Augmented Enteral Protein in Critical Illness: Evidence Update and Clinical Implications

Augmented enteral protein refers to the intentional delivery of protein at doses exceeding standard nutritional requirements—often ≥1.2 g/kg/day, and in some trials, up to 2.2 g/kg/day—during critical illness. This approach has been widely promoted to mitigate muscle wasting, enhance functional recovery, and improve clinical outcomes in critically ill patients. Despite guideline endorsements (1-3), actual protein delivery in the ICU often falls short, typically ranging between 0.6–0.7 g/kg/day, approximating requirements for healthy individuals. Until recently, the clinical impact of increasing protein provision beyond standard care remained uncertain.

Key Evidence from Recent Trials and Meta-Analysis

Initial support for augmented protein delivery was based on small RCTs that suggested attenuation of muscle loss and modest improvements in ICU outcomes. These findings informed international recommendations. However, three major studies published between 2023 and 2025 provide more definitive insights:

• EFFORT Protein Trial (2023)

  This pragmatic, registry-based RCT enrolled 1301 high-risk ICU patients across 85 centers and compared high-dose protein (≥2.2 g/kg/day) with usual care (≤1.2 g/kg/day). No improvement was found in time-to-discharge-alive or 60-day mortality. Importantly, a subgroup analysis suggested harm in patients with acute kidney injury (AKI) and higher organ dysfunction scores (4).

  
  

• PRECISe Trial (2024)

  Conducted in 10 ICUs, this double-blind RCT randomized 935 mechanically ventilated patients to high (2.0 g/kg/day) or standard (1.3 g/kg/day) protein. The high-protein group experienced significantly lower health-related quality of life (mean EQ-5D-5L difference −0.05; p=0.031) and a higher rate of gastrointestinal intolerance, with no difference in survival or functional outcomes (5).

  
  

• Updated Systematic Review and Meta-Analysis (2024)

  A comprehensive review by Lee et al. aggregated data from 23 RCTs (n=3303), comparing higher (mean 1.49 g/kg/day) vs lower (mean 0.92 g/kg/day) protein intake. No mortality benefit was observed (RR 0.99; 95% CI 0.88–1.11). In AKI patients, however, higher protein was associated with significantly increased mortality (RR 1.42; 95% CI 1.11–1.82; number needed to harm = 7). Limited evidence suggested a possible benefit when higher protein was combined with early physical rehabilitation, though this was based on small studies (6).

TARGET Protein Trial (2025)

The TARGET Protein trial was a cluster-randomized, crossover study across 8 ICUs in Australia and New Zealand that enrolled 3,397 critically ill patients. It compared augmented (100 g/L) versus usual (63 g/L) protein enteral formulas, both isocaloric. The primary outcome—number of days alive and free from hospitalization at day 90—did not differ between groups (median 62 vs 64 days; p=0.46). Secondary outcomes, including mortality and ICU stay, were also unaffected. No benefit was observed in any prespecified subgroups (7).

Clinical Implications & Practical Takeaways

• No demonstrated benefit: Higher enteral protein does not improve mortality, ICU/hospital length of stay, or time to discharge.

• Potential harm in AKI: Strong evidence supports avoiding augmented protein in patients with AKI due to increased mortality risk.

• Reduced quality of life: Higher protein intake was associated with worse post-ICU quality of life in one trial.

• Uncertain synergy with rehab: Combining early physical therapy with protein augmentation may hold promise, but evidence remains limited.

• Targeted use only: Routine high-dose protein is not recommended; strategies should be individualized.

  
  

Conclusion

Augmenting enteral protein during the acute phase of critical illness does not improve outcomes and may be harmful in specific populations, notably those with AKI. The findings from recent high-quality trials and a robust meta-analysis challenges current guideline recommendations and support a more cautious, individualized approach to protein provision in the ICU.

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References

1. Compher  C, Bingham  AL, McCall  M,  et al.  Guidelines for the provision of nutrition support therapy in the adult critically ill patient: the American Society for Parenteral and Enteral Nutrition.   JPEN J Parenter Enteral Nutr. 2022;46(1):12-41. doi:10.1002/jpen.2267PubMedGoogle ScholarCrossref

2. Singer  P, Blaser  AR, Berger  MM,  et al.  ESPEN guideline on clinical nutrition in the intensive care unit.   Clin Nutr. 2019;38(1):48-79. doi:10.1016/j.clnu.2018.08.037PubMedGoogle ScholarCrossref

3. Singer  P, Blaser  AR, Berger  MM,  et al.  ESPEN practical and partially revised guideline: Clinical nutrition in the intensive care unit.   Clin Nutr. 2023;42(9):1671-1689. doi:10.1016/j.clnu.2023.07.011

4. Heyland  DK, Patel  J, Compher  C,  et al; EFFORT Protein Trial team.  The effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein).   Lancet. 2023;401(10376):568-576. doi:10.1016/S0140-6736(22)02469-2PubMedGoogle ScholarCrossref

5. Bels  JLM, Thiessen  S, van Gassel  RJJ,  et al; PRECISe study team.  Effect of high versus standard protein provision on functional recovery in people with critical illness (PRECISe).   Lancet. 2024;404(10453):659-669. doi:10.1016/S0140-6736(24)01304-7PubMedGoogle ScholarCrossref

6. Lee  ZY, Dresen  E, Lew  CCH,  et al.  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.   Crit Care. 2024;28(1):15. doi:10.1186/s13054-023-04783-1

7. Summers MJ, Chapple LS, Karahalios A, et al. Augmented Enteral Protein During Critical Illness: The TARGET Protein Randomized Clinical Trial. JAMA. 2025;334(4):319–328. doi:10.1001/jama.2025.9110