Exogenous glutamine: The clinical evidence

Thomas Bongers, MRCP; Richard D. Griffiths, BSc, MD, FRCP, ILTM; Anne McArdle, BSc, PhD

We know that critically ill patients suffering from undernutrition with a limited nutritional reserve have a poorer outcome. Furthermore, having a low body mass index has been
shown to be an independent predictor of excess mortality in
multiple organ failure. Therefore, nutritional support has
gained increasing interest in critical illness with the hope of
preventing or attenuating the effects of malnutrition. A negative nitrogen balance is the characteristic metabolic feature in
critical illness, with the major protein loss derived from skeletal muscle. In particular, glutamine concentrations are rapidly
reduced in plasma and muscle.
Over the last 20 yrs or so, increasing evidence is emerging
to support the use of glutamine supplementation in critical

n the 1960s, glutamine was considered a nonessential amino acid

and was therefore not part of the
then available total parenteral nutrition regimes. This was at least in part
influenced by the technical difficulties in
preparing and storing glutamine-containing solutions. L-glutamine has a very
poor solubility, is not heat stable, and
therefore has to be stored at 4C. Since
glutamine is readily synthesized in most
tissues and therefore classified as a dietary nonessential amino acid, it was considered appropriate to omit it.
Although it is certainly true that glutamine is nonessential in the healthy human being, it has been suggested otherwise during situations of extreme stress,
particularly of prolonged duration. The
mechanism for the reduction of muscle
glutamine represents a demand for increased rates of glutamine utilization at
the whole-body level and a relative im-

From the Division of Metabolic and Cellular Medicine, School of Clinical Science, University of Liverpool, UK.
Dr. Bongers has received a grant from FreseniusKabi. Dr. Griffiths has received travel expenses and
honoraria from Fresenius-Kabi. Dr. McArdle has not
disclosed any potential conflicts of interest.
For information regarding this article, E-mail:
rdg@liverpool.ac.uk
Copyright 2007 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000279193.23737.06

Crit Care Med 2007 Vol. 35, No. 9 (Suppl.)

illness. Clinical trials have found a mortality and morbidity

advantage with glutamine supplementation. The advantage
appears to be greater the more glutamine is given and greater
again when given parenterally. Various modes of action have
been postulated. Glutamine seems to have an effect on the
immune system, antioxidant status, glucose metabolism, and
heat shock protein response. However, the benefit of exogenous glutamine on morbidity and mortality is not universally
accepted. This review critically appraises the current clinical
evidence regarding glutamine supplementation in critical illness. (Crit Care Med 2007; 35[Suppl.]:S545S552)
KEY WORDS: critical illness; glutamine; heat shock protein; mortality; skeletal muscle

pairment of de novo synthesis in skeletal

muscle leading to a failure of systemic
delivery to other organs and a conditional
deficiency (1). The lung and the brain
also produce glutamine, but skeletal
muscle, by virtue of its size and its ability
to synthesize glutamine de novo, is the
most important source of glutamine for
the bloodstream. The initial response to
septic stress is to export glutamine to the
splanchnic bed and immune system from
the free amino acid pool in muscle. This
leads to protein breakdown and de novo
synthesis of glutamine, which may be as
much as 85% of the turnover (2) from the
released amino acids. Tumor necrosis
factor- (3) and endotoxin (4) have been
shown to increase glutamine synthetase
messenger RNA in both lung and muscle,
but in animals with cachectic muscle the
increases in glutamine synthetase protein
levels are seen predominantly in lung tissue, signifying its greater importance
when muscle mass is diminished. This
benefit is lost in the presence of concomitant lung disease.
The major fate of enteral dietary glutamine is to be extracted in the first pass
by the gut and liver (5). The intestinal
lumen can also transport glutamate in
large amounts and use it in the oxidative
processes or synthesis of proline, citrulline, arginine, and glutathione (6). Elsewhere in the body on the arterial interface, glutamine rather than glutamate is

