Clinical Nutrition ESPEN 17 (2017) 75e85

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Clinical Nutrition ESPEN

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Original article

Glutamine dipeptide-supplemented parenteral nutrition improves the

clinical outcomes of critically ill patients: A systematic evaluation of
randomised controlled trials
Peter Stehle a, *, Bjo
€ rn Ellger b, Dubravka Kojic c, Astrid Feuersenger d, Christina Schneid d,
John Stover , Daniela Scheiner d, Martin Westphal e
d

a
Department of Nutrition and Food Sciences, University of Bonn, Bonn, Germany
b
Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Münster, Münster, Germany
c
Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany
d
Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany
e
Fresenius Kabi AG, Bad Homburg, Germany

a r t i c l e i n f o s u m m a r y

Article history:
Background & aims: Early randomised controlled trials (RCTs) testing whether parenteral nutrition
Received 5 July 2016
regimens that include glutamine dipeptides improves the outcomes of critically ill patients demon-
Accepted 26 September 2016
strated convincingly that this regimen associates with reduced mortality, infections, and hospital stays.
However, several new RCTs on the same question challenged this. To resolve this controversy, the present
Keywords:
meta-analysis was performed. Stringent eligibility criteria were used to select only those RCTs that tested
Meta-analysis
Critical illness the outcomes of critically ill adult patients without hepatic and/or renal failure who were haemody-
Glutamine namically and metabolically stabilised and who were administered glutamine dipeptide strictly ac-
Parenteral glutamine dipeptide cording to current clinical guidelines (via the parenteral route at 0.3e0.5 g/kg/day; max. 30% of the
Clinical outcome prescribed nitrogen supply) in combination with adequate nutrition.
Methods: The literature research (PubMed, Embase, Cochrane Central Register of Controlled Trials)
searched for English and German articles that had been published in peer-review journals (last entry
March 31, 2015) and reported the results of RCTs in critically ill adult patients (major surgery, trauma,
infection, or organ failure) who received parenteral glutamine dipeptide as part of an isoenergetic and
isonitrogenous nutrition therapy. The following data were extracted: infectious complications, lengths of
stay (LOS) in the hospital and intensive care unit (ICU), duration of mechanical ventilation, days on
inotropic support, and ICU and hospital mortality rates. The selection of and data extraction from studies
were performed by two independent reviewers.
Results: Fifteen RCTs (16 publications) fulfilled all selection criteria. They involved 842 critically ill pa-
tients. None had renal and/or hepatic failure. The average study quality (Jadad score: 3.8 points) was well
above the predefined cut-off of 3.0. Common effect estimates indicated that parenteral glutamine
dipeptide supplementation significantly reduced infectious complications (relative risk [RR] ¼ 0.70, 95%
CI 0.60, 0.83, p < 0.0001), ICU LOS (common mean difference [MD] 1.61 days, 95% CI 3.17, 0.05,
p ¼ 0.04), hospital LOS (MD 2.30 days, 95% CI 4.14, 0.45, p ¼ 0.01), and mechanical ventilation
duration (MD 1.56 days, 95% CI 2.88, 0.24, p ¼ 0.02). It also lowered the hospital mortality rate by
45% (RR ¼ 0.55, 95% CI 0.32, 0.94, p ¼ 0.03) but had no effect on ICU mortality. Visual inspection of funnel
plots did not reveal any potential selective reporting of studies.
Conclusions: This meta-analysis clearly confirms that when critically ill patients are supplemented with
parenteral glutamine dipeptide according to clinical guidelines as part of a balanced nutrition regimen, it
significantly reduces hospital mortality, infectious complication rates, and hospital LOS. The latter two

Abbreviations: Ala, alanine; APACHE, acute physiology and chronic health evaluation; CI, confidence interval; df, degree of freedom; Gln, glutamine; Gly, glycine; LOS,
length of stay; MD, common mean difference; N, nitrogen; PN, parenteral nutrition; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analysis; RCT,
randomised controlled trial; RR, risk ratio; RRT, renal replacement therapy; SAPS, simplified acute physiology score; SOI, severity of illness; TPN, total parenteral nutrition.
* Corresponding author. Department of Nutrition and Food Sciences e Nutritional Physiology, University Bonn, Nußallee 9, D-53115 Bonn, Germany. Fax: þ49 228 733217.
E-mail addresses: pstehle@uni-bonn.de (P. Stehle), bjoern.ellger@ukmuenster.de (B. Ellger), dubravka.kojic@med.uni-heidelberg.de (D. Kojic), astrid.feuersenger@
fresenius-kabi.com (A. Feuersenger), Christina.schneid@fresenius-kabi.com (C. Schneid), john.stover@fresenius-kabi.com (J. Stover), daniela.scheiner@fresenius-kabi.com
(D. Scheiner), martin.westphal@fresenius-kabi.com (M. Westphal).

