GLUTAMINE AND ICU INFECTION, PART II

Effect of a Glutamine-Enriched Enteral Diet on

Intestinal Permeability and Infectious Morbidity at
28 Days in Critically Ill Patients With Systemic
Inflammatory Response Syndrome: A Randomized,
Single-Blind, Prospective, Multicenter Study
Ramón Conejero, MD, Alfonso Bonet, MD, Teodoro Grau, MD, Angel Esteban, PhD,
Alfonso Mesejo, MD, Juan Carlos Montejo, MD, Jorge López, MD, and
José Antonio Acosta, MD
From the From the Intensive Care Unit, University Hospital of Getafe, Madrid, Spain; and the
Research Laboratory Unit, Elche University Hospital, Alicante University, Madrid, Spain

OBJECTIVES: We investigated the effect of a glutamine-enriched enteral diet on intestinal permeability

and infectious morbidity and mortality in critically ill patients who developed systemic inflammatory
response syndrome after an acute event.
METHODS: Eleven intensive care units in tertiary-care hospitals participated in a prospective, randomized,
single blind, multicenter trial. Eighty-four patients with systemic inflammatory response syndrome of any
etiology were randomly allocated to receive a glutamine-enriched enteral diet or a control diet without
glutamine.
RESULTS: Most patients received the planned caloric intake. The number of infected patients was smaller
in the glutamine group than in the control group (11 versus 17 patients, P ⬍ 0.05), with a relative risk
of 0.5 (95% confidence interval ⫽ 0.3– 0.9). The most frequent infection was nosocomial pneumonia, with
11 (33%) patients in the control group and 6 (14%) in the glutamine group. There were no differences with
respect to other infections, mortality, or length of stay. Intestinal permeability as assessed by the
lactulose-mannitol test was unchanged in both groups.
CONCLUSION: Glutamine-enriched enteral diets can decrease nosocomial infections in patients with
systemic inflammatory response syndrome. Nutrition 2002;18:716 –721. ©Elsevier Science Inc. 2002

KEY WORDS: glutamine, enteral nutrition, systemic inflammatory response syndrome, critically ill patients,
clinical outcomes

Supported in part by grant 1995 from Abbott Laboratories and the Spanish
Society of Enteral and Parenteral Nutrition.
Planning Committee: Ramón Conejero, MD (University Hospital of San
Juan, Alicante), Alfonso Bonet, MD (University Hospital of Josep Trueta,
Girona), Teodoro Grau MD (University Hospital of Getafe, Madrid), and
Angel Esteban, PhD (University Hospital of Elche).
Members participating in the study: José Marı́a Sirven, MD, and Juan
Carlos Yébenes, MD (University Hospital of Josep Trueta, Girona); Al-
fonso Mesejo, MD, and Carmen Ortega, MD (Clinical Hospital of Valen-
cia); Juan Carlos Montejo, MD (12 Octubre Hospital, Madrid); Jorge
López, MD (Leganés Hospital, Madrid); José Antonio Acosta, MD, and R.
Carrasco, MD (University Hospital of Alicante); Mercé Planas, MD (Valle
de Hebrón Hospital, Barcelona); Carmela Sánchez Alvarez, MD (General
Hospital of Murcia); Francisco Garcı́a Córdoba, MD, and Gumersindo
Gonzalez Dı́az, MD (Morales Meseguer Hospital, Murcia); A. Catalina,
MD, and M. A. Gonzalez López, MD (Del Rio Ortega Hospital, Vallado-
lid); and Inmaculada Albert, MD (Del Mar Hospital, Barcelona).
Correspondence to: Teodoro Grau, MD, Intensive Care Unit, Hospital
Universitario de Getafe, Cta de Toledo km 12.5, 2895 Getafe, Madrid
Spain. E-mail: tgrau@hugf.insalud.es
INTRODUCTION
Nosocomial infections are a common problem in critically ill
patients and increase patients’ catabolism, morbidity, and mortal-
ity.1,2 These infections seem to be related to decreased immune
function and gut-barrier malfunction.3,4 Moreover, acutely ill pa-
tients show a reduction of plasmatic glutamine levels that may
reflect an increased need for this amino acid in intestinal mucosa
and immunocompetent cells.5
Glutamine is liberated by the muscle and the lung and acts as
the carrier of nitrogen to the intestinal cells, the kidney, and the
immune cells.5 Glutamine is an oxidative fuel for enterocytes, and
it is a nucleotide donor for cell proliferation.6 Patients with trauma
and sepsis have an increased consumption of glutamine in the
splanchnic organs leading to decreased plasma levels despite an
increased liberation from the peripheral tissues. Moreover, gut
glutamine supplementation increases lymphocyte count, enhances
T-lymphocyte response in surgical patients, and improves intesti-
nal immune cell function.7 One study recently found that glu-
tamine also plays also a roll in the metabolism of glutathione, a
potent oxygen radical scavenger.8

