Anesth Analg 2008; 106:1820-1826
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e31816a643f
CRITICAL CARE AND TRAUMA
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|| For the Finnsepsis Study Group
From the *Department of Intensive Care Medicine, Tampere University Hospital, Finland; Department of Anesthesia and Intensive Care Medicine, Helsinki University Hospital, Finland; and Department of Intensive Care Medicine, Satakunta Central Hospital, South Karelian Central Hospital, and ||Kuopio University Hospital, Finland.
Address correspondence and reprint requests to Sari Karlsson, Tampere University Hospital, Teiskontie 35, 33521 Tampere, Finland. Address e-mail to sari.karlsson{at}pshp.fi.
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Abstract
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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.
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Introduction
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In intensive care, the incidence of severe sepsis continues to increase, with high mortality.1,2 In severe sepsis, vascular permeability increases in response to systemic inflammation mediated by endotoxin and various cytokines. Macrophages and lymphocytes can produce vascular endothelial growth factor (VEGF). Some studies have shown that serum VEGF concentrations are increased 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, 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 progression, 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 alveolar space are lower in patients with acute respiratory distress syndrome (ARDS) than in ventilated patients without ARDS.16
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 relationship between VEGF and organ dysfunction in a large, unselected homogenous adult patient population with severe sepsis and septic shock. In addition, we evaluated the value of VEGF in the prediction of hospital mortality.
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METHODS
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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 published elsewhere.18 Briefly, all consecutive ICU admissions (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 American 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 inflammatory 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 Consortium (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 (Quantikine®, R&D Systems; Minneapolis, MN) that recognizes the soluble isoforms (VEGF121 and 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 immobilized antibody. After any unbound substances were washed away, an enzyme-linked polyclonal antibody specific for VEGF was added to the wells. After a wash to remove any unbound antibody-enzyme reagent, a substrate solution for color reaction 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 wavelength 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 different levels and a pooled serum sample. The interassay 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 controls: R&D medium level control and a pooled serum sample. The intraassay CV% for R&D medium 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–Whitney 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% confidence 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).
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RESULTS
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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 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).
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Table 1. Comparison of Vascular Endothelial Growth Factor (VEGF) Study Cohort with the Rest of Finnsepsis Study Patients
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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 concentrations 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 Table 2. The severity of circulatory or respiratory dysfunction was not associated with VEGF concentrations (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. Accordingly, 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).
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 admission) 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 survival (–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).
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DISCUSSION
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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. Significantly lower VEGF concentrations in nonsurvivors do not, however, predict hospital mortality. Low circulating VEGF levels are associated with hematological and renal dysfunction, suggesting that VEGF production 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 agreement with these previous results: low serum VEGF concentrations were associated with high maximum SOFA scores and poor outcome. VEGF increases endothelial 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 differences 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 increasing 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 rebound 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 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 sustained VEGF production in patients with severe sepsis.17 Our VEGF concentrations were measured in serum samples. Plasma samples have been preferred by some investigators because platelet-mediated secretion of VEGF during the clotting process could interfere with the results.28,29 However, it has been shown recently that VEGF concentrations were correlated 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 (Spearmann 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 different 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 (Quantikine®), 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 hematological 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.
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ACKNOWLEDGMENTS
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The authors acknowledge all investigators and study nurses of the Finnsepsis study in the participating hospitals and especially Seija Laitinen, chief medical laboratory technologist, for performing the VEGF analyses.
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Appendix 1
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Footnotes
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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.
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Abstract
Introduction