http://dx.doi.org/10.1016/j.clnesp.2016.09.007
2405-4577/© 2016 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
76 P. Stehle et al. / Clinical Nutrition ESPEN 17 (2017) 75e85
effects indicate that glutamine dipeptide supplementation also confers economic benefits in this setting.
The present analysis indicates the importance of delivering glutamine dipeptides together with adequate
parenteral energy and nitrogen so that the administered glutamine serves as precursor in various
biosynthetic pathways rather than simply as a fuel.
© 2016 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights
1. Introduction
Apart from its role as building block for the endogenous protein
synthesis, the amino acid glutamine (Gln) is the transporter ni-
trogen between organs, regulates amino acid metabolism, serves as
metabolic fuel for rapidly proliferating cells, and is a precursor of
bioactive metabolites [1e4]. Since Gln can be endogenously syn-
thesized de novo and released by protein hydrolysis, it is classified
as a dispensable nutrient for healthy humans. However, in severe
disease states (e.g., trauma, abdominal major surgery, and burns),
the stress-mediated hormonal changes that develop alter Gln
metabolism in the whole body [5e9]: as a result, various organs
(e.g., gut, liver, and kidneys) and cells (e.g., enterocytes and
immunocompetent cells) need more Gln for the necessary syn-
thesis of acute-phase proteins and radical-scavenging metabolites
such as glutathione. Since the endogenous capacity of the body to
release Gln generally cannot adapt to meet these increased needs,
the metabolically stressed body becomes depleted of Gln, as indi-
cated by marked decreases of intracellular Gln in the muscle tissue
and, to a lower extent, in plasma [10]. This depletion in turn asso-
ciates with metabolic impairment such as insufficient protein
synthesis; most importantly, it worsens the clinical outcomes of
severely ill patients [9e13]. Consequently, Gln is considered to be
an indispensable substrate in the hypermetabolic situations that
characterize critical illness [4,11e13]. Because of galenic reasons,
however, the so-called “standard” amino acid solutions for
parenteral nutrition (PN) therapy are free of Gln. Consequently, a
total PN regimen administrating even high doses of such a standard
amino acid preparation (>1.5 g/kg BW/d) cannot prevent Gln
depletion [13].
Beginning in the 1980s, randomised controlled trials (RCTs)
were performed to evaluate whether parenteral supplementation
with nutritive amounts of a Gln source (about 10e12 g/day) would
prevent or reduce the Gln depletion in various PN-requiring patient
groups and improve their outcomes. These RCTs were mainly single
centre trials and the supplemented Gln source was either free Gln
(bed-side preparation due to its limited chemical stability) or stable
Gln dipeptides in ready-to-use solutions [14e16]. Consistent with
the working hypotheses of these early RCTs, Gln supplementation
ameliorated the disease-specific Gln depletion compared to stan-
dard treatment. This in turn improved various functions (e.g.,
maintenance of gut barrier function and gut-associated lymphoid
tissue) and strengthened the biochemical pathways needed to fight
the disease-associated metabolic stress (e.g., the cellular synthesis
of short-life proteins). Most importantly, it reduced mortality and
morbidity rates and the length of hospital stay (LOS) [17e19]. These
RCTs led to changes in international guidelines, which then started
to recommend that parenteral delivery of Gln dipeptides should be
part of the nutritional care in critical illness [20,21].
Within the last decade, several single and multi-centre RCTs that
tested the usefulness of Gln-supplemented PN in various patient
groups and following various designs have been performed.
Recently, three meta-analyses have been initiated with obviously
lacking consistency and only partly supporting the earlier recom-
mendation for Gln use in critically ill patients [22e24]. These
reserved.
discrepancies may reflect some weaknesses in the meta-analysis
criteria that determined study inclusion. Most importantly, these
meta-analyses included the RCTs that used free Gln. This is prob-
lematic because most of these studies did not indicate the “true”
Gln content in the solutions before administration. Moreover, free
Gln and Gln dipeptides may differ in terms of their kinetics, which
in turn may influence the degree of Gln uptake by the target sites.
Thus, studies that used free Gln may not be equivalent to those that
employed Gln dipeptide; meta-analyses should consider these RCTs
separately. In addition, two of the three recent meta-analyses,
namely, those by Bollhalder et al. [23] and Tao [24], included both
critically ill and post-surgery patients in their cohorts. However,
these patient groups vary markedly in terms of clinical outcomes,
especially mortality and morbidity rates, and thus may not be
directly comparable. This suggests that RCTs that employed mix-
tures of these patient groups to evaluate the effect of Gln supple-
mentation on these outcome variables may suffer from bias.
These shortcomings encouraged us to perform the present
meta-analysis which focused specifically and stringently on only
those RCTs that examined the outcomes of critically ill adult pa-
tients without hepatic and/or renal failure who were haemody-
namically and metabolically stabilised and who were administered
glutamine dipeptide strictly according to current clinical guidelines
(i.e., via the parenteral route at 0.3e0.5 g/kg/day; max. 30% of the
prescribed nitrogen supply) in combination with adequate nutri-
tion. The control group received isoenergetic and isonitrogenous
supplements without Gln dipeptide supplementation.
2. Methods
This meta-analysis was performed and reported according to
the PRISMA (Preferred Reporting Items for Systematic Reviews and
Meta-Analysis) guideline [25].
2.1. Identification of potentially eligible studies
