Glutamine in Critically Ill Patients

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.



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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

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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

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“ (…) 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

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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)

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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”

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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.)


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.


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Glutamine depletion is increased withthe severity of the disease

Roth E et al. 1986

Benefits of glutamine in PN therapy... Further evidence

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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

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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

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a neurotoxin

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Glutamine help protect or treat sepsis in two main ways :

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Glutamine in TPN

Increases protein synthesis andnitrogen balance

Improves gutfunction

Improves immunefunction

Reduced hospital stay

Improvedmood

Reduced waterretention

clinical benefits of glutamine in TPN

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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

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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.)

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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

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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

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The role of glutamine in glutathione synthesis

Glutathione(Glutamic acid-Cysteine-Glycine)

GlutamineNH3

Glutamine

intracellular

extracellular

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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 !

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Published meta-analyses Published meta-analyses on PN glutamineon PN glutamine

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• 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

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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


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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:


World J Gastroengeral 2006; 12 (46): 7537 - 7541

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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:


Enteral or Enteral or Parenteral ?Parenteral ?

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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.

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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).

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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).



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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.



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

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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.”

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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?

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Dipeptiven® Sales Folder, 2004

Glutamine may be benefecial in the following patient groups

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• 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

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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.

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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

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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)

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Thank you for Thank you for listeninglistening

Palace Hotel, Sun City, Johannesburg, South

Africa

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Thank you for listeningThank you for listening

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“ “ Thank you for listening “Thank you for listening “

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BACK UP

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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

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Six-Month Outcome of Critically Ill patients given Glutamine supplemented Parenteral Nutrition

Griffith RD, Jones C, Palmer ATE

Nutrition 1997; 13: 295-302

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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

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Six-Month Outcome of Critically Ill patients givenGlutamine supplemented Parenteral Nutrition (Griffith et al.1997)

=> Glutamine-therapy reduces 6-month mortality.

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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

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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

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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

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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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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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Glutamine in Critically Ill Patients