Transcript glutaminetherapy - Critical Care Nutrition

Daren K. Heyland
Professor of Medicine
Queen’s University, Kingston, ON Canada
Conclusions
Nutrition 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 Therapy
Emphasis on metabolic and
nutritional effects
Emphasis 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
kcal
Adequacy
of EN
Prescribed Engergy
2000
1800
1600
1400
1200
1000
800
600
400
200
0
Energy Received From Enteral Feed
Caloric Debt
1
3
5
7
9
11
13
15
17
19
21
Days
Prolonged ICU stay, discharged weak and
debilitated. Dies on day 43 in hospital from
massive PE
To what extent did
nutrition therapy (or lack
thereof) play a role in
this patient’s demise?
endothelial dysfunction
activation of coagulation
• infection
• trauma
• I/R
• hypoxemic/
hypotensive
Role of
GIT
Activation of
PMN’s
Microcirculatory
Dysfunction
elaboration of cytokines,
NO, and other mediators
generation of OFR
(ROS + RNOS)
mitochondrial
dysfunction
=
oxidative stress
cellular = energetic
failure
Key nutrient deficiencies
(e.g. glutamine, selenium)
organ = failure
Death
Loss of Gut Epithelial Integrity
Bacteria
INTESTINAL EPITHELIUM
SIRS
DISTAL ORGAN
INJURY
(Lung, Kidneys)
via thoracic duct
Mitochondrial Function
Cell
mitochondria
Respiratory
chain
ROS
nDNA
mtDNA
nucleus
Mitochondria are the power house of the cell, generate energy through
oxidative phosphorylation (OXPHOS)
RNS
In Search of the Magic
Nutriceutical
Mucosal Barrier Integrity
Oxidative Stress
Mito
Function
Cellular Immune Function
Inflammation
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
Glutamine
Glutamine: A conditionally
essential amino acid
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
The “Oudemans-van Straaten-Study”
“high”
“low”
=> Low plasma glutamine at
ICU admission is related to
mortality.
Potential Beneficial Effects of Glutamine
Enhanced
insulin
sensitivity
Enhanced Heat
Shock Protein
Decreased Free
Radical availability
(Anti-inflammatory action)
Inflammatory Cytokine
Attenuation
Glutamine
Therapy
Glutathione
Synthesis
Critical Illness
Preservation
of TCA Function
Preserved
Cellular
EnergeticsATP content
GLN
GLN
Pool
pool
Fuel for
Enterocytes
NF- B
?
Maintenance of Reduced
Translocation
Intestinal
Enteric Bacteria
Mucosal Barrier or Endotoxins
Nuclotide
Synthesis
Maintenance of
Fuel
for
Anti-catabolic
Lymphocyte
Lymphocytes
effect
Function
Preservation of
Muscle mass
Reduction of
Infectious
complications
Glutamine-regulated genes in the
Pancreatic B cell line
Induction of Heat Shock Protein
Leads to Protein Stabilization
Induction
Hsp 72
Protein
Stress:
e.g. HEAT
HSP-bound protein
stabilized for
survival and repair
No
Induction
Aggregation, denaturation,
degradation
Paul Wischmeyer
IV Glutamine Enhances Serum HSP-70 in
Critically Ill Patients with Sepsis/SIRS
GLN Patients Control Patients
6
Serum HSP 70 (ng/ml)
ALA-GLN
treatment leads to
significant
enhancement of
serum HSP-70 with
7 days of treatment
5
*
4
3
2
ALA-GLN
1
mediated
enhancement of
0
Baseline
1 week
HSP-70 correlates
with decreased
Study Date
ICU length of stay
and time on
ventilator
Ziegler Intensive Care Medicine, 31:1079-1086, 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
Updated Jan 2009, see www.criticalcarenutrition.com
Antioxidant-supplemented
specialized diets?
