Departments of 1 Diabetes, Net protein loss and
large decreases in plasma glutamine concentration are characteristics
of critical illness. We have used [2-15N]glutamine and
[1-13C]leucine to
investigate whole body glutamine and leucine kinetics in a group of
critically ill patients and matched healthy controls. Glutamine
appearance rate (Ra,Gln) was
similar in both groups. However, in the patients, the proportion of
Ra,Gln arising from protein
breakdown was higher than in the control group (43 ± 3 vs. 32 ± 2%, P < 0.05). Glutamine metabolic
clearance rate (MCR) was 92 ± 8% higher
(P < 0.001), whereas plasma
glutamine concentration was 38 ± 5% lower
(P < 0.001) than in the control
group. Leucine appearance rate (whole body proteolysis) and
nonoxidative leucine disposal (whole body protein synthesis) were 59 ± 14 and 49 ± 15% higher in the patients
(P < 0.001). Leucine oxidation and MCR were increased in the patients by 104 ± 37 and 129 ± 39%, respectively (P < 0.05). These
results demonstrate that critical illness is associated with a
major increase in protein turnover. The acute decrease in
plasma glutamine concentration and the unaltered plasma
Ra,Gln suggest that the increase
in proteolysis is insufficient to meet increased demand for glutamine
in this severe catabolic state.
stable isotopes; leucine; age
CRITICAL ILLNESS resulting from trauma, surgery, or
sepsis is associated with altered metabolism characterized by an
increased catabolic rate, negative nitrogen balance, wasting of lean
body mass, immunosuppression, and compromised wound healing. The muscle loss is thought to be due to the mobilization of amino acids for high
priority use by organs in the splanchnic area for gluconeogenesis, oxidation, ureagenesis, and protein synthesis and also as substrates for the immune system and wound healing (18).
Glutamine is the most abundant amino acid in both plasma and the free
intracellular amino acid pool in skeletal muscle (4). Because most
tissues have the ability to synthesize glutamine, it is defined as a
nonessential amino acid. However, free glutamine concentrations are
extremely labile, and marked decreases have been reported in a variety
of catabolic states (3, 37). This suggests that during serious illness
a deficiency in glutamine availability may develop and has led to the
idea that glutamine is a conditionally essential amino acid (24). At
present, glutamine is not routinely added to parenteral nutrition
solutions, but recent clinical trials suggest that glutamine
supplementation improves both nitrogen balance and gut mucosal
integrity and decreases the number of infections and length of hospital
stay (36, 42).
The use of
[1-13C]leucine as a
tracer to measure rates of whole body protein breakdown and synthesis
is a well-established technique that has been applied to a variety of
clinical conditions (19). The measurement of whole body plasma
glutamine flux by use of glutamine labeled with
15N has also been developed,
allowing experimental and clinical investigations of glutamine
metabolism. Healthy subjects and the effects of various catabolic
hormones on glutamine metabolism have been studied (7, 10, 11, 20, 28).
However, despite the current clinical interest in the benefits of
glutamine supplementation, there have been very few tracer studies
investigating glutamine metabolism in patient groups, particularly
critically ill patients. To our knowledge there have been no published
reports of studies using stable isotope tracer techniques to measure
glutamine metabolism in critically ill patients soon after the onset of
illness in a general intensive care unit (ICU).
The aim of the present study was to use
[2-15N]glutamine and
[1-13C]leucine to
investigate whole body glutamine and leucine metabolism in a group of
critically ill patients and a group of matched healthy controls. The
importance of matching the critically ill group for age and weight was
also studied by comparing glutamine and leucine kinetics in a young and
an elderly control group.
Materials
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
Subjects
Seven severely ill patients (age range 32-76 yr) in the ICU of St. Thomas' Hospital were studied. Details of their clinical and metabolic characteristics are given in Table 1. The severity of illness was evaluated on the day of the study by use of the APACHE II and TISS score systems (Table 1). Five of the patients had undergone emergency abdominal surgery within 24 h before the study. Patients 3 and 5 had had previous infections, but none of the patients had evidence of active infection (negative blood, sputum, and urine culture) during the study period. All patients were studied after a fasting period of between 12 and 24 h. Six of the seven patients were admitted acutely and had previously been self caring and independent, responsible for their own diet. The remaining patient (patient 5) had been receiving an oral hospital diet for 19 days before the study.
