Fish Oil and ARDS: What s s the Connection? Margaret J. Neff, MD MSc Associate Professor of Medicine Pulmonary & Critical Care Medicine

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1 Fish Oil and ARDS: What s s the Connection? Margaret J. Neff, MD MSc Associate Professor of Medicine Pulmonary & Critical Care Medicine

2 ARDS: Where are we now? Understanding of the disease process What s known to work What doesn t work Is there a role for fish oil in treatment? Trials completed Trials ongoing

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4 Acute Respiratory Distress Syndrome (ARDS) First clinically described in 1967 Acute onset of respiratory failure Bilateral infiltrates on CXR Hypoxemia Not due solely to CHF or volume overload Alveolar inflammation Endothelial and epithelial injury

5 ARDS Definition American-European Consensus Conference Convened to standardize definition CXR: bilateral infiltrates on CXR PaO2/FiO2 < 300 for Acute Lung Injury < 200 for ARDS No evidence of left atrial hypertension PAWP < 18mmHg if available

6 ARDS Risk Factors Sepsis Trauma Massive Transfusion Overdose Aspiration Pancreatitis

7 ALI Pathophysiology Inflammatory process and increased vascular permeability Bronchoalveolar lavage fluid: neutrophil predominant those with persistent neutrophils in BAL tend to have a worse clinical course

8 30-40% mortality ARDS Outcomes Decreased from 60% 20yrs ago 1/3 of those who die, do so within 1 st 72hrs < 15% die from unsupportable respiratory failure Pulmonary function at one year Mild-moderate deficits Quality of life and neuropsychiatric fxn Some decline

9 Proven Therapies for ARDS Lung Protective Ventilation Tidal Volume of 6ml/kg Using predicted body weight to calculate Static pressures of < 30cm H20 1 NEJM 342(18):1301-8

10 LPV Results Stopped early due to positive result Mortality reduced 22% in LPV group 40% (12 ml/kg), 31% (6 ml/kg)

11 FACTT Study Liberal vs conservative fluid mgmt No difference in mortality Conservative strategy resulted in better lung fxn and shorter time on vent & in ICU Fluid strategy initiated after shock resuscitation PAC vs CVC No difference in mortality More complications in PAC NEJM 2006; 354(21): & NEJM 2006;354(24):

12 Proven Pharmacologic Therapies for ARDS Ø

13 ARDSnet Steroid Trial NIH sponsored ARDS network ( LaSRS ) 10 sites nationally conducting ARDS studies Enrolled patients at day 7-28 of ARDS Receive steroids 2mg/kg/d (tapered over 2 weeks) 180 patients enrolled No difference in mortality (increased with steroids if given >14 days after ALI) Steroids: more vent-free days, shock-free days; also more neuromuscular complications NEJM 2006;354(16):1671

14 Other anti-inflammatory agents Ibuprofen Ketoconazole Lisophylline Studies all negative What about fish oil??

15 Biologic Rationale Activated neutrophils release eicosanoid inflammatory mediators Derived from arachidonic-acid acid (AA) Eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) are Omega-3 fatty acids found in fish oil Inhibit eicosanoid production through 4 different mechanisms. Result: decrease inflammation Some animal data supporting its use in ALI and sepsis

16 Existing Literature Fish oil in other diseases IgA nephropathy Crohn s disease Various cancers Cardiovascular disease

17 Existing Literature Fish oil in animal models of sepsis and ALI Improved survival in rodent models of endotoxic shock and chronic sepsis Decreased pulmonary edema in pig ALI Reduced pulmonary hypertension in rabbit ALI

18 Existing Literature Oxepa Commercial feeding formula by Ross Products EPA + DHA combined with γ-linoleic acid (GLA) and antioxidants Vit E and C, taurine, β-carotene, L-carnitineL High fat, low carbohydrate Several industry-sponsored sponsored animal studies

19 Oxepa Existing Literature 3 small RCT s s in ALI and sepsis Control groups received Pulmocare Also made by Ross High fat, low carbohydrate No fish oil

20 1st trial: Gadek, et al. Crit Care Med 1999 Design/Methods 146 patients randomized to Oxepa or Pulmocare P/F , > 10% BALF PMN s, enteral access Day 1 1 when tolerating 75% caloric goal Avg. 38 hours after study entry BAL on days 4 and 7

21 1st trial: Gadek,, et al. Crit Care Med 1999 Results 98 patients had all 3 BALs Oxepa group mean 6.9g EPA, 2.9g DHA, and 5.8g GLA per day Better oxygenation days 4 and 7 Decreased duration of mechanical ventilation, ICU length of stay, and organ failure Decreased BAL neutrophils days 4 & 7 Not affect hospital length of stay or mortality

