The effects of higher versus lower protein delivery in critically ill patients: an updated systematic review and meta-analysis of randomized controlled trials with trial sequential analysis

Lee ZY 1 , Dresen E 2 , Lew CCH 3 , Bels J 4 , Hill A 5 , Hasan MS 6 Show all authors , Ke L 7 , van Zanten A 8 , van de Poll MCG 4 , Heyland DK 9 , Stoppe C 10

Affiliations 

  • 1 Department of Anaesthesiology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. [email protected]
  • 2 University Hospital Würzburg, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, Würzburg, Germany
  • 3 Department of Dietetics and Nutrition, Ng Teng Fong General Hospital, 1 Jurong East Street 21, Singapore, 609606, Singapore
  • 4 Department of Intensive Care Medicine, Maastricht University Medical Centre, Maastricht, 6229HX, The Netherlands
  • 5 Department of Anesthesiology and Department Intensive Care Medicine, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany
  • 6 Department of Anaesthesiology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
  • 7 Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210000, Jiangsu Province, China
  • 8 Department of Intensive Care Medicine, Gelderse Vallei Hospital, Ede & Wageningen University & Research, Wageningen, The Netherlands
  • 9 Clinical Evaluation Research Unit, Department of Critical Care Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada
  • 10 Department of Cardiac Anesthesiology and Intensive Care Medicine, Charité, Berlin, Germany
Crit Care, 2024 Jan 06;28(1):15.
PMID: 38184658 DOI: 10.1186/s13054-023-04783-1

Abstract

BACKGROUND: A recent large multicentre trial found no difference in clinical outcomes but identified a possibility of increased mortality rates in patients with acute kidney injury (AKI) receiving higher protein. These alarming findings highlighted the urgent need to conduct an updated systematic review and meta-analysis to inform clinical practice.

METHODS: From personal files, citation searching, and three databases searched up to 29-5-2023, we included randomized controlled trials (RCTs) of adult critically ill patients that compared higher vs lower protein delivery with similar energy delivery between groups and reported clinical and/or patient-centred outcomes. We conducted random-effect meta-analyses and subsequently trial sequential analyses (TSA) to control for type-1 and type-2 errors. The main subgroup analysis investigated studies with and without combined early physical rehabilitation intervention. A subgroup analysis of AKI vs no/not known AKI was also conducted.

RESULTS: Twenty-three RCTs (n = 3303) with protein delivery of 1.49 ± 0.48 vs 0.92 ± 0.30 g/kg/d were included. Higher protein delivery was not associated with overall mortality (risk ratio [RR]: 0.99, 95% confidence interval [CI] 0.88-1.11; I2 = 0%; 21 studies; low certainty) and other clinical outcomes. In 2 small studies, higher protein combined with early physical rehabilitation showed a trend towards improved self-reported quality-of-life physical function measurements at day-90 (standardized mean difference 0.40, 95% CI - 0.04 to 0.84; I2 = 30%). In the AKI subgroup, higher protein delivery significantly increased mortality (RR 1.42, 95% CI 1.11-1.82; I2 = 0%; 3 studies; confirmed by TSA with high certainty, and the number needed to harm is 7). Higher protein delivery also significantly increased serum urea (mean difference 2.31 mmol/L, 95% CI 1.64-2.97; I2 = 0%; 7 studies).

CONCLUSION: Higher, compared with lower protein delivery, does not appear to affect clinical outcomes in general critically ill patients but may increase mortality rates in patients with AKI. Further investigation of the combined early physical rehabilitation intervention in non-AKI patients is warranted.

PROSPERO ID: CRD42023441059.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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