Vascular Endothelial Growth Factor in Severe Sepsis and

Septic Shock
Sari Karlsson, MD*
Ville Pettilä, MD, PhD†
Jyrki Tenhunen, MD, PhD*
Vesa Lund, MD, PhD‡
Seppo Hovilehto, MD§
Esko Ruokonen, MD, PhD储
For the Finnsepsis Study Group
BACKGROUND: Vascular endothelial growth factor (VEGF) levels have been shown to
be elevated in severe sepsis. We investigated the value of VEGF in predicting organ
dysfunction and hospital mortality in adult patients with severe sepsis.
METHODS: We conducted a prospective observational cohort study in 24 closed
multidisciplinary intensive care units (ICU) in Finland. All ICU admission episodes
(4500) were screened for severe sepsis from November 1, 2004, to February 28, 2005.
Patients were eligible if they fulfilled the criteria for severe sepsis.
RESULTS: Severe sepsis was found in 470 patients. Laboratory samples were
obtained after informed consent from 250 patients at study entry (day 0) and from
215 patients after 72 h. These samples were compared with samples from 30
healthy individuals. The ICU mortality was 13.2% and hospital mortality 26%.
Median serum VEGF concentrations on day 0 were 423 pg/mL (interquartile range
[IQR] 159 and 858 pg/mL), and after 72 h were 521 pg/mL (IQR 182 and 1092
pg/mL), which were both higher than in healthy controls (P ⫽ 0.029 and 0.003,
respectively). Low VEGF concentrations were associated with more severe renal
and hematological dysfunction (Sequential Organ Failure Assessment scores 3– 4
compared with scores 0 –2). VEGF concentrations in day 0 and after 72 h were
lower in nonsurvivors (P ⫽ 0.01 and ⬍0.01, respectively) than in survivors, but the
receiver operating characteristic curve analyses of concentrations of VEGF on day
0 and at 72 h revealed areas under the curve of 0.58 and 0.63 (95% confidence limits
0.48 – 0.68 and 0.54 – 0.72, P ⫽ 0.1 and 0.009, respectively).
CONCLUSIONS: VEGF concentrations are increased in patients with severe sepsis.
Low concentrations are associated with hematological and renal dysfunction.
VEGF concentrations were lower in nonsurvivors than in survivors, but did not
adequately predict hospital mortality in patients with severe sepsis.
(Anesth Analg 2008;106:1820 –6)

I n intensive care, the incidence of severe sepsis contin-

ues to increase, with high mortality.1,2 In severe sepsis,
vascular permeability increases in response to systemic
inflammation mediated by endotoxin and various cyto-
kines. Macrophages and lymphocytes can produce vas-
cular endothelial growth factor (VEGF). Some studies
have shown that serum VEGF concentrations are in-
creased in polytrauma and severe sepsis.3,4
Vascular permeability factor was isolated in 1983.5
VEGF was identified in 1989,6 and in the same year,
From the *Department of Intensive Care Medicine, Tampere
University Hospital, Finland; †Department of Anesthesia and Inten-
sive Care Medicine, Helsinki University Hospital, Finland; and
Department of Intensive Care Medicine, ‡Satakunta Central Hospi-
tal, §South Karelian Central Hospital, and 储Kuopio University
Hospital, Finland.
Accepted for publication January 14, 2008.
Part of this study was presented as an abstract at the 19th annual
congress of the European Society of Intensive Care Medicine in
Barcelona on September 26, 2006.
Supported by Institutional Research Grant program (EVO) of
Helsinki University Hospital and Tampere University Hospital.
Address correspondence and reprint requests to Sari Karlsson,
Tampere University Hospital, Teiskontie 35, 33521 Tampere, Fin-
land. Address e-mail to sari.karlsson@pshp.fi.
Copyright © 2008 International Anesthesia Research Society
DOI: 10.1213/ane.0b013e31816a643f
1820
these two substances were found to be identical.7,8
VEGF is a potent hypoxia-induced mediator in the
formation of new capillaries (angiogenesis).9 There are
seven different VEGFs (VEGF-A, -B, -C, -D, -E, -F, and
placental growth factor PlGF), which have different
physiological and biological properties.10 There are at
least 6 VEGF-A isoforms of different sizes (with 121,
145, 165, 183, 189, and 206 amino acid residues).11
VEGFs are involved, for instance, in wound healing,
cardiovascular diseases, tumor growth and progres-
sion, ocular neovascularization, and inflammatory
diseases such as rheumatoid arthritis.