22 2nd trial: Singer, et al Crit Care Med 2006;34(4) Design/Methods 100 patients randomized to Oxepa or Pulmocare P/F <250, enteral access No BAL Results Patients fed Oxepa Increased lung compliance Decreased duration of MV (p=0.028) and ICU LOS (p=0.044)

23 Limitations with prior studies Control groups fed high-fat diet May have been pro-inflammatory Oxepa has multiple ingredients Benefit of individual components unknown Poor design for nutrient trials in ICU Reliant on delivery of food Many patients do not tolerate full enteral feeds Pharmaconutrients are like drugs No need to mix nutrients with feeds If not in food, how administer fish oil?

24 Atlantic Herring Arctic Cod

25 Do you like your fish oil raw? Or Pickled?

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27 The effects of Ω-3 fatty acids (EPA and DHA) on lung and systemic inflammation in patients with ALI: the fish oil study Principal Investigator: Renee Stapleton, MD

28 Fish Oil Design 2-arm, blinded, Phase II RCT of EPA and DHA versus placebo in patients with established ALI Pharmaconutrient study, not a study of enteral nutrition Powered for biologic endpoints Primary endpoint: IL-8 8 in BAL fluid Other endpoints: biochemical, physiologic, and clinical outcomes

29 Study Design Enrollment 45 per arm (90 total) Inclusions Acute Lung Injury P/F < 300 CXR with bilateral infiltrates No evidence of heart failure Age >18 years

30 Exclusions 1. ICU LOS expected to be <48 hours 2. No GI tract access 3. History of VT/VF 4. Actively bleeding; Platelets <30,000; INR >3.0; Xigris 5. Severe head trauma (GCS <8 or need for ventriculostomy) 6. Post-cardiac arrest with suspected significant anoxic brain injury 7. Pregnant 8. Enrollment in other ICU interventional study 9. Patients with >1 1 of the following at advanced stage: Child-Pugh class C liver disease Hematologic malignancy Metastatic cancer 10. History of bone marrow or solid organ transplant

31 Fish Oil Study Study intervention: Fish oil product vs placebo Pharmaceutical grade (Nordic Naturals ) EPA and DHA: 8 grams/day (divided q6h) Given enterally q 6hours as long as have a feeding tube x 14 days or until unassisted breathing Bronchoscopy at baseline and days 5 and 9 Study monitoring: Baseline labs and then daily x 14 days while receiving study drug then weekly until day 28 Daily assessment for adverse events

32 Study Endpoints Primary BAL IL-8 Secondary BAL LTB 4, IL-6, IL-1β, PMNs,, MIP-1α,, type III PCP Serum IL-8, LTB 4, IL-6, IL-1β Pulmonary physiology Compliance, oxygenation Organ failure Clinical outcomes Mortality, ventilator-free days, ICU and hospital LOS, infections

33 Potential Limitations No Oxepa comparison group Why not test against something that has already worked? Benefit from Oxepa may be from antioxidants or borage oil Enteral delivery of fish oil Some good data for parenteral administration but IV not approved in US

34 Anticipated Adverse Events GI: Abdominal discomfort, diarrhea, steatorrhea Hematologic (possible) Platelet dysfunction Thrombocytopenia Many studies using doses up to 18g/day of EPA in outpatients without heme side effects CV: conflicting results regarding effect on arrhythmias in patients with CAD

35 Progress of Fish Oil Study Started enrolling at Harborview Aug 2006 Added additional sites in Boise, Toronto, and Vermont in June 2007 Completed study (90 patients) Dec enrolled at Harborview Over 2/3 had 2 or 3 bronchoscopies Thanks for all your help!! No study-related serious adverse events Results pending!

36 ARDSnet Fish Oil Study Randomized, controlled trial of omega-3 fatty acids + anti-oxidants vs placebo in patient with ALI/ARDS Factorialized with a trial of trophic vs full feeds So, not a pure pharmaconutrient study Primary outcome: ventilator free days No bronchoscopy EDEN-OMEGA study

37 EDEN-OMEGA Study Protocol includes use of LPV and fluid conservative protocol, once not in shock Harborview started enrolling in June patients so far 272 in entire network (12 centers) Goal: 1000 patients 1 st safety evaluation occurring this month

38 Summary Good physiologic evidence from small trials that fish oil may decrease inflammation in ALI/ARDS Studies ongoing to evaluate impact on inflammation and clinical outcomes Other possible therapies: anti-oxidants?

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