Nutrition 18:716 –721, 2002 0899-9007/02/$22.00

©Elsevier Science Inc., 2002. Printed in the United States. All rights reserved. PII S0899-9007(02)00864-X
Nutrition Volume 18, Number 9, 2002 Effect of a Glutamine-Enriched Diet on SIRS 717

Bowel rest, catabolism, and glutamine deficiency in very sick TABLE I.

patients impair intestinal function.3 Mucosal atrophy may lead to
a malabsorption syndrome and increase intestinal permeability.5 DIET COMPOSITION PER LITER
Bacterial translocation might be a related phenomenon and the key
step to perpetuate the systemic inflammatory response and multi- Control Glutamine
ple organ failure in these patients.9 It seems logical that enteral
nutrition and glutamine supplementation could reduce these Calories 1200 1000
phenomena. Non-protein calories/g of nitrogen 90/1 94/1
We investigated the effect of a glutamine-enriched enteral diet Proteins, g (%) 66.2 (22) 52.5 (21)
on intestinal permeability and infectious morbidity and mortality Fat, g (%) 40.2 (30) 15.5 (13)
in critically ill patients who developed systemic inflammatory MCT, g (%) 7.1 (18) 8.2 (53)
response syndrome (SIRS) after an acute event. Polyunsaturated fatty acids, g (%) 13.6 (34) 6.7 (43)
Linoleic acid, g 11.7 6.6
␣-Linolenic acid, g 1.7 1.5
MATERIALS AND METHODS ␻-6:␻-3 7 4.4
Carbohydrates, g (%) 148.2 (48) 165 (66)
This study was designed as a multicenter, prospective, single-blind
Amino acid (g/100 g of protein)
trial of patients admitted to any one of the 11 participating inten-
Histidine 3.49 2.0
sive care units (ICUs) who developed SIRS after an acute event.
Isoleucine 5.45 4.8
Patients were enrolled if we predicted that they would need to be
Leucine 10.15 8.0
fed by the enteral route for at least 7 d. The institutional review
Lysine 8.03 6.2
board of each participating hospital approved the study. Informed
Methionine/cystine 3.64 3.7
consent was obtained from the patients or their relatives according
Phenilalanine/tyrosine 11.21 8.3
to the Spanish laws. Our funding sources had no role in the
Treonine 4.7 4.5
acquisition, analysis, or interpretation of data or in the submission
Tryptophan 1.21 1.3
of this report.
Valine 6.97 5.7
Alanine 3.79 2.0
Patients Arginine 3.64 8.5
Aspartic acid 8.03 5.0
Patients entered into the study were followed prospectively until Glutamic acid 28.03 7.0
ICU discharge or after 28 d of follow-up during the study period. Glutamine 0 27.0
SIRS, sepsis, septic shock, and multiple organ dysfunction syn- Glycine 2.12 1.5
drome were defined as follows.10 Proline 11.36 2.4
● SIRS was defined as a systemic inflammatory response to a Serine 5.93 2.3
variety of severe clinical insults manifest by at least two of
the following conditions: 1) temperature higher than 38°C or
MCT, medium-chain triglycerides
lower than 36°C; 2) heart rate faster than 90 beats/min; 3)
respiratory rate faster than 20 breaths/min or an arterial
partial pressure of carbon dioxide below 4.3 kPa; and 4)
white blood cell count larger than 12 000 cells/mm3, smaller dialysis), liver failure (serum bilirubin ⱖ 43 ␮M/L and/or
than 4000 cells/mm3, or more than 10% of immature forms. history of chronic liver disease), cancer, infection with the
● Sepsis was defined as the systemic response to infection.
human immunodeficiency virus, and previous use of steroids,
Such a response is manifested by at least two of the follow- salicylates, other anti-inflammatory drugs, and immunosup-
ing conditions as a result of infection: 1) temperature higher pressive drugs.
than 38°C or lower than 36°C; 2) heart rate faster than 90
beats/min; 3) respiratory rate faster than 20 breaths/min or an Randomization and Blinding
arterial partial pressure of carbon dioxide below 4.3 kPa; and
4) white blood cell count larger than 12 000 cells/mm3, The patient allocation schedule was done with a computer-
smaller than 4000 cells/mm3, or more than 10% of immature generated random-numbers table, with stratification according to
forms. centers. Each hospital received a sequence of 12 numbered,
● Septic shock was defined as sepsis with hypotension despite opaque, sealed envelopes. In addition, competitive recruitment
adequate fluid resuscitation and the presence of perfusion between participating centers was allowed until any center reached
abnormalities including, but not limited to, lactic acidosis, a maximum of 20 patients (20% of the calculated size). The
oliguria, or an acute alteration in mental status. Patients on investigators remained blinded to treatment group for the diagnosis
inotropic or vasopressor agents could not be hypotensive at of nosocomial infection, statistical analysis, and the final number
