Glutamine supplementation to critically ill patients?
Wernerman Critical Care
Glutamine supplementation to critically ill patients?
0 Department of Anesthesia and Intensive Care Medicine, Karolinska University Hospital, Huddinge , Stockholm , Sweden
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Introduction
A recent study (Reducing Deaths due to Oxidative Stress,
REDOXS) reported harm in critically ill patients who
received glutamine supplementation [1]. This is in
contrast to a number of earlier studies reporting beneficial
effects or failing to demonstrate any effect [2], [3].
Naturally, this finding raises a number of questions,
which are not answered by combining all existing studies
into a large meta-analysis. This overview will discuss
existing clinical data, including dosing and selection of
patients. In addition, suggested mechanisms will be
discussed from a clinical perspective. Finally, possibilities
for future research will be outlined.
Rationale for supplementation
The background to the suggestion that critically ill
patients should receive glutamine supplementation is
that plasma glutamine concentration at intensive care
unit (ICU) admission is an independent predictor of an
unfavorable outcome [4], [5]. Empirically, a plasma
concentration of 420 μmol/l has repeatedly been reported
as a cut-off for a low plasma glutamine concentration
associated with a higher risk of mortality in adults [4],
[5]. In principle, the same effect applies in critically ill
pediatric patients, but here the low mortality rates have
not made it possible to demonstrate a mortality
disadvantage, although a morbidity disadvantage has been
reported [6]. Approximately one third of ICU admissions
are consistently found to have a low plasma glutamine
concentration, and this is independent from conventional
risk-scoring [1], [4]–[6]. In a study from Stockholm, the
mortality associated with a low ICU admission glutamine
concentration was to a large extent due to the post-ICU
mortality within 6 months from ICU admission [5].
In addition to the predictive value of a low plasma
glutamine concentration at ICU admission for an
unfavorable outcome, there seem to be a similar
prediction also for high plasma glutamine concentrations
at admission [5]. This group of patients, however, is much
smaller, and the evidence for this prediction is mostly in
form of case series. It has been reported that acute liver
failure is quite often associated with high or very high
plasma glutamine concentrations [7]. Chronic liver
insufficiency and acute-on-chronic liver failure are not
accompanied by high plasma glutamine concentrations.
In single cases, it has been observed that terminal
patients with multiple organ failure (not necessarily
including advanced liver failure) have very high plasma
glutamine concentrations. One can speculate that this
observation may relate to impaired cellular integrity in
general.
In parallel to the association between a low plasma
glutamine and an unfavorable outcome, there is an
extensive literature about the essential role of glutamine
in a number of experimental systems, including whole
animals. Cell division demands an increase in nucleotide
production, and glutamine is a main precursor for this
type of synthesis. Cell culture media usually contain a
much higher free glutamine concentration than does
human plasma, and lowering of glutamine concentration
in cell culture media is associated with a lower rate of cell
division. Many cultured cells prefer glutamine over
glucose as their main energy source, and imposing
stressful events to the cell culture is reported to enhance
the preference for glutamine over glucose as energy
substrate. In tissues and whole animals, it is the rapidly
replicating cells that seem to be particularly dependent
on glutamine availability. Enterocytes in the
gastrointestinal tract and immune-competent cells are reported
to be particularly sensitive to glutamine depletion.
Histological changes and bacterial translocation in the
gut occur when there is glutamine shortage, and
provision of glutamine can reverse this effect. Similarly,
for immune-competent cells, markers of immune
function deteriorate during glutamine shortage, to return
back to normal upon restoration of glutamine availability.
Targets for supplementation
With this background, the suggestion that glutamine
shortage should be compensated for by supplementation
is not far-fetched and consequently a number of clinical
studies have been performed, mainly in critically ill
patients. Behind the suggestion to supplement there are
two different philosophies: To substitute a deficiency or
to administer a pharmacological agent
(pharmaconutrition). It is recommended that these two philosophies
be separated because the target for treatment is different
in the two cases. To supplement to normal levels would
mean adding supplementation in order to reach normal
plasma concentrations, or normal availability in tissues if
more invasive monitoring is possible. To administer a
pharmaconutrition agent on the other hand, would mean
that (...truncated)