Original Research

Journal of Intensive Care Medicine

2023, Vol. 38(1) 95-105
Biomarkers of Glycocalyx Injury and © The Author(s) 2022
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Endothelial Activation are Associated with DOI: 10.1177/08850666221109186
journals.sagepub.com/home/jic
Clinical Outcomes in Patients with Sepsis:
A Systematic Review and Meta-Analysis

Jaime Fernández-Sarmiento, MD, PhD1,2 ,

Carlos Federico Molina, MD, PhD2,
Lina María Salazar-Pelaez, BsC, MSc, PhD2, Steffanie Flórez, MD1,
Laura Carolina Alarcón-Forero, MD1, Mauricio Sarta, MD3,
Ricardo Hernández-Sarmiento, MD1 , and
Juan Carlos Villar, MD, MSc, PhD4

Abstract
Objective: Sepsis is one of the main causes of morbidity and mortality worldwide. Microcirculatory impairment, especially dam-
age to the endothelium and glycocalyx, is often not assessed. The objective of this systematic review and meta-analysis was to
summarize the available evidence of the risk of unsatisfactory outcomes in patients with sepsis and elevated glycocalyx injury and
endothelial activation biomarkers.
Design: A systematic search was carried out on PubMed/MEDLINE, Embase, Cochrane and Google Scholar up to December 31,
2021, including studies in adults and children with sepsis which measured glycocalyx injury and endothelial activation biomarkers
within 48 hours of hospital admission. The primary outcome was the risk of mortality from all causes and the secondary out-
comes were the risk of developing respiratory failure (RF) and multiple organ dysfunction syndrome (MODS) in patients with
elevations of these biomarkers.
Measurements and Main Results: A total of 17 studies (3,529 patients) were included: 11 evaluated syndecan-1 (n=2,397)
and 6 endocan (n=1,132). Syndecan-1 was higher in the group of patients who died than in those who survived [255 ng/mL (IQR:
139-305) vs. 83 ng/mL (IQR:40-111); p=0.014]. Patients with elevated syndecan-1 had a greater risk of death (OR 2.32; 95% CI
1.89, 3.10: p<0.001), MODS (OR 3.3; 95% CI 1.51, 7.25: p=0.003;), or RF (OR 7.53; 95% CI 1.86-30.45: p=0.005). Endocan was
higher in patients who died [3.1 ng/mL (IQR 2.3, 3.7) vs. 1.62 ng/mL (IQR 1.2, 5.7); OR 9.53; 95% CI 3.34, 27.3; p<0.001], who
had MODS (OR 8.33; 95% CI 2.07, 33.58; p=0.003) and who had RF (OR 9.66; 95% CI 2.26, 43.95; p=0.002).
Conclusion: Patients with sepsis and abnormal glycocalyx injury and endothelial activation biomarkers have a greater risk of
developing respiratory failure, multiple organ failure, and death. Microcirculatory impairment should be routinely evaluated in
patients with sepsis, using biomarkers to stratify risk groups.

Keywords
septic shock, syndecan-1, microcirculation, endothelium, mortality, respiratory failure, endocan

