NHLBI 2012.

Methods	Study design: prospective, randomized controlled trial Study dates: January 2008 to April 2011 Setting: 44 ICUs of the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network Country: USA
Participants	Inclusion criteria participants within 48 hours of Acute Lung Injury onset who had received mechanical ventilation < 72 hours and indication for enteral nutrition Exclusion criteria Chronic lung disease Unable to provide consent Outside acute lung injury time window Outside mechanical ventilation time window Fatal underlying disease Severe liver disease Moribund Refractory shock Physician refusal Intracranial haemorrhage Total parenteral nutrition Not committed to full support Refused consent Severe neuromuscular disease Severe malnutrition Other Sample size 500 participants for each arm, to detect a 2¼‐day difference in ventilator‐free days (VFDs), assuming a mean of 14 ± 10.5 VFDs. power: 91% α: 0.05 Age (years): intervention group: 52 ± 17; Control group: 52 ± 16 Sex (male, %): intervention group: 53; Control group: 49 Primary disease of the participants Diagnosis:% intervention group/% control group Medical ICU: 61; 63 Primary lung injury category % intervention group/control group Pneumonia 67; 63 Sepsis 16; 13 Aspiration 8; 11 Trauma 3; 4 Transfusion 1; 2 Disease severity score: APACHE III Intervention group: 92 ± 28; Control group: 90 ± 27 Mechanical ventilation 100% in each group (inclusion criterion) Comorbidities: % intervention group; % control group Diabetes: 27; 29 No other data available Nutrition status: not available Level of inflammation: not available
Interventions	Intervention (trophic) Group 1 (n = 508) Initial feeding at 10 ml/hr (10 to 20 kcal/hr for the first 272 participants who also received the omega‐3 or control supplement (240 ml volume a day) After the Data and Safety Monitoring Board stopped the OMEGA portion of the factorial design, the initial trophic feeding rate was changed to 20 kcal/hr to approximate the calories that had been delivered in the OMEGA study Enteral nutrition was advanced to full‐energy feeding rates following the same protocol used for the full‐feeding group if they were still receiving mechanical ventilation at 144 hrs Control Group 2 (n = 492) Enteral nutrition was initiated at 25 mL/hr and advanced to goal rates as quickly as possible Full feeding rates were calculated with goals of 25 to 30 kcal/kg a day of nonprotein calories and 1.2 to 1.6 g/kg a day of protein Co‐interventions Both feeding strategies specified when and for how long to hold enteral nutrition for GRVs greater than 400 mL and for other gastrointestinal intolerances. As in usual ICU practice, participants were maintained in the semirecumbent position whenever possible. Blood glucose control was accomplished using institution‐specific insulin protocols targeting ranges of 80 to 150 mg/dL (to convert to mmol/L, multiply by 0.0555), with tighter control allowed.
Outcomes	Primary outcome Ventilator‐free days (VFDs) through day 28 Secondary outcomes Failure‐free days: cardiovascular, renal, hepatic, coagulation ICU‐free days 60‐day mortality Development of infections: ventilator‐associated pneumonia, clostridium difficile colitis, bacteraemia How measured or definition VFDs: defined as the number of days from the time of initiating UAB to day 28 after randomization ICU‐free days: calculated similarly to VFDs 60‐day mortality: mortality rate at 60 days Subgroups Not available
Funding sources	Supported by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268200536165C and HHSN268200536179C
Declarations of interest	Authors have not disclosed any potential conflicts of interest.
Notes	The initial 272 participants were also simultaneously randomized to a separate trial (the OMEGA study) comparing a nutritional supplement containing omega‐3 fatty acids and antioxidants with an isocaloric, isovolemic control in a 2 x 2 factorial design. After the Data and Safety Monitoring Board stopped the OMEGA portion of the factorial design, participants randomized to the initial trophic‐feeding group received additional calories to compensate for the calories that had been received in the OMEGA study (240 ml volume a day). We asked the first author for some data not reported in the manuscript or reported differently. He gave us the data we used in the meta‐analysis for the following outcomes: 28‐day mortality, length of ICU stay (days from randomization to first ICU discharge); length of mechanical ventilation (ventilator days up to day 28); hyperglycaemia (participants with any on‐study glucose > 200 mg/dl); incidence of total infectious complications and of diarrhoea, and the amount of calories received by both groups of participants. The author also informed they did not have duplicate participants with the Rice 2011 study.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomized by a web‐based randomization system, stratified by site and presence of shock at enrolment, to receive either trophic or full enteral feeding for the first 6 days of mechanical ventilation.
Allocation concealment (selection bias)	Low risk	Participants were randomized by a web‐based randomization system, stratified by site and presence of shock at enrolment, to receive either trophic or full enteral feeding for the first 6 days of mechanical ventilation.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Unblinded study. Details on healthcare processes to be followed by personnel (e.g. co‐interventions) were not described in order to make an appropriate judgement on possible performance bias.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessment was not blinded but most outcomes were objective.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Only 1 participant lost, from the control group. All analyses were by intention‐to‐treat.
Selective reporting (reporting bias)	Low risk	All planned outcomes were reported. All analyses were by intention‐to‐treat.
Other bias	Low risk	No evidence of other bias