Immunonutrition

1. Immunonutrition
in the Critically Ill?
Role of Arginine-supplemented diets
Daren K. Heyland, MD, FRCPC, MSc
Professor of Medicine,
Queen’s University, Kingston, Ontario

7. JAMA 2001;286:944

8. JAMA 2001;286:944

10. Outcomes
Clinically
Important
Surrogate
Not Clinically
Important
Mortality
QoL
Morbidity
•disease
•complication
s
•LOS
Nutritional
•weight
•NB
•a.a.
Physiology
Lab animals
hypothesis
generating

11. 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®)
0
10
20
30
40
50
60
70
80
90
100
Hospital Mortality
Stresson
Control
No other differences in Outcome
No subgroup differences
Kieft Int Care Med 2005;31:524

12. Updated Analysis:
Effect on Mortality
www.criticalcarenutrition.com

13. Updated Analysis:
Effect on Infectious Complications
www.criticalcarenutrition.com

14. 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?

15. =
Homogenous Patient
Populations?

16. Heyland JAMA 2001;286:944
Effect of Immunonutrition: A meta-
analysis

17. Elective Surgical Patient
•cellular immune
dysfunction
– T-cell
•decrease cytokine
activation
–IL-2, IFN

18. Elective Surgical Patient
arginase 1
arginine
expression of zeta chain
Taheri Clin Cancer Res 2001 ;7:958
MYELOID SUPPRESSOR CELLS

19. P
G
E
1
P
G
E
1
+
IL
-1
3
P
G
E
2
P
G
E
2
+
IL
-1
3
P
G
E
3
P
G
E
3
+
IL
-1
3
+
C
o
n
tro
l
Effect of Different Types of Oils on
Arginase 1 Expression
Effect of Different Prostaglandins on Arginase expression in RAW 264.7
cells
Arginase expression may be modified by the type of Fatty Acid
PGE1 – Borage Oil
PGE2 – Corn Oil
PGE3 – fish Oil
Bansal JPEN 2005 29;S75

20. Elective Surgical Patient
•Replete arginine levels
•Inhibit Arginase 1
Restoring
Immunocompetence

21. Immunonutrition in Surgical Patients
As of 2006

22. Insult
• infection
• trauma
• I/R
• hypoxemic/
hypotensive
Activation of
PMN’s
=
oxidative stress
Death
organ = failure
Pathophysiology of Critical Illness
mitochondrial
dysfunction
Role of
GIT
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

23. Metabolic Effects of Arginine
enteral / parenteral
supply
L-Arginine L-CitrullineL-Ornithine
Polyamine Synthesis

• Putrescine
• Spermidine
• Spermine
Hormone release
• GH
• IGF
• Insulin
• Glucagon
• Prolactin
• catecholamines
Urea
Nitrogenous compounds
• Nitric oxide
• Nitrite
• Nitrate
Suchner Brit J Nutrition 2001

24. Mitaka Shock 2003;19: 305
Underlying Pathophysiology
Role of Nitric Oxide

25. Figert… Ochoa Surg Forum 1998
Arginine Metabolism after Trauma in Mice

26. Rixen Shock 1997;7:17
Underlying Pathophysiology
Role of Nitric Oxide

27. cNOS
cNOS + iNOS
E
f
f
e
c
t
o
f
A
r
g
i
n
i
n
e

i
n
d
u
c
e
d
N
O
f
o
r
m
a
t
i
o
n
H
a
r
m
f
u
l
B
e
n
e
f
i
t
i
a
l
Arginine / NO
availability
Optimal NO-Balance
- Hemodynamic instability
- Immune Suppression
- Cytotoxicity
- Organe dysfunction
- Microcirculation ­
- Immune augmentation ­
Suchner Brit J Nutrition 2001

28. Is it plausible that Arginine-
supplemented diets may do harm?
Randomized, double
blind, placebo-
controlled
Beagles
Parenteral L-arginine (+
NAC) vs placebo
Canine model of E. coli
peritonitis
Kalil Crit Care Med 2006;34:2719

29. Is it plausible that Arginine-
supplemented diets may do harm?
Arginine administration
associated with:
Plasma arginine
NO products
And worse shock,
worse organ injury
Increased mortality!
Kalil Crit Care Med 2006;34:2719
No effect of
NAC

