SHOULD THERAPEUTIC AGENTS FOR SEPSIS TARGET THE GLYCOCALYX?
SHOULD THERAPEUTIC
AGENTS FOR SEPSIS TARGET
THE GLYCOCALYX?
Dr. Seema Bhargava
Dr. Seema Bhargava
Senior Consultant & Chairperson
Senior Consultant & Chairperson
Department of Biochemistry &
Department of Biochemistry &
Professor, GRIPMER
Professor, GRIPMER
Sir Ganga Ram Hospital
Sir Ganga Ram Hospital
New Delhi, India
New Delhi, India
Systemic Inflammatory Response Syndrome (SIRS)/Sepsis
Criteria for Dx of SIRS
•
Core temperature
>38.3
C / <36
C
•
Heart rate >90 bpm / >2SD
•
Respiratory rate >30 bpm
or
PaCO2 <32 mm Hg
•
WBC count >12,000 cells/mm
3
or
<4,000 cells/mm
3
or
>10% immature neutrophils
S
e
p
s
i
s
=
K
n
o
w
n
o
r
s
u
s
p
e
c
t
e
d
i
n
f
e
c
t
i
o
n
+
2 SIRS criteria
A
C
C
P
/
S
C
C
M
C
o
n
s
e
n
s
u
s
C
o
n
f
e
r
e
n
c
e
(
1
9
9
2
)
C
r
i
t
C
a
r
e
M
e
d
1
9
9
2
;
2
0
:
8
6
4
–
8
7
4
Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.
SIRS, Sepsis, Severe Sepsis and Septic shock
S
e
v
e
r
e
S
e
p
s
i
s
S
e
p
s
i
s
+
1
o
r
g
a
n
d
y
s
f
u
n
c
t
i
o
n
S
e
p
t
i
c
S
h
o
c
k
Severe
Sepsis
+
Hypotension despite fluid
resuscitation
ACCP/SCCM Consensus Conference (1992)
D
e
f
i
n
i
t
i
o
n
s
f
o
r
s
e
p
s
i
s
a
n
d
o
r
g
a
n
f
a
i
l
u
r
e
a
n
d
g
u
i
d
e
l
i
n
e
s
f
o
r
t
h
e
u
s
e
o
f
i
n
n
o
v
a
t
i
v
e
t
h
e
r
a
p
i
e
s
i
n
s
e
p
s
i
s
.
C
r
i
t
C
a
r
e
M
e
d
1
9
9
2
;
2
0
:
8
6
4
–
8
7
4
Dilemmas in sepsis
Dilemmas in sepsis
Publication
Publication
S
a
l
i
e
n
t
f
i
n
d
i
n
g
s
:
P
C
T
d
i
f
f
e
r
e
n
t
i
a
t
e
s
c
u
l
t
u
r
e
-
n
e
g
a
t
i
v
e
s
e
p
s
i
s
f
r
o
m
S
I
R
S
a
t
a
c
u
t
o
f
f
o
f
1
.
4
3
n
g
/
m
l
,
w
i
t
h
9
2
%
s
e
n
s
i
t
i
v
i
t
y
a
n
d
8
3
%
n
e
g
a
t
i
v
e
p
r
e
d
i
c
t
i
v
e
v
a
l
u
e
(
A
U
C
0
.
8
9
2
)
P
C
T
d
i
f
f
e
r
e
n
t
i
a
t
e
s
c
u
l
t
u
r
e
-
p
o
s
i
t
i
v
e
s
e
p
s
i
s
f
r
o
m
S
I
R
S
a
t
a
c
u
t
o
f
f
o
f
2
.
4
9
n
g
/
m
l
,
w
i
t
h
9
4
.
4
%
s
e
n
s
i
t
i
v
i
t
y
a
n
d
9
1
.
5
%
n
e
g
a
t
i
v
e
p
r
e
d
i
c
t
i
v
e
v
a
l
u
e
(
A
U
C
0
.
9
5
9
)
I
m
p
a
c
t
F
a
c
t
o
r
:
2
.
5
8
Next Question
Next Question
Identification of a marker or markers to effectively
differentiate between sepsis, severe sepsis and septic
shock
HOW?