In particular, VEGF-A is of interest in the present
context when acting on endothelial cells, causing
vasodilatation by induction of endothelial nitric oxide
synthase.12 VEGF also has antiapoptotic effects on
endothelium.13 More importantly, VEGF-A was found
to be an important mediator of vascular permeability.5
It has also been shown that the normal lung contains
VEGF in the alveolar space, suggesting that VEGF
may be a survival factor for lung epithelial cells.14,15
VEGF levels in the epithelial lining fluid in the alveo-
lar space are lower in patients with acute respiratory
distress syndrome (ARDS) than in ventilated patients
without ARDS.16
Vol. 106, No. 6, June 2008
 Recently, it has been shown that sepsis is associated
with a time-dependent increase in circulating levels of
VEGF and PlGF in both animal and human models of
sepsis.17
The aim of this study was to evaluate the relation-
ship between VEGF and organ dysfunction in a large,
unselected homogenous adult patient population with
severe sepsis and septic shock. In addition, we evalu-
ated the value of VEGF in the prediction of hospital
mortality.
METHODS
Patient Selection
This study was a part of the Finnsepsis study,
which was a prospective observational cohort study
investigating the incidence, related organ failure, and
outcome of severe sepsis in Finland. The Finnsepsis
study was conducted in 24 intensive care units (ICUs)
after local ethics committee approval. The design,
methodology, and primary results have been pub-
lished elsewhere.18 Briefly, all consecutive ICU admis-
sions (4500 adult patients) and subsequent episodes of
critical care were screened for severe sepsis during a
4-mo period (from November 1, 2004, to February 28,
2005). Patients were eligible if they fulfilled the Ameri-
can College of Chest Physicians/Society of Critical
Care Medicine criteria for severe sepsis.19 Study entry
(day 0) was defined as the time when criteria for
confirmed or suspected infection, systemic inflamma-
tory response syndrome, and organ dysfunction were
first met. APACHE II (Acute Physiology and Chronic
Health Evaluation) and SAPS II (Simplified Acute
Physiology Score) scores,20,21 organ dysfunction with
SOFA (Sequential Organ Failure Assessment) scores,22
maximum SOFA scores with ␦ SOFA,23 and ICU and
hospital mortalities were recorded. All data were
recorded in the Finnish Intensive Care Quality Con-
sortium (Intensium Ltd., Kuopio) database.
Blood Samples
Blood samples for VEGF analyses were drawn after
obtaining informed consent within 24 h of the study
entry (day 0) and 72 h thereafter. Failure to obtain
consent was a reason for exclusion. The samples for
VEGF analyses were collected at the same time as the
other blood samples for the Finnsepsis study and this
was a predetermined laboratory analysis.
Serum samples were collected and stored at ⫺80°C
for later analysis. The samples were compared with
those of healthy controls (n ⫽ 30). The mean age of
healthy controls was 36 ⫾ 7 yr and there were an equal
number of males and females (M/F 15/15).
VEGF Analysis
VEGF concentrations in sera were measured in
duplicate for each sample using a commercial
enzyme-linked immunosorbent assay kit (Quan-
tikine威, R&D Systems; Minneapolis, MN) that rec-
ognizes the soluble isoforms (VEGF121 and
Vol. 106, No. 6, June 2008
VEGF165). We used multiwell microplates precoated
with a monoclonal antibody specific for VEGF.
Standards and samples were pipetted into the wells
and any VEGF present was bound by the immobi-
lized antibody. After any unbound substances were
washed away, an enzyme-linked polyclonal anti-
body specific for VEGF was added to the wells.
