1. Publication
- Title: Augmented Enteral Protein During Critical Illness: The TARGET Protein Randomized Clinical Trial
- Acronym: TARGET Protein
- Year & Journal: JAMA, published July 22, 2025 (2025;334(4):319-328)
- Citation: Summers MJ, Chapple LS, Karahalios A, et al; TARGET Protein Investigators; ANZICS CTG. JAMA. 2025;334(4):319-328. doi:10.1001/jama.2025.9110
2. Context & Rationale
Background: International guidelines recommend augmented protein (≥1.2 g/kg/day) during critical illness based on observational data, but impact on patient-centered outcomes was unproven at scale. Critical illness causes severe catabolism and persistent functional disability among survivors.
Research Question/Hypothesis: In critically ill patients receiving enteral nutrition, does augmented protein delivery increase days alive and free of the index hospital at day 90, compared with usual-dose protein?
3. Design & Methods
- Study Type: Pragmatic, cluster-randomized, cross-sectional, double cross-over, open-label trial
- Setting & Centers: 8 mixed adult ICUs, Australia/New Zealand; May 2022–Aug 2023
- Population: Adults ≥18y receiving enteral nutrition within 72h of ICU admission
- Intervention: Augmented-protein isocaloric formula (100g protein/L)
- Comparator: Usual-protein isocaloric formula (63g protein/L)
- Design: Each ICU used each formula for 3-month periods over 12 months (4 ICUs started augmented, 4 started usual); 3412 patients
- Statistical Power & Follow-Up: Primary: days alive and free of index hospital at day 90.
4. Key Results
3412 patients across 8 ICUs.
Outcome | Augmented Protein | Usual Protein | Notes |
Days alive/free of hospital at day 90 (primary) | Mean 62.3 days (95% CI 60.8–63.8) | Similar | No significant difference |
Mortality (ICU, hospital, 90-day) | No significant difference | — | — |
Length of stay, MV duration | No significant difference | — | — |
5. Internal Validity Assessment
Cluster-randomized, cross-sectional, double cross-over design (each ICU as its own control) with registry-linked objective outcome ascertainment. Overall: Moderate-to-strong — large sample (3412), robust cross-over design; cluster (not individual) randomization is the main limitation.
6. External Validity Assessment
Broad, pragmatic ICU population across 8 Australian/New Zealand ICUs — highly representative of general ICU nutrition practice.
7. Strengths & Limitations
Strengths: Large sample; pragmatic, registry-embedded, cluster cross-over design; clear, well-powered null result.
Limitations: Open-label, cluster randomization; formula-based (not individually titrated) delivery.
8. Interpretation & Practice Impact
Augmenting enteral protein does not improve days alive and free of hospital at day 90 — joins EFFORT Protein and PRECISe as a third major trial finding no clinical benefit from higher protein targets in critical illness.
9. Controversies & Subsequent Evidence
A JAMA correspondence exchange (Berris & Elango; Summers et al. reply, October 2025) followed publication. Directly complements the 2026 mechanistic trial (Summers et al., AJRCCM) which found higher protein doses don't even further augment muscle protein synthesis — together providing a coherent "bench to bedside" null result.
10. Summary & Executive Takeaway
Summary: TARGET Protein, a cluster-randomized cross-over trial across 8 ICUs, randomized 3412 patients (by ICU-period) to augmented (100g/L) vs usual (63g/L) enteral protein. Augmenting protein did not improve days alive/free of hospital at day 90, nor mortality or LOS.
Overall Takeaway: The third major trial to find no clinical benefit from augmented enteral protein delivery in critically ill patients — reinforcing a shift away from routine protein-dose escalation as an ICU nutrition strategy.
11. Bibliography
- Heyland DK, et al. EFFORT Protein. Lancet. 2023;401(10376):568-576.
- Bels JLM, et al. PRECISe. Lancet. 2024;404:659-669.
- Summers MJ, et al. Muscle protein synthesis mechanistic trial. Am J Respir Crit Care Med. 2026;212(5):964-971.