Pathophysiology of sepsis
Disruption of the glycocalyx is a known event
The Glycocalyx
Basement membrane
Endothelial cell lining
Phospholipid bilayer of
endothelial cell
Glycocalyx with its comprising
components in a latticework
Blood vessel with its vessel wall
and blood components
10
The Glycocalyx
Basement membrane
Endothelial cell lining
Phospholipid bilayer of
endothelial cell
Glycocalyx with its comprising
components in a latticework
Blood vessel with its vessel wall
and blood components
11
Hyaluronan & Syndecan
Hyaluronan & Syndecan
Glycocalyx components
Glycocalyx components
Study Objectives
Methods: Inclusion & Exclusion criteria
•
Inclusion Criteria
–
Age ≥18 years
–
Patients admitted to the intensive care unit with community
acquired Sepsis, Severe sepsis or Septic shock
•
Exclusion Criteria
–
Post-operative patients
–
Lethal condition
–
Malignancy
–
Immunocompromised
–
Transferred from other ICU’s
Methodology
Methodology
D
a
y
s
1
,
3
,
5
,
a
n
d
7
B
l
o
o
d
d
r
a
w
n
f
r
o
m
a
l
l
s
u
b
j
e
c
t
s
F
o
l
l
o
w
i
n
g
a
n
a
l
y
t
e
s
e
s
t
i
m
a
t
e
d
i
n
s
e
r
u
m
:
•
H
y
a
l
u
r
o
n
a
n
-
C
o
m
p
e
t
i
t
i
v
e
E
n
z
y
m
e
L
i
n
k
e
d
I
m
m
u
n
o
s
o
r
b
e
n
t
A
s
s
a
y
(
T
e
c
o
M
e
d
i
c
a
l
,
S
w
i
t
z
e
r
l
a
n
d
)
•
S
y
n
d
e
c
a
n
-
S
o
l
i
d
P
h
a
s
e
S
a
n
d
w
i
c
h
E
l
i
s
a
(
D
i
a
c
l
o
n
e
,
B
e
s
a
n
c
o
m
C
e
d
e
x
,
F
r
a
n
c
e
)
•
T
N
F
-
-
C
h
e
m
i
l
u
m
i
n
e
s
c
e
n
t
I
m
m
u
n
o
a
s
a
s
y
(
I
m
m
u
l
i
t
e
,
S
i
e
m
e
n
s
)
•
I
n
t
e
r
l
e
u
k
i
n
-
1
0
-
S
o
l
i
d
P
h
a
s
e
S
a
n
d
w
i
c
h
E
l
i
s
a
(
D
i
a
c
l
o
n
e
,
B
e
s
a
n
c
o
m
C
e
d
e
x
,
F
r
a
n
c
e
)
•
S
O
F
A
a
n
d
A
P
A
C
H
E
I
I
s
c
o
r
e
s
RESULTS
RESULTS
Patient baseline characteristics
17
D
A
Y
1
D
A
Y
3
D
A
Y
5
D
A
Y
7
Receiver Operating Characteristic Curve
Receiver Operating Characterstics of Hyaluronan
Receiver Operating Characterstics of Hyaluronan
S
u
r
v
i
v
o
r
s
v
s
N
o
n
-
S
u
r
v
i
v
o
r
s
Receiver Operating
Receiver Operating
Characterstics of Syndecan
S
u
r
v
i
v
o
r
s
v
s
N
o
n
-
S
u
r
v
i
v
o
r
s
Hyaluronan: Association with Mortality, Organ Dysfunction
scores and inflammatory markers at all Time-points
Syndecan: Association with Mortality, Organ Dysfunction
scores and inflammatory markers at all Time-points
Summary
S
S
e
e
r
r
u
u
m
m
l
l
e
e
v
v
e
e
l
l
s
s
o
o
f
f
H
H
y
y
a
a
l
l
u
u
r
r
o
o
n
n
a
a
n
n
a
a
n
n
d
d
S
S
y
y
n
n
d
d
e
e
c
c
a
a
n
n
29
C
C
o
o
n
n
c
c
l
l
u
u
s
s
i
i
o
o
n
n
s
s
G
G
l
l
y
y
c
c
o
o
c
c
a
a
l
l
y
y
x
x
c
c
o
o
m
m
p
p
o
o
n
n
e
e
n
n
t
t
s
s
[
[
h
h
y
y
a
a
l
l
u
u
r
r
o
o
n
n
a
a
n
n
a
a
n
n
d
d
s
s
y
y
n
n
d
d
e
e
c
c
a
a
n
n
]
]
c
c
o
o
u
u
l
l
d
d
b
b
e
e
u
u
s
s
e
e
d
d
f
f
o
o
r
r
d
d
i
i
a
a
g
g
n
n
o
o
s
s
i
i
s
s
i
i
.
