The Journal of Nutrition

7th Amino Acid Assessment Workshop

Clinical Use of Glutamine Supplementation1,2

Jan Wernerman*
Department of Anesthesia and Intensive Care Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, 14186
Stockholm, Sweden

Abstract
Endogenous production of glutamine may become insufficient during critical illness. The shortage of glutamine is reflected
as a decrease in plasma concentration, which is a prognostic factor for poor outcome in sepsis. Because glutamine is a
precursor for nucleotide synthesis, rapidly dividing cells are most likely to suffer from a shortage. Therefore, exogenous
glutamine supplementation is necessary. In particular, when i.v. nutrition is given, extra glutamine supplementation
becomes critical, because most present formulations for i.v. use do not contain any glutamine for technical reasons. The
major part of endogenously produced glutamine comes from skeletal muscle. For patients staying a long time in the
the export of glutamine. The metabolic and nutritional adaptation in long-staying ICU patients is poorly studied and is one of
the fields that needs more scientific evidence for clinical recommendations. To date, there is evidence to support the
clinical use of glutamine supplementation in critically ill patients, in hematology patients, and in oncology patients. Strong
evidence is presently available for i.v. glutamine supplementation to critically ill patients on parenteral nutrition. This must
be regarded as the standard of care. For patients on enteral nutrition, more evidence is needed. To guide administration of
glutamine, there are good arguments to use measurement of plasma glutamine concentration for guidance. This will give
an indication for treatment as well as proper dosing. Most patients will have a normalized plasma glutamine concentration
by adding 2025 g/24 h. Furthermore, there are no reported adverse or negative effects attributable to glutamine
supplementation. J. Nutr. 138: 2040S2044S, 2008.

Introduction
A profound depletion of glutamine in plasma and in tissues
occurs in critical illness. Glutamine is unstable in aqueous
solution and therefore was not included in crystalline amino acid
solutions for parenteral use until the dipeptide technique was
introduced in the 1990s. It was not far fetched to hypothesize
that supplementation with glutamine would counteract or
attenuate metabolic catabolism during critical illness. In particular, studies of the physiology and kinetics of glutamine
provided evidence that glutamine availability may be affected
(13). Starting 20 y ago, a number of reports demonstrated
beneficial effects from glutamine supplementation in various

Published in a supplement to The Journal of Nutrition. Presented at the

conference The Seventh Workshop on the Assessment of Adequate and Safe
Intake of Dietary Amino Acids held November 23, 2007 in Tokyo. The
conference was sponsored by the International Council on Amino Acid Science
(ICAAS). The organizing committee for the workshop was David H. Baker,
Dennis M. Bier, Luc A. Cynober, Yuzo Hayashi, Motoni Kadowaki, Sidney M.
Morris Jr, and Andrew G. Renwick. The supplement coordinators were David H.
Baker, Dennis M. Bier, Luc A. Cynober, Motoni Kadowaki, Sidney M. Morris Jr,
and Andrew G. Renwick. Supplement coordinator disclosures: all of the
coordinators received travel support from ICAAS to attend the workshop.
2
Author disclosures: J. Wernerman, part of the travel expenses and costs for
the stay in Tokyo for the authors participation in the 7AAAW meeting was
covered by ICAAS.
* To whom correspondence should be addressed. E-mail: jan.wernerman@
karolinska.se.

2040S

patient groups and, in parallel, virtually no reports of negative

effects or adverse effects attributable to glutamine supplementation have been published. Today, glutamine supplementation
is the standard of care when i.v. nutrition is given to critically ill
patients (4). Glutamine supplementation in enteral nutrition is
still controversial.
Physiology
Glutamine is a nonessential amino acid and the major part of the
de novo synthesis in the human body is in skeletal muscle (5,6).
Other organs with a net export of glutamine are the brain and
there are several independent reports of a net export from the
lungs (79). From these tissues, glutamine is transported via the
blood stream to organs in the splanchnic area. Cells utilizing
glutamine are immune competent cells, enterocytes, and to some
extent also hepatocytes. The main use for glutamine in the basal
state as well as during critical illness is as an oxidative substrate.
This involves the handling of the amino groups, the major part
of which ends up as urea. The endogenous production of
glutamine as estimated by isotopic techniques is 4080 g/24 h
(1012). A production of the same magnitude is also found when
using pharmacokinetic techniques (1,13). Both techniques may
underestimate the actual de novo glutamine synthesis, because
the distribution volume of glutamine is large and the equilibration time is therefore long (14). Measurements in critically ill
patients indicate that the endogenous glutamine synthesis rate or
rate of appearance remains similar to that in the basal state (1).
0022-3166/08 $8.00 2008 American Society for Nutrition.

