PharmaconutritionA New Emerging Paradigm

Daren K. Heyland, MD, FRCPC, MScProfessor of Medicine,

Queen’s University, Kingston, Ontario

The First Ever Recorded Clinical Trial

[Nebuchadnezzar, king of Babylon, carried away children of Israel, into his court ]

5 And the king appointed them a daily provision of the king's meat, and of the wine which he drank:

8 Daniel would not defile himself with the portion of the king's meat, nor with the wine

10 Prince of the eunuchs said unto Daniel, I fear the king, who hath appointed your meat and your drink: for why should he see your faces worse liking than the children which are of your sort? then shall ye make me endanger my head to the king.

Book of Daniel 1:1-15

11 Then said Daniel to Melzar, whom the prince of the eunuchs had set over Daniel,

12 Prove thy servants, I beseech thee, ten days; and let them give us pulse to eat, and water to drink.

13 Then let our countenances be looked upon before thee, and the countenance of the children that eat of the portion of the king's meat: and as thou seest, deal with thy servants.

14 So he consented to them in this matter, 15 And at the end of ten days their countenances appeared

fairer and fatter in flesh than all the children which did eat the portion of the king's meat.

The First Ever Recorded Clinical Trial

Book of Daniel 1:1-15

16 [from all the children of Israel in the King’s Court] Thus Melzar took away the portion of their meat, and the wine that they should drink; and gave them pulse.

Translating Research Findings into Practice !

Book of Daniel 1:1-16

www.criticalcarenutrition.com

Updated October 2008

Summarizes 198 trials studying 21283 patients

34 topics 17 recommendations

Validation of the CPG’s: Results of a Prospective Observational

Study • Summary

– Patients and Sites that were more consistent with CPG recommendations tended to receive more EN

Adoption of Canadian CPGs will likely lead to improved nutrition support practices in ICUs

Heyland CCM 2004;32:2260

www.criticalcarenutrition.com

Our efforts to translate best evidence into practice!

www.criticalcarenutrition.com

Immunonutrition

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

GlutamineGlutamineArginineArginine

Largest Randomized Trial of Immunonutrition

Good Methods Multicenter RCT double-blinded ITT analysis

Heterogeneous group of patients (597) Elective and urgent surgery (50%) Trauma (8%) Medical including septic (42%)

high protein entered formula enriched with

arginine (10 g/L), Glutamine Antioxidants omega 3 FAs (Stresson®)

0102030405060708090

100

Hospital Mortality

StressonControl

No other differences in Outcome

No subgroup differences

Kieft Int Care Med 2005;31:524

Updated Analysis: Effect on Mortality

www.criticalcarenutrition.com

Updated Analysis:Effect on Infectious

Complications

www.criticalcarenutrition.com

Why is it not working?

Old

Immunonutrition

New

Pharmaconutrients

Nutrition Nutrients

Combined nutrients Single nutrients

Heterogeneous populations

Homogenous

Patients

Weak methods Rigorous

Small single center Large multicenter

Heyland Int Care Med 2005;31:501

Nutrition vs Nutrients

Impacts mortality! arginine

glutamine antioxidants

omega-3 fatty acids

Impacts morbidity EN vs PNEarly EN

small bowel feeding

Pharmaconutrients Impact Outcomes!

www.criticalcarenutrition.com

1 10 1000.1.01

Glutamine

Antioxidants

Fish/Borage OilsPlus AOX

Effect on Mortality

Arginine

Nutrition vs Nutrients• Vitamin A Supplementation for extremely Low Birth

weight Infants reduces chronic lung diseaseNEJM 1999;340:1962

• B carotene supplementation in AIDS associated with improved survival

Eur J Clin Nutr; 2006;60:1266

• N-3 fatty acids associated with survival advantage post-MI

Circulation 2002; 105: 1897

• L-Arginine associated with higher post infarction mortality

JAMA 2006; 295: 58

Examples of Placebo-controlled trials where nutrients are tested in addition to standard care

Cocktail Approach? • Specific nutrients found to have effects on

immune system, metabolism, and GI structure and functionArginineGlutamineOmega-3 fatty acidsNucleic acidsothers

• Rationale for combining substances into products?