the time that perfusion abnormalities were measured. of patients recruited until the end of the study.
● Multiple organ dysfunction syndrome was defined as the
presence of altered organ function in an acutely ill patient Diet Composition and Energy Requirements
such that homeostasis could not be maintained without
intervention. Patients were randomly allocated to a control or a glutamine-
● Age, sex, weight, primary diagnosis, group (medical, surgi- supplemented diet. Abbott Laboratories (Madrid, Spain) supplied
cal, or trauma), Acute Physiology and Chronic Health Eval- both diets. Both diets contained intact proteins. The control diet
uation (APACHE II) score, the need for mechanical ventila- provided, per liter, 66.6 g of protein with a 90:1 ratio of non-
tion, and the presence of sepsis or septic shock and their protein calories to nitrogen, and excluded glutamine. The
origin were recorded on admission. Exclusion criteria were glutamine-enriched diet provided, per liter, 52.5 g of protein with
age younger than 18 y, pregnancy, expected survival of less 30.5 g of glutamine and a 94:1 ratio of non-protein calories to
than 24 h, previous cardiopulmonary resuscitation, severe nitrogen (Table I). Caloric needs were estimated by the Harris-
malnutrition, diabetes, chronic gastrointestinal disease of any Benedict formula, using height and ideal weight, with the addition
etiology, renal failure (serum creatinine ⱖ 220 ␮M/L and/or of a fixed stress factor of 1.3. The goal was to achieve the
718 Conejero et al.
calculated caloric requirements in the first 72 h of enteral nutrition.
Caloric intake was measured at days 3 and 7 of treatment.
Diet Administration Protocol
Enteral access route, gastric or jejunal, was decided by the local
investigator. Jejunal tubes were placed by endoscopy or in the
radiology suite according to the routine of each participating
center. Abdominal plain film was made before diet administration
to confirm enteral tube placement in the stomach or jejunum.
Investigators were encouraged to maintain the patients in a semi-
recumbent position (30 degrees). Enteral nutrition was adminis-
tered according to a previously established protocol.11 The diet
was infused throughout the 24 h, at constant rate by an infusion
pump, and the containers and delivery systems were changed after
24 h of use. Diets were administered at full strength and started at
42 mL/h the first day and advanced at 20-mL/h increments every
12 h until the caloric goal was achieved. The following data were
recorded in accordance to the management protocol: time of first
feeding, type and caliber of feeding tube, access route, and dura-
tion of tube use.
Gastrointestinal complications were defined as follows.
● abdominal distention: abdominal changes at the daily phys-
ical examination, with tympanism and/or the absence of
bowel sounds
● increased gastric residuals: gastric residuals were checked
every 6 h and considered high when the recovered volume
was at least 200 mL
● vomiting: enteral formula ejected from the mouth
● diet regurgitation: enteral formula in oral or nasal cavities
with or without exteriorization
● diarrhea: at least five liquid stools in a 24-h period or an
estimated volume of at least 2000 mL/day
● constipation: need for treatment with laxatives or enemas
according to the treating physician
All gastrointestinal complications were recorded prospectively,
including the number of episodes, day of presentation, and dura-
tion and were treated according to a previously established proto-
col.11 Reasons for definitive enteral nutrition withdrawal also were
recorded.
Laboratory Tests
Mandatory laboratory tests were done 1 and 7 d after ICU admis-
sion and included serum glucose, cholesterol, albumin, prealbu-
min, creatinine, nitrogen balance, and 3-methyl-histidine in urine;
3-methyl-histidine was determined by high-performance liquid
chromatography. Intestinal permeability was assessed with the
lactulose-mannitol test on the day of admission before feeding and
on day 7 in the first 43 patients. This test was previously assessed
in 54 critically ill patients and met the criteria of this study.12 The
test was done after stopping the diet infusion 6 h before mannitol
and lactulose administration. In this test, 10 g of lactulose and 5 g
of mannitol in 100 mL of water were administered at 9:00 AM via
the feeding tube, and it was cleaned and clamped. For 5 h (from
9:00 AM to 2:00 PM), urine was collected in a bag containing 5%
chlorhexidine solution to avoid bacterial contamination and sugar
