A Phase II Randomized Trial of Fish Oil in Patients With Acute Lung Injury (ALI)

• ClinicalTrials.gov Identifier: NCT00351533
• Recruitment Status: Completed
• First Posted: July 13, 2006
• Results First Posted: October 3, 2011
• Last Update Posted: October 3, 2011
• Sponsor: University of Washington
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); American Thoracic Society; Acute Respiratory Distress Syndrome Foundation; American Society for Parenteral and Enteral Nutrition
• Information provided by (Responsible Party): Renee Stapleton, University of Washington

Study Description

Brief Summary:

The purpose of this study is to determine whether fish oil (containing omega-3 fatty acids) given enterally is safe and effective in reducing lung and systemic inflammation seen in acute lung injury.

Condition or disease	Intervention/treatment	Phase
Respiratory Distress Syndrome, Adult; Acute Lung Injury; Acute Respiratory Distress Syndrome	Drug: Fish oil (eicosapentaenoic acid and docosahexanoic acid)	Phase 2

Detailed Description:

Acute lung injury (ALI) is common among critically ill patients and is associated with a high case fatality. Only one intervention has been shown to improve survival in a large clinical trial, and new therapies targeting the inflammatory response are needed. Nutrient interventions may provide benefit; specifically there is plausible biologic rationale for administering n-3 fatty acids (n-3 FAs) found in fish oil to patients with ALI, as n-3 FAs decrease formation of eicosanoid inflammatory mediators. However, although promising results have emerged from prior studies, fish oils have only been tested in ALI patients in a commercial enteral formula containing additional nutrients, and the control group received a high-fat enteral formula that may have been proinflammatory. Therefore, no conclusion can be drawn about the independent effect of fish oils. Furthermore, the inclusion of key pharmaconutrients in feeding formulas, instead of delivering them separately as pharmaceuticals, limits exposure to the agent, as intensive care unit (ICU) patients commonly receive less than 60% of prescribed caloric needs. Finally, specialized feeding formulas are very expensive, and it may be substantially cheaper to administer pharmaconutrients separately. We believe it is time to begin to approach nutrient trials in critically ill patients differently -- to move away from including them in feeding formulas and begin delivering them like pharmaceuticals. With appropriate scientific investigation and the use of non-nutrient placebos, this novel and innovative approach is a new paradigm of investigating nutrient delivery to critically ill patients.

This study is a phase II randomized controlled trial to determine the effects of enteral eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA), both n-3 FAs found in fish oil, versus placebo on the pulmonary and systemic environments, and on clinical outcomes, in patients with ALI. We will investigate the effect of fish oil administration on several biological markers of injury and inflammation in bronchoalveolar lavage fluid and serum, on pulmonary physiologic outcomes, and on clinical outcomes.

Comparison(s): Mechanically ventilated patients with acute lung injury randomized to receive enteral fish oil versus compared to mechanically ventilated patients with acute lung injury randomized to receive placebo.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind Study of the Effect of Fish Oil (Eicosapentaenoic Acid and Docosahexanoic Acid) on Lung and Systemic Inflammation in Patients With Acute Lung Injury (ALI)
• Study Start Date: July 2006
• Actual Primary Completion Date: January 2009
• Actual Study Completion Date: August 2009

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1; Enteral fish oil	Drug: Fish oil (eicosapentaenoic acid and docosahexanoic acid); Liquid fish oil 7.5cc enterally every 6 hours
Placebo Comparator: 2; Enteral saline	Drug: Fish oil (eicosapentaenoic acid and docosahexanoic acid); Liquid fish oil 7.5cc enterally every 6 hours

Outcome Measures

Primary Outcome Measures :

1. Change in Bronchoalveolar Lavage Fluid (BALF) Interleukin (IL)-8 [ Time Frame: Days 1 and 5 ]
   30 patients in the fish oil group and 36 patients in the enteral saline group underwent the 2nd bronchoalveolar lavage (BAL). Participants did not undergo BALs after baseline if they were not intubated or had expired, but clinical followup data (e.g. mortality) were collected.

Secondary Outcome Measures :

