Clinical utility of biomarkers of endothelial activation in sepsis-a systematic review

cc11145 1364-8535 Research Clinical utility of biomarkers of endothelial activation in sepsis-a systematic review XingKatharinekatharine_xing@yahoo.com MurthySrinivassgmurthy@gmail.com LilesW ConradConrad.liles@uhn.ca SinghMJeffreyjeff.singh@uhn.ca

Division of Hematology, University of British Columbia, Vancouver General Hospital, 855 12th Ave W, Vancouver, BC V5Z 1M9, Canada

Divisions of Pediatric Infectious Disease and Critical Care, University of Toronto, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada

McLaughlin-Rotman Centre for Global Health, University Health Network, 101 College Street, Suite 406 Toronto, ON M5G 1L7, Canada

Department of Medicine, University of Toronto, 1 King's College Circle Medical Sciences Building-Room 2109, Toronto, ON M5S 1A8, Canada

Interdepartmental Division of Critical Care Medicine, University of Toronto, Queen Street Wing, Room 4-042, 30 Bond Street, Toronto, ON M5B 1W8, Canada

Critical Care 1364-8535 2012 16 1 R7 http://ccforum.com/content/16/1/R7 10.1186/cc1114522248019 141020112911201116120121612012 2012Xing et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Sepsisendotheliumbiomarkerangiopoietincoagulation

Abstract

Introduction

A strong biologic rationale exists for targeting markers of endothelial cell (EC) activation as clinically informative biomarkers to improve diagnosis, prognostic evaluation or risk-stratification of patients with sepsis.

Methods

The objective was to review the literature on the use of markers of EC activation as prognostic biomarkers in sepsis. MEDLINE was searched for publications using the keyword 'sepsis' and any of the identified endothelial-derived biomarkers in any searchable field. All clinical studies evaluating markers reflecting activation of ECs were included. Studies evaluating other exogenous mediators of EC dysfunction and studies of patients with malaria and febrile neutropenia were excluded.

Results

Sixty-one studies were identified that fulfilled the inclusion criteria. Overall, published studies report positive correlations between multiple EC-derived molecules and the diagnosis of sepsis, supporting the critical role of EC activation in sepsis. Multiple studies also reported positive associations for mortality and severity of illness, although these results were less consistent than for the presence of sepsis. Very few studies, however, reported thresholds or receiver operating characteristics that would establish these molecules as clinically-relevant biomarkers in sepsis.

Conclusions

Multiple endothelial-derived molecules are positively correlated with the presence of sepsis in humans, and variably correlated to other clinically-important outcomes. The clinical utility of these biomarkers is limited by a lack of assay standardization, unknown receiver operating characteristics and lack of validation. Additional large-scale prospective clinical trials will be required to determine the clinical utility of biomarkers of endothelial activation in the management of patients with sepsis.

Introduction

Sepsis is a complex syndrome that results from a host's response to invasive infection 12, and severe sepsis with organ dysfunction and septic shock are leading causes of death in critically ill patients 3. A tool that would predict prognosis or allow risk-stratification of patients is needed to inform healthcare providers, families and decision makers, and facilitate the study and implementation of evolving therapeutic interventions.

A biomarker is defined as "...a characteristic that is objectively measured as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to therapeutic intervention" 4. Despite the proposal of over 100 distinct biological molecules as biomarkers for sepsis, no useful single biomarker, or combination thereof, has yet been identified 5.

A hallmark of sepsis is a change in microvascular function. Widespread endothelial damage and apoptosis appears to be directly involved (see Figure 1), with numerous associations observed between sepsis and endothelial cell (EC) activation 678910. Consequently, there is a strong biologic rationale for targeting markers of endothelial activation as biomarkers of sepsis. A large number of EC-active molecules have been investigated as potential biomarkers for the early diagnosis, triage and prognostication of sepsis. These include regulators of endothelial activation, such as vascular endothelial growth factor (VEGF), endocan and the angiopoeitin pathway (Ang-1/2), adhesion molecules such as s-ICAM-1, sVCAM-1, and sE-selectin-1), mediators of permeability and vasomotor tone (s-Flt and endothelin-1); and mediators of coagulation (vWF, ADAMTS13).

Figure 1

Endothelial activation induces increased production of adhesion molecules such as ICAM-1, VCAM-1, E-selectin and P-selectin

Endothelial activation induces increased production of adhesion molecules such as ICAM-1, VCAM-1, E-selectin and P-selectin. E-selectin induces leukocyte rolling, and ICAM-1 and VCAM-1 bind leukocyte function antigen 1 (LFA1) and very late antigen 4 (VLA4), respectively, to induce firm leukocyte adhesion. Activation is partially mediated by VEGF binding to VEGF receptor 1 (VEGFR1, also known as Flt-1) and VEGF receptor 2 (VEGFR2). Soluble Flt-1 binds VEGF competitively to render an anti-inflammatory response in the setting of sepsis. Ang-1 is constitutively secreted by pericytes and smooth muscle cells. Upon activation, Ang-2 is rapidly released by Weibel-Palade bodies, competitively interfering with Ang-1/Tie2 signaling and thereby increasing expression of adhesion molecules.

Given the potential for, and growing interest in, EC-derived molecules as biomarkers in sepsis, we conducted a systematic review of the current published literature of biomarkers to determine their performance in predicting the severity of sepsis and clinical outcomes. This systematic review will serve as an update and supplement to other recent reviews in the literature 511121314, given the rapidly evolving nature of the field.

Materials and methods

Data sources

We systematically and inclusively identified all studies evaluating markers of endothelial activation, (including angiopoietins and sTie2R, sVEGF and sFlt-1, sICAM-1, sVCAM-1, sE-selectin, endothelin-1, endocan, VWF and ADAMTS13) in sepsis. We electronically searched MEDLINE (1950 to Week 2, September 2011) and EMBASE (1980 to Week 37, 2011) databases for all pertinent English language studies. (Please see Additional file 1, Search Strategy).

Additional file 1

Search Strategy.

Click here for file

Study selection methods

Study selection was performed independently by three reviewers (KX, SM, JMS), with disagreements resolved through arbitration by a fourth reviewer (WCL). A study was included if it (1) studied adult patients with sepsis or the systemic inflammatory response syndrome (SIRS), or studied patients at risk for sepsis or SIRS, and (2) evaluated a clinical endpoint (the development of sepsis, sepsis severity, development of organ dysfunction or mortality). Studies of patients less than 18 years of age, patients with febrile neutropenia, patients with malaria, interventional clinical trials studying a specific intervention or medication and case reports were excluded.

Study data extraction and analysis

For each of the selected studies, we extracted the biomarker(s) evaluated, study size and patient population, and details of the primary and secondary outcomes. Outcomes of interest for each biomarker were tabulated and compared across studies where appropriate. Study design, standardization of sepsis definition and other methodological data were extracted and each study was subject to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for assessing the quality of evidence 15. Due to the anticipated broad study heterogeneity and disparate study outcomes, we did not attempt to numerically combine or perform a meta-analysis of study results.

Results

Our search identified 1,243 unique articles (see Figure 2). A total of 84 studies met our predefined inclusion and exclusion criteria, of which a further 23 studies were excluded after retrieval of full-text publication for the following reasons: 14 studies did not report a clinical outcome 1617181920212223242526272829, 4 studies did not include a relevant patient population 303132, 3 studies were interventional trials 333435, and 2 studies were not in English and the English abstracts provided insufficient information to allow adjudication of study inclusion 3637. The remaining 61 studies were included in our review.

Figure 2

Study flow diagram

Study flow diagram.

All studies were observational designs, including secondary analyses of data collected during prospective clinical trials. Most studies used standard consensus definitions of sepsis. Interpretation of the magnitude of effect or association between biomarkers and sepsis or clinical outcomes was limited by a lack of standardization in individual biomarker assays, an absence of identified or validated thresholds or cut-points in individual biomarker levels, and a lack of reported odds ratios or relative risk. Several studies identified positive associations between biomarker levels and severity of sepsis (for example, sepsis, severe sepsis and septic shock), but given the aforementioned limitations and heterogeneity across studies in this association, we did not deem this to be sufficient evidence of a dose-response association to upgrade the quality level of these studies given the aforementioned limitations. Consequently, all studies were assigned a GRADE level of 'low quality' with respect to the association between individual biomarker levels and sepsis 15.

The Angiopoietin system

We identified 11 studies investigating angiopoietin 2 (Ang-2) as a biomarker in human sepsis (see Table 1- Studies Evaluating Angiopoietin-2). All but one were prospective observational studies 38394041424344, with one secondary analysis of a previously conducted cohort study 45.

Table 1

Studies evaluating angiopoietin-2

Study

Year

Population

Standard Criteria for SIRS/Sepsis

Association with Sepsis

Other Outcomes

Parikh et al., 43

2006

ICU patients with sepsis (22) and hospitalized controls (29)

2003 ACCP/SCCM 2

Ang-2 higher in patients severe sepsis than patients with sepsis and controls (23.2 vs. 4.8 and 3.5 ng/mL respectively; P < 0.01)

Van der Heijden et al., 45

2008

112

Mechanically ventilated patients, with sepsis (24) and without (88)

1992 ACCP/SCCM 1

Ang-2 higher in patients with sepsis than without sepsis (4.1 vs. 0.4 ng/mL; P < 0.01)

Higher Ang-2 associated with ALI/ARDS (P < 0.001) and higher in ARDS than in ALI (P > 0.001); Independently associated with the severity of pulmonary leak (r = 0.41; P = 0.014).

Orfanos et al., 38

2007

ICU patients

1992 ACCP/SCCM 1

Ang-2 higher in severe sepsis compared to patients without SIRS or sepsis (P < 0.05 by analysis of variance)

Ang-2 levels correlated with levels of circulating TNF (P < 0.05)

Giamarellos-Bourboulis et al., 40

2008

Trauma patients admitted to ICU (54) and healthy controls (6)

2003 ACCP/SCCM 2

Ang-2 higher in sepsis and severe sepsis than in healthy controls, or trauma patients with sterile SIRS (P < 0.05); Predictive of sepsis/severe sepsis (P = 0.017, 0.002 respectively); Increases in serial Ang-2 predicted development of sepsis (P < 0.05)

Ang-2 correlated with 28-day survival (P = 0.015)

Kumpers et al., 42

2008

Patients admitted to medical ICU (43) and healthy controls (29)

2003 ACCP/SCCM 2

Ang-2 higher in septic patients than in patients without sepsis (16.5 vs. 2.8 ng/mL; P < 0.001); Not correlated with severity of sepsis (median Ang-2 16.5 vs. 28.1 ng/mL; P = 0.12);

Ang-2 correlated with mortality (P = 0.001)

Davis et al., 44

2010

124

Patients admitted to a mixed ICU

1992 ACCP/SCCM 1

Ang-2 higher in patients with severe sepsis compared to patients with sepsis without organ failure and non-septic controls (12.4 vs. 6.1 and 2.7 ng/mL, respectively; P < 0.0001).