consumption. An aliquot was frozen for analysis in one center.
Lactulose and mannitol in urine were determined by enzymatic
spectrophotometry according to the methods of Northrop et al.13
and Lunn et al.14
Outcome Assessment
Primary endpoints were nosocomial infections rate during ICU
stay or after 28 d of treatment. ICU mortality and ICU length of
stay were secondary endpoints. The ratio of lactulose to mannitol
and 3-methyl-histidine were the secondary endpoints. APACHE II
Nutrition Volume 18, Number 9, 2002
score and multiple organ failure also were recorded. An ICU
doctor not involved in patient care prospectively diagnosed noso-
comial infections according to criteria of the Centers for Disease
Control (CDC).15 Pneumonia was defined as a chest radiographic
examination showing new or progressive infiltrate, consolidation
and cavitation (interpreted by a radiologist blinded to a patient’s
treatment assignment), and at least two of the following: temper-
ature above 38.5°C or below 35°C, a white blood cell count larger
than 10 ⫻ 109/L or smaller than 3 ⫻ 109/L, isolation of pathogens
from the sputum or bronchial aspirates or bronchial brushing,
isolation of a pathogen from blood cultures, and diagnostic single
antibody titer (immunoglobulin M) or a four-fold increase in
paired serum samples (immunoglobulin) for pathogens. Bactere-
mia was diagnosed when a pathogen was isolated from the blood
with a temperature above 38.5°C or below 35°C or a white blood
cell count larger than 10 ⫻ 109/L or smaller than 3 ⫻ 109/L, and
it was not related to infection at another site. Intra-abdominal
infection was diagnosed when a pathogen were isolated from
culture of purulent material during surgery or drainage or when
there was an abscess or other evidence of intra-abdominal infec-
tion during surgery. Deep wound infection was diagnosed if a
purulent drainage was obtained from the deep fascia, or the wound
spontaneously dehisced or was opened by the surgeon. Urinary
tract infection was diagnosed if the urine culture showed at least
105 colonies of a pathogen. Catheter-related sepsis was diagnosed
if the patient had local signs of infection at the entry site, a
temperature above 38.5°C or below 35°C, a white blood cell count
larger than 10 ⫻ 109/L or smaller than 3 ⫻ 109/L that resolved
after catheter removal with no other infection site, the semiquan-
titative culture of the catheter tip showing more than 15 colony-
forming units/mL, or isolation of a pathogen from blood cultures.
The planning committee solved any discrepancy between investi-
gators. Positive bacterial results were recorded.
Data Management and Statistical Analysis
Each investigator filled out the report forms. The patient reports
were sent to a data management center for review and analysis. At
the very least, each center was monitored twice for review of the
inclusion and exclusion criteria and the adherence to the protocol
including allocation concealment. When necessary, additional data
were obtained; if any discrepancy with the criteria or the protocol
appeared, the planning committee made the final decision. When
the data were verified, the database was then locked.
Sample size was calculated to decrease nosocomial infection,
with a 48% patient infection rate in the control group, with the use
of data previously collected by our group, and a 20% rate in the
glutamine-enriched group. The calculated sample size was 102
patients, with 80% power and 5% significance. An intermediate
analysis was planned after recruiting 60% of patients. Statistical
analysis was done by intent to treat. Continuous data were assessed
for normality; the tests were two-tailed Student’s t test for normal
data and the Mann-Whitney U test for non-normal distributions.
Two-tailed chi-square test was applied for proportions. Rela-
tive risk was calculated for the outcome endpoints. Laboratory
test results had a logarithmic transformation before use with
multivariate analysis of variance for intragroup and intergroup
comparisons.
RESULTS
Eighty-four patients were randomly allocated, with 37 (44%) to the
control group and 47 to the glutamine-enriched diet group. Eight
patients died or were moved to other hospitals in the first 48 h after
admission and were not eligible for analysis. In the first week of
treatment, two patients died, one in the control group and one in
the glutamine-enriched group (Table II). Competitive randomiza-
tion between centers resulted in two samples of unequal size, but
Nutrition Volume 18, Number 9, 2002 Effect of a Glutamine-Enriched Diet on SIRS 719

