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)