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A group of 12 control subjects were recruited for the study; their physical characteristics are shown in Table 2. All were in good general health. There was no recent relevant medical history, and none of the controls was on any regular medication. The healthy adults were divided into two groups on the basis of age, young (<35 yr) and elderly (>60 yr).
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The protocol was approved by the Ethics Committee, Guy's and St. Thomas' National Health Service Trust. All control subjects provided informed written consent; written consent was obtained from relatives or friends of ICU patients.
Study Protocol
ICU patients.
All ICU patients were fasted for 12 h before the start of the study.
Indwelling arterial and central venous lines were used for blood
sampling and for the tracer infusion, respectively. After baseline
sampling, priming boluses of
[1-13C]leucine (1 mg/kg) and
NaH13CO3
(0.2 mg/kg) were injected, and 4-h constant infusions of
[2-15N]glutamine (2.5 mg · kg
1 · h
1)
and [1-13C]leucine (1 mg · kg
1 · h
1)
were started. Blood and breath samples were taken at 210, 215, 220, 225, 230, and 240 min for steady-state measurement of plasma glutamine
and
-ketoisocaproic acid enrichment, glutamine and leucine
concentrations, and breath
13CO2
enrichment. Blood samples were also taken at baseline and steady state
for the measurement of metabolite and hormone levels [plasma
albumin, C-reactive protein, glucose, insulin, insulin-like growth
factor I (IGF-I), cortisol, thyroid hormones, and amino acids].
For glutamine analysis, 0.5-ml lithium heparin plasma aliquots were
mixed with 100 µl of internal standard (100 nmol/l [U-13C5]glutamine).
All samples were stored at
70°C until analysis.
Healthy subjects. After an overnight fast, the healthy subjects were admitted to the research area of the Diabetes and Endocrine Day Centre (St. Thomas' Hospital). Height and weight were recorded and body composition was measured using the technique of bioelectrical impedance (Tanita, Tokyo, Japan) (25). Cannulas were inserted into an antecubital vein for isotope infusion and a superficial vein of the contralateral hand for blood sampling. During the sampling period, the hand was placed in a heated box (air temperature 60°C) to produce arterialized venous blood (1). An infusion protocol identical to that of the ICU patients was used.
Total CO2 production, resting energy expenditure, and oxygen consumption were measured at steady state with indirect calorimetry (Medgraphics, Cardiokinetics, Salford, UK).Experimental Methods
The isotopic enrichment and concentration of glutamine were determined from the tert-butyldimethylsilyl derivative by use of a method modified from Wolfe (41). Glutamine concentration was determined by reverse isotope dilution with L-[U-13C5]glutamine (Bioquote, North Yorkshire, UK) as the internal standard. Analysis by gas chromatography-mass spectrometry (GC-MS; MSD 5971A, Hewlett-Packard, Berkshire, UK) used electron impact ionization with selected ion monitoring of the [M-butyl]+ ions at mass-to-charge ratios of m/z 432, 433, and 436. The isotopic enrichment ofCalculations
Measurements of leucine and glutamine metabolism were calculated using standard isotope dilution equations. Leucine appearance rate, a measure of whole body protein breakdown (Ra,Leu; in µmol · minGlutamine Ra,
Rd, and MCR values were calculated
using analogous equations. Because glutamine is a nonessential amino
acid, Ra,Gln is derived from both
protein breakdown (BGln) and de
novo synthesis (DGln). Glutamine
release from protein breakdown was estimated as 0.78 × Ra,Leu (14), and
DGln was calculated as DGln = Ra,Gln BGln (21).