The systematic literature search (PubMed, Embase, and the
Cochrane Central Register of Controlled Trials) sought to identify all
eligible English and German articles that had ever been published
in peer-review journals (last entry March 31, 2015). The following
search terms were used. At least one of the terms in each of the
following four lists had to be present in the title and/or abstract of
the article: (1) ‘randomized’, ‘randomised’, ‘clinical trial’, ‘clinical
study’, (2) ‘critical ill’, ‘critically ill’, ‘critical illness’, ‘critical care’,
‘intensive care’, ‘intensive care units’, ‘surgery’, ‘traumatic injury’,
‘infection’, ‘organ failure’, ‘trauma’, ‘ICU’, (3) ‘nutrition’, ‘nutritional
support’, ‘supplementation’, ‘parenteral nutrition’, ‘parenteral
nutrition solution’, ‘supplemental parenteral’, ‘total parenteral’,
‘parenteral’, ‘intravenous’, ‘i.v.’, ‘iv’, (4) ‘glutamine/glutamin’, ‘GLN’,
‘GLN dipeptide’, ‘glutamine dipeptide/glutamin-dipeptid’, ‘alanyl-
glutamine’, ‘Ala-Gln’, ‘glycyl-glutamine’, ‘Gly-Gln’. In addition, the
reference lists of 33 review articles identified during the literature
search were checked to ensure complete identification of eligible
articles.
 P. Stehle et al. / Clinical Nutrition ESPEN 17 (2017) 75e85
2.2. Study selection
All original studies from peer-reviewed journals that met the
following eligibility criteria were considered in the meta-analysis:
a) study design: prospective RCTs (blinded and non-blinded) that
compared parenteral treatment with glutamine dipeptides to
parenteral treatment without any glutamine source, b) treatments:
the intervention consisted of parenteral glutamine dipeptides in
combination with supplemental or total PN for at least 3 days while
the control treatment consisted of isoenergetic and isonitrogenous
supplements (amino acids other than Gln) combined with sup-
plemental or total PN for at least 3 days; thus, in both treatments,
adequate energy and protein (nitrogen, N) delivery was prescribed,
c) population: critically ill (see below) adult (18 years) patients,
and d) outcomes: at least one of the following outcomes of interest
was reported: infectious complications, hospital or intensive care
unit (ICU) LOS, duration of mechanical ventilation, and/or hospital
or ICU mortality.
Patients were defined as critically ill if they had major surgery,
trauma, infection (e.g., pneumonia), or organ failure that required
measures to support vital functions (e.g., mechanical ventilation,
haemodynamic stabilisation) for more than 72 h. In articles where a
proper definition of the term ‘critically ill’ was not given, the patient
characteristics were assessed and categorised by a medical pro-
fessional. Hints found that patients with hepatic and/or renal fail-
ure gave rise to exclude the article from analysis. Kidney failure
(e.g., loss of the functional capacity of the kidneys) and acute liver
failure (with haemorrhage and shock) compromise the metabolic
handling of supplemental Gln and thus are a contraindication to
Gln (dipeptide) supplementation [20,21].
In articles where the ages of the individual patients at study
entry were not reported, the mean ages of the study groups were
examined: when both study groups had an average age of 30
years, the study was considered to be eligible for inclusion.
Two independent and experienced reviewers manually
screened the title and/or abstract of the articles that were flagged
during the search for adherence to the above eligibility criteria.
When the reviewers disagreed about the eligibility of a particular
article, the whole text of the article was read and a consensus de-
cision was reached.
The scientific quality of the trials included was evaluated
calculating the so called Jadad score. This simple marker of study
quality was described by Moher et al. and is based on five questions
on randomisation, blinding, and dropouts [26]. Scores above a
defined cut-off of 3.0 indicate that reliable conclusions can be
drawn.
2.3. Data extraction
Data extraction d using a predefined database form considered
infectious complications, ICU stay, hospital stay, duration of me-
chanical ventilation, duration of inotropic support, and ICU and
hospital mortality rates. A second independent experienced
reviewer controlled the data extraction process for quality.
Extraction was only performed when comprehensive data for the
whole study population were clearly identifiable. Thus, if only the
data of one study group or single cases were reported, the endpoint
was not included in our analyses.
If the number of patients with infectious complications was
presented in separate time intervals or the number of patients was
only quantified according to the type of infectious complication, the
total number of patients with any infectious complications was
estimated as the harmonic mean of all possible outcomes (rounded
to the nearest integer). The mean ± standard deviation LOS (days)
was extracted from all publications. When LOS was expressed as
77
median and interquartile range instead of mean and standard de-
viation, a symmetrical and approximately normal data distribution
(unless indicated otherwise in the publication) was assumed. Thus,
the median was used without correction in the meta-analysis and
the width of the interquartile range (third quartileefirst quartile)
divided by 1.35 served as an estimate of the standard deviation.
When only ranges (minimum to maximum) of LOS were given, the
width of the range divided by 4.66 (which assumes that 98% of the
values are located within the range) served as an estimate of the
standard deviation (see above).
2.4. Statistical methods
For the continuous endpoints (length of ICU stay, length of
hospital stay, and duration of mechanical ventilation), the effect
size was the difference in means (MD). For the binary endpoints
(experienced any infectious complications, ICU mortality, and
hospital mortality), the effect size was the relative risk (RR).
Fixed effect models were used for common point estimate and