1. Change in BALF Leukotriene B4 [ Time Frame: Days 1 and 5 ]
   30 patients in the fish oil group and 36 patients in the enteral saline group underwent the 2nd bronchoalveolar lavage (BAL). Participants did not undergo BALs after baseline if they were not intubated or had expired, but clinical followup data (e.g. mortality) were collected.
2. Change in BALF Interleukin-6 [ Time Frame: Days 1 and 5 ]
   30 patients in the fish oil group and 36 patients in the enteral saline group underwent the 2nd bronchoalveolar lavage (BAL). Participants did not undergo BALs after baseline if they were not intubated or had expired, but clinical followup data (e.g. mortality) were collected.
3. Change in BALF Monocyte Chemotactic Protein-1 [ Time Frame: Days 1 and 5 ]
   30 patients in the fish oil group and 36 patients in the enteral saline group underwent the 2nd bronchoalveolar lavage (BAL). Participants did not undergo BALs after baseline if they were not intubated or had expired, but clinical followup data (e.g. mortality) were collected.
4. Change in BALF Neutrophil Count [ Time Frame: Days 1 and 5 ]
   30 patients in the fish oil group and 36 patients in the enteral saline group underwent the 2nd bronchoalveolar lavage (BAL). Participants did not undergo BALs after baseline if they were not intubated or had expired, but clinical followup data (e.g. mortality) were collected.
5. Static Lung Compliance [ Time Frame: Day 5 ]
   30 patients in the fish oil group and 36 patients in the enteral saline group remained intubated on day 5 and had this outcome available.
6. Oxygenation [ Time Frame: Day 5 ]
   PaO2/FiO2 is the ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen. 30 patients in the fish oil group and 36 patients in the enteral saline group remained intubated on day 5 and had this outcome available.
7. Change in Plasma Interleukin-8 [ Time Frame: Days 1 and 5 ]
   30 patients in the fish oil group and 36 patients in the enteral saline group underwent 2nd blood draw on day 5. Participants did not undergo blood draws after baseline if they were discharged from the ICU or had expired, but clinical followup data (e.g. mortality) were collected.
8. Change in Plasma Leukotriene B4 [ Time Frame: Days 1 and 5 ]
   30 patients in the fish oil group and 36 patients in the enteral saline group underwent 2nd blood draw on day 5. Participants did not undergo blood draws after baseline if they were discharged from the ICU or had expired, but clinical followup data (e.g. mortality) were collected.
9. Change in Plasma Interleukin-6 [ Time Frame: Days 1 and 5 ]
   30 patients in the fish oil group and 36 patients in the enteral saline group underwent 2nd blood draw on day 5. Participants did not undergo blood draws after baseline if they were discharged from the ICU or had expired, but clinical followup data (e.g. mortality) were collected.
10. Change in Plasma Surfactant Protein D [ Time Frame: Days 1 and 5 ]
    30 patients in the fish oil group and 36 patients in the enteral saline group underwent 2nd blood draw on day 5. Participants did not undergo blood draws after baseline if they were discharged from the ICU or had expired, but clinical followup data (e.g. mortality) were collected.
11. Change in Plasma vonWillebrand Factor [ Time Frame: Days 1 and 5 ]
    30 patients in the fish oil group and 36 patients in the enteral saline group underwent 2nd blood draw on day 5. Participants did not undergo blood draws after baseline if they were discharged from the ICU or had expired, but clinical followup data (e.g. mortality) were collected.
12. Worst Multiple Organ Dysfunction Score (MODS) During First 28 Days After Study Enrollment [ Time Frame: Throughout hospital stay ]

    Full scale name is Multiple Organ Dysfunction Score (MODS), a scale measuring degree of organ dysfunction in critically ill patients.

    Minimum score is 0 and maximum score is 24, with 0 indicating no organ failure and 24 indicating severe failure of multiple organs.