.
e
e
.
.
t
t
o
o
d
d
i
i
f
f
f
f
e
e
r
r
e
e
n
n
t
t
i
i
a
a
t
t
e
e
b
b
e
e
t
t
w
w
e
e
e
e
n
n
s
s
e
e
p
p
s
s
i
i
s
s
,
,
s
s
e
e
v
v
e
e
r
r
e
e
s
s
e
e
p
p
s
s
i
i
s
s
a
a
n
n
d
d
s
s
e
e
p
p
t
t
i
i
c
c
s
s
h
h
o
o
c
c
k
k
.
.
H
H
y
y
a
a
l
l
u
u
r
r
o
o
n
n
a
a
n
n
a
a
n
n
d
d
s
s
y
y
n
n
d
d
e
e
c
c
a
a
n
n
c
c
o
o
u
u
l
l
d
d
a
a
l
l
s
s
o
o
b
b
e
e
u
u
s
s
e
e
d
d
f
f
o
o
r
r
p
p
r
r
o
o
g
g
n
n
o
o
s
s
i
i
s
s
i
i
.
.
e
e
.
.
t
t
o
o
i
i
d
d
e
e
n
n
t
t
i
i
f
f
y
y
s
s
u
u
r
r
v
v
i
i
v
v
o
o
r
r
s
s
a
a
n
n
d
d
n
n
o
o
n
n
-
-
s
s
u
u
r
r
v
v
i
i
v
v
o
o
r
r
s
s
.
.
R
R
e
e
q
q
u
u
i
i
r
r
e
e
d
d
:
:
F
F
u
u
r
r
t
t
h
h
e
e
r
r
m
m
u
u
l
l
t
t
i
i
c
c
e
e
n
n
t
t
r
r
i
i
c
c
s
s
t
t
u
u
d
d
i
i
e
e
s
s
o
o
n
n
t
t
h
h
e
e
s
s
e
e
a
a
s
s
w
w
e
e
l
l
l
l
a
a
s
s
o
o
t
t
h
h
e
e
r
r
g
g
l
l
y
y
c
c
o
o
c
c
a
a
l
l
y
y
x
x
c
c
o
o
m
m
p
p
o
o
n
n
e
e
n
n
t
t
s
s
t
t
o
o
d
d
e
e
m
m
o
o
n
n
s
s
t
t
r
r
a
a
t
t
e
e
c
c
o
o
m
m
p
p
a
a
r
r
a
a
t
t
i
i
v
v
e
e
c
c
l
l
i
i
n
n
i
i
c
c
a
a
l
l
u
u
t
t
i
i
l
l
i
i
t
t
y
y
o
o
f
f
t
t
h
h
e
e
s
s
e
e
m
m
a
a
r
r
k
k
e
e
r
r
s
s
.
.
A
A
l
l
s
s
o
o
t
t
h
h
i
i
s
s
w
w
o
o
u
u
l
l
d
d
g
g
i
i
v
v
e
e
f
f
u
u
r
r
t
t
h
h
e
e
r
r
d
d
i
i
r
r
e
e
c
c
t
t
i
i
o
o
n
n
a
a
s
s
t
t
o
o
t
t
h
h
e
e
u
u
s
s
e
e
f
f
u
u
l
l
n
n
e
e
s
s
s
s
o
o
f
f
t
t
h
h
e
e
r
r
a
a
p
p
y
y
t
t
a
a
r
r
g
g
e
e
t
t
t
t
i
i
n
n
g
g
t
t
h
h
e
e
s
s
e
e
m
m
a
a
r
r
k
k
e
e
r
r
s
s
30
A
A
c
c
k
k
n
n
o
o
w
w
l
l
e
e
d
d
g
g
e
e
m
m
e
e
n
n
t
t
s
s
Ms Dimple Anand
PhD student
Dr. Sumit Ray
Critical Care Intensivist
Patients
Enrolled subjects
ICMR [Indian Council of Medical Research] for
funding the project
31
Dr. Seema Bhargava, a senior consultant and professor at Sir Ganga Ram Hospital in New Delhi, India, raises the question of whether therapeutic agents for sepsis should focus on targeting the glycocalyx. The glycocalyx, a protective layer on cell surfaces, plays a crucial role in various physiological processes. Understanding its significance in sepsis treatment could pave the way for more effective therapeutic strategies in managing this life-threatening condition.