the associated 95% confidence intervals (CI) derivation. The com-
mon effect estimate was calculated as the weighted average of the
effects estimated in the individual studies. For continuous end-
points, the inverse variance approach was applied, namely, the
weight for each study was the inverse of the variance of the effect
estimate. For binary endpoints, the ManteleHaenszel approach was
used [27].
In the case of zero cells (e.g., no events in one treatment group)
and when the RR was undefined, a zero cell correction was used
(addition of 0.5 to all zero cells of the contingency table of the
study).
The null-hypothesis of this meta-analysis was that there was no
difference between the intervention and control arms. This null-
hypothesis was tested for each variable at the 5% significance
level according to the meta-analytical approach in exploratory
manner. No adjustments of the significance level were made for the
comparisons for multiple endpoints because all meta-analyses are
of exploratory nature. Thus, p-values were intended to be inter-
preted in a descriptive and supportive manner. In other words, a p-
value of <0.05 indicates only that there is a small likelihood that the
observed difference occurred by chance: it cannot be interpreted as
a valid type I error probability.
A heterogeneity test (weighted ManteleHaenszel chi-squared
test) was conducted for each meta-analysis. When the results
were significant (p  0.05), the possible causes were investigated
and discussed.
All statistical analyses were performed by using the software
package RevMan 5.2 (The Nordic Cochrane Centre, Copenhagen,
The Cochrane Collaboration, 2013).
Funnel plots were inspected visually for asymmetric distribu-
tion that could be caused by the non-publication of small studies
with contrary results or decreasing effects with increasing sample
size. Furthermore, to determine the risk of bias within studies, in-
formation about the concealment of randomisation, blinding, and
funding of the individual studies was collected to measure the
Jadad score (see above) [26].
3. Results
3.1. Study identification and selection
As outlined in Fig. 1, 2035 publications were retrieved by the
literature search. After removing duplicates, 1422 publications
were screened. Of these, 192 articles were identified as potentially
eligible for inclusion. After careful examination, 176 publications
were excluded because they were not original research articles
78 P. Stehle et al. / Clinical Nutrition ESPEN 17 (2017) 75e85
Fig. 1. Flow diagram depicting the selection of the studies.
(n ¼ 75), they lacked information regarding predefined endpoints
(n ¼ 26), the article was not in English or German (n ¼ 15), the
prescribed energy and N intake of the intervention and/or control
treatments was inadequate (n ¼ 13), patients below 18 years were
included (n ¼ 9), the data had already been reported in another
article (n ¼ 8), other Gln sources than dipeptide were administered
(n ¼ 4), the full-text article was not available (n ¼ 3), patients who
did not meet our criteria for “critical illness” were included (n ¼ 18),
the comparator treatment was unsuitable or lacking (n ¼ 2), the Gln
dipeptide was not administered parenterally (n ¼ 2), and/or the
study design was retrospective (n ¼ 1).
Finally, we included 16 publications on 15 RCTs (Duska et al.
reported different aspects of the same RCT in two publications). The
mean Jadad score of all studies was 3.8 points (single scores not
shown).
3.2. Study characteristics
The details of the 16 publications are summarized in Table 1. The
studies encompassed 842 critically ill patients whose diagnosis
ranging from severe sepsis, secondary peritonitis, acute severe
pancreatitis, and multiple trauma to severe burns. Dechelotte et al.
[30] and Grau et al. [36] reported both the intention-to-treat (ITT)
and per-protocol (PP) results; in both cases, we selected the PP
population data. In the study by Duska et al. [31,32], only inter-
vention group 1 (peptide supplementation) and control group 3
data were included in our analysis. This was because the patients in
intervention group 2 received (in addition to Gln peptide) growth
hormone treatment.
In all but one of the publications, Gln peptide was administered
according to patient weight; only Cai et al. [28] administered 10 g
dipeptide per day irrespective of patient weight. Gln dipeptides
were administered at a dose of 0.3e0.5 g/kg/day. With the excep-
tion of Dechelotte et al. [30], who administered a solution of alanine
and proline, the isonitrogenous control medication was prepared
by increasing the amount of “standard” amino acid solution used in
PN. In seven studies, the feeding protocol duration was fixed and
ranged between 5 (Pe rez-Barcena et al. [38,39]) and 14 days (Cai
et al. [28]). In another seven studies, the duration of feeding was
based on the clinical situation and ranged from 3 (Grau et al. [36])
to 21 days (Estivariz et al. [33]). In the remaining study (Sahin et al.
[40]), the feeding period was not described. In all but one study, the
PN including Gln dipeptide started immediately after admission to
the ICU; the exception was the study reported by Duska et al.
[31,32], where PN including Gln dipeptide started only 4 days after
trauma onset.
3.3. Infectious complications
Twelve studies reported the infectious complications. The pa-
tients (n ¼ 643) were predominantly affected by pneumonia,
wound infections, bacteremia, fungemia, catheter sepsis, urinary
tract infections, abscesses, and cellulitis. In 11 studies, the patients
receiving parenteral Gln dipeptide supplementation generally had
lower total infectious complication rates than the patients in the
control group (Fig. 2). In terms of the common effect estimate, Gln
supplementation significantly reduced the rate of infectious com-
plications (RR 0.70, 95% CI 0.60, 0.83, p < 0.0001, heterogeneity
I2 ¼ 31%, p ¼ 0.15).
Table 1
Characteristics of the trials that were included in the meta-analysis.

