Transcript A Randomized Trial of Empiric Antibiotics and Invasive

Pharmaconutrition: Selected
Nutrients and Their Influence on
Patient Outcomes
The Canadian Clinical Practice Guidelines
Daren K. Heyland, MD, FRCPC, MSc
Queen’s University, Kingston, Ontario
Updated July 2006
www.criticalcarenutrition.com
Immunonutrition:
Cocktail Approach?
• Specific nutrients found to have effects on
immune system, metabolism, and GI structure and
function
 Arginine
 Glutamine
 Omega-3 fatty acids
 Nucleic acids
 others
• Individual effect on clinical outcomes?
Pathophysiology of Critical Illness
endothelial dysfunction
activation of coagulation/complement
Insult
• infection
• trauma
• I/R
• hypoxemic/
hypotensive
Role of
GIT
Arginine
Activation of
PMN’s
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
Elective Surgical Patient
• cellular immune
dysfunction
–
T-cell
• decrease cytokine
activation
– IL-2, IFN
Elective Surgical Patient
arginase
arginine
expression of zeta chain
Taheri Clin Cancer Res 2001 ;7:958
=
1.18 (0.88,1.58)
Population
Nutrients
Which Nutrients?
Which Patients?
Elective
Surgery
Critically Ill
General
Septic
Trauma
Burns
Acute Lung
Injury
Arginine
Glutamine
Omega 3
FFA
Antioxidants
Canadian Clinical Practice Guidelines JPEN 2003;27:355
www.criticalcarenutrition.com
Underlying Rationale for
Framework
o No scientific rationale for combining
nutrients together; need to consider them
alone
o Empirical evidence that the nutrients have
different treatment effects across
populations
Which Nutrient for Which Population?
Population
Nutrients
Elective
Surgery
Critically Ill
General
Septic
Trauma
Burns
Acute Lung
Injury
Benefit
No benefit
Harm
No benefit
No benefit
No benefit
Glutamine
Possible
Benefit
PN
Beneficial
(? receiving
EN)
…
EN
Possibly
Beneficial
EN
Possibly
Beneficial
…
Omega 3
FFA
…
…
…
…
…
Possible
Benefit
Antioxidants
…
Possible
Benefit
…
…
…
…
Arginine
Canadian Clinical Practice Guidelines JPEN 2003;27:355
Arginine-supplemented
diets?
Underlying Pathophysiology
Role of Nitric Oxide
Mitaka Shock 2003;19: 305
Optimal NO-Balance
cNOS
- Microcirculation 
- Immune augmentation 
Harmful
Arginine / NO
availability
cNOS + iNOS
- Hemodynamic instability
- Immune Suppression
- Cytotoxicity
- Organe dysfunction
Suchner Brit J Nutrition
Effect of Argininesupplemented diets on Mortality
www.criticalcarenutrition.com
Effect of Arginine-supplemented
diets on Infectious complications
www.criticalcarenutrition.com
Effect of Arginine-supplemented
diets in Critically Ill Patients
• Possible mortality in septic pts.
Crit Care Med 1995;23:436
Dent, Crit Care Med 2003
Bertolini Int Care Med 2003;29:834
•  cost.
• Lack of treatment effect.
But what about ...
Glutamine supplementation?
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
Effect of Glutamine:
A Systematic Review of the Literature
Infectious Complications
www.criticalcarenutrition.com
Effect of Glutamine:
A Systematic Review of the Literature
Mortality
www.criticalcarenutrition.com
Results of subgroup analysis
Mortality
EN
PN
Infection
0.80 (0.45-1.43) 0.83 (0.64-1.08)
P=0.46
P=0.16
0.67 (0.48-0.92) 0.75(0.54-1.04)
P=0.01
P=0.08
EN vs PN?
Benefit of Parenteral
Glutamine in Patients on EN?
Fish Oil supplemented diets?