After a wash to remove any unbound antibody-
enzyme reagent, a substrate solution for color reac-
tion was added to the wells. The color develops in
proportion to the amount of VEGF bound in the
initial step. After the color development stopped,
the intensity of color was measured. This assay is
sensitive to 9 pg/mL of VEGF, as announced. The
optical density at 450 nm was measured with wave-
length correction at 540 nm [Multiskan RC plate
reader (Thermolabsystems, Helsinki, Finland)], and
VEGF concentration was determinated with Genesis
(Life Sciences, UK) computer software capable of
generating a 4-parameter logistic curve fit. In each
run, there were two commercial controls with dif-
ferent levels and a pooled serum sample. The inter-
assay coefficients of variation (CV%) for R&D low
control mean concentration 106 pg/mL and R&D
high control mean concentration 620 pg/mL were
7.3% (n ⫽ 12) and 9.3% (n ⫽ 12), respectively. For a
pooled serum sample, the interassay CV% was 6.9%.
The intraassay precision was tested with two con-
trols: R&D medium level control and a pooled
serum sample. The intraassay CV% for R&D me-
dium control mean concentration 345 pg/mL was
5.7% (n ⫽ 10), and for a pooled serum sample, mean
concentration 96 pg/mL the CV% was 6.5% (n ⫽ 10).
Statistical Analyses
Data are presented as medians and interquartile
range (25th to 75th percentiles, interquartile range,
IQR), absolute values and percentages, or means ⫾
sd. The nonparametric data between survivors and
nonsurvivors were compared with the Mann–Whit-
ney U-test and categorical variables with the ␹2 test.
To determine the prognostic accuracy of VEGF at
both time points, receiver operating characteristic
(ROC) curves were constructed and the areas under
the curve (AUC) were calculated with 95% confi-
dence intervals. The Spearman correlation was used
to test the relations between the estimated time of
onset of sepsis and changes in VEGF concentrations.
The level of P ⬍ 0.05 was considered statistically
significant in all tests. The analyses were performed
using the SPSS 14.0 software (SPSS, Chicago, IL).
RESULTS
Blood samples for VEGF analysis were obtained
from 250 of 470 (53.2%) patients of the whole
Finnsepsis study population. Two hundred and fifty
samples were obtained at baseline (day 0) and 215
samples were taken 72 h later. Fourteen patients
died before the second sample was obtained, and in
© 2008 International Anesthesia Research Society 1821
Table 1. Comparison of Vascular Endothelial Growth Factor (VEGF) Study Cohort with the Rest of Finnsepsis Study Patients
Other Finnsepsis
VEGF patients patients P
No. of patients 250 220
Age 59.4 (15.6) 59.8 (14.8) 0.81
Male 172 (68.8%) 143 (65%) 0.31
APACHE IIa 23.8 (9.1) 24.6 (9.0) 0.37
SAPS IIb 43.5 (16.8) 46.0 (16.9) 0.16
SOFA on day 1c 8.3 (3.6) 8.5 (3.6) 0.83
SOFAmaxd 10.9 (4.3) 10.4 (4.4) 0.31
Septic shocke 173 (69.2%) 162 (73.6%) 0.29
Infection type
Community acquired 161 (64.4%) 116 (52.7%) 0.035
Hospital acquired 84 (33.6%) 97 (44.1%) 0.035
Source of infection
Pulmonary 102 (40.8%) 96 (43.6%) 0.53
Intraabdominal 82 (32.8%) 68 (30.9%) 0.66
Skin or soft tissue 24 (9.6%) 24 (10.9%) 0.60
Urinary tract 11 (4.4%) 11 (5.0%) 0.76
Other 35 (14.0%) 28 (12.7%) 0.69
Blood culture positive 70 (28.0%) 58 (26.4%) 0.69
Postoperative admission 65 (26.0%) 71 (32.3%) 0.15
ICU mortality 33 (13.2%) 40 (18.2%) 0.14
Hospital mortality 66 (26.4) 67 (30.1) 0.39
Data are presented as absolute values (percentages) or means (standard deviation).
a
Acute Physiology and Chronic Health Evaluation.
b
Simplified Acute Physiology Score.
c
Sequential organ failure assessment score (SOFA) on the day following study entry.
d
Maximum SOFA score.
e
Cardiovascular failure with SOFA score 3– 4.