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intensive care unit (ICU), the muscle mass decreases rapidly, which leaves a tissue of diminishing size to maintain

Rationale for glutamine supplementation

The rationale for treatment with glutamine supplementation in
critically ill patients is the shortage of glutamine, the clinical
evidence, and the fact that it is not harmful to patients.
There were 2 single-center studies of multiple organ failure
patients of total parenteral nutrition that showed a survival
benefit when glutamine was supplemented at the level of 2025
g/24 h (16,17). The survival advantage in these studies shows as
a tendency within the ICU stay, which becomes significant at the
6-mo follow-up. This fact has been discussed, as there is no
report of a direct relation between the glutamine depletion over
time and mortality. However, a low plasma glutamine at ICU
admittance is an independent predictor of mortality (4). What
happens during the restoration phase following ICU discharge is
still an open question. A possible hypothesis for this group of
patients is that the glutamine depletion and the general muscle
protein depletion go hand-in-hand and that the post-ICU
mortality is comparable to the general mortality in a group of
patients with severe malnutrition. In addition, there are a
number of studies focusing on morbidity in terms of infectious
morbidity, length of stay, or hospital economics (1823). Such
reports exist both for parenteral glutamine and enterally
administrated glutamine. For enterally administrated glutamine,
there is a comparatively large study of a general ICU patient
group with a mixture of short stayers and long stayers that fails
to demonstrate any advantage in morbidity or mortality (24).
For other patient groups, such as hematological patients,
oncological patients, and patients with gastrointestinal diseases,
clinical studies demonstrate decreased morbidity (25,26). In
summary, there is clear evidence that when critically ill patients
receive parenteral nutrition, i.v. supplementation with glutamine
brings a survival advantage. The clinical evidence is not yet
conclusive for patients receiving enteral nutrition or combined
enteral and parenteral nutrition. Several multi-center studies will
be conducted in the next few years that will hopefully shed more
light on this topic (27,28). The major problem with the existing
evidence in these groups of patients is the mixture of ICU short

stayers and long stayers, which introduces a large variability of

prognosis in terms of mortality within the study group.
The shortage of glutamine as reflected by the plasma concentration is a prognostic factor (2,3,2931). There is also a depletion in tissues such as skeletal muscle, where the concentration
decreases to 25% of normal. The reason for the intracellular
depletion is not fully understood. A decrease in intracellular
glutamine concentration occurs during starvation in healthy
subjects and also following medium-size elective surgery
(32,33). In the latter case, it is normalized over a period of 2
wk, while for starved healthy subjects it is normalized over a few
days (34). Both of these states represent mild catabolism, which
obviously resets the gradient between extracellular and intracellular glutamine differently. In healthy volunteers and in nonmalnourished patients undergoing elective surgery, there is no
change of plasma glutamine concentration but only a drop in
tissue concentration (32,35). Hypothetically, whatever regulates
the gradient for glutamine across the cell membrane resets it in
this situation. For the critically ill patients, on the other hand, the
decrease occurs both in plasma and intracellularly and the latter
seems to be more pronounced, also decreasing the gradient.
Of all studies involving glutamine supplementation by enteral
or parenteral route, there are virtually no reports of adverse
effects or harmful effects. This included patients in studies of
tolerance and pharmacokinetics, who were shown to have
extremely high plasma glutamine levels (. 2 mmol/L) (36). The
only condition known to be accompanied by very high plasma
glutamine concentrations is acute liver failure, whereas chronic
liver failure is not accompanied by high plasma glutamine levels
(37). The pathophysiology behind these high concentrations is
not well characterized. There is no literature reporting that a
high glutamine concentrations are associated with any of the
symptoms of acute liver failure or the prognosis.
Route of administration
Administration of glutamine containing dipeptides results in an
almost immediate hydrolysis into the constituent amino acids
(38,39). This peptidase activity is probably present on the
surface of the endothelium. The half-life of glutamine containing
dipeptides is ,3 min in healthy volunteers and ,10 min in ICU
patients (36,38,39). In tolerance studies, dipeptides have not
accumulated or been excreted via the kidneys (36,40). So
glutamine becomes readily available after administration of the
dipeptide. When given i.v., the plasma concentration immediately responds to the exogenous supply. In critically ill patients,
this results in a normalization of the plasma level in all patients
(41). The clearance and the distribution kinetics is highly
variable (36); therefore, the dosage of glutamine may be guided
by determinations of plasma concentration.
When exogenous glutamine is administered i.v., the distribution is uniform throughout the body. The concentrated
dipeptide, alanyl-glutamine (at 200 g/L), with an osmolality
,900 mOsm, can be safely administered also in a peripheral
vein (42). This means that i.v. glutamine supplementation may
also be administered when central venous lines are not available.
All cells in the body may utilize this glutamine and there are no
restrictions in uptake, although the concentration gradient in
skeletal muscle, for example, is not in favor of an uptake.
Experimental studies have demonstrated that intestinal mucosal
cells may have a facilitated uptake across the brush border
membrane, which is the cellular surface toward the intestinal
lumen (43,44). The relevance of that finding in vivo is not well
documented. On the contrary, the atrophy of the intestine in
animals may be attenuated by i.v. administration of glutamine
Clinical Use of Glutamine Supplementation

