Evaluation of the citrulline generation test (CGT) using intravenous administration of glutamine-alanine in ICU patients with multiple organ dysfunction.

Citrulline, a non-protein amino acid (not incorporated into proteins), is
produced by the small intestine from its precursor glutamine and subsequently
released into the systemic circulation unaffected by the liver. Citrulline is
subsequently converted into arginine by the kidney. Since the small bowel is by
far the main source of circulating citrulline, this amino acid is thought to be
an attractive marker of enterocyte function.
Fasting plasma citrulline concentrations, however, cannot be used in this
context. Therefore, the so-called *citrulline generation test* (CGT) was
developed in which we assessed the enterocyte capacity to convert orally
administered glutamine into citrulline. We observed a significant rise (about
40% on average) in plasma citrulline concentrations following a standardized
oral bolus of alanine-glutamine (Dipeptiven) in all healthy subjects (n=20). In
contrast, patients with known enterocyte dysfunction displayed a more
attenuated or even absent rise in plasma citrulline concentrations. Therefore,
this new test appeared to hold promise for better diagnostic accuracy for
detection of enterocyte dysfunction compared to fasting citrulline
concentrations. In addition, the CGT was able to differentiate patients with
enterocyte damage due to coeliac disease, short bowel syndrome and radiation
enteritis from healthy subjects.

Significant malabsorption has been shown to frequently occur in critically ill
patients in the ICU, possibly related to diminished intestinal blood flow. At
present, we have no ideal tools to assess malabsorption or enterocyte function
in these critically ill patients. Faecal fat loss can be examined, as well as
faecal energy loss, however, clinical data concerning these methods are
limited. Sugar absorption tests are often used to detect mucosal
hyperpermeability, but difficult to interpret and hampered by disturbed renal
function or intestinal transit time. Therefore, we propose that the CGT may
well be a useful tool in identifying ICU patients at risk for malabsorption by
applying a more functional assessment of enterocyte function.
Recently, we performed a study in order to derive discriminatory/reference CGT
values in the ICU setting, and the primary aim of this study was to assess CGT
values in *stable* ICU patients who tolerated enteral nutrition fully meeting
their protein-energy requirements. Secondly, we determined whether there are
any differences in CGT curves between oral and intravenous administration of
glutamine. The latter administration route might be more feasible in ICU
patients, by eliminating the potential effects of decreased or increased
gastro-intestinal transit time, as changes in transit time theoretically might
induce erroneous CGT outcomes following enteral administration of glutamine. In
addition, we put the hypothesis forward that the CGT curve obtained following
oral glutamine merely reflects function of the (proximal) small bowel. In
contrast, intravenous glutamine administration can be utilized by the complete
small intestine by arterial extraction. This might, in theory, produce CGT
curves reflecting enterocyte function (capacity) of the entire small intestine
rather than just the proximal part. A tertiary aim was to determine differences
in plasma citrulline concentrations when sampled venous and arterial,
respectively. In this previous study we found that intravenous glutamine
administration resulted in the highest citrulline responds and least variation
and that arterial citrulline sampling induced higher citrulline values compared
to venous sampling.

In the current study (proposal) we aim to extent these CGT discriminatory
values patients with multiple organ failure to determine whether this group
suffers from enterocyte dysfunction. As stated earlier, the CGT closely
reflects the ability of the enterocyte to convert glutamine into citrulline,
thus representing the enterocyte function capacity
In addition, such assessment may be important with regard to stratifying
nutritional support and monitoring intestinal barrier function

Primary aim
To apply the CGT (intravenously and arterial sampling) in patient with multiple
organ failure for the assessment of enterocyte function as a measure for
intestinal (small bowel) barrier function.

Secondary aims
To compare the CGT with other methods assessing (mal)absorption and small bowel
function such as bomb calorimetry and sugar absorption tests.
To correlate CGT values with diagnostic categories, severity of illness,
severity of organ failure, and nutritional indices.

prospective observational study

The CGT is already incorporated in our unit for diagnostics in patients eg.
with short bowel syndrome. There are no risks involved, it is a routine
procedure with blood taken from a arterial line.

The sugar absorption test also is a routine test, with the administration of a
glucose mixture through a nasogastric or duodenal tube and the collection of
urine. No risks are involved.

Bomcalorimetry involves the 72 hr collection of faeces through a
feaces-collector, which is a routine procedure.