Glutamine Therapy: A life-saving therapy?

Daren K. HeylandProfessor of Medicine

Queen’s University, Kingston, ON Canada

ConclusionsNutrition Therapy : Modulating the Inflammatory

Response and Improving Patient Outcomes

Adjunctive Supportive Care

Proactive Primary Therapy

What’s new about this paradigm?

Old

Nutrition Support

New

Nutrition TherapyEmphasis on metabolic and

nutritional effectsEmphasis on clinical outcomes

Minimize substrate loss Achieve pharmacological effect

Heterogeneous patients Homogeneous Patients

Focus on nutrition Focus on nutrients

Small single center Large multicenter

Weak methods Strong methods

• Mr KT• 76 per’d diverticulum• Septic shock, ARDS, MODS• Day 1- high NG drainage, distended abdomen• Day 3- trickle feeds• Feeds on and off again for whole first week• No PN, no small bowel feeds, no specialized nutrients

Prolonged ICU stay, discharged weak and debilitated. Dies on day 43 in hospital from

massive PE

Adequacy of EN

Adequacy of EN

0200

400600

8001000

12001400

16001800

2000

1 3 5 7 9 11 13 15 17 19 21

Days

kcal

Prescribed Engergy

Energy Received From Enteral Feed

Caloric Debt

• infection• trauma• I/R• hypoxemic/ hypotensive

= oxidative stress

Death

organ = failure

mitochondrial dysfunction

Key nutrient deficiencies(e.g. glutamine, selenium)

activation of coagulation

generation of OFR (ROS + RNOS)

endothelial dysfunction

elaboration of cytokines, NO, and other mediators

cellular = energetic failure

Microcirculatory Dysfunction

Loss of Gut Epithelial Integrity

INTESTINAL EPITHELIUM

SIRS

Bacteria

DISTAL ORGAN DISTAL ORGAN INJURY INJURY (Lung, Kidneys)(Lung, Kidneys)

via thoracic duct

mitochondria

Cell

Respiratorychain

nucleus

nDNA mtDNA

Mitochondria are the power house of the cell, generate energy through oxidative phosphorylation (OXPHOS)

Mitochondrial Function

ROS

RNS

Mucosal Barrier Integrity

Inflammation

Cellular Immune Function

Oxidative StressMito

Function

In Search of the Magic Nutriceutical

Glutamine supplementation?

Glutamine: A conditionally essential amino acid

• The most abundant amino acid in the body• Usually considered non essential amino acid • Has many essential metabolic functions • Not usually present in parenteral nutrition

products due to manufacturing reasons

GlutamineGlutamine

Glutamine levels drop:- following extreme physical exercice- after major surgery- during critical illness

Low glutamine levels are associated with:- immune dysfunction- higer mortality in critically ill patients

Novak F, Heyland DK, A Avenell et al., Crit Care Med 2002 Oudemans-van Straaten HM, Bosman RJ, Treskes Met al., Intensive Car Med 2001

Glutamine: A conditionally essential amino acid

=> Low plasma glutamine at ICU admission is related to mortality.

The “Oudemans-van Straaten-Study”

“high”

“low”

Potential Beneficial Effects of Glutamine

Fuel forFuel forEnterocytesEnterocytes

Fuel forFuel forLymphocytesLymphocytes

Nuclotide Nuclotide SynthesisSynthesis

Maintenance ofMaintenance ofIntestinalIntestinalMucosal BarrierMucosal Barrier

Maintenance ofMaintenance ofLymphocyteLymphocyteFunctionFunction

Preservation Preservation of TCA Functionof TCA Function

Decreased FreeRadical availability (Anti-inflammatory action)

GlutathioneGlutathioneSynthesisSynthesis

GLNGLNpoolpool

GlutamineTherapy

Enhanced HeatEnhanced Heat Shock ProteinShock Protein

Anti-cataboliceffect

Preservation of Muscle mass

Reduced Reduced TranslocationTranslocationEnteric BacteriaEnteric Bacteriaor Endotoxinsor Endotoxins

Reduction ofReduction ofInfectious Infectious complicationscomplications

Inflammatory Cytokine Inflammatory Cytokine AttenuationAttenuation

NF-BNF-B??

