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Journal of Critical Care 30 (2015) 271275

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Journal of Critical Care


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Correlation of lactate/albumin ratio level to organ failure and mortality in


severe sepsis and septic shock
Biao Wang, MD ,1, Gang Chen, MD 1, Yifei Cao, MD, Jiping Xue, MD, Jia Li, MD, Yunfu Wu, MD
Department of Critical Care Medicine, The Afliated Suzhou Municipal Hospital, Nanjing Medical University, Suzhou, Jiangsu, PR China

a r t i c l e

i n f o

Keywords:
Lactate/albumin ratio
Severe sepsis and septic shock
MODS
Resuscitation
Inammation

a b s t r a c t
Background: This study examines the clinical utility of the increased lactate/albumin ratio as an indicator of
multiple-organ dysfunction syndrome (MODS) and mortality in severe sepsis and septic shock.
Methods: We designed a prospective cohort study in an intensive care unit, and 54 patients with severe sepsis or
septic shock were included. Data were used to determine a relationship between lactate/albumin ratio and the
development of MODS and mortality. These associations were determined by the Mann-Whitney test, multiple
logistic regression, plotting the receiver operating characteristic curve and Spearman test.
Results: Lactate/albumin ratio level was higher in MODS patients on day 1 (median [interquartile range, or IQR],
2.295 [1.818-3.065]; n = 30, P b .0001) than in those without (median [IQR], 1.550 (1.428-1.685); n = 24), and
on day 2, (median [IQR], 1.810 [1.377-2.448]; n = 26, P = .0022) it was higher than in those without (median
[IQR], 1.172 (1.129-1.382); n = 23) on day 2. We found that lactate/albumin ratio was an independent predictor
of the development of MODS (odds ratio, 5.5; P = .033; 95% condence interval, 1.1-26.1) during intensive care
unit stay. The area under the receiver operating characteristic curve showed that lactate/albumin ratio
could predict MODS (0.8458) and mortality (0.8449). Furthermore, the higher the Acute Physiology and
Chronic Health Evaluation II score, the more lactate/albumin ratio was discovered on day 1 (r = 0.5315,
P b .0001) and day 2 (r = 0.5408, P b .0001), whereas the lower partial pressure of oxygen in arterial
blood/fraction of inspired oxygen ratio, the more lactate/albumin ratio was illustrated on day 1 (r = 0.5143,
P b .0001) and day 2 (r = 0.5420, P b .0001).
Conclusions: Increased lactate/albumin ratio correlates with the development of MODS and mortality in patients
with severe sepsis and septic shock.
2014 Elsevier Inc. All rights reserved.

1. Introduction
Sepsis is a major cause of intensive care unit (ICU) admission and is
associated with high morbidity and mortality rates [1]. Severe sepsis
and septic shock are frequently complicated by multiple-organ dysfunction syndrome (MODS). When 3 or more organs are involved, MODS
causes 60% to 98% death [2,3]. Certainly, the severity of organ dysfunction is an important determinant of prognosis in sepsis [4].
When oxygen delivery fails to meet tissue oxygen demand in critical
illness, there are oxygen debt, global tissue hypoxia, anaerobic metabolism, and lactate production. Numerous studies have established that
the lactate level was a diagnostic, therapeutic, and prognostic marker of
global tissue hypoxia in circulatory shock [57]. Previous studies have
shown that a lactate concentration greater than 4 mmol/L in the presence
of the systemic inammatory response syndrome (SIRS) criteria signicantly increases mortality rate in normotensive patients [8].

Corresponding authors at: Department of Critical Care Medicine, The Afliated Suzhou
Municipal Hospital, Nanjing Medical University, 16 Baida West Rd, Suzhou, Jiangsu
215001, PR China. Tel.: +86 512 62364071.
E-mail addresses: biaowangsz@163.com (B. Wang), icuwu@163.com (Y. Wu).
1
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.jcrc.2014.10.030
0883-9441/ 2014 Elsevier Inc. All rights reserved.

