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Glutamine dipeptide-supplemented parenteral nutrition maintains intestinal function in the critically III
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1596
TREMEL ET AL.
Table1. Patient
GASTROENTEROLOGY Vol. 107, No. 6
Characteristics
Patient no.
at Study
Sex/Age (~0
Test group 1 2 3 4 5 6 Control group 7 a 9 10 11 12
use of the constituent traumatized
and
with glutamine balance
and
F/52 F/51
75 75
M/53 M/59
80 90
M/57 F/45 F/60 M/58
a5 60 70 75
surgical
patients, resulted
maintenance
TPN
supplemented
in improved
dipeptide
or complaints
this
acids.23924 In severely
study
were
examined
no unde-
noted.
the effect
of Ala-Gln
to TPN
on intestinal
function
cally
receiving
long-term
treatment.
randomly women;
allocated weight,
to an experimental
80.7
SEMI) and a control
care unit patients group
76.7 + 4.4 kg; age, 55 + 2.3 years). Patient
included globin,
creatinine, hematocrit,
were
(3 men and 3
(4 men and 2 women;
shown in Table 1. Daily routine albumin,
laboratory
total protein,
+
weight,
characterization
is
tests in all patients electrolytes,
white blood cell and platelet
hemo-
counts, blood
urea, glucose, and Quick. On days 1, 3,6, and 9, liver enzyme, blood lipid, and short-life mined.
protein
Urine was collected
calculated.
Selected
concentrations
daily, and creatinine
pertinent
data acquired
are shown in Table 2. On day 9, no evidence
were deterclearance was
on days 1 and 9 of malnutrition,
as judged from serum albumin and short-life protein concentrations, and no signs of advanced liver or kidney failure (only mildly
or moderately
elevated
therapy.
values of standard
all 12 patients
tests) were
ventilation.
the patients
were weaned
at the earliest
from TPN regimens.
Medication
2 days after beginning
(according
between
motoricity
and prokinetic
All patients
had mechanical
Rate and time of weaning
tions) was not different
six percent
+ 5.6 kg; age, 65 + 4.6 years [mean
group
on the clinical condition,
of
was independent to standard
indica-
the groups; antibiotics
affect-
or motility
(e.g., macrolide
an-
drugs) were not given.
had 9 days of TPN with isonitrogenous
g nitrogen/kg)
Patients ill intensive
Initially,
Depending
tibiotics
in criti-
Materialsand Methods Twelve critically
admission.
ing gastrointestinal
as a supplement ill patients
Congenital heart disease, bypass surgery, sepsis Congenital heart disease, acute myocardial infarction, shock Mitral valve replacement, sepsis Pneumonia, sepsis Cardiopulmonary resuscitation, cerebral hypoxemia lntracerebral mass bleeding, coma
nutrition
glutamine
infusion,
Congenital heart disease, bypass surgery, sepsis Congenital heart disease, bypass surgery, sepsis Aortic valve replacement, respiratory failure Chronic obstructive pulmonary disease, pneumonia, respiratory failure Apoplexy, decerebration Apoplexy, coma
from the respirator,
nitrogen
of the intracellular
and after
side effects
Therefore,
a5 90 60 110
free amino
Diagnoses
Body wt (kg)
M/75 M/63 F/76 M/51
dipeptides
poo1.14V25 During sirable
Entry
and isoenergetic
of the nonprotein
(155 kJ/kg)
(0.26
nutrition.
Sixty-
energy was derived from glucose-
fructose-xylitol
(CombiSteril
burg, Germany)
and 34% from a soybean oil- based long-chain
triglyceride
fat emulsion
is postulated
that
favorable
light
in
the of
FGX; Fresenius
(Lipovenos ongoing
insulin received
(Aminosauren
10% DP; Fresenius
ay-‘)
the
acids.kg-‘.d mg.kg-‘.day-’ control
group
without
peptide
containing
received
corresponding
supplementation
is after
a 10% amino
acid
AG; 1.5 g amino Ala-Gln .day-‘),
amounts
(300
and the
of nitrogen
in the form of a conventional
(Traumasteril;
of the amino acid solutions
Fresenius
AG). Com-
is shown in Table 3.
The nature, purpose, and possible experimental procedures were explained spouses before obtaining
AG). It
mixture
intolerance
dipeptide
and 50 mg nitrogen.kg-’
10% amino acid solution position
20%; Fresenius
use of the carbohydrate
severe trauma.26 The test group solution
AG, Bad Hom-
their voluntary
risks involved in the to the patients or their consent.
Analyses
noted. On admission, the patients were treated as necessary with fluids, electrolytes, albumin, and whole blood (concentrated
On the evening of days 8 and 9 of the study, a modified D-xylose test was performed.27 In this test, the carbohydrate is administered on the 8th day intravenously (10 g; 10% solu-
red cells). After resuscitation, any essential surgical were performed. Number and type of operation were the same in both groups. The aim was to have in a stable condition when they entered the study
tion in saline) and 24 hours later via a nasogastric tube (25 g in 250 mL water). Repeated measurements of D-xylose serum levels after administration of both intravenous and oral test doses facilitate formal kinetic studies using a two-compart-