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This is also supported by the observation that the quantitative

efflux of glutamine from muscle remains consistent or is only
slightly elevated in critically ill subjects compared with the basal
state in healthy volunteers (5,15). A major difference between
healthy volunteers and critically ill subjects is that the latter
group usually is constantly fed enterally or parenterally over
time. This makes the amino acid balance across muscle fairly
similar in terms of the proportions between the individual amino
acids in the fed critically ill patients and healthy volunteers in the
basal state. The situation in the fed state of healthy individuals,
when there is an uptake of all amino acids except glutamine, is
not seen in critically ill patients. Although the physiology is well
known in general terms, there are still a number of unsettled
questions. It has not been clarified whether there is a relation
between plasma concentration and rate of appearance for
glutamine. No correlation between the size of the export of
glutamine from muscle and plasma concentration has been
reported, but there may be a relation between plasma concentration and the splanchnic uptake. Although this is very likely, it
has never been demonstrated, to the authors knowledge, in
critically ill subjects. For glutamate, the situation is more
complicated. It has been demonstrated that the uptake in cardiac
or skeletal muscle is concentration dependent, but what regulates the export of glutamate from liver and whether the export
is concentration dependent is not well characterized in critically
ill patients.

and the translocation of bacteria is also counteracted by i.v.

glutamine (4547).
When exogenous glutamine is administered enterally, there is
an immediate uptake in the upper part of the gastrointestinal
tract (48). The effects of enteral glutamine supplementation on
plasma concentration are highly variable and often marginal in
size (20,40,48,49). The major portion of the administered
glutamine is utilized in the gut itself by enterocytes and immune
competent cells and the rest is utilized in the liver, and through
this first pass elimination, the major part of the given dose is
utilized (12,40). Still, as enterocytes and immune competent
cells are the target cells, this may be sufficient for an improvement in the clinical outcome, but the uneven distribution may
also be a problem. In critical illness, an additional problem may
be the uncertainty concerning the absorption and utilization of
any enterally administered nutrient. This may add uncertainty,
in particular when the effect upon plasma concentration is only
marginal. In summary, parenteral administration probably has
advantages, while the disadvantage is the higher cost.

Recommendations
Solid evidence is presently available for i.v. glutamine supplementation to critically ill patients on parenteral nutrition.
Existing studies are confined to ICU, and continued post-ICU
glutamine supplementation together with parenteral nutrition is
not supported by clinical studies but is perhaps a reasonable
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Supplement

Unanswered questions
The most important issue for ongoing and future research is
whether enterally provided glutamine will be as effective as
parenterally provided. Existing studies of enteral glutamine
supplementation mix patients of long and short ICU stay, which
makes the results inconclusive. Another issue of importance is
the role of glutamine supplementation when enteral and parenteral nutrition is combined, which often is the case in the ICU.
Finally, the possible influence of exogenously provided glutamine on the endogenous production is also an issue that needs to
be solved.
In summary, the clinical use of glutamine supplementation
has evidence to support its use in critically ill patients in the
ICU and in hematology and oncology patients. There is strong
evidence for glutamine supplementation for patients on parenteral

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Dosage and therapeutic goals

