Table 1.
Primary and secondary outcomes in randomized controlled trials of nutritional interventions in critical illness (2010–2025)
| Author, year | Comparison; number of patients | Primary outcome | Other outcomes | Main results |
|---|---|---|---|---|
| Reported some functional outcomes | ||||
| Bels 2024 [11▪▪] | High vs. standard enteral protein in ICU patients; n = 935 | EQ-5D-5L score at 30, 90 and 180 days adjusted for baseline score | Time to discharge alive, days alive and at home by day 90, longitudinally measured functional outcomes (6 min walking distance, MRC, handgrip strength) | Worse health-related quality of life in high protein group |
| Heyland 2022 [10] | Enteral glutamine vs. placebo in patients with severe burns; n = 1200 | Time to discharge alive | 6-month mortality, hospital mortality, LOS, MV duration, gram-negative bacteremia. SF-36 and ADL were assessed in 1/3 of patients |
No difference |
| Chapple 2020 [34] | High vs. standard enteral protein in ICU patients; n = 120 | Mean daily protein delivery (g/kg/d) | 28-day, 90-day mortality, ICU and hospital LOS, ventilator-free days, ICU-free days, vasopressor support, RRT, residence at day 90, EQ-5D-5L at day 90 | Higher protein delivery (1.52 vs. 0.99 g/kg/d protein), no difference in clinical outcomes including 90-day mortality or quality of life |
| Allingstrup 2017 [38] | Early goal-directed (EGD) vs. standard energy and protein in ICU patients; n = 199 | physical component summary (PCS) score of SF-36 at 6 months | 28-day, 90-day and 6-month mortality, LOS, MV, RRT, new organ failure, infections, energy and protein balance, hypo- and hyperglycemia and insulin dose | No difference, except higher energy and protein balance and more hyperglycemia and insulin in the EGD group |
| Doig 2015 [39] | IV amino acid supplement (up to 100 g/day) vs. standard care in ICU patients; n = 474 | Duration of renal dysfunction | ICU and hospital mortality, ICU and hospital LOS, MV duration, organ dysfunction, RRT use, RAND-36 General Health and Physical Function, ECOG Performance Status at day 90 |
No difference in duration of renal dysfunction. Improved eGFR and urine output. No difference in mortality or quality of life |
| Doig 2013 [40] | Early PN vs. standard of care in ICU patients with contraindications to EN; n = 1372 | 60-day mortality | Quality of life and physical function (RAND-36) at 60 days, organ failures, LOS, MV, RRT, infection, days with antibiotics and pressure ulcer treatment | No difference, except fewer days of MV in the PN group |
| Casaer 2011 [41,42▪▪] | Early vs. late supplemental PN in ICU patients; n = 4640 | Duration of dependency on ICU | New infection, antibiotics, organ dysfunction and support, LOS, 6-min walking distance and activities of daily life at hospital discharge. Additional 2 year follow-up published separately assessing mortality and nutrition risk score as well as SF-36 physical and mental component scores [42▪▪]. |
Higher likelihood for discharge alive earlier, less infections and cholestasis in the late group; Two-year mortality and physical functioning were similar in both groups. |
| Did not report any functional outcomes | ||||
| Summers 2025 [33▪▪] | Augmented vs. usual protein in ICU patients; n = 3397 | Days free of index hospitalization and alive by day 90 | MV duration, LOS, tracheotomy, new RRT, discharge destination | No difference |
| Panwar 2024 [43▪] | Intermittent vs. continuous EN in ICU patients; n = 120 | GI intolerance | Hospital mortality, MV-free days, EN volume reached | No difference |
| Heyland 2023 [35] | High vs. standard protein by any route, n = 1301 | Time-to-discharge-alive from hospital up to 60 days | 60-day and hospital mortality, ICU and hospital LOS, duration of MV, nutritional adequacy, re-admission to ICU and hospital. | No difference, subgroup analysis suggested worse outcome in patients with acute kidney injury and high organ failure scores in the high protein group |
| Reignier 2023 [44] | Low vs. standard energy and protein (any route) in ventilated patients with shock; n = 3044 | 90-day mortality and time to readiness for ICU discharge | 28-day, ICU and hospital mortality, ICU and hospital LOS, SOFA score, calories and proteins delivered; body weight, ICU-acquired infection. glucose and insulin, liver enzymes, GI complications | Faster recovery and fewer complications (vomiting, diarrhoea, bowel ischaemia, liver dysfunction) in the low group |
| Reignier 2018 [45] | Early EN vs. early PN in ventilated patients with shock; n = 2410 | 28-day mortality | 90-day, ICU and hospital mortality, ICU and hospital LOS, SOFA score, calories and proteins delivered; body weight, ICU-acquired infection, glucose and insulin, liver enzymes, GI complications | No difference except more GI complications in the EN group |
| TARGET investigators 2018 [30,46] | Energy-dense vs. routine EN in ICU patients; n = 3957 | 90-day mortality | 28-day and in-hospital mortality, ICU- and hospital-free days, days free of organ support, MV, vasopressors, new renal replacement therapy, positive blood cultures and intravenous antimicrobials. A long term follow up [30], not including the entire ITT population, surveyed EuroQol 5D-5L. |