In addition to lactate, serum albumin may be an important marker


for prognosis [9]. Serum albumin is a negative acute-phase protein;
thus, the degree of hypoalbuminemia correlates with the intensity of
the inammatory response in critically ill patients [9]. Therefore, lactate
and serum albumin levels should diverge during sepsis.
Although lactate is important in patients with severe sepsis and
septic shock, the use of a ratio between lactate and albumin would
provide a variable capable of merging information that a positive correlation between MODS and mortality is not clear. This study was designed to
investigate whether lactate/albumin ratio is an independent prognostic
marker for MODS and mortality in patients with severe sepsis and septic
shock, especially the lactate concentration greater than 4 mmol/L.
2. Materials and methods
2.1. Patients
This study is an analysis of collected data from 36 male and 18
female patients (totaling 54) who were admitted to the 40-bed ICU.
Patients with severe sepsis or septic shock from October 1, 2012, to
September 30, 2013, were enrolled. This study was approved by
the Institutional Review Board for Human Research at the Afliated

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B. Wang et al. / Journal of Critical Care 30 (2015) 271275

Suzhou Municipal Hospital, Nanjing Medical University, and written


informed consent within 1 hour of arrival [10] was obtained. Patients
were followed up until death or transferring out of ICU. Patients with
an age less than 18 years, myocardial infarction, pulmonary edema,
hemorrhagic shock, trauma, seizure, pregnancy, or do-not-attemptresuscitation orders, or who required immediate surgery were
excluded. Patients' baselines included age, sex, vital signs, severity of
illness (Acute Physiology and Chronic Health Evaluation II [APACHE II]
and Sequential Organ Failure Assessment [11]), mechanical ventilation,
vasoactive drug used, blood gas analysis, hematologic, and biochemical
tests. All patients received central venous and arterial catheterization
and were cured according to the 2012 International Guidelines of
Surviving Sepsis Campaign [12]. Volume resuscitation using crystalloids
or colloids was initiated to achieve a central venous pressure of 8 to
12 mm Hg. Vasoactive agents were used to maintain a mean arterial
pressure 65 mm Hg. Urine output 0.5 mL kg 1 h 1 also served as a
target goal. Antibiotics were given according to clinicians' decisions
related to the local prevalence of bacteria in the annual report of the
Infection Control Committee of the institute.

2.2. Denition
Severe sepsis was dened as sepsis-induced tissue hypoperfusion or
organ dysfunction [12]. Septic shock was dened as sepsis-induced
hypotension persisting despite adequate uid resuscitation. Sepsisinduced tissue hypoperfusion is dened as infection-induced hypotension,
elevated lactate, or oliguria [12]. Multiple-organ dysfunction syndrome
was dened as the development of potentially reversible physiologic
derangement involving 2 or more organ systems not involved in the
disorder that resulted in ICU admission, and arising in the wake of a
potentially life-threatening physiologic insult [13]. Six-hour lactate
clearance (percent) was dened using the following formula: lactate at
ICU admission (hour 0) minus lactate at hour 6, divided by lactate at
ICU admission, then multiplied by 100 as day 1 lactate clearance, whereas
24-hour lactate clearance was dened as day 2 lactate clearance.

2.3. Data collection


Baseline vital signs, central venous oxygen saturation (ScvO2),
central venous pressure, arterial lactate, lactate clearance, 24-hour net
input/output of uid balance, serum albumin level, white blood cell
counts, platelet counts, and partial pressure of oxygen in arterial blood
(PaO2)/fraction of inspired oxygen (FIO2) ratio were obtained in the ICU.
Additional variables were required to calculate the APACHE II score as
an indicator of organ dysfunction. The clinicians caring for the patients
in the ICU and in the hospital were blinded to the data collection process,
and the study investigators did not inuence clinical decision making.