the major transported substrate across

cell membranes. This may be the key to
the importance of the systemic plasma
levels and (parenteral) delivery of glutamine for many tissues. Not only do we
synthesize glutamine in many tissues,
but we also hold it free in solution in
skeletal muscle at a gradient of 32:1 over
plasma levels by active transport mechanisms.
This observation was first made by
Vinnars et al. (7), who showed that following surgery, trauma, or sepsis, the
free glutamine pool in muscle is reduced.
Despite the rapid decrease in the intramuscular concentration of free glutamine, transport out of muscle is maintained and clearance from the plasma by
other tissues is increased, indicating activated transport mechanisms (8). Detailed stable isotope studies of glutamine
metabolism in critically ill patients support the extensive and robust large animal studies that show net flux of glutamine from skeletal muscle to vital
organs. Jackson et al. (9) demonstrated in
newly admitted intensive care unit (ICU)
patients a similar production rate but increased metabolic clearance rate from
plasma, consistent with increased utilization by other tissues and only modest
correction of low plasma levels with 28g/day glutamine infusions (10). Later on
during an intensive care stay, the efflux of
glutamine cannot be maintained and
S545

plasma delivery declines. In children with

burns, the plasma levels of glutamine
were reduced, whole body flux of glutamine was 40% greater, but the turnover in the skeletal tissues was reduced
maintaining the net efflux near normal
(11). A decrease in muscle glutamine production was confirmed by Biolo et al. (12)
in a large study of 20 severely burned
patients 2 wks into their critical illness. It
is suggested that muscle has competing
demands to meet the increased requirement for systemic glutamine delivery vs.
the internal glutamate supply problems
for the transamination of pyruvate to alanine in the nonoxidative removal of pyruvate. This deficiency appears to be maintained even when moderate amounts of
glutamine are supplemented parenterally
(13). A further study investigated the
dose response of parenteral glutamine
supplementation. Plasma glutamine concentration responded by normalization of
plasma glutamine levels in a dosedependent way, while free muscle glutamine concentration, as well as muscle
protein synthesis and muscle protein
content, did not change significantly
(14). There is therefore strong evidence
to contend that glutamine should be regarded as a conditionally essential
amino acid in critical illness. Despite this
evidence, the view that glutamine is a
conditionally essential amino acid in critical illness has been challenged recently
(15). Whether we class the observed low
tissue and plasma concentrations as deficiency or merely as a response to critical
illness is probably secondary; more important is whether a low plasma and/or
tissue glutamine concentration has an effect on morbidity or mortality. This question was addressed by an observational
study from the Netherlands published in
2001 (16). In this study, plasma glutamine was measured in 80 critically ill
patients. A low glutamine concentration
was associated with higher mortality and
a trend toward higher severity scores. It
was further noticed that the low plasma
glutamine group was considerably older,
possibly consistent with a reduced muscle bulk. In the light of these findings, it
is interesting to remember that a low
body mass index is an independent predictor of excess mortality in multiple organ failure, and this becomes evident at
about 25 days into the illness (17). It is
worthy of note that under normal circumstances, glutamine is the most abundant nonessential free amino acid in the
body.
S546

Work from other researchers suggested that glutamine may work as a

pharmacologic agent at higher concentrations in a dose-dependent way. Certainly, animal works seem to suggest an
association between glutamine dose and
response (18), but this does not preclude
these effects alongside that of correcting
a deficiency.
The preceding observations raise several questions:
Can glutamine substitution normalize
plasma and/or tissue glutamine levels?
Can glutamine substitution influence
clinical outcome?
If so, is this effect seen in the elderly
too?

Clinical Outcome
The important question is whether exogenous glutamine provision will affect
outcome. However, to understand the
available data requires an appreciation of
the time scales and consequences that
could reasonably be expected. It is apparent when caring for patients under intensive care that some patients die early
from the failure of a single organ that was
involved in the primary pathology, and
this usually involves just the brain or the
heart or the lung. While patients die later
from multiple organ failure, which is associated with the development of secondary infections and is often a combined
system failure (e.g., lung, liver, and kidney), this is more a feature of nonrecovery from initial or maintained insults.
For instance, although an acute inflammatory response is an early feature of
most ICU presentations, it is now appreciated that an optimized immune system,
still capable of mounting normal inflammatory signaling, is a feature of survival.
Perhaps the greatest challenge with any
nutritional replacement therapy is to appreciate the likely time scales involved to
show a clinically meaningful response.
The analogy of scurvy is useful to consider. A benefit will be most strongly
shown in those who are most deficient for
a prolonged period sufficient to affect
many systems, for example, the most severely ill with gut failure dependent
solely on a glutamine-deficient parenteral
nutrition (analogous to 18th century
mariners needing to have been at sea for
6 months without fresh fruit or vegetables before scurvy developed). Glutamine
also needs to be given in a sufficient dose
(e.g., low-dose continuous enteral deliv-