Rationale for Antioxidants
Infection
Inflammation
Ischemia
OFR
CONSUMPTION
OFR
PRODUCTION
Depletion of
Antioxidant Enzymes
OFR Scavengers
Vitamins/Cofactors
OFR production > OFR consumption = OXIDATIVE
STRESS
Impaired
- organ function
- immune function
- mucosal barrier function
Complications and Death
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 levels
Lipid peroxidation and inflammation
Organ failure
Mortality
Oxidative Stress Connected to
Organ Failure
60
50
40
With Organ
Failure
Without Organ
Failure
30
20
10
0
% increase in TBARS
Motoyama Crit Care Med 2003;31:1048
Rationale for Antioxidants
• 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
Rationale for Antioxidants
Huet CCM 2007; 35: 821
Underlying Pathophysiology
of Critical Illness (2)
• preserved ATP
•Recovery of mt DNA
•Regeneration of mito
proteins
Genetic down
regulation
Tissue
hypoxia
cytokine
effect
Prolonged
inflammation
NO
Endocrine
effects
Survivors
↓ mitochondrial
activity
•↓mt DNA
•↓ ATP, ADP,
NADPH
•↓ Resp chain
activity
•Ultra structural
changes
Metabolic
Shutdown
Death
Mitochondrial Dysfunction is a TimeDependent Phenonmenon
Hypoxia Accelerates Nitric Oxide Inhibition of Complex 1 Activity
21% O2
1% O2
Nitration of Complex 1 in Macrophages
activated with LPS and IFN
Frost Am J Physio Regul Interg Comp Physio 2005;288:394
Mitochondrial Damage
Cell
mitochondria
Respiratory
chain
ROS
nDNA
mtDNA
RNS
nucleus
LPS exposure leads to GSH depletion and
oxidation of mtDNA within 6-24 hours
Potentially Irreversible by 48 hours
Levy Shock 2004;21:110 Suliman CV research 2004;279
mtDna/nDNA Ratio by Day 28 Survival
mtDna/nDNA Ratio
2.0
P=0.04
Alive Individuals
Expired Individuals
Alive Reg line
Expired Reg Line
1.5
1.0
0.5
0.0
0
5
10
15
20
25
Day
Heyland JPEN 2007;31:109
Effect of Antioxidants on Mitochondrial Function
Heyland JPEN 2007;31:109
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
Effect on SOFA scores
• Increased selenium levels
• Increased GSH-Px activity
• No difference in
• RRT (5 vs 7 patients)
• mortality (44% vs 50%)
• Other clinical outcomes
*p=<0.006
*
*
•
Mishra Clinical Nutrition 2007;26:41-50
Randomized, Prospective Trial of Antioxidant
Supplementation in Critically Ill Surgical Patients
controls
 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

treated
Tendency to less
pulmonary morbidity and
shorter duration of vent
days
Nathens Ann Surg 2002;236:814
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
p=0.11
100
90
80
70
60
50
40
30
20
10
0
Selenium
Placebo
28 day Mortality
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
Effect of Combined Antioxidant
Strategies in the Critically Ill
Effect on Mortality
Updated Jan 2009, see www.criticalcarenutrition.com
Biological Plausibility!
Mitochondrial dysfunction
Antioxidants
Inflammation/oxidative stress
Antioxidants
Organ dysfunction
Antioxidants
Pharmaconutrients Impact Outcomes!
Effect on Mortality
Glutamine
Antioxidants
Fish/Borage Oils
Plus AOX
Arginine
.01
0.1
1
10
100
www.criticalcarenutrition.com
What’s new about this paradigm?
Old
Nutrition Support
New
Nutrition Therapy
Emphasis on metabolic and
nutritional effects
Minimize substrate loss
Emphasis on clinical outcomes
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
t ic
a l C ar e
i als G
ro
i
d
a
Tr
a n Cri
A multicenter randomized trial of
glutamine and antioxidant supplementation
in critical illness
up C an
The Research Protocol
The Question(s)
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?
REducing Deaths from OXidative Stress:
The REDOXS study
Factorial 2x2 design
1200 ICU patients
Evidence of
organ failure
R
glutamine
R
Concealed
Stratified by
 site
 Shock
placebo
antioxidants
placebo
antioxidants
R
placebo
Combined Entered and Parental Nutrients
Group
Enteral Supplement
(Glutamine AOX)
Parenteral Supplement
(Glutamine AOX)
A
Glutamine + AOX
+
Glutamine + Selenium
B
Placebo + AOX
+
Placebo + Selenium
C
Glutamine + Placebo
+
Glutamine + Placebo
D
Placebo + Placebo
+
Placebo + Placebo
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
Glutamine 30 gms
Vit C 1500 mg
Vit E 500 mg
B-carotene 10 mg
Zinc 20mg
Selenium 300ug