2.4. Statistical analysis


Data are presented as median (IQR [interquartile range]) or number
(%). Because most continuous variables were normal or skewed, nonparametric approaches were used in the study. Baseline characteristics of
quantitative variables between 2 groups were compared using the
Mann-Whitney test for continuous and ordinal variables. 2 Tests were
used for nominal variables. All independent variables on the univariate
analysis were included in the initial model and were then selected into
a multivariate logistic regression analysis to identify the net effects of
each individual factor using a P value less than .05. The odds ratio (OR)
and corresponding 95% condence intervals (CIs) for each variables
were computed. Continuous variables were checked for the assumption
of linearity in the logit. Colinearity among several variables was evaluated
using the Spearman correlation coefcient. The ability of the models to
predict the patient development of MODS and mortality was assessed
using the area under the receiver operating characteristic (ROC); the
respective areas under the curves were calculated. Sensitivity, specicity,
and positive and negative predictive values were calculated using
previously described methods [14]. A P value less than .05 was considered
statistically signicant. All analyses were conducted using SPSS software
(version 13.0; SPSS, Chicago, Ill) and Prism for Windows (version 5.0;
Graphpad Software Inc, San Diego, Calif).

Table 1
Baseline characteristics of patients with severe sepsis and septic shock
Variables

Age (y)
Male sex (%)
APACHE II score
SOFA score
Albuin (g/dL)
Platelet (109/L)
WBC (109/L)
Fluid balance (/L)
Lactate (mmol/L)
Lactate clearance (%)
Temperature (C)
Heart rate (beats/min)
PaO2/FIO2 ratio
MAP (mm Hg)
CVP (mm Hg)
Hematocrit (%)
Creatinine (mg/dL)
ScvO2 (%)
Mechanical ventilation (%)
PRBC transfusion (%)
Vasopressor (%)
Prothrombin time (s)
D-Dimer (ng/mL)
Lactate/albumin ratio

Day 1

Day 2

MODS (n = 30)

Without MODS (n = 24)

MODS (n = 26)

Without MODS (n = 23)

75.5 (69.75-81.25)
21 (70)
26 (25-28)
10 (8-11)
2.9 (2.6-3.125)
143.5 (112.8-184)
15.95 (12.95-18.3)
3 (2.6-3.5)
5.95 (5.075-8.525)
17.92 (15.3-21.3)
37.25 (36.8-37.6)
92.5 (82.75-102.8)
147.5 (128.3-173)
69.5 (64.5-74)
5.75 (5.3-6.2)
32 (30-35.25)
2.5 (1.45-2.8)
46 (42-49)
16 (53.3)
6 (20)
9 (30)
16.2 (14.68-17.45)
3559 (1503-4639)

72 (68-75.75)
15 (62.5)
23 (20.25-25.75)
9 (8-10)
3.0 (2.7-3.275)
151 (122.5-225.3)
15.65 (12.73-18.23)
2.65 (2.425-2.9)
4.55 (4.4-5.6)
10.9 (9-11.3)
37.2 (36.8-37.75)
85.5 (75.25-100.3)
182.5 (158-206)
72.5 (66.25-76)
6.2 (5.3-6.9)
31 (29.25-33)
2.5 (1.5-2.775)
51.5 (48-56.75)
11 (45.8)
4 (16.7)
6 (25)
16.85 (15.38-18.68)
3439 (1267-4457)

NS
NS
.0002
.0821
.4473
.5479
.632
.0128
.0006
b.0001
.8821
.111
.004
.1526
.1478
.3098
.6947
.0353
.5839
.754
.6836
.226
.5083

75.5 (71.25-81.25)
19 (73)
26 (25-28.25)
9.5 (8-11)
2.85 (2.6-3.125)
150.5 (122-185.3)
15.85 (12.73-18.3)
2.15 (1.8-2.525)
4.5 (4.05-7.025)
24.4 (17.7-26.6)
37.25 (36.8-37.68)
95 (84.75-105.3)
177.5 (152-207)
79 (72.75-81.25)
8.2 (7.75-8.525)
31 (29-35.25)
2.3 (1.825-2.525)
65 (64-70)
13 (50)
2 (8)
5 (19.2)
17 (15.75-18.75)
3574 (1535-4667)

