The protein paradox in critical illness: rethinking dose, timing, and patient selection after PRECISe and TARGET protein

Critical illness is accompanied by profound proteolysis and muscle wasting, creating a strong physiological rationale for increasing protein delivery. However, EFFORT Protein, PRECISe, and TARGET Protein have not shown patient-centered benefit from broadly applied higher-protein strategies, and analyses in acute kidney injury (AKI) have raised concern about possible unfavorable effect modification. Mechanistic studies help explain this paradox: amino-acid availability can be preserved while incorporation into myofibrillar protein is blunted, and increasing a single protein dose from 20 to 40 g raises circulating amino-acid availability without significantly increasing postprandial muscle protein synthesis. A nested TARGET Protein study further showed that a less negative nitrogen balance with augmented protein was accompanied by greater urea generation. Evidence on timing remains heterogeneous, and calendar-day definitions do not reliably identify anabolic readiness. We therefore propose a hypothesis-generating Need-Utilization-Tolerance framework that separates protein requirement from the capacity to use additional amino acids and to tolerate their metabolic load. Future trials should move beyond fixed g/kg/day comparisons toward phase- and phenotype-responsive strategies linked to functional recovery.