TABLE II. TABLE IV.

PATIENT FLOW ACROSS THE STUDY PRIMARY OUTCOMES: CALORIC INTAKE, MORTALITY, AND
NOSOCOMIAL INFECTIONS RATE
Control Glutamine
group group Total Control Glutamine
group group
Randomized patients 37 47 84 (n ⫽ 33) (n ⫽ 43) P RR (CI)
Exclusions in the first 48 h
Deaths or transferred 2 2 4 Days of enteral feeding† 11 (7–28) 10 (7–24) 0.3
Feeding problems 2 2 4 Jejunal route 3 7 0.4
Eligible for analysis 33 43 76 Planned caloric intake* 1812 ⫾ 270 1832 ⫾ 254 0.7
Fed ⬍ 3 d Caloric intake at day 3* 1400 ⫾ 435 1380 ⫾ 380 0.6
Deaths 1 1 2 Caloric intake at day 7* 1460 ⫾ 430 1428 ⫾ 330 0.7
Gastrointestinal complications 3 0 3 Number of infections 17 11 0.02 0.5 (0.3–0.9)
Fed ⱖ 3 d 29 42 71 MODS 6 12 0.6 0.6 (0.2–1.9)
Deaths at 28 d 9 14 0.8 0.8 (0.3–2.1)
(from ICU admission)
ICU LOS† 15 (4–102) 14 (4–63) 0.7 —
the demographic data were comparable in both groups. Diagnosis,
APACHE II score, sepsis, and shock also were similar (Table III). * Mean ⫾ standard deviation.
The incidence of gastrointestinal complications was also similar. † Median and interquartile range.
Six patients had diarrhea (two in the control group and four in the CI, 95% confidence interval; ICU, intensive care unit; LOS, length of
glutamine-enriched group), six had constipation (four and two, stay; MODS, multiple organ dysfunction syndrome; RR, relative risk.
respectively), five had abdominal distention (three and two, re-
spectively), and 20 had increased gastric residuals (10 and 10,