No difference Long-term follow up: no difference in occupancy, hours worked or effectiveness at work (n = 818), disability (n = 1208) or participation in key life activities (n = 705). |
| Rugeles 2016 [47] | High-protein hypocaloric vs. normocaloric EN in ICU patients; n = 120 | Delta SOFA within 48h | 28-day mortality, ΔSOFA at 96 h, insulin requirements, hyper- and hypoglycemia, ICU LOS, MV days | Lower insulin requirements in the hypocaloric group |
| Petros 2016 [48] | Hypocaloric vs. normocaloric nutrition in ICU patients; n = 100 | Nosocomial infections during the ICU stay | ICU, hospital, and 28-day mortality, insulin demand, GI intolerance | More infections, less insulin and less GI intolerance in the hypocaloric group |
| Arabi 2015 [49] | Low vs. standard EN in ICU patients; n = 894 | 90-day mortality | ICU and hospital mortality, 28- and 180-day mortality, SOFA scores, days free from MV and ICU, hospital LOS, hypoglycemia, -kalemia, -magnesemia and phosphatemia, red blood cells transfusions, ICU-associated infections, feeding intolerance (vomiting, abdominal distention, or a GRV >200 ml) and diarrhea. | No difference |
| Peake 2014 [50,51] | Energy-dense (1.5 kcal/ml) vs. routine (1.0 kcal/ml) EN in mechanically ventilated ICU patients; n = 112 | Daily calorie delivery from study EN. | 90-day mortality, ICU and hospital mortality, ICU and hospital LOS, ventilator-free days, GI tolerance. One-year follow-up (n = 39), published separately [50]: SF-36v2 Physical and Mental Component Summary scores, EQ-5D-5L, employment status |
46% increase in calorie delivery. Borderline nonsignificant difference in 90-d mortality (20% vs. 37%, P = 0.057). One-year follow-up: No difference in quality of life or EQ-5D-5L scores. More patients employed in energy-dense group. |
| Heyland 2013 [52] | Glutamine, antioxidants, both or placebo in ICU patients; n = 1223 | 28-day mortality | Hospital and 6-month mortality, time to discharge alive from ICU and hospital, ICU and hospital LOS, time to MV discontinuation, SOFA scores, infection rates. | No difference. Subgroup of patients with multiple organ failure showed increased mortality with glutamine. |
| Heidegger 2013 [36] | Supplemental PN vs. no supplemental PN in patients not reaching energy target after 3 days in the ICU, n = 153 | Nosocomial infection after intervention (8 days) to day 28 | Antibiotic-free days, duration of MV, ICU and hospital LOS until day 28, ICU and 28-day mortality, duration of RRT, insulin, glycemia, CRP, liver tests, phosphatemia, steroids | Less nosocomial infections between days 9 and 28 in the SPN group. More episodes of hyperglycemia in the SPN group |
| Rice 2012 [31,32,53] | Initial trophic vs. full feeding in mechanically ventilated patients with acute lung injury; n = 1000 | Ventilator-free days to study day 28 | 60-day mortality; ICU- and organ failure–free days, daily percentage of goal EN, GI intolerance, new infections Separate follow up trials on cognitive function were published [31,32], assessing 6 min walking distance, cognitive impairment, SF-36, employment status. |
No difference except less GI intolerance in the low/trophic group No difference in one year functional outcome analysis. |
| Arabi 2011 [54] | Permissive underfeeding vs. standard feeding in ICU patients; n = 240 | 28-day mortality | ICU, hospital, and 180-day mortality; ICU and hospital LOS; MV duration, health-care associated infections, RRT, transfusions, hypoglycemia and -kalemia. | Lower hospital mortality in the permissive underfeeding group |
| Rice 2011 [55] | Initial trophic vs. full feeding in mechanically ventilated patients with acute respiratory failure; n = 200 | Ventilator-free days to study day 28 | 28-day and hospital mortality; ICU-, hospital- and organ failure–free days, GI intolerance, new infections | No difference except less GI intolerance in the low/trophic group |
Summary of outcomes reported in randomized controlled trials (≥100 patients) comparing nutritional interventions in critically ill adults. Studies are categorized by whether functional outcomes were assessed in the primary publication and ordered by publication year. The table includes trial characteristics (intervention type and sample size), primary outcomes, secondary outcomes, and main findings. Bold text indicates functional outcome measures aligned with CONCISE recommendations. Secondary analyses and follow-up studies, where applicable, are summarized together with original studies.
ADL, activities of daily living; EGD, early goal-directed; EN, enteral nutrition; EQ-5D-5L, EuroQol 5-dimension 5-level questionnaire; GI, gastrointestinal; GRV, gastric residual volume; ICU, intensive care unit; ITT, intention-to-treat; LOS, length of stay; MRC, Medical Research Council scale; MV, mechanical ventilation; PCS, physical component summary; PN, parenteral nutrition; RAND-36, RAND 36-Item Health Survey; RRT, renal replacement therapy; SF-36, Short Form-36 Health Survey; SOFA, Sequential Organ Failure Assessment; SPN, supplemental parenteral nutrition.