procedures and illness the patients 2 days after
MUCOSA AND GLUTAMINE IN THE CRITICALLY ILL
December 1994
Table 2. Nutritional
Assessment
1597
and Liver and Kidney Function Test Results on Day 1 (Study Entry) and Day 9 @-XylOSe
Test) Test group patients 1 Albumin
(g/L)
Retinal-binding 100 mL) Prealbumin
protein
2.y3.9 mL)
(m&/l00
Urea (mg/lOO Creatinine
mL) clearance
(mL/minl
(mg/lOO
6.6/-
1.9/1.2
3.7/5.2
1.4/3.5
12.0/6.4
17.9/23.0
10.0/16.0
1.4/0.9
2.3/1.1
1.3/0.8
1.1/0.5
46.3/44.5
44.5/42.0
46.0/30.3
18.6/22.5
79.4/68.7
27.7/96.4
12.9/49.0
63.4/161.5
3.0/3.3
2.9/3.7
3.9/3.5
22.0/38.0
13.0/19.0
12.0/9.0
1.2/1.5
0.9/1.4
3.2/1.6
7
100
protein
38.0/93.0
urea
(mg/loo
Creatinine
mL)
33.6/36.6 121.1/86.4
(mL/min)
2.7/2.2
(kU/L) (U/L)
(mg/lOO
Values
ment
Nonal (4.2)
range
29-52
2.9
(2.0)/3.0
15.7
1.ap.9
(6.3)/14.8
1.5
(0.5)/1.0
(1.8)
3-6
(8.9)
10-40
(0.5)
0.6-1.0
30.0/73.4
38.3
(11.4)/40.6
(18.0)
106.9/109.3
15.5/27.7
51.0
(38.3V85.4
(47.8)
5.0/3.3
1.7/1.0
3.0
9.0/28.0
2.2/0.8
17.3
0.4/0.3
(1.4)/2.8 (11.1)/37.4
3.1
(3.7)/2.2
23-35 >50
(1.1)
1.37-9.3
(32.9)
<22
(2.8)
0.2-1.2
group patients
9
10
39.7/29.9
11
23.2/22.2
Mean
12
--/28.6
39.4/36.1
32.8
(SD)
(7.2)/28.8
(4.6)
l.l/11.3/0.9/0.7 14.5/13.7 119.4/169.7 3.2/3.3
4.2/4.0 20.3/17.5 1.5/0.7 40.8/33.9 81.2/64.8 2.7/2.9
40.0/20.0 0.5/0.4
31.0/30.0 3.0/5.6
1.2/1.2
3q3.0
4.0/6.0
8.1/6.7
21.0/16.0
27.0/40.3
0.7/0.4
0.7/0.6
0.6/0.6
22.3/17.9
15.0/24.4
2.6
109.0/112.2 --/4.8
5.0/4.0 0.9/0.8
--/69.0 0.7/0.3
(12.4)
(0.3)/0.6
(0.1)
(10.9)/26.8
23.9
151.1/128.1 4.8/3.7
(2.0)
(7.0)/20.8
0.9
17.0/34.0
42.3/66.1 1.0/1.6
(1.4)/4.0
17.0
(9.5)
104.0(37.7)/104.6 (40.6) 2.9(1.4)/3.1(1.1)
pywic
transaminase
NOTE.
0.9/0.8
rnL)
Glutamine Birlirubin
14.4/23.4
mLj
clearance
Cholinesterase
(SD)
(6.6)/27.8
44.3/31.0
lO.O/-
10.4/7.8
33.9/26.2
2.1/5.6 (n@/lOO (mg/lOO
32.1
(mg/
mL)
Creatinine
0.9/0.7
1.2/2.1
8
28.0/29.8
(g/L)
Prealbumin
Mean
21.3/21.8
27.3/-
mL)
Retinal-binding
6
37.3/-
1.9/1.2
Control
Albumin
5
39.0/25.4
12.0/4.9
(kU/L)
Glutamine pyruvic transaminase (U/L) Bilirubin
4
35.0/30.0
14.8/23.6
mL)
Cholinesterase
3
32.1/29.1
(It&?/
(mg/lOO
Creatinine
2
27.7/32.5
27.0/92.0
mL)
1.8/3.0
are expressed
model
as day l/day
serum
small intestinal
absorption.
Measurements formed
concentrations
of D-xylose
according
mecha-
of
D-XylOSe
in serum
and urine
absorption
Bateman
function
was based that
means of a nonlinear
on variables
was fitted
were per-
regression
of the
derived
to the measured
using a computer
from a data by
program
of
et al.” as follows: C(t) = A (eeket - eekat),
in which dependent
C is serum
concentration
general constant
rate constant rate constant
of D-xylose of
corresponding determined
D-XylOSe
half-life.
absorption
from
ke is
the body; ka is
from the lumen;
The area under
by approximation
A is dose-
by extrapolation);
elimination
and t is
the curve (AUC) was
according
to the trapezoidal
rule.
The cumulative
of six patients
excretion
in the
five of six patients
test
group
in the
had
control
lower group
of D-xylose
3.8 + 0.9 g in the control
group
the mean value in the controls of normal
during
the 5-
was 7.4 + 1 .l g in the test group
as given
and
(P < 0.05; Figure
l),
being lower than the limit
by Craig and Atkinson.*’
The course of serum D-xylose concentration groups
after 9 days of TPN
serum
concentrations
is shown
of D-xylose
were significantly
in the two
in Figure
2 hours
2. The
after enteral
different
between
the
groups (38.7 5 3.0 vs. 27.8 + 2.9 mg/lOO mL in peptide and control groups, the lower limit
respectively;
of normal
five of the six patients
P < 0.05). Considering
at 2 hours (30 mg/lOO
mL),
in the control group had decreased
values. The results
from the pharmacokinetic in Table 4. Significantly
tide-supplemented
evaluation higher
was observed
are
maximum
in the dipep-
group (P < 0.05). Similarly,
under the calculated curves until the maximum concentration and over the entire experimental were considerably greater the conventional solution.
R0SUltS and
of D-XylOSe than the 5-hour
output
D-xylose serum concentration
Differences were evaluated with the U test according to Wilcoxon, Mann, and Whitney tests. All data are expressed as mean + SEM.
Five
urinary
hour test period
summarized
Statistics
excretion
higher
administration
of D-xylose;
(calculated
had
reference value of 5.6 g.32-34
were used to evaluate
to Roe and Rice.‘” Pharmacokinetics
D-xylose
Yamaoka
by renal and nonrenal
the T-hour urinary excretion
and the 2-hour
25.8(14.9)/56.2 (45.8) 1.5(0.9)/1.9 (2.1)
9.
and elimination
nisms. ‘a,*’ In addition,
--/122.0 1.8/1.1
the areas serum period
with the dipeptide than with However, no differences were
observed for the time at maximum serum concentration and for the absorption or elimination half-life times.
1598
TREMEL ET AL.
