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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Respiratory Distress Syndrome, Adult, Acute Lung Injury, Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Drug: Fish oil (eicosapentaenoic acid and docosahexanoic acid)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Enteral fish oil | Drug: Fish oil (eicosapentaenoic acid and docosahexanoic acid)<br>* Liquid fish oil 7.5cc enterally every 6 hours<br>|
| Placebo Comparator: 2<br>Enteral saline | Drug: Fish oil (eicosapentaenoic acid and docosahexanoic acid)<br>* Liquid fish oil 7.5cc enterally every 6 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Bronchoalveolar Lavage Fluid (BALF) Interleukin (IL)-8 | 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. | Days 1 and 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in BALF Leukotriene B4 | 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. | Days 1 and 5 | 
| Change in BALF Interleukin-6 | 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. | Days 1 and 5 | 
| Change in BALF Monocyte Chemotactic Protein-1 | 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. | Days 1 and 5 | 
| Change in BALF Neutrophil Count | 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. | Days 1 and 5 | 
| Static Lung Compliance | 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. | Day 5 | 
| Oxygenation | 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. | Day 5 | 
| Change in Plasma Interleukin-8 | 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. | Days 1 and 5 | 
| Change in Plasma Leukotriene B4 | 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. | Days 1 and 5 | 
| Change in Plasma Interleukin-6 | 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. | Days 1 and 5 | 
| Change in Plasma Surfactant Protein D | 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. | Days 1 and 5 | 
| Change in Plasma vonWillebrand Factor | 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. | Days 1 and 5 | 
| Worst Multiple Organ Dysfunction Score (MODS) During First 28 Days After Study Enrollment | 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. | Throughout hospital stay | 
| Ventilator-free Days During First 28 Days After Study Enrollment | 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. | 28 days | 
| ICU-free Days During First 28 Days After Study Enrollment | 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. | 28 days | 
| Hospital Length of Stay |  | At end of hospital admission | 
| Hospital Mortality |  | At end of hospitalization | 
| 60-day Mortality |  | 60 days from day of enrollment into study | 
| Change in Bronchoalveolar Lavage Fluid (BALF) Interleukin (IL)-8 | 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. | Days 1 and 9 | 
| Change in BALF Leukotriene B4 | 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. | Days 1 and 9 | 
| Change in BALF Interleukin-6 | 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. | Days 1 and 9 | 
| Change in BALF Monocyte Chemotactic Protein-1 | 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. | Days 1 and 9 | 
| Change in BALF Neutrophil Count | 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. | Days 1 and 9 | 
| Change in Plasma Interleukin-8 | 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. | Days 1 and 9 | 
| Change in Plasma Leukotriene B4 | 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. | Days 1 and 9 | 
| Change in Plasma Interleukin-6 | 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. | Days 1 and 9 | 
| Change in Plasma Surfactant Protein D | 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. | Days 1 and 9 | 
| Change in Plasma vonWillebrand Factor | 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. | Days 1 and 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Respiratory distress syndrome, adult, Acute lung injury, Acute respiratory distress syndrome, ARDS, human, Fish oils, Fatty Acids, Omega-3, Docosahexaenoic Acids, Eicosapentaenoic Acid