The Pathophysiology of Disrupted Endothelial Barrier Integrity in Septic shock

Sepsis is a condition characterized by life-threatening organ dysfunction
resulting from dysregulated host responses to infection. Septic shock is a
subset of sepsis in which underlying circulatory, cellular and metabolic
abnormalities are profound enough to substantially increase the risk of
mortality. Mortality of septic shock is a staggering 40%, which is largely due
to organ failure.

Sepsis is characterized by the presence of inflammatory-induced acute
endothelial integrity loss. However, it is largely unknown which pathways are
involved in mediating endothelial permeability. Increased endothelial
permeability results in loss of fluids into the interstitium. Fluid deficiency
is further aggravated by vasodilation, resulting in hypotensive and shocked
states. Therefore, volume resuscitation with crystalloids is one of the key
components of treating sepsis. However, the downside of resuscitation is the
occurrence of edema. Most likely, fluid resuscitation results in an increased
gradient of leakage over the permeable endothelium. Of note, compared to a
liberal fluid balance, a restrictive fluid balance reduces the occurrence of
organ failure. This poses a dilemma to the treatment of sepsis, as fluid
therapy is both a cornerstone of therapy as well as a foe in the occurrence of
organ failure, calling for alternative strategies. Plasma may be a candidate
resuscitation fluid.

In trauma animal models, plasma was found to improve the condition of the
glycocalyx lining the vessels walls, with improved endothelial barrier
integrity, thereby preventing edema and organ failure. This finding prompts the
question whether plasma is also effective in sepsis. In an animal model of
sepsis, plasma transfusion improved survival compared to saline resuscitation
and attenuated markers for inflammation and endothelial injury. Furthermore, we
found that in sepsis patients, transfusion of plasma was associated with a
decrease in levels of markers of endothelial activation, including von
Willebrand Factor (vWF) antigen and syndecan-1 levels. To date, the mechanism
behind this is unknown.

On a further note, not all plasma products may exert the same effects. In
pediatric patients, use of solvent detergent (SD) plasma compared to fresh
frozen plasma (FFP) was associated with improved survival which emphasizes that
certain components in plasma mediate the protective effects on the endothelial
barrier. The aim of this study is two-fold: to investigate mechanisms by which
mechanisms sepsis induces endothelial barrier dysfunction and permeability and
to investigate the effects of plasma and specific plasma components on the
endothelial barrier function. This will be done ex vivo using blood samples
from patients with septic shock in various models of endothelial barrier
function.

In this study we aim to investigate which pathways in septic patients
exacerbate endothelial injury and dysfunction, furthermore do we want to
investigate to what extent, and due to which components plasma transfusion can
improve the endothelial dysfunction is sepsis.

Primary objective:
1. To identify mediators in sepsis that promote loss of endothelial cell
function.

Secondary objectives:
2. To identify if plasma has protective/restorative effects on the endothelium
in sepsis.
3. To identify components of plasma that mediate endothelial stabilization.
4. To identify differences in effect between different plasma products: SD
plasma and FFP.

An observational cohort study will be conducted. in patients with (a suspicion
of) septic shock that are admitted to the intensive care unit (ICU). Blood
samples will be retrieved at 2 time points. The first blood sample will be
retrieved within 12 hours of ICU admission . The second blood sample will be
taken 7 days after admission or at the moment of ICU discharge, whichever comes
first. Demographic and clinical data will be collected from EPIC. Blood samples
will be stored at * 80 C° for further analyses.

The patient does not benefit from participation. The proposed study aims to
find new and improved ways to restore and protect the endothelium in sepsis,
which may benefit sepsis patients in the future. Risks of blood sampling from
an arterial line are negligible and do not interfere with standard care.