Pharmaconutrition: Selected Nutrients and Their Influence on Patient Outcomes The Canadian Clinical Practice Guidelines Daren K. Heyland, MD, FRCPC, MSc

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

www.criticalcarenutrition.com

Updated July 2006

Immunonutrition: Cocktail Approach?

• Specific nutrients found to have effects on immune system, metabolism, and GI structure and functionArginineGlutamineOmega-3 fatty acidsNucleic acidsothers

• Individual effect on clinical outcomes?

Insult

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

Activation ofPMN’s

= oxidative stress

Death

organ = failure

Pathophysiology of Critical Illness

mitochondrial dysfunction

Role ofGIT

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

activation of coagulation/complement

generation of OFR (ROS + RNOS)

endothelial dysfunction

elaboration of cytokines, NO, and other mediators

cellular = energetic failure

Arginine

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)

Elective

Surgery

Critically Ill

General Septic Trauma Burns Acute Lung Injury

Arginine

Glutamine

Omega 3 FFA

Antioxidants

Population

Nutrients

Which Nutrients?Which Patients?

Canadian Clinical Practice Guidelines JPEN 2003;27:355


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

Elective

Surgery

Critically Ill


Arginine 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

… … … …

Population

Nutrients

Which Nutrient for Which Population?


Arginine-supplemented diets?

Mitaka Shock 2003;19: 305

Underlying PathophysiologyRole of Nitric Oxide

cNOS

cNOS + iNOS

Eff

ect o

f A

rgin

i ne

ind u

ced

NO

for

mat

ion

Har

mfu

lB

enef

itia

l

Arginine / NO availability

Optimal NO-Balance

- Hemodynamic instability- Immune Suppression- Cytotoxicity- Organe dysfunction

- Microcirculation - Immune augmentation

Suchner Brit J Nutrition 2001

Effect of Arginine-supplemented diets on

Mortality



Effect of Arginine-supplemented diets on

Infectious complications

• 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 ...

Effect of Arginine-supplemented diets in Critically Ill Patients

Glutamine supplementation?

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

Effect of Glutamine:A Systematic Review of the Literature


Infectious Complications

Effect of Glutamine:A Systematic Review of the Literature


Mortality

Results of subgroup analysis

EN vs PN?

Mortality Infection

EN 0.80 (0.45-1.43)

P=0.46

0.83 (0.64-1.08)

P=0.16

PN 0.67 (0.48-0.92)

P=0.01

0.75(0.54-1.04)

P=0.08

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

Borage Oil

DGLA

PGE1 and LessInflammatory Eicosanoids

Substitution of AABy DGLA

resulting in:

Fish Oil

GLA EPA

Less Inflammatory Eicosanoids

(TXA3, PGE3, LTB5)

Substitution of AABy EPA

Resulting in:

Arachidonic Acid

CyclooxygenaseLipoxygenase

Pro-InflammatoryEicosanoids

(LTB4, TXA2, PGE2)

Decrease in

Mechanisms of Action

Effect of Fish Oils/Borage Oils and antioxidants in Critically Ill

with ALI

• RCT of 146 critically ill patients with ALI and BAL+ for WBCs

• Double-blinded; ITT

• Experimental: Oxepa®

• Control: high fat diet

• Groups well matched at baseline

0

5

10

15

20

25

VentDays

ICUDays

ICUDeaths

Oxepacontrol

Gadek Crit Care Med 1999;27:1409

P=0.03 P=0.17P=0.02


with ALI• RCT of 100 critically ill

patients with ALI

• Single center

• unblinded; not ITT



• Oxepa associated with improved oxygenation and lung compliance

0

10

20

30

40

50

60

VentDays

ICUDays

ICUDeaths

Oxepacontrol

Singer Crit Care Med 2006:34;1033


with ALI• RCT of 165 critically ill patients

with ARDS secondary to sepsis

• Double-blinded; not ITT



• Oxepa associated with:

• improved oxygenation

• More Vent free days

• More ICU free days

• Fewer new organ failures

05

101520253035404550

VentDays

ICUDays

ICUDeaths

Oxepacontrol

Pontes -Arruda Crit Care Med 2006:34;2345

P=0.04

Overall Effect on Mortality


• treatment effect of antioxidants?

• treatment effect of borage oils?

• comparison to standard enteral feeding products?

Interpretation of Studies?

How do you interpret the findings?

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


1 . P re -e x is t in g d e f ic ie n c ie s - d u e to o ld a g e , s m o k in g , m a ln u tr i tio n , c h ro n ic d is e a se s

2 . In c re a s e d re q u ire m e n ts - h ig h a n tio x id a n t c o n s u m p tio n fro m h ig h ra d ic a l fo rm a tio n - h ig h d e m a n d s in h yp e rm e ta b o lis m

3 . In c re a s e d lo s s e s - s k in e xu d a te in b u rn s , b lo o d lo s s , d ia ly s is , g a s tr ic a s p ira te , in te s tin a l

f is tu la

4 . R e d u c e d s u p p ly - p o s ttra u m a tic , p o s to p e ra tiv e d e la y o f a d e q u a te n u tr i tio n / a n tio x id a n t

s u p p ly - in te r ru p t io n s in n u tr ie n t s u p p ly b e c a u s e o f c l in ic a l / d ia g n o s tic

p ro c e d u re s


Effect of Combined Antioxidant

Strategies in the Critically Ill

Effect on Mortality

Elective

Surgery

Critically Ill


Arginine 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

… … … …

Population

Nutrients

Which Nutrient for Which Population?


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

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

Documents

Pharmaconutrition: Selected Nutrients and Their Influence on Patient Outcomes The Canadian Clinical Practice Guidelines Daren K. Heyland, MD, FRCPC, MSc