Ang-2 not predictive of 28-day mortality (P = 0.32)

Siner et al., 39

2009

Patients admitted to ICU

1992 ACCP/SCCM 1

Ang-2 not correlated with severity of sepsis

Ang-2 correlated with mortality (P = 0.02)

Ricciuto et al. 48

2011

Patients with severe sepsis

1992 ACCP/SCCM 1

Admission levels of Ang-2 and Ang-2/Ang-1 ratio were not associated with 28-day mortality Serially measured Ang-2 levels correlated directly with the MOD score (P = .003)

Ebihara et al. 49

2011

25 patients treated with Polymyxin-B column hemoperfusion 11 developed ALI

1992 ACCP/SCCM 1

Positive correlation between Ang-1 and PaO2/FiO2 ratio (r = 0.427; P < 0.001) Inverse correlation between Ang-2 and PaO2/FiO2 ratio (r = 0.302; P = 0.003)

Page et al., 50

2011

16 invasive streptococcal infection and toxic shock 21 invasive steptococcal infection alone

S. pyogenes isolated from normally sterile site and 2009 Consensus definition of streptococcal toxic shock

Ang-2:Ang-1 ratio increased in Streptococcal Toxic Shock Syndrome compared to those with uncomplicated invasive streptococcal infection (P < 0.05)

Kranidoti et al., 41

2009

107

ICU patients with Ventilator Associated pneumonia (90) and healthy controls (17)

2003 ACCP/SCCM 1

Ang-2 higher in septic patients compared to healthy controls. (P < 0.001)

Ang-2 correlated with mortality (P < 0.05); Ang-2 levels greater than 9.7 ng/mL associated with sepsis-related mortality (OR = 3.3; P = 0.033)

ACCP, American College of Chest Physicians; ALI, Acute Lung Injury; APACHE II, Acute Physiology and Chronic Health Evaluation II; ARDS, Acute Respiratory Distress Syndrome; ED, emergency department; MOF, Multiple Organ Failure; SAPS, Simplified Acute Physiology Score; SCCM, Society of Critical Care Medicine; SIRS, systemic inflammatory response syndrome; SOFA, Sequential Organ Failure Assessment

Association with sepsis

Seven studies evaluated the association between Ang-2 levels and sepsis, reporting higher levels of Ang-2 in patients with sepsis compared to patients without sepsis in the ward setting 4344, the ICU 38404245, and patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) 45. Ang-2 levels were also higher in sepsis than in either patients with sterile SIRS 40 or healthy controls 41. Kumpers et al. also reported that Ang-2 concentrations were elevated in all ICU patients (irrespective of sepsis status) compared to healthy controls 42. One study found that patients who did not have SIRS/sepsis on admission but subsequently developed SIRS/sepsis, had significant increases in Ang-2 over time 40.

There were inconsistent reports of the association between Ang-2 and the severity of sepsis (as defined by sepsis, severe sepsis and septic shock), with one positive study 44 and four studies that failed to observe a consistent correlation 38394142. Higher levels of Ang-2 were also reported in patients with severe sepsis compared to septic ICU patients without organ dysfunction 384344, non-septic hospitalized controls 4344, and ICU patients without SIRS 38.

None of the studies identified a cut point or threshold of circulating Ang-2 that allowed differentiation of patients with sepsis and without sepsis, or stratification of patients with respect to sepsis severity based on baseline or serial serum Ang-2 concentrations.

Association with clinical outcome

Three studies 394042 observed associations between circulating Ang-2 levels and severity of illness as defined by Acute Physiology and Chronic Health Evaluation II (APACHE II) 46 or Sequential Organ Failure Assessment score (SOFA) 47, and five studies reported a relationship between increasing Ang-2 levels and increasing mortality 3940414248. Kumpers et al. found that circulating Ang-2 levels were independently associated with 30-day survival after adjustment for APACHE II score, SOFA score and serum lactate levels 42. Kranidioti et al. found that Ang-2 concentrations were associated with sepsis-related mortality at baseline and every day for the first seven days in ICU, and Ang-2 levels greater than 9.7 ng/mL were associated with a three-fold increased risk of sepsis-related mortality 41. Siner et al. found higher Ang-2 levels were associated with hospital motality, and the patient cohort could be stratified for hospital mortality by admission Ang-2 levels 39. Ricciuto et al. observed that serial measurements of Ang-2 were associated with 28-day mortality and multiple organ dysfunction (MOD) score 48.

One study found Ang-2 was independently associated with the severity of lung injury as measured by pulmonary leak, and was predictive for the development of ARDS 45. A second study found an inverse correlation between Ang-2 and PaO2/FiO2 ratio 49. Page et al. found that the Ang-2/Ang-1 ratio was significantly increased in patients with invasive streptococcal infection who developed toxic shock syndrome, compared to those with uncomplicated infection 50.

The leukocyte adhesion pathway

We identified 19 studies investigating sICAM-1 as a sepsis biomarker (see Table 2-Studies evaluating sICAM), 12 studies for sVCAM-1 (see Table 3-Studies Evaluating sVCAM-1), 23 studies for sE-selectin-1 (Table 4-Studies Evaluating sE-selectin-1), and 2 studies for endocan (see Table 5-Studies Evaluating Endocan). All were prospective studies or secondary analyses of prospective studies. These studies focused on emergency room patients with suspected infections or shock 5152, and critically ill patients admitted to intensive care units, including medical and surgical patients 51535455565758596061626364656667686970717273747576, patients with ventilator-associated pneumonia (VAP) 73, trauma 6263666775, and post-cardiopulmonary resuscitation 74.

Table 2

Studies evaluating sICAM

Study

Year

Population

Standard Criteria for SIRS/Sepsis

Associations with sepsis

Other outcomes

Shapiro et al., 51

2010

221

ED patients with sepsis without organ dysfunction (71), severe sepsis without shock (66), septic shock (71), and non-infected controls (13)

1992 ACCP/SCCM 1

sICAM-1 elevated in septic shock compared with non-infected controls (P < 0.05);

sICAM-1 associated with increasing sepsis severity P < 0.05; modest correlation with SOFA and APACHE-II; predicts mortality and severe sepsis (AUC of 0.72 (95% CI 0.57 to 0.87), 0.61 (95% CI 0.53 to 0.69))

Schuetz et al., 52

2011

161

Patients with hypotension: 69 sepsis 35 cardiac 12 hemorrhagic 12 unknown

Clinical classification based on clinical and microbiological data

ICAM-1 higher in sepsis compared to non-sepsis (P < 0.05)

Hofer et al., 55

2009

147

Surgical ICU patients with severe sepsis (101) and major abdominal surgery (28), and healthy controls (18)

2003 ACCP/SCCM 2

sICAM-1 higher in the septic group than postoperative and volunteer groups at diagnosis (444.7 ng/ml vs 213.7 ng/ml and 219.6 ng/ml, respectively; P < 0.001)

Not predictive of mortality at the time of diagnosis of sepsis, but non-survivors had trend to higher sICAM-1 levels at 48 h and 120 h (683.2 vs 434.1 ng/ml, P = 0.067; 360.2 vs 467.8 ng/ml, P = 0.083, respectively) compared to survivors

Stief et al., 54

2007

ICU patients with Sepsis (62), healthy controls (24)

Clinical definition of sepsis

Higher in sepsis than controls (2.56 ug/ml vs 0.19 ug/ml; P < 0.05)

Scherpereel et al., 53

2006

ICU patients with sepsis (63), SIRS (7), healthy controls (20)

1992 ACCP/SCCM 1

sICAM-1 higher in sepsis compared to SIRS P < 0.02

sICAM-1 not predictive of mortality or severity of sepsis

Kinoshita et al., 56

2002

Gram negative sepsis from intra-abdominal infection admitted to surgical ICU (47), healthy controls (9)

1992 ACCP/SCCM 1

sICAM-1 higher in sepsis than healthy controls

Not correlated with mortality in those with ARDS; Higher in those with ARDS than those without P < 0.05

Paterson et al., 57

2000

ICU patients with SIRS (10), healthy controls (6)

1992 ACCP/SCCM 1

sICAM-1 not reported in healthy controls

Not correlated with mortality

Weigand et al., 58

1999

Surgical ICU patients with septic shock (14), healthy controls (7)

1992 ACCP/SCCM 1

sICAM-1 significantly higher in sepsis than controls (P < 0.05)

sICAM-1 significantly higher in nonsurvivors than survivors, sensitivity and specificity for cutoff of 800 ng/ml was 74.1%

Froon et al., 73

1998

ICU patients with sepsis and VAP

1992 ACCP/SCCM 1

sICAM-1 higher in VAP patients complicated by severe sepsis or septic shock than other VAP patients, but statistical significance not achieved

Not predictive of mortality, and correlates poorly with SAPS-II (r = 0.16, P = 0.30)

Kayal et al., 59

1998

ICU patients with severe sepsis or septic shock (25), ICU controls (7), healthy controls (9)

1992 ACCP/SCCM 1

sICAM-1 higher in septic patients than in noninfected ICU controls and healthy volunteers (P < 0.0001); higher in septic shock than those without septic shock (P < 0.05)

sICAM-1 correlated with mortality; correlated with SAPS and MOF score (r = 0.53, P < 0.01 for MOF)

Boldt et al., 60

1997

Surgical ICU patients with post-operative sepsis (30), healthy controls (not stated)

1992 ACCP/SCCM¹

sICAM-1 higher in septic patients than healthy controls

Higher in older than younger patients P < 0.05, and tends to increase in older patients and decrease in younger patients over time

Egerer et al., 61

1997

ICU patients with infection (8), severe sepsis (16)

1992 ACCP/SCCM 1

sICAM-1 higher in severe sepsis compared with patients with infection (P > 0.05)

Not correlated with mortality in patients with severe sepsis

Takakuwa et al., 62

1997

ICU admissions with sepsis (20), trauma (14)

Clinical definition of SIRS and sepsis

sICAM-1 level higher in septic than trauma patients (987.7 vs 472.1 ng/ml; P = 0.0002)

sICAM-1 correlated with endotoxin, TNF-α, IL-6, IL-8, Type II PLA2 (Type II phospholiaps A2), NO (P < 0.05 for all)

Boldt et al., 63

1996

Surgical ICU patients with postoperative sepsis (15), trauma (15)

1992 ACCP/SCCM 1

sICAM-1 higher in sepsis than trauma (1,266 vs 444 ng/ml; P < 0.01)

Endo et al., 64

1996

ICU patients with sepsis with MOF (8), sepsis without MOF (15), MOF without sepsis (5)

Clinical diagnosis of sepsis

sICAM-1 higher in septic patients with or without MOF than patients with MOF but no infection (1103.3 vs 356.0 ng/ml, and 862.5 vs 356.0 ng/ml, respectively, P < 0.05))

sICAM-1 level higher in septic patients with MOF than those without (P = 0.0401)

Moss et al., 66

1996

ICU patients with sepsis (19), trauma (36) controls (5)

Clinical diagnosis of sepsis

sICAM-1 higher in septic patients than trauma and controls (573 vs 148 and 235 ng/ml, respectively, P < 0.001)

Nakae et al., 67

1996

ICU patients with sepsis (21), trauma (13)

1992 ACCP/SCCM 1

sICAM-1 higher in septic patients than in trauma patients (987 vs 472 pg/ml; P = 0.0002)

sICAM-1 correlated with endotoxin, TNF-alpha and IL-8 (P < 0.05 for all)

Sessler et al., 68

1995

ICU patients with sepsis (25), SIRS (25), ICU controls (4), healthy volunteers (12)

1992 ACCP/SCCM 1

sICAM-1 higher in sepsis than ICU controls and healthy controls (1,259 vs 585 ng/ml, P < 0.001; 1,259 vs 355 ng/ml, P < 0.0001); sICAM-1 is higher in SIRS than ICU controls and healthy controls (937 vs 585 ng/ml, P < 0.05; 937 vs 355 ng/ml, P < 0.001); higher in sepsis vs SIRS (1,259 vs 937 ng/ml; P = 0.12)

sICAM-1 elevated with increasing severity of illness: septic shock, severe sepsis and sepsis (1,551, 796, and 542 ng/ml, respectively, ANOVA P = 0.017); correlated with cumulative MOF score, shock severity score (r = 0.46, P = 0.021; r = 0.50, P < 0.009); higher in nonsurvivors vs survivors (1,697 vs 854 ng/ml; P = 0.0096)

Cowley et al., 65

1994

125

ICU patients with sepsis (21), severe sepsis (14), ICU controls (5), healthy controls (85)

Clinical definition of SIRS and sepsis

sICAM-1 higher in severe sepsis, uncomplicated sepsis, and ICU controls than healthy controls P < 0.05.

sICAM-1 with no significant difference between severe sepsis, uncomplicated sepsis and ICU controls. Not correlated with mortality

ACCP, American College of Chest Physicians; ALI, Acute Lung Injury; APACHE II, Acute Physiology and Chronic Health Evaluation II; ARDS, Acute Respiratory Distress Syndrome; ED, emergency department; MOF, Multiple Organ Failure; SAPS, Simplified Acute Physiology Score; SCCM, Society of Critical Care Medicine; SIRS, Systemic Inflammatory Response Syndrome; SOFA, Sequential Organ Failure Assessment

