Omega3 Fatty Acids in Critically Ill Patients

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Omega-3 Fatty Acidsin Critically Ill Patients

• Renee D. Stapleton, MD MSc
• Pulmonary and Critical Care Medicine
• University of Vermont
• May 31, 2008

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Outline

• Mechanisms of action Why might fish oils (?-3s)
  be effective in acute lung injury (ALI) and
  sepsis?
• Existing data
• Recommendations
• Future directions

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• MECHANISMS OF ACTION

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Why might fish oils work?Inflammation in
critical illness

• ALI and sepsis involve uncontrolled activation of
  host proinflammatory response
• Activated monocytes/macrophages release cytokines
• IL-1, IL-6, IL-8, TNF-a
• Neutrophils are then activated
• Produce proteases, oxidants, and lipid-derived
  mediators including eicosanoids

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Eicosanoids

• PGE2, PGI2, TXA2, LTB4
• Released from activated neutrophils
• Derived from arachidonic-acid (AA) in immune cell
  membranes
• Fever, pain, vascular permeability,
  vasodilatation, leukocyte chemotaxis, platelet
  aggregation, ROS generation
  

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Fish Oil EPA and DHA

• Eicosapentaenoic acid (EPA) and docosahexanoic
  acid (DHA)
• ?-3 fatty acids in fish oil
• 5 known mechanisms of anti-inflammatory action

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EPA and DHAInflammatory Mechanisms
n-6 pathway n-3 pathway
a-linolenic acid
Linoleic acid
1-series PG and TX
3. The good eicosanoids
?-linoleic acid (GLA)
COX
3-series LT
LOX
dihomo-?-linoleic acid
3-series PG and TX
4. inhibition
COX
2. inhibition
Eicosapentaenoic acid (EPA)
Arachidonic acid (AA)
COX
2-series PG and TX
LOX
1. replacement
LOX
Docosahexanoic acid (DHA)
5-series LT
4-series LT
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EPA and DHAInflammatory Mechanisms

• EPA replaces AA in immune cell membranes
• Substrate restriction
• EPA inhibits metabolism of free AA
• EPA is itself metabolized to less inflammatory
  eicosanoids
• Inhibition of DHGLA ? AA in liver
• Recent advancement resolvins and protectins

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Resolvins and Protectins

• Novel endogenous lipid mediators involved in
  inflammation resolution
• Derived from EPA and DHA
• Inhibit inflammatory cytokine release and
  production, dendritic cell migration, and
  superoxide anion generation
• Shorten duration of inflammation in models of
  peritonitis, colitis, hepatitis, acute kidney
  injury, and peridontitis
• Inhibit LPS-induced TNF-a release
• No reports in ALI

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Mechanisms of Action Summary

• Critical illness is a heightened inflammatory
  state
• Through multiple actions, EPA and DHA block
  inflammatory processes and hasten inflammation
  resolution
• May have actions both early and later in ALI and
  sepsis

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• EXISTING LITERATURE

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Fish Oil in ALI and Sepsis Existing Literature in
Humans

• 2 small RCTs in ALI, 1 RCT in sepsis
• Intervention commercial high-fat feeding formula
• fish oil (EPA DHA) and borage oil (?-linoleic
  acid)
• Antioxidants (vit E and C, taurine, ß-carotene,
  L-carnitine)
• Control commercial high-fat feeding formula
• no fish oil
• Beneficial effects shown in these 3 RCTs
• Meta-analysis shows decreased mortality
  (RR0.63, 95CI 0.48-0.84, p0.002)

Nutritional Clinical Practice Guidelines,
www.criticalcarenutrition.com
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Two RCTs in ALIn(1)148, n(2)100
p0.016
pns
p0.027
pns
1. Gadek Crit Care Med 1999271409-20. 2.
Singer Crit Care Med 2006341033-8.
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Two RCTs in ALIn(1)148, n(2)100
pns
p0.165
1. Gadek Crit Care Med 1999271409-20. 2.
Singer Crit Care Med 2006341033-8.
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One RCT in Sepsis n165, most had ALI
plt0.001
plt0.001
Pontes-Arruda, et al. Crit Care Med
2006342325-33.
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One RCT in Sepsis
p0.04
Pontes-Arruda, et al. Crit Care Med
2006342325-33.
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Fish Oil in ALI and SepsisLimitations with These
Studies

• Control groups fed high-fat ?-6 diet
• Possibly pro-inflammatory?
• Paradigm of nutrient trials in ICU patients
• Not generalizable since reliant on delivery of
  food
• Why not study pharmaconutrients like
  pharmaceuticals?
• What is causing the effect?
• Fish oil alone or combination of ingredients?

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• Recommendations

• We recommend the use of an enteral formula with
  fish oils, borage oils and antioxidants in
  patients with acute lung injury.

Nutritional Clinical Practice Guidelines,
www.criticalcarenutrition.com
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Future Directions

• Research questions
• Which ingredient is responsible for the
  beneficial effects (fish oil alone or
  combination)?
• What are the mechanisms of action at work?
• Compare fish oil formula with a standard feeding
  formula that is commonly used
• Large simple trials in patients with ALI, sepsis,
  and general critical illness
• Does fish oil prevent development of ALI in
  patients at risk for the syndrome?

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Current Trials

• NIH ARDS Network OMEGA study
• RCT of BID module containing fish oil, borage
  oil, and anti-oxidants in 1000 patients with ALI
• Brazil, Dr. Pontes-Arruda
• RCT of commercial fish oil-containing formula
  compared with standard (not high fat) formula in
  patients with sepsis
• The Fish Oil Trial
• Phase II RCT at 5 sites in North America of
  enteral fish oil alone versus placebo (saline) in
  patients with ALI

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Thank you