitted to the ICU, 523 under-went analysis of their glycemic control. Twenty-four-hour control of blood glucose levels was variable. Rates of ICU and hospital mortality were 5.2% and 5.7%, respectively; median lengths of stay were 1.8 (interquartile range, 0.9 to 3.7) days and 6 (inter-quartile range, 4.5 to 8.3) days, respectively. Multivariable logistic regression demonstrated that increased administration of insulin was positively and significantly associated with ICU mortality (odds ratio, 1.02 [95% confidence interval, 1.01 to 1.04] at a prevailing glucose level of 111 to 144 mg/dL [6.1 to 8.0 mmol/L] for a 1-IU/day increase), suggesting that mortality benefits are attributable to glycemic control rather than increased administration of insulin. Also, the regression models suggest that a mortality benefit accrues below a predicted threshold glucose level of 144 to 200 mg/dL (8.0 to 11.1 mmol/L), with a speculative upper limit of 145 mg/dL (8.0 mmol/L) for the target blood glucose level. Conclusions: Increased insulin administration is positively associated with death in the ICU, regardless of the prevailing blood glucose level. Thus control of glucose levels rather than of absolute levels of exogenous insulin appears to account for the mortality benefit associated with intensive insulin therapy demonstrated by others.
Article
Objective Analyze the clinical usefulness of lactate clearance (CL6) immediately after admission to the intensive care unit (ICU) in the first 6 hours. Setting Surgical-ICU. Centro de Asistencia del Síndicato Médico of Uruguay. Design Prospective, analytic and observational study performed between December 1, 2004 and March 31, 2006 in patients over 18 years whose arterial lactate level is higher than 2 mEq/l on admission to the ICU. Lactate clearance (CL6) was defined as the quotient between admissions (L0) minus the six hour lactate level (L6) divided by the admission lactate level. Sensitivity, specificity, positive and negative prognostic value for different CL6 cutoff were analyzed. The optimal CL6 was considered as the cutoff with the highest sum of sensitivity plus specificity. Results One hundred and eight patients were included; 64 patients died (mortality intra-ICU 59.3%). ICU mortality related variables, identified by Cox regression analysis, were CL6 (HR = 0.458; CI 95%, 0.239-0.876), L0 (HR = 1.16; CI 95%, 1.033-1.303) and SAPSII (HR = 1.019; CI 95%, 1.006-1.034). A CL6 equal to or lower than 0.4 was considered as optimal cutoff with a positive prognostic value of 74% and negative prog nostic value of 61%. It was also associated with lower survival adjusted by the SAPSII value and L0. Conclusions In critically ill surgical patients, whose CL6 on admission was over 2 mEq/l, lactate clearance in the first six hours could be useful to predict the ICU outcome.
Article
To determine whether there was a difference between epinephrine and norepinephrine in achieving a mean arterial pressure (MAP) goal in intensive care (ICU) patients. Prospective, double-blind, randomised-controlled trial. Four Australian university-affiliated multidisciplinary ICUs. Patients who required vasopressors for any cause at randomisation. Patients with septic shock and acute circulatory failure were analysed separately. Blinded infusions of epinephrine or norepinephrine to achieve a MAP >or=70 mmHg for the duration of ICU admission. Primary outcome was achievement of MAP goal >24 h without vasopressors. Secondary outcomes were 28 and 90-day mortality. Two hundred and eighty patients were randomised to receive either epinephrine or norepinephrine. Median time to achieve the MAP goal was 35.1 h (interquartile range (IQR) 13.8-70.4 h) with epinephrine compared to 40.0 h (IQR 14.5-120 h) with norepinephrine (relative risk (RR) 0.88; 95% confidence interval (CI) 0.69-1.12; P = 0.26). There was no difference in the time to achieve MAP goals in the subgroups of patients with severe sepsis (n = 158; RR 0.81; 95% CI 0.59-1.12; P = 0.18) or those with acute circulatory failure (n = 192; RR 0.89; 95% CI 0.62-1.27; P = 0.49) between epinephrine and norepinephrine. Epinephrine was associated with the development of significant but transient metabolic effects that prompted the withdrawal of 18/139 (12.9%) patients from the study by attending clinicians. There was no difference in 28 and 90-day mortality. Despite the development of potential drug-related effects with epinephrine, there was no difference in the achievement of a MAP goal between epinephrine and norepinephrine in a heterogenous population of ICU patients.