ery may all be consumed in first pass

metabolism, analogous to the use for
many years of the low vitamin C-containing lime juice over the more effective
lemon or orange juice) and for sufficiently long periods (e.g., not continuing
glutamine after the initial treatment period in those not recovering within intensive care; glutamine needs to be given for
more than a few days and maintained
during the voyage to affect survival). Giving too little for too short a treatment
period may well have little impact on
survival; furthermore, choosing an early
end point (e.g., 28 days) may not disclose
a real effect. Evidence suggests that therapies that conserve or restore optimal
circulation (19) and metabolism (20)
have shown real outcome benefit. Providing the optimal nutritional environment
is central, and the glutamine story is an
illustration of such a deficiency arising
(21), whereby its correction improves
survival from multiple organ failure (22).

Parenteral Glutamine
Supplementation
Various trials have investigated the
role of enteral and parenteral glutamine
substitution in critical illness. One of the
earliest trials on glutamine substitution
in critical illness in a randomized controlled fashion was published in 1997 by
Griffiths et al (23). They investigated a
select group of 84 critically ill patients
who were unable to receive enteral feeding and for whom major sepsis was the
predominant feature. In a double-blind
manner, they were randomized to glutamine, substituted total parenteral nutrition (TPN), or isocaloric and isonitrogenous TPN. On an intention-to-treat
basis, a significantly reduced mortality
benefit after 6 months in the glutamine
group was observed, an outcome chosen
to better reflect the known time scales of
recovery of such patients. Survival in the
glutamine group was 24 of 42 compared
with 14 of 42 in the control group (23).
Figure 1 shows the survival curve from
ICU admission to 6 months.
Using previously unpublished data,
the same authors (24) showed that glutamine recipients have a significantly
lower incidence of catheter-related infections (p .026) but overall only a nonsignificant and modest reduction in acquired infections. Since the opportunity
for new infections is so high in these
patients, this is not surprising, but more
importantly there was a later reduction in
Crit Care Med 2007 Vol. 35, No. 9 (Suppl.)

Figure 1. Survival curves for study patients from intensive care unit (ICU) admission to 6 months. Survival
is similar for the first 20 days but then significantly decreases in the control parenteral nutrition group
compared with the glutamine parenteral nutrition group (14 of 42 vs. 24 of 42; p .049). The survival
curve from similar matched patients requiring total parenteral nutrition (TPN) before the study commenced is shown for comparison. Reproduced with permission from Griffiths et al (23).

infection. The difference in survival noted

was almost entirely explained by reduced
intensive care mortality from multiple
organ failure in those patients remaining
in ICU for a longer period and requiring
5 days of parenteral feed (p .05). In
these very sick patients, colonization
with Candida was high, but fewer glutamine recipients acquired infections after a longer time on feeding and none
died, whereas six control patients acquired Candida infections and died from
multiple organ failure (p .02). This is a
clinical illustration of how glutamine
may restore the impaired T-cell-mediated
acquired immunity and allow optimal recovery. There soon followed the largest
parenteral study to date, which was published in 1999 (25). In this study, 168
patients who needed parenteral nutrition
were randomized to either glutamine,
supplemented TPN, or control TPN of
isocaloric and isonitrogenous values.
This study could not show a significant
difference in 6-month mortality or infectious complications. However, there was
a nonsignificant trend toward improved
in-hospital mortality in medical and hematological patients in the glutamine
group. Major criticisms of this study were
a lack of patient homogeneity and the fact
that far fewer of the most severely ill
patients in intensive care (as in the previous study) and potentially at higher risk
of deficiency were recruited.
Two further studies used the dipeptide
alanyl-glutamine, which overcomes the
solubility and stability issues. In a French
Crit Care Med 2007 Vol. 35, No. 9 (Suppl.)