Study No. of patients f/m Blinded Illness/Indication Primary endpoint(s) Feeding as prescribed (total intake Intervention Nitrogen source Duration of
defined from PN and enteral) control group intervention

Cai et al. 2008 [28] 20/90 n.r. Severe sepsis No En: basal energy expenditure 10 g Ala-Gln/day AA solution 2 weeks
(25e26 kcal/kg/day) Pr:
1.5e1.6 g AA/kg/day
Çekmen et al. 2011 [29] 15/15 Yes Critical illness No En: >80% of basal energy 0.5 g Ala-Gln/kg/day AA solution 5 days
expenditure (Kabiven®)
Pr: 1.5 g AA/kg/day
0.7 g alanine þ 5 days

P. Stehle et al. / Clinical Nutrition ESPEN 17 (2017) 75e85

Dechelotte et al. 2006 [30] 30/84 Yes Critical illness Nosocomial/ En: 37.5 kcal/kg/day 0.5 g Ala-Gln/kg/day
wound infections Pr: 1.5 g AA/kg/day proline/kg.d
Duska et al. 2008 [31,32] 6/24 Yes Critical illness No En: 80% of measured energy 0.3 g/Ala-Gln/kg/day AA solution 2 weeks
expenditure
Pr: 1.5 g AA/kg/day
Estivariz et al. 2008 [33] 19/40 Yes Critical illness after surgery Nosocomial infections En: 1.3  basal energy 0.5 g Ala-Gln/kg/day AA solution up to 21 days
expenditure (Clinisol®)
Pr: 1.5 g AA/kg/day
Fuentes-Orozco et al. 2004 [34] 13/20 Yes Secondary peritonitis Infectious morbidity En: 30 kcal/kg/day 0.4 g Ala-Gln/kg/day AA solution 10 days
Pr: 1.5 g AA/kg/day
Fuentes-Orozco et al. 2008 [35] 20/24 Yes Acute severe pancreatitis Infectious morbidity En: 30 kcal/kg/day 0.4 g Ala-Gln/kg/day AA solution 10 days
Pr: 1.5 g AA/kg/day
Grau et al. 2011 [36] 45/82 Yes Critical illness Nosocomial infections En: 25 kcal/kg/day 0.5 g Ala-Gln/kg per day AA solution 3 days, up
Pr: 1.6 g AA/kg/day to 9 days
Grintescu et al. 2015 [37] 19/63 No Multiple trauma Blood glucose level En: 25 kcal/kg/day 0.5 g Ala-Gln/kg/day AA solution 7 days
Pr: 1.5 g AA/kg/day
rez-Ba
Pe rcena et al. 2008 [38] 22/8 Yes Critical illness No En: 28 kcal/kg/day 0.5 g Ala-Gln/kg/day AA solution 5 days
Pr: 1.75 g AA/kg/day
rez-Ba
Pe rcena et al. 2010 [39] 6/37 Yes Trauma No En: 28 kcal/kg/day 0.5 g Ala-Gln/kg/day AA solution 5 days
Pr: 1.75 g AA/kg/day
Sahin et al. 2007 [40] 40 (total; sex n.r.) n.r. Acute pancreatitis No En: basal energy requirements 0.3 g Ala-Gln/kg/day AA solution 10-11 days
(24e25 kcal/kg/day)
Pr: 1.4 g AA/kg/day
Xian-li et al. 2004 [41] 19/22 n.r. Severe acute pancreatitis No En: 25 kcal/kg/day 0.4 g Ala-Gln/kg/day AA solution 2 weeks
Pr: 1.25 g AA/kg/day
Zhou et al. 2004 [42] 30 (total; sex n.r.) Yes Severe burns No En: 35 kcal/kg/day 0.5 g Ala-Gln/kg/day AA solution 12 days
Pr: 1.6 g AA/kg/day (NovaminR)
Ziegler et al. 2005 [43] 10/19 Yes Critical illness No En: 1.3  basal energy expenditure 0.5 g Ala-Gln/kg/day AA solution 7 days
Pr: 1.5 g AA/kg/day (Clinisol®)

PN: parenteral nutrition; AA: amino acids; Ala-Gln: L-alanyl-L-glutamine (Dipeptiven®); Pr: Protein; En: energy; ICU: intensive care unit; n.r.: not reported.

