Transcript A Randomized Trial of Empiric Antibiotics and Invasive

Immunonutrition
in the Critically Ill?
Role of Arginine-supplemented diets
Daren K. Heyland, MD, FRCPC, MSc
Professor of Medicine,
Queen’s University, Kingston, Ontario
JAMA 2001;286:944
JAMA 2001;286:944
Outcomes
Clinically
Important
Mortality
QoL
Morbidity
•disease
•complication
s
•LOS
Surrogate
Nutritional
•weight
•NB
•a.a.
hypothesis
generating
Not Clinically
Important
Physiology
Lab animals
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
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?
Homogenous Patient
Populations?
=
Effect of Immunonutrition: A meta-analysis
Heyland JAMA 2001;286:944
Elective Surgical Patient
• cellular immune
dysfunction
–
T-cell
• decrease cytokine
activation
– IL-2, IFN
Elective Surgical Patient
MYELOID SUPPRESSOR CELLS
arginase 1
arginine
expression of zeta chain
Taheri Clin Cancer Res 2001 ;7:958
Effect of Different Types of Oils on
Arginase 1 Expression
Effect of Different Prostaglandins on Arginase expression in RAW 264.7
cells
PGE1 – Borage Oil
PGE2 – Corn Oil
PGE3 – fish Oil
Arginase expression may be modified by the type of Fatty Acid
Bansal JPEN 2005 29;S75
Elective Surgical Patient
• Replete arginine levels
• Inhibit Arginase 1
Restoring
Immunocompetence
Immunonutrition in Surgical Patients
As of 2006
Pathophysiology of Critical Illness
endothelial dysfunction
activation of coagulation/complement
Insult
• infection
• trauma
• I/R
• hypoxemic/
hypotensive
Role of
GIT
Activation of
PMN’s
elaboration of cytokines,
NO, and other mediators
generation of OFR
(ROS + RNOS)
mitochondrial
dysfunction
=
oxidative stress
cellular = energetic
failure
Key nutrient deficiencies
(e.g. glutamine, selenium)
organ = failure
Death
Metabolic Effects of Arginine
Urea
L-Ornithine
enteral / parenteral
supply
L-Arginine
L-Citrulline
Polyamine Synthesis
Hormone release
Nitrogenous compounds
• Putrescine
• Spermidine
• Spermine
• GH
• IGF
• Insulin
• Glucagon
• Prolactin
• catecholamines
• Nitric oxide
• Nitrite
• Nitrate
Suchner Brit J Nutrition 2001
Underlying Pathophysiology
Role of Nitric Oxide
Mitaka Shock 2003;19: 305
Arginine Metabolism after Trauma in Mice
Figert… Ochoa Surg Forum 1998
Underlying Pathophysiology
Role of Nitric Oxide
Rixen Shock 1997;7:17
Optimal NO-Balance
cNOS
- Microcirculation 
- Immune augmentation 
Harmful
Arginine / NO
availability
cNOS + iNOS
- Hemodynamic instability
- Immune Suppression
- Cytotoxicity
- Organe dysfunction
Suchner Brit J Nutrition 2001
Is it plausible that Argininesupplemented diets may do harm?
 Randomized, double
blind, placebocontrolled
 Beagles
 Parenteral L-arginine (+
NAC) vs placebo
 Canine model of E. coli
peritonitis
Kalil Crit Care Med 2006;34:2719
Is it plausible that Argininesupplemented diets may do harm?
Arginine administration
associated with:
Plasma arginine
NO products
And worse shock,
worse organ injury
Increased mortality!
No effect of
NAC
Kalil Crit Care Med 2006;34:2719
Is it plausible that Argininesupplemented diets may do harm?
16
 3 RCTs
 3 different products
 All describing excess
mortality in patients with
infection
14
12
10
Arginine
Control
8
6
4
2
1) Bower Crit Care Med 1995;23:436
2) Dent, Crit Care Med 2003;30:A17
3) Bertolini Intesive Care Med 2003;29:834
0
mortality
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
35
P=0.05
30
25
20
Impact
Control
15
10
5
0
Mortality
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.
But what about ...
•  cost.
• Possible mortality in septic pts (3 studies)
Heyland DK. Intensive Care Med 2003;17:267-271
VALUES:
Homogeneity
Validity
Safe
Effect size
Feasible
Confidence interval
Low cost
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
RCT’s of Arginine-containing
diets
5/22 (23%) concealed randomization
o 12/22 (55%) were double-blinded
10/22 (45%) performed Intention-to-treat
analysis
o
o
Analyzing the Data
 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
Immunonutrition: Does it make a
Impact?
ICU Length of Stay
% Mortality
45
12
40
10
p=0.02
35
8
30
25
IED
Control
20
IED
Control
6
15
4
10
2
5
0
0
ITT
Compliance
ITT
Compliance
Crit Care Med 1998;26:1164
Intention-to-treat
Analysis
Compliance Analysis
IED
Control
CCM 1998;26:1164
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
Arginine diets in ICUs in the world
and Australia
% of Arginine enriched formula use
20
15
10
5
0
ICUs in Australia
ICUs in the world
International Audit of 165 ICUs
Total % Patients Ever on EN receiving formula
N=2773
Arginine-supplemented
5.3 % (0.0-92.3)
formulas
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)