respectively). Despite the high gastrointestinal complication rate,

TABLE III. only three patients in the control group did not receive the planned
caloric intake and needed total parenteral nutrition. Only four
DEMOGRAPHIC DATA
patients did not achieve their caloric goals in the first 72 h. Caloric
intake on days 3 and 7 were similar in both groups.
Twenty-three (30%) patients died, 9 (27%) in the control group
Control Glutamine
and 14 (33%) in the glutamine-enriched group (Table IV). ICU
group group P
length of stay and multiple organ failure rate were similar in both
groups. The number of patients who had at least one nosocomial
n Patients 33 43 infection was smaller in the glutamine-enriched group than in the
Male 25 29 0.34 control group (11 versus 17 patients, P ⬍ 0.05), with a relative risk
Age (y)* 54 (21–58) 57 (18–85) 0.61 of 0.5 (95% confidence interval ⫽ 0.3– 0.9). The most frequent
Weight (kg)† 69 ⫾ 13 71 ⫾ 9 0.85 infection was nosocomial pneumonia, with 11 (33%) patients in
APACHE II* 18 (6–46) 20 (6–34) 0.76 the control group and 6 (14%) in the glutamine-enriched group.
Patients on mechanical ventilation 26 34 0.20 There were no differences with respect to other infections. Micro-
Days on mechanical ventilation 14 (5–29) 14 (5–25) 0.2 biologic results showed a significant preponderance of gram-
Patients on inotropic support 12 16 0.9 negative bacteria in the control group (11 patients) when compared
Patients with acute renal failure 6 7 0.8 with that in the glutamine-enriched group (3 patients), with no
Primary diagnosis 0.48 significant increase of gram-positive organisms (Table V).
Medical 26 32 Most laboratory tests showed no significant differences be-
Community pneumonia 14 16 tween groups (Table VI). Cholesterol increased significantly on
COPD 3 4 day 7 in the control group and prealbumin increased significantly
Stroke 4 2 on day 7 in the glutamine-enriched group. The level of 3-methyl-
Other CNS diseases 2 2 histidine did not change, and nitrogen balance remained negative
Urologic sepsis 1 2 on days 1 and 7 in both groups. The lactulose-mannitol test showed
Surgical 3 4 no significant intra- and intergroup differences, with a wide range
CNS 1 2 of data on days 1 and 7. The ratios on day 1 were 0.391 (inter-
Cardiovascular 2 1 quartile range ⫽ 0.145– 0.768) in the control group and 0.143
Gynecologic 0 1 (0.068 – 0.406) in the glutamine group. The ratios on day 7 were
Trauma 4 7 0.163 (0.087– 0.436) in the control group and 0.109 (0.042– 0.269)
Multiple trauma 3 2 in the glutamine group.
CNS trauma 1 5
Sepsis on admission 20 28 0.68
Lung 17 20 DISCUSSION
CNS 2 6
Urinary tract 1 2 The study was finished earlier than planned because we found a
Shock on admission 8 17 0.32 infection rate significantly higher than we had calculated (P ⬍
0.02), and the number of patients needed to be treated to find any
* Median and interquartile range. significance in mortality or ICU length of stay was much higher
† Mean ⫾ standard deviation. than planned. We found that glutamine-supplemented enteral feed-
APACHE II, Acute Physiology and Chronic Health Evaluation; COPD, ings can decrease the infection rate in critically ill patients with
chronic obstructive pulmonary disease; CNS, central nervous system. SIRS. Both groups were comparable in terms of severity and
720 Conejero et al. Nutrition Volume 18, Number 9, 2002