Mechanisms of Action
• Mediator formation depends on the phospholipid fatty
acid content of arachidonic acid (AA) in inflammatory
cell membranes
• It is possible to modulate the content of AA in
inflammatory cell membranes by changing lipid
composition of the diet
Mechanisms of Action
GLA
Arachidonic Acid
Borage Oil
EPA
Fish Oil
Cyclooxygenase
Lipoxygenase
Substitution of AA
By EPA
Resulting in:
DGLA
Substitution of AA
By DGLA
resulting in:
PGE1 and Less
Inflammatory
Eicosanoids
Decrease in
Pro-Inflammatory
Eicosanoids
(LTB4, TXA2, PGE2)
Less Inflammatory
Eicosanoids
(TXA3, PGE3, LTB5)
Effect of Fish Oils/Borage Oils
and antioxidants in Critically Ill
with ALI
25
• RCT of 146 critically ill
patients with ALI and BAL+
for WBCs
20
15
• Double-blinded; ITT
• Experimental: Oxepa®
Oxepa
control
10
• Control: high fat diet
5
• Groups well matched at
baseline
0
Vent
Days
ICU
ICU
Days Deaths
P=0.03 P=0.02 P=0.17
Gadek Crit Care Med 1999;27:1409
Effect of Fish Oils/Borage Oils
and antioxidants in Critically Ill
with ALI
• RCT of 100 critically ill
patients with ALI
• Single center
• unblinded; not ITT
60
50
40
30
• Experimental: Oxepa®
20
• Control: high fat diet
10
• Oxepa associated with
improved oxygenation and
lung compliance
Oxepa
control
0
Vent
Days
ICU
Days
ICU
Deaths
Singer Crit Care Med 2006:34;1033
Effect of Fish Oils/Borage Oils
and antioxidants in Critically Ill
with ALI
• RCT of 165 critically ill
patients with ARDS
secondary to sepsis
• Double-blinded; not ITT
• Experimental: Oxepa®
• Control: high fat diet
• Oxepa associated with:
• improved oxygenation
• More Vent free days
• More ICU free days
50
45
40
35
30
25
20
15
10
5
0
Oxepa
control
Vent
Days
ICU
ICU
Days Deaths
P=0.04
• Fewer new organ failures
Pontes -Arruda Crit Care Med 2006:34;2345
Overall Effect on Mortality
www.criticalcarenutrition.com
Interpretation of Studies?
• treatment effect of antioxidants?
• treatment effect of borage oils?
• comparison to standard enteral feeding
products?
How do you interpret
the findings?
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
Rationale for Antioxidants
1. Pre-existing deficiencies
- due to old age, smoking, malnutrition, chronic diseases
2. Increased requirements
- high antioxidant consumption from high radical formation
- high demands in hypermetabolism
3. Increased losses
- skin exudate in burns, blood loss, dialysis, gastric aspirate, intestinal
fistula
4. Reduced supply
- posttraumatic, postoperative delay of adequate nutrition/ antioxidant
supply
- interruptions in nutrient supply because of clinical/ diagnostic
procedures
Effect of Combined Antioxidant
Strategies in the Critically Ill
Effect on Mortality
Which Nutrient for Which Population?
Population
Nutrients
Elective
Surgery
Critically Ill
General
Septic
Trauma
Burns
Acute Lung
Injury
Benefit
No benefit
Harm
No benefit
No benefit
No benefit
Glutamine
Possible
Benefit
PN
Beneficial
(? receiving
EN)
…
EN
Possibly
Beneficial
EN
Possibly
Beneficial
…
Omega 3
FFA
…
…
…
…
…
Possible
Benefit
Antioxidants
…
Possible
Benefit
…
…
…
…
Arginine
Canadian Clinical Practice Guidelines JPEN 2003;27:355
ro
a n Cri
REducing Deaths from OXidative Stress:
ials G
i
ad
a l C ar e
Tr
t ic
The REDOXS study
up C an
Factorial 2x2 design
1200 ICU patients
Evidence of
organ failure
R
glutamine
R
Concealed
Stratified by
 site
 Shock
placebo
antioxidants
placebo
antioxidants
R
placebo
Critical Care Nutrition Web Site
www.criticalcarenutrition.com
– web based clinical practice
guidelines
– summaries of evidence
– online survey of current practice
– benchmarking (other sites and
the clinical practice guidelines)
– tools (protocols, etc)
– research related news