Table 3

Studies evaluating sVCAM-1

Study

Year

Population

Standard Criteria for SIRS/Sepsis

Association with sepsis

Other outcomes

Shapiro et al., 51

2010

221

ED patients with sepsis without organ dysfunction (71), severe sepsis without shock (66), septic shock (71), and non-infected controls (13)

1992 ACCP/SCCM 1

sVCAM-1 elevated in septic shock compared with non-infected controls (P < 0.05)

sVCAM-1 associated with sepsis severity P < 0.04; predicts mortality and severe sepsis (AUC of 0.57 (95% CI 0.35 to 0.79), 0.60 (95% CI 0.52 to 0.69))

Hofer et al., 55

2009

147

Surgical ICU patients with severe sepsis (101), major abdominal surgery (28), healthy controls (18)

2003 ACCP/SCCM 2

sVCAM-1 did not differentiate between septic, postoperative and healthy controls

sVCAM-1 not predictive of mortality at the time of diagnosis of sepsis, but nonsurvivors had elevated sVCAM-1 at 48 h and 120 h compared to survivors(1,275.1 vs 882.0 ng/ml, P = 0.027; 1,685.5 vs 748.5 ng/ml; P = 0.021, respectively)

Kinoshita et al., 56

2002

Gram negative sepsis from intra-abdominal infection admitted to surgical ICU (47), healthy controls (9)

1992 ACCP/SCCM 1

sVCAM-1 higher in patients than healthy controls

sVCAM-1 did not differentiate those with ARDS from those without; not predictive of mortality in those with ARDS

Presterl et al., 69

1999

ICU patients with Candida (20) and bacterial sepsis (20)

1992 ACCP/SCCM 1

At all times (days 1, 7, 14) sVCAM-1 levels higher in Candida sepsis than bacterial sepsis (P < 0.05)

sVCAM-1 not correlated with mortality

Knapp et al., 78

1998

Patients with sepsis (28 gram positive, 11 gram negative), 15 healthy controls

1992 ACCP/SCCM 1

sVCAM-1 elevated in sepsis compared with healthy controls (P < 0.05)

sVCAM-1 does not correlate with mortality in gram positive sepsis; does not distinguish between gram positive and gram negative sepsis

Boldt et al., 60

1997

Surgical ICU patients with post-operative sepsis (30), healthy controls (not stated)

1992 ACCP/SCCM 1

sVCAM-1 higher in septic patients than healthy controls

Higher in older than younger patients P < 0.05, and tends to increase in older patients and decrease in younger patients over time

Takakuwa et al., 62

1997

ICU admissions with sepsis (20), trauma (14)

Clinical definition of SIRS and sepsis

sVCAM-1 higher in septic than trauma patients (2,536 vs 1,019.0 ng/ml; P = 0.0004)

sVCAM-1 level correlated with TNF-α, IL-6, IL-8, NO, sE-selectin-1 ((P < 0.05 for all)

Boldt et al., 63

1996

Surgical ICU patients with postoperative sepsis (15), trauma (15)

1992 ACCP/SCCM 1

sVCAM-1 is higher in sepsis than trauma (1,042 vs 689 ng/ml; P < 0.05)

Endo et al., 64

1996

ICU patients with sepsis with MOF (8), sepsis without MOF (15), MOF without sepsis (5)

Clinical diagnosis of sepsis

sVCAM-1 higher in septic patients with or without MOF than patients with MOF but no infection (2,654.9 vs 945.0 ng/ml, P = 0.0295; 2,045.0 vs 945.0 ng/ml, P = 0.0037)

sVCAM-1 did not differ between septic patients with and without MOF (2,654.9 vs 2,045.0 ng/ml; P = 0.1315)

Furian et al., 76

2011

Patients admitted to ICU with severe sepsis or septic shock

1992 ACCP/SCCM 1

sVCAM-1 not associated with left ventricular function or size.

Schuetz et al., 52

2011

161

Patients with hypotension: 69 sepsis, 35 cardiac, 12 hemorrhagic, 12 unknown

Clinical classification based on clinical and microbiological data

VCAM-1 higher in sepsis compared to non-sepsis (P < 0.05)

Cowley et al., 65

1994

125

ICU patients with sepsis (21), severe sepsis (14), ICU controls (5), healthy controls (85)

Clinical definition of SIRS and sepsis

sVCAM-1 is higher in sepsis than controls

sVCAM-1 higher in severe sepsis than uncomplicated sepsis at baseline (P = 0.06) and peak concentrations P < 0.01. Not correlated with mortality

ACCP, American College of Chest Physicians; ALI, Acute Lung Injury; APACHE II, Acute Physiology and Chronic Health Evaluation II; ARDS, Acute Respiratory Distress Syndrome; ED, emergency department; MOF, Multiple Organ Failure; SAPS, Simplified Acute Physiology Score; SCCM, Society of Critical Care Medicine; SIRS, Systemic Inflammatory Response Syndrome; SOFA, Sequential Organ Failure Assessment

Table 4

Studies evaluating sE-selectin-1

Study

Year

Population

Standard Criteria for SIRS/Sepsis

Association with sepsis

Other outcomes

Schuetz et al., 52

2011

161

Patients with hypotension: 69 sepsis, 35 cardiac, 12 hemorrhagic, 12 unknown

Clinical classification based on clinical and microbiological data

E-selectin higher in sepsis compared to non-sepsis (P < 0.05) E-selectin independently associated with sepsis after adjustment for age, sex, blood pressure and mortality (P = 0.001) with AUC of 0.74 for discrimination of sepsis and non-sepsis

Shapiro et al., 51

2010

221

ED patients with sepsis without organ dysfunction (71), severe sepsis without shock (66), septic shock (71), and non-infected controls (13)

1992 ACCP/SCCM 1

sE-selectin-1 levels elevated in septic shock compared with non-infected controls

sE-selectin-1 associated with sepsis severity P < 0.001; predicts mortality and severe sepsis (AUC of 0.65 (95% CI 0.49 to 0.82) and 0.71 (95% CI 0.64 to 0.78) respectively)

Stief et al., 54

2007

ICU patients with Sepsis (62), healthy controls (24)

Clinically diagnosed sepsis

sE-selectin-1 elevated in sepsis compared to reference value (190 ng/ml vs 55 ng/ml; P < 0.05))

Kinoshita et al., 56

2002

Gram negative sepsis from intra-abdominal infection admitted to surgical ICU (47), healthy controls (9)

1992 ACCP/SCCM 1

sE-selectin-1 does not differentiate between ARDS from non ARDS

Not predictive of mortality in those with ARDS

Geppert et al., 74

2000

ICU patients on day two post successfulCPR (25), non-critically ill controls (7)

1992 ACCP/SCCM 1

sE-selectin-1 higher in SIRS compared to controls (96.2 ng/ml vs 42.8 ng/ml; P = 0.23), but does not differentiate patients with SIRS vs patients without SIRS

Higher in non-survivors than survivors (114.2 ng/ml vs 85.7 ng/ml; P = 0.025)

Osmanovic et al., 72

2000

ICU patients with sepsis with MOF (9), healthy controls (18)

Clinical definition of sepsis

sE-selectin-1 higher in sepsis compared to healthy controls (118 vs 28.5 ng/ml; P < 0.001)

Hynninen et al., 70

1999

ICU patients with severe sepsis (11), severe acute pancreatitis (9)

1992 ACCP/SCCM 1

sE-selectin does not differentiation between those with severe acute pancreatitis and severe sepsis

Higher in those with higher SOFA scores (SOFA ≥ 10, P = 0.043), but not correlated with mortality

Presterl et al., 69

1999

ICU patients with candida (20) and bacterial sepsis (20)

1992 ACCP/SCCM 1

sE-selectin-1 lower in patients with Candida sepsis than bacterial sepsis (P < 0.05) on Day 1

Higher in non-survivors

Takala et al., 71

1999

Hospitalized patients with sepsis with organ failure (8) and without organ failure (12); healthy controls (56)

1992 ACCP/SCCM 1

sE-selectin-1 level elevated in septic patients compared to healthy adults P < 0.001

Not correlated with organ failure

Weigand et al., 58

1999

Surgical ICU patients with septic shock (14), healthy controls (7)

1992 ACCP/SCCM 1

sE-selectin-1 higher in sepsis than healthy controls (P < 0.05)

Not predictive of mortality or severity of disease

Froon et al., 73

1998

ICU patients with sepsis and VAP

1992 ACCP/SCCM 1

sE-selectin-1 higher in patients with severe sepsis or septic shock than other VAP patients, but statistical significance not achieved

Day 2 sE-selectin-1 higher in nonsurvivors than survivors (114.3 vs 67.0 ng/ml; P = 0.04); Correlates poorly with SAPSII (r = 0.18, P = 0.25)

Kayal et al., 59

1998

ICU patients with severe sepsis or septic shock (25), ICU controls (7), healthy controls (9)

1992 ACCP/SCCM 1

sE-selectin-1 higher in septic patients than noninfected ICU controls and healthy volunteers (p < 0.0001); higher in those with septic shock than those without (p < 0.05)

sE-selectin-1 higher in nonsurvivors than survivors on day 0 (286 vs 195 ng/ml; P < 0.05), but decreases after Day 3 of sepsis to reach a level similar to that of survivors Day 14; correlated with SAPS and MOF score (r = 0.45, P < 0.05 for MOF)

Knapp et al., 78

1998

Patients with sepsis (28 gram positive, 11 gram negative), 15 healthy controls

1992 ACCP/SCCM 1

sE-selectin-1 higher in septic patients than controls p < 0.05

sE-selectin-1 higher in nonsurvivors than survivors of gram positive sepsis on day 0, 4 and 7 (175 vs 85 ng/ml, P < 0.01; 155.7 vs 78.8 ng/ml, P < 0.05; 180 vs 76.1 ng/ml, P < 0.001, respectively); does not differentiate gram positive from gram negative infections.

Boldt et al., 60

1997

Surgical ICU patients with post-operative sepsis (30), healthy controls (not stated)

1992 ACCP/SCCM 1

sE-selectin-1 higher in septic patients than healthy controls

Higher in older than younger patients P < 0.05, and tends to increase in older patients and decrease in younger patients over time

Cummings et al., 79

1997

119

ICU patients with sepsis (67), SIRS (44), ICU controls (8)

1992 ACCP/SCCM 1

sE-selectin-1 higher in culture positive sepsis than culture negative sepsis, SIRS and ICU controls (15.39 vs 4.87, 2.33, and 1.97 ng/ml, respectively; P < 0.0001)

Day 1 levels higher for nonsurvivors than survivors (10.61 vs 4.35 ng/ml of log transformed mean sE-selectin-1; P < 0.05); sE-selectin-1 correlates strongly to the degree of hemodynamic compromise (P < 0.0001), and moderately with the peak MOF score (r = 0.30, P = 0.001)

Egerer et al., 61

1997

ICU patients with infection (8), severe sepsis (16)

1992 ACCP/SCCM 1

Higher in patients with severe sepsis and MOF than those with infection alone (P < 0.05)

Higher in nonsurvivors than survivors on Day 7-8, P < 0.05

Takakuwa et al., 62

1997

ICU admissions with sepsis (20), trauma (14)

No Standard Definition

sE-selectin-1 higher in sepsis than trauma (287.9 vs 195.0 ng/ml; P = 0.0055)

sE-selectin-1 level correlated with TNF-α, IL-8, Type II PLA2, sICAM-1 (P < 0.005 for all)

Boldt et al., 63

1996

Surgical ICU patients with postoperative sepsis (15), trauma (15)

1992 ACCP/SCCM 1

sE-selectin-1 higher in sepsis than trauma (340 vs 57.9 ng/ml; P < 0.05)

Endo et al., 64

1996

ICU patients with sepsis with MOF (8), sepsis without MOF (15), MOF without sepsis (5)

Clinical diagnosis of sepsis

sE-selectin-1 higher in septic patients with or without MOF than patients with MOF but no infection (345.2 vs 121.8 ng/ml, P = 0.0016; 266.2 vs 121.8 ng/ml, P = 0.0054)

sE-selectin-1 did not differ significantly between septic patients with and without MOF (345.2 vs 266.2 ng/ml; P = 0.2939)