Preserved CellularEnergetics- ATP content

GLNGLNPoolPool

Critical IllnessCritical Illness

Enhanced insulin sensitivity

Glutamine-regulated genes in the Pancreatic B cell line

Induction of Heat Shock Protein Leads to Protein Stabilization

InductionInduction

Hsp 72Hsp 72ProteinProtein

HSP-bound proteinHSP-bound proteinstabilized forstabilized forsurvival and repairsurvival and repair

No No InductionInduction

Aggregation, denaturation, Aggregation, denaturation, degradationdegradation

Stress:e.g. HEAT

Paul Wischmeyer

0

1

2

3

4

5

6

Baseline 1 week

Study Date

Seru

m H

SP 7

0 (n

g/m

l)

GLN Patients Control Patients

*

IV Glutamine Enhances Serum HSP-70 IV Glutamine Enhances Serum HSP-70 in Critically Ill Patients with in Critically Ill Patients with

Sepsis/SIRSSepsis/SIRSALA-GLN ALA-GLN treatment leads treatment leads to significant to significant enhancement of enhancement of serum HSP-70 serum HSP-70 with 7 days of with 7 days of treatmenttreatment

ALA-GLN ALA-GLN mediated mediated enhancement of enhancement of HSP-70 HSP-70 correlates with correlates with decreased ICU decreased ICU length of stay length of stay and time on and time on ventilatorventilator

Ziegler Intensive Care Medicine, Ziegler Intensive Care Medicine, 31:1079-1086, 200531:1079-1086, 2005

Mechanism of Glutamine

• 3 RCTs of enteral glutamine

• Burns patients– Increased plasma glutamine

– Improved permeability

– Decreased endotoxin levels

– Reduced GNB infections

– Reduced hospital LOS

– Reduced mortality

Garrell CCM 2003;31:2444, Zhou JPEN 2003 27;241; Peng Burns 2004;30:135

Effect of Glutamine:A Systematic Review of the Literature

Infectious Complications

Updated Jan 2009, see www.criticalcarenutrition.com

Effect of Glutamine:A Systematic Review of the Literature


Mortality

Antioxidant-supplemented specialized diets?

OFRCONSUMPTION

OFR

PRODUCTION

Depletion ofAntioxidant Enzymes

OFR Scavengers Vitamins/Cofactors

InfectionInflammation

Ischemia

OFR production > OFR consumption =Impaired- organ function- immune function- mucosal barrier function

Complications and Death

OXIDATIVESTRESS

Rationale for Antioxidants

• Endogenous antioxidant defense mechanisms• Enzymes (superoxide dismutase, catalase,

glutathione perioxidase, glutathione reductase including their cofactors Zn and Selenium)

• Sulfhydryl group donors (glutathione)• Vitamins E, C, and B-carotene


Low endogenous levelsLipid peroxidation and inflammation

Organ failure

Mortality

Oxidative Stress Connected to Organ Failure

Motoyama Crit Care Med 2003;31:1048

0

10

20

30

40

50

60

% increase in TBARS

With OrganFailureWithout OrganFailure

• 21 patients with septic shock

• Exposed plasma from patients to naïve human umbilical vein endothelial cells and quantified degree of oxidative stress by a fluorescent probe (2,7,-dichorodihydrofluorescien diacetate)


Huet CCM 2007; 35: 821


Huet CCM 2007; 35: 821

Death

MetabolicShutdown

Survivors

•↓mt DNA•↓ ATP, ADP, NADPH•↓ Resp chain activity•Ultra structural changes

↓ mitochondrial activityProlonged

inflammationNO

Endocrineeffects

cytokine effect

Genetic down regulation

Tissue hypoxia

• preserved ATP•Recovery of mt DNA•Regeneration of mito proteins

Underlying Pathophysiology of Critical Illness (2)

