How to understand the results of studies of glutamine supplementation
Wernerman Critical Care
How to understand the results of studies of glutamine supplementation
0 Karolinska University Hospital Huddinge & Karolinska Institutet , K32 14186 Stockholm , Sweden
The lack of understanding of the mechanisms behind possible beneficial and possible harmful effects of glutamine supplementation makes the design of interventional studies of glutamine supplementations difficult, perhaps even hazardous. What is the interventional target, and how might it relate to outcomes? Taking one step further and aggregating results from interventional studies into meta-analyses does not diminish the difficulties. Therefore, conducting basic research seems to be a better idea than groping in the dark and exposing patients to potential harm in this darkness.
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Introduction
Meta-analyses do not bring much clarity over the
possible beneficial effect of glutamine supplementation to
critically ill patients. This is related to five issues: (a) The
patients with hypoglutaminemia, who are the ones who
have an association between a possible glutamine
shortage and unfavorable outcomes, have never been properly
investigated. (b) The mechanism that associated
hypoglutaminemia with enhanced morbidity and mortality is
not known. (c) The artificial separation according to
route of administration has not been very helpful in
interpreting the results. (d) The variable doses of
glutamine and the combination with other nutrients have
further blurred the interpretation of results. Finally, (e)
the absence of characterization of nutritional status of
the patients studied and the variable time course of
critical illness at supplementation also contribute to the
difficulty to digest the results presented.
Hypoglutaminemia
A situation in which mechanism of action is not
understood makes the meta-analysis technique particularly
hazardous. The impact of route of administration,
dosing, combination with other nutrients, definition of
shortage, and time course of treatment all call for
subgroup analyses in which the individual studies in the end
will stand quite alone with their specific treatment
protocols. Meta-analyses may be a useful tool when the
mechanism of action is known and the peculiarities of
the individual studies can be evaluated in that context.
When the mechanism is obscure, results become much
more speculative, and the value of combining studies
into a meta-analysis is discounted and may even become
confusing.
Until today, only one study provides plasma glutamine
concentration at the time of study start [1]. It is
unfortunate that the study protocol did not select the patients
with hypoglutaminemia to randomization. Another
unfortunate factor is that the intervention was not confined
to glutamine supplementation but also included
omega3 fatty acids, and therefore post hoc subgroup analyses
of the hypoglutaminemic subject did not shed any light
on the effect of glutamine supplementation in that
particular group. So to summarize, the hypothesis that
glutamine supplementation may be beneficial in critically ill
patients with hypoglutaminemia is still not addressed.
Mechanism of action
The failure to understand the mechanism that associates
hypoglutaminemia with an unfavorable outcome in
critical illness is a crucial issue. Much more effort should be
spent on exploring the pathophysiology of
hypoglutaminemia in critically ill subjects. Extrapolation of results
from animal studies has not been very helpful. Patients
with hyperglutaminemia obviously do not need
supplementation. This is a small group within the critically ill
patients, often associated with hepatic failure [2, 3]. This
is not confined to patients with acute fulminant liver
failure but also applies to a large fraction of the patients
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with chronic or acute-on-chronic liver failure.
Hyperglutaminemia may also occur in other critically ill patients
and is shown to be associated with an unfavorable
outcome [3]. Also, a high, but normal, plasma glutamine
concentration during glutamine supplementation is
related to post-intensive care unit (post-ICU) mortality
[4]. In this case, however, this was strongly related to
discharge Sequential Organ Failure Assessment (SOFA)
scoring, making interpretation difficult. Overall, the
mechanism behind hypo- and hyperglutaminemia and
the relation to outcome in critical illness need to be
further explored before starting (...truncated)