DESIGN: A post hoc subgroup analysis of the effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicenter, pragmatic, registry-based randomized trial.

SETTING: Eighty-five adult ICUs across 16 countries.

PATIENTS: Patients with obesity defined as a body mass index (BMI) greater than or equal to 30 kg/m 2 ( n = 425).

INTERVENTIONS: In the primary study, patients were randomized into a high-dose (≥ 2.2 g/kg/d) or usual-dose protein group (≤ 1.2 g/kg/d).

MEASUREMENTS AND MAIN RESULTS: Protein intake was monitored for up to 28 days, and outcomes (time to discharge alive [TTDA], 60-d mortality, days of mechanical ventilation [MV], hospital, and ICU length of stay [LOS]) were recorded until 60 days post-randomization. Of the 1301 patients in the primary study, 425 had a BMI greater than or equal to 30 kg/m 2 . After adjusting for sites and covariates, we observed a nonsignificant slower rate of TTDA with higher protein that ruled out a clinically important benefit (hazard ratio, 0.78; 95% CI, 0.58-1.05; p = 0.10). We found no evidence of difference in TTDA between protein groups when subgroups with different classes of obesity or patients with and without various nutritional and frailty risk variables were examined, even after the removal of patients with baseline acute kidney injury. Overall, 60-day mortality rates were 31.5% and 28.2% in the high protein and usual protein groups, respectively (risk difference, 3.3%; 95% CI, -5.4 to 12.1; p = 0.46). Duration of MV and LOS in hospital and ICU were not significantly different between groups.

RESEARCH QUESTION: In critically ill patients, what is the association between preexisting malnutrition and time to discharge alive (TTDA), and does high protein treatment modify this association?

STUDY DESIGN AND METHODS: This multicenter randomized controlled trial involving 16 countries was designed to investigate the effects of high vs usual protein treatment in 1,301 critically ill patients. The primary outcome was TTDA. Multivariable regression was used to identify if preexisting malnutrition was associated with TTDA and if protein delivery modified their association.

RESULTS: The prevalence of preexisting malnutrition was 43.8%, and the cumulative incidence of live hospital discharge by day 60 was 41.2% vs 52.9% in the groups with and without preexisting malnutrition, respectively. The average protein delivery in the high vs usual treatment groups was 1.6 g/kg per day vs 0.9 g/kg per day. Preexisting malnutrition was independently associated with slower TTDA (adjusted hazard ratio, 0.81; 95% CI, 0.67-0.98). However, high protein treatment in patients with and without preexisting malnutrition was not associated with TTDA (adjusted hazard ratios of 0.84 [95% CI, 0.63-1.11] and 0.97 [95% CI, 0.77-1.21]). Furthermore, no effect modification was observed (ratio of adjusted hazard ratio, 0.84; 95% CI, 0.58-1.20).

INTERPRETATION: Malnutrition was associated with slower TTDA, but high protein treatment did not modify the association. These findings challenge current international critical care nutrition guidelines.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03160547; URL: www.

METHODS: This international, investigator-initiated, pragmatic, registry-based, single-blinded, randomised trial was undertaken in 85 intensive care units (ICUs) across 16 countries. We enrolled nutritionally high-risk adults (≥18 years) undergoing mechanical ventilation to compare prescribing high-dose protein (≥2·2 g/kg per day) with usual dose protein (≤1·2 g/kg per day) started within 96 h of ICU admission and continued for up to 28 days or death or transition to oral feeding. Participants were randomly allocated (1:1) to high-dose protein or usual dose protein, stratified by site. As site personnel were involved in both prescribing and delivering protein dose, it was not possible to blind clinicians, but patients were not made aware of the treatment assignment. The primary efficacy outcome was time-to-discharge-alive from hospital up to 60 days after ICU admission and the secondary outcome was 60-day morality. Patients were analysed in the group to which they were randomly assigned regardless of study compliance, although patients who dropped out of the study before receiving the study intervention were excluded. This study is registered with ClinicalTrials.gov, NCT03160547.

FINDINGS: Between Jan 17, 2018, and Dec 3, 2021, 1329 patients were randomised and 1301 (97·9%) were included in the analysis (645 in the high-dose protein group and 656 in usual dose group). By 60 days after randomisation, the cumulative incidence of alive hospital discharge was 46·1% (95 CI 42·0%-50·1%) in the high-dose compared with 50·2% (46·0%-54·3%) in the usual dose protein group (hazard ratio 0·91, 95% CI 0·77-1·07; p=0·27). The 60-day mortality rate was 34·6% (222 of 642) in the high dose protein group compared with 32·1% (208 of 648) in the usual dose protein group (relative risk 1·08, 95% CI 0·92-1·26). There appeared to be a subgroup effect with higher protein provision being particularly harmful in patients with acute kidney injury and higher organ failure scores at baseline.

INTERPRETATION: Delivery of higher doses of protein to mechanically ventilated critically ill patients did not improve the time-to-discharge-alive from hospital and might have worsened outcomes for patients with acute kidney injury and high organ failure scores.

METHODS: We conducted a prospective observational study in 13 international ICUs involving mechanically ventilated cardiac surgery patients with an ICU stay of at least 72 h. Collected data included the energy and protein prescription, type of and time to the initiation of nutrition, and actual quantity of energy and protein delivered (maximum: 12 days).

RESULTS: Among 237 enrolled patients, enteral nutrition (EN) was started, on average, 45 h after ICU admission (range, 0-277 h; site average, 53 [range, 10-79 h]). EN was prescribed for 187 (79%) patients and combined EN and parenteral nutrition in 33 (14%). Overall, patients received 44.2% (0.0%-117.2%) of the prescribed energy and 39.7% (0.0%-122.8%) of the prescribed protein. At a site level, the average nutrition adequacy was 47.5% (30.5%-78.6%) for energy and 43.6% (21.7%-76.6%) for protein received from all nutrition sources.

METHODS: An international survey using an electronic questionnaire was conducted in August 2019 and repeated in May 2022. An electronic questionnaire was sent to 52 members or affiliates of the International Clinical Nutrition Section of the American Society for Parenteral and Enteral Nutrition. Questions addressed the availability of parenteral nutrition admixtures and their components, reimbursement, and prescribing pre- and post-COVID-19 pandemic. All participating countries were categorized by their economic status.

RESULTS: Thirty-six country representatives responded, answering all questions. Parenteral nutrition was available in all countries (100%), but in four countries (11.1%) three-chamber bags were the only option, and in six countries a multibottle system was still used. Liver-sparing amino acids were available in 18 (50%), kidney-sparing in eight (22.2%), and electrolyte-free in 11 (30.5%) countries (30.5%). In most countries (n = 28; 79.4%), fat-soluble and water-soluble vitamins were available. Trace elements solutions were unavailable in four (11.1%) countries. Parenteral nutrition was reimbursed in most countries (n = 33; 91.6%). No significant problems due to the coronavirus pandemic were reported.