Download Presentation
Please find below an Image/Link to download the presentation.
The content on the website is provided AS IS for your information and personal use only. It may not be sold, licensed, or shared on other websites without obtaining consent from the author. Download presentation by click this link. If you encounter any issues during the download, it is possible that the publisher has removed the file from their server.
E N D
Presentation Transcript
SHOULD THERAPEUTIC AGENTS FOR SEPSIS TARGET THE GLYCOCALYX? Dr. Seema Bhargava Senior Consultant & Chairperson Department of Biochemistry & Professor, GRIPMER Sir Ganga Ram Hospital New Delhi, India
Systemic Inflammatory Response Syndrome (SIRS)/Sepsis ACCP/SCCM Consensus Conference (1992) Crit Care Med 1992; 20:864 874 Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Criteria for Dx of SIRS Core temperature >38.3 C / <36 C Heart rate >90 bpm / >2SD Burns Pancreatitis SIRS INFECTION Trauma Respiratory rate >30 bpm or PaCO2 <32 mm Hg Other Sepsis WBC count >12,000 cells/mm3 or <4,000 cells/mm3 or >10% immature neutrophils = Known or suspected infection + 2 SIRS criteria
SIRS, Sepsis, Severe Sepsis and Septic shock Severe Sepsis Sepsis + 1 organ dysfunction Other Pancreatitis INFECTION SEVERE SEPSIS SIRS Septic Shock Severe Sepsis + Hypotension despite fluid resuscitation Trauma Burns ACCP/SCCM Consensus Conference (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.Crit Care Med 1992; 20:864 874
Dilemmas in sepsis Early diagnosis Segregation into sepsis and SIRS Differentiation between sepsis, severe sepsis and septic shock Prognosis Increased morbidity and mortality Refractory hypotension and organ failure
Publication Impact Factor: 2.5 Salient findings: PCT differentiates culture-negative sepsis from SIRS at a cut off of 1.43 ng/ml, with 92% sensitivity and 83% negative predictive value (AUC 0.892) PCT differentiates culture-positive sepsis from SIRS at a cut off of 2.49 ng/ml, with 94.4% sensitivity and 91.5% negative predictive value (AUC 0.959)
Next Question Identification of a marker or markers to effectively differentiate between sepsis, severe sepsis and septic shock HOW? Pathophysiology of sepsis Disruption of the glycocalyx is a known event 8
The Glycocalyx Basement membrane Endothelial cell lining Phospholipid bilayer of endothelial cell TNF IL-10 Glycocalyx with its comprising components in a latticework Blood vessel with its vessel wall and blood components
The Glycocalyx Basement membrane Endothelial cell lining Phospholipid bilayer of endothelial cell TNF IL-10 Glycocalyx with its comprising components in a latticework Blood vessel with its vessel wall and blood components 10
Hyaluronan & Syndecan Glycocalyx components Syndecan Widely distributed anionic non-sulphated GAG Single transmembrane domain GAG G-protein coupled receptors 11
Study Objectives 1.To study the evolution of hyaluronan and syndecan (glycocalyx components) as prognostic markers for sepsis 2. To correlate their serum levels with a) Progression of disease b) Survival status c) Organ failure d) Inflammatory mediators
Methods: Inclusion & Exclusion criteria Inclusion Criteria Age 18 years Patients admitted to the intensive care unit with community acquired Sepsis, Severe sepsis or Septic shock Exclusion Criteria Post-operative patients Lethal condition Malignancy Immunocompromised Transferred from other ICU s