13. Ventilator-free Days During First 28 Days After Study Enrollment [ Time Frame: 28 days ]
    Ventilator-free days is a common outcome measure in critical care research. A ventilator-free day is a day that a participant is alive and not receiving mechanical ventilation during the first 28 days after s/he enrolled in the study.
14. ICU-free Days During First 28 Days After Study Enrollment [ Time Frame: 28 days ]
    ICU-free days is a common outcome measure in critical care research. An ICU-free day is a day that a participant is alive and not in the intensive care unit (ICU) during the first 28 days after s/he enrolled in the study.
15. Hospital Length of Stay [ Time Frame: At end of hospital admission ]
16. Hospital Mortality [ Time Frame: At end of hospitalization ]
17. 60-day Mortality [ Time Frame: 60 days from day of enrollment into study ]
18. Change in Bronchoalveolar Lavage Fluid (BALF) Interleukin (IL)-8 [ Time Frame: Days 1 and 9 ]
    15 patients in the fish oil group and 27 patients in the enteral saline group underwent the 3rd bronchoalveolar lavage (BAL). Participants did not undergo BALs after baseline if they were not intubated or had expired, but clinical followup data (e.g. mortality) were collected.
19. Change in BALF Leukotriene B4 [ Time Frame: Days 1 and 9 ]
    15 patients in the fish oil group and 27 patients in the enteral saline group underwent the 3rd bronchoalveolar lavage (BAL). Participants did not undergo BALs after baseline if they were not intubated or had expired, but clinical followup data (e.g. mortality) were collected.
20. Change in BALF Interleukin-6 [ Time Frame: Days 1 and 9 ]
    15 patients in the fish oil group and 27 patients in the enteral saline group underwent the 3rd bronchoalveolar lavage (BAL). Participants did not undergo BALs after baseline if they were not intubated or had expired, but clinical followup data (e.g. mortality) were collected.
21. Change in BALF Monocyte Chemotactic Protein-1 [ Time Frame: Days 1 and 9 ]
    15 patients in the fish oil group and 27 patients in the enteral saline group underwent the 3rd bronchoalveolar lavage (BAL). Participants did not undergo BALs after baseline if they were not intubated or had expired, but clinical followup data (e.g. mortality) were collected.
22. Change in BALF Neutrophil Count [ Time Frame: Days 1 and 9 ]
    15 patients in the fish oil group and 27 patients in the enteral saline group underwent the 3rd bronchoalveolar lavage (BAL). Participants did not undergo BALs after baseline if they were not intubated or had expired, but clinical followup data (e.g. mortality) were collected.
23. Change in Plasma Interleukin-8 [ Time Frame: Days 1 and 9 ]
    15 patients in the fish oil group and 27 patients in the enteral saline group underwent 3rd blood draw on day 9. Participants did not undergo blood draws after baseline if they were discharged from the ICU or had expired, but clinical followup data (e.g. mortality) were collected.
24. Change in Plasma Leukotriene B4 [ Time Frame: Days 1 and 9 ]
    15 patients in the fish oil group and 27 patients in the enteral saline group underwent 3rd blood draw on day 9. Participants did not undergo blood draws after baseline if they were discharged from the ICU or had expired, but clinical followup data (e.g. mortality) were collected.
25. Change in Plasma Interleukin-6 [ Time Frame: Days 1 and 9 ]
    15 patients in the fish oil group and 27 patients in the enteral saline group underwent 3rd blood draw on day 9. Participants did not undergo blood draws after baseline if they were discharged from the ICU or had expired, but clinical followup data (e.g. mortality) were collected.
26. Change in Plasma Surfactant Protein D [ Time Frame: Days 1 and 9 ]
    15 patients in the fish oil group and 27 patients in the enteral saline group underwent 3rd blood draw on day 9. Participants did not undergo blood draws after baseline if they were discharged from the ICU or had expired, but clinical followup data (e.g. mortality) were collected.
27. Change in Plasma vonWillebrand Factor [ Time Frame: Days 1 and 9 ]
    15 patients in the fish oil group and 27 patients in the enteral saline group underwent 3rd blood draw on day 9. Participants did not undergo blood draws after baseline if they were discharged from the ICU or had expired, but clinical followup data (e.g. mortality) were collected.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Requiring positive-pressure mechanical ventilation
• ALI criteria: PaO2/FiO2 <300, bilateral infiltrates on chest radiograph, no left atrial hypertension
• Age > 17 years

Exclusion Criteria:

• Expected ICU length of stay <48 hours
• Unable to undergo bronchoalveolar lavage at enrollment
• Unable to obtain enteral access
• Post-cardiac arrest with suspected significant anoxic brain injury
• Expected survival < 28 days
• Pregnant
• Platelet count < 30,000, active bleeding, or international normalized ratio (INR)>3.0
• History of ventricular tachycardia or fibrillation
• Receiving recombinant human activated protein C (rh-APC) for sepsis
• Acquired immune deficiency syndrome (AIDS) with CD4 count < 200
• Metastatic cancer
• History of bone marrow, lung, liver, cardiac, kidney, or pancreas transplant

Contacts and Locations

Locations

United States, Idaho

St. Alphonsus Medical Center

Boise, Idaho, United States, 83706

United States, Oregon

Oregon Health Sciences University

Portland, Oregon, United States, 97239

United States, Vermont

University of Vermont/Fletcher Allen Health Care

Burlington, Vermont, United States, 05401

United States, Washington

Harborview Medical Center

Seattle, Washington, United States, 98104

Canada, Ontario

St. Michael's Hospital

Toronto, Ontario, Canada, M5B1W8

Sponsors and Collaborators

University of Washington

National Heart, Lung, and Blood Institute (NHLBI)

American Thoracic Society

Acute Respiratory Distress Syndrome Foundation

American Society for Parenteral and Enteral Nutrition

Investigators

• Principal Investigator: Renee D. Stapleton, MD, MSc; University of Vermont

More Information

• Responsible Party: Renee Stapleton, Assistant Professor, University of Washington
• ClinicalTrials.gov Identifier: NCT00351533
• Other Study ID Numbers: 28503-A; 05-7895-A 03
• First Posted: July 13, 2006
• Results First Posted: October 3, 2011
• Last Update Posted: October 3, 2011
• Last Verified: August 2011

Keywords provided by Renee Stapleton, University of Washington:

Respiratory distress syndrome, adult; Acute lung injury; Acute respiratory distress syndrome; ARDS, human; Fish oils; Fatty Acids, Omega-3; Docosahexaenoic Acids; Eicosapentaenoic Acid

Additional relevant MeSH terms:

Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Lung Injury; Syndrome; Wounds and Injuries; Disease; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Thoracic Injuries