Early Versus Delayed Enteral Feeding and Omega-3 Fatty Acid/Antioxidant Supplementation for Treating People With Acute Lung Injury or Acute Respiratory Distress Syndrome (The EDEN-Omega Study)

ALI/ARDS involves extensive inflammation in the lungs that can lead to rapid respiratory
failure. These conditions are most commonly caused by pneumonia, generalized infection, or
severe trauma to the lungs, but can also be less commonly caused by smoke or salt water
inhalation, drug overdose, or shock.

For some people, ALI/ARDS resolves without treatment, but many severe cases result in
hospitalization in the intensive care unit (ICU), where 30% to 40% of cases end in
mortality. Current treatments for ALI/ARDS include assisted breathing with a ventilator,
supportive care, and management of the underlying causes. Enteral feeding, in which patients
receive nutrition through a feeding tube, plays an important role in treatment, too. Some
recent studies have shown that, compared to delayed feeding, enteral feeding initiated soon
after a patient begins assisted breathing is associated with a shorter hospital stay and a
better chance of survival. However, other studies show the opposite, and studies on optimal
feeding volume and composition have conflicting results. Studies have also indicated that
enhancing enteral feeding with omega-3 fatty acid and antioxidant supplements may help
reduce lung inflammation, improving overall recovery rates. This study will evaluate the
effects of early versus delayed full-calorie enteral feeding on mortality, ventilator-free
days, ICU-free days, and organ failure in people with ALI/ARDS. The study will also
determine whether supplementation with omega-3 fatty acid and antioxidants adds any
beneficial effect.

Upon admission to the ICU, a dietary evaluation will be done on each participant to
determine goal, or full-calorie, feeding rates, which will be based on body weight and daily
energy consumption. Participants will also undergo baseline assessments and procedures,
which will include vital sign measurements, blood draws, a frontal chest radiograph,
ventilator settings, and placement of feeding tube. Participants will be randomly assigned
to receive initial enteral feedings that are either minimal (trophic) or full-calorie. They
will also be randomly assigned to receive either omega-3 fatty acid and antioxidant
supplementation or placebo. All participants will begin enteral feeding within 6 hours of
treatment assignment.

Participants assigned to initial minimal enteral feedings will receive feedings at 10 cubic
centimeters (cc) per hour, to be continued at this rate for 144 hours, provided that the
participant remains on the ventilator. After the 144 hours, the feeding rate will be
advanced to full-calorie rates.

Participants assigned to initial full-calorie enteral feedings will receive feedings at 25
cc per hour, and the feeding rate will be increased by 25 cc per hour every 6 hours until
goal rate is reached. During enteral feedings, gastric residual volumes (GRVs) will be
checked every 6 to 12 hours to assure acceptable levels. Participants will complete enteral
feedings upon hospital discharge, Day 28 of treatment, death, or ability to achieve 48 hours
of unassisted breathing. Omega-3 fatty acid, antioxidant, and placebo supplements will be
administered with a syringe into the participant's feeding tube every 12 hours until Day 21
or discontinuation of the ventilator.

Blood pressure, heart rate, ventilation settings, and various blood factors will be measured
during treatment. Phone-based follow-up assessments will occur at Months 6 and 12 after ICU
discharge and will include measurements of health-related quality of life; psychological,
neurocognitive, and physical activity outcomes; healthcare utilization; and mortality.

Inclusion Criteria:

- Must meet the following three criteria at study entry within a 24-hour period: 1)
PaO2/FiO2 less than or equal to 300 (if altitude is more than 1000 meters, then
PaO2/FiO2 less than or equal to 300 x [barometric pressure/760]), 2) bilateral
infiltrates (patchy, diffuse, homogeneous, or asymmetric) consistent with pulmonary
edema on frontal chest radiograph, and 3) requirement for positive pressure
ventilation via endotracheal tube

- No clinical evidence of left-sided cardiac failure to account for bilateral pulmonary
infiltrates

- Intention of primary medical team to enterally feed the patient

- Undergoes enteral feeding within 48 hours of meeting inclusion criteria

Exclusion Criteria:

- Neuromuscular disease that impairs ability to breath without assistance, such as
cervical spinal cord injury at level C5 or higher, amyotrophic lateral sclerosis,
Guillain-Barré syndrome, or myasthenia gravis

- Pregnant or breastfeeding

- Severe chronic respiratory disease. More information about this criterion can be
found in the protocol.

- Burns on greater than 40% total body surface area

- Malignancy or other irreversible disease or condition for which 6-month mortality is
estimated to be greater than 50%. More information about this criterion can be found
in the protocol.

- Allogeneic bone marrow transplant within the 5 years before study entry

- Patient, surrogate, or physician not committed to full support (exception: a patient
will not be excluded if he/she would receive all supportive care except for attempts
at resuscitation from cardiac arrest)

- Severe chronic liver disease (Child-Pugh score of 11 to 15)

- Diffuse alveolar hemorrhage from vasculitis

- Morbid obesity, defined as 1 kg/cm body weight

- Unwilling or unable to use the ARDS network 6 mL/kg PBW ventilation protocol

- Moribund patient not expected to survive 24 hours

- No intent to obtain central venous access for monitoring intravascular pressures

- More than 72 hours since mechanical ventilation initiated

- Refractory shock. More information about this criterion can be found in the protocol.

- Unable to obtain enteral access

- Presence of partial or complete mechanical bowel obstruction

- Presence of ischemia or infarction

- Current total parenteral nutrition (TPN) use or intent to use TPN within 7 days of
study entry

- Severe malnutrition with body mass index less than 18.5 or loss of more than 30%
total body weight in the 6 months before study entry

- Laparotomy expected within 7 days of study entry

- Unable to raise head of bed 30 to 45 degrees

- Short-bowel syndrome or absence of gastrointestinal tract

- Presence of high-output (greater than 500 cc/day) enterocutaneous fistula

- International normalized ratio greater than 5.0, platelet count less than 30,000/mm3,
or history of bleeding disorder

- Intracranial hemorrhage within the 1 month before study entry

- Allergy to enteral formula, omega-3 fatty acids, GLA, vitamin E, vitamin C,
beta-carotene, taurine, or L-carnitine

- Requirement for, or physician insistence on, enteral formula supplemented with
omega-3 fatty acids (ex: Oxepa®, Impact®) or providing omega-3 fatty acid, GLA, or
antioxidant supplementation