Introduction
Sepsis is a life-threatening dysfunction of one or more organs
caused by a dysregulated host response to an infection.1,2 It is
the final common pathway of serious infectious diseases and con-
stitutes a significant public health problem, responsible for 20% of
all deaths worldwide.3 Eighty percent of these cases occur in
middle and low-income countries.4,5 Sepsis is treatable and
early recognition of the impairment of various organs, especially
cardiovascular injury, is essential for improving the outcomes.6–10
Various sepsis models have reported that microcirculatory
injury occurs frequently, affecting the endothelium and its
1
Department of Pediatrics and Intensive Care, Fundación Cardioinfantil-
Instituto de Cardiología, Universidad de La Sabana, Bogotá, Colombia
2
Universidad CES Graduate School, Medellín, Colombia
3
Department of Pediatrics and Intensive Care, Universidad del Rosario,
Fundación Cardioinfantil-Instituto de Cardiología, Bogotá, Colombia
4
Departament of Research, Fundación Cardioinfantil-Instituto de Cardiología,
Bogotá, Colombia
Corresponding Author:
Jaime Fernández Sarmiento, Universidad de La Sabana, Campus Universitario
del Puente del Común, Km 7 Autopista Norte de Bogotá,
Chía – Cundinamarca – Colombia - Suramérica.
Email: jaimefe@unisabana.edu.co
96
glycocalyx (ie, the proteoglycan and glycosaminoglycan-rich
layer lining the blood vessel lumen).11–14 Under physiological
conditions, the glycocalyx is responsible for regulating vascular
permeability, modulating the release of nitric oxide and contrib-
uting to adequate hemostasis, among other functions.11–15 In
patients with sepsis or inflammatory conditions, endothelial
glycocalyx damage contributes significantly to magnifying
this inflammatory response by increasing vascular permeability
and leukocyte migration and contributes to the characteristic
coagulation abnormalities of patients with sepsis.9–14
Some components of the endothelial glycocalyx can be mea-
sured in the serum and may provide an early alert of microcir-
culatory damage. Therefore, they could be useful as prognostic
biomarkers and could predict the response to treatment of
patients with sepsis.12,16–20 The components that can be
detected in the blood include the proteoglycans (50-90%
heparan sulfate) and syndecan, which is the main component
of the endothelial glycocalyx.12,21–23 In fact, in inflammatory
conditions such as sepsis, syndecan is cleaved by several
inflammatory mediators (eg, cytokines or reactive oxygen
species) and can be detected in these patients’ plasma. Its eleva-
tion has been associated with coagulation disorders, multiple
organ damage and death.11,23–28
Likewise, endocan (endothelial cell-specific molecule 1) is
another endothelial biomarker which has been studied in
patients with sepsis.29 At a vascular level, this proteoglycan is
mainly synthesized by pulmonary and renal endothelial cells
and secreted into the systemic circulation through the stimuli
of certain proinflammatory cytokines (IL-1β, TNF-α) and bac-
terial lipopolysaccharides.29–33 One of endocan’s functions is
to bind to the integrin LFA-1, keeping it from interacting
with the ICAM-1 ligand, which inhibits leukocyte diapedesis,
partially explaining the potential anti-inflammatory effects of
endocan during pulmonary insult.34–36 Given the importance
of microcirculatory impairment in patients with sepsis and its
lack of recognition, the objective of our study was to perform
a systematic review and meta-analysis of the main studies eval-
uating the principal biomarkers of glycocalyx injury and endo-
thelial activation as predictors of the risk of unsatisfactory
clinical outcomes in patients with sepsis.
Materials and Methods
