Markers for gut wall integrity : a novel diagnostic and prognostic tool in adult trauma patients?

While uncontrollable hemorrhage and severe central nervous system injury are
responsible for the majority of trauma-related death in the first 24 hours,
cricital care complications such as multi organ failure replace hemorrhage as a
major cause of trauma-related death after this initial period. Mortality rates
in trauma are therefore for a large extent due to complications in organ
systems not necessarily affected by the primary trauma. Injured patients are at
risk for the development of systemic inflammatory response syndrome (SIRS).
This score is related to outcome in trauma. Approximately 30% of patients
admitted to a level I trauma center will develop SIRS (as defined by a SIRS
score >1) (Napolitano 2000, Malone 2001) Using a SIRS score consisting of
temperature, respiratory rate, heart rate and neutrophils count the presence of
SIRS can be assessed. (Malone 2001)

The subsequent development of multiple organ failure (MOF) relies on the
excessive production of inflammatory mediators like cytokines, chemokines and
complement and by derangement of the regulation of the innate and adaptive
immune responses. A compromised hepatosplanchnic bloodflow has been postulated
to play a central role in the transition of SIRS into MOF. Damage to liver or
intestine due to a reduced bloodflow might cause release of constitutive
hepatic and intestinal proteins in the systemic circulation. (Hanssen 2008,
Derikx 2009) These proteins can subsequently act as *danger signals* and
(further) activate the already activated immune system, which contributes to
the development of SIRS. Recognition of patients at risk of developing SIRS and
subsequent multiple organ failure (MOF) is therefore important, as high risk
patients will be treated according to the *damage control* principle, which
implies treating only immediate life-threatening injuries followed by
stabilization of the patient in the ICU, before returning to the operating
theatre for definitive surgery.

Fatty Acid Binding Proteins (FABP) are proteins involved in the regulation of
cellular lipid balance. While Intestinal-FABP is solely present in mature
enterocytes and appears immediately in serum when the cell membrane integrity
is compromised, Liver-FABP is present mainly in the liver. Half-life of both is
short. Both have been determined to be accurate markers for
ischemia-reperfusion induced damage in both animal models and patients. This
also holds true for urine claudin levels, a marker for damage to the intestinal
epithelial tight junctions and thus intestinal barrier function.
Early data suggests that the extent of intestinal damage (as measured by I-FABP
levels) might be associated with the presence of shock and injury severity in
trauma patients. (De Haan 2009) The same holds true for urine Claudin-3 levels,
a marker for damage to the intestinal epithelial tight junctions and thus
intestinal barrier function. (Thuijls 2009) The highest level of FABP*s were
associated with the presence of intra-abdominal injury, suggesting that FABP
levels might be used as a marker for intra-abdominal injury. These parameters
might also enable us to identify patients who are at risk for SIRS/MOF, and in
whom major surgery should therefore be delayed until patients are stabilized in
the ICU or via a damage control surgical procedure.

In trauma patients the gut barrier will be impaired due to diminished
splanchnic bloodflow. This can be assessed by I-FABP/L-FABP and Claudin-3
levels.
We hypothesize that FABP/Claudin levels may be used as a diagnostic tool for
the identification of intra-abdominal injury necessitating intervention
(surgical or otherwise) and as a prognostic marker for the development of
SIRS/MOF (and morbidity and mortality) in trauma patients.
Finally we hypothesize that that-FABP/L-FABP and Claudin-3 levels are
associated with the severity of the inflammatory and metabolic response on the
biochemical level as measured by the cytokines TNFa, IL6, IL10 on one hand and
lactate, base excess and PT/INR on the other, as the inflammatory response
develops in time. The increase in FABP/Claudin levels might precede the
increase in other inflammatory markers, suggesting that loss of gut barrier is
an early and aggravating event during the response to traumatic injur

Primary objective: to investigate the possible role of FABP/Claudin levels as a
diagnostic marker for significant intra-abdominal injury (necessitating
therapeutical intervention).

Secondary objective: to establish the use of plasma levels of I-FABP/L-FABP and
urine Claudin-3 levels as prognostic markers for SIRS, injury severity,
morbidity and mortality in severely injured patients.

Tertiary objective: to investigate whether gut wall integrity loss precedes the
inflammatory/metabolic response or the other way around.

Prospective cohort study. 600 adult trauma patients will be enrolled. For the
first 12 hours after trauma (or emergency surgery) blood and urine will be
collected every three hours. Afterwards, during daily routine bloodtests
samples for the present study will also be taken from the second day of
admission until discharge. Blood will be centrifuged and kept in -80 until
analysis. For all tests commercially available ELISA's and Western Blots are
available.

During the first 12 hours blood/urine will be collected every three hours. Most
patients will have an iv line or arterial line and a bladder catheter, so this
will be easily performed. Subsequently patients will undergo daily blood and
urine testing. As hematological testing is routinely performed on a daily
basis in severely injured patients, burden and risks are neglectable. As most
patiets will have a bladder catheter urine sampling is also without risk or
burden. In patiens without a catheter a normal urine sample is enough, there
will be no invasive procedures to obtain urine. When routine testing will not
be necessary, patients have to undergo a daily venapunction. Risks are minimal.
This study aims at finding diagnostic and prognostic markers in trauma
patients. Therefore it can only be performed in trauma patients. There can be
large benefits for future trauma patients, as it may become possible to
identify patients at risk for intra-abdominal injury and complications such as
SIRS/MOF in an early stage. The patients in the present study may benefit from
the frequent laboratory controls, which may detect (threatening) complications
in an early stage.