multicenter randomized control trial,

114 ICU patients predominantly undergoing complicated surgery or trauma
showed on intention-to-treat analysis a
significant reduction in complicated outcomes (41.4% vs. 60.7%; p .05) that
was predominately related to reduced infectious rate and pneumonias (26). There
was no difference in survival in this group
of patients in whom the age and predicted
risk of death were lower. The median
duration of feed was about 6 7 days, but
the maximum feed duration was limited
to only 10 days. This also may be critical
to any effect on outcome since it is possible that a longer period on the control
and treatment parenteral feeding is required for an effect on survival to become
apparent in those who were most deficient.
The time scale effect was emphasized by a
study involving 144 ICU patients in Germany (27). In this randomized but unblinded study, the investigators decided a
priori to analyze the data of 95 patients
treated for 5 days and 68 patients
treated for 9 days. Plasma glutamines
were low, as expected, and even by 5 days
had not returned to normal since the feeding only contained 0.2 g/kg body weight of
glutamine compared with 0.35 g/kg used in
earlier studies. There was a small but nonsignificant difference in clinical outcome in
those patients fed for a shorter period, but
for those fed for 9 days, the survival measured at 6 months was significantly better,
22 of 33 vs. 13 of 35 (p .05).
A recent systemic review tried to address important criticisms concerning

the paucity of trials and the small number of patients involved in these trials
(28). The authors used electronic databases to search for randomized controlled
trials of glutamine supplementation in
surgical and critically ill patients. The
authors identified 14 trials. When aggregated, glutamine supplementation was
associated with a risk ratio (RR) of 0.78
(95% confidence interval [CI], 0.58
1.04) for mortality. Glutamine supplementation was further associated with a
lower rate of infectious complications
(RR, 0.81; 95% CI, 0.64 1.00) and a
shorter hospital stay (2.6 days; 95% CI,
4.5 0.7). The mortality benefit was even
more striking in the trials that used the
parenteral route (RR, 0.71; 95% CI, 0.51
0.99) and higher glutamine concentrations (RR, 0.73; 95% CI, 0.531.00). The
addition of trials published more recently
has not altered the overall conclusion,
and when the three level 1 and five level
2 studies were aggregated, glutaminesupplemented parenteral nutrition was
associated with a significant reduction in
mortality in critically ill patients (RR,
0.67; 95% CI, 0.48 0.92, p .01) using a
range of glutamine of 0.2 0.57 g/kg/day
(29). The results of studies currently underway in North America and Scandinavia are awaited.

Enteral Glutamine
Supplementation
The evidence for enteral glutamine
substitution is less convincing so far. A
large study from western Australia randomized 363 relatively well-nourished
critically ill patients to an enteral supplement of about 19 g of glutamine per day
(30). Neither mortality (glutamine 15%
[27 of 179] vs. control 16% [30 of 184])
nor severe sepsis incidence (glutamine
21% [38 of 179] vs. control 23% [43 of
184]) was affected. As is typical in intensive care, about 8% of patients required
parenteral nutrition instead and did not
receive the feed. The lack of any effect on
mortality seems to be an observation consistent with previous lower dose enteral
glutamine studies and may reflect the
systemic availability of glutamine through
the enteral route that is too limited for it
to be sufficient to significantly influence
survival in the sicker patients.
This is probably not surprising if we
remember that rapidly dividing cells (enterocytes) use glutamine as an energy
source and so readily use enterally supplied glutamine. This would suggest that
S547

glutamine given enterally will not appear,

or will appear in a lesser amount, in the
systemic circulation, which in turn may
be the reason for its limited effect on
clinical outcome. This was convincingly
shown in a study from 2005 that compared enteral with parenteral glutamine
administration (31). In this study, 20 g of
alanine-glutamine dipeptide infusion was
given over 4 hrs. Plasma glutamine concentration rose significantly with enteral
and parenteral substitution but significantly more so when administration was
parenteral. These findings suggest the
need for relatively higher glutamine
doses, when given enterally, to achieve
the same systemic concentrations. Furthermore, only parenteral alanine-glutamine influenced the measured systemic
arginine concentration. The significance
of this observation remains to be seen.