Search Strategy and Selection Criteria
A systematic literature search was performed in the main
medical databases, with no language restriction. This system-
atic review was prospectively registered on PROSPERO
(CRD42020217935 – available at https://www.crd.york.ac.uk/
PROSPERO). The PRISMA and MOOSE guidelines were
used for reporting this study’s findings.37
Children one month of age and older as well as adults with
sepsis of any origin and severity, including sepsis with organ
dysfunction and septic shock, were included. The definition
of sepsis used for this study was that of the campaign for
improving the sepsis survival of adults and children (the
Journal of Intensive Care Medicine 38(1)
American College of Chest Physicians/Society of Critical
Care Medicine [ACCP/ SCCM] Consensus Conference
Committee Surviving Sepsis Campaign Guidelines) as well as
the Sepsis-3 definition for adults.2,4
The following inclusion criteria were used: serum measure-
ments of endothelial glycocalyx injury biomarkers (ie,
syndecan-1, syndecan-2, syndecan-3, syndecan-4, heparan
sulfate, hyaluronate) and a vascular endothelial activation bio-
marker (endocan) obtained within 48 h of the patient’s admis-
sion to clinical care (emergency room, floor or intensive
care). This criterion applied to studies only on humans and
with a description of the clinical outcomes of interest associated
with sepsis (ie, mortality, length of stay in intensive care, length
of hospital stay, respiratory failure, multiple organ failure, and
the need for and use of vasopressors). We did not include
studies evaluating glycocalyx injury by video microscopy.
Studies with any methodological design were included, as
well as grey literature or peer-reviewed articles. Studies of pre-
clinical models, studies of pregnant women, letters to the editor,
narrative reviews and studies which did not describe clinical
outcomes were excluded.
A systematic literature search was performed in the
Cochrane library, PubMed/MEDLINE, Embase, LILACS and
Google Scholar up to December 31, 2021. The following
MESH terms were used: ((sepsis) OR (septic shock)) AND
(endothelium)) OR (syndecan-1)) OR (syndecans)) OR
(CD138)) OR (CD138 antigens)) OR (heparan sulfate)) OR
(syndecan 4)) OR (ryudocan)) OR (endocan)) OR (endothelial-
specific molecule 1)) OR (ESM-1 protein)) OR (endocan
protein)) OR (glycocalyx)) AND (((epidemiological studies)
OR (clinical trial)) NOT (review)). AND (mortality) OR
(Death) OR (length of stay) OR (hospital stay) or (vasopressor)
OR (vasoactive score). If full-text access or complete data were
not available, the authors were contacted to request this infor-
mation or to answer questions regarding the study findings.
Study Selection and Data Processing
First, the titles and abstracts were reviewed. Then the full text
was reviewed, and data were extracted from the studies which
met the inclusion criteria (JF, LA, SF, MS). If there were
doubts regarding the eligibility criteria, a second investigator
(CFM) made the decision of whether to include the study.
One author (JF) designed a standard extraction form which
was applied to the studies which met the inclusion criteria.
The other authors (CFM, LMS, RH, JCV) reviewed and vali-
dated this data extraction form as well as the extracted informa-
tion. The data obtained are summarized in Table 1. The
biomarkers were evaluated with standard measurement units
(in ng/mL), using the ELISA technique.
Methodological Quality Assessment
The quality of the studies was evaluated in terms of their exter-
nal validity, evaluating the target population, generalizability
and random error. Their internal validity was also assessed,
 Table 1. Studies Evaluating Endothelial Glycocalyx Injury in Patients with Sepsis.