Statistics
All data are presented as means ± SE. Steady state for plasma glutamine enrichment and concentration was confirmed as an insignificant correlation with time (P > 0.05) by use of repeated-measures ANOVA (NCSS 6.0, Dr. J. Hintze, Kaysville, UT). Comparisons between groups were made by standard two-tailed unpaired t-tests with equal or unequal variance as necessary. The cortisol and insulin data were log transformed before analysis. ![]() |
RESULTS |
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ICU Patients vs. Matched Controls
Table 1 shows the details of the seven ICU patients studied. The severity of the illness is indicated by the TISS and APACHE II scores (9, 23). These indexes identified the patients as being severely ill and dependent on cardiorespiratory and nutritional support. The seven healthy volunteers selected as controls were well-matched to the ICU patients for sex, age, weight, and body mass index (BMI, Table 1). Figure 1 shows the plasma glutamine enrichments and concentrations for the ICU patients and their matched controls during the final 30 min of the tracer infusion. The glutamine and leucine data for the ICU patients and their matched controls are summarized in Figs. 2 and 3. Glutamine MCR was significantly higher in ICU patients compared with the matched controls (P < 0.001). There was no difference in whole body Ra,Gln (or Rd,Gln) between the two groups. However, there was a significant increase (P < 0.05) in the proportion of Ra,Gln arising from protein breakdown and a resulting decrease in the proportion arising from de novo synthesis in the critically ill patients (P < 0.05).
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|
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Ra,Leu, OxLeu, MCRLeu, and NOLD were all significantly higher in the critically ill patients (P < 0.001, P < 0.05, P < 0.05, and P < 0.001, respectively). Net 24-h protein balance (Fig. 4) was significantly more negative in the critically ill subjects (P < 0.01).
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The plasma amino acid profiles are given in Table 3. Plasma threonine (P < 0.01), serine (P < 0.001), glutamine (P < 0.001), glycine (P < 0.01), alanine (P < 0.001), leucine (P < 0.05), lysine, (P < 0.01), histidine (P < 0.01), and arginine (P < 0.01) concentrations were significantly lower in the patients, whereas phenylalanine (P < 0.01) and aspartate (P < 0.01) levels were significantly higher. Metabolite and hormone profiles are shown in Table 4. Thyroid hormone and IGF-I levels were significantly lower (P < 0.05) in the patients. There was no difference in the plasma glucose or insulin levels between the two groups. Cortisol levels were higher in the ICU patients (P = 0.069, range 242-2,393 nmol/l).
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Control Subjects
The characteristics of the control subjects are shown in Table 2. They were divided into two groups on the basis of age; both groups contained three males and three females. The elderly (>60) group had a mean age of 68 ± 2 yr, whereas the young (<35) group had a mean age of 28 ± 2 yr. The mean weights of the groups were 80.3 ± 4.2 and 69.8 ± 3.0 kg, respectively (P = 0.068). BMI and fat mass were significantly higher in the elderly group, 28.1 ± 1.60 vs. 23.2 ± 0.42 kg/m2 (P < 0.05) and 28.8 ± 4.7 vs. 17.1 ± 2.2 kg (P < 0.05), respectively. Lean body mass (LBM) was not significantly different between the two groups (51.5 ± 6.3 vs. 52.7 ± 4.6 kg).Table 5 summarizes the glutamine and
leucine data from the healthy volunteers. Whole body plasma glutamine
flux (Ra,Gln) was significantly
lower in the elderly group (4.15 ± 0.33 vs. 5.20 ± 0.22 µmol · min1 · kg
1,
P < 0.05), but there was
no difference in the proportion of Ra,Gln arising from de novo
glutamine synthesis or protein breakdown in the two groups. However,
when the results were expressed per kilogram LBM, the difference in
Ra,Gln was no longer evident (6.96 ± 0.37 vs. 6.69 ± 0.51 µmol · min
1 · kg
LBM
1). There were no
significant differences in glutamine MCR or in any of the measurements
of leucine metabolism (Ra,Leu,
OxLeu, MCRLeu, and NOLD) in the two
groups of volunteers, whether the results were expressed per kilogram
body weight or per kg LBM.
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Table 3 shows that plasma amino acid profiles were similar in both groups of healthy volunteers, with the exception of decreased circulating serine (P < 0.05) and histidine (P < 0.05) and increased plasma cystine concentrations in the elderly subjects. Metabolite and hormone profiles are shown in Table 4. Plasma glucose levels were significantly higher (P < 0.05) in the elderly volunteers. Cortisol levels were significantly higher (P < 0.05), and IGF-I levels were significantly lower (P < 0.05) in the elderly group, but there were no differences in insulin or thyroid hormone levels.
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DISCUSSION |
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There is currently intense clinical interest in glutamine metabolism in critical illness. Previous studies have reported whole body glutamine turnover measurements in healthy controls, burn patients (20), enterectomized patients (12), and patients with insulin-dependent diabetes (13), but there have been no studies investigating glutamine metabolism in acute critical illness. In this study we have shown that, despite a marked decrease in plasma glutamine concentration, whole body plasma glutamine flux was unchanged in critically ill patients. Measured whole body glutamine flux reflects interorgan glutamine transport rates through plasma (10).
