Casaer 2011.

Methods	RCT, multi‐centre, 2‐arm, parallel design
Participants	Total number of randomized participants: 4640 Inclusion criteria Adults admitted to participating ICUs, scored ≥ 3 on NRS, did not meet any of exclusion criteria Exclusion criteria < 18 years of age Moribund or coded DNR Enrolled in another trial Had short‐bowel syndrome Had home ventilation In a diabetic coma Referred with nutritional regimen Pregnant or lactating No central catheter Taking oral nutrition Readmitted to ICU NRS score < 3 Other reason (not described by study authors) Did not give consent People with chronic malnourishment (BMI < 17 kg/m²) before admission to ICU Referral from another ICU with an established regimen of EN or PN Primary diagnoses Cardiac surgery Complicated abdominal or pelvic surgery Transplantation Trauma Burns Reconstructive surgery Complicated pulmonary or oesophageal surgery Respiratory disease Complicated vascular surgery Gastroenterological or hepatic disease Complicated neurosurgery Haematological or oncological disease Neurological disease Cardiovascular disease Renal disease Neurological presentation of medical disease Metabolic disorder Other (not described by study authors) Baseline characteristics EN group Age, mean (SD): 64 (± 15) years Gender, M/F: 1486/842 APACHE II, mean (SD): 23 (± 10) EN + PN group Age, mean (SD): 64 (± 14) Gender, M/F: 1486/826 APACHE II, mean (SD): 23 (± 11) Country: Belgium Setting: 7 ICUs
Interventions	EN group (study authors referred to this group as "late‐initiation group") n = 2328; 15 discontinued intervention owing to protocol violation (inadvertent administration of ≥ 1 L/day PN for ≥ 2 days during intervention period); 2328 analysed as ITT Details: IV 20% glucose solution (target for total energy intake was 400 kcal/day on 1st ICU day, and 800 kcal/day on 2nd ICU day), and EN via duodenal feeding tube. If EN was insufficient after 7 days, PN was initiated on day 8 to reach caloric goal. Continuous insulin infusion adjusted to obtain blood glucose level 80 to 100 mg/dL EN + PN group (study authors referred to this group as "early‐initiation group") n = 2312; 0 losses; 2312 analysed Details: IV 20% glucose solution (target for total energy intake was 400 kcal/day on first ICU day, and 800 kcal/day on second ICU day). On day 3, PN initiated with dose targeted to 100% of caloric goal through combined EN + PN (except when clinicians predicted that participant would tolerate sufficient EN or oral feeding on day 3). Amount of PN was calculated as amount that was not effectively delivered by EN. Calculations of caloric goal included protein energy and based on ideal bodyweight, age, and gender. PN was reduced and eventually stopped if participant was able to meet > 80% caloric goal with EN or able to resume normal oral feeding. Continuous insulin infusion adjusted to obtain blood glucose level 80 to 100 mg/dL
Outcomes	Death (number of participants alive at discharge from ICU in ≤ 8 days, death in the ICU and in hospital, survival up to 90 days) Rates of complications, and hypoglycaemia Number of ICU days and time to discharge from the ICU Number of participants with new infections (airways, lungs, bloodstream, urinary tract, wounds) Duration of antibiotic therapy Inflammation Time to weaning from mechanical ventilation and need for tracheostomy Acute kidney injury (using RIFLE) Renal replacement therapy Need for and duration of pharmacological or mechanical haemodynamic support Liver dysfunction Duration of hospital stay Functional status at discharge (6‐minute walk test and participants who were independent in ADL) Healthcare costs
Notes	Funding/declarations of interest: supported by Methusalem programme of the Flemish government, Research Fund of the Catholic University of Leuven, Belgium; the Research Foundation Flanders, Belgium; and the Clinical Research Fund of the University Hospitals Leuven, Belgium. In addition, the Catholic University of Leuven received unrestricted research grant from Baxter Healthcare for less than one‐third of study costs. Baxter Healthcare were not involved in the design of study, collection, analysis, or interpretation of data, in preparation of manuscript for publication. Study dates: August 2007 to November 2010
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Use of a digital system to prepare order of envelopes
Allocation concealment (selection bias)	Low risk	Use of sequentially numbered, sealed, opaque envelopes, and block size was concealed from treating physicians and nurses
Blinding of participants and personnel (performance bias) All outcomes	High risk	No details and we assumed that investigators made no attempts to blind personnel
Blinding of outcome assessment (detection bias) All outcomes (except mortality)	Low risk	All outcome assessors were blinded to group allocation
Blinding of outcome assessment (detection bias) Mortality	Low risk	All outcome assessors were blinded to group allocation
Incomplete outcome data (attrition bias) All outcomes	Low risk	Small number of losses in 1 group, unlikely to influence outcome data
Selective reporting (reporting bias)	Low risk	Prospective clinical trials registration (NCT00512122). Outcomes reported same as clinical trials registration documents. We noted that duration of ICU was reported but not listed in the registration documents, but primary outcomes were generally all reported
Baseline characteristics	Low risk	Appeared comparable
Other bias	Low risk	Protocol for glycaemic management was the same for both groups. No other sources of bias identified