Rice 2011.

Methods	Study design: prospective, randomized controlled trial Study dates: August 2003 to July 2009 Setting: 2 ICUs at a single academic centre Country: USA
Participants	Inclusion criteria Participants expected to require mechanical ventilation ≥ 72 hrs and indication for enteral nutrition Exclusion criteria > 48 hours elapsed since inclusion criteria met Participant, legal representative, or physician refuses consent or is unavailable to provide consent Participant, legal representative, or physician not committed to full support Presence of malignant or irreversible condition and estimated 28‐day mortality > 50% Severe or refractory shock Chronic respiratory disease that requires home oxygen or results in severe exercise restriction Moribund participants not expected to survive 24 hours from start of enteral nutrition (as decided by primary medical team) Child‐Pugh score > 9 Presence of partial or complete mechanical bowel obstruction, or ischaemia, or infarction Current parenteral nutrition use or intention to use within 7 days Severe malnutrition with BMI < 18.5 and/or loss of > 30% total body weight in the previous 6 months Neuromuscular disease impairing the ability to ventilate spontaneously Laparotomy expected within 7 days Unable to raise head of bed 45 ° > 30% total body surface area burns Absence of GI tract/short‐bowel syndrome (defined as entire length of small bowel totaling 4 feet or less) Presence of high‐output (> 500 cc/day) enterocutaneous fistula Age < 13 years Allergy to enteral formula Sample size 94 participants were randomized in each arm. An independent sample t test, designed to demonstrate a 15% relative increase of 3.0 VFDs with 80% power and a 2‐sided P value of 0.05. The study enrolled 200 to allow for a 5% withdrawal rate and compensate for the single interim analysis. Age (years): intervention group: 53 ± 19; Control group: 53 ± 19 Sex (male, %): intervention group: 39.8; Control group: 46.1 Primary disease of the participants: 100% medical diagnosis Acute lung injury: 21; 20 Pneumonia: 15; 19 Altered mental status/neurologic: 14; 15 Sepsis: 10; 12 Overdose: 10; 7 Disease severity score: APACHE II Intervention group: 26.9 ± 8.1; Control group: 26.9 ± 6.6 Mechanical ventilation 100% in each group (inclusion criteria) Comorbidities:% intervention group/ % control group Hypertension 42; 37 Cardiac disease 24; 23 Diabetes 22; 23 Chronic renal insufficiency 18; 12 Chronic obstructive pulmonary disease 16; 18 Immunosuppression 14; 16 Peptic ulcer disease 4; 4 Gastroesophageal reflux 4; 4 Nutrition status: not available Albumin concentration (g/dL) 2.8± 0.6; 2.8± 0.7 Level of inflammation: not available
Interventions	Group 1 (n = 98): trophic group Initial feeding at 10ml/hr; the same feeding rate for 6 days. In participants still ventilated after 6 days, enteral nutrition was advanced to full‐energy target feeding rates using the same protocol as for the full‐energy feeding group. Most participants received a commercially‐available standard formula containing 1 to 1.2 kcal/cm3. Group 2 (n = 102): control group Full feeding rate targeting 25 to 30 kcal/kg ideal body weight/day of non‐protein energy and 1.2 to 1.6 g/kg ideal body weight/day of protein. Most participants received a commercially‐available standard formula containing 1 to 1.2 kcal/cm3. Initial feeding at 25 ml/hr; feeding rate increased by 25 ml/hr every 6 hrs until full‐energy feeding rate was reached. Co‐interventions For both groups, in participants who were extubated and then required re‐intubation, enteral nutrition was started and managed according to the study protocol through study day 28. Elevated gastric residual volumes (GRV) were defined as > 300 cc of gastric contents withdrawn from the gastric tube at one time. GRVs were checked every 6 hours while feeding rates were being increased to full‐energy rates and every 12 hours if the participant was receiving trophic rates or once full‐energy rate was achieved. Gastric residuals were only measured in participants with post‐pyloric feeding tubes if a separate gastric port on the feeding tube or separate gastric tube was in place. Since a single, isolated elevated GRV has been shown to be a poor predictor of enteral nutrition intolerance, feeding rates were not adjusted after a single elevated GRV. After the first episode of elevated GRV, 300 cc was replaced and the feeding rate was maintained. GRV was rechecked in 2 hours. If this recheck was also above 300 cc, feeds were held until GRV decreased below 300 cc and restarted at a rate of 25 cc/hr < the previous rate in the full‐energy group and at 10 cc/hr in the trophic group.
Outcomes	Length of mechanical ventilation Ventilator‐free days (VFDs) How measured or definition Defined as the number of days from the time of initiating UAB to day 28 after randomization, assuming survival for at least 48 consecutive hours of UAB Time points measured and time points reported If a participant survived for > 48 hours after UAB, but required assisted breathing again (for any reason) before day 28, only the number of days of UAB prior to day 28 were included. Participants who died prior to the earlier of 28 days or hospital discharge were counted as having zero VFDs, regardless of whether or not they ever achieved UAB Length of stay (ICU): ICU‐free days: calculated similarly to VFDs Hospital mortality: hospital mortality: mortality rate at hospital discharge Subgroups Subgroup: acute lung injury, sepsis, or pneumonia Subgroup: BMI of ≥ 35
Funding sources	Supported, in part, by grants K23HL81431(TWR), P30DK058404 (TWR), and 1 UL1 RR024975 (TWR, GRB) from the National Institutes of Health (Bethesda, MD)
Declarations of interest	Dr Rice, Dr Bernard, and Dr Wheeler received funding from the National Institutes of Health. The remaining authors have not disclosed any potential conflicts of interest.
Notes	Variables were assessed by intention‐to‐treat analyses. Upon our request, the data for the following outcomes was provided by the first author: hospital and 28‐day mortality, length of mechanical ventilation, length of ICU stay and incidence of infectious complications. None of the participants included in this study was included in NHLBI 2012.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Permuted block scheme with a random block size of 2, 4 or 6 participants.
Allocation concealment (selection bias)	Low risk	Assignments were placed in consecutively‐numbered, opaque envelopes that were sealed before the start of the study by personnel not associated with the trial.
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	Open‐label study but most outcomes were objective. The number of ventilator‐free days to study day 28 was the primary efficacy measure. Secondary end points included 28‐day and hospital all‐cause mortality, organ‐failure‐free days, ICU‐free days, and hospital‐free days to study day 28. Only gastrointestinal intolerance and infections are more subjective.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants had complete follow‐up to death or hospital discharge.
Selective reporting (reporting bias)	Low risk	All outcomes reported
Other bias	Low risk	No evidence of other bias