Moss et al., 66

1996

ICU patients with sepsis (19), trauma (36) controls (5)

Clinical diagnosis of sepsis

Higher in sepsis than trauma and controls (573 vs 148 and 235 ng/ml, respectively, P < 0.001)

Simons et al., 75

1996

Multiple trauma patients, infectious complications in 14

Not specified

sE-selectin-1 higher in patients who subsequently developed infection, organ dysfunction, or both, by 36 h. P = 0.08

sE-selectin-1 higher in non-survivors than survivors (P = 0.0018)

Cowley et al., 65

1994

125

ICU patients with sepsis (21), severe sepsis (14), ICU controls (5), healthy controls (85)

Clinical definition of SIRS and sepsis

sE-selectin higher in sepsis than controls (P < 0.01).

sE-selectin-1 higher in severe sepsis than uncomplicated sepsis on presentation (P < 0.01) and more pronounced with peak values (P < 0.001). Not correlated with mortality

Newman et al., 80

1993

ICU patients with sepsis with positive blood cultures (17), healthy controls (71)

Clinical definition of sepsis

Higher in septic shock than controls (23.3 vs 0.92 ng/ml; P < 0.05); not elevated in uncomplicated sepsis compared to controls

ACCP, American College of Chest Physicians; ALI, Acute Lung Injury; APACHE II, Acute Physiology and Chronic Health Evaluation II; ARDS, Acute Respiratory Distress Syndrome; ED, emergency department; MOF, Multiple Organ Failure; SAPS, Simplified Acute Physiology Score; SCCM, Society of Critical Care Medicine; SIRS, Systemic Inflammatory Response Syndrome; SOFA, Sequential Organ Failure Assessment

Table 5

Studies evaluating Endocan

Study

Year

Population

Standard Criteria for SIRS/Sepsis

Association with sepsis

Other outcomes

Scherpereel et al., 53

2006

ICU patients with sepsis (63), SIRS (7), healthy controls (20)

1992 ACCP/SCCM 1

Higher in sepsis than SIRS or healthy controls (2.71 vs 0.77 and 0.68 ng/ml; P < 0.001);higher in septic shock than severe sepsis and uncomplicated sepsis (6.11 vs 1.97 and 1.95 ng/ml; P < 0.05, P < 0.02)

Endocan on ICU admission higher in nonsurvivors than patients still alive after 10 days (6.98 vs 2.54 ng/ml; P < 0.01), using a cutoff of 6.2 ng/ml, sensitivity and specificity are 75% and 84% respectively.

Bechard et al., 23

2000

Patients with septic shock (8), healthy controls (20)

1992 ACCP/SCCM 1

Higher in septic shock than healthy controls (7.815 vs 1.081 ng/ml; P = 0.0173)

ACCP, American College of Chest Physicians; ALI, Acute Lung Injury; APACHE II, Acute Physiology and Chronic Health Evaluation II; ARDS, Acute Respiratory Distress Syndrome; ED, emergency department; MOF, Multiple Organ Failure; SAPS, Simplified Acute Physiology Score; SCCM, Society of Critical Care Medicine; SIRS, Systemic Inflammatory Response Syndrome; SOFA, Sequential Organ Failure Assessment

Soluble ICAM-1

Association with sepsis

All studies comparing sICAM-1 in septic patients and healthy controls reported higher levels in septic patients 54555859656668. sICAM-1 was also found to be significantly higher in sepsis than in patients with trauma 61626667, postoperative patients 55, patients with other forms of shock 52, and non-septic ICU patients 596668. One study reported that sICAM-1 levels were similar in septic patients and ICU patients without sepsis 65. Two studies explicitly compared sICAM-1 in patients with sepsis and SIRS 5368, but only one found higher sICAM-1 in sepsis 53. Several studies observed that baseline sICAM-1 levels were similar in non-septic patients and healthy controls 555966.

The association between sICAM-1 levels and sepsis severity was variable. Seven studies investigated this association, with four studies reporting higher sICAM-1 levels with increasing severity of sepsis 59646877 and three negative studies 536165.

Association with clinical outcome

Eleven studies reported data on mortality. Five of these studies reported that increasing sICAM-1 levels correlated with mortality 5558596877, but six studies found no such correlation 535657616573. One study found a trend towards increased mortality with increasing sICAM-1 levels over time 55.

Two studies evaluated the discriminative characteristics of sICAM-1 5158. Weigand et al. reported that a sICAM-1 threshold of 800 ng/ml could differentiate survivors from non-survivors with a sensitivity and specificity of 74.1%, although this value was derived from a small sample of 14 post-surgical patients with relatively high mortality (50%) 58. Shapiro reported on a group of 221 patients presenting to the emergency department with suspected infections, of which 208 had sepsis of varying severity. The presenting sICAM-1 value predicted mortality with an area under the receiver operating characteristic (ROC) curve of 0.72 (95% CI (0.57 to 0.870)). However, a cutoff value was not reported 77.

Several studies reported moderate to poor correlation of sICAM-1 with the degree of severity of illness or number of organ failures as defined by APACHE II, SOFA, Multiple Organ Failure Score and Simplified Acute Physiology Score 59687377.

One study reported varying kinetics of sICAM-1 according to age: In 30 patients with postoperative sepsis, Boldt et al. reported that older patients had higher sICAM-1 levels than younger patients (P < 0.05), and sICAM-1 tended to increase over time in older patients while decreasing over time in younger patients 60.

Soluble VCAM-1 (sVCAM-1)

We identified 12 studies evaluating sVCAM-1 (see Table 3-Studies Evaluating sVCAM-1) in sepsis. These studies evaluated sVCAM-1 in emergency department patients 51, postoperative patients 5563, patients admitted to ICU 5662, critically-ill trauma patients 60 and patients with sepsis 64656978. Three studies compared sVCAM-1 levels with healthy control groups 556578.

Association with sepsis

Six studies reported that sVCAM-1 levels were significantly greater in patients with sepsis than in healthy controls 6578, trauma patients 6263, non-infected patients 77 and patients with multiple organ failure due to causes other than sepsis 64. Four studies reported that sVCAM-1 levels effectively differentiated septic from non-septic patients 62636477, but one study reported sVCAM-1 levels were not significantly different between septic patients, postoperative patients and healthy controls 55. One study reported higher sVCAM-1 levels in patients with shock due to sepsis compared to other forms of shock 52.

Three studies attempted to correlate sVCAM-1 with increasing sepsis severity 646577. Shapiro et al. found a moderate degree of correlation with severe sepsis with an area under the ROC curve of 0.60 (95% CI 0.52 to 0.69) 77. Cowley et al. reported that baseline and peak values of sVCAM-1 were higher in ICU patients with severe sepsis than in uncomplicated sepsis 65. Conversely, another study reported that sVCAM-1 was not different in septic patients with or without organ failure 64.

Association with clinical outcome

Six of the 10 identified studies examined mortality outcomes, with 2 studies reporting an association between higher sVCAM-1 levels and mortality 5577, and 4 studies showing no significant correlation with mortality in patients with ARDS 56, gram-positive sepsis 78, and septic patients admitted to ICU 6569. Hofer et al. found no correlation between baseline sVCAM-1 and mortality in septic patients but reported significantly higher sVCAM-1 levels at 48 and 120 hours in non-survivors compared to survivors.

Only one study addressed correlation of sVCAM-1 with clinical severity scores, and reported modest correlation with SOFA and APACHE II 77.

Two studies reported variability of sVCAM-1 in sepsis across different patient populations 6469. Presterl et al. investigated the difference of sVCAM-1 level in Candida sepsis compared to bacterial sepsis, and found that sVCAM-1 was higher in Candida sepsis at days 1, 7 and 14 69. Similar to sICAM-1, Endo et al. found higher sVCAM-1 levels with increasing age, and observed that the dynamics of serial sVCAM-1 were different in patients stratified by age. Specifically, sVCAM-1 values increased over the course of sepsis time in older patients and decreased in younger patients 64.

One study found that sVCAM-1 was not associated with left ventricular size or function in patients with sepsis or septic shock 76.

Soluble E-selectin

Twenty-three studies were identified that evaluated sE-selectin as a biomarker in sepsis (see Table 4-Studies Evaluating sE-selectin-1).

Association with sepsis

The majority of identified studies reported higher levels of sE-selectin in sepsis compared to healthy controls or other patient groups without sepsis. Ten studies specifically reported significantly elevated sE-selectin levels in sepsis when compared with healthy controls 54585965667172787980. Geppert et al. reported higher sE-selectin levels in patients with SIRS following cardiopulmonary resuscitation compared to controls 74. sE-selectin was also reported to be significantly higher in septic patients compared to trauma patients 626366, ICU controls 5979, patients with infection but without systemic sepsis 6177, patients with shock from other causes 52, and patients with multiple organ failure without infection 64. Hynninen et al. concluded that sE-selectin values were not statistically different in patients with severe sepsis from those with severe acute pancreatitis 70.

Association with clinical outcome

The reported association of sE-selectin and disease severity has been inconsistent. Five studies showed a correlation between the marker and increasing sepsis severity 5961657779, although three studies did not find a significant correlation 647173.

Thirteen of the identified studies evaluated the association between sE-selectin and mortality, with nine studies reporting a significant positive correlation 596169737475777879 and four studies reporting no correlation 56586570. Among the studies reporting positive association, there was significant heterogeneity in the strength and type of association. One study of ICU patients with severe sepsis and septic shock reported that baseline sE-selectin-1 levels were higher in non-survivors than survivors, but the difference existed only for the first three days of sepsis 59. In contrast, two other studies demonstrated a more persistent divergence of sE-selectin-1 between survivors and non-survivors of sepsis: Knapp et al. reported that sE-selectin-1 remained significantly elevated in non-survivors compared to survivors throughout the first seven days of sepsis 78, while Egerer reported that sE-selectin peaked in survivors of sepsis on the second day and decreased thereafter, whereas it continued to rise in patients who subsequently died 61. One other study found that sE-selectin-1 predicted mortality in patients presenting to the emergency department with suspected infections, with an area under the ROC curve of 0.65 51.

Only a few studies examined correlation between sE-selectin-1 and clinical severity of illness scores, and none found strong correlations. Shapiro et al. showed that sE-selectin correlated modestly with SOFA and APACHE-II 51. Hynnien et al. reported that levels of sE-selectin were higher in patients with a SOFA score ≥ 10 compared to individuals with a score less than 10 70. sE-Selectin was also reported to correlate moderately or poorly with SAPSII 5973 and MOF score 5979.

Three studies evaluated variability in sE-selectin levels in different patient groups 606979. Boldt et al. showed sE-selectin levels in septic patients increased across age groups 60. Cummings et al. showed higher levels in bacteremic sepsis than in non-bacteremic sepsis 79, and Presterl et al. found higher levels of sE-selectin in bacterial sepsis than in Candida sepsis 69.

Endocan

Two prospective observational studies were identified evaluating endocan as a biomarker in sepsis 2353 (see Table 5-Studies Evaluating Endocan).

Association with sepsis

Both studies reported that serum endocan was increased in septic patients. Schepereel et al. reported in their prospective study that endocan levels were higher in patients with sepsis than in patients with SIRS or healthy controls 53. Bechard et al. showed that endocan levels were higher in patients with septic shock than in healthy controls 23.

Association with clinical outcome

Scherpereel et al. reported that mean endocan levels were higher in patients with septic shock than in patients with severe sepsis or sepsis. Furthermore, endocan levels measured at ICU admission were higher in non-survivors than in patients who were alive at 10 days. Using a threshold of 6.2 ng/ml, the sensitivity and specificity of endocan for predicting mortality were 75% and 84% respectively 53.

Mediators of permeability and vasomotor tone

We identified seven studies that examined soluble VEGF (see Table 6-Studies evaluating VEGF), two studies examining soluble FLT (Table 7-Studies Evaluating sFLT) and four studies examining endothelin-1 as biomarkers in sepsis (see Table 8-Studies Evaluating Endothelin-1). All but two were prospective studies, with two secondary analyses of previously conducted cohort studies 4581. Patients recruited were emergency room patients with suspected infection 5177 or ICU patients 4245518182838485868788.