Glutamine MCR was increased in the patients, suggesting that this may be the primary mechanism for the fall in glutamine concentration. Because amino acids are removed from blood by a transporter, we would expect this removal to exhibit Michaelis-Menten kinetics (i.e., nonlinear kinetics). There will thus be an inverse relationship between clearance and concentration. Thus, if Ra decreases, concentration will fall and clearance will rise. However, glutamine Ra-to-Rd ratio was unchanged in the ICU patients despite a fall in glutamine concentration. The increase in glutamine MCR in the ICU patients must therefore be due to a change in the transport process, e.g., an increase in efficiency.
The percentage of the glutamine flux arising from protein breakdown was increased in this patient group, but the observed decrease in plasma glutamine concentration indicates that this increase was insufficient to meet the increased demand for glutamine. Marked alterations were also observed in protein metabolism, as reflected by the increases in leucine Ra, NOLD, MCR, and oxidation. These changes resulted in an increased net negative protein balance in the critically ill patients.
Marked differences were observed in the circulating levels of amino acids between the patients and their matched controls. In addition to the decreased plasma glutamine concentration, the levels of the essential amino acids leucine, lysine, threonine, and histidine were lower in the patients. Similar changes have been observed in previous studies (18, 33), and it has been suggested that elevated levels of stress hormones, by increasing splanchnic amino acid uptake, may be responsible for the decreased plasma amino acid concentrations (39). The decrease in glutamine levels may indicate an inability of glutamine synthetic mechanisms to meet the increased metabolic demand of critical illness. These findings have led to the suggestion that glutamine may behave as a "conditionally essential" amino acid. In contrast, there was an increase in the plasma phenylalanine concentration. This response has been observed in previous studies, and evidence suggests that levels of phenylalanine continue to rise with continuing illness (18, 33).
The metabolic response to critical illness is an integrated process, with elevated levels of cytokines and inflammatory mediators and increased concentrations of the "catabolic" hormones (catecholamines, glucocorticoids, and glucagon) (35). Changes observed in the patients in this study included elevated plasma cortisol concentration and decreased levels of free thyroid hormones.
Previous studies have investigated the effects of catabolic hormone infusions on glutamine metabolism in healthy volunteers. These have demonstrated that elevation of plasma cortisol to levels observed after trauma resulted in a 15% increase in whole body protein breakdown and a 40% increase in glutamine flux (11). This increase in flux was primarily due to a 55% increase in de novo glutamine synthesis, and it resulted in a significant increase in the plasma glutamine concentration. More recently, this cortisol-mediated increase in flux was shown to be dose dependent (7). In contrast, a triple hormone infusion of epinephrine, cortisol, and glucagon increased whole body glutamine flux and MCR and decreased plasma glutamine concentration (20). These studies suggest that these counterregulatory hormones may regulate the rate of glutamine metabolism, possibly through effects on glutamine transporters (30); however, they cannot fully mimic the complex changes occurring in critically ill patients.
Although there are no comparable studies in ICU patients, whole body
glutamine flux has been measured in patients after burn injury by use
of a similar stable isotope technique (20). Whole body glutamine flux
was higher in burns patients compared with the values we obtained (7.2 ± 0.6 vs. 4.9 ± 0.3 µmol · min1 · kg
1).
Although the decreases in plasma glutamine concentration were similar
in the two studies, a significant increase (60%) in glutamine flux was
reported in the burns patients compared with a control group, in
contrast to the unchanged value in the present study. These changes
were associated with a marked elevation in glutamine MCR in the burns
patients (200%) compared with control subjects, in contrast to the
92% increase recorded in our patient group. However, these
measurements were made 2 wk after the burn injury, whereas the patients
in the present study were studied within days of admission to the ICU.
