Efficacy and safety of higher versus lower protein provision with meaningful dose separation in critically ill adults: a systematic review and meta-analysis of randomized controlled trials
Background Optimal protein provision in critically ill patients remains uncertain. We conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of higher versus lower or standard protein provision in critically ill adults. Methods Randomized controlled trials comparing higher versus lower/standard protein provision in critically ill adults were included. The primary analysis focused on trials with a between-group protein difference of at least 0.3 g/kg/day. Mortality was analyzed separately by time point, including 28/30-day, 60-day, 90-day, in-hospital, and ICU mortality. Secondary outcomes included mechanical ventilation duration, ICU and hospital length of stay, nutrition/metabolic markers, muscle-related outcomes, and safety. Risk ratios (RRs) and mean differences (MDs) were pooled using random-effects models. Certainty of evidence was assessed using GRADE. Results Twenty-six studies were included. Higher protein provision did not significantly reduce mortality at any time point. For 28/30-day mortality, no statistically significant difference was observed, although the point estimate was lower with higher protein provision (RR = 0.82, 95% CI 0.58–1.17; I2 = 0%). No significant differences were observed for 60-day mortality (RR = 0.85, 95% CI 0.52–1.39; I2 = 51.1%), 90-day mortality (RR = 1.03, 95% CI 0.93–1.14; I2 = 0%), in-hospital mortality (RR = 1.04, 95% CI 0.78–1.39; I2 = 0%), or ICU mortality (RR = 0.84, 95% CI 0.57–1.26; I2 = 0%). Higher protein provision did not significantly shorten mechanical ventilation duration (MD = −0.74 days, 95% CI−1.92–0.43; I2 = 79.0%), ICU stay, or hospital stay. Higher protein provision was associated with a more favorable Day 3 nitrogen balance (MD = 6.39 g/day, 95% CI 2.77–10.01; I2 = 51.7%), but was not associated with a significant increase in gastrointestinal intolerance. Conclusions Higher protein provision did not significantly reduce mortality or consistently improve clinical recovery outcomes in critically ill adults. It was associated with more favorable early nitrogen balance, but evidence for patient-centered benefit and safety remains limited.