an additional 21 patients, samples were not taken

for other nonspecific reasons. Basic characteristics,
disease severity, organ failure, and mortality in the
VEGF study group were similar to those of other
Finnsepsis patients, except that there were more
patients with community-acquired infections in the
VEGF group (Table 1).
In septic patients, median VEGF concentration on
day 0 was 423 pg/mL (IQR 159 and 858 pg/mL),
which was higher than the median VEGF level of
260 pg/mL (IQR 126 and 459 pg/mL, P ⫽ 0.029) in
healthy controls. After 72 h, VEGF levels were still
higher in septic patients, with median VEGF con-
centrations of 521 pg/mL (IQR 182 and 1092
pg/mL) versus healthy controls (P ⫽ 0.003). VEGF
concentrations were lower in nonsurvivors than in
surviving patients at both time points (P ⫽ 0.012
and 0.009, respectively, Fig. 1). However, the ROC
curves for day 0 or 72 h levels showed no significant
AUC of 0.58 and 0.63 (95% confidence limits 0.48 to
0.68 and 0.54 – 0.72, P ⫽ 0.1 and 0.009, respectively).
The ROC curve for hospital mortality and SOFA
score at the time day 0 VEGF samples were taken
showed AUC of 0.73 (95% confidence limits
0.65– 0.82, P ⫽ 0.000).
The associations between VEGF concentrations and
the dysfunction of different organ systems having
maximum SOFA scores 0 –2 and 3– 4 are presented in Figure 1. Vascular endothelial growth factor (VEGF) concen-
Table 2. The severity of circulatory or respiratory trations in survivors and nonsurvivors.

1822 Vascular Endothelial Growth Factor in Severe Sepsis ANESTHESIA & ANALGESIA
Table 2. Vascular Endothelial Growth Factor (VEGF) Concentrations in Dysfunction of Different Organ Systems
N SOFAmax 0–2
Cardiovascular 57
Respiratory 70
Hematological 168
Renal 180
Hepatic 96
Concentrations (pg/mL) are presented as medians (interquartile range, IQR). The P value refers to VEGF concentrations on day 0 between different severities of organ dysfunction (SOFAmax 0 –2
and SOFAmax 3– 4).
Figure 2. Changes in vascular endo-
thelial growth factor (VEGF) con-
centrations (␦VEGF) and SOFA
score (␦SOFA) in survivors and
nonsurvivors.
dysfunction was not associated with VEGF concentra-
tions (P ⫽ 0.66 and 0.14 and P ⫽ 0.94 and 0.40,
respectively). In contrast, VEGF concentrations were
decreased in patients with the most severe degrees of
renal, hematological, or liver dysfunction. Accord-
ingly, VEGF levels were associated with the severity
of overall organ dysfunctions: the patients in the highest
maximum SOFA score quartile (SOFA max score 14 –24)
had lower VEGF levels on day 0 (165 pg/mL [IQR 54
and 466] vs 494 pg/mL [IQR 192 and 904], P ⫽ 0.00) and
72 h later (208 pg/mL [IQR 52 and 339] vs 626 pg/mL
[IQR 262 and 1042], P ⫽ 0.00) than patients with SOFA
max scores between 8 and 13. VEGF concentrations on
day 0 were lower in patients with positive blood cultures
than in patients with negative blood cultures (median
274 pg/mL [IQR 82 and 720] vs 495 pg/mL [IQR 184 and
868], P ⫽ 0.03). There were no differences at 72 h (P ⫽
0.11). No association was found between platelet count
and VEGF levels on day 0 or at 72 h (P ⫽ 0.17 and 0.32,
respectively).