Age Glycocalyx Time of Risk of

Author Country (IQR) N injury biomarker assessment Diagnosis Primary Outcome Secondary Outcome Bias *

Beurskens et al Holland 67 21 Syndecan-1 ICU admission Septic shock Mortality MODS *******
2020 (61-76)
Holzmann M Germany 61 55 Syndecan-1 Day 1, 2 Major abdominal surgery Mortality MODS, ICU stay *******
et al 2018 (51-70)
Inkinen N et al FInland 66 619 Syndecan-1 24 h admission Sepsis Mortality Acute kidney injury, fluid *********
2019 (65-75) overload
Loakeimidou A Greece 69 175 Endocan ICU admission and Sepsis Change in injury MODS *****
et al 2017 (48-90) 24 h later biomarkers over
time
Johansen M Denmark 65 1113 Syndecan-1 Admission Septic shock Mortality MODS *******
et al 2015 5(8-75)
Mihajlovic D Serbia 61 60 Endocan 24 horas after the Sepsis MOFS and PTand PTTas predictors of *******
et al 2014 (43-79) onset of the mortality the clinical course and
disease prognosis
Mitsunuri I et al Japan 73 54 Syndecan -1 Admission, day 1, Septic shock Mortality Coagulopathy, respiratory *********
2018 (65-81) 2, 4 failure, MODS
Nelson A et al Sweden 65 36 Syndecan-1 ICU admission Septic shock from any Mortality MODS ***
2008 (28-87) source
Nelson A et al Sweden 67 137 Syndecan-1, 2, 3, PICU admission ICU patients Mortality MODS ********
2017 (53-75) 4.
Orbegozo D Belgium 61 96 Endocan At ARDS diagnosis ARDS Mortality Time on mechanical *******
et al 2017 (44-78) and at 8 AM the ventilation, hospital stay
following day
Ostrowski S Denmark 61 321 Syndecan-1 Prior to beginning Local infection or Mortality MODS, ICU stay *******
et al 2015 (46-73) antibiotics hospital-acquired sepsis
Palud A et al France 61 20 Endocan ICU admission Septic shock MOFS N/R *****
2015 (54-68)
Pauly D et al Germany 57 150 (60 Endocan Days 1, 3 and 8 Severe sepsis-septic shock 30-day mortality 6-month mortality *******
2015 (26-88) controls) after ICU
admission
Smart et al Australia 59 138 Syndecan-1, Admission, 3 h, 24 Sepsis in the emergency Mortality MODS, transfer to ICU ********
2017 (52-66) Hyaluronate h room, local infections and
healthy subjects
Smart et al Australia 66 72 Syndecan-1, Admission to the Pneumonia and septic Mortality Respiratoryfailure, need *******
2018 (61-71) Endocan, emergency room, shock for mechanical ventilation
Hyaluronate 1 h, 3 h, 24 h
Wei S et al 2018 USA 40 512 Syndecan-1 4 h after admission Trauma New-onset sepsis Mortality, MODS, hospital ********
(30-51) stay
Whitney et al USA 5 (4-13) 119 Endocan, 72 h after Sepsis with or without Dysfunction of two N/R ******
2020 admission, 6 days, ARDS, healthy control or more organs and
14 days. group mortality

*Evaluated using the Newcastle-Ottawa scale.

MODS: multiple organ dysfunction syndrome. ICU: intensive care unit, ARDS: acute respiratory distress syndrome. PT: prothrombin time. PTT: partial thromboplastin time. N/R: not reported. N: number of

