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The Role of Glutamine in The Role of Glutamine in Critically IllCritically Ill
Hasanul Arifin
Round Table Discussion31 Januari 2009, Medan
04/19/23 2
The first significant find on glutamine metabolism was by Sir Hans Krebs in 1930. He displayed the hydrolysis and biosynthesis of
glutamine in the kidney. Eight years later, Rose showed that glutamine
is a non-essential amino acid
The year 2000 was The year 2000 was the centenary of the birth of the centenary of the birth of
Sir Hans Krebs who established the Sir Hans Krebs who established the metabolic foundation for ourmetabolic foundation for ourunderstanding of glutamine understanding of glutamine
(Krebs, 1935).(Krebs, 1935).
Proceedings of the Nutrition Society (2001), 60, 403.410 DOI:10.1079/PNS200197
The evidence for glutamine use in the critically-illRichard D. Griffiths
Glutamine is the most abundant free Glutamine is the most abundant free amino acid, comprising about 25% of amino acid, comprising about 25% of the plasma amino acids and 60% of the plasma amino acids and 60% of
the muscle free amino acids.the muscle free amino acids.
Proceedings of the Nutrition Society (2001), 60, 403.410 DOI:10.1079/PNS200197
The evidence for glutamine use in the critically-illRichard D. Griffiths
04/19/23 5
Glutamine (GLN): Features
Amino acid
Rich in nitrogen (N)
Synthesized in the body in many tissues (muscles! ) Stored in muscles
Nonessential Conditionally essential
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Stimulates hepatic glycogen synthesis
Metabolic fuel for rapidly proliferating tissues
(enterocyte, immune (enterocyte, immune cells,)cells,)
Maintain skeletal muscle
Stimulates protein synthesis
Inhibits protein degradation
L-glutamine
Nitrogen and carbon transport
Carrier of nitrogen (as ammonia) and carbon (as glutamate) between tissues
Acid-Base balance
Biosynthesis
Precursor of amino acids, peptide, protein,nucleic acids
Substrate for gluconeogenesis
Potential source of glutamate for glutathione synthesismetabolic functions
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LUNGSLUNGS
SKELETAL MUSCLESKELETAL MUSCLE
BRAINBRAIN
PLASMA PLASMA GLUTAMINE GLUTAMINE
POOLPOOLLIVERLIVER
IMMUNE IMMUNE CELLSCELLS
GUTGUT
KIDNEYKIDNEY
Normal glutamine flux between tissues in the basal stateNormal glutamine flux between tissues in the basal state
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LUNGSLUNGS
SKELETAL MUSCLESKELETAL MUSCLE
BRAINBRAIN
PLASMA PLASMA GLUTAMINE GLUTAMINE
POOLPOOL
LIVERLIVER
IMMUNE IMMUNE CELLSCELLS
GUTGUT
KIDNEYKIDNEY
Trauma induces conciderable changes in glutamine fluxTrauma induces conciderable changes in glutamine flux
04/19/23 9
VascularVascular
GlutamineGlutamine--poolpool LiverLiver
KidneyKidneyGutGut
BrainBrain
LungLung
Skeletal muscleSkeletal muscle
LymphocytesLymphocytesMakrophagesMakrophages
What is the glutamine flow – in normaland catabolic metabolism (trauma/ sepsis)?
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Glutamine synthesis and expenditure are well-balanced
- GLN becomes a conditionally essential amino acid
CRITICAL ILLNESS (e.g. TRAUMA , SEPSIS, BURNS and Surgery)
HEALTHY people
GLN = non-essential amino acid GLN synthesis / expenditure are well-balanced
Conditionally essential … What does that mean?
- GLN requirement is increased: => GLN consumption exceeds synthesis=> State of GLN deficiency=> Important functions cannot be fulfilled sufficiently
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GLN requirement is increased: GLN consumption exceeds synthesis
State of GLN deficiency Important functions cannot be fulfilled sufficiently
GLN becomes a conditionally essential amino acid
CRITICAL ILLNESS (e.g.TRAUMA , SEPSIS, BURNS and SURGERY)
Conditionally essential … What does that mean?
