Effect of C1-esterase inhibitor on systemic inflammation in trauma patients with a femur or pelvic fracture.

Systemic inflammation in response to femur or pelvic fracture and fixation is
associated with complications, such as acute respiratory distress syndrome
(ARDS) and multiple organ dysfunction syndrome (MODS). The injury itself, but
also the additional fixation procedure give a release of pro-inflammatory
cytokines, in particular interleukin (IL)-6. This results in an aggravation of
the initial systemic inflammatory response, and will cause in some patients an
increased risk on the development of inflammatory complications, like ARDS and
MODS. Which can lead to higher morbidity, mortality and prolonged hospital
stay.
Various strategies, such as damage control orthopedics, have been proposed to
prevent these complications. Another strategy is to decrease the inflammatory
reaction caused by the surgical procedure, and by interventions focused on
inhibition of the innate inflammatory response. This will lower the risk of
complications.
A promising candidate is the endogenously produced serum protein C1-esterase
inhibitor (C1-INH). This protein is an acute phase protein, produced by the
liver in response to inflammatory conditions. C1-INH is a major inactivator of
the complement system, but important additional anti-inflammatory properties
have been demonstrated. A previous study of from our laboratory showed that
administration of the drug C1-INH significantly reduced the concentration of
circulating pro-inflammatory cytokines such as IL-6, during human experimental
endotoxemia. Treatment with C1-INH has been proven to be safe in treatment with
humans, even in high dosages and in pregnant patients with C1-INH deficiency.

A previous study of from our laboratory showed that administration of the drug
C1-INH (100E/kg) significantly reduced the concentration of circulating pro-
inflammatory cytokines, such as IL-6, in healthy male volunteers during human
experimental endotoxemia.

The aim of this study is to demonstrate that administration of C1-INH, in
trauma patients with a femur fracture, reduces the release of early
pro-inflammatory cytokines and, therefore, will attenuate the humane
inflammatory response. Consequently, administration of C1-INH may attenuate the
onset of SIRS and the occurrence of organ failure and can, therefore, be a
potential drug for the prevention of late inflammatory complications in injured
patients.

A prospective double-blind randomized placebo-controlled trial in
trauma-patients, between 18 and 80 years old, admitted to the shock room of our
trauma centre with a femur or pelvic fracture and an injury severity score of
>=18.

A first blood sample will be taken within 12 hours after trauma, this blood
sample serves as a reference for the degree of inflammation. A second blood
sample will be drawn pre-procedural just before the femoral fixation, when the
patient is anaesthetized. Then the patient is randomized and C1-INH or placebo
is administrated intravenously. The third blood sample is taken 2 hours after
the first (femoral or pelvic fixation-procedure) skin incision and the fourth
withdrawal will take place 6 hours after the procedure. Teh remaining samples
will be taken 24, 48 hours, 7 and 12 days after surgery.
As long as the patient is admitted on the Intensive Care Unit, blood samples
can be taken from the arterial catheter. When the patients leave the ICU, they
will be asked if he/she will provide us an additional sample.

Subjects will receive once a single dose of 200E/kg C1-INH intravenously or
placebo (saline 0.9%).

C1-INH is a normal compnent of the humane blood. No side effects are described
by administration of C1-INH.
Patients could, theoretically, develop an allergic reaction after admission of
C1-INH, manifesting as urticaria or anaphylatic shock, this has never been
described.

The blood is drawn from the arterial line, if possible. The patient does not
experience any discomfort of this procedure. The placement of an arterial line
is standard care in this groiup of trauma patients. If the arterial line is
removed, the blood will be drawn through vena puncture. This will be combined
with clinical blood withdrawl.