72 (68-76)
14 (60.9)
23 (21-26)
9 (8-10)
3.0 (2.7-3.3)
152 (130-235)
15.6 (12.5-18.6)
1.8 (1.6-2.1)
3.6 (3.4-4.7)
21.8 (17.6-22.8)
37.2 (36.8-37.6)
86 (75-102)
192 (163-220)
79 (74-82)
8.7 (7.8-9.4)
31 (29-33)
2 (1.5-2.3)
68 (64-72)
10 (43.4)
1 (4)
3 (13)
17.2 (15.6-18.7)
3426 (1536-4159)

NS
NS
.0001
.2041
.3928
.5611
.7258
.0803
.0097
.1024
.6586
.0712
.3164
.5466
.2248
.3864
.0753
.3986
.648
.9498
.4421
.944
.4229

2.295 (1.818-3.065)

1.550 (1.428-1.685)

b.0001

1.810 (1.377-2.448)

1.172 (1.129-1.382)

.0022

SOFA indicates Sequential Organ Failure Assessment score; WBC, white blood cell; MAP, mean arterial pressure; CVP, central venous pressure; PRBC, packed red blood cell; NS,
nonsignicant (P N .05).

B. Wang et al. / Journal of Critical Care 30 (2015) 271275


Table 2
Multivariate logistic regression modeling using statistically signicant univariate variables
associated with MODS in patients with severe sepsis and septic shock
Associated with mortality

Odds ratio

95% CI

Lactate/albumin ratio
PaO2/FIO2 ratio
APACHE II score
ScvO2
Lactate clearance
Fluid balance
Lactate

5.5
0.4
2.6
1.1
0.7
1.4
0.6

1.1-26.1
0.2-1.0
1.0-6.6
0.4-2.2
0.3-1.6
0.6-3.2
0.2-2.3

.033
.043
.049
.991
.456
.485
.453

P value for difference between groups b.05.

3. Results
Fifty-four patients aged 74 years (68.75-80.25 years) were enrolled
in this study. There were 30 (55.6%) patients with MODS on day 1 and
26 (53%) on day 2. The mortality rate was 9% (n = 5; 4 patients in
MODS group) on day 1. The characteristics of patients with and without
MODS on days 1 and 2 are listed in Table 1.
In Table 1, although the lactate clearance and uid balance were
signicantly different on day 1 but not on day 2, lactate/albumin ratio
was higher in patients with MODS on days 1 and 2. The results support
that the lactate clearance and uid balance are not the main reason for
a high lactate/albumin ratio in patients with MODS. In addition, 27
patients required mechanical ventilation on day 1. PaO2/FIO2 ratio and
ScvO2 of patients with MODS were lower than those without MODS
on day 1 rather than day 2.
Univariate analyses were primarily used for the selection of variables,
based on a P value less than .05 (Table 1). The selected variables including
lactate/albumin ratio, PaO2/FIO2 ratio, APACHE II score, ScvO2, lactate
clearance, uid balance, and lactate were further analyzed by multiple
logistic regression analysis. The results are presented in Table 2.
Lactate/albumin ratio (OR, 5.5; P = .033; 95% CI, 1.1-26.1), PaO2/FIO2
ratio (OR, 0.4; P = .043; 95% CI, 0.2-1.0), and APACHE II score (OR,
2.6; P = .049; 95% CI, 1.06.6) remained signicant predictors of
MODS after controlling for other variables. ScvO2, lactate clearance,
uid balance, and lactate failed to maintain their prognostic value for
the MODS development in the adjusted analysis.
Fig. 1 shows lactate/albumin ratio levels in patients with and without
MODS and mortality on day 1. Lactate/albumin ratio was higher in
patients with MODS (2.514 0.165, n = 30, P b .0001) than in those
without (1.703 0.094, n = 24). Similarly, the patients with mortality
had increased levels of lactate/albumin ratio (2.876 0.235, n = 5)
compared with without (2.080 0.119 mL/kg, n = 49, P = .0122).
Fig. 2 illustrates the relationship between lactate/albumin ratio and
APACHE II score (A, day 1, r = 0.5315, P b .0001; B, day 2, r = 0.5408,