Article
To evaluate the correlation between the lactate in artery blood and lactate clearance rate and prognosis in patients with septic shock in intensive care unit (ICU). Prospectively studied 221 consecutive patients with septic shock from December 2005 to December 2007, the diagnosis of septic shock was made based on the criteria of 2001 ACCP/SCCM. For inclusion in the study, we required admission of the patients within 24 h of septic shock diagnosed. The criteria for exclusion from the study were an age of less than 18 years, pregnancy, serious inadequacy of liver and renal, needing blood purification, or acidosis result of biguanides drugs, or do-not-resuscitate. The eligible patients assigned to early goal-directed therapy. The 6-, 24- and 72-hour lactate clearance rate were calculated, the relationship between the level of lactate, lactate clearance rate, the APACHE II score, the number of failed organ and the 28-day mortality were evaluated. One hundred and five patients with septic shock were admitted, 74 male and 31 female, the mean age was 70 +/- 12 years. The 28-day mortality was 54.3%. The average APACHE II score at baseline was 20 +/- 8, the number of failed organs was 3.0 +/- 1.1 and the average concentration of lactate in artery blood at baseline was (3.8 +/- 3.6) mmol/L. Significant differences of the lactate at 0-, 6-, 24- and 72-hour were found between death group and survival group. There were 69 patients whose lactate in artery blood at baseline was > 2 mmol/L, 24 survived. The lactate clearance rate of 6- and 24-hour in survival group were significantly higher than death group (P < 0.01, P < 0.05, respectively), but the lactate clearance rate of 72-hour was not (P > 0.05). By using a multivariate logistic regression analysis, it showed that the lactate clearance rate of 6-hour was the independent predictive factor of survival. The area under the receiver operating characteristic curve (ROC) was 0.564, 0.649, 0.754, 0.784, respectively according to the level of the lactate at 0-, 6-, 24-hour and the 6-hour lactate clearance rate. The cutoff of 6-hour lactate clearance rate was >or= 30.0%, resulting in a sensitivity of 60.0% and a specificity of 77.3%. Dynamic observation of lactate level is very important for the survival in the patients with septic shock. Patients with elevated lactate and not decreased rapidly have a worse outcome. The 6-hour lactate clearance rate might be the indicator for predicting the prognosis of patients with septic shock.
Article
Analyze the clinical usefulness of lactate clearance (CL6) immediately after admission to the intensive care unit (ICU) in the first 6 hours. Surgical-ICU. Centro de Asistencia del Síndicato Médico of Uruguay. Prospective, analytic and observational study performed between December 1, 2004 and March 31, 2006 in patients over 18 years whose arterial lactate level is higher than 2 mEq/l on admission to the ICU. Lactate clearance (CL6) was defined as the quotient between admissions (L0) minus the six hour lactate level (L6) divided by the admission lactate level. Sensitivity, specificity, positive and negative prognostic value for different CL6 cutoff were analyzed. The optimal CL6 was considered as the cutoff with the highest sum of sensitivity plus specificity. One hundred and eight patients were included; 64 patients died (mortality intra-ICU 59.3%). ICU mortality related variables, identified by Cox regression analysis, were CL6 (HR=0.458; CI 95%, 0.239-0.876), L0 (HR=1.16; CI 95%, 1.033-1.303) and SAPSII (HR=1.019; CI 95%, 1.006-1.034). A CL6 equal to or lower than 0.4 was considered as optimal cutoff with a positive prognostic value of 74% and negative prognostic value of 61%. It was also associated with lower survival adjusted by the SAPSII value and L0. In critically ill surgical patients, whose CL6 on admission was over 2 mEq/l, lactate clearance in the first six hours could be useful to predict the ICU outcome.