Vol. 106, No. 6, June 2008
N SOFAmax 3–4 P
374 (138 and 849) 172 418 (153 and 828) ns
330 (167 and 868) 159 457 (148 and 826) ns
548 (222 and 917) 61 148 (54 and 361) 0.00
456 (190 and 866) 49 281 (61 and 675) ⬍0.02
510 (185 and 883) 5 55 (32 and 320) ⬍0.02
The change in VEGF concentration (␦VEGF ⫽ VEGF
72 h ⫺ VEGF day 0) was positive in 56.7% (n ⫽ 122) and
negative in 41.9% (n ⫽ 90) of the 215 patients in whom
␦VEGF could be determined. The change in SOFA score
(␦SOFA, maximum SOFA score ⫺ SOFA score at admis-
sion) is presented in Figure 2. There was no correlation
with ␦VEGF and change in SOFA scores on the days the
blood samples were taken (P ⫽ 0.24). The onset of severe
sepsis before hospital admission could be estimated in
149 of 161 patients with community-acquired infections
(⬍12 h, 12–24 h, 24 –36 h, 36 – 48 h, ⬎48 h). A significant
correlation (⫺0.20 by Spearman, P ⫽ 0.022) between the
change in VEGF concentrations and the different onset
times of patients with community-acquired severe sepsis
was found. There was also a significant association
between the change in VEGF concentrations and sur-
vival (⫺0.24 by Spearman, P ⫽ 0.016): The survivors had
a more positive ␦VEGF (median 103 pg/mL, IQR ⫺90
and 413) than nonsurvivors (median ⫺2.0 pg/mL, IQR
⫺178.5 to 125.5, P ⫽ 0.037 for the difference).
© 2008 International Anesthesia Research Society 1823
DISCUSSION
The main finding of this study was that, although
VEGF concentrations are increased in severe sepsis,
low VEGF levels are associated with more severe
forms of organ dysfunction and mortality. Signifi-
cantly lower VEGF concentrations in nonsurvivors do
not, however, predict hospital mortality. Low circulat-
ing VEGF levels are associated with hematological
and renal dysfunction, suggesting that VEGF produc-
tion in severe sepsis may be disturbed.
Previous studies have suggested that VEGF is an
important mediator of inflammation and that high
VEGF concentrations correlate with the severity of
organ dysfunction.4,17,24 Our results are not in agree-
ment with these previous results: low serum VEGF
concentrations were associated with high maximum
SOFA scores and poor outcome. VEGF increases en-
dothelial permeability.22 Indeed, it has been shown
that VEGF is significantly elevated in ARDS patients
compared with ventilated patients without ARDS.25
Mura et al. have shown in animal acute lung injury
that the VEGF expression may depend on the stage of
the disease. The acute inflammatory response may
first release VEGF into the alveolar space and increase
vascular permeability, but later epithelial injury may
reduce the expression of VEGF and its receptors and
lead to cell death.15 We did not find any relation
between the severity of septic lung injury (severe
oxygenation impairment with a SOFA score 3– 4) and
high serum VEGF concentrations.
A different time pattern may partly explain differ-
ences between the studies.4,17,24 Yano et al. found that
peak VEGF concentrations occur in the first 24 h and
VEGF levels remain elevated up to several days.17 In
an earlier study by van der Flier et al.,24 18 patients
with severe sepsis had a peak VEGF concentration on
the first day after severe sepsis criteria were met. In
our study, the unselected cohort of severe sepsis
patients was larger than in previous studies, and more
than half of our patients (56.7%) had further increas-
ing VEGF concentrations over the first 72 h.
Severe sepsis is a continuum of dynamic processes,
from systemic inflammation response syndrome to
sepsis, severe sepsis, and septic shock. Even though all
patients included in this study fulfilled the criteria of
severe sepsis, the severity of illness varies widely. In
our opinion, there are insufficient data to define which
time interval should be used for the analysis of VEGF;
for this study, three days were used.