79
80 P. Stehle et al. / Clinical Nutrition ESPEN 17 (2017) 75e85

Fig. 2. Forest plot comparing the patients with parenteral GLN dipeptide supplementation to the patients receiving isoenergetic and isonitrogenous control treatment in terms of
infectious complications. Gln: glutamine; MeH: ManteleHaenszel approach; CI: confidence interval; df: degree of freedom.

3.4. LOS in ICU and hospital
The LOS in the ICU was reported in 11 trials. The study of Duska
et al. had to be excluded because they only reported the median
LOS in the corresponding publications [31,32]. The mean ICU LOS in
the remaining 10 trials (599 patients) ranged between 10 and 25
days. Six studies reported that the critically ill patients who
received Gln dipeptides had a significantly shorter stay in the ICU
than the patients receiving the control regimen. In two other
studies, the two groups had equivalent ICU LOS. In the remaining
two publications, the Gln dipeptide-supplemented treatment
associated with a longer ICU stay. Altogether, the studies showed
that the Gln dipeptide supplementation significantly reduced the
LOS in the ICU by approximately 1.5 days (MD 1.61, 95% CI 3.17,
0.05, p ¼ 0.04, heterogeneity I2 ¼ 0%, p ¼ 0.78) (Fig. 3).
Hospital LOS was reported in 11 studies (538 patients) and the
means ranged from 15 to 45 days. All but three studies reported
that the Gln group had a significantly shorter LOS in the hospital
than the control group. Overall, the Gln group spent 2.3 fewer days
in hospital than the control group (MD 2.30, 95% CI 4.14, 0.45,
p ¼ 0.01, heterogeneity I2 ¼ 0%, p ¼ 0.73) (Fig. 4).
3.5. Duration of mechanical ventilation
Nine studies evaluated the duration of mechanical ventilation.
The results of Duska et al. [31,32] had to be excluded due to lack of
information with regard to the precision of data collection. In the
remaining nine studies (n ¼ 579), the patients receiving parenteral
Gln dipeptides required mechanical ventilation for a significantly
shorter duration: their mean duration of mechanical ventilation
was approximately 1.5 days shorter than that of the control group
(MD 1.56, 95% CI 2.88, 0.24, p ¼ 0.02, heterogeneity I2 ¼ 0%,
p ¼ 0.74) (Fig. 5).
3.6. Mortality rates in the ICU and during hospital stay
Seven studies (535 patients) reported the ICU mortality rate;
significant effects of Gln dipeptide treatment could not be observed
(RR 0.90, 95% CI 0.61, 1.31, p ¼ 0.57, heterogeneity I2 ¼ 0%, p ¼ 0.76)
(Fig. 6).
The meta-analysis of hospital mortality rates (seven studies
including 290 patients reported these data) showed that there was
a strong tendency for the patients receiving Gln dipeptides to have
less hospital mortality than the controls (RR 0.56, 95% CI 0.31, 1.02,
p ¼ 0.06, heterogeneity I2 ¼ 8%, p ¼ 0.37).
Notably, the study performed by Çekmen et al. [29] was not
included in the latter analysis because it was unclear whether the
number of deaths that was reported referred to deaths in the ICU
and/or during the total hospital stay. Assuming that the number of
deaths were hospital stay deaths and including this figure in our
analysis of hospital mortality rates (total number of patients
increased to 320), the Gln-treated patients had a significantly lower
hospital mortality rate than the control group (RR 0.55, 95% CI 0.32,
0.94, p ¼ 0.03, heterogeneity I2 ¼ 0%, p ¼ 0.48) (Fig. 7).

Fig. 3. Forest plot comparing the patients with parenteral GLN dipeptide supplementation to the patients receiving isoenergetic and isonitrogenous control treatment in terms of
intensive care unit (ICU) length of stay. Gln: glutamine; IV: inverse variance approach; CI: confidence interval; df: degree of freedom.
 P. Stehle et al. / Clinical Nutrition ESPEN 17 (2017) 75e85 81

Fig. 4. Forest plot comparing the patients with parenteral GLN dipeptide supplementation to the patients receiving isoenergetic and isonitrogenous control treatment in terms of
mean length of stay in hospital. Gln: glutamine IV: inverse variance approach, CI: confidence interval, df: degree of freedom.

Fig. 5. Forest plot comparing the patients with parenteral GLN dipeptide supplementation to the patients receiving isoenergetic and isonitrogenous control treatment in terms of
duration of mechanical ventilation (days). Gln: glutamine; IV: inverse variance approach; CI: confidence interval; df: degree of freedom.

Fig. 6. Forest plot comparing the patients with parenteral GLN dipeptide supplementation to the patients receiving isoenergetic and isonitrogenous control treatment in terms of
intensive care unit (ICU) mortality. “Events” refers to the number of patients who died. Gln: glutamine; MeH ManteleHaenszel approach; CI: confidence interval; df: degree of
freedom.

