Effects of higher versus lower protein intake in critically ill patients: a systematic review and meta-analysis.

Background: The optimal protein dose for critically ill patients remains uncertain, and emerging evidence suggests that the effects of higher protein intake may differ across clinically relevant subgroups. Methods: PubMed, Embase, Web of Science, Scopus, and the Cochrane Library were searched for randomized controlled trials (RCTs) evaluating protein delivery in critical illness adults (up to July 2026). Higher and lower protein groups were defined according to each trial's original allocation. Primary outcome was all-cause mortality. Secondary outcomes included mechanical ventilation (MV) duration, Intensive care unit (ICU) length of stay (LOS), muscle outcomes, health-related quality of life (HRQoL), biochemical outcomes, and adverse events. Results were reported as risk ratios (RRs) or mean difference (MD) and 95% confidence intervals (CIs). Trial Sequential Analysis (TSA) was performed to control for random error, and the certainty of evidence was rated using the GRADE framework. Results: Thirty three RCTs involving 11,622 participants were included. No significant differences were observed between higher and lower protein groups for all-cause mortality (RR 1.02, 95% CI 0.97 to 1.08), MV duration (MD -0.48, 95% CI -1.08 to 0.13), or ICU LOS (MD -0.18, 95% CI -0.86 to 0.51), with TSA confirming these null findings. Some muscle metrics favored the higher protein group; however, there was a trend towards poorer HRQoL (SMD -0.12, 95% CI -0.24 to 0.00). The higher protein group showed improved nitrogen balance (MD 5.58, 95% CI 2.89 to 8.27) and higher serum albumin levels (SMD 0.18, 95% CI 0.07 to 0.29), but increased urea (MD 2.06, 95% CI 1.49 to 2.64) and blood urea nitrogen concentrations (MD 2.94, 95% CI 1.32 to 4.56). Sensitivity analyses restricted to 27 isocaloric-design trials yielded consistent results. Subgroup analyses revealed that higher protein intake was linked to increased mortality in patients with acute kidney injury (RR 1.46, 95% CI 1.14 to 1.87); however, higher protein intake combined with rehabilitation interventions was associated with reduced mortality (RR 0.68, 95% CI 0.50 to 0.93), shorter MV duration (MD -1.45, 95% CI -2.61 to -0.29), and beneficial muscle effects. Conclusion: Higher protein intake was not associated with better clinical outcomes. While it may increase mortality in patients with AKI, combining it with physical rehabilitation yields survival and clinical benefits, warranting confirmation in future factorial RCTs. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251109618, identifier [CRD420251109618].