Table 6

Studies evaluating VEGF

Study

Year

Population

Standard criteria for SIRS/sepsis

Association with sepsis

Other outcomes

Shapiro et al., 77

2008

ED patients with septic shock (17), suspected infection without shock (66), and non-infected controls

Suspected infection based on treating clinician

VEGF levels higher in septic shock and infected patients without shock compared with non-infected controls (P < 0.01)

VEGF correlated with APACHE-II score at presentation (P = 0.01)

Karlsson et al., 82

2008

280

Septic ICU patients (250) and healthy controls (30)

1992 ACCP/SCCM 1

VEGF levels higher in severe sepsis compared with healthy controls at 0 and 72 h (P = 0.029, 0.003, respectively)

VEGF lower in non-survivors at 0 and 72 h (P = 0.012, 0.009, respectively), no correlation with SOFA scores

Kumpers et al., 42

2008

Medical ICU (43) and healthy controls (29)

2003 ACCP/SCCM 2

VEGF levels lower in non-septic and septic patients compared with healthy controls (P < 0.0001)

No association with severity of sepsis

Van der Heijden et al., 45

2008

112

Mechanically ventilated patients with sepsis (24) and without (88)

1992 ACCP/SCCM 1

VEGF levels higher in patients with sepsis than without sepsis (63.6 vs 20.7 pg/ml, P = 0.012)

VEGF trended higher in patients compared with controls (P = 0.268); No association with incidence of ALI/ARDS

Van der Flier et al., 83

2005

Severe sepsis (18) and healthy controls (40)

1992 ACCP/SCCM 1

VEGF levels elevated in sepsis compared with healthy controls (134 vs 55 pg/ml, P < 0.001)

VEGF correlated with mortality (P = 0.018)

Yang et al., 101

2011

101

81 pneumonia and septic shock 20 pneumonia without organ dysfunction

1992 ACCP/SCCM 1

VEGF levels lower in septic shock vs. pneumonia (P = 0.005)

Day 1 VEGF did not discriminate survivors from non-survivors (P = 0.46)

Rafat et al., 84

2007

Medical ICU with sepsis (32), without sepsis (15), and healthy controls (15)

1992 ACCP/SCCM 1

VEGF levels elevated in septic compared with non-septic patients (1,351 vs 477 pg/ml, P < 0.01)

VEGF not correlated with mortality (P < 0.48)

ACCP, American College of Chest Physicians; ALI, Acute Lung Injury; APACHE II, Acute Physiology and Chronic Health Evaluation II; ARDS, Acute Respiratory Distress Syndrome; ED, emergency department; MOF, Multiple Organ Failure; SAPS, Simplified Acute Physiology Score; SCCM, Society of Critical Care Medicine; SIRS, Systemic Inflammatory Response Syndrome; SOFA, Sequential Organ Failure Assessment

Table 7

Studies evaluating sFLT

Study

Year

Population

Standard criteria for SIRS/sepsis

Association with sepsis

Other outcomes

Schuetz et al., 52

2011

161

Patients with hypotension: 69 sepsis, 35 cardiac, 12 hemorrhagic, 12 unknown

Clinical classification based on clinical and microbiological data

sFlt-1 higher in sepsis compared to non-sepsis (P < 0.05) SFlt-1 independently associated with sepsis after adjustment for age, sex, blood pressure and mortality (P = 0.03) with AUC 0.70 for discrimination of sepsis from non-sepsis

Shapiro et al., 77

2008

ED patients with septic shock (17), suspected infection without shock (66), and non-infected controls

Suspected infection based on treating clinician

sFLT levels elevated with worsening disease: non-infected, suspected infection without shock, septic shock (159, 386 and 551 ng/dL, respectively, P < 0.01)

sFLT correlated with APACHE-II, SOFA scores upon presentation and at 24 h (P < 0.05 for all)

Shapiro et al., 51

2010

221

ED patients with sepsis without organ dysfunction (71), severe sepsis without shock (66), septic shock (71), and non-infected controls (13)

1992 ACCP/SCCM 1

sFLT levels elevated in septic shock compared with non-infected controls (243 vs 41 ng/ml, P < 0.001)

sFLT correlated with SOFA, APACHE-II, lactate; Predicted severe sepsis and mortality (AUC of 0.82 (95% CI 0.76 to 0.88), 0.91 (95% CI 0.87 to 0.95))

ACCP, American College of Chest Physicians; ALI, Acute Lung Injury; APACHE II, Acute Physiology and Chronic Health Evaluation II; ARDS, Acute Respiratory Distress Syndrome; ED, emergency department; MOF, Multiple Organ Failure; SAPS, Simplified Acute Physiology Score; SCCM, Society of Critical Care Medicine; SIRS, Systemic Inflammatory Response Syndrome; SOFA, Sequential Organ Failure Assessment

Table 8

Studies evaluating Endothelin-1

Study

Year

Population

Standard criteria for SIRS/sepsis

Association with sepsis

Other Outcomes

Schuetz et al., 81

2007

Consecutive ICU admissions with SIRS, sepsis, septic shock

1992 ACCP/SCCM 1

Endothelin-1 rises with sepsis, septic shock, compared with SIRS (64.3, 131.6, 23.1 pmol/L, respectively; P < 0.01 between SIRS and sepsis, P < 0.05 between sepsis and septic shock)

Endothelin-1 not correlated with mortality (p = 0.87)

Piechota et al., 85

2007

Medical ICU patients with sepsis

1992 ACCP/SCCM 1, severity graded by procalcitonin and C-reactive protein level

Endothelin-1 correlates with CRP and PCT levels as estimates of level of sepsis severity (P < 0.05 for both)

Endothelin-1 correlates with SOFA score (p < 0.001)

Weitzberg et al., 86

1991

Sepsis (6) and healthy controls (10)

Bone et al., 102

Endothelin-1 elevated in sepsis compared with healthy controls (11.3 vs. 2.4 pmol/l, P < 0.01)

n/a

Furian et al. 76

2011

Patients admitted to ICU with severe sepsis or septic shock

1992 ACCP/SCCM 1

Endothelin-1 levels associated with left ventricular and right ventricular function. (p = 0.002)

Pittet et al., 87

1991

Sepsis (14), post-operative cardiac surgery (15) and healthy controls (11)

Bone et al., 102

Endothelin-1 elevated in septic patients compared with healthy controls (19.9 vs 6.1 pg/ml, P < 0.0001)

Endothelin-1 inversely correlated with cardiac index (p < 0.005); correlated with APACHE-II scores (p < 0.01)

ACCP, American College of Chest Physicians; ALI, Acute Lung Injury; APACHE II, Acute Physiology and Chronic Health Evaluation II; ARDS, Acute Respiratory Distress Syndrome; ED, emergency department; MOF, Multiple Organ Failure; SAPS, Simplified Acute Physiology Score; SCCM, Society of Critical Care Medicine; SIRS, Systemic Inflammatory Response Syndrome; SOFA, Sequential Organ Failure Assessment

Soluble VEGF

Four studies reported a positive association with sepsis, with higher levels in septic patients compared with non-septic critically ill patients 778384 and healthy controls 82. In contrast, Van der Heijden et al. did not find a significant difference in soluble VEGF between septic and non-septic ICU patients 45 and Kumpers et al. reported lower serum VEGF levels in patients with sepsis compared to healthy controls 42. Van der Flier et al. reported significantly elevated VEGF levels in non-survivors compared with survivors 83, in contrast to Karlsson et al. who reported significantly lower VEGF levels in non-survivors 82.

Soluble FLT (sFlt)

Both studies reporting sFLT were prospective studies from the same centre, studying emergency room patients with suspected infections, with non-infected patients serving as controls. There was some overlap between the two studies, with some patients reported in both cohorts. sFLT was shown to be elevated with increasing severity of illness 77, and was also predictive of severe sepsis and mortality, both upon presentation and longitudinally during hospitalization 51.

Endothelin-1

Two studies reported that endothelin-1 was significantly elevated in patients with sepsis compared with healthy controls 8687. An additional two studies reported a correlation with severity of illness as defined by other biomarkers 85 or ACCP/SCCM criteria 81. There was no documented association between endothelin-1 levels and mortality in the one study that examined this outcome 81.

Mediators of coagulation

We identified 14 relevant studies studying von Willebrand Factor (vWF) and sepsis (see Table 9-Studies Evaluating von Willebrand Factor). All studies reported assays of either VWF:Ag and/or VWF:RCo activity. Four studies presented data on ADAMTS13 (see Table 10-Studies Evaluating ADAMTS13), which reported either ADAMTS13 antigen levels or ADAMTS13 activity.

Table 9

Studies evaluting von Willebrands factor

Study

Year

Population

Standard criteria for SIRS/sepsis

Association with sepsis

Other outcomes

Claus et al., 89

2009

ICU patients with severe sepsis (11), non-elective cardiac surgery (22), elective cardiac surgery as ICU controls (24), and post-exercise as healthy controls (6)

1992 ACCP/SCCM 1

VWF:Ag higher in patients with sepsis and post non-elective cardiac surgery than ICU controls (P < 0.05)

VWF:Ag shows tendency to discriminate survivors from nonsurivors

Bockmeyer et al., 90

2008

ICU patients with sepsis (11), non-elective cardiac surgery (22), and elective cardiac surgery as ICU controls (24)

Not specified

VWF:Ag higher in sepsis and in non-elective cardiac surgery than ICU controls (both P < 0.001)

VWF:Ag correlated with mortality (P < 0.05)

van der Heijden et al., 45

2008

112

Mechanically ventilated patients, with sepsis (24) and without (88)

1992 ACCP/SCCM 1

VWF higher in patients with sepsis than without sepsis (P < 0.001)

VWF correlated with mortality (P = 0.006); VWF higher in those with ALI/ARDS than those without (P < 0.001)

Hovinga et al., 95

2007

Medical and surgical ICU patients with severe sepsis or septic shock (40), and healthy controls (40)

1992 ACCP/SCCM 1

VWF:Ag and VWF:RCO higher in sepsis than controls (P < 0.001)

VWF not correlated with disease severity, organ dysfunction, or mortality

Martin et al., 91

2007

ICU patients with severe sepsis (30), sepsis-unrelated organ failure (29), and healthy controls (30)

1992 ACCP/SCCM 1

VWF:Ag tends to differentiate severe sepsis from sepsis-unrelated organ failure (P > 0.05)

VWF:Ag not correlated with mortality

Scherpereel et al., 53

2006

ICU patients with sepsis (63), SIRS (7), and healthy controls (20)

1992 ACCP/SCCM 1

VWF higher in sepsis than SIRS (P < 0.02)

VWF correlated with mortality (P = 0.039)

Ware et al., 94

2001

ICU patients with ALI, ARDS (45% due to sepsis)

Temperature > 38° or < 35°C, systolic blood pressure < 90 mmHg (or a drop of 20 mm Hg or more in the systolic blood pressure from baseline), both present for at least 2 h; AND a clinically identifiable source of infection 103

VWF:Ag higher in patients with sepsis than those without (P < 0.05)

VWF correlated with mortality (P < 0.005); higher in those with longer duration of ventilation P < 0.005; not correlated with illness severity scores (SAPSII, Lung Injury Score)

Garcia-Fernandez et al., 92

2000

ICU patients with SIRS and acute renal failure (40), and healthy controls (40)

1992 ACCP/SCCM 1

VWF higher in SIRS than controls (P < 0.001)

Bajaj et al., 97

1999

Ward and ICU patients with ARDS (18), at risk of ARDS (15), and healthy controls (27)

Clinical diagnosis of sepsis

VWF does not differentiate patients with ARDS due to sepsis from other etiologies

VWF higher in ARDS (P < 0.001) and at risk ARDS (P < 0.01) compared to controls but did not differ significantly between these two groups

Kayal et al., 59

1998

ICU patients with severe sepsis or septic shock (25), ICU controls (7), healthy controls (9)

1992 ACCP/SCCM 1

VWF:Ag higher in sepsis than noninfected ICU controls and healthy controls (P < 0.0001); higher in septic shock than those without septic shock (P < 0.01)

VWF:Ag correlated with mortality (P < 0.01); correlated with SAPS and MOF score (r = 0.57, P < 0.01 for MOF)