Specific Circumstances
Infection. Critically ill patients are at
increased risk of sepsis, which is a major
cause of mortality in the ICU. Moreover, a
significant number of patients are admitted to intensive care due to sepsis as a
primary diagnosis. It is therefore not surprising that sepsis and its avoidance are a
major focus in current intensive care research. It has been suggested for some
time now that glutamine is a major fuel
supply for immune cells. This appears to
be the case for all immune-competent
cells. Moreover, optimal phagocytic and
secretory activity of immune cells may be
dependent on adequate glutamine supply
(32). Oehler et al. (33) investigated the
effect of glutamine depletion on human
leukocytes. They found that lymphocytes
were less able to produce an adequate
heat shock protein response to 42C heat
with a reduced glutamine concentration
of 0.125 mM, which is 25% of the physiologic glutamine level, at the time of the
stress response (33). A study from 2003
investigated the role of glutamine and
peripheral blood polymorphonuclear
cells. The investigators showed that increased glutamine levels 4 mM reduced
the tumor necrosis factor- release after
4 and 24 hrs of lipopolysaccharide stimulation (34). Furthermore, glutamine
concentrations of 4 mM led to an increase of heat shock protein after lipopolysaccharide stimulation. Various clinical studies have shown a benefit on
infectious complications in patients with
glutamine supplementation, although
others have not. A review from 2005 by
S548

Dhaliwal and Heyland (35) suggested glutamine supplementation in critical illness. The authors identified numerous
randomized controlled trials with reduced rates of infection in patients with
glutamine supplementation and concluded that enteral and parenteral glutamine supplementation is associated
with reduced infectious morbidity in critically ill patients (35).
Burn Injury. For some time now, various authors have concentrated on the
benefit of glutamine in patients with severe burn injuries. We know that patients
suffering from major burn injuries are in
an extreme catabolic state. Moreover,
burn patients are at increased risk of infectious complications due to the loss of
the normal barrier mechanism of the
skin. It is therefore not surprising that
glutamine appears to be an ideal and necessary compound of nutrition in severe
burn injury. In 2001, Wischmeyer et al.
(36) reported on 26 severely burned patients who received enteral nutrition plus
40 g of parenteral glutamine or an amino
acid control. The authors specifically
chose the parenteral route to guarantee
systemic delivery of glutamine. They
showed a significant reduction in mortality and Gram-negative bacteremia (36). A
Canadian study from 2003 investigated
the role of enteral glutamine substitution
(37). This double-blind trial comprised 45
patients with severe burn injuries (40%
total body surface area). Patients were
randomized either to receive enteral glutamine boluses (4.3 g every 4 hrs) or to
serve as isonitrogenous control. The investigators found a three-fold increase in
positive blood cultures in the control
group and worsened mortality (12 vs. 2
patients). A further randomized doubleblind controlled study from the same year
looked into continuous enteral glutamine
substitution in severely burned patients
(0.35 g/kg of body weight/day glutamine
vs. isocaloric and isonitrogenous control)
(38). The researchers recruited 40 severely burned patients with a total body
surface burn area between 50% and 80%.
Feed was started on day 1 after burn
injury. Full feeding was established at day
4 and continued until day 12 after burn
injury. The authors showed a significant
increase in the plasma glutamine concentration after day 12, a reduced infection
rate, a reduced length of hospital stay,
and an overall reduced hospital cost in
the glutamine group. However, no mortality benefit was observed. A further
study from 2005 compared enteral glu-

tamine substitution with isocaloric and

isonitrogenous control. The study
showed a reduced hospital stay but no
mortality benefit (39). A recent review
addressed the question of glutamine substitution in burn patients. The author
stated, Glutamine supplementation does
appear to confer significant clinical and
cost advantages in critical illness. Burned
patients may be one particular group who
benefit (40). However, large randomized
controlled trials are lacking. Further attention needs to be focused on the route
of administration and the duration of glutamine administration.

Glucose Metabolism
It has been suggested in the literature
that glutamine, as parenteral infusion,
can beneficially influence insulin-mediated glucose utilization (41) and in
healthy adults can beneficially influence
postprandial insulin action, glucose disposal, and fat oxidation (42). These findings reinforced the hope that glutamine
is beneficial during clinical situations associated with insulin resistance, which is
frequently seen in critical illness. Two
randomized controlled trials from 2006
investigated this hypothesis further. In
the large French randomized control trial
study discussed earlier (26), as well as
showing a substantially reduced infection
and pneumonia rate the investigators
found a significant reduction of hyperglycemia and a significant reduction in the
number of patients requiring insulin. An
elegant study specifically examined insulin resistance in trauma. The authors randomized 40 patients with multiple trauma
to receive either 0.4 g of glutamine per kg
of body weight per day or isocaloric and
isonitrogenous control (43). To assess insulin sensitivity, euglycemic clamp was
performed on day 4 and day 8. The investigators found that improved insulin sensitivity in multiple trauma patients was positively associated with parenteral glutamine
supplementation. In the light of these studies, it is probably reasonable to accept the
beneficial effect that glutamine has on insulin-dependent glucose metabolism. This
is clinically relevant when we review the
current evidence on glycemic control in
surgical and medical intensive care patients
and its importance in view of morbidity and
mortality (20, 44).