97
patients included.
98
determining information, selection and confounding bias. The
risk of bias in the observational studies (cohorts, case-control
studies) was evaluated using the Newcastle-Ottawa scale.38
We planned to use version 2.0 of the Cochrane risk-of-bias
tool for clinical trials, but our systematic search found no
studies with this methodological design which met the inclusion
criteria.
Outcomes
The primary outcome was the risk of mortality from any cause
and at any time during hospitalization in patients with sepsis
and septic shock who had altered glycocalyx injury and endo-
thelial activation biomarkers Sepsis was defined as the presence
of a viral or bacterial systemic infection causing organ dysfunc-
tion. Septic shock was taken to be any sepsis with cardiovascu-
lar dysfunction causing hypotension, affecting perfusion or
requiring vasoactive medications. These definitions were used
for both children and adults.
The secondary outcomes were the risk of developing multi-
ple organ dysfunction syndrome (MODS), respiratory failure,
or acute kidney injury in patients with altered glycocalyx
injury and endothelial activation biomarkers. Multiple organ
failure syndrome was defined as the dysfunction of two or
more organs in patients with sepsis, using a SOFA scale
score greater than 2. Respiratory failure was considered to be
the need for a fraction of inspired oxygen greater than 0.5 at
any time during the hospital stay, or the need for invasive or
non-invasive mechanical ventilation.
Data Analysis
The sources of heterogeneity were evaluated according to the
type of design, sampling methods and exposure measurement.
The Higgins index was used to evaluate heterogeneity, with a
value greater than 20% considered to indicate heterogeneity
between the studies. For comparison purposes, when
medians, ranges or IQRs were reported, they were converted
to means and SDS according to the method proposed by Wan
et al.39 Results are presented as odds ratios (ORs) with 95%
confidence intervals (95% CI) for dichotomous variables and
as mean differences (95% CI) for continuous variables. An
analysis of pooled medians was performed for continuous var-
iables with a non-normal distribution and they were compared
using the Mann-Whitney U test. The Mantel-Haenszel random-
effects model was used for the analyses and the fixed-effects
method was used for studies with low heterogeneity. A p <
0.05 was considered to be statistically significant. The statistical
analyses were performed using Review Manager software
version 5.4 (ReVman 5.4).
Results
A total of 736 studies in 10 countries were found in the various
databases consulted (Figure 1). After excluding duplicate and
non-relevant studies, reviews, and animal or pre-clinical
Journal of Intensive Care Medicine 38(1)
studies, 17 studies were included which evaluated endothelial
glycocalyx injury or endothelial activation biomarkers and
met all the inclusion criteria for this meta-analysis.18,22,36,40–53
All the studies had an observational design and included adult
patients, except for one study included in the endocan biomarker
analysis which included children. Of all the included studies, 11
evaluated syndecan-1 (n = 2397) as the biomarker of glycocalyx
injury and its association with death and other unsatisfactory out-
comes. Of this group of patients, 1826 had sepsis with organ dys-
function or septic shock, while 571 had other diseases or
included healthy controls (Table 1). In addition, six studies
were included which evaluated endocan (n = 1132) and its asso-
ciation with the clinical outcomes of interest. Other biomarkers
such as hyaluronate, syndecan-2, syndecan-3, syndecan-4 and
heparan sulfate were not included, as we could not find research
reports with complete information and relevant outcomes with
clinical applicability.
Of the included studies evaluating syndecan-1, seven only
analyzed patients in critical care, while the other four included
individuals assessed all the way from admission to the emer-
gency room to their subsequent transfer to intensive care. All
the studies were carried out in adults. Two studies in children
with sepsis were not included as they did not clearly describe
the outcomes in the study population and this information
was not provided upon contacting the authors. Six were multi-
center studies and none were multinational. Three studies
included surgical patients and one of these studied patients