Moss et al., 66

1996

ICU patients with sepsis (19), trauma (36), healthy controls (11)

Clinical diagnosis of sepsis

VWF:Ag higher in septic patients than trauma patients and controls (both P < 0.001)

Moss et al., 98

1995

Hospitalized patients at risk of ARDS, including sepsis (30)

Clinical diagnosis of sepsis

VWF:Ag not predictive of the development of ARDS

Lorente et al., 93

1993

ICU patients with septic shock

1992 ACCP/SCCM 1

VWF:Ag not predictive of mortality

Rubin et al., 96

1990

ICU patients with nonpulmonary sepsis

Clinical diagnosis of sepsis

VWF:Ag correlated with mortality (P < 0.005) and ALI (P < 0.01)

ACCP, American College of Chest Physicians; ALI, Acute Lung Injury; APACHE II, Acute Physiology and Chronic Health Evaluation II; ARDS, Acute Respiratory Distress Syndrome; ED, emergency department; MOF, Multiple Organ Failure; SAPS, Simplified Acute Physiology Score; SCCM, Society of Critical Care Medicine; SIRS, Systemic Inflammatory Response Syndrome; SOFA, Sequential Organ Failure Assessment

Table 10

Studies evaluating ADAMTS13

Study

Year

Population

Standard criteria for SIRS/sepsis

Association with sepsis

Other outcomes

Claus et al., 89

2009

ICU patients with severe sepsis (11), non-elective cardiac surgery (22), elective cardiac surgery as ICU controls (24), and post-exercise as healthy controls (6)

1992 ACCP/SCCM 1

ADAMTS13 activity lower in sepsis than ICU reference group (P < 0.001)

ADAMTS13 activity correlated with mortality (P < 0.05)

Bockmeyer et al., 90

2008

ICU patients with sepsis (11), non-elective cardiac surgery (22), and elective cardiac surgery as ICU controls (24)

Not specified

ADAMTS13 activity lower in sepsis than ICU controls (P < 0.01)

ADAMTS13 activity correlated with mortality (P < 0.01)

Hovinga et al., 95

2007

Medical and surgical ICU patients with severe sepsis or septic shock (40), and healthy controls (40)

1992 ACCP/SCCM 1

ADAMTS13 activity lower in sepsis than healthy controls (P < 0.001)

ADAMTS13 activity not correlated with disease severity, organ dysfunction, or mortality

Martin et al., 91

2007

ICU patients with severe sepsis (30), sepsis-unrelated organ failure (29), and healthy controls (30)

1992 ACCP/SCCM 1

ADAMTS13 activity lower in severe sepsis than sepsis-unrelated organ failure (P < 0.05) and healthy controls (P < 0.05)

ADAMTS13 activity correlated with APACHE II (r = -0.66, P < 0.0001), number of organ failures (r = -0.66, P < 0.0001), and mortality (P = 0.02 by log rank test)

ACCP, American College of Chest Physicians; ALI, Acute Lung Injury; APACHE II, Acute Physiology and Chronic Health Evaluation II; ARDS, Acute Respiratory Distress Syndrome; ED, emergency department; MOF, Multiple Organ Failure; SAPS, Simplified Acute Physiology Score; SCCM, Society of Critical Care Medicine; SIRS, Systemic Inflammatory Response Syndrome; SOFA, Sequential Organ Failure Assessment

Von Willebrand factor (vWF)

Association with sepsis

Eight studies examined the capability of circulating vWF levels to differentiate patients with sepsis from patients with other illnesses. Two studies found that vWF levels were significantly higher in septic patients compared to patients with systemic inflammation from other causes 8990, other non-septic critically-ill patients 455390, and healthy controls 5989. Two studies reported higher levels in patients with sepsis than in patients with SIRS or healthy controls, but the differences did not reach statistical significance 919293. In a cohort of patients with ALI/ARDS, Ware et al. reported that vWF was significantly increased in septic patients compared with those without sepsis (P < 0.05) 94.

Hovinga et al. in a secondary analysis of a clinical trial, reported that vWF activity was significantly higher in septic patients than in healthy controls, but vWF was not correlated with sepsis severity or survival 95. Two other studies found a significant correlation between VWF and sepsis severity 5994.

Association with clinical outcome

Four studies looked at its correlation with ALI/ARDS, with two studies showing its ability to differentiate those with ALI/ARDS from those without 4596, and two studies showing that it is not predictive of ALI/ARDS 9798.

Ten of the identified studies presented mortality data, with six studies showing a significant correlation of vWF with mortality 455359909496, with one study reporting a plasma vWF:Ag of 450% the upper normal limit predicted death with a sensitivity of 44% and a specificity of 91% 94. Four studies did not find a significant correlation with mortality 89919395.

ADAMTS13

Three studies showed that ADAMTS13 is significantly lower in sepsis than other critically ill nonseptic patients 899091. One study showed significant correlation with disease severity 91, while a second did not 95. Three studies showed ADAMTS13 levels correlated with mortality 899091, although one study did not find a significant correlation 95.

Discussion

We report a comprehensive and exhaustive systematic review of biomarkers reflecting endothelial activation for the diagnosis, triage and prognostication of sepsis in humans. The reviewed literature demonstrates positive associations between multiple EC-derived molecules and sepsis, supporting the critical role of EC activation in the septic response. Multiple other studies also reported positive associations for mortality and severity of illness, although these results were less consistent than for sepsis per se. Very few studies, however, reported thresholds or receiver operating characteristics that would establish these molecules as clinically-relevant biomarkers in sepsis.

Of the potential biomarkers reviewed, the angiopoeitin-1/2 system may hold the most promise. Multiple studies reported consistent associations between elevations in circulating Ang-2 levels and sepsis in varied samples of critically ill patients. All studies evaluating Ang-2 used standard sepsis definitions, with consistent association between Ang-2 levels and sepsis, as well as relatively consistent associations between Ang-2 and other clinical outcomes. The strength of association is also supported in the identified studies by: (1) a demonstrable dose-response relationship with higher Ang-2 levels in severe sepsis and organ dysfunction, and increasing with increasing severity of illness, and (2) a temporal progression with Ang-2 levels increasing over time in those patients who developed sepsis and in patients with increasing severity of sepsis as defined by SIRS, sepsis and septic shock. Unfortunately, no studies provided a cut point or threshold that would make Ang-2 clinically useful as a biomarker in the diagnosis or stratification of patients presenting with presumed sepsis.

One general limitation with all of the identified studies is the lack of standardized assays for the studied molecules. Very few studies reported threshold values for prognostic analysis or receiver operating characteristics of the potential biomarkers. Furthermore, almost all studies were either single centre or single laboratory, and most assays were non-standardized ELISAs, and thus the absolute values reported in each study may vary according to the type of assay, as well as the type of sample used (for example, plasma vs. serum). These issues led to important limitations in the generalizability and strength of inference that can be drawn from the identified studies. Where possible, we have reported absolute values in the tables to allow readers to appreciate the scope of variation, as well as absolute differences in levels between groups.

There are several limitations to our study. We searched for known endothelial-derived markers by name, and it is possible that other novel markers were missed. We attempted to address this limitation by hand-searching the reference list of identified studies to include all relevant studies of selected endothelial-derived markers. Many of the identified publications are single-centre studies or retrospective analyses of previously collected specimens, which limit generalizability to other jurisdictions and populations. As previously mentioned, lack of standardization in the reported assays makes quantitative comparison of a biomarker across studies impossible, and thus we can only report similarities in the direction and relative magnitude of association across studies.

The identified studies were most commonly small prospective or retrospective cohort studies evaluating levels of a potential biomarker in patients with sepsis and a comparative control group. Almost all studies used established consensus criteria for the definition of sepsis to limit misclassification of patients. There was significant heterogeneity in patient populations across studies, however, including patients with presumed sepsis identified in any one of the emergency department, medical ward and medical, surgical and trauma intensive care units. It is conceivable that the receiver operating characteristics of any given biomarker may vary according to the differential inflammatory state, concurrent injuries and pathophysiology of these different patient groups.

If EC-derived biomarkers are to become clinically useful, future work will require standardization of analytical techniques and rigorous evaluation of receiver operating characteristics to define the role and reliability of these molecules. Although some recent studies reported receiver operating characteristics or threshold biomarker levels, the lack of standard assays limits the interpretation and clinical utility of these efforts. Future work must include: (1) the description of the operating characteristics of biomarkers, (2) the use of explicitly defined threshold serum levels, (3) measured with a standardized assay.

It may be impossible to achieve the high degree of sensitivity and specificity required for clinical diagnosis with a single biomarker assay, and a multiplexed combination of markers may be necessary to improve predictive value and clinical utility of biomarkers. Careful selection and combinations of biomarkers with relative specificity to disease states (for example, the observed association between Ang-2 and ARDS/pulmonary leak, or the differential association of sVCAM and sE-Selectin in fungal sepsis) would be one way of improving the clinical utility of these novel molecules. Following identification of useful serum biomarker thresholds with standard assays, we speculate that evaluation of multiplexed biomarker panels may prove useful as a diagnostic strategy.

Given the epidemiologic rise of sepsis in both the developed 99 and developing world 100, novel diagnostics and therapeutics for sepsis are urgently needed, and endothelial-derived biomarkers will likely play a crucial role.

Conclusions

We report a systematic review of the published literature and findings that multiple molecules reflecting endothelial activation are correlated with the presence of sepsis in humans. We also found variable degrees of correlation between biomarkers and other clinical outcomes. The clinical utility or application of these molecules as biomarkers in sepsis, however, is limited by a lack of standardization in analytical assays, a lack of data regarding receiver operating characteristics and, in the few cases where thresholds have been reported, a lack of validation in representative patient populations.

Key messages

• Multiple molecules reflecting endothelial activation are correlated with the presence of sepsis in humans and other clinically important outcomes.

• The clinical utility or application of these molecules as biomarkers in sepsis; however, is limited by a lack of standardization in analytical assays, a lack of data regarding receiver operating characteristics and a lack of validation.

• The consistent association with sepsis, demonstrable dose-response relationship, and temporal progression in patients who develop sepsis make Angiopoietin-2 an attractive potential biomarker in sepsis.

• Future research should focus on standardization of assays and identification of cut points or thresholds that make biomarkers clinically useful in the diagnosis or stratification of patients presenting with presumed sepsis.

• Evaluation of multiplexed panels with biomarkers of differential response characteristics may prove useful as a diagnostic strategy.

Abbreviations

ACCP: American College of Chest Physicians; ADAMTS13: a disintegrin and metalloproteinase with a thrombospondin type 1 motif, Member 13; ALI: Acute Lung Injury; Ang 1/2: Angiopoeitin 1/2; APACHE II: Acute Physiology and Chronic Health Evaluation II; ARDS: Acute Respiratory Distress Syndrome; EC: endothelial cell; ED: emergency department; ICU: intensive care unit; MOF: Multiple Organ Failure; SAPS: Simplified Acute Physiology Score; SCCM: Society of Critical Care Medicine; s-Flt: soluble Flt (soluble Vascular Endothelial Growth Factor receptor); sICAM-1: Intercellular Adhesion Molecule-1; SIRS: Systemic Inflammatory Response Syndrome; SOFA: Sequential Organ Failure Assessment; sVCAM-1: Vascular Cell Adhesion molecule-1; VEGF: Vascular Endothelial Growth Factor; vWF: von Willebrand Factor; vWFA: von Willebrand Factor antigen; vWFRCo: von Willebrand Factor ristocetin cofactor.

Competing interests

The authors declare they have no competing interests.

Authors' contributions

KX conceived of the study, participated in study design, participated in literature review and data extraction, and drafted the initial manuscript. WCL conceived of the study, participated in study design and provided critical revisions to the manuscript for intellectual content. JMS participated in study design, participated in literature review and data extraction, drafted the initial manuscript and provided critical revisions to the manuscript for intellectual content. SM participated in the literature review and data extraction, and drafted the initial manuscript. All authors participated in data synthesis and interpretation of results. All authors read and approved the final manuscript.

Acknowledgements

WCL is the recipient of a Canada Research Chair (Infectious Diseases and Inflammation) from the Canadian Institutes of Health Research (CIHR).

Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care MedicineBoneRCBalkRACerraFBDellingerRPFeinAMKnausWAScheinRMSibbaldWJChest19921011644165510.1378/chest.101.6.164413036222001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions ConferenceLevyMMFinkMPMarshallJCAbrahamEAngusDCookDCohenJOpalSMVincentJLRamsayGCrit Care Med2003311250125610.1097/01.CCM.0000050454.01978.3B12682500Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of careAngusDCLinde-ZwirbleWTLidickerJClermontGCarcilloJPinskyMRCrit Care Med2001291303131010.1097/00003246-200107000-0000211445675Biomarkers and surrogate endpoints: preferred definitions and conceptual frameworkClin Pharmacol Ther200169899511240971Sepsis biomarkers: a reviewPierrakosCVincentJLCrit Care201014R1510.1186/cc8872287553020144219Endothelial cell apoptosis in sepsis: a case of habeas corpus?HotchkissRSKarlIECrit Care Med20043290190210.1097/01.CCM.0000115264.93926.EC15090992Endothelial cell apoptosis in sepsisHotchkissRSTinsleyKWSwansonPEKarlIECrit Care Med200230S22522810.1097/00003246-200205001-0000912004240Malaria and bacterial sepsis: similar mechanisms of endothelial apoptosis and its prevention in vitroHemmerCJVogtAUnverrichtMKrauseRLademannMReisingerECCrit Care Med2008362562256810.1097/CCM.0b013e31818441ee18679107The endothelium in sepsis: source of and a target for inflammationHackCEZeerlederSCrit Care Med200129S212711445730Increased death receptor pathway of apoptotic signaling in septic mouse aorta: effect of systemic delivery of FADD siRNAMatsudaNTeramaeHYamamotoSTakanoKTakanoYHattoriYAm J Physiol Heart Circ Physiol2010298H9210110.1152/ajpheart.00069.200919855068Markers of endothelial damage in organ dysfunction and sepsisReinhartKBayerOBrunkhorstFMeisnerMCrit Care Med200230S30231210.1097/00003246-200205001-0002112004252Inflammation, endothelium, and coagulation in sepsisSchoutenMWiersingaWJLeviMvan der PollTJ Leukoc Biol20088353654518032692The role of the endothelium in severe sepsis and multiple organ dysfunction syndromeAirdWCBlood20031013765377710.1182/blood-2002-06-188712543869Bench-to-bedside review: endothelial cell dysfunction in severe sepsis: a role in organ dysfunction?ValletBCrit Care2003713013810.1186/cc186427061212720559GRADE: an emerging consensus on rating quality of evidence and strength of recommendationsGuyattGHOxmanADVistGEKunzRFalck-YtterYAlonso-CoelloPSchünemannHJBMJ200833692492610.1136/bmj.39489.470347.AD233526118436948A prospective multicenter cohort study of the association between global tissue hypoxia and coagulation abnormalities during early sepsis resuscitationTrzeciakSJonesAEShapiroNIPusateriAEArnoldRCRizzutoMAroraTParrilloJEDellingerRPEmergency Medicine Shock Research Network (EMShockNet) investigatorsCrit Care Med2010381092110010.1097/CCM.0b013e3181cf6fbc20124888Angiopoietin-2, marker and mediator of endothelial activation with prognostic significance early after trauma?GanterMTCohenMJBrohiKChesebroBBStaudenmayerKLRahnPChristiaansSCBirNDPittetJFAnn Surg200824732032610.1097/SLA.0b013e318162d61618216540Biological markers of lung injury before and after the institution of positive pressure ventilation in patients with acute lung injuryCepkovaMBradySSapruAMatthayMAChurchGCritical Care200610R12610.1186/cc5037175107716956410Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortalityYanoKLiawPCMullingtonJMShihSCOkadaHBodyakNKangPMToltlLBelikoffBBurasJSimmsBTMizgerdJPCarmelietPKarumanchiSAAirdWCJ Exp Med20062031447145810.1084/jem.20060375211832916702604Increased diffusion of soluble adhesion molecules in meningitis, severe sepsis and systemic inflammatory response without neurological infection is associated with intrathecal shedding in cases of meningitisMegarbaneBMarchalPMarfaing-KokaABelliardOJacobsFCharyIBrivetFGIntensive Care Med20043086787410.1007/s00134-004-2253-115067502Activated polymorphonuclear leukocytes enhance production of leukocyte microparticles with increased adhesion molecules in patients with sepsisFujimiSOguraHTanakaHKohTHosotsuboHNakamoriYKuwagataYShimazuTSugimotoHJ Trauma20025244344810.1097/00005373-200203000-0000511901317Increased hepatosplanchnic inflammation precedes the development of organ dysfunction after elective high-risk surgeryPoezeMRamsayGBuurmanWAGreveJWDentenerMTakalaJShock20021745145810.1097/00024382-200206000-0000212069179Characterization of the secreted form of endothelial-cell-specific molecule 1 by specific monoclonal antibodiesBechardDMeigninVScherpereelAOudinSKervoazeGBertheauPJaninATonnelALassallePJ Vasc Res20003741742510.1159/00002575811025405Stimulation of inflammatory markers after blunt traumaGiannoudisPVSmithRMBanksREWindsorACDicksonRAGuillouPJBr J Surg19988598699010.1046/j.1365-2168.1998.00770.x9692580Increased plasma von Willebrand factor in the systemic inflammatory response syndrome is derived from generalized endothelial cell activationMcGillSNAhmedNAChristouNVCrit Care Med19982629630010.1097/00003246-199802000-000319468168Evaluation of a soluble E-selectin enzyme-linked immunosorbent assay under posttraumatic conditionsKneidingerRBahramiSRedlHSchlagGRobinsonMWeichselbraunICremerJJ Lab Clin Med199612852052310.1016/S0022-2143(96)90050-58900296Coagulation, fibrinolysis, and kallikrein systems in sepsis: relation to outcomeHesselvikJFBlombackMBrodinBMallerRCrit Care Med19891772473310.1097/00003246-198908000-000022502362The interaction of soluble Tie2 with angiopoietins and pulmonary vascular permeability in septic and nonseptic critically ill patientsvan der HeijdenMvan Nieuw AmerongenGPvan HinsberghVWGroeneveldABShock20103326326810.1097/SHK.0b013e3181b2f97819543148Angiopoietin-2 in patients requiring renal replacement therapy in the ICU: relation to acute kidney injury, multiple organ dysfunction syndrome and outcomeKumpersPHaferCDavidSHeckerHLukaszAFliserDHallerHKielsteinJTFaulhaber-WalterRIntensive Care Med20103646247010.1007/s00134-009-1726-719956923Serial changes in neutrophil-endothelial activation markers during the course of sepsis associated with disseminated intravascular coagulationGandoSKameueTMatsudaNHayakawaMHoshinoHKatoHThromb Res20051169110010.1016/j.thromres.2004.09.02215907522Posttraumatic immune modulation in chronic alcoholics is associated with multiple organ dysfunction syndromevon HeymannCLangenkampJDubiszNvon DossowVSchaffartzikWKernHKoxWJSpiesCJ Trauma2002529510310.1097/00005373-200201000-0001711791058Strongly enhanced serum levels of vascular endothelial growth factor (VEGF) after polytrauma and burnGradSErtelWKeelMInfangerMVonderschmittDJMalyFEClin Chem Lab Med19983637938310.1515/CCLM.1998.0649711425The influence of early hemodynamic optimization on biomarker patterns of severe sepsis and septic shockRiversEPKruseJAJacobsenGShahKLoombaMOteroRChildsEWCrit Care Med2007352016202410.1097/01.CCM.0000281637.08984.6E17855815[Effect of fluid resuscitation on adhesion molecule and hemodynamics in patients with severe sepsis]FangXLFangQCaiGLYanJZhongguo Wei Zhong Bing Ji Jiu Yi Xue20061853954116959151Continuous heparinization and circulating adhesion molecules in the critically illBoldtJPapsdorfMPiperSNRotheAHempelmannGShock19991113189921711[The significance of postburn changes in plasma levels of ICAM-1, IL-10 and TNFalpha during early postburn stage in burn patients]KuangXMaKDuanTZhonghua Shao Shang Za Zhi20021830230412515646[Clinical significance of soluble selectins and matrix metalloproteinases-9 in patients after successful cardiopulmonary resuscitation]LiPJYangXHZhangLPCaoWQinJYaoWZhongguo Wei Zhong Bing Ji Jiu Yi Xue20041613714115009958Angiopoietin-2 is increased in severe sepsis: correlation with inflammatory mediatorsOrfanosSEKotanidouAGlynosCAthanasiouCTsigkosSDimopoulouISotiropoulouCZakynthinosSArmaganidisAPapapetropoulosARoussosCCrit Care Med20073519920610.1097/01.CCM.0000251640.77679.D717110873Elevated serum angiopoietin 2 levels are associated with increased mortality in sepsisSinerJMBhandariVEngleKMEliasJASiegelMDShock20093134835310.1097/SHK.0b013e318188bd0618791490Kinetics of angiopoietin-2 in serum of multi-trauma patients: correlation with patient severityGiamarellos-BourboulisEJKanellakopoulouKPelekanouATsaganosTKotzampassiKCytokine20084431031310.1016/j.cyto.2008.09.00318952457Angiopoietin-2 is increased in septic shock: evidence for the existence of a circulating factor stimulating its release from human monocytesKranidiotiHOrfanosSEVakiIKotanidouARaftogiannisMDimopoulouIKotsakiASavvaAPapapetropoulosAArmaganidisAGiamarellos-BourboulisEJImmunol Lett2009125657110.1016/j.imlet.2009.06.00619539650Excess circulating angiopoietin-2 is a strong predictor of mortality in critically ill medical patientsKumpersPLukaszADavidSHornRHaferCFaulhaber-WalterRFliserDHallerHKielsteinJTCrit Care200812R14710.1186/cc7130264631019025590Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humansParikhSMMammotoTSchultzAYuanHTChristianiDKarumanchiSASukhatmeVPPLoS Med20063e4610.1371/journal.pmed.0030046133422116417407Angiopoietin-2 is increased in sepsis and inversely associated with nitric oxide-dependent microvascular reactivityDavisJSYeoTWPieraKAWoodberryTCelermajerDSStephensDPAnsteyNMCrit Care201014R8910.1186/cc9020291172320482750Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patientsvan der HeijdenMvan Nieuw AmerongenGPKoolwijkPvan HinsberghVWGroeneveldABThorax20086390390910.1136/thx.2007.08738718559364APACHE II: a severity of disease classification systemKnausWADraperEAWagnerDPZimmermanJECrit Care Med19851381882910.1097/00003246-198510000-000093928249The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care MedicineVincentJLMorenoRTakalaJWillattsSDe MendoncaABruiningHReinhartCKSuterPMThijsLGIntensive Care Med19962270771010.1007/BF017097518844239Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsisRicciutoDRdos SantosCCHawkesMToltlLJConroyALRajwansNLaffertyEICookDJFox-RobichaudAKahnamouiKKainKCLiawPCLilesWCCrit Care Med20113970271010.1097/CCM.0b013e318206d28521242795Angiopoietin balance in septic shock patients with acute lung injury: effect of direct hemoperfusion with polymyxin B-immobilized fiberEbiharaIHirayamaKNagaiMKakitaTSakaiKTajimaRSatoCKurosawaHTogashiAOkadaAUsuiJYamagataKKobayashiMTher Apher Dial20111534935421884468Systemic dysregulation of angiopoietin-1/2 in streptococcal toxic shock syndromePageAVKotbMMcGeerALowDEKainKCLilesWCClin Infect Dis201152e15716110.1093/cid/cir12521460306The association of endothelial cell signaling, severity of illness, and organ dysfunction in sepsisShapiroNSchuetzPYanoKSorasakiMParikhSMJonesAETrzeciakSNgoLAirdWCCrit Care201014R18210.1186/cc9290321928820942957Endothelial cell activation in emergency department patients with sepsis-related and non-sepsis-related hypotensionSchuetzPJonesAEAirdWCShapiroNIShock20113610410810.1097/SHK.0b013e31821e4e0421522043Endocan, a