GASTROENTEROLOGY Vol. 107, No. 6
Discussion
for physiological
The small bowel mucosa is a rapidly
regenerating
tissue. Use of parenteral
nutrition
as the source of nutri-
ents results in impaired
function
and villous
Several factors have been proposed
these changes, such as the absence of luminal dietary
amines,
and/or
fermentable
changes
in neurohormonal
growing
body of evidence
atrophy.2-5
to be responsible fibers”
events.38
as well as
In recent
has indicated
for
substrates,35 years, a
that the onset
of hypoplasia and hypofunction occurs as early as after 3 days of TPN in ratszT3 and that the absence of glutamine in conventional
TPN formulas
may be partly responsible
for this process.5,39V40There is now convincing that during tamine
long-term
parenteral
is the principal
epithelial
cells.’ Accordingly,
with convincing
addition
healing
dard TPN preserved
of the injured
or even enhanced
transport,
absorption,
an experimental procedure.
showed
with
two-step
It is concluded
Table 3. Composition
bowel
Monosaccharide morphology TPN
after
absorptive
and barrier
function
of the
graft.42
Recent
studies
suggest
that patients
velop glutamine depletion quirements are accelerated or parenteral
glutamine
efits include
maintained
supplementation.6*7239
mine concentrations, enhanced
protein
translocation,‘” The present
or restored
improved
These ben-
intracellular
nitrogen
gluta-
balance,‘7.‘9V25243
synthesis,‘7943’44 decreased
and reduced clinical
effect of glutamine function
who tend to de-
at a time when intestinal remay also benefit from enteral
study attempted
supplementation
by examination
bacterial
hospitalization.‘9~20 to elaborate on gastrointestinal
of the enteral
absorption
ity. The D-xylose test used is feasible in a clinical and is easily tolerated
by patients.
nutrients.
is to be considered
during
Therefore,
as an integrated
efficacy of the entire
The conventional of serum
D-
of the
this simple test
assessment
of the
duodenum.27229,45+46
test is based on single measurements
D-xylose 5 hours
portion
which is also the major site of absorption
for many important absorption
capacsetting
The carbohydrate
xylose is chiefly taken up by the proximal small intestine,
the
concentration
after an enteral
and urinary
excretion
load of the test sub-
this procedure is criticized because stance. *’ Generally, of the great variability of the results.27,29,45 In the present study,
great efforts were made to exclude
known
factors
transplantation
glutamine
is essential
l-
of Amino Acid (Peptide) Solutions Control solution (Traumasteril 10%) W)
L-lsoleucine L-Leucine L-Lysine (as hydrochloride) t.-Methionine L-Phenylalanine L-Threonine L-Ttyptophan L-Valine L-Arginine I.-Histidine Glycine L-Alanine L-Proline L-Serine NAcetyl-Lcysteine (= 0.65 g L-cysteine) Nacetyktyrosine (= 1.68 g L-tyrosine) L-alanyk-glutamine (= 8.18 g alanine + 13.42 g glutamine)
mucosal
fed rats without5
and mucosal
that
nitrogen structure,
intestinal
Ala-Gln-enriched small
provi-
source to stan-
in parenterally
septic complications.41
water
glu-
mucosa.6’7 Similarly,
as stable glutamine
and function
be preserved
overall
of intestinal
or with systemic could
studies
improves
maintenance
of Ala-Gln
cellularity
animal
glutamine
supports
and promotes
regimens,
fuel for the intestinal
evidence that enteral or parenteral
sion of exogenous economy,
feeding
metabolic
evidence
intestinal
Test solution (Aminosauren 10% DP) (g/L)
5.00 7.40 6.60 4.30 5.10 4.40 2.00 6.20 12.00 3.00 14.00 15.00 15.00 -
5.00 7.40 6.60 3.66 3.573 4.40 2.00 6.20 12.36 3.09 8.00 -
-
0.87
-
2.07
-
11.00 5.00
20.00
*
1lr TPN-
Figure 1. Cumulative 5-hour excretion of Bxylose after a gastric dose of 25 g on the ninth day of the study. The patients received TPN without (TPN-; n = 6) or with (TPN+; n = 6) Ala-Gln supplementation. *P < 0.05.
MUCOSA AND GLUTAMINE IN THE CRITICALLY ILL
December 1994
possibly
influencing
the results.
A modified
TaMe 4. Phannacokinetic
test (com-
intravenous and enteral administration of the Dxylose) was performed in patients with similar age and
Evaluation
bined
sex distribution and/or
(Table
kidney
Repeated
functions
and under
similar
of liver
medication.
enabled formal kinetic analysis the distinct Ddata.*“*’ Consequently,
absorption
differences
evaluation indicate important pacity during critical illness. edge, using
impairment
determinations
of the obtained xylose
1) without
as derived
from the kinetic
changes in absorption caAccording to our knowl-
there are no previously published this modified method in intensive
reference data care unit pa-
tients. Urinary
excretion
and serum concentration
were at lower limit
of normal*’ in control
of D-xylose patients
ures 1 and 2). These findings
indicate
tion capacity
portion
of the small intes-
Indeed,
the calculated
of the proximal
tine with conventional may be consistent
TPN.
with a reduction
as the possible
morphological (Figures
measured
data
evaluation
(Table
apparently
maintained
supplemented
fects of glutamine
all
2B) as well as kinetic
in patients
TPN during
data
In contrast,
that intestinal critical
function
receiving illness.
dipeptide-supplemented
Maximum o-xylose serum concentration (mg/IOO mL) Time at maximum serum concentration (hour)
Test group
Control group
41.2 + 6.0
27.2 2 2.8”
2.4 -c 0.2 1.2 2 0.04 2.1 -f 0.3
fi,za (hour) fi/ze (hour) AUC during the entire experimental period (mg, h-1.100 mL_‘) AUC until maximum serum concentrate (mg. h-l. 500 mL_l)
135.7
2.1 -+ 0.3 1.3 ? 0.2 1.9 * 0.3
92.8 ? 10.3”
2 17.6
56.4 2 9.2
31.7 ? 4.5a
NOTE. Results are mean -c SEM. “Significant difference with test group; P < 0.05.
absorp-
of the mucosal surface
correlate.
1 and
4) suggest
a reduced
(Fig-
1599
is
Ala-Gln-
Beneficial
ef-
TPN on gut
integrity
in patients
with
inflammatory
bowel
disease
and neoplastic disease have also been reported by van der H&t et a1.47 After 2 weeks of TPN, intestinal permeability (determined
as the ratio between
mannitol
after an enteral
receiving
glycyl-L-glutamine
tients without
glutamine
hypothesis
that provision
tides promotes Although definitive glutamine
with
increased
supplementation. our data
to 13.2 in all pa-
These obser-
strongly
of parenteral
and
in patients
(20 g corresponding
whereas permeability
combined
lactulose
load) was unaltered
g glutamine), vations
urinary
support
glutamine
the
dipep-
gut integrity. the
present
statements
knowledge
concerning
on the intestinal
does
not
the specific
mucosa,
permit
action
of
it is of interest
to
consider some possible modes of operation,
Indeed, gluta-
mine loading is associated with increased glucagon concentration in the portal blood,48 and a high concentration of this hormone glutaminase,49 lization
induces an increased thus facilitating
(personal
also conceivable
communication,
activity
enhanced
of intestinal
glutamine
February
uti-
1993). It is
that the specific effect of glutamine
in
enhancing intestinal cellularity is partly due to a stimulation of enteroglucagon secretion,‘” thereby regulating uptake and utilization of glutamine. A crucial and yet unresolved question is the appropriate daily requirement of glutamine during critical ill-
Flgure 2. Absorption kinetics of Dxylose after 9 days of TPN (A) with conventional glutamine (dipeptide)-free nutrition and (B) with Ala-Gln supplementation. Individual nonlinear regressions and the calculated mean function (short and long vertical rules, respectively) are shown. For the calculation, see Materials and Methods. Normal reference concentration of 30 mg/lOO mL at 2-hour sampling is indicated.