Article
To evaluate whether the level and duration of increased blood lactate levels are associated with daily Sequential Organ Failure Assessment (SOFA) scores and organ subscores and to evaluate these associations during the early and late phases of the intensive care unit stay. Retrospective observational study. Mixed intensive care unit of a university hospital. 134 heterogeneous intensive care unit patients. None. We calculated the area under the lactate curve above 2.0 mmol/L (lactateAUC>2). Daily SOFA scores were collected during the first 28 days of intensive care unit stay to calculate initial (day 1), maximal, total and mean scores. Daily lactateAUC>2 values were related to both daily SOFA scores and organ subscores using mixed-model analysis of variance. This was also done separately during the early (<2.75 days) and late (>2.75 days) phase of the intensive care unit stay.Compared with normolactatemic patients (n = 78), all median SOFA variables were higher in patients with hyperlactatemia (n = 56) (initial SOFA: 9 [interquartile range 4-12] vs. 4 [2-7]; maximal SOFA: 10 [5-13] vs. 5 [2-9]; total SOFA: 28 [10-70] vs. 9 [3-41]; mean SOFA: 7 [4-10] vs. 4 [2-6], all p < .001). The overall relationship between daily lactateAUC>2 and daily SOFA was an increase of 0.62 SOFA-points per 1 day.mmol/L of lactateAUC>2 (95% confidence interval, 0.41-0.81, p < .00001). During early intensive care unit stay, the relationship between lactateAUC>2 and SOFA was 1.01 (95% confidence interval, 0.53-1.50, p < .0005), and during late intensive care unit stay, this was reduced to 0.50 (95% confidence interval, 0.28-0.72, p < .0005). Respiratory (0.30, 0.22-0.38, p < .001) and coagulation (0.13, 0.09-0.18, p < .001) subscores were most strongly associated with lactateAUC>2. Blood lactate levels were strongly related to SOFA scores. This relationship was stronger during the early phase of intensive care unit stay, which provides additional indirect support for early resuscitation to prevent organ failure. The results confirm that hyperlactatemia can be considered as a warning signal for organ failure.
Article
Hyperlactatemia and its reduction after admission in the intensive care unit (ICU) have been related to survival. Because it is unknown whether this equally applies to different groups of critically ill patients, we compared the prognostic value of repeated lactate levels (a) in septic patients versus patients with hemorrhage or other conditions generally associated with low-oxygen transport (LT) (b) in hemodynamically stable versus unstable patients. In this prospective observational two-center study (n = 394 patients), blood lactate levels at admission to the ICU (Lac(T0)) and the reduction of lactate levels from T = 0 to T = 12 hours (DeltaLac(T0-12)) and from T = 12 to T = 24 hours (DeltaLac(T12-24)), were related to in-hospital mortality. Reduction of lactate was associated with a lower mortality only in the sepsis group (DeltaLac(T0-12): hazard ratio [HR] 0.34, p = 0.004 and DeltaLac(T12-24): HR 0.24, p = 0.003), but not in the LT group (DeltaLac(T0-12); HR 0.78, p = 0.52 and DeltaLac(T12-24); HR 1.30, p = 0.61). The prognostic values of Lac(T0), DeltaLac(T0-12), and DeltaLac(T12-24) were similar in hemodynamically stable and unstable patients (p = 0.43). Regardless of the hemodynamic status, lactate reduction during the first 24 hours of ICU stay is associated with improved outcome only in septic patients, but not in patients with hemorrhage or other conditions generally associated with LT. We hypothesize that in this particular group a reduction in lactate is not associated with improved outcome due to irreversible damage at ICU admission.