Fig. 7. Forest plot comparing the patients with parenteral GLN dipeptide supplementation to the patients receiving isoenergetic and isonitrogenous control treatment in terms of
hospital mortality. “Events” refers to the number of patients who died. Gln: glutamine; MeH ManteleHaenszel approach; CI: confidence interval; df: degree of freedom.
82 P. Stehle et al. / Clinical Nutrition ESPEN 17 (2017) 75e85

3.7. Risk of bias across the studies 4. Discussion

Visual inspection of funnel plots did not reveal any potential
selective reporting of studies. Indeed, for all endpoints, the
graphical displays of the effect estimate versus the standard error
were very consistent with the expected funnel-shaped distribution
(Fig. 8).
In our meta-analysis, we included all eligible RCTs that had been
published up until 2015 and that had compared critically ill pa-
tients who received Gln dipeptides as part of a prescribed PN
therapy to those whose isonitrogenous and isoenergetic therapy
did not include glutamine. The aim was to rigorously examine

Fig. 8. Funnel plots for (a) infectious complications, (b) length of stay in the intensive care unit, (c) hospital length of stay, (d) duration of mechanical ventilation, (e) mortality in the
intensive care unit, and (f) mortality in the hospital. RR: relative risk; MD: mean difference; SE: standard error.
 P. Stehle et al. / Clinical Nutrition ESPEN 17 (2017) 75e85
previous claims, namely, that Gln (dipeptide) administration in
critically ill patients reduces their infectious complication rates,
length of hospital stay, need for mechanical ventilation, and hos-
pital mortality rates. These findings had led to the widely held
notion that supplying parenteral Gln dipeptide in nutritive
amounts can, at least in part, meet the increased demand for Gln in
hypercatabolic situations and can thereby support the endogenous
reaction towards life-threatening metabolic stress. This notion was
incorporated in international guidelines for critical care nutrition
[18,20,21], after which parenteral Gln supplementation was
accepted as a standard of care and became practised internationally
in clinical situations.
These scientifically sound recommendation was questioned
when the results of REDOXS, an international multi-centre RCT that
were published in 2013 [44e46]. As a consequence, considerable
uncertainty about the general need for Gln supplementation in
critically ill patients grew up amongst clinicians [47,48]. The
REDOXS study assessed whether early treatment of patients with
multi-organ failure with Gln administered via both the parenteral
and enteral routes influenced ICU mortality. It showed that this
treatment regime did not have any beneficial effects on ICU mor-
tality and subgroup analyses even suggested that it had harmful
effects under specific conditions [44]. However, it should be noted
that in that trial, Gln was delivered via a “pharmacological”
approach, namely, it was not combined with adequate energy and
nitrogen intake. Moreover, the overall dose that each patient
received exceeded 0.5 g/kg/day, which is the upper limit that was
studied in the previous studies. Moreover, one-third of the patients
had renal dysfunction, which is a clear contraindication for very
early nutrition and the use of glutamine. Finally, the subgroup
analyses that suggested such Gln therapy could be harmful in
certain settings were inadequate: the sample sizes were too small
and the analyses were post-hoc analyses. Given these limitations of
the REDOXS trial, it is surprising that it led to widespread questions
about the use of Gln as part of a balanced parenteral nutrition
therapy.
To clarify this suddenly unclear situation, several meta-analyses
on the effect of parenteral Gln supplementation in critically ill pa-
tients were performed and reported in 2013e2014. In the meta-
analysis of Bollhalder et al. [23], 40 RCTs that involved 3107 criti-
cally ill or post-surgical patients were assessed. They found that
parenteral Gln supplementation significantly reduced infections
and length of hospital stay. However, although the treatment also
tended to reduce the short-term mortality, this difference did not
achieve statistical significance. Nevertheless, when only the trials
that evaluated supplemental Gln doses of >0.2 g/kg/day (in accor-
dance with current evidence-based recommendations such as
those by ESPEN [20]) were studied, the reduction in short-term
mortality became significant (p ¼ 0.003) along with the reduc-
tion in infections (p ¼ 0.006) and hospital LOS (p ¼ 0.001). These
observations were true for all patient populations, namely, the
post-surgical, critically ill, and mixed cohorts. Similarly, in 2014,
Wischmeyer et al. reported their meta-analysis of 26 well-designed
trials that were published between 1997 and 2012 and involved
2484 critically ill patients. This analysis indicated the treatment
significantly reduced hospital mortality and LOS [22]. In the same
year, Tao et al. [24] reported their Cochrane database review of RCTs
that had been published up until May 2013. They found that Gln
supplementation in critically ill and/or post-surgical patients
reduced infection rates, number of days on mechanical ventilation,
and hospital LOS but had no effect on short-term mortality. How-
ever, a subgroup analysis of the studies that employed intravenous
Gln revealed that it significantly reduced short-term mortality,
both during the hospital stay and within the first month [24].
However, although these meta-analyses are generally consistent
83
with the position taken by the medical community before the
REDOXS trial was published, they all suffer from design weak-
nesses. For example, trials that were performed with both post-
surgical and critically ill patient populations were included.