ness. Accordingly, in the present study, administration of 12 g glutamine per day as dipeptide Ala-Gln to severely ill patients obviously preserved intestinal function compared with glutamine-free TPN. Similarly, provision of 13 g glutamine as glycyl-L-glutamine prevented deterioration of gut permeability in patients with inflammatory bowel disease and neoplastic disease.47 In excellent agreement with these results, administration of the same
1600
TREMEL ET AL.
amounts nated
of glutamine
trauma-induced
improved
nitrogen
synthesis.43 vision
GASTROENTEROLOGY Vol. 107, No. 6
to postoperative muscle
of a physiological
for metabolic
glutamine
data suggest
amount
the increased
fuel during
critical
and
protein
19. Ziegler TR, Young LS, Benfell K, Scheltinga M, Hortos K. Bye R,
that daily pro-
of glutamine intestinal
AA, Antin JH, Schloerb PR, Wilmore DW. Glutamine-enriched intravenous feedings attenuate extracellular fluid expansion after a standard stress. Ann Surg 1991;214:385-395.
elimi-
depletion
balance’4,25*43 and promoted
These combined
g) can compensate
patients
Morrow FD, Jacobs DO, Smith RJ, Antin JH, Wilmore DW. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, doubleblind, controlled study. Ann Intern Med 1992; 116:821-828.
(12 - 15
requirement
illness.
20. Schloerb PR, Amare M. Total parenteral nutrition with glutamine in bone marrow transplantation and other clinical applications (a randomized, double-blind study). JPEN 1993; 17:407-413. 21. Stehle P, Pfaender P, Fiirst P. lsotachophoretic analysis of a
References
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2. Johnson LR, Copeland EM, Dudrick SJ, Lichtenberger GM, Castro GA. Structural and hormonal alterations in the gastrointestinal tract of parenterally fed rats. Gastroenterology 1975;68:11771183. 3. Hughes CA, Dowling RH. Speed of onset of adaptive mucosal hypoplasia and hypofunction in the intestine of parenterally fed rats. Clin Sci 1980;59:317-327. 4. Koga Y, lkeda K, lnokuchi K, Watanabe H, Hashimoto N. The digestive tract in total parenteral nutrition. Arch Surg 1975; 110:742-745. 5. Tamada H, Nezu R, lmamura I, Matsuo Y, Takagi Y, Kamata S, Okada A. The dipeptide alanyl-glutamine prevents intestinal mucosal atrophy in parenterally fed rats. JPEN 1992; 16:110116. 6. Souba WW, Klimberg VS, Plumley DA, Salloum RM, Flynn TC, Bland KI, Copeland Ill EM. The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection. J Surg Res 1990;48:383-391. 7. Souba WW. Glutamine: a key substrate for the splanchnic bed. Annu Rev Nutr 1991; 11:285-308. 8. Windmueller HG, Spaeth AE. Respiratory fuels and nitrogen metabolism in vivo in small intestine of fed rats. Quantitative importance of glutamine, glutamate and aspartate. J Biol Chem 1980;255:107-112. 9. Fox AD, Kripke SA, De Paula JA, Berman JM, Settle RG. Rombeau JL. Effect of a glutaminesupplemented enteral diet on methotrex10.
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22.
Fijrst P. Peptides in clinical nutrition. Clin Nutr 1991; lO(Suppl 1):19-24.
23. Albers S, Wernerman J, Stehle P, Vinnars E, Fiirst P. Availability of amino acids supplied intravenously in healthy man as synthetic dipeptides: kinetic evaluation of L-alanyl-Lglutamine and glycyl-Ltyrosine. Clin Sci 1988; 75:463-468. 24. Albers S, Wernerman J, Stehle P, Vinnars E, Furst P. Availability of amino acids supplied by constant intravenous infusion of synthetic dipeptides in healthy man. Clin Sci 1989; 76:643-648. 25. Stehle P, Zander J, Mertes N, Albers S, Puchstein Ch, Lawin P, Fiirst P. Effect of parenteral glutamine peptide supplements on muscle glutamine loss and nitrogen balance after major surgery. Lancet 1989; 1:231-233. 26. Georgieff M, Moldawer LL, Bistrian BR, Blackburn GL. Xylitol, an energy source for intravenous nutrition after trauma. JPEN 1985;9:199-209. 27. Craig RM, Atkinson AJ Jr. BXylose testing: a review. Gastroenterology 1988; 95:223-231. 28. Craig RM, Murphy P, Gibson TP, Quintanilla A, Chao GC, Cochrane C, Patterson A, Atkinson CuJr. Kinetic analysis of o-xylose absorp tion in normal subjects and in patients with chronic renal failure. J Lab Clin Med 1983;101:496-506. 29. Worwag EM, Craig RM, Jansyn EM, Kirby D, Hubler GL, Atkinson AJ Jr. DXylose absorption and disposition in patients with moderately impaired renal function. Clin Pharmacol Ther 1987;41: 351-357. 30.
Roe HJ, Rice EW. A photometric method for determination of free pentoses in animal tissue. J Biol Chem 1948;173:507-512.
