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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
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
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?
19. PGE1PGE1+IL-13
PGE2PGE2+IL-13
PGE3PGE3+IL-13
+Control
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
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
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
35. Methodological Quality ofMethodological Quality of
RCT’s of Arginine-containingRCT’s of Arginine-containing
dietsdiets
o 5/22 (23%) concealed randomization
o 12/22 (55%) were double-blinded
o 10/22 (45%) performed Intention-to-treat
analysis
36.
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
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
%ofArginineenrichedformulause
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 supplementation 7.2 % (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)
Editor's Notes
Zeta chain an essential component of the t cell receptor complex and the signal transduction pathway leading to I cell activation
IL-2 necessary for normal T-cell proliferation
ITV necessary for normal inflammatory response
Zeta chain an essential component of the t cell receptor complex and the signal transduction pathway leading to I cell activation
IL-2 necessary for normal T-cell proliferation
ITV necessary for normal inflammatory response
Arginine is considered a non essential amino acid althought its availability is reduced in trauma and sepsis. There is a considerable body of literature that suggests that argnine effect hormone release and poly amine release- these growth factors increase substrates necessary for the synthesis of connective tissue (leads to wound healing). However, argnine also gives rise to an increase in nitrogenous compounds such as NO.
in severely traumatized patients
Add slide showing current utilization of arginine diets in ICUs in the world and Australia