Methodology Days 1,3,5, and 7 Blood drawn from all subjects Following analytes estimated in serum: Hyaluronan- Competitive Enzyme Linked Immunosorbent Assay (Teco Medical, Switzerland) Syndecan- Solid Phase Sandwich Elisa (Diaclone, Besancom Cedex, France) TNF- - Chemiluminescent Immunoasasy (Immulite, Siemens) Interleukin-10 - Solid Phase Sandwich Elisa (Diaclone, Besancom Cedex, France) SOFA and APACHE II scores
Patient baseline characteristics Sepsis (N = 15) Severe Sepsis (N = 45) Septic Shock (N = 90) p Value 54 + 16.5 53.4 + 16 Age, Mean + S.D 52.2 + 16.3 ns Gender (M/F) 8/7 27/18 56/34 ns Mortality N (%) 1 (6.66%) 6 (13.3%) 34 (37.7%) 0.002 APACHE II Mean + S.D. 9 + 6.2 20.1 + 7.0 25.1 + 7.4 0.004 SOFA SCORE Mean + S.D. <0.001 4.8 + 2.1 8.5 + 3.7 12.1 + 3.5
DAY 1 DAY 3 DAY 5 DAY 7
Receiver Operating Characterstics of Hyaluronan Survivors vs Non-Survivors Days Variable Cut Off Sensitivity % 73 Specificity % 44 PPV % 33 NPV % 81.3 Day 1 220 0.573 (0.47-0.67) Day 3 344 0.671 64 71.3 47 84 (0.55-0.79) Day 5 321 0.720 71 76 49.02 89.1 3 (0.61-0.82) Day 7 441 0.827 (0.73-0.91) 61 90 62 90
Receiver Operating Characterstics of Syndecan Survivors vs Non-Survivors Days AUC Cut Off Sensitivity % Specificity % PPV % NPV % Day 1 625 0.644 56 71 42 81 (0.54-0.74) Day 3 389 0.756 85.4 55 41.7 91 (0.66-0.84) Day 5 898 0.801 52.9 94 72 86.3 (0.71-0.98) Day 7 455 0.751 59 86 48.1 91 (0.621-0.881)
Hyaluronan: Association with Mortality, Organ Dysfunction scores and inflammatory markers at all Time-points Hyaluronan Day 1 Day 3 Day 5 Day 7 r=0.387 APACHE II p<0.001 r=0.387 r=0.406 r=0.327 r=0.289 SOFA p<0.001 p<0.001 p<0.001 p=0.002 r=0.338 r=0.341 r=0.258 r=0.256 TNF- p=0.001 p=0.002 p=0.043 p=0.033 r=0.232 r=0.264 r=0.260 r=0.256 IL-10 p=0.032 p=0.017 p=0.023 p=0.049
Syndecan: Association with Mortality, Organ Dysfunction scores and inflammatory markers at all Time-points Syndecan Day 1 Day 3 Day 5 Day 7 r=0.294 APACHE II p<0.001 r=0.437 r=0.354 r=0.494 r=0.217 SOFA p<0.001 p=0.003 p<0.001 p=0.026 r=0.234 r=0.321 r=0.382 p=ns TNF- p=0.029 p=0.010 p=0.001 r=0.215 r=0.229 r=0.354 r=0.266 IL-10 p=0.05 p=0.050 p=0.004 p=0.044
Summary Serum levels of Hyaluronan and Syndecan Both markers show a significant positive correlation with - Organ dysfunction - Mortality scores - Pro- & Anti-inflammatory markers Serum levels on admission categorize the patient into sepsis, severe sepsis and septic shock Serial measurements differentiate survivors from non-survivors with the following: Cut-off Specificity NPV H 441 ng/ml 90% 90% S 898 ng/ml 94% 86%
Conclusions Conclusions Glycocalyx components [hyaluronan and syndecan] could be used for diagnosis i.e. to differentiate between sepsis, severe sepsis and septic shock. Hyaluronan and syndecan could also be used for prognosis i.e. to identify survivors and non- survivors. Required: Further multicentric studies on these as well as other glycocalyx components to demonstrate comparative clinical utility of these markers. Also this would give further direction as to the usefulness of therapy targetting these markers 29
Acknowledgements Acknowledgements Ms Dimple Anand PhD student Dr. Sumit Ray Critical Care Intensivist Patients Enrolled subjects ICMR [Indian Council of Medical Research] for funding the project 30
THANK YOU 31