new endothelial marker in human sepsisScherpereelADepontieuFGrigoriuBCavestriBTsicopoulosAGentinaTJourdainMPuginJTonnelABLassallePCrit Care Med20063453253710.1097/01.CCM.0000198525.82124.7416424738Analysis of hemostasis alterations in sepsisStiefTWIjaghaOWeisteBHerzumIRenzHMaxMBlood Coagul Fibrinolysis20071817918610.1097/MBC.0b013e328040bf9a17287636Cell death serum biomarkers are early predictors for survival in severe septic patients with hepatic dysfunctionHoferSBrennerTBoppCSteppanJLichtensternCWeitzJBrucknerTMartinEHoffmannUWeigandMACrit Care200913R9310.1186/cc7923271746519538738Neutrophil-related inflammatory mediators in septic acute respiratory distress syndromeKinoshitaMOnoSMochizukiHJ Intensive Care Med20021730831610.1177/0885066602238033Increased nuclear factor kappa B activation in critically ill patients who diePatersonRLGalleyHFDhillonJKWebsterNRCrit Care Med2000281047105110.1097/00003246-200004000-0002210809280Circulating intercellular adhesion molecule-1 as an early predictor of hepatic failure in patients with septic shockWeigandMASchmidtHPourmahmoudMZhaoQMartinEBardenheuerHJCrit Care Med1999272656266110.1097/00003246-199912000-0000810628605Elevated circulating E-selectin, intercellular adhesion molecule 1, and von Willebrand factor in patients with severe infectionKayalSJaisJPAguiniNChaudiereJLabrousseJAm J Respir Crit Care Med19981577767849517590Does age influence circulating adhesion molecules in the critically ill?BoldtJMullerMHeesenMPapsdorfMHempelmannGCrit Care Med1997259510010.1097/00003246-199701000-000198989183The circulating adhesion molecules sICAM-1 and sE-selection in patients with sepsisEgererKRohrUKrauschDKoxWAnaesthesist19974659259810.1007/s0010100504429304360Assessment of inflammatory cytokines, nitrate/nitrite, type II phospholipase A2, and soluble adhesion molecules in systemic inflammatory response syndromeTakakuwaTEndoSInadaKKasaiTYamadaYOgawaMRes Commun Mol Pathol Pharmacol19979843529434314Circulating adhesion molecules in the critically ill: a comparison between trauma and sepsis patientsBoldtJMullerMKuhnDLinkeLCHempelmannGIntensive Care Med19962212212810.1007/BF017207188857119Levels of soluble adhesion molecules and cytokines in patients with septic multiple organ failureEndoSInadaKKasaiTTakakuwaTYamadaYKoikeSWakabayashiGNiimiMTaniguchiSYoshidaMJ Inflamm1995462122198878795Increased circulating adhesion molecule concentrations in patients with the systemic inflammatory response syndrome: a prospective cohort studyCowleyHCHeneyDGearingAJHemingwayIWebsterNRCrit Care Med19942265165710.1097/00003246-199404000-000227511496Endothelial cell activity varies in patients at risk for the adult respiratory distress syndromeMossMGillespieMKAckersonLMooreFAMooreEEParsonsPECrit Care Med1996241782178610.1097/00003246-199611000-000048917025Changes in adhesion molecule levels in sepsisNakaeHEndoSInadaKTakakuwaTKasaiTRes Commun Mol Pathol Pharmacol1996913293388829772Circulating ICAM-1 is increased in septic shockSesslerCNWindsorACSchwartzMWatsonLFisherBJSugermanHJFowlerAAAm J Respir Crit Care Med1995151142014277735595Cytokines in sepsis due to <it>Candida albicans </it>and in bacterial sepsisPresterlELassniggAMueller-UriPEl-MenyawiIGraningerWEur Cytokine Netw19991042343010477399Interleukin 1 receptor antagonist and E-selectin concentrations: a comparison in patients with severe acute pancreatitis and severe sepsisHynninenMValtonenMMarkkanenHVaaraMKuuselaPJouselaIPiilonenATakkunenOJ Crit Care199914636810.1016/S0883-9441(99)90015-110382785Markers of systemic inflammation predicting organ failure in community-acquired septic shockTakalaAJouselaIJanssonSEOlkkolaKTTakkunenOOrpanaAKaronenSLRepoHClin Sci19999752953810.1042/CS1999007310545303Soluble selectins in sepsis: Microparticle-associated, but only to a minor degreeOsmanovicNRomijnFPHTMJoopKSturkANieuwlandRThromb Haemost20008473173211057883Prediction of clinical severity and outcome of ventilator-associated pneumonia. Comparison of simplified acute physiology score with systemic inflammatory mediatorsFroonAHBontenMJGaillardCAGreveJWDentenerMAde LeeuwPWDrentMStobberinghEEBuurmanWAAm J Resp Crit Care Med1998158102610319769255Soluble selectins and the systemic inflammatory response syndrome after successful cardiopulmonary resuscitationGeppertAZornGKarthGDHaumerMGwechenbergerMKoller-StrametzJHeinzGHuberKSiostrzonekPCrit Care Med2000282360236510921565Elevated selectin levels after severe trauma: a marker for sepsis and organ failure and a potential target for immunomodulatory therapySimonsRKHoytDBWinchellRJRoseRMHolbrookTJ Trauma19964165366210.1097/00005373-199610000-000108858024Ventricular dysfunction and dilation in severe sepsis and septic shock: Relation to endothelial function and mortalityFurianTAguiarCPradoKRibeiroRVBeckerLMartinelliNClausellNRohdeLEBioloAJ Crit Care2011A prospective, observational study of soluble FLT-1 and vascular endothelial growth factor in sepsisShapiroNIYanoKOkadaHFischerCHowellMSpokesKCNgoLAngusDCAirdWCShock20082945245710.1097/SHK.0b013e31815072c118598002Prognostic value of MIP-1 alpha, TGF-beta 2, sELAM-1, and sVCAM-1 in patients with gram-positive sepsisKnappSThalhammerFLockerGJLaczikaKHollensteinUFrassMWinklerSStoiserBWilfingABurgmannHClin Immunol Immunopathol19988713914410.1006/clin.1998.45239614928Soluble E-selectin levels in sepsis and critical illness. Correlation with infection and hemodynamic dysfunctionCummingsCJSesslerCNBeallLDFisherBJBestAMFowlerAAAm J Resp Crit Care Med19971564314379279220Soluble E-selectin is found in supernatants of activated endothelial cells and is elevated in the serum of patients with septic shockNewmanWBeallLDCarsonCWHunderGGGrabenNRandhawaZIGopalTVWiener-KronishJMatthayMAJ Immunol19931506446547678280Circulating precursor levels of endothelin-1 and adrenomedullin, two endothelium-derived, counteracting substances, in sepsisSchuetzPChrist-CrainMMorgenthalerNGStruckJBergmannAMullerBEndothelium20071434535110.1080/10623320701678326243017018080871Vascular endothelial growth factor in severe sepsis and septic shockKarlssonSPettilaVTenhunenJLundVHovilehtoSRuokonenEFinnsepsis StudyGAnesth Analg20081061820182610.1213/ane.0b013e31816a643f18499616Plasma vascular endothelial growth factor in severe sepsisvan der FlierMvan LeeuwenHJvan KesselKPKimpenJLHoepelmanAIGeelenSPShock200523353810.1097/01.shk.0000150728.91155.4115614129Increased circulating endothelial progenitor cells in septic patients: correlation with survivalRafatNHanuschCBrinkkoetterPTSchulteJBradeJZijlstraJGvan der WoudeFJvan AckernKYardBABeckGCCrit Care Med2007351677168410.1097/01.CCM.0000269034.86817.5917522579Plasma endothelin-1 levels in septic patientsPiechotaMBanachMIrzmanskiRBarylskiMPiechota-UrbanskaMKowalskiJPawlickiLJ Intensive Care Med20072223223910.1177/088506660730144417722367Elevated plasma levels of endothelin in patients with sepsis syndromeWeitzbergELundbergJMRudehillACirc Shock1991332222272065442Elevated plasma endothelin-1 concentrations are associated with the severity of illness in patients with sepsisPittetJFMorelDRHemsenAGunningKLacroixJSSuterPMLundbergJMAnn Surg199121326126410.1097/00000658-199103000-0001413583381998407Plasma soluble vascular endothelial growth factor receptor-1 levels predict outcomes of pneumonia-related septic shock patients: a prospective observational studyYangK-YLiuK-TChenY-CChenC-SLeeY-CPerngR-PFengJ-YCritical Care201115R1110.1186/cc9412322204121219633Variations in the ratio between von Willebrand factor and its cleaving protease during systemic inflammation and association with severity and prognosis of organ failureClausRABockmeyerCLBuddeUKentoucheKSossdorfMHilbergTSchneppenheimRReinhartKBauerMBrunkhorstFMLoscheWThromb Haemost200910123924719190805Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factorBockmeyerCLClausRABuddeUKentoucheKSchneppenheimRLoscheWReinhartKBrunkhorstFMHaematologica20089313714010.3324/haematol.1167718166799Decreased ADAMTS-13 (A disintegrin-like and metalloprotease with thrombospondin type 1 repeats) is associated with a poor prognosis in sepsis-induced organ failureMartinKBorgelDLerolleNFeysHBTrinquartLVanhoorelbekeKDeckmynHLegendrePDiehlJLBaruchDCrit Care Med2007352375238210.1097/01.CCM.0000284508.05247.B317944029Hemostatic disturbances in patients with systemic inflammatory response syndrome (SIRS) and associated acute renal failure (ARF)Garcia-FernandezNMontesRPurroyARochaEThromb Res2000100192510.1016/S0049-3848(00)00306-611053612Time course of hemostatic abnormalities in sepsis and its relation to outcomeLorenteJAGarcia-FradeLJLandinLde PabloRTorradoCRenesEGarcia-AvelloAChest19931031536154210.1378/chest.103.5.15368486040von Willebrand factor antigen is an independent marker of poor outcome in patients with early acute lung injuryWareLBConnerERMatthayMACrit Care Med2001292325233110.1097/00003246-200112000-0001611801836ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shockHovingaJAKZeerlederSKesslerPRomani de WitTvan MourikJAHackCEten CateHReitsmaPHWuilleminWALammleBJ Thromb Haemost200752284229010.1111/j.1538-7836.2007.02743.x17764538Elevated von Willebrand factor antigen is an early plasma predictor of acute lung injury in nonpulmonary sepsis syndromeRubinDBWiener-KronishJPMurrayJFGreenDRTurnerJLuceJMMontgomeryABMarksJDMatthayMAJ Clin Invest19908647448010.1172/JCI1147332967492384595Plasma levels of the three endothelial-specific proteins von Willebrand factor, tissue factor pathway inhibitor, and thrombomodulin do not predict the development of acute respiratory distress syndromeBajajMSTricomiSMIntensive Care Med1999251259126610.1007/s00134005105410654210von Willebrand factor antigen levels are not predictive for the adult respiratory distress syndromeMossMAckersonLGillespieMKMooreFAMooreEEParsonsPEAm J Respir Crit Care Med199515115207812545The epidemiology of sepsis in the United States from 1979 through 2000MartinGSManninoDMEatonSMossMN Engl J Med20033481546155410.1056/NEJMoa02213912700374Management of septic shock: where do we stand?SankarJLodhaRKabraSKIndian J Pediatr2008751167116910.1007/S12098-008-0241-019132319Plasma soluble vascular endothelial growth factor receptor-1 levels predict outcomes of pneumonia-related septic shock patients: a prospective observational studyYangKYLiuKTChenYCChenCSLeeYCPerngRPFengJYCrit Care201115R1110.1186/cc9412322204121219633Sepsis syndrome: a valid clinical entity. Methylprednisolone Severe Sepsis Study GroupBoneRCFisherCJJrClemmerTPSlotmanGJMetzCABalkRACrit Care Med19891738939310.1097/00003246-198905000-000022651003Identification of patients with acute lung injury. Predictors of mortalityDoyleRLSzaflarskiNModinGWWiener-KronishJPMatthayMAAm J Respir Crit Care Med1995152181818248520742