immunonutrition in the critically ill? role of arginine-supplemented diets daren k. heyland, md,...
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Immunonutrition in the Critically Ill?
Role of Arginine-supplemented diets
Daren K. Heyland, MD, FRCPC, MScProfessor of Medicine,
Queen’s University, Kingston, Ontario
JAMA 2001;286:944
JAMA 2001;286:944
Outcomes
Clinically Important
Surrogate
Not Clinically Important
MortalityQoL
Morbidity•disease
•complications•LOS
Nutritional•weight
•NB•a.a.
PhysiologyLab animals
hypothesis
generating
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
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?
=
Homogenous Patient Populations?
Heyland JAMA 2001;286:944
Effect of Immunonutrition: A meta-analysis
Elective Surgical Patient
• cellular immune dysfunction – T-cell
• decrease cytokine activation – IL-2, IFN
Elective Surgical Patient
arginase 1
arginine
expression of zeta chain
Taheri Clin Cancer Res 2001 ;7:958
MYELOID SUPPRESSOR CELLS
PGE1
PGE1
+ IL
-13
PGE2
PGE2
+ IL
-13
PGE3
PGE3
+ IL
-13
+ C
ontro
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
Elective Surgical Patient
• Replete arginine levels• Inhibit Arginase 1
Restoring Immunocompetence
Immunonutrition in Surgical Patients
As of 2006
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
Metabolic Effects of Arginine
enteral / parenteralsupply
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
Mitaka Shock 2003;19: 305
Underlying PathophysiologyRole of Nitric Oxide
Figert… Ochoa Surg Forum 1998
Arginine Metabolism after Trauma in Mice
Rixen Shock 1997;7:17
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
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
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
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
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
ImpactControl
P=0.05
Benefit in subgroup APACHE<15
Galban Crit Care Med 2000; 28:643-648
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 ...
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
Rebuttal
Methodological Quality of Methodological Quality of RCT’s of Arginine-RCT’s of Arginine-containing dietscontaining diets
o 5/22 (23%) concealed randomizationo 12/22 (55%) were double-blinded
o 10/22 (45%) performed Intention-to-treat analysis
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 feedsmore sensitive than ITT but less valid
Compliance analysis includes only patients who receive a critical volume of
study feedshighly biased, more likely to misinform
Analyzing the DataAnalyzing the Data
0
5
10
15
20
25
30
35
40
45
ITT Compliance
IEDControl
0
2
4
6
8
10
12
ITT Compliance
IEDControl
% 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
IED
Control
CCM 1998;26:1164
Compliance Analysis
Intention-to-treat Analysis
Corporate Endorsement!
Dear DoctorNutricia 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
Arginine diets in ICUs in the world and Australia
0
5
10
15
20
% o
f A
rgin
ine
enri
ched
fo
rmu
la u
se
ICUs in Australia ICUs in the world
International Audit of 165 ICUs
Total % Patients Ever on EN receiving formulaN=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)