- HEALTHY people
GLN = non-essential amino acidGLN-synthesis / expenditure are well-balanced
Consequences of Consequences of Glutamine deficiencyGlutamine deficiency
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Glutamine consumer mucosa cell, macrophages (1)
No chance for bacteria to break through when mucosa is intact
Basal membrane
Bowel lumen
Macrophages
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Mucosa atrophy in glutamine depletion
Damaged macrophages
Atrophy
Glutamine consumer mucosa cell, macrophages (2)
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Gut-derived sepsis, glutamine and the inflammatoryGut-derived sepsis, glutamine and the inflammatoryresponse syndromeresponse syndrome
Current Opinion in Clinical Nutrition and Metabolic Care 2002, 5:69±75
04/19/23 16
“ (…) A rapid depletion of glutamine stores during critical illness has been reported. A plasma glutamine concentration < 0.42 mmol/L is a risk factor for poor outcome.
Therefore it is likely that during critical illness, the status of glutamine moves from ‘conditionally essential’ to essential (…)”
Glutamine, a life-saving nutrient, but why? Preiser JC, Wernermann J. Crit Care Med 2003
04/19/23 17
Background: Glutamine and Critical Illness
GLN concentrations fall precipitously after injury or illness, including sepsis and septic shock (Wischmeyer PE, NutrClinPract 2003)
GLN deficiency at onset of critical illness/sepsis is correlated with increased mortality (Oudemans-van Straaten, HM et al. Intensive Care Med, 2001)
04/19/23 18
Plasma glutamine depletion and patient outcome in acute ICU admission
Oudemans-van Straaten HM, Bosman RJ, Treskes M, van der Spoel HJI, Zandstra DF
Intensive Care Medicine (2001) 27: 84-90
The “Oudemans-van Straaten-Study”
04/19/23 19
Prospective study
Intensive Care Unit (ICU)
Blood sampling for the determination of plasma glutamine (within 24 hours after ICU-admission)
Severity of illness and predicted mortality were quantified by currently used ICU scoring systems (APACHE II, etc.)
The “Oudemans-van Straaten-Study”
Design
Setting
Interventions
Measurements
Patients 80 severely ill patients, non-electively admitted to ICU
Objective To evaluate whether low plasma glutamine is related to severity of illness and hospital mortality
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Low plasma glutamine at ICU admission is related to mortality.
The “Oudemans-van Straaten-Study”
04/19/23 21
Glutamine depletion is increased withthe severity of the disease
Roth E et al. 1986
Benefits of glutamine in PN therapy... Further evidence
04/19/23 23
Glutamine: Further Evidence…Clinical Studies (1/2)
GLN improves glucose homeostasis
Dechelotte 2006 Critically ill patients Glutamine dipeptide
Bakalar 2006 Multiple Trauma Patients Glutamine dipeptide
GLN improves nitrogen balance
Morlion 1998; Jiang 1999,
Song 2004
Surgical patients Glutamine dipeptide
GLN maintains gut integrity
Tremel 1994 Critically ill patients Glutamine dipeptide
Decker-Baumann 1999 Colorectal cancer patients (Chemotherapy)
Glutamine dipeptide
04/19/23 24
Glutamine: Further Evidence…Clinical Studies (2/2)
GLN strengthens immune defense
Morlion 1998, Jacobi 1998 Surgical patients Glutamine dipeptide
Piccirillo 2003 BMT Glutamine dipeptide
Scheid 2004 Acute leukemia Glutamine dipeptide
Song 2004 Burn patients Glutamine dipeptide
Beneficial effects Beneficial effects of glutamine therapyof glutamine therapy
04/19/23 26
a neurotoxin
04/19/23 27
Glutamine help protect or treat sepsis in two main ways :
04/19/23 28
Glutamine in TPN
Increases protein synthesis andnitrogen balance
Improves gutfunction
Improves immunefunction