The leucine kinetic data in the critically ill indicated an increase in whole body protein synthesis and breakdown of 49 and 59%, respectively, and an increase in leucine oxidation (105%), indicating use of protein as an oxidative fuel. In addition, the plasma leucine concentration was decreased as a result of the increased utilization of leucine (indicated by the elevated leucine MCR). Isotope tracer methdology has been used to investigate whole body protein turnover in a variety of catabolic states, with conflicting results. A study in patients with multiple organ failure, using [1-13C]leucine, demonstrated significant increases in protein breakdown, synthesis, and leucine oxidation compared with control subjects (2). Plasma cortisol concentration was found to be the most significant predictor of protein breakdown and leucine oxidation in these patients.
In contrast, studies of protein metabolism after elective hysterectomy have shown that both whole body protein synthesis and breakdown decrease compared with the preoperative state (8). Ribosomal analysis and tracer studies have also shown that muscle protein synthesis decreases after uncomplicated elective surgery (15, 31, 40). With use of [15N]alanine as a tracer, a 37% increase in protein synthesis and a 79% increase in protein breakdown have been reported in fed patients 3-5 days after multiple skeletal trauma compared with controls receiving a similar diet (5). More recently, it has been shown that albumin and fibrinogen synthesis increased, whereas muscle protein synthesis decreased, in fed head-trauma patients (27). It is likely that the apparently conflicting data from these studies reflect the heterogeneity of the patient populations, the severity of illness, the nutritional status, the prior health of the patients, and the timing of the studies.
The major limitation of the whole body protein measurement is that this approach reflects the average rates of protein turnover in all tissues. However, during times of severe stress, different tissues in the body may behave differently. The majority of the measured increases in proteolysis may reflect increased muscle protein breakdown, as skeletal muscle is the largest protein pool in the human body. It is likely that, in part, the increase in protein synthesis reflects the increased synthesis of acute-phase proteins by the liver, tissue repair, and the immune response (leukocyte proliferation and cytokine production). This alteration of protein balance would account for the clinical observations of lean tissue loss in ICU patients.
The importance of matching the critically ill group for age and weight was studied by comparing glutamine and leucine kinetics in a young and an old control group. Leucine MCR, oxidation rate, incorporation into and release from body protein were similar in the control groups. This is in line with previously reported data suggesting that there is no independent effect of age on the measurements of leucine metabolism in postabsorptive adults, whether the results are expressed per kilogram body weight (17) or per kilogram LBM (6, 17, 38). The Ra,Gln value in the young control subjects was similar to previously published values for healthy adults in the same age range (e.g., 7, 11, 29). In contrast, the Ra,Gln value for the elderly group of controls was significantly lower than that in the young controls. However, the increase in body weight in the elderly group resulted from an increase in fat mass, not a decrease in LBM. When the results were expressed per kilogram LBM, there was no age-associated decrease in Ra,Gln, suggesting that the apparent difference in Ra is related to age-associated changes in body composition rather than altered glutamine metabolism.
It is difficult to measure body composition accurately in ICU patients. Bioelectric impedance is the most accessible method, and this was used in the controls in the present study. However, as there is some doubt about the practicality and validity of bioelectrical impedance measurements of body composition in critically ill patients (22, 26), these results suggest that matched controls are necessary when glutamine metabolism is measured in ICU patients.
The patients for our study were recruited in the ICU from patients in whom the clinical decision had been made to use parenteral nutrition. Unlike previous studies reporting glutamine metabolism and most of the studies of leucine metabolism in catabolic patients, we have studied a heterogeneous group. We chose to study these patients because they represent a group in whom there is considerable clinical interest in the potential benefits of glutamine supplementation. The study demonstrates that critical illness is associated with marked alterations in protein metabolism. The increased glutamine clearance with a normal Ra,Gln resulted in a decrease in glutamine concentration, suggesting that the increase in protein breakdown was insufficient to meet the demand for glutamine in these catabolic patients.
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ACKNOWLEDGEMENTS |
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We are grateful to the nurses and staff of Mead Ward (ICU), St Thomas' Hospital, for their patience and support. We acknowledge the assistance of Dr. F. Shojaee-Moradie, S. Imuere, and M. Chaudhury, and the Department of Chemical Pathology, with sample analysis. We also thank P. Forsey, of the hospital pharamacy, for preparation of the tracer solutions.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: N. Jackson, Dept. of Diabetes, Endocrinology and Metabolic Medicine, Fourth Floor North Wing, St. Thomas' Hospital, London SE1 7EH, UK.
Received 30 April 1998; accepted in final form 15 September 1998.
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