Immunonutrition in the Critically Ill? Role of Arginine-supplemented diets

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Immunonutrition in the Critically Ill?Role of
Arginine-supplemented diets

• Daren K. Heyland, MD, FRCPC, MSc

Professor of Medicine, Queens University,
Kingston, Ontario
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JAMA 2001286944
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NO!
JAMA 2001286944
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Outcomes

• Mortality
• QoL
• Morbidity
• disease
• complications
• LOS
• Nutritional
• weight
• NB
• a.a.
• Physiology
• Lab animals

Clinically Important
Surrogate
hypothesis generating
Not Clinically Important
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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)

No other differences in Outcome No subgroup
differences
Kieft Int Care Med 200531524
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Updated Analysis Effect on Mortality
www.criticalcarenutrition.com
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Updated AnalysisEffect on Infectious
Complications
www.criticalcarenutrition.com
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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?

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Homogenous Patient Populations?

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Effect of Immunonutrition A meta-analysis
Heyland JAMA 2001286944
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Elective Surgical Patient

• cellular immune dysfunction
• T-cell
• decrease cytokine activation
• IL-2, IFN

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Elective Surgical Patient
MYELOID SUPPRESSOR CELLS
arginase 1
arginine
expression of zeta chain
Taheri Clin Cancer Res 2001 7958
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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 29S75
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Elective Surgical Patient

• Replete arginine levels
• Inhibit Arginase 1

Restoring Immunocompetence
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Immunonutrition in Surgical Patients
As of 2006
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Pathophysiology of Critical Illness
Key nutrient deficiencies (e.g. glutamine,
selenium)
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Metabolic Effects of Arginine
enteral / parenteral supply
Urea
L-Arginine
L-Citrulline
L-Ornithine

• Polyamine Synthesis
• Putrescine
• Spermidine
• Spermine

• Hormone release
• GH
• IGF
• Insulin
• Glucagon
• Prolactin
• catecholamines

• Nitrogenous compounds
• Nitric oxide
• Nitrite
• Nitrate

Suchner Brit J Nutrition 2001
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Underlying PathophysiologyRole of Nitric Oxide
Mitaka Shock 200319 305
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Arginine Metabolism after Trauma in Mice
Figert Ochoa Surg Forum 1998
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Underlying PathophysiologyRole of Nitric Oxide
Rixen Shock 1997717
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Optimal NO-Balance
cNOS
- Microcirculation ?- Immune augmentation ?
Benefitial
Effect of Arginine induced NO formation
Arginine / NO availability
Harmful
cNOS iNOS
- Hemodynamic instability- Immune Suppression-
Cytotoxicity- Organe dysfunction
Suchner Brit J Nutrition 2001
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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 2006342719
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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!

No effect of NAC
Kalil Crit Care Med 2006342719
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Is it plausible that Arginine-supplemented diets
may do harm?

• 3 RCTs
• 3 different products
• All describing excess mortality in patients with
  infection

1) Bower Crit Care Med 199523436
2) Dent, Crit Care Med 200330A17
3) Bertolini Intesive Care Med 200329834
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Benefit in Sepsis?

• Multicenter RCT
• Not blinded
• Loose definition of sepsis
• 181 Critically ill patients with infection and
  APACHEgt10
• ?cointerventions
• Only assessed ICU mortality
• Non ITT

P0.05
Benefit in subgroup APACHElt15
Galban Crit Care Med 2000 28643-648
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Canadian Clinical Practice Guidelines
CommitteeARGININE DISCUSSION
But what about ...

• Lack of tx effect for mortality and infections.
• ? cost.
• Possible? mortality in septic pts (3 studies)
• Heyland DK. Intensive Care Med 200317267-271

VALUES Validity Effect size Confidence
interval Homogeneity Safe Feasible Low cost
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Diets Supplemented with arginine and select
other nutrients

• RecommendationBased 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
200327355-373
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Rebuttal
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Methodological Quality of RCTs of
Arginine-containing diets

• 5/22 (23) concealed randomization
• 12/22 (55) were double-blinded
• 10/22 (45) performed Intention-to-treat analysis

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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 recd 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

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Immunonutrition Does it make a Impact?
ICU Length of Stay
Mortality
p0.02
Crit Care Med 1998261164
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Intention-to-treat Analysis
Compliance Analysis
IED
Control
CCM 1998261164
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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
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Arginine diets in ICUs in the world and Australia
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International Audit of 165 ICUs
Total Patients Ever on EN receiving
formula N2773
Arginine-supplemented formulas 5.3 (0.0-92.3)
Glutamine supplementation 7.2 (0-100)
Fish/Borage oilsAOX (All) 1.4 (0-40)
Fish/Borage oilsAOX (ARDS) 4.1 (0-100)
Polymeric 91.2 (0-100)