Reduced hospital stay
Improvedmood
Reduced waterretention
clinical benefits of glutamine in TPN
04/19/23 29
GASTROINTESTINAL TRACT (protects mucosa barrier) - Major fuel
- Supports nucleotide biosynthesis- May protect epithelial cells against endotoxin/oxidant related injury
- Enhances glutathione concentration post-stress
HEART - Major fuel for cardiomyocytes
IMMUNE CELLS (supports immune function)- Major fuel - Supports neutrophile killing and macrophage function
KIDNEY - Acid/base regulation
- Central role in N transport within the body - NH3 metabolism
Proposed organ-specific effects of GLN in critical illness
Modified from Wischmeyer P, Nutr Clin Pract 2003
GlutamineTherapy
Glutamine Therapy
LUNG - Major fuel for endothelial cell
- Preserves cell metabolism following endotoxin injury
04/19/23 30
Glutamine Pool
Proinflammatory cytokines
Muscle Break down (Cellular GLN stores / Hydratation state)
Muscle Break down (Cellular GLN stores / Hydratation state)
Negative Nitrogen Balance
Negative Nitrogen Balance
Nucleotide Nucleotide Synthesis
Glutathione Synthesis
Glutathione Synthesis
Fuel for Enterocytes Fuel for Enterocytes
Fuel for Immune cells Fuel for Immune cells
Impaired intestinal barrier
Impaired immune cell
Function
Impaired intestinal barrier
Impaired immune cell
Function
Surgical trauma
Impaired antioxidative capacity
Glutamine: The essentialamino acid in catabolic states (surgery, trauma etc.)
04/19/23 31
Reduces Bacterial Translocation
Enhances HeatShock Protein
NucleotideSynthesis
LymphocyteProliferation ↑
Insulin-mediated Glucose Regulation
GlutathioneSynthesis ↑
Intracellular Water ↑
Maintenance of Gut Integrity
Maintenance of Immune Function
Beneficial Effects on Cytokine Biology
Attenuates ExtracellularEdema
Attenuates Oxidant Stressand Injury
CounteractsHyperglycemia
Preserves Cellular Energetics
Eliminates Bacterial/FungalPathogens
GLN Therapy
Potential mechanisms for GLN‘s beneficial effects in critically ill patients
Modified from Wischmeyer P, Nutr Clin Pract 2003
Glutamine and Glutamine and Cellular Protective Cellular Protective
MechanismsMechanisms
04/19/23 33
Glutamine as anGlutamine as an antioxidantantioxidant
Glutathione
• vital role as an antioxidative substance by protecting cells against toxic effects of harmful radicals (leading to increased oxidative stress DEATH).
Glutathione = TripeptideGlutamic acid - Cysteine - Glycine
04/19/23 34
The role of glutamine in glutathione synthesis
Glutathione(Glutamic acid-Cysteine-Glycine)
GlutamineNH3
Glutamine
intracellular
extracellular
04/19/23 35
2 NADP+
2 NADPHVITAMIN E•
VITAMIN E
H2O
Glutamine
H2O2
VITAMIN C
VITAMIN C• 2 GSH
GSSG
RO•, ROO•,HO•, NO•
ROH
Se
len
ium
GLUTATHION-GLU-GLY-CYS
2 O2 • - + 2H+
Zin
c
-Carotene
H2O2 1O23O2
3-Carotene
OCl -
Endogenuous ROSproduction
Vitamin C, E, ß-carotene, selenium, zinc and glutamine act as an antioxidant network
Thus it is important to provide glutamine and vitamin C, E, ß-carotene, selenium and zinc together.
Mice fed supplemented enteral diets andthen challenged with endotoxin showed
maintenance of glutathione levels, with increased numbers of T-cells, and
glutamine prevented the apoptosis of B-cells in the Peyer’s patches while arginine,
glycine or n-3 fatty acids did not
(Manhart et al. 2000).Clinical Nutrition 19, 265.269
Glutamine has beenGlutamine has beenshown to be protective to intestinal shown to be protective to intestinal
cells through heat-shockcells through heat-shockprotein 70 generationprotein 70 generation
Wischmeyer PE, Musch MW, Madonna MB, Thisted R & Chang EB (1997) Glutamine protects intestinal epithelial cells: role of inducible HSP70.
