Transcript Pharmaconutrition A New Emerging Paradigm Daren K. Heyland, MD, FRCPC, MSc

Pharmaconutrition
A New Emerging Paradigm
Daren K. Heyland, MD, FRCPC, MSc
Professor 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
The First Ever Recorded Clinical Trial
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.
Book of Daniel 1:1-15
Translating Research Findings into
Practice !
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.
Book of Daniel 1:1-16
 Updated October 2008
 Summarizes 198 trials studying 21283 patients
 34 topics
17 recommendations
www.criticalcarenutrition.com
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
Our efforts to translate best
evidence into practice!
www.criticalcarenutrition.com
www.criticalcarenutrition.com
Immunonutrition
• Specific nutrients found to have effects on
immune system, metabolism, and GI
structure and function
Arginine
Glutamine
Omega-3 fatty acids
Nucleic acids
others
Arginine
Glutamine
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®)
100
90
80
70
60
50
40
30
20
10
0
Stresson
Control
Hospital Mortality
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
Rigorous
Large multicenter
Weak methods
Small single center
Heyland Int Care Med 2005;31:501
Nutrition vs Nutrients
Impacts morbidity
EN vs PN
Early EN
small bowel
feeding
Impacts mortality!
arginine
glutamine
antioxidants
omega-3 fatty
acids
Pharmaconutrients Impact Outcomes!
Effect on Mortality
Glutamine
Antioxidants
Fish/Borage Oils
Plus AOX
Arginine
.01
0.1
1
10
100
www.criticalcarenutrition.com
Nutrition vs Nutrients
• Vitamin A Supplementation for extremely Low Birth
weight Infants reduces chronic lung disease
NEJM 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
function
 Arginine
 Glutamine
 Omega-3 fatty acids
 Nucleic acids
 others
• Rationale for combining substances into products?
Pharmaconutrition:
Which Nutrient for Which Population?
Population
Elective
Surgery
Nutrients
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
…
…
…
…
Canadian Clinical Practice Guidelines JPEN 2003;27:355
www.criticalcarenutrition.com
Homogenous Patient
Populations?
=
Effect of Parenteral
Nutrition on Mortality
Mortality
Malnourished
Non-malnourished
Quality score <7
p=0.12
Quality score >= 7
Published before 1988
p=0.07
Published after 1989
Lipids
No Lipids
Critically Ill
p=0.025
Surgical
Overall Effect
0.1
1
10
TPN
Harmful
TPN
Benefical
Risk ratio (log scale)
Heyland JAMA 1998
Effect of Immunonutrition: A meta-analysis
Heyland JAMA 2001;286:944
In Search of the Magic
Nutraceutical
Mucosal Barrier Integrity
Oxidative Stress
Mito
Function
Cellular Immune Function
Inflammation
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
Influence of early antioxidant supplements on clinical
evolution and organ function in critically ill cardiac surgery,
major trauma and subarachnoid hemorrhage patients.
250
 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
200
150
Cardiac
Trauma
SAH
100
50
0
0
1
2
3
4
5
CRP levels daily in the Control groups
Significant reduction with AOX in Cardiac and
Trauma but not SAH
Berger Crit Care 2008
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
Baseline Risk of Patients Impacts on
Magnitude of Treatment Effect
JAMA 1999;282:664
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
Average Yearly Score
12
10
8
6
4
2
0
1976 1983 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
RCT Average Patient Population Size per Year
250
200
150
100
50
0
19761983198519861987198819891990199119921993199419951996199719981999200020012002200320042005200620072008
Number of RCTs and Multicenter Trials over Time
16
14
12
10
8
RCTs
6
Multicenter
RCTs
4
2
0
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
Effect of Glutamine
in the Critically ill Patient: Mortality
www.criticalcarenutrition.com
Effect of Combined Antioxidant
Strategies in the Critically Ill
Mortality
www.criticalcarenutrition.com
The Research Protocol
The Question(s)
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?
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
Heyland JPEN 2007;31:109
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
Inferences
Glutamine/day
Antioxidants
per day
Parenterally
Enterally
0.35 gms/kg
30 gms
500 mcg
Selenium
Vit C 1500 mg
Vit E 500 mg
B carotene 10 mg
Zinc 20 mg
Se 300 ug
• 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
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
Conclusions
Nutrition 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
o
o
o
Which nutrient?
What patient?
At what time point?
For how long?