Mitochondrial Dysfunction is a Time-Dependent Phenonmenon

Hypoxia Accelerates Nitric Oxide Inhibition of Complex 1 Activity

Nitration of Complex 1 in Macrophages activated with LPS and IFN

21% O2 1% O2

Frost Am J Physio Regul Interg Comp Physio 2005;288:394

mitochondria

Cell

Respiratorychain

nucleus

nDNA mtDNA

Mitochondrial Damage

ROS

RNS

LPS exposure leads to GSH depletion and oxidation of mtDNA within 6-24 hours

Levy Shock 2004;21:110 Suliman CV research 2004;279

Potentially Irreversible by 48 hours

mtDna/nDNA Ratio by Day 28 Survival

0 5 10 15 20 250.0

0.5

1.0

1.5

2.0

Alive IndividualsExpired IndividualsAlive Reg lineExpired Reg Line

P=0.04

Day

mtD

na

/nD

NA

Ra

tio

Heyland JPEN 2007;31:109

Effect of Antioxidants on Mitochondrial Function


Smallest Randomized Trial of Selenium in Sepsis

Single center RCT double-blinded ITT analysis

40 patients with severe sepsis Mean APACHE II 18

Primary endpoint: need for RRT standard nutrition plus 474 ug x 3 days,

316 ug x 3 days; 31.6 ug thereafter vs 31.6 ug/day in control

Mishra Clinical Nutrition 2007;26:41-50

Smallest Randomized Trial of Selenium in Sepsis

• Increased selenium levels

• Increased GSH-Px activity

• No difference in

• RRT (5 vs 7 patients)

• mortality (44% vs 50%)

• Other clinical outcomes

Mishra Clinical Nutrition 2007;26:41-50

*p=<0.006

* *

Effect on SOFA scores

•

Randomized, Prospective Trial of AntioxidantSupplementation in Critically Ill Surgical

Patients

Nathens Ann Surg 2002;236:814

Surgical ICU patients, mostly trauma

770 randomized; 595 analysed

alpha-tocopherol 1,000 IU (20 mL) q8h per naso- or orogastric tube and 1,000 mg ascorbic acid IV q8h or placebo

Tendency to less pulmonary morbidity and shorter duration of vent days

controls

treated

Largest Randomized Trial of Antioxidants

Multicenter RCT in Germany double-blinded non-ITT analysis

249 patients with severe sepsis

standard nutrition plus 1000 ug bolus followed by 1000 ug/day or placebo x14 days

0102030405060708090

100

28 day Mortality

SeleniumPlacebo

Greater treatment effect observed in those

patients with: •supra normal levels vs normal levels of selenium

•Higher APACHE III

•More than 3 organ failures Crit Care Med 2007;135:1

p=0.11

Effect of Combined Antioxidant

Strategies in the Critically IllEffect on Mortality


Biological Plausibility!

Inflammation/oxidative stress

Mitochondrial dysfunction

Organ dysfunction

Antioxidants

Antioxidants

Antioxidants

Pharmaconutrients Impact Outcomes!

www.criticalcarenutrition.com

1 10 1000.1.01

Glutamine

Antioxidants

Fish/Borage OilsPlus AOX

Effect on Mortality

Arginine

What’s new about this paradigm?

Old

Nutrition Support

New

Nutrition TherapyEmphasis on metabolic and

nutritional effectsEmphasis on clinical outcomes

Minimize substrate loss Achieve pharmacological effect

Heterogeneous patients Homogeneous Patients

Focus on nutrition Focus on nutrients

Small single center Large multicenter

Weak methods Strong methods

REducing Deaths from OXidative Stress:

The REDOXS study

A multicenter randomized trial of glutamine and antioxidant

supplementation in critical illness

The Research Protocol

In critically ill patients with a clinical evidence of acute multi organ dysfunction fed enterally– What is the effect of glutamine

supplementation compared to placebo– What is the effect of antioxidant

supplementation compared to placebo

…on 28 day mortality?