Antioxidant Effect
Reactive oxygen species are assumed
to play a key role in the underlying pathoCrit Care Med 2007 Vol. 35, No. 9 (Suppl.)

physiology of multisystem organ failure

in critically ill patients. When oxygen
availability is limited in the tissues of
vital organs due to hypoperfusion, the
cells shift from aerobic to anaerobic metabolism, thereby lowering the cellular
energy charge. As a result, increased
adenosine triphosphate hydrolysis, a subsequent increase in adenosine monophosphate levels, and an accumulation of
purine metabolites are found in ischemic
tissues. Furthermore, during activation
of the immune response, neutrophils,
macrophages, and other competent immune cells may activate a plasmamembrane-associated nicotinamide adenine dinucleotide phosphate (reduced
form) oxidase system, capable of oxidizing nicotinamide adenine dinucleotide
phosphate to nicotinamide adenine dinucleotide (oxidized form), leading to further generation of superoxide radicals.
Spontaneous dismutation of the superoxide radical generates hydrogen peroxide
and molecular oxygen at physiologic pH.
Reactive oxygen species not only lead to
direct damage of cellular components but
also trigger the release of cytokines that
further activate the inflammatory cascade
(45, 46). Glutathione is an important endogenous scavenger of reactive oxygen
species, and glutamine is an important
substrate for glutathione. Therefore, research has focused on the relationship
between glutamine and glutathione and
further on the effect of low glutamine
concentrations on glutathione concentrations during critical illness. In intensive care patients with septic complications following surgery, muscle free
glutamine is depleted to 25% of the
normal concentration (47). In parallel,
during the first week in the ICU, muscle
glutathione concentration is reduced to
the same level, or greater, compared with
patients undergoing elective surgery. Importantly, in this situation there is a significant correlation between muscle free
glutamine and muscle total glutathione
concentration as well as the ratio of oxidized glutathione to total glutathione (48).
Furthermore, the same group showed that
glutamine supplementation can attenuate
muscle glutathione depletion (49).

mation as seen during severe critical illness. An adequate HSP response is therefore believed to be critical for cell survival
in these circumstances. Skeletal muscle
normally adapts following stress, such
that it is protected against subsequent
damage (50). This adaptation occurs following a variety of insults. Free radicals
are being generated, which in turn lead
to a rapid adaptive response in the activity of protective enzymes, such as superoxide dismutase and catalase, and an in-

crease in the cellular content of HSPs

(50). An increase in these protective enzymes and HSPs protects the tissue
against subsequent exposure to damage
(51). All HSPs act to preserve cellular
integrity. Cells stressed by a sublethal
insult that induces the expression of
HSPs are rendered more resistant to subsequent extreme stress. One of the possible mechanisms underlying stress tolerance involves the concept that the proper
folding of proteins in a cell requires an

Heat Shock Protein

The expression of stress or heat shock
proteins (HSPs) is one of the most highly
conserved mechanisms of cellular protection and may be central to protecting
against the assault from systemic inflamCrit Care Med 2007 Vol. 35, No. 9 (Suppl.)

Figure 2. Top panel, heat shock protein (HSP) 1: function of HSPs in the unstressed cell. Bottom
panel, HSP2: protective effect of an increased content of HSPs in skeletal muscle. HsF1; heat shock
factor 1.