American Journal of Physiology 272, E879.E884.
Glutamine… Good in Theory and
in Practise !
04/19/23 40
Published meta-analyses Published meta-analyses on PN glutamineon PN glutamine
04/19/23 41
• Selection criteria
Randomized clinical trials
Surgical or critically ill adults (excluding cancer, pediatrics, VLBW)
Glutamine (EN or IV) vs. placebo
Clinically important outcomes
Evaluate the impact of GLN on clinically important outcomes (mortality, morbidity, length of hospital stay)
Evaluate the impact of GLN on clinically important outcomes (mortality, morbidity, length of hospital stay)
Crit Care Med 30: 2022; 2002
04/19/23 42
Results:
Critically ill patients: MORTALITY
Surgical patients: LENGTH OF HOSPITAL STAY
INFECTIOUS COMPLICATIONS
Greater treatment effect with parenteral GLN at a high dose
Glutamine: Meta-Analysis (1/4)
Length of hospital stay (significant)
Infectious complications (significant)
Results:
Clinical Nutrition Supplements (2004) 1, 17-23
Glutamine: Meta-Analysis (2/4)
04/19/23 44
Nine randomised studies on GLN supplemented PN therapy in abdominal surgery (total n= 373).
Improved N-balance (significant)
Decreased infection rate (significant)
Reduced lenght of hospital stay (significant)
Results:
Glutamine: Meta-Analysis (3/4)
World J Gastroengeral 2006; 12 (46): 7537 - 7541
04/19/23 45
Three randomised studies on GLN supplemented PN therapy in BMT patients fit to the chosen criteria, (total n= 108).
Length of hospital stay (significant)
Incidence of positive blood cultures
Results:
Glutamine: Meta-Analysis (4/4)
Enteral or Enteral or Parenteral ?Parenteral ?
04/19/23 47
This trial evaluated 363 patients requiring mechanical This trial evaluated 363 patients requiring mechanical ventilation (median APACHE II score=14); of these, 85 ventilation (median APACHE II score=14); of these, 85 had trauma. had trauma. Intervention: Intervention: The intervention solution contained 20 g/l The intervention solution contained 20 g/l glutamine and the control solution was isojoulic and glutamine and the control solution was isojoulic and isonitrogenous.isonitrogenous.
04/19/23 48
The outcomes
• similar in the two groups: – death within 6 months:
• glutamine group 15% (27 of 179) vs control group 16% (30 of 184); p=0.75; relative-risk, 0.95 (95% confidence interval,0.71–1.28);
– severe sepsis: glutamine group 21% (38 of 179) vs control group
23% (43 of 184); p=0.62; relative risk, 0.94 (95% confidence interval, 0.72–1.22).
04/19/23 49
Conclusion:Conclusion:
This clinical trial This clinical trial did not support the use
of enteral glutamine supplements in similar supplements in similar cohorts of critically ill patients.cohorts of critically ill patients.
Intensive Care Med (2003) 29:1710–1716Intensive Care Med (2003) 29:1710–1716DOI 10.1007/s00134-003-1937-2DOI 10.1007/s00134-003-1937-2
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There is a lack of clinical evidence showing enteral supplements can significantly raise plasma or tissue glutamine levels for a
sustained period. Indeed, there is contrary evidence that suggests plasma glutamine levels are slower to recover with the same dose
of glutamine given by the enteral route compared with the parenteral route (Fish et al. 1997).
Proceedings of the Nutrition Society (2001), 60, 403.410 DOI:10.1079/PNS200197
The evidence for glutamine use in the critically-illRichard D. Griffiths
04/19/23 51
The enteral route may be sufficient when given early to thenon-infected patient (e.g. following trauma) to improve
GALT function and the immune defence against infection (Houdijk et al. 1998), but adequately
delivery is a challenge.However, for the already severely-stressed or infected ICUpatient enteral supplements alone may be inadequate, and
parallel parenteral support is likely to be required.
Proceedings of the Nutrition Society (2001), 60, 403.410 DOI:10.1079/PNS200197
The evidence for glutamine use in the critically-illRichard D. Griffiths
Recommendations for glutamine-therapy?