The Question(s)

1200 ICU patientsEvidence of

organ failureR

glutamine

placebo

ConcealedStratified by

site

R

R

antioxidants

placebo

Factorial 2x2 design

placebo

antioxidants Shock

REducing Deaths from OXidative Stress:

The REDOXS study

Group Enteral Supplement Parenteral Supplement (Glutamine AOX) (Glutamine AOX)

A Glutamine + AOX + Glutamine + Selenium

B Placebo + AOX + Placebo + Selenium

C Glutamine + Placebo + Glutamine + Placebo

D Placebo + Placebo + Placebo + Placebo

Combined Entered and Parental Nutrients

Glutamine Dipeptides • Free L-glutamine has limited solubility and stability

• Synthetic dipeptides (ala-gln, gly-gln) overcome these difficulties

• 8.5 gms of dipeptide=6 gms of glutamine

Vit C 1500 mg

Vit E 500 mg

B-carotene 10 mg

Zinc 20mg

Selenium 300ug

Glutamine 30 gms

Optimal Dose?

• High vs Low dose: – observations of meta-analysis

• Providing experimental nutrients in addition to standard enteral diets

Optimizing the Dose of Glutamine Dipeptides

and Antioxidants in Critically ill Patients:

A phase 1 dose finding study of glutamine and antioxidant

supplementation in critical illness

JPEN 2007


In critically ill patients with a clinical evidence of hypoperfusion...

• What is the maximal tolerable dose (MTD) of glutamine dipeptides and antioxidants as judged by its effect on multiorgan dysfunction?

The Question


• Single Center • Open-label • Dose-ranging study • Prospective controls

The Design

• Critically Ill patients in shock

Patients

The Research ProtocolIntervention

GroupN Dose of Dipeptides (glutamine)

Parenterally*(gm/kg/day)

Enterally^(gm/day)

AOX

1 30 0 0 0

2 7 .5 (.35) 0 0

3 7 .5 (.35) 21 (15) ½ can

4 7 .5 (.35) 42 (30) full can

5 7 .5 (.35) 42 (30) full can + 500ug

IV Selenium

The Research ProtocolOutcomes

•Primary: ∆SOFA• Secondary (groups 2-5);

• Plasma levels of Se, Zn , and vitamins• TBARS•Glutathione •Mitochondrial function (ratio)

Control

N = 30

Group 2

N =7

Group 3

N= 7

Group 4

N= 7

Group 5

N=7

All

N=58

Age (Mean) 64.2 65.5 65.2 65.6 71.8 65.6

Female (%) 11 (37%) 2(29%) 1(14%) 2(29%) 3(43%) 19(33%)

APACHE II score (Mean) 23.2 25.1 22.1 21.9 20.6 22.8

Etiology of shock

Cardiogenic (%)

Septic (%)

Hypovolemic (%)

6 (86%)

1(14%)

3 (43%)

4 (57%)

3 (43%)

4 (57%)

1(14%)

5(71%)

1(14%)

13(46%)

14(50%)

1(4%)

ICU days (Median) 6.4 14.3 7.9 13.1 9.7 8.0

28 day mortality (%) 9(30%) 3(43%) 2(29%) 3(43%) 1(14%) 18(31%)