S549

intricate set of folding machinery known

as molecular chaperones. HSPs are believed to work as molecular chaperones.
Thus, when induced following cellular
stress, HSPs appear to repair denatured/
injured proteins or promote their degradation following irreparable injury (52)
(Fig. 2). The protective effect of increased
HSP concentration was very elegantly
shown in a severe sepsis model of SpragueDawley rats. Sepsis was induced by a twopuncture cecal ligation technique. At the
time of the operation, an adenovirus expressing HSP 70 (AdHSP) was administered via endotracheal tube. The sepsisinduced lung injury was markedly reduced,
as was mortality in these animals (53).
A recent study in severe trauma patients found a correlation between survival and the ability to mount an HSP
response, with a survival benefit in the
high HSP concentration group (54)
clearly suggesting that the HSP response
plays a significant role in critical illness.
Glutamine appears to regulate protein
turnover in cell cultures of myotubes,
increasing the half-life of long-lived proteins. This may be related to the increase
in HSP 70 (55). Furthermore, glutamine
appears to be a potent enhancer of the
stress response (56 58). Preliminary
work in a rodent sepsis model confirms
that systemic sepsis induces HSP 70 and
that glutamine infusions facilitate further
HSP expression. This is associated with a
striking preservation of the ability of
muscle to contract. Others have shown
that glutamine infusions, over a range of
doses (0.15 0.75 g/kg), are able to enhance HSPs in multiple organs of the rat
(18). This induction occurs as early as 1
hr postadministration and persists for up
to 72 hrs postadministration. The authors demonstrated that glutamine infusion before a septic insult was associated
with protection against endotoxin-induced septic shock in the rat and could
markedly decrease end-organ injury and
overall mortality. Further experiments illustrated that glutamine given after a
septic insult enhanced HSP 70 and 25
expressions, protected against acute lung
injury, and reduced end-organ injury and
overall mortality (59). The survival benefit from glutamine was abrogated if an
HSP inhibitor was administered. Indeed,
it has been suggested that glutamine deficiency renders the cells incapable of an
adequate HSP response (33). Consequently, it has been suggested that glutamine substitution influences the HSP
response in humans, and indeed the obS550

served survival benefit of glutamine

added to parenteral nutrition to meet a
developing deficiency in the critically ill
might reflect this. Moreover, it has been
demonstrated that glutamine substitution added to parenteral nutrition correlates with increased HSP 70 response in
the critically ill (60). It has been postulated that the severity of illness correlates
with the need for glutamine substitution.
This could be a further reason why enteral glutamine supplementation does
not appear to carry a significant benefit
compared with parenteral supplementation, as severity of illness appears to correlate with gastrointestinal failure.
Half of severely ill intensive care patients are 65 yrs old, with upward of
25% 75 yrs of age. The ability of cells to
induce HSPs following stress is reduced
in aged humans and animals. Tissues
from aged animals and blood cells from
elderly humans both show a reduced production of stress proteins following thermal stress (61). It has recently been confirmed that this attenuated response
occurs in skeletal muscle of aged rodents
following a physiologic stress. The HSP
70 content of resting skeletal muscle was
reduced in muscles from aged rodents,
and the production in response to a period of contractile activity was severely
blunted in comparison with young animals (62, 63). This lack of adaptation in
HSP content in the aged animals may be
related to a more general failure of adaptation to stress. Moreover, as mentioned
previously, it has been observed that a
low glutamine concentration might be
associated with older age (16). Furthermore, HSP response in trauma might be
blunted in older age (54). Evidence is still
lacking whether glutamine supplementation in this high-risk group can improve
plasma glutamine concentration, HSP response, and ultimately outcome.

CONCLUSION
Over the last 20 yrs, increasing evidence has emerged to support the use of
glutamine supplementation in critical illness. Clinical trials have found mortality
and morbidity advantages with glutamine
supplementation. The advantage appears
to be greater the more glutamine is
given. Furthermore, the advantage is
greater again when glutamine is given
parenterally. Various modes of action
have been postulated. Glutamine seems
to affect the immune system, antioxidant
status, glucose metabolism, and heat

shock protein response. However, all trials on the subject so far recruited an
unsatisfactory number of patients. This
fact, together with the findings of several
trials that could not demonstrate beneficial effects of glutamine supplementation
(30, 64, 65), warrants a large randomized
controlled trial (45), however difficult
that may be. It must not be forgotten,
however, that glutamine is a naturally
occurring amino acid that appears to
have a very favorable side-effect profile
even when given in large doses. This
would justify its use in critical illness
with the limited evidence available. Despite the brave undertaking of the large
trial by the Canadian Critical Care Trials
Network, further questions might not be
answered by this trial.
As mentioned, glutamine appears to
influence the HSP response. However,
the HSP response appears to be attenuated in the elderly. Can the administration of glutamine overcome the blunted
HSP response in the elderly, who clearly
are a high-risk group?
Furthermore, other researchers have
proposed a pharmacologic action of glutamine rather than the correction of a
deficiency. Certainly animal works seem
to suggest a dose response. Does glutamine have a dose response in humans,
and, if so, how do we titrate the required
dose?

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