Recommendations from European Societies (1/2)
Austrian Society for Clinical Nutrition (2002)
Glutamine is indicated in patients with SIRS / MODS and/ or after prolonged enteral fasting (> 7 days)
Glutamine is not stable in its free form – must be provided as dipeptide (alanyl-L-glutamine or glycyl-L-glutamine)”
Recommended dosage > 20 g Glutamine/ d
SIRS = Systemic Inflammatory Response Syndrom
MODS = Multi-Organ Dysfunction
04/19/23 54
For elective surgery the working group considers the indication for the parenteral administration of glutamine in severely malnourished patients who cannot be fed enterally and therefore need PN.
German Guideline PN 2007: Surgery and Transplantation - in press
Recommendations from European Societies (1/2)
ESPEN Course Book, Basics in Clinical Nutrition (2004)
Nutritional support in critically ill and septic patients:
“The results of a few more recent studies suggest that glutamine, particularly when given intravenously (infused as glutamine dipeptides) given at a dosage of 20g GLN per day may have positive effects on outcome on critical illness.”
04/19/23 56
High-dose parenteral GLN (up to 0.3 g/ kg BW per day) appears to demonstrate the greatest potential benefit
Suggestions for clinical use of GLN:
-Critically ill patients
-Pre- or postsurgical patients
-Oncology patients
0.35- 0.57 g GLN/ kg BW per day
Nutrition in Clinical Practice 18: 377-385, 2003
No evidence of harm has been observed in studies conducted to date
To whom should GLUTAMINE To whom should GLUTAMINE be administered? be administered?
04/19/23 59
Dipeptiven® Sales Folder, 2004
Glutamine may be benefecial in the following patient groups
04/19/23 60
• 15 ICU patients with head trauma and brain injuries
• Rate of glutamine infusion: 0.34 g gln/kg over 20 hour-period for one day or placebo the other day/randomized
• Microdialysis catheter placed close to the injured area
• Measurement of brain glutamate during IV glutamine supplementation
Results & Conclusion• iv glutamine in clinically relevant doses leaves the cerebral glutamate
unaffected. • The results suggest it to be safe, in terms of intracerebral glutamate
concentration, to use iv glutamine as a nutritional adjunct to head trauma patients.
Glutamine in head trauma patients
Berg et al. Intensive Care Med 2006, 32: 1741-1746
GLN therapy: GLN therapy: Start and durationStart and duration
04/19/23 62
GLN therapy
Study results show greater treatment effect when administered for at least 5-7 days.
=> Goeters 2002: Reduction in MORTALITY in subgroup receiving GLUTAMINE > 9 d
GLN-therapy should start as soon as PN starts.
There is no rationale to withold GLN. Therapy should start early and continued for at least 5 days.
There is no rationale to withold GLN. Therapy should start early and continued for at least 5 days.
04/19/23 64
Glutamine : Contra-indications
Contra-indications
Severe renal insufficiency (creatinine < 25 ml/ minute)
Severe hepatic insufficiency
Severe metabolic acidosis
Hypersensitivity of any of the ingredients
Patients with inborn errors of amino acid metabolism
04/19/23 65
Bagaimana cara pemberian ?Bagaimana cara pemberian ?
• Lindungi dengan kaloriLindungi dengan kalori
• Campurkan kedalam larutan asam Campurkan kedalam larutan asam amino lain yang lengkap susunan asam amino lain yang lengkap susunan asam
aminonya.aminonya.
