Enteral high protein misses the TARGET
And also OOPS
Anorexia is a key feature of serious illness, and one would think this is somehow adaptive. Yet it’s also true that high catabolism and muscle wasting during the acute phase of critical illness are associated with debility and worsened outcomes.
There is no evidence that any nutritional strategy can mitigate these complex biological processes, which doesn’t mean we shouldn’t try, up to a point.
Lacking definitive evidence confirming a restrictive approach to nutrition is safe, and in the hope of mitigating muscle loss, guidelinists (I just made this term up, much like the recommendations themselves) have advised that the critically ill be fed high-protein enteral formulations.
American guidelines (ASPEN) have advised 1.2–2 g/kg/day of protein, and European guidelines (ESPEN) a minimum protein delivery of 1.3 g/kg/day. For reference, healthy people are advised to eat roughly half this much protein daily.
At least for mechanically ventilated patients, randomized trials suggest that disregarding this guidance does not seem to be harmful.
And it may be possible to go too far with a high-protein diet in the ICU, the EFFORT Protein trial suggested.
Protein requirements in supplemental nutrition during critical illness (EFFORT Protein trial)
Protein requirements in supplemental nutrition during critical illness remain essentially unknown, and multiple randomized trials have shown no benefit to any altered nutritional product vs. its control. In the absence of evidence, guidelines recommend differing protein targets for critically ill patients.
It showed no reduction in length of stay or mortality among patients treated with higher protein doses.
Concerningly, patients with acute kidney injury or additional organ failure appeared to be harmed by a high (>2.2 g/kg/day) protein dose.
Then there was the PrECiSe TrIaL (I may have mixed up the capitalized letters, because I didn’t feel like switching browser tabs to check).
It showed no benefit and a nominally 4% higher mortality in the high protein group. More patients in the high protein arm developed symptoms of gastrointestinal intolerance (odds ratio 1.76, statistically significant).
After 6 months, those in the high protein group had slightly lower quality of life scores. This was assessed with the EQ-5D-5L tool, which measures mobility, self-care, usual activities, pain/discomfort and anxiety/depression. There were many patients lost to follow-up, though.
Higher protein doses no help, possible harm in large randomized trial
All nutritional strategies in critical care are based on hypothesis and conjecture. No strategy for delivery of caloric content (e.g., higher or lower) or mix of macronutrients has been shown to be beneficial over any other.
TARGET-Protein
Now we come to TARGET-Protein, conducted in Australia and New Zealand by ANZICS, published in JAMA in June 2025 and presented at the CCR25 meeting.
RESULTS FROM CCR25: June 16, 2025
The Critical Care Reviews meeting has become a major annual event in critical care, and 2025 continues the tradition. Multiple important randomized trial results were announced at the June 11-13 meeting in Belfast, Ireland, and their papers were simultaneously published in top medical journals, including the
This should have settled the question definitively, and probably did.
It was a stepped wedge cluster randomized trial in which 4 ICUs each switched en bloc repeatedly between using a high protein (Nutrison Protein Intense, 100 g protein/L) or regular protein (Nutrison Protein Plus 63 g protein/L) for three-month periods.
The intervention group received more protein than the usual protein group, and similar calories in total.
After 90 days among 3,397 enrolled patients:
There was a non-significant 2-day reduction (worsening) in the primary outcome of days alive and out of the hospital in the augmented protein group.
1.4% fewer patients in the augmented protein group were alive (72.6% vs 74.0%, non-significant).
There were no differences in other secondary outcomes.
Unfortunately, the power calculations were based on 8 ICUs rotating between the two therapies rather than the 4 that were planned all along.
Whoops!
It sounds like this was just a good old-fashioned human goof. (Clinical trialists: They’re just like us!)
The error didn’t make a difference, since the direction of the trial disfavored high protein. The unplanned halving in power would have been an issue only if there was a borderline statistical benefit to higher protein.
Conclusion
There is no apparent benefit to augmenting protein delivery in critically ill patients, and the available (inconclusive) evidence suggests that it might sometimes be harmful.
Please vote to select the corny sign-off line of this post:
If you’re giving high doses of protein, you’re way off target.
Let’s keep the extra protein in the supplement aisle at Target™.
For these guidelines, it might be better to miss the target.
References
Lee, ZY., Yap, C.S.L., Hasan, M.S. et al. The effect of higher versus lower protein delivery in critically ill patients: a systematic review and meta-analysis of randomized controlled trials. Crit Care 25, 260 (2021). https://doi.org/10.1186/s13054-021-03693-4
I can't sign off with one of the suggested choices. None is sarcastic enough for me !