273

P b .0001), or PaO2/FIO2 ratio (C, day 1, r = 0.5143, P b .0001; D, day 2,


r = 0.5420, P b .0001) in patients with severe sepsis or septic shock.
The higher the APACHE II score and the lower the Pa O 2 /FIO 2 ratio,
the more lactate/albumin ratio was found. The data are expressed as
Spearman test.
Comparisons between areas under the ROC curve for lactate/albumin
ratio, APACHE II scores, and PaO2/FIO2 ratio on day 1 in prediction of
clinical outcomes are listed in Table 3 (n = 54; 30 patients with
MODS, 5 patients with mortality). Values for areas under the ROC curves
showed that day 1 lactate/albumin ratio levels could be used to predict
MODS (0.8458) and mortality (0.8449). The areas under the ROC curves
for APACHE II scores and PaO2/FIO2 ratio on day 1 were similar in
predicting MODS (PaO2/FIO2 ratio, 0.7306; APACHE II score, 0.7951)
and mortality (PaO2/FIO2 ratio, 0.7857; APACHE II score, 0.8041), but
less than lactate/albumin ratio.
We plotted a pair of diagnostic sensitivity and specicity values for
every individual cutoff by an ROC graph with the 1 specicity on
the x-axis and sensitivity on the y-axis. We selected 1.735 as a cutoff
value of lactate/albumin ratio level, which was highly sensitive and
specic in predicting development of MODS. Sensitivities, specicities,
and predictive values of elevated lactate/albumin ratio (N 1.735) for
the development of MODS and mortality are shown in Table 4. The
sensitivity of elevated lactate/albumin ratio was 80% in MODS and
100% in mortality. The specicity of increased lactate/albumin ratio
was 79% in MODS and 51% in mortality. The positive and negative predictive value of increased lactate/albumin ratio was 83% and 76% in
MODS and 17% and 100% in mortality, respectively.
4. Discussion
The aim of this study was to assess the association of lactate/albumin
ratio and prognosis of MODS and mortality in patients with severe
sepsis and septic shock. Our study suggested that lactate/albumin ratio
was independently associated with MODS and mortality of these
patients. Increased lactate/albumin ratio was associated with MODS
and subsequent development of organ failure. With the cutoff value of
1.735, lactate/albumin ratio offered good diagnostic sensitivity, specicity,
and positive and negative predictive value for MODS and mortality in
those patients.
Consistent with previous studies, malnutrition, inammation,
and hypoperfusion were common in patients with severe sepsis.
Hyperlactatemia (N 2 mmol/L) has been shown to be an independent
predictor of mortality in critically ill patients [15,16], such as those
with sepsis, with or without organ failure [15,1719], trauma [20], and
SIRS [21]. The Surviving Sepsis Campaign [12] and early goal-directed
therapy [22] recommend resuscitation of sepsis patients with lactate
greater than 4 mmol/L. Although there were various explanations

Fig. 1. Lactate/albumin ratio in severe sepsis or septic shock patients with (n = 30) and without (n = 24) MODS (A), and in patients with (n = 5) and without (n = 49) mortality (B).
P value was expressed.

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B. Wang et al. / Journal of Critical Care 30 (2015) 271275

Fig. 2. The relationship between lactate/albumin ratio and APACHE II score (A, day 1, r = 0.5315, P b .0001; B, day 2, r = 0.5408, P b .0001), or PaO2/FIO2 ratio (C, day 1, r = 0.5143,
P b .0001; D, day 2, r = 0.5420, P b .0001) in patients with severe sepsis by Spearman test.

regarding the mechanisms responsible for lactate accumulation in severe


sepsis and septic shock, it remains a robust surrogate marker for the
development of MODS and poor outcome [23,24]. A recurring theme in
these studies was the inammatory response plays a crucial mechanistic
intermediate between lactate clearance and the development of MODS.
Albumin levels were also associated with prognosis after critical illness
and could be a reliable indicator of frailty, high susceptibility to stressors,
and unstable homeostasis [25]. Although the phenomenon that the
lower albuminemia, the poorer prognosis was also found, there was no
statistical signicance in univariate analysis (P = .075; Table 1) in our
study. This was probably because the sample size of our study was not
large enough.
The measurement of single lactate measurements has several
limitations. First, blood lactate concentrations reect the interaction
between the production and elimination of lactate. For example, a sepsis
patient with hepatic dysfunction may have a higher lactate. Second, an
increased lactate concentration may indicate mechanisms other
than cellular hypoxia, such as up-regulation in epinephrine-stimulated
Na/K-adenosine triphosphatase activity in skeletal muscle [23], and inhibition of pyruvate metabolism or an increase in its production [26]. Given
these limitations, we used a lactate/albumin ratio as a severity index.
Our study showed that patients with MODS had statistically signicant of uid balance, lactate clearance, and ScvO2 than did those without
MODS on day 1. Similar trend on day 2 was noted, but the data were not