31. Yamaoka K, Tanigawara J, Nakagawa T, Uno T. A pharmacokinetic analysis program (MULTI) for microcomputer. J Pharmacobiodyn 1981;4:879-885. 32. Greenberger NS, lsselbacher KS. In: Petersdorf RG, Adams RP. Bramwald E, lsselbacher KS, Martin JB, Wilson SD, eds. Harrison’s principles of internal medicine. New York: McGraw-Hill, 1983. 33. Miller P. Der DXylose-Test. In: Engelhardt A, Lommel H, eds. Malapsorption Maldigestion. Weinheim, Germany: Verlag Chemie, 1974:155-163. 34. Richterlich R, Colombo JP. Klinische Chemie. 4th ed. Basel: Karger Verlag. 1978:462. 35. Clark RM. Evidence of both luminal and systemic factors in the control of rat intestinal epithelial replacement. Clin Sci 1976;50: 139-145. 36. Seidel ER, Haddox MK, Johnson LR. lleal mucosal growth during intraluminal infusion of ethylamine or putrescine. Am J Physiol 1985;249:G434-G438. 37. Jacobs LR, Lupton JR. Effect of dietary fibers on rat large bowel mucosal growth and cell proliferation. Am J Physiol 1984;246:6378-G385. 38. Johnson LR. Regulation of gastrointestinal growth. In: Johnson LR, ed. Physiology of the gastrointestinal tract. New York: Raven, 1987:201-219.
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39. 40. 41.
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Smith RJ, Wilmore DW. Glutamine nutrition and requirements. JPEN 1990; 14:94S-99s. Baskerville A, Hambleton P, Benbough JE. Pathological features of glutaminase toxicity. Br J Exp Pathol 1980;61:132-138. Yoshida S, Leskiw MJ, Schluter MD, Bush KT, Nagele RG, LanzaJacoby S, Stein TP. Effect of total parenteral nutrition, systemic sepsis, and glutamine on gut mucosa in rats. Am J Physiol Endocrinol Metab 1992;263:E368-E373. Schroeder P, Schweizer E, Blamer A, Deltz E. Glutamine prevents mucosal injury after small bowel transplantation. Transplant Proc 1992; 24:1104. Hammarqvist F. Wernerman J, Von der Decken A, Vinnars E. Alanyl-glutamine counteracts the depletion of free glutamine and the postoperative decline in protein synthesis in skeletal muscle. Ann Surg 1990;212:637-644. Barua JM, Wilson E, Downie S, Weryk B, Cuschieri A, Rennie MJ. The effect of alanylglutamine peptide supplementation on muscle protein synthesis in post-surgical patients receivingglutamine-free amino acids intravenously (abstr). Proc Nutr Sot 1992; 51:104A. Wormsley KG. Use of labelled triolein, vitamin A and uXylose in the diagnosis malabsorption. Gut 1963;4:261-272.
46. 47.
48.
49. 50.
1601
Peled Y, Doron 0, Laufer H, Bujanover Y, Gilat T. DXylose absorp tion test. Urine or blood? Dig Dis Sci 1991;36:188-192. Van der Hulst RRWJ, Van Kreel BK, Von Meyenfeldt MF, Brummer R-JM, Arends J-W, Deutz NEP, Soeters PB. Glutamine and the preservation of gut integrity. Lancet 1993;341:1363-1365. Li S, Nussbaum MS, McFadden DW, Zhang F-S, LaFrance RJ, Dayal R, Fischer JE. Addition of Lglutamine to total parenteral nutrition and its effects on portal insulin and glucagon and the development of hepatic steatosis in rats. J Surg Res 1990;48: 421-426. Geer RJ, Williams PE, Lairmore T. Glucagon: an important stimulator of gut and hepatic metabolism. Surg Forum 1987;27-28. Buchanan KD. Hormones and the small intestine. Curr Opin Gastroenterol 1987;3:233-237.
Received May 3, 1993. Accepted July 22, 1994. Address requests for reprints to: Ludwig Sacha Weilemann, M.D., Medical Clinic II, Johannes-Gutenberg-University, Langenbeckstrasse 1, 55131 Mainz, Germany. Fax: (49) 613-123-2469. Supported by Fresenius AG (Bad Homburg, Germany).
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TREMEL ET AL.
Table1. Patient
GASTROENTEROLOGY Vol. 107, No. 6
Characteristics
Patient no.
at Study
Sex/Age (~0
Test group 1 2 3 4 5 6 Control group 7 a 9 10 11 12
use of the constituent traumatized
and
with glutamine balance
and
F/52 F/51
75 75
M/53 M/59
80 90
M/57 F/45 F/60 M/58
a5 60 70 75
surgical
patients, resulted
maintenance
TPN
supplemented
in improved
dipeptide
or complaints
this
acids.23924 In severely
study
were
examined
no unde-
noted.
the effect
of Ala-Gln
to TPN
on intestinal
function
cally
receiving
long-term
treatment.
randomly women;
allocated weight,
to an experimental
80.7
SEMI) and a control
care unit patients group
76.7 + 4.4 kg; age, 55 + 2.3 years). Patient
included globin,
creatinine, hematocrit,
were
(3 men and 3
(4 men and 2 women;
shown in Table 1. Daily routine albumin,
laboratory
total protein,
+
weight,
characterization
is
tests in all patients electrolytes,
white blood cell and platelet
hemo-
counts, blood
urea, glucose, and Quick. On days 1, 3,6, and 9, liver enzyme, blood lipid, and short-life mined.
protein
Urine was collected
calculated.
Selected
concentrations
daily, and creatinine
pertinent
data acquired
are shown in Table 2. On day 9, no evidence
were deterclearance was
on days 1 and 9 of malnutrition,
as judged from serum albumin and short-life protein concentrations, and no signs of advanced liver or kidney failure (only mildly
or moderately
elevated
therapy.
values of standard
all 12 patients
tests) were
ventilation.
the patients
were weaned
at the earliest
from TPN regimens.
Medication
2 days after beginning
(according
between
motoricity
and prokinetic
All patients
had mechanical
Rate and time of weaning
tions) was not different
six percent
+ 5.6 kg; age, 65 + 4.6 years [mean
group
on the clinical condition,
of
was independent to standard
indica-
the groups; antibiotics
affect-
or motility
(e.g., macrolide
an-
drugs) were not given.
had 9 days of TPN with isonitrogenous
g nitrogen/kg)
Patients ill intensive
Initially,
Depending
tibiotics
in criti-
Materialsand Methods Twelve critically
admission.
ing gastrointestinal
as a supplement ill patients
Congenital heart disease, bypass surgery, sepsis Congenital heart disease, acute myocardial infarction, shock Mitral valve replacement, sepsis Pneumonia, sepsis Cardiopulmonary resuscitation, cerebral hypoxemia lntracerebral mass bleeding, coma
nutrition
glutamine
infusion,
Congenital heart disease, bypass surgery, sepsis Congenital heart disease, bypass surgery, sepsis Aortic valve replacement, respiratory failure Chronic obstructive pulmonary disease, pneumonia, respiratory failure Apoplexy, decerebration Apoplexy, coma
from the respirator,
nitrogen
of the intracellular
and after
side effects
Therefore,
a5 90 60 110
free amino
Diagnoses
Body wt (kg)
M/75 M/63 F/76 M/51
dipeptides
poo1.14V25 During sirable
Entry
and isoenergetic
of the nonprotein
(155 kJ/kg)
(0.26
nutrition.