with trauma (Table 1).
For endocan, all the studies were done on patients in inten-
sive care. Five of them included adult patients, while one was
performed on children.53 Another two studies were not
included, as they only sought to determine the relationship
between endocan and other biomarkers. All the studies were
performed at a single center, and two included healthy controls
(Table 1). Most of the studies simultaneously measured other
biomarkers of endothelial activation and inflammation (eg,
angiopoietin, interleukins). However, these were not analyzed
since that was not an objective of this study. In general, all
the studies showed a correlation between the glycocalyx
injury biomarkers and inflammatory response biomarkers.
Three studies included a control group of healthy patients.
Regarding the evaluated outcomes, six studies reported 28 or
90-day mortality. Five did not clearly describe the group who
died or had incomplete information. Different scales were
used to measure multiple organ failure, but the SOFA scale
was used to evaluate the outcomes and was described in the
four studies included. In three of these, respiratory failure or
the need for mechanical ventilation and its association with
endothelial injury biomarkers, particularly syndecan-1, was
described.
The risk of bias was low to moderate for most of the studies
(Figures 2 and 3). All the included studies were cohort studies,
prospective or retrospective, and no clinical trials were found.
Since all the studies were cohort studies, the version of the
Newcastle-Ottawa scale for this type of studies was applied,
evaluating the three groups: selection, comparability and
Fernández-Sarmiento et al.
Figure 1. Article selection process according to the PRISMA guidelines for reporting systematic reviews and meta-analyses.
outcomes. We did not find strong evidence of publication bias
in the analyzed studies (Supplement 1 – funnel plot of the pub-
lication bias for syndecan-1 and mortality). We only reported
and included studies with comparative data.
In the 2397 patients in whom syndecan-1 was measured,
those with sepsis had significantly higher levels (median 177
ng/ml IQR: 82-216) than those without (median 29 ng/ml
IQR:18-77) (p = 0.016). In addition, syndecan-1 was abnormal
in a significant proportion of the patients with sepsis or septic
shock who died (34.3%; 208/606), and it was higher in these
patients (median 255 ng/ml IQR 139-305) than in those who
survived (median 83 ng/ml IQR 40-111) (p = 0.014). In the
fixed effects model analysis, given the low heterogeneity of
the included studies (I2 9%), we found that patients with
sepsis and elevated levels of syndecan-1 had a greater risk of
dying (OR 2.42; 95% CI 1.89, 3.10: p < 0.001) (Figure 4).
Syndecan-1 was more often found to be abnormal in patients
with sepsis who had MOFS (37.2% vs. 23.1%; OR 3.3; 95%
CI, 1.5, 7.25; p = 0.003) than in those who did not develop mul-
tiple organ dysfunction (Figure 5). Likewise, patients who pro-
gressed to respiratory failure were more likely to have elevated
syndecan-1 (75.2%: 725/ 963) than the group of patients
99
without respiratory failure (42.5%: 564/1327; OR 7.53; 95%
CI 1.86-30.45; p = 0.005) (Figure 6).
For endocan, 1132 patients were included. The patients with
sepsis had significantly higher levels of endocan (median 3.01
ng/ml IQR: 2.2-5.5) than the controls without sepsis (median
1.3 IQR 0.8-1.5) (p = 0.021). In addition, endocan levels were
higher in the patients who died (median 3.1 IQR 2.3-7.0) com-
pared with those who survived (median 1.62 IQR 1.2-5.7). The
random effects model analysis showed a greater risk of death in
patients with high levels of endocan (OR 9.53 95% CI
3.34-27.3; p < 0.001) (Figure 7). Likewise, patients with abnor-
mal levels of this biomarker have a higher risk of developing
MODS (OR 8.33 95% CI 2.07-33.58) and respiratory failure
(OR 9.66 95% CI 2.26- 43.95) (Figures 8 and 9).
Discussion
To our knowledge, this is the first meta-analysis evaluating the
importance of glycocalyx injury and endothelial activation bio-
markers as predictors of unsatisfactory outcomes in patients
with sepsis. This systematic review of 17 studies (11 with
syndecan-1, 6 with endocan; n = 3529) in patients with sepsis
100
Figure 2. Evaluation of the risk of bias in the included studies on patients with sepsis.
found that there is a greater risk of death, multiple organ failure