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
The Research Protocol
The Question
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 Research Protocol
The Design
•
•
•
•
Single Center
Open-label
Dose-ranging study
Prospective controls
Patients
• Critically Ill patients in shock
The Research Protocol
Intervention
Group
N
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 Protocol
Outcomes
•Primary: ∆SOFA
• Secondary (groups 2-5);
• Plasma levels of Se, Zn , and vitamins
• TBARS
•Glutathione
•Mitochondrial function (ratio)
Baseline Characteristics
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
6 (86%)
1(14%)
3 (43%)
4 (57%)
3 (43%)
4 (57%)
1(14%)
5(71%)
1(14%)
13(46%)
14(50%)
1(4%)
Etiology of shock
Cardiogenic (%)
Septic (%)
Hypovolemic (%)
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%)
Effect on SOFA
20
18
16
14
12
10
8
6
4
2
0
P=<0.0001
Total SOFA Score for Group 4
Individuals
Expired Individuals
Reg Line
Total Sofa Score
Total Sofa Score
Total SOFA Score for Control Group
20
18
16
14
12
10
8
6
4
2
0
P= 0.0467
Expired Individuals
Reg Line
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Day
Day
Total SOFA Score for Group 5
P=0.0897
Individuals
Expired Individuals
Reg Line
Total Sofa Score
Total Sofa Score
Total SOFA Score for Group 2
20
18
16
14
12
10
8
6
4
2
0
20
18
16
14
12
10
8
6
4
2
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
P= 0.0005
Day
Total SOFA Regression Lines
Individuals
Expired Individuals
Reg Line
Total SOFA Score
Total Sofa score
Total SOFA Score for Group 3
P= <0.0001
Individuals
Expired Individuals
Reg Line
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Day
20
18
16
14
12
10
8
6
4
2
0
Individuals
P=0.1941
20
18
16
14
12
10
8
6
4
2
0
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
2
4
6
8
Day
Day
4 vs 5: p=0.17
10
Control
Group 2
Group 3
Group 4
Group 5
12
14
Effect on TBARS
TBARS Group 2
P=0.82
Individuals
Expired Individuals
Average Slope
0.150
0.125
0.100
0.075
0.050
0.025
0.000
0
5
10
15
20
25
Day
TBARS Group 5
P=0.03
0.175
TBARS
(nmol/mg protein)
TBARS
(nmol/mg protein)
0.175
Individuals
Expired Individuals
0.150
0.125
Average Slope
0.100
0.075
0.050
0.025
TBARS Group 3
0.150
P=0.90
0
0.125
10
15
20
25
Day
Average Slope
0.100
0.075
0.050
TBARS Average Slopes
0.025
0.175
0.000
0.150
0
5
10
15
20
25
Day
TBARS Group 4
0.175
TBARS
(nmol/mg protein)
5
Individuals
Expired Individuals
0.150
Individuals
Expired Individuals
Average Slope
P=0.11
0.125
0.100
TBARS
(nmol/mg protein)
TBARS
(nmol/mg protein)
0.000
0.175
P=0.25
Group
Group
Group
Group
0.125
0.100
0.075
0.050
0.025
0.000
0
0.075
2
4
6
8
Day
0.050
0.025
0.000
0
5
10
15
Day
20
25
10
12
14
2
3
4
5
Effect on Glutathione
GSH Group 2
1600
P=0.03
Individuals
Expired Individuals
Average Slope
GSH (  Mol/L)
1400
1200
1000
800
600
GSH Group 5
400
1600
200
5
10
15
20
25
Day
GSH Group 3
1600
1400
GSH (  Mol/L)
Individuals
Expired Individuals
Average Slope
P=0.14
1200
GSH (  Mol/L)
0
Individuals
Expired Individuals
Average Slope
P=0.61
1400
0
1200
1000
800
600
400
200
0
1000
0
5
10
800
15
20
25
Day
600
400
200
0
0
5
10
15
20
GSH Average Slopes
25
Day
P=0.40
GSH (  Mol/L)
1400
Group 2
Group 3
Group 4
Group 5
1400
Individuals
Expired Individuals
Average Slope
1200
1000
800
600
GSH (  Mol/L)
1600
P=0.61
1600
GSH Group 4
1200
1000
800
600
400
200
400
0
200
0
0
2
4
6
8
Day
0
5
10
15
Day
20
25
10
12
14
Effect of Antioxidants on Mitochondrial Function
Heyland JPEN 2007;31:109
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!
Conclusions
Nutrition Therapy : Modulating the Inflammatory
Response and Improving Patient Outcomes
Adjunctive
Supportive
Care
Proactive
Primary
Therapy
To what extent did
nutrition therapy (or lack
thereof) play a role in
this patient’s demise?
kcal
Adequacy
of EN
Prescribed Engergy
2000
1800
1600
1400
1200
1000
800
600
400
200
0
Energy Received From Enteral Feed
Caloric Debt
1
3
5
7
9
11
13
15
17
19
21
Days
Prolonged ICU stay, discharged weak and
debilitated. Dies on day 43 in hospital from
massive PE
How are you performing at your site?
Can you be the Best of the Best?
Further Information: www.criticalcarenutrition.com
Thank YOU