Hypoperfusion and activated protein C after out of hospital cardiac arrest:
triggers for hyperfibrinolysis

Out of hospital cardiac arrest (OHCA), also known as cardiopulmonary arrest, is
the cessation of systemic blood flow due to cardiac failure. Previous studies
in animals and humans showed an increase in activation of coagulation after
resuscitation in patients with out of hospital cardiac arrest.3,4
Hyperfibrinolysis is a state of enhanced fibrinolysis, frequently associated
with a high rate of clot breakdown and bleeding. In particular, patients with
signs of hypoperfusion due to cessation of systemic circulation more frequently
show hyperfibrinolysis, probably due to hypoperfusion-induced activation of the
protein-C pathway. We recently found that almost 50% of all OHCA patients
develop hyperfibrinolysis, and this was associated with indirect markers of
tissue hypoperfusion. The study was however limited by several factors and its
retrospective nature.

This study will therefore prospectively investigate the relation between tissue
hemoglobin oxygenation and the occurrence of hyperfibrinolysis in the context
of altered levels of hyperfibrinolytic markers in patients with out of hospital
cardiac arrest.

Our research group recently found that almost 50% of all OHCA patients develop
hyperfibrinolysis, and found an interesting association between the degree of
hyperfibrinolysis and hypoperfusion. Hypoperfusion was determined by base
excess (BE), arterial oxygen pressure (pO2), arterial carbon dioxide pressure
(pCO2), lactate, pH and cardiopulmonary resuscitation (CPR) time. Moreover,
data tended to show worse patient outcome in cases of severe hyperfibrinolysis.
The study was however limited by several factors and its retrospective nature.
In particular, as arterial blood gas analyses were static and not precise
enough as indicators of tissue perfusion, studies using specific longitudinal
tissue hemoglobin oxygenation measurements are warranted to determine the
relation between hypoperfusion and hyperfibrinolysis. Furthermore, the relation
between hypoperfusion and hyperfibrinolysis in the context of alterations in
the levels of activated protein C, PAI-1 and TAFI has never been investigated
in patients after OHCA.

In the present study we aim to investigate the relation between tissue
hemoglobin oxygenation as indicator of tissue perfusion and the occurrence of
hyperfibrinolysis in the context of altered levels of activated protein C,
PAI-1 and TAFI in patients admitted to the emergency department of the VU
University Medical Center with out of hospital cardiac arrest.

Primary objective:
- What is the correlation between hypoperfusion as measured by tissue
hemoglobin oxygenation and the onset time and level of hyperfibrinolysis
measured by ROTEM in patients with out of hospital cardiac arrest?

Secondary objectives:
- How are fibrinolytic markers, especially the activation of protein C,
associated with the degree of hypoperfusion and hyperfibrinolysis in patients
with out of hospital cardiac arrest?
- What is the role of the lysis onset time in relation to the onset time of
hypoperfusion?

This study is retrospective, single center, observational study.
The study will be performed in the departments of Anesthesiology, Emergency
Medicine and Intensive Care Medicine of the VUmc in Amsterdam.

Study period:
- The study ends when the required sample size is reached.

Study procedure:
- Upon emergency department admission, patients receive a non-invasive cerebral
oxymetry probe for tissue hemoglobin oxygenation measurements using Near
Infrared Spectroscopy (NIRS).
- Blood sampling starts upon emergency department admission acording to routine
clinical care. Subsequent blood samples will be drawn at 2, 4 and 24 hours
following patient admission (3 x 20 ml). Blood samples will be used for routine
coagulation measurements, ROTEM, platelet activation and the determination of
hyperfibrinolytic markers.
- Patients with return of spontaneous circulation (ROSC) will be admitted tot
the intensive care department, where they will be exposed to a cooling protocol
for ischemic protection (routine procedure).

Blood sampling using a peripheral intravenous catheter is a standard procedure
in all OHCA patients admitted to the shock room. The use of an intravenous
catheter will therefore not add up to patient discomfort in the present study.
The volume of blood drawn for the present study does not increase the risk for
anemia in the patients. OHCA are routinely admitted to a special or intensive
care ward, and the intravenous catheter will in most patients not be removed
until admission to a general ward (> 24 hours). The non-invasive cerebral
tissue hemoglobin oxygenation measurements are performed with a probe that is
integrated in a forehead patch. These measurements are already performed during
cardiothoracic procedures in order to monitor cerebral tissue perfusion, and do
not add up to patient discomfort.

There are no benefits for patients when they enter the study.