30. Is it plausible that Arginine-
supplemented diets may do harm?
3 RCTs
3 different products
All describing excess
mortality in patients with
infection
0
2
4
6
8
10
12
14
16
mortality
Arginine
Control
1) Bower Crit Care Med 1995;23:436
2) Dent, Crit Care Med 2003;30:A17
3) Bertolini Intesive Care Med 2003;29:834

31. Benefit in Sepsis?
Multicenter RCT
Not blinded
Loose definition of
sepsis
181 Critically ill patients
with infection and
APACHE>10
?cointerventions
Only assessed ICU
mortality
Non ITT
0
5
10
15
20
25
30
35
Mortality
Impact
Control
P=0.05
Benefit in subgroup
APACHE<15
Galban Crit Care Med 2000; 28:643-648

32. Canadian Clinical Practice
Guidelines Committee:
ARGININE: DISCUSSION
•Lack of tx effect for mortality and infections.
"­ cost.
•Possible­ mortality in septic pts (3 studies)
Heyland DK. Intensive Care Med 2003;17:267-271
VALUES: Validity Effect size Confidence interval
Homogeneity Safe Feasible Low cost
But what about ...

33. Diets Supplemented with arginine
and select other nutrients
•Recommendation:
Based on 3 level 1 studies and 15 level 2
studies, we recommend that diets supplemented
with arginine and other select nutrients not be
used for critically ill pts.
Canadian Clinical Practice Guidelines JPEN
2003;27:355-373

34. Rebuttal

35. Methodological Quality of Methodological Quality of
RCT’s of Arginine-containing RCT’s of Arginine-containing
dietsdiets
o5/22 (23%) concealed randomization
o12/22 (55%) were double-blinded
o10/22 (45%) performed Intention-to-treat
analysis

37. Intention-to-treat
includes all randomized patients
less sensitive but most robust estimate of treatment effect
Efficacy analysis
includes only patients who met the eligibility criteria and
actually rec’d feeds
more sensitive than ITT but less valid
Compliance analysis
includes only patients who receive a critical volume of
study feeds
highly biased, more likely to misinform
Analyzing the DataAnalyzing the Data

38. 0
5
10
15
20
25
30
35
40
45
ITT Compliance
IED
Control
0
2
4
6
8
10
12
ITT Compliance
IED
Control
% Mortality ICU Length of Stay
p=0.02
Immunonutrition: Does it make a Immunonutrition: Does it make a
Impact?Impact?
Crit Care Med 1998;26:1164

39. IED
Control
CCM 1998;26:1164
Compliance Analysis
Intention-to-treat
Analysis

40. Corporate Endorsement!
Dear Doctor
Nutricia has been closely following the debate over the so-called "immune
enhancing diets" or "immunutrition" (IED). Recent publications and studies
have questioned the use of IEDs. This month the Canadian Critical Care
Clinical Practice Guidelines Committee has published new guidelines for
nutrition support in critically ill patients (October 2003); these guidelines
clearly advise against the use of IEDs for critically ill patients. The guidelines
explicitly state as follows…
" According to 2 Level 1 studies and 12 level 2 studies, we recommend that
diets supplemented with arginine and other select nutrients not be used for
critically ill patients" (1)
After full consideration of recent scientific publications and the new evidence
based Canadian guidelines, Nutricia has decided, in the best interests of
patients and carers, to discontinue the availability of Stresson/Stresson Multi
Fibre. Nutricia recommend to you to follow, from now on, the
recommendations of the Canadian guidelines.
Nutricia Oct 03

41. Arginine diets in ICUs in the world
and Australia
0
5
10
15
20
%

o
f

A
r
g
i
n
i
n
e

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

u
s
e
ICUs in Australia ICUs in the world

42. International Audit of 165 ICUs
Total % Patients Ever on EN receiving formula
N=2773
Arginine-supplemented
formulas
5.3 % (0.0-92.3)
Glutamine supplementation7.2 % (0-100)
Fish/Borage oils+AOX (All)1.4 % (0-40)
Fish/Borage oils+AOX (ARDS)4.1 % (0-100)
Polymeric 91.2 % (0-100)