Elective

Surgery

Critically Ill

General Septic Trauma Burns Acute Lung Injury

Arginine Benefit No benefit Harm No benefit No benefit No benefit

Glutamine Benefit PN Beneficial

(? receiving EN)

… EN Possibly

Beneficial

EN Possibly

Beneficial

…

Omega 3 FFA

… … … … … Beneficial

Antioxidants … Possible Benefit

… … … …

Population

Nutrients

Pharmaconutrition: Which Nutrient for Which Population?

Canadian Clinical Practice Guidelines JPEN 2003;27:355

www.criticalcarenutrition.com

=

Homogenous Patient Populations?

Effect of Parenteral Nutrition on Mortality

Risk ratio (log scale)

Malnourished

Non-malnourished

Quality score <7

Quality score >= 7

Published before 1988

Published after 1989

Lipids

No Lipids

Critically Ill

Surgical

Overall Effect0.1 1 10

TPN Benefical

TPN Harmful

Mortality

p=0.12

p=0.07

p=0.025

Heyland JAMA 1998

Heyland JAMA 2001;286:944

Effect of Immunonutrition: A meta-analysis

Mucosal Barrier Integrity

Inflammation

Cellular Immune Function

Oxidative StressMito

Function

In Search of the Magic Nutraceutical

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

Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma and subarachnoid

hemorrhage patients.

0

50

100

150

200

250

0 1 2 3 4 5

CardiacTraumaSAH

CRP levels daily in the Control groups

Significant reduction with AOX in Cardiac and Trauma but not SAH

Berger Crit Care 2008

RCT 200 patients IV supplements for 5 days

after admission (Se 270 mcg, Zn 30 mg, Vit C 1.1 g, Vit B1 100 mg) with a double loading dose on days 1 and 2 (AOX group), or placebo.

No affect on clinical outcomes

Effect of Antioxidants on Mortality:Relationship to Control Group Mortality

Baseline Risk of Patients Impacts on Magnitude of Treatment Effect

A meta-analysis found calcuim supplementation to be effective in preventing preeclampsia

Large RCT found no risk reduction in health nulliparous women

Exploration of heterogeneity across studies Stratify for high and low baseline risk

JAMA 1999;282:664

JAMA 1999;282:664

Baseline Risk of Patients Impacts on Magnitude of Treatment Effect

Why is it not working?

Old

(Immunonutrition)

New

(Pharmaconutrients)

Nutrition Nutrients

Combined nutrients Single nutrients

Heterogeneous populations

Homogenous

Patients

Weak methods Rigorous

Small single center Large multicenter

A Review of the True Methodological Quality of Nutrition Support Trials

Conducted in the Critically Ill: Time for Improvement!

• Appraised the methodological quality of 111 nutrition RCTs and compared to sepsis trials in ICU setting

• Compared to sepsis trials, nutrition trials were:– less likely to use blinding (31% vs 80%)

– less likely to present ITT analysis (58% vs 93%).

– less likely to conceal randomization (17% vs 30%)

– more likely to have excessive amounts of lost to follow up (18% vs 0)

Doig Anesth Analg 2005;100:527-33

REducing Deaths from OXidative Stress:

The REDOXS study

A multicenter randomized trial of glutamine and antioxidant

supplementation in critical illness

Effect of Glutamine in the Critically ill Patient: Mortality

www.criticalcarenutrition.com

Effect of Combined Antioxidant

Strategies in the Critically Ill

www.criticalcarenutrition.com

Mortality

The Research Protocol

In enterally fed, critically ill patients with a clinical evidence of acute multi organ dysfunction – 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

Heyland JPEN 2007;31:109

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

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

Heyland JPEN Mar 2007

Parenterally Enterally

Glutamine/day 0.35 gms/kg 30 gms

Antioxidantsper day

500 mcg Selenium

Vit C 1500 mgVit E 500 mg

B carotene 10 mgZinc 20 mgSe 300 ug

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

• High risk, sick homogenous population • Preceded by:

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

– a dosing optimizing study• Funded by CIHR

ConclusionsNutrition Therapy : Modulating the Stress Response

Adjunctive Supportive Care

Proactive Primary Therapy

Implications of the New Paradigm?

• Research– explosion of research opportunities

– Methodological challenges

• Education– included in critical care curriculum?

• Models of Care Delivery– Expect Physicians to order pharmaconutrients just like

they order antibiotics? who will they consult for difficult cases? Revitalized Nutrition Support Teams?

Blind Administration of Pharmacologically Active

Nutrients?

Hotchkiss NEJM 2003;348:138

Pharmaconutrition: The Future

o Which nutrient?o What patient?o At what time point?o For how long?