Low VEGF concentrations were associated with
hematological and renal dysfunction in our study. It
has been shown that VEGF production correlates with
platelet count in cancer patients after chemotherapy-
induced thrombocytopenia, and that a platelet re-
bound is followed by a peak in VEGF production.26
However, the platelet counts for the time points at
which the samples were taken did not correlate with
VEFG levels in our patients or in one of the earlier
1824 Vascular Endothelial Growth Factor in Severe Sepsis
studies.24 Interestingly, in the present study, VEGF
levels were very low in five patients with severe
hepatic failure. Yano et al. found that heart, liver, and
kidney were major sources of sepsis-induced VEGF
production in animal models of sepsis.17 One can
therefore speculate that existing septic organ failure
may result in reduced VEGF response. Similar results
have been reported by Grad et al., who showed that
low VEGF concentrations were associated with an
increased occurrence of complications (sepsis, ARDS,
and multiple organ failure) in polytrauma and burn
patients.3
Our investigation has a few limitations. The
samples were taken only at two time points and
patients must have been at different phases in the
course of sepsis. Onset of sepsis can only be estimated,
and T0 was the day severe sepsis was diagnosed, and
the patient was enrolled in the study. The half-life of
VEGF has been reported to be short: 33.7 ⫾ 13 min
based on pharmacokinetic studies with recombinant
VEGF.27 Nonetheless, previous studies have shown
increased VEGF levels up to 29 days, indicating sus-
tained VEGF production in patients with severe sep-
sis.17 Our VEGF concentrations were measured in
serum samples. Plasma samples have been preferred
by some investigators because platelet-mediated se-
cretion of VEGF during the clotting process could
interfere with the results.28,29 However, it has been
shown recently that VEGF concentrations were corre-
lated between plasma and serum in paired samples in
otherwise healthy women having controlled ovarian
hyperstimulation. Serum values were higher than
plasma values, the factor being about six-fold (Spear-
mann correlation coefficient 0.61, P ⬍ 0.005).30 It is
possible that in severe sepsis serum and plasma levels
are not directly correlated, which may explain differ-
ent results seen in previous studies with smaller
patient groups. It is also possible that VEGF release
from platelets may have influenced our results. On the
other hand, one of our main findings was low serum
VEGF concentrations in nonsurvivors with identical
sampling and sample processing. Although VEGF
concentrations were not associated with platelet
counts in our study, it is possible that low VEGF
concentrations can reflect more diminished release
than disturbed production in patients with the most
severe forms of sepsis. The VEGF analyses were made
in all studies with the same ELISA method (Quan-
tikine威), which detects the soluble VEGF121 and
VEGF 165 isoforms.
In conclusion, VEGF levels are elevated in severe
sepsis, but are lower in nonsurvivors. Low VEGF
concentrations are associated with severe hemato-
logical and renal dysfunction, possibly indicating
disturbed VEGF production during severe sepsis.
Clinically, VEGF does not seem to be a useful tool
for the prediction of an unfavorable outcome in the
critical care setting.
ANESTHESIA & ANALGESIA
Appendix. Participants of the Finnsepsis Study
Hospital Investigator
Satakunta Central Hospital Hospital Dr. Vesa Lund
Savonlinna Central Hospital Dr. Markku Suvela
Central Finland Central Hospital Dr. Raili Laru-Sompa
Mikkeli Central Hospital Dr. Heikki Laine
Pohjois-Karjala Central Hospital Dr. Sari Karlsson
Seinäjoki Central Hospital Dr. Kari Saarinen
Etela-Karjala Central Hospital Dr. Seppo Hovilehto
Päijät-Häme Central Hospital Dr. Pekka Loisa
Kainuu Central Hospital Dr. Tuula Korhonen
Vaasa Central Hospital Dr. Pentti Kairi
Kanta-Häme Central Hospital Dr. Ari Alaspää
Lappi Central Hospital Dr. Outi Kiviniemi
Keski-Pohjanmaa Central Hospital Dr. Tadeusz Kaminski
Kymenlaakso Central Hospital Dr. Jussi Pentti, Dr. Seija Alila
Helsinki University Hospital Dr. Ville Pettilä, Dr. Marjut Varpula, Dr. Marja Hynninen
Helsinki University Hospital (Jorvi) Dr. Tero Varpula
Helsinki University Hospital (Peijas) Dr. Rita Linko
Tampere University Hospital Dr. Esko Ruokonen, Dr. Pertti Arvola
Kuopio University Hospital Dr. Ilkka Parviainen
Oulu University Hospital Dr. Tero Ala-Kokko, Dr. Jouko Laurila
Länsi-Pohja Central Hospital Dr. Jorma Heikkinen

ACKNOWLEDGMENTS 13. Gerber HP, Dixit V, Ferrara N. Vascular endothelial growth

The authors acknowledge all investigators and study
nurses of the Finnsepsis study in the participating hospitals
and especially Seija Laitinen, chief medical laboratory tech-
nologist, for performing the VEGF analyses.
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