Baseline Characteristics

4 vs 5: p=0.17

Total SOFA Score for Control Group

0 2 4 6 8 10 12 14 16 18 20 22 24 26 2802468

101214161820

Expired IndividualsIndividuals

Reg Line

P=<0.0001

Day

To

tal

So

fa S

co

re

Total SOFA Score for Group 2

0 2 4 6 8 10 12 14 16 18 20 22 24 26 2802468

101214161820

IndividualsExpired IndividualsReg Line

P=0.0897

Day

To

tal

So

fa S

co

re


0 2 4 6 8 10 12 14 16 18 20 22 24 26 2802468

101214161820


P= <0.0001

Day

To

tal

So

fa s

co

re


0 2 4 6 8 10 12 14 16 18 20 22 24 26 2802468

101214161820

Individuals

Expired Individuals

Reg Line

P= 0.0467

Day

To

tal

So

fa S

co

re


0 2 4 6 8 10 12 14 16 18 20 22 24 26 2802468

101214161820


P= 0.0005

Day

To

tal

So

fa S

co

re

Total SOFA Regression Lines

0 2 4 6 8 10 12 1402468

101214161820

ControlGroup 2Group 3

Group 4Group 5

P=0.1941

Day

To

tal

SO

FA

Sco

re

Effect on SOFA

TBARS Group 2

0 5 10 15 20 250.000

0.025

0.050

0.075

0.100

0.125

0.150

0.175

Average SlopeExpired Individuals

P=0.82Individuals

Day

TB

AR

S

(nm

ol/

mg

pro

tein

)

TBARS Group 3

0 5 10 15 20 250.000

0.025

0.050

0.075

0.100

0.125

0.150

0.175Individuals

Expired IndividualsP=0.90

Average Slope

Day

TB

AR

S

(nm

ol/

mg

pro

tein

)

TBARS Group 4

0 5 10 15 20 250.000

0.025

0.050

0.075

0.100

0.125

0.150

0.175Individuals

Average SlopeExpired IndividualsP=0.11

Day

TB

AR

S

(nm

ol/

mg

pro

tein

)

TBARS Group 5

0 5 10 15 20 250.000

0.025

0.050

0.075

0.100

0.125

0.150

0.175

Average Slope

Expired Individuals

P=0.03Individuals

Day

TB

AR

S

(nm

ol/

mg

pro

tein

)

TBARS Average Slopes

0 2 4 6 8 10 12 140.000

0.025

0.050

0.075

0.100

0.125

0.150

0.175Group 2

Group 4Group 5

Group 3

P=0.25

Day

TB

AR

S

(nm

ol/

mg

pro

tein

)

Effect on TBARS

GSH Group 2

0 5 10 15 20 250

200

400

600

800

1000

1200

1400

1600

Expired Individuals

P=0.03

Average Slope

Individuals

Day

GS

H (

Mo

l/L

)

GSH Group 3

0 5 10 15 20 250

200

400

600

800

1000

1200

1400

1600Individuals


Average Slope

Day

GS

H (

Mo

l/L

)

GSH Group 4

0 5 10 15 20 250

200

400

600

800

1000

1200

1400

1600Individuals


Average Slope

Day

GS

H (

Mo

l/L

)

GSH Group 5

0 5 10 15 20 250

200

400

600

800

1000

1200

1400

1600Individuals


Average Slope

Day

GS

H (

Mo

l/L

)

GSH Average Slopes

0 2 4 6 8 10 12 140

200

400

600

800

1000

1200

1400

1600P=0.61

Group 2

Group 3Group 4

Group 5

Day

GS

H (

Mo

l/L

)

Effect on Glutathione

Effect of Antioxidants on Mitochondrial Function


Inferences

• High dose appears safe • High dose associated with

– no worsening of SOFA Scores– greater resolution of oxidative stress– greater preservation of glutathione– Improved mitochondrial function

REDOXS: A New Paradigm!

• Nutrients dissociated from nutrition• Focus on single nutrient administration• Rigorous, large scale, multicenter trial

of nutrition related intervention powered to look at mortality

• sick homogenous population • Preceded by:

– standardization of nutrition support thru the development and implementation of CPGs

– a dosing optimizing study• Funded by CIHR

REDOXS Study

A new way of thinking!

ConclusionsNutrition Therapy : Modulating the Inflammatory

Response and Improving Patient Outcomes

Adjunctive Supportive Care

Proactive Primary Therapy

Prolonged ICU stay, discharged weak and debilitated. Dies on day 43 in hospital from

massive PE

Adequacy of EN

Adequacy of EN

0200

400600

8001000

12001400

16001800

2000

1 3 5 7 9 11 13 15 17 19 21

Days

kcal

Prescribed Engergy

Energy Received From Enteral Feed

Caloric Debt

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Further Information: www.criticalcarenutrition.com

Thank YOU

Documents

Glutamine Therapy: A life-saving therapy?