When glutamine is administered i.v., there is a dose-response
effect in the sense that the higher the dose, the higher the plasma
concentration (41,50). Elimination kinetics is by the first order
and even large doses are eliminated within 8 h after determination of the infusion (36). In the limited number of critically ill
patients so far studied in terms of glutamine kinetics, there is
no evidence of a feedback mechanism where exogenous
supplemented glutamine decreased the endogenous production
(1,36,51,52). There are also no studies available on the longterm effects of exogenous glutamine supplementation.
In postoperative patients, a daily i.v. glutamine dose of 20 g
attenuates the decrease otherwise seen in skeletal muscle (32
34). This dose was originally chosen from a calculation of the
decline in the free glutamine pool. When tested in critically ill
patients, it proved to be sufficient to normalize the decreased
plasma concentration in the majority of ICU patients, while it
did not affect the decreased free glutamine concentration in
muscle (41). Lower doses of exogenous glutamine given i.v. are
not sufficient to normalize the plasma concentration in ICU
patients (5). The dose response of exogenous glutamine given
enterally is less well characterized. It is dependent upon the
group of subjects investigated, the concomitant administration
of enteral feeding, and whether the mode of feeding is bolus or
continuous (12,20,40,48,5355).
For patients staying a long time in the ICU, the export of
glutamine from muscle tissue remains unaltered, at least during
the initial 3 wk (5). The muscle mass decreases rapidly, which
leaves a tissue of diminishing size to keep up the export (31).
In vitro measurement of the capacity for glutamine synthesis
indicates a priori an increased production (56). Whether ICU
patients staying a very long time eventually will be depleted in
their capacity for endogenous glutamine production is still an
open question. The metabolic and nutritional adaptation in this
group of patients is poorly studied and is one of the fields that
requires more scientific evidence for clinical recommendations.

extrapolation of existing data. However, the distinction between

ICU and post-ICU is very different between countries. The group
of patients confined to parenteral nutrition is small in number,
whereas the patients on combined enteral and parenteral are the
majority of long stayers in the ICU. Upcoming studies will
hopefully provide evidence of whether this patient group will
benefit from glutamine supplementation. The costs of i.v.
glutamine supplementation are sometimes regarded as a problem. By routine determinations of plasma glutamine concentration, patients who are depleted of glutamine can be defined and
treatment can be monitored to restore plasma glutamine to the
normal concentration interval.
There are virtually no contraindications to glutamine supplementation in any form. The only patient group with a high
plasma glutamine level, those with acute hepatic insufficiency, is
not a nutritional problem. Usually within a limited period of
time, they will regain liver function or receive a transplant.
Patients in chronic liver failure are often malnourished and
should not be excluded from glutamine therapy. As for kidney
failure in critical illness, this should be treated by dialysis, when
exogenous glutamine supplementation becomes even more important. The losses of amino acids into the dialysate are ;10 g/
hemodialysis session in intermittent dialysis and in continuous
renal replacement therapy the losses of glutamine are usually 35
g/24 h. These losses are in addition to an insufficient endogenous
glutamine production (1,57). This makes glutamine supplementation even more important, and it should be in the range of
2535 g/24 h.
For neurosurgical patients, in particular patients with head
injuries, there are concerns that the elevated level of glutamate
interstitially in the brain may be influenced by exogenous
glutamine supplementation. The elevated glutamate has been
reported to be an indicator of an unfavorable outcome. However, these observations are perhaps more anecdotal than
evidence based. Nevertheless, there are concerns that glutamine
may result in an elevation of glutamate. In a safety study, elevated
plasma glutamine concentration secondary to exogenous glutamine supplementation did not affect plasma glutamate or
intracerebral glutamate levels, as monitored by microdialysis
(58). Furthermore, the efflux of glutamine from the brain was
also unaffected by exogenous glutamine supplementation (51).
Theoretically, there could be an impairment of the glutamate
elimination via the glutamine pathway if the efflux of glutamine
from the brain was diminished. In conclusion, there is no
contraindication of using glutamine to head trauma patients
and studies investigating if glutamine supplementation to this
patient group may have advantageous effects upon outcome are
encouraged.

nutrition. This is regarded as the standard of care. For patients on

enteral nutrition, more evidence is needed. To guide the administration of glutamine, measurement of plasma glutamine concentration is advocated. This will give an indication for treatment as
well as proper dosing. Most patients will have a normalized plasma
glutamine concentration by adding 2025 g/24 h. For patients on
continuous renal replacement therapy, a bit more (2535 g/24 h) is
recommended. In addition to clinical evidence, there is rationale
for glutamine supplementation by the understanding of the role of
glutamine in physiology. Furthermore, importantly, there are no
reported adverse effects or negative effects attributable to glutamine supplementation. More evidence from ongoing multi-center
studies will be generated during the next few years.
Other articles in this supplement include references (5968).

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Clinical Use of Glutamine Supplementation

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