and respiratory failure in patients with high levels of these
biomarkers.
Microcirculation involvement in patients with sepsis is
common and well-described, including in COVID-19
patients.6,10–13 Documenting this injury using biomarkers of
endothelial integrity will help us clarify the molecular basis
for explaining the severity, prognosis and response to treatment
in patients with sepsis. Traditionally, the focus has been on
detecting macrocirculation abnormalities in sepsis. However,
the phenomenon known as hemodynamic incoherence is
increasingly recognized and indicates that often the microcircu-
lation abnormalities in advanced stages of sepsis may be disso-
ciated from the macrocirculation.54 Ospina-Tascon et al
demonstrated that late fluid administration did not improve sub-
lingual microcirculatory flow despite increased cardiac
output.55 Microcirculation abnormalities in this stage in
which there is no response to fluids could favor the develop-
ment of organ dysfunction rather than accomplish the goals
of fluid resuscitation.
Meanwhile, the endothelial glycocalyx is a carbohydrate-rich
layer covering the endoluminal surface of all blood vessels. It is
made up of proteoglycans, glycosaminoglycans (GAGs) and
glycoproteins, as the non-soluble, endothelial cell-dependent
components.11,21 Of the first component, 50% to 90% are
heparan sulfate proteoglycans (eg, syndecans, glypicans, perle-
cans) which are anchored to the endothelial cell through the
transmembrane domain of its protein core.21–23 Proteoglycans
are considered to be the main axis of the glycocalyx, to which
the GAG chains are joined, leading to the production of
soluble proteoglycans, which are located in the upper portion
of this structure. Hyaluronic acid is a non-sulfated GAG found
in the most superficial portion of the glycocalyx (it is not
joined to the transmembrane protein) and is not considered to
be part of the vertebral column of the proteoglycans, being syn-
thesized and degraded at a rate of 5 g per day.13,25,28
Glycocalyx “shedding” may occur due to oxidative damage
or hyperglycemia, or be triggered by microbial virulence factors
Journal of Intensive Care Medicine 38(1)
and various inflammatory mediators. In patients with sepsis,
cytokines like TNF-alpha, IL-1 and IL-6, in particular, favor
cleavage of the glycocalyx components as they participate in
the activation of various matrix metalloproteinases. This leads
to elevated circulating levels of certain glycocalyx components
(syndecan-1, perlecans, glypicans), which may be used as
markers of endothelial dysfunction, such as the dysfunction
that occurs in sepsis.11,13,38,39
In addition, the glycocalyx has a soluble component which
interacts with those anchored to the endothelial cell to give
good stability, being in dynamic equilibrium with the blood
flow, and dependent on special microenvironmental conditions
such as pH and the production of membrane-bound elements by
the endothelial cell’s Golgi bodies and endoplasmic reticu-
lum.56 The soluble component of the glycocalyx is made up
of a broad range of molecules such as proteins and proteogly-
cans, which are produced by the endothelium or come from
the systemic circulation. They may bind to the component
joined to the endothelial cell through receptors or enzymes
(fibroblast growth factor receptors, lipase lipoproteins and low-
density lipoproteins), or also by binding to the GAGs, espe-
cially heparan sulfate, which has numerous protein binding
sites due to its specific patterns of sulfation.11,18,19,56 Various
glycocalyx degradation products may be measured using
mass spectrophotometry or ELISA techniques, as well as with
new video microscopes which analyze the sublingual circula-
tion. The latter has the advantage of determining the real-time
perfused boundary region (PBR), which is a variable inversely
related to glycocalyx injury. Studies in adults have shown its
usefulness in detecting endothelial injury and glycocalyx degra-
dation in patients with sepsis, and have indicated that it could be
a useful tool for directing treatment strategies in patients with
sepsis.51,54
According to this study’s findings, patients with higher
levels of syndecan-1 have a greater risk of progressing to mul-
tiple organ failure and death. In addition, some of the included
studies analyzed the relationship between syndecan-1 and bio-
markers of increased vascular permeability (eg, angiopoietin-1,
Fernández-Sarmiento et al. 101