statistical signicant. Lactate/albumin ratio, in its association with


MODS and mortality, does not seem to function solely as a marker of
clinically apparent hypoperfusion or hypotension. Howell et al [27]
showed that serum lactate was associated with mortality independent
of blood pressure. In addition, ScvO2, lactate clearance, uid balance,
and lactate were signicantly different on day 1, and serum lactate
was still signicantly different on day 2 but not on multiple logistic
regression analysis to maintain their prognostic value for the MODS.
So the uid balance may improve early identication of severe sepsis
and septic shock requiring resuscitation. Moreover, lactate/albumin
ratio sustained higher in patients with MODS and mortality both on
days 1 day 2 (Fig. 1). Therefore, early lactate/albumin ratio is signicantly
associated with increased risk of organ dysfunction, resuscitative therapies, and critical illness.
In Table 1, the PaO2/FIO2 ratio was signicantly different between
2 groups on day 1. The reason may be the response to the SIRS, along
with alterations in coagulopathy. The process can initiate or propagate
a systemic inammatory response and thus could play a role in the
development of MODS. In Fig. 2, the higher the APACHE II score and
the lower the PaO2/FIO2 ratio, the more lactate/albumin ratio was
found on days 1 and 2. The APACHE II score and PaO2/FIO2 ratio have
already been used to evaluate the illness severity and associated with
the development of MODS in septic patients [28].

Table 4
Diagnostic sensitivity, specicity, and predictive value of lactate/albumin ratio N 1.735 for
MODS and mortality

Table 3
Areas under the ROC curves for variables on day 1
Area Under ROC curve

Lactate/albumin ratio
PaO2/FIO2 ratio
APACHE II score

MODS (95% CI)

Mortality (95% CI)

0.8458 (0.7389-0.9527)
0.7306 (0.5938-0.8673)
0.7951 (0.6740-0.9163)

0.8449 (0.7231-0.9667)
0.7857 (0.6492-0.9222)
0.8041 (0.6273-0.9809)

Sensitivity
Specicity
Positive predictive valve
Negative predictive valve

MODS (%)

Mortality (%)

80
79
83
76

100
51
17
100

B. Wang et al. / Journal of Critical Care 30 (2015) 271275

With a cutoff value of 1.735, this study has demonstrated that


patients with lactate/albumin ratio greater than 1.735 on day 1 had a
higher chance of development of MODS and mortality during their ICU
stay. The area under the ROC curve conrms that lactate/albumin ratio
on day 1 was superior to APACHE II and PaO2/FIO2 ratio in predicting
the development of MODS and mortality. In addition, lactate/albumin
ratio on day 1 offered good sensitivity, specicity, and positive and
negative predictive values for MODS and mortality.
There are several limitations to our study. First, we recognized that
therapy received in the emergency department could confound the
association between lactate/albumin ratio level and subsequent MODS
and mortality. How the use of early goal-directed therapy affects this
relationship is unknown and warrants further study. In addition, this
was a single-center and relatively small-sized study, represents actual
practice. Third, our study was potentially prone to selection, ascertainment, and misclassication bias. All patients were elderly and prone
to have further comorbidities, such as liver disease and chronic renal
insufciency, and these diseases process on the lactate level itself.
In conclusion, lactate/albumin ratio is an independent predictor for
the development of MODS and mortality in patients with early severe
sepsis and septic shock.

Acknowledgments
This project was supported by Science and Education of Public
Health of Suzhou, China (KJXW2013028).

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