daren k. heyland professor of medicine queen’s university, kingston, on canada
TRANSCRIPT
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
Updated Jan 2009, see www.criticalcarenutrition.com
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
Rationale for Antioxidants
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)
Rationale for Antioxidants
Huet CCM 2007; 35: 821
Rationale for Antioxidants
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
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
• 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
Updated Jan 2009, see www.criticalcarenutrition.com
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
The Research Protocol
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
The Research Protocol
• 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
Total SOFA Score for Group 3
0 2 4 6 8 10 12 14 16 18 20 22 24 26 2802468
101214161820
IndividualsExpired IndividualsReg Line
P= <0.0001
Day
To
tal
So
fa s
co
re
Total SOFA Score for Group 4
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
Total SOFA Score for Group 5
0 2 4 6 8 10 12 14 16 18 20 22 24 26 2802468
101214161820
IndividualsExpired IndividualsReg Line
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
Expired IndividualsP=0.14
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
Expired IndividualsP=0.40
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
Expired IndividualsP=0.61
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
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!
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
How are you performing at your site?
Can you be the Best of the Best?
Further Information: www.criticalcarenutrition.com
Thank YOU