TABLE V. parenteral route had better survival with lower costs,19,20 and
similar results were found in surgical patients.21 Trauma patients
FREQUENCY OF INFECTIONS AND MICROORGANISMS who received glutamine-enriched enteral feedings, in a manner
ISOLATED similar to that used in our study, yielded similar results in noso-
comial infections, in particular pneumonia, and the overall rate of
Control Glutamine patients infected.22 The CDC criteria employed for this study can
group group overestimate the true incidence of nosocomial pneumonia, but it
(n ⫽ 33) (n ⫽ 43) P was applied to both groups. Other techniques, such as quantitative
cultures of tracheal aspirates or the use of protected brush cathe-
Infections ters, might have improved the results, but, as others have pointed
Pneumonia 11 6 0.04 out,23 there are difficulties in unifying the diagnostic criteria of the
Bacteremia 3 3 0.7 nosocomial pneumonia in multicenter studies. Because the pro-
Catheter-related 2 1 0.4 posed solutions were not implemented in the clinical setting, we
Urinary tract 1 1 0.8 believed that the clinical diagnosis according to objective criteria
Microorganisms as established by CDC recommendations were adequate.
Staphylococcus aureus 3 5 0.7 Enteral feeding in critically ill patients is the preferred route of
Staphylococcus coagulase(⫺) 0 1 0.4 nutrition, and glutamine and other substrates seem to preserve
Enteric bacteria 11 3 0.001 intestinal mucosal integrity and lymphoid tissue in the gastroin-
Pseudomonas sp. 4 1 testinal tract, thus avoiding increased intestinal permeability and
Klebsiella sp. 3 1 bacterial translocation.16,17 Bacterial translocation might amplify
Escherichia coli 3 1 the inflammatory response seen in patients with SIRS and facilitate
Acinetobacter sp. 1 0 the appearance of bacteremia and secondary infections by enteric
Candida 1 1 0.8 microorganisms.3,4 Intestinal permeability can be assessed with
Enterococci sp. 1 0 0.3 molecular markers or biologically inert substances such as 51Cr-
ethylene-tetraacetic acid or polyethylene glycol or by assessing the
absorption capability of intestinal cells of an enteral load of two
sugars (usually lactulose and mannitol, ramose, or ribose). The
demographic data, and they had similar diagnoses. Mortality was ratio of lactulose to mannitol in urine is one of the preferred tests
not different between groups. Most patients tolerated enteral nu- to assess intestinal permeability.24 One study found that healthy
trition without significant gastrointestinal complications, and volunteers had an increased ratio of lactulose to mannitol in urine
losses from this cause were non-significant. Most patients achieved after a single dose of endotoxin.25 Critically ill and burn patients
the planned caloric goal within the first 3 d of treatment. seem to have an increased ratio of lactulose to mannitol compared
There is an increasing number of studies showing that glu- with normal controls, and this ratio correlated with severity scores
tamine given to catabolic patients produces positive biochemical and infectious complications.26,27 Unfortunately, our study found
and clinical effects. Glutamine promotes positive nitrogen balance, no significant differences in this ratio. There are several reasons
preserves muscle mass, enhances immune function, and maintains that could explain these results. First, a wide range of our data
intestinal mucosa integrity and intestinal flora.16,17 In our study, never achieved significance; second, our patient population dif-
we did not find improved nitrogen balance in the glutamine- fered from that in which the benefit of glutamine was previously
enriched group despite the results of other studies.18 Nevertheless, demonstrated such as bone marrow transplant. Patients were more
most clinical studies in different settings showed a decreased heterogeneous in terms of primary illness, but they were very sick,
infection rate in patients receiving glutamine.18 –22 Bone marrow with high APACHE II scores and a high rate of shock on admis-
transplant patients treated with glutamine-enriched parenteral nu- sion, and such symptoms can overcome the effect of glutamine on
trition had fewer infections and shorter hospital stays.18 Critically enterocytes. Third, glutamine may act more as a nutritional sub-
ill patients receiving supplemented glutamine by the enteral or strate or have more immune effects than a pharmacologic agent for

TABLE VI.