Sixty-
energy was derived from glucose-
fructose-xylitol
(CombiSteril
burg, Germany)
and 34% from a soybean oil- based long-chain
triglyceride
fat emulsion
is postulated
that
favorable
light
in
the of
FGX; Fresenius
(Lipovenos ongoing
insulin received
(Aminosauren
10% DP; Fresenius
ay-‘)
the
acids.kg-‘.d mg.kg-‘.day-’ control
group
without
peptide
containing
received
corresponding
supplementation
is after
a 10% amino
acid
AG; 1.5 g amino Ala-Gln .day-‘),
amounts
(300
and the
of nitrogen
in the form of a conventional
(Traumasteril;
of the amino acid solutions
Fresenius
AG). Com-
is shown in Table 3.
The nature, purpose, and possible experimental procedures were explained spouses before obtaining
AG). It
mixture
intolerance
dipeptide
and 50 mg nitrogen.kg-’
10% amino acid solution position
20%; Fresenius
use of the carbohydrate
severe trauma.26 The test group solution
AG, Bad Hom-
their voluntary
risks involved in the to the patients or their consent.
Analyses
noted. On admission, the patients were treated as necessary with fluids, electrolytes, albumin, and whole blood (concentrated
On the evening of days 8 and 9 of the study, a modified D-xylose test was performed.27 In this test, the carbohydrate is administered on the 8th day intravenously (10 g; 10% solu-
red cells). After resuscitation, any essential surgical were performed. Number and type of operation were the same in both groups. The aim was to have in a stable condition when they entered the study
tion in saline) and 24 hours later via a nasogastric tube (25 g in 250 mL water). Repeated measurements of D-xylose serum levels after administration of both intravenous and oral test doses facilitate formal kinetic studies using a two-compart-
procedures and illness the patients 2 days after
MUCOSA AND GLUTAMINE IN THE CRITICALLY ILL
December 1994
Table 2. Nutritional
Assessment
1597
and Liver and Kidney Function Test Results on Day 1 (Study Entry) and Day 9 @-XylOSe
Test) Test group patients 1 Albumin
(g/L)
Retinal-binding 100 mL) Prealbumin
protein
2.y3.9 mL)
(m&/l00
Urea (mg/lOO Creatinine
mL) clearance
(mL/minl
(mg/lOO
6.6/-
1.9/1.2
3.7/5.2
1.4/3.5
12.0/6.4
17.9/23.0
10.0/16.0
1.4/0.9
2.3/1.1
1.3/0.8
1.1/0.5
46.3/44.5
44.5/42.0
46.0/30.3
18.6/22.5
79.4/68.7
27.7/96.4
12.9/49.0
63.4/161.5
3.0/3.3
2.9/3.7
3.9/3.5
22.0/38.0
13.0/19.0
12.0/9.0
1.2/1.5
0.9/1.4
3.2/1.6
7
100
protein
38.0/93.0
urea
(mg/loo
Creatinine
mL)
33.6/36.6 121.1/86.4
(mL/min)
2.7/2.2
(kU/L) (U/L)
(mg/lOO
Values
ment
Nonal (4.2)
range
29-52
2.9
(2.0)/3.0
15.7
1.ap.9
(6.3)/14.8
1.5
(0.5)/1.0
(1.8)
3-6
(8.9)
10-40
(0.5)
0.6-1.0
30.0/73.4
38.3
(11.4)/40.6
(18.0)
106.9/109.3
15.5/27.7
51.0
(38.3V85.4
(47.8)
5.0/3.3
1.7/1.0
3.0
9.0/28.0
2.2/0.8
17.3
0.4/0.3
(1.4)/2.8 (11.1)/37.4
3.1
(3.7)/2.2
23-35 >50
(1.1)
1.37-9.3
(32.9)
<22
(2.8)
0.2-1.2
group patients
9
10
39.7/29.9
11
23.2/22.2
Mean
12
--/28.6
39.4/36.1
32.8
(SD)
(7.2)/28.8
(4.6)
l.l/11.3/0.9/0.7 14.5/13.7 119.4/169.7 3.2/3.3
4.2/4.0 20.3/17.5 1.5/0.7 40.8/33.9 81.2/64.8 2.7/2.9
40.0/20.0 0.5/0.4
31.0/30.0 3.0/5.6
1.2/1.2
3q3.0
4.0/6.0
8.1/6.7
21.0/16.0
27.0/40.3
0.7/0.4
0.7/0.6
0.6/0.6
22.3/17.9
15.0/24.4
2.6
109.0/112.2 --/4.8
5.0/4.0 0.9/0.8
--/69.0 0.7/0.3
(12.4)
(0.3)/0.6
(0.1)
(10.9)/26.8
23.9
151.1/128.1 4.8/3.7
(2.0)
(7.0)/20.8
0.9
17.0/34.0
42.3/66.1 1.0/1.6
(1.4)/4.0
17.0
(9.5)
104.0(37.7)/104.6 (40.6) 2.9(1.4)/3.1(1.1)
pywic
transaminase
NOTE.
0.9/0.8
rnL)
Glutamine Birlirubin
14.4/23.4
mLj
clearance
Cholinesterase
(SD)
(6.6)/27.8
44.3/31.0
lO.O/-
10.4/7.8
33.9/26.2
2.1/5.6 (n@/lOO (mg/lOO
32.1
(mg/
mL)
Creatinine
0.9/0.7
1.2/2.1
8
28.0/29.8
(g/L)
Prealbumin
Mean
21.3/21.8
27.3/-
mL)
Retinal-binding
6
37.3/-
1.9/1.2
Control
Albumin
5
39.0/25.4
12.0/4.9
(kU/L)
Glutamine pyruvic transaminase (U/L) Bilirubin
4
35.0/30.0
14.8/23.6
mL)
Cholinesterase
3
32.1/29.1
(It&?/
(mg/lOO
Creatinine
2
27.7/32.5
27.0/92.0
mL)
1.8/3.0
are expressed
model
as day l/day
serum
small intestinal
absorption.