angiopoietin-2, and tyrosine kinase with immunoglobulin-like

loop epidermal growth factor homology domain 2 [ Tie-2]), leu-
kocyte migration and adhesion (intercellular adhesion molecule
[ICAM], vascular cell adhesion molecule [VCAM], E-selectin),
and platelet activation (von Willebrand factor, soluble thrombo-
modulin).41,45,49,50–57 The relationship between these biomark-
ers, which evaluate different endothelial functions, could
explain why microcirculation involvement and damage in
sepsis an important component in disease progression and the
development of multiple organ failure is. Hippensteel et al
found a direct relationship between the volume of intravenous
fluids administered and the elevation of endothelial glycocalyx
injury biomarkers, which was associated with greater inpatient
mortality.58 Therefore, including an evaluation of these bio-
markers in the diagnostic approach would help to better under-
stand the pathophysiological phenomena which are occurring
and carry out more rational interventions to avoid increasing
the systemic injury caused by the inflammatory response in
sepsis.59–65
On the other hand, patients with abnormal endocan in the
included studies had a greater risk of mortality, organ failure
and respiratory failure. The conflicting findings related to
endocan between clinical studies and animal models should
be understood and interpreted with caution. In the murine
model of pulmonary insult, pretreatment with endocan
decreased the levels of various cytokines (ie, TNF-α,
interferon-β, IL-1β, IL-6) and modulated pulmonary epithelial
cell apoptosis.66 This apparent discrepancy between the func-
tions of human and mouse endocan may be explained by the
differences between their respective cellular sources and glyca-
nation levels.67,68 The endocan detected in preclinical models is
produced by nonendothelial cells in the lungs, kidneys and
spleen. In healthy mice, the main circulating endocan is nongly-
cosylated and nonendothelial, very different from the primary
circulating form in humans, which is endothelial and fully
glycosylated.
In human studies, endocan has not been correlated with ele-
vated procalcitonin or C-reactive protein in sepsis.30 However,
it has been found to be a good early predictor of bacteremia, the
need for vasopressor support and progression to respiratory
failure.29–32 Endocan may be very valuable as a predictive bio-
marker and an indicator of the potential development of compli-
cations in patients with sepsis.
Accordingly, high endocan levels in patients with sepsis
have proven to be a better prognostic marker for ARDS than
the Lung Injury Prediction Score (LIPS), with an AUC of
0.93 (95% CI 0.87-1.00; p < 0.001) versus 0.55 (95% CI
0.39-0.71; p = 0.59), respectively.67 In fact, high levels of
endocan have been associated with an increased need for
mechanical ventilation.46 In this regard, the included studies
showed a correlation between endocan levels and acute sys-
temic inflammation, associated with a greater risk of multiple
Figure 3. Risk of bias in the included studies, determined by the
Newcastle-Ottawa scale.
organ failure and respiratory failure in patients with sepsis
and ARDS.46,50,53,65–67
102 Journal of Intensive Care Medicine 38(1)

Figure 4. Forest plot 1 of the risk of death in patients with sepsis with abnormal syndecan-1.

Figure 5. Forest plot of the relationship between MODS and syndecan-1 in patients with sepsis. MODS: multiple organ dysfunction syndrome.

Figure 6. Forest plot of the relationship between respiratory failure and syndecan-1 in patients with sepsis. RF: respiratory failure.

Figure 7. Forest plot of the relationship between endocan and mortality in patients with sepsis.
Fernández-Sarmiento et al. 103

Figure 8. Forest plot of the relationship between endocan and multiple organ dysfunction syndrome in patients with sepsis.

Figure 9. Forest plot of the relationship between endocan and respiratory failure.

Finally, we believe our study has several limitations. First,
when we evaluated outcomes such as MODS or respiratory
failure we found high heterogeneity among the studies, which
could cause an unavoidable bias. In addition, we found inherent
consistency and clarity problems with some data, as well as
insufficient information or non-reporting (in some studies) of
the proposed strategies for controlling confounding in observa-
tional designs. Another limitation is that the time at which the
blood sample was drawn for biomarker measurement was not
consistently reported. Since the pathophysiological process in
sepsis is highly dynamic, it is very probable that the biomarker
results are time dependent.69 In addition, sepsis is a very hetero-
geneous disease, with different patterns of presentation and
associated molecular mechanisms (ie, endotypes). Therefore,
biomarkers should be measured in a serial fashion to establish
a tendency showing the clinical course of sepsis.
Authors’ Note
All authors approved the final manuscript as submitted and agree to be
accountable for all aspects of the work.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
Ethical Approval
Not applicable, because this article does not contain any studies with
human or animal subjects.

ORCID iDs
Conclusions
Jaime Fernández-Sarmiento https://orcid.org/0000-0003-2874-
In patients with sepsis, abnormalities in endothelial glycocalyx 2949
injury biomarkers, especially syndecan-1, and in endothelial acti- Ricardo Hernández-Sarmiento https://orcid.org/0000-0003-3840-
vation biomarkers like endocan are associated with a greater risk 0563
of death, multiple organ failure and respiratory failure.
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