TAKE HOME MESSAGETAKE HOME MESSAGE
Take home messageTake home message GLN levels are low following major
surgery / in critical illness Low plasma GLN is associated
with increased mortality GLN therapy influences patients‘outcome
positively and is safe GLN is not provided by regular amino acid solutions
GLN therapy should start early/ continued for > 5 days GLN can be considered as a pharmaconutrient GLN as source of glutathione (anti oxidant)
GLN levels are low following major surgery / in critical illness
Low plasma GLN is associated with increased mortality
GLN therapy influences patients‘outcome positively and is safe
GLN is not provided by regular amino acid solutions GLN therapy should start early/ continued for > 5 days
GLN can be considered as a pharmaconutrient GLN as source of glutathione (anti oxidant)
04/19/23 68
Thank you for Thank you for listeninglistening
Palace Hotel, Sun City, Johannesburg, South
Africa
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Thank you for Thank you for listeninglistening
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Thank you for listeningThank you for listening
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Thank you for Thank you for listeninglistening
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“ “ Thank you for listening “Thank you for listening “
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BACK UP
04/19/23 78
The dipeptide concept – a conclusion
“The availability of stable dipeptide preparations certainly facilitates, for the first time, adequate amino acid nutrition of critically ill, malnourished or stressed patients in the routine clinical setting and, thus, represents a new dimension in artificial nutrition.”
Fuerst, P. Journal of Nutrition 2001
Significant clinical data on MORTALITY
04/19/23 80
Six-Month Outcome of Critically Ill patients given Glutamine supplemented Parenteral Nutrition
Griffith RD, Jones C, Palmer ATE
Nutrition 1997; 13: 295-302
04/19/23 81
Six-Month Outcome of Critically Ill patients given Glutamine supplemented Parenteral Nutrition (Griffith et al.1997)
Design
Patients
Nutrition Regime
Parameter
Prospective, randomized, double-blind trial
84 critically ill patients APACHE II > 10
Isonitrogenious, isokaloric TPN
Study group: 15-23 g glutamine per day
Mortality, Costs
04/19/23 82
Six-Month Outcome of Critically Ill patients givenGlutamine supplemented Parenteral Nutrition (Griffith et al.1997)
=> Glutamine-therapy reduces 6-month mortality.
04/19/23 83
Parenteral L-alanyl-L-glutamine improves 6-month outcome in critically ill patients
Goeters C, Wenn A, Mertes N, Wempe C, Van Aken H, Stehle P, Bone HG
Critical Care Medicine 2002, Vol 30, No.9
04/19/23 84
Prospective, open, randomized trial
Critically ill patients (N=144) in the ICU with indication for PN, including patients with disturbance in renal and hepatic function,
=>N= 95 for Sub-group analysis, treatment > 9 days
Standard TPN, iso-kcal, iso-N
Control group: standard TPN
Study group: 0.3 g Ala-Gln/ kg BW per day (Dipeptiven® )
Average length of hospital sty in ICU and hospital, mortality in ICU within 30 d and 6 months
Design
Patients
Nutrition Regime
Parameter
Parenteral L-alanyl-L-glutamine improves 6-month outcome in critically ill patients (Goeters et al. 2002)
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Parenteral L-alanyl-L-glutamine improves 6-month outcome in critically ill patients (Goeters et al. 2002)
Improved survival in patients receiving glutamine > 9 days
04/19/23 86
H2N-COOCHCH2
CH2
COO
Glutamate=> one amino group
+ -NH2
ATP ADP
H2N-COOCHCH2
CH2
C OH2N-
Glutamine=> two amino groups
Back up: Glutamine- Endogenous synthesis
Alpha-ketoglutarate (no NH2 group) glutamate glutamine
Glutamine in Critically Ill Glutamine in Critically Ill Patients : What is the benefit ?Patients : What is the benefit ?
Hasanul Arifin
2007 ISICM, MEDAN02-03 November 2007
Glutamine: the conditionally essential amino acid
Consequences of Glutamine deficiency
04/19/23 89
Glutamine consumer= > mucosa cell, macrophages (1)
No chance for bacteria to break through when mucosa is intact
Basal membrane
Bowel lumen
Macrophages
04/19/23 90
Mucosa atrophy in glutamine depletion
Damaged macrophages
Atrophy
Glutamine consumer = > mucosa cell, macrophages (2)
04/19/23 91
Back up: Glutamine concentration in muscle tissue reduced up to 50 % within three days after trauma
Stehle, Klin.Ern.35, Zuckschwerdt(1991), 1Hammarqvist, Amino Acids, Landes (1994), 27
healthy trauma0
5
10
15
20
mm
ol
/ l
ICW
healthy trauma
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