LABORATORY TEST RESULTS*

Control group (n ⫽ 29) Glutamine group (n ⫽ 42)

Day 1 Day 7 Day 1 Day 7 P

Glucose (serum, mM/L) 7.27 (4.50–15.0) 7.16 (4.83–20.5) 8.05 (5.44–21.2) 7.11 (4.83–15.7) 0.8
Cholesterol (serum, mM/L) 3.08 (1.42–6.80) 3.75 (1.89–8.66) 2.40 (1.55–5.07) 3.70† (1.32–6.67) 0.2
Albumin (serum, g/L) 28 (17–38) 23 (17–36) 25 (17–39) 27† (17–38) 0.5
Prealbumin (serum, mg/L) 90 (50–270) 129† (20–312) 103 (20–250) 140 (49–370) 0.4
3-methyl-histidine (urine, ␮M/d) 367 (85–1375) 362 (105–1958) 369 (96–1493) 291 (114–1441) 0.06
3-methyl-histidine: creatinine 0.038 (0.013–0.482) 0.047 (0.016–0.289) 0.045 (0.019–0.412) 0.033 (0.020–0.166) 0.09
(urine, adimensional)
Lactulose:mannitol 0.391 (0.145–0.768) 0.163 (0.087–0.436) 0.143 (0.068–0.406) 0.109 (0.042–0.269) 0.4
(urine, adimensional)
Nitrogen balance (g/d)‡ ⫺2.63 (⫺22.3 ⫾ 5.29) ⫺3.30 (⫺18.9 ⫾ 7.22) ⫺6.70 (⫺22.6 ⫾ 3.00) ⫺5.60 (⫺30.8 ⫾ 10.5) 0.3

* Multivariate analysis of variance. Data are expressed as median and interquartile range.
† Significative effects (P ⬍ 0.05) within subjects.
‡ Mann-Whitney U test. Data are expressed as mean ⫾ standard deviation.
Nutrition Volume 18, Number 9, 2002
the intestinal cells. Moreover, the relation between intestinal per-
meability and bacterial translocation is not clearly established.9
Nevertheless, enteric bacteria were more common in the control
group than in glutamine-enriched group without changes in noso-
comial infections caused by gram-positive microorganisms. These
results are similar to those obtained in others studies22 and may
represent the clinical effect of glutamine on infections of intestinal
origin.
Moreover, this clinical effect of glutamine might have been
amplified by the small lipid contents of the study diet. The control
diet had more polyunsaturated fatty acids and linoleic acid than the
study diet. Dietary lipids provide a rich source of energy, but they
also provide substrates for the production of eicosanoids that are
involved in the modulation of immune functions and can increase
susceptibility to infection.28 The low ␻-6:␻-3 ratio of the study
diet might have been partly responsible for the enhanced immu-
nologic response and might have increased the host’s natural
resistance to infections.29
We found that a glutamine-supplemented enteral diet in criti-
cally ill patients with SIRS can decrease the nosocomial infection
rate, in particular that of pneumonia. Despite this clear benefit, we
found no effect on nitrogen balance or intestinal permeability as
assessed with the lactulose-mannitol test. The sensitivity and spec-
ificity of this test, severity of illness in our patients, and the weak
relation between intestinal permeability and bacterial translocation
might explain these results. However, the patients treated with
glutamine had fewer infections caused by gram-negative bacteria,
so it may have some effects on the colonic intestinal wall or
immune intestinal tissue not measured by the lactulose-mannitol
test, which is much more sensitive to permeability changes in the
small intestine. It seems clear that there is potential for gain by
including glutamine in the enteral nutrition support of seriously ill
patients, but there are some questions that need to be answered.
Are the benefits of glutamine related mainly to a nutritional effect
or does it act as a pharmacologic agent that modifies the immune
response, intestinal permeability, or both? We also need to estab-
lish whether the overall population of ICU patients, including
those who are less severely ill, could benefit from this intervention.
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