Measurements formed
concentrations
of D-xylose
according
mecha-
of
D-XylOSe
in serum
and urine
absorption
Bateman
function
was based that
means of a nonlinear
on variables
was fitted
were per-
regression
of the
derived
to the measured
using a computer
from a data by
program
of
et al.” as follows: C(t) = A (eeket - eekat),
in which dependent
C is serum
concentration
general constant
rate constant rate constant
of D-xylose of
corresponding determined
D-XylOSe
half-life.
absorption
from
ke is
the body; ka is
from the lumen;
The area under
by approximation
A is dose-
by extrapolation);
elimination
and t is
the curve (AUC) was
according
to the trapezoidal
rule.
The cumulative
of six patients
excretion
in the
five of six patients
test
group
in the
had
control
lower group
of D-xylose
3.8 + 0.9 g in the control
group
the mean value in the controls of normal
during
the 5-
was 7.4 + 1 .l g in the test group
as given
and
(P < 0.05; Figure
l),
being lower than the limit
by Craig and Atkinson.*’
The course of serum D-xylose concentration groups
after 9 days of TPN
serum
concentrations
is shown
of D-xylose
were significantly
in the two
in Figure
2 hours
2. The
after enteral
different
between
the
groups (38.7 5 3.0 vs. 27.8 + 2.9 mg/lOO mL in peptide and control groups, the lower limit
respectively;
of normal
five of the six patients
P < 0.05). Considering
at 2 hours (30 mg/lOO
mL),
in the control group had decreased
values. The results
from the pharmacokinetic in Table 4. Significantly
tide-supplemented
evaluation higher
was observed
are
maximum
in the dipep-
group (P < 0.05). Similarly,
under the calculated curves until the maximum concentration and over the entire experimental were considerably greater the conventional solution.
R0SUltS and
of D-XylOSe than the 5-hour
output
D-xylose serum concentration
Differences were evaluated with the U test according to Wilcoxon, Mann, and Whitney tests. All data are expressed as mean + SEM.
Five
urinary
hour test period
summarized
Statistics
excretion
higher
administration
of D-xylose;
(calculated
had
reference value of 5.6 g.32-34
were used to evaluate
to Roe and Rice.‘” Pharmacokinetics
D-xylose
Yamaoka
by renal and nonrenal
the T-hour urinary excretion
and the 2-hour
25.8(14.9)/56.2 (45.8) 1.5(0.9)/1.9 (2.1)
9.
and elimination
nisms. ‘a,*’ In addition,
--/122.0 1.8/1.1
the areas serum period
with the dipeptide than with However, no differences were
observed for the time at maximum serum concentration and for the absorption or elimination half-life times.
1598
TREMEL ET AL.
GASTROENTEROLOGY Vol. 107, No. 6
Discussion
for physiological
The small bowel mucosa is a rapidly
regenerating
tissue. Use of parenteral
nutrition
as the source of nutri-
ents results in impaired
function
and villous
Several factors have been proposed
these changes, such as the absence of luminal dietary
amines,
and/or
fermentable
changes
in neurohormonal
growing
body of evidence
atrophy.2-5
to be responsible fibers”
events.38
as well as
In recent
has indicated
for
substrates,35 years, a
that the onset
of hypoplasia and hypofunction occurs as early as after 3 days of TPN in ratszT3 and that the absence of glutamine in conventional
TPN formulas
may be partly responsible
for this process.5,39V40There is now convincing that during tamine
long-term
parenteral
is the principal
epithelial
cells.’ Accordingly,
with convincing
addition
healing
dard TPN preserved
of the injured
or even enhanced
transport,
absorption,
an experimental procedure.
showed
with
two-step
It is concluded
Table 3. Composition
bowel
Monosaccharide morphology TPN
after
absorptive
and barrier
function
of the
graft.42
Recent
studies
suggest
that patients
velop glutamine depletion quirements are accelerated or parenteral
glutamine
efits include
maintained
supplementation.6*7239
mine concentrations, enhanced
protein
translocation,‘” The present
or restored
improved
These ben-
intracellular
nitrogen
gluta-
balance,‘7.‘9V25243
synthesis,‘7943’44 decreased
and reduced clinical
effect of glutamine function
who tend to de-
at a time when intestinal remay also benefit from enteral
study attempted
supplementation
by examination
bacterial
hospitalization.‘9~20 to elaborate on gastrointestinal
of the enteral
absorption
ity. The D-xylose test used is feasible in a clinical and is easily tolerated
by patients.
nutrients.
is to be considered
during
Therefore,
as an integrated
efficacy of the entire
The conventional of serum
D-
of the
this simple test
assessment
of the
duodenum.27229,45+46
test is based on single measurements
D-xylose 5 hours
portion
which is also the major site of absorption
for many important absorption
capacsetting
The carbohydrate
xylose is chiefly taken up by the proximal small intestine,
the
concentration
after an enteral
and urinary
excretion
load of the test sub-
this procedure is criticized because stance. *’ Generally, of the great variability of the results.27,29,45 In the present study,
great efforts were made to exclude
known
factors
transplantation
glutamine
is essential
l-
of Amino Acid (Peptide) Solutions Control solution (Traumasteril 10%) W)
L-lsoleucine L-Leucine L-Lysine (as hydrochloride) t.-Methionine L-Phenylalanine L-Threonine L-Ttyptophan L-Valine L-Arginine I.-Histidine Glycine L-Alanine L-Proline L-Serine NAcetyl-Lcysteine (= 0.65 g L-cysteine) Nacetyktyrosine (= 1.68 g L-tyrosine) L-alanyk-glutamine (= 8.18 g alanine + 13.42 g glutamine)
mucosal
fed rats without5
and mucosal
that
nitrogen structure,
intestinal
Ala-Gln-enriched small
provi-
source to stan-
in parenterally
septic complications.41
water
glu-
mucosa.6’7 Similarly,
as stable glutamine
and function
be preserved
overall
of intestinal
or with systemic could
studies
improves
maintenance
of Ala-Gln
cellularity
animal
glutamine
supports
and promotes
regimens,
fuel for the intestinal
evidence that enteral or parenteral
sion of exogenous economy,
feeding
metabolic
evidence
intestinal
Test solution (Aminosauren 10% DP) (g/L)
5.00 7.40 6.60 4.30 5.10 4.40 2.00 6.20 12.00 3.00 14.00 15.00 15.00 -
5.00 7.40 6.60 3.66 3.573 4.40 2.00 6.20 12.36 3.09 8.00 -
-
0.87
-
2.07
-
11.00 5.00
20.00
*
1lr TPN-
Figure 1. Cumulative 5-hour excretion of Bxylose after a gastric dose of 25 g on the ninth day of the study. The patients received TPN without (TPN-; n = 6) or with (TPN+; n = 6) Ala-Gln supplementation. *P < 0.05.