Moreover, trials that used free Gln were considered: chemical
instability of free Gln may, however, lead to a lower Gln intake as
prescribed which could essentially bias the therapeutic effects. For
the cellular uptake of Gln dipeptide, specific and highly effective
transport systems are available [49]. Thus, uptake kinetics and/or
target sites may be different compared to free Gln. In addition, trials
that did not comment on the pre-described nutrition therapy were
included. In relation to this, it is important to keep in mind the
recent “power couple” hypothesis-forming analysis of Oshima
et al., who proposed that “..the optimal and combined provision of
energy and protein optimises the outcomes of ICU patients.” [50].
In contrast to the meta-analyses published earlier, we specif-
ically searched for RCTs in only critically ill patients who received
Gln dipeptides as Gln source and only in combination with a pre-
scribed parenteral nutrition regime. These strong criteria led to the
identification of the 15 RCTs (16 publications) that we used in our
analysis (Table 1).
As we hypothesized, our meta-analysis strongly confirmed that
compared to patients who did not receive Gln dipeptides but equal
amounts of energy and nitrogen, Gln dipeptide supplementation as
part of a prescribed parenteral nutrition associated with signifi-
cantly lower rates of infectious complications and hospital mor-
tality. Furthermore, patients in the Gln dipeptide group had
significantly shorter stays in the ICU and the hospital and needed
shorter periods of mechanical ventilation. We cautiously suggest
that the observations of the REDOXS RCT and even the harmful
effects of Gln supplementation that were reported by Heyland et al.
[44] might be explained by the fact that the patients did not receive
an adequate nutrition therapy, either one or energy and protein
supply were insufficient. Under these conditions, Gln will simply be
used as energy fuel: it will not be available for acute-phase protein
synthesis nor will it be able to serve as a precursor of immunoactive
metabolites like glutathione. Provision of high-dose Gln (>0.5 g/kg/
d) both parenterally and enterally cannot overcome this problem.
Along with improving the clinical outcomes of individual pa-
tients, Gln supplementation in critical care settings also confers
economic benefits: this is indicated by the reductions in the ICU
and hospital ward stays and the lower frequency of infections in the
hospital [51,52]. These reduced hospital stay and case-dependent
treatment costs more than adequately compensate for the
increased costs associated with parenteral Gln treatment.
4.1. Study strengths and limitations
The greatest strength of our meta-analysis is our highly precise
and stringent inclusion and exclusion criteria, including the fact
that we only included studies that only provide Gln dipeptides as
part of a prescribed nutritional regime. A bias due to the use of
different Gln sources, can, thus, be excluded. The quality of the
studies included is very high as demonstrated by the Jadad score
analysis of our included studies. Moreover, tests of asymmetry did
not show any statistically significant hints of publication bias
(Fig. 8).
It should be kept in mind that in only four trials the sample sizes
were calculated on the basis of results from previous clinical studies
that defined the same primary endpoint. Thus, the statistical power
of many of the individual studies can be questioned. It is also
obvious that not all investigators defined a primary endpoint,
which is nowadays mandatory for intervention trials. Moreover, the
studies may suffer generally from the problem that strong criteria
such as mortality and morbidity rates within a limited time interval
84 P. Stehle et al. / Clinical Nutrition ESPEN 17 (2017) 75e85
are not only influenced by the nutritional status and the general
nutrition therapy but also by the severity of the underlying disease
and the acute medical treatment. These confounders could not be
considered in our analysis because scores that measure the severity
of illness such as APACHE (acute physiology and chronic health
evaluation) or SAPS (simplified acute physiology score) were not
reported in most studies. The acute medical treatment was also
largely not reported.
5. Conclusions
Our meta-analysis clearly indicated that when critically ill pa-
tients received Gln dipeptide supplementation as part of a balanced
PN, it reduced the rate of infectious complications, the length of ICU
and hospital stay, the number of days on mechanical ventilation,
and the hospital mortality rate. Most importantly, in all of the
clinical trials that were included in our study, the administration of
Gln dipeptides was entirely consistent with the clinical guidelines
[20], namely, via the parenteral route, in approved and recom-
mended doses (0.3e0.5 g/kg/day; max. 30% of the prescribed ni-
trogen supply), in combination with adequate nutrition, and in
patients who were haemodynamically and metabolically stabilised.
Conflicts of interest statement and funding
PS is a consultant of Fresenius Kabi Germany. AF, CS, JS, DS, and
MW are employees of Fresenius Kabi Germany. The study was
funded by an unrestricted educational grant from Fresenius Kabi
Deutschland.
Authorship statement
PS, AF, and CS contributed equally to the conception and design
of the study and drafted the manuscript. BE and DK contributed to
the interpretation of the data. JS, DS, and WM revised the manu-
script for important intellectual content. All authors have read and
approved the final manuscript.
Acknowledgments
We thank M.A.R.C.O. GmbH & Co. KG (Duesseldorf, Germany) for
the statistical analysis of the meta-analysis.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.clnesp.2016.09.007.
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