Optimal delivery of enteral protein in the critically ill: A systematic review and meta-analysis of randomised controlled trials

Abstract

Background and aim: Critically ill patients experience acute muscle wasting, associated with impaired clinical outcomes. It has been suggested that greater dietary protein delivery may attenuate muscle wasting and improve outcomes, but the optimal dose is unknown. The aim of this systematic review and meta-analysis was to evaluate the effect of enteral protein delivered to achieve doses recommended within international guidelines (1.2-2.0 g/kg bodyweight/day) compared to enteral protein delivered below international guidelines (<1.2 g/kg/day) on mortality and clinical, patient-centred, and muscle outcomes. Methods: A systematic review of databases MEDLINE, EMBASE, CINAHL, and CENTRAL was performed from database inception through to 2 July 2025. Randomised controlled trials (RCTs) of adult critically ill patients comparing 'greater protein' delivery (1.2-2.0 g/kg/day) versus 'lesser protein' delivery (<1.2 g/kg/day) predominantly via enteral nutrition (EN), with similar energy delivery, were identified. Risk ratios were pooled for binary outcomes and mean differences or standardised mean differences for continuous outcomes using random-effects models. Subgroup analyses investigated the effect of exclusive EN; acute kidney injury (AKI) as defined within individual trials; and higher severity of illness (Sequential Organ Failure Assessment score >= 9) for the primary outcome (mortality). Results: From a total of 10,414 citations, 14 RCTs were included, comprising n = 6553 patients (n = 3248 greater protein; n = 3305 lesser protein) from 13 individual patient RCTs and one cluster randomised cross-over trial. Greater protein delivery did not affect mortality (pooled RR 1.01, 95% CI 0.92, 1.12, p = 0.795; I-2= 0%; tau(2)= 0.00; 12 RCTs: greater protein n = 3197; lesser protein n = 3243). Other clinical outcomes were not different; however, the point estimate suggested decreased quality of life for greater protein compared to lesser protein (pooled standardised mean difference -0.11, 95% CI -0.24, 0.01, p = 0.081; I-2= 0%; tau(2)= 0.00; 2 RCTs, n = 921: greater protein n = 456; lesser protein n = 465). In patients with an AKI (as defined within individual trials), greater protein delivery was associated with increased mortality (pooled effect estimate 1.29, 95% CI 1.05, 1.58, p = 0.015; I-2= 0%; tau(2)= 0.00; 3 RCTs, n = 755: greater protein n = 390; lesser protein n = 365), with ICEMAN evaluation suggesting that the evidence for effect modification was of moderate credibility. Conclusions: Greater protein delivery does not reduce mortality or improve any clinical outcomes compared with lesser protein, and may be associated with increased mortality in patients with AKI, though subgroup definitions varied across trials. (c) 2026 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).