MUCOSA AND GLUTAMINE IN THE CRITICALLY ILL
December 1994
possibly
influencing
the results.
A modified
TaMe 4. Phannacokinetic
test (com-
intravenous and enteral administration of the Dxylose) was performed in patients with similar age and
Evaluation
bined
sex distribution and/or
(Table
kidney
Repeated
functions
and under
similar
of liver
medication.
enabled formal kinetic analysis the distinct Ddata.*“*’ Consequently,
absorption
differences
evaluation indicate important pacity during critical illness. edge, using
impairment
determinations
of the obtained xylose
1) without
as derived
from the kinetic
changes in absorption caAccording to our knowl-
there are no previously published this modified method in intensive
reference data care unit pa-
tients. Urinary
excretion
and serum concentration
were at lower limit
of normal*’ in control
of D-xylose patients
ures 1 and 2). These findings
indicate
tion capacity
portion
of the small intes-
Indeed,
the calculated
of the proximal
tine with conventional may be consistent
TPN.
with a reduction
as the possible
morphological (Figures
measured
data
evaluation
(Table
apparently
maintained
supplemented
fects of glutamine
all
2B) as well as kinetic
in patients
TPN during
data
In contrast,
that intestinal critical
function
receiving illness.
dipeptide-supplemented
Maximum o-xylose serum concentration (mg/IOO mL) Time at maximum serum concentration (hour)
Test group
Control group
41.2 + 6.0
27.2 2 2.8”
2.4 -c 0.2 1.2 2 0.04 2.1 -f 0.3
fi,za (hour) fi/ze (hour) AUC during the entire experimental period (mg, h-1.100 mL_‘) AUC until maximum serum concentrate (mg. h-l. 500 mL_l)
135.7
2.1 -+ 0.3 1.3 ? 0.2 1.9 * 0.3
92.8 ? 10.3”
2 17.6
56.4 2 9.2
31.7 ? 4.5a
NOTE. Results are mean -c SEM. “Significant difference with test group; P < 0.05.
absorp-
of the mucosal surface
correlate.
1 and
4) suggest
a reduced
(Fig-
1599
is
Ala-Gln-
Beneficial
ef-
TPN on gut
integrity
in patients
with
inflammatory
bowel
disease
and neoplastic disease have also been reported by van der H&t et a1.47 After 2 weeks of TPN, intestinal permeability (determined
as the ratio between
mannitol
after an enteral
receiving
glycyl-L-glutamine
tients without
glutamine
hypothesis
that provision
tides promotes Although definitive glutamine
with
increased
supplementation. our data
to 13.2 in all pa-
These obser-
strongly
of parenteral
and
in patients
(20 g corresponding
whereas permeability
combined
lactulose
load) was unaltered
g glutamine), vations
urinary
support
glutamine
the
dipep-
gut integrity. the
present
statements
knowledge
concerning
on the intestinal
does
not
the specific
mucosa,
permit
action
of
it is of interest
to
consider some possible modes of operation,
Indeed, gluta-
mine loading is associated with increased glucagon concentration in the portal blood,48 and a high concentration of this hormone glutaminase,49 lization
induces an increased thus facilitating
(personal
also conceivable
communication,
activity
enhanced
of intestinal
glutamine
February
uti-
1993). It is
that the specific effect of glutamine
in
enhancing intestinal cellularity is partly due to a stimulation of enteroglucagon secretion,‘” thereby regulating uptake and utilization of glutamine. A crucial and yet unresolved question is the appropriate daily requirement of glutamine during critical ill-
Flgure 2. Absorption kinetics of Dxylose after 9 days of TPN (A) with conventional glutamine (dipeptide)-free nutrition and (B) with Ala-Gln supplementation. Individual nonlinear regressions and the calculated mean function (short and long vertical rules, respectively) are shown. For the calculation, see Materials and Methods. Normal reference concentration of 30 mg/lOO mL at 2-hour sampling is indicated.
ness. Accordingly, in the present study, administration of 12 g glutamine per day as dipeptide Ala-Gln to severely ill patients obviously preserved intestinal function compared with glutamine-free TPN. Similarly, provision of 13 g glutamine as glycyl-L-glutamine prevented deterioration of gut permeability in patients with inflammatory bowel disease and neoplastic disease.47 In excellent agreement with these results, administration of the same
1600
TREMEL ET AL.
amounts nated
of glutamine
trauma-induced
improved
nitrogen
synthesis.43 vision
GASTROENTEROLOGY Vol. 107, No. 6
to postoperative muscle
of a physiological
for metabolic
glutamine
data suggest
amount
the increased
fuel during
critical
and
protein
19. Ziegler TR, Young LS, Benfell K, Scheltinga M, Hortos K. Bye R,
that daily pro-
of glutamine intestinal
AA, Antin JH, Schloerb PR, Wilmore DW. Glutamine-enriched intravenous feedings attenuate extracellular fluid expansion after a standard stress. Ann Surg 1991;214:385-395.
elimi-
depletion
balance’4,25*43 and promoted
These combined
g) can compensate
patients
Morrow FD, Jacobs DO, Smith RJ, Antin JH, Wilmore DW. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, doubleblind, controlled study. Ann Intern Med 1992; 116:821-828.
(12 - 15
requirement
illness.
20. Schloerb PR, Amare M. Total parenteral nutrition with glutamine in bone marrow transplantation and other clinical applications (a randomized, double-blind study). JPEN 1993; 17:407-413. 21. Stehle P, Pfaender P, Fiirst P. lsotachophoretic analysis of a
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39. 40. 41.
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Received May 3, 1993. Accepted July 22, 1994. Address requests for reprints to: Ludwig Sacha Weilemann, M.D., Medical Clinic II, Johannes-Gutenberg-University, Langenbeckstrasse 1, 55131 Mainz, Germany. Fax: (49) 613-123-2469. Supported by Fresenius AG (Bad Homburg, Germany).