The effect of higher versus lower protein delivery in critically ill patients: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background The optimal protein dose in critical illness is unknown. We aim to conduct a systematic review of randomized controlled trials (RCTs) to compare the effect of higher versus lower protein delivery (with similar energy delivery between groups) on clinical and patient-centered outcomes in critically ill patients. Methods We searched MEDLINE, EMBASE, CENTRAL and CINAHL from database inception through April 1, 2021.We included RCTs of (1) adult (age ≥ 18) critically ill patients that (2) compared higher vs lower protein with (3) similar energy intake between groups, and (4) reported clinical and/or patient-centered outcomes. We excluded studies on immunonutrition. Two authors screened and conducted quality assessment independently and in duplicate. Random-effect meta-analyses were conducted to estimate the pooled risk ratio (dichotomized outcomes) or mean difference (continuous outcomes). Results Nineteen RCTs were included (n = 1731). Sixteen studies used primarily the enteral route to deliver protein. Intervention was started within 72 h of ICU admission in sixteen studies. The intervention lasted between 3 and 28 days. In 11 studies that reported weight-based nutrition delivery, the pooled mean protein and energy received in higher and lower protein groups were 1.31 ± 0.48 vs 0.90 ± 0.30 g/kg and 19.9 ± 6.9 versus 20.1 ± 7.1 kcal/kg, respectively. Higher vs lower protein did not significantly affect overall mortality [risk ratio 0.91, 95% confidence interval (CI) 0.75–1.10, p = 0.34] or other clinical or patient-centered outcomes. In 5 small studies, higher protein significantly attenuated muscle loss (MD −3.44% per week, 95% CI −4.99 to −1.90; p < 0.0001). Conclusion In critically ill patients, a higher daily protein delivery was not associated with any improvement in clinical or patient-centered outcomes. Larger, and more definitive RCTs are needed to confirm the effect of muscle loss attenuation associated with higher protein delivery. PROSPERO registration number: CRD42021237530

Medical nutrition therapy and clinical outcomes in critically ill adults: a European multinational, prospective observational cohort study (EuroPN)

“…To overcome this knowledge gap, some authors extracted protein intake from large, randomized studies originally designed to study the effects of a different calorie intake. Two recent meta-analyses found that protein intakes between 0.7 and 1.3 g/kg day were unimportant for morbidity or mortality [ 3 , 31 ] and a post hoc analysis of the PermiT trial [ 32 ] revealed similar results. Our results suggest a U-shaped relationship between protein and time until weaning, but not mortality.…”

“…In parallel, 1.3 g/kg protein equivalents per day can be delivered progressively. These recommendations are more conservative than those propagated by the preceding ESPEN guideline [ 2 ] acknowledging evidence of a detrimental effect of high calorie intakes during the acute phase, and that a higher protein intake during the first week of critical illness may improve clinical outcomes [ 3 ].…”

Protein intake and outcome of critically ill patients: analysis of a large international database using piece-wise exponential additive mixed models

“…The recent meta-analysis by Lee et al [ 10 ] analyzed the effect of a high protein intake in 19 randomized studies (1731 patients) and found that increasing average daily protein intake by 0.4 g/kg per day (from 0.9 to 1.3 g/kg per day) did not affect overall mortality or other clinical or patient-centered outcomes. However, most of the included studies were of moderate quality, small and single-center.…”

“…The vast majority of observational studies found a significant association between an early high protein intake and better outcome [ 4 ], whereas some post hoc analyses of randomized studies suggested the opposite [ 5 , 6 ]. Several meta-analyses evaluated protein intake in randomized studies originally examining the effect of a different calorie intake; these analyses showed that protein intake was largely unimportant for outcome [ 7 – 10 ].…”

Nutrition priorities in obese critically ill patients

“…Higher versus lower protein did not significantly affect overall mortality (risk ratio, 0.91; 95% CI 0.75-1.10) or other clinical outcomes [66]. In five small studies (273 patients), higher versus lower protein significantly attenuated muscle loss (mean difference À3.44% per week; P < 0.0001) [66]. There are several ongoing trials addressing the dose of protein in the critically ill populations [67][68][69][70].…”