Author Response: Challenges in Implementing High Protein Nutrition for ICU Patients

Dear Editor,

We are grateful to the correspondents for their engagement with our work and for the constructive critique provided. We address the methodological and clinical points raised, as outlined below:

At the time of study initiation, the 2019 European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines recommended administering approximately 1.3 gm/kg/day of protein based on actual body weight, following the achievement of energy targets.¹ Given the lack of a universally accepted definition for “high protein,” we selected a target of 1.5 gm/kg/day, which exceeds both international and regional recommendations. Current Asian guidelines advocate for 1.2–1.3 gm/kg/day during the acute phase, with escalation beyond 1.5 gm/kg/day reserved for the postacute phase or prolonged catabolic states.² This threshold was supported by earlier meta-analyses, such as that by Lee et al., which defined “high protein” as 1.1–1.6 gm/kg/day and “low protein” as 0.7–1.1 gm/kg/day, with a minimum intergroup difference of 0.2 gm/kg/day.³

Similar categorization was employed in a recent randomized trial from China, wherein patients received 0.8 gm/kg/day vs 1.5 gm/kg/day in the low- and high-protein arms, respectively.² Accordingly, our high-protein intervention was deemed consistent with, and in some cases, exceeding the standard of care at the time of trial design.

The 2016 and 2021 American Society for Parenteral and Enteral Nutrition guidelines recommend a protein intake range of 1.2–2.0 gm/kg/day, citing potential associations with improved clinical outcomes, including mortality reduction, although the 2021 update retained this range due to ongoing limitations in the evidence base.^4,5 The most recent 2023 ESPEN update reaffirmed the target of 1.3 gm/kg/day.⁶

In our study, both intervention groups achieved their respective protein and caloric targets within 48 hours of initiating enteral nutrition. The optimal timing for protein administration remains an area of uncertainty. While Weijs et al. and Bendavid et al. reported improved survival with early protein delivery, other retrospective data suggest potential harm when higher protein amounts are administered between days 3 and 5, despite lower mortality with overall higher intake.^7–9 Given substantial heterogeneity in study designs, patient selection, routes of nutrition, and timing, these findings are not directly comparable. The 2023 ESPEN guidelines highlight the need for well-powered randomized controlled trials (RCTs) to further elucidate these relationships.⁶

Importantly, our cohort did not experience any significant feeding-related complications, such as high gastric residuals, vomiting, diarrhea, or feed interruptions, thereby demonstrating the practical feasibility of achieving 1.5 gm/kg/day protein intake early in the intensive care unit (ICU) course among appropriately selected patients.

Muscle ultrasound measurements were conducted by two intensivists each with more than 8 years of experience in point-of-care ultrasonography (POCUS). Although formal interobserver reliability testing was not performed, this limitation was acknowledged. Key imaging endpoints, such as muscle echogenicity and pinnation angle, were derived using automated software, minimizing operator bias. While minor variations in manual measurements of muscle thickness and cross-sectional area may exist, their magnitude is likely minimal in relation to the overall muscle dimensions and unlikely to affect the study's conclusions meaningfully. Nonetheless, we recognize that future studies should incorporate standardized, reproducible ultrasound assessment protocols.

The hypothesis that higher-risk patients derive the most benefit from nutritional intervention is not consistently supported by subgroup analyses in large RCTs. Stratification by age, nutritional risk screening (NRS), modified Nutrition Risk in Critically Ill score, or body mass index did not demonstrate a survival or recovery advantage with early high-calorie or high-protein feeding.^10–13 In fact, several analyses, including post hoc evaluations of the PermiT and EPaNIC trials, identified worse outcomes among patients presumed to be at higher nutritional risk when aggressive early feeding was administered.^11,12

It is important to clarify that our study did not evaluate biochemical or molecular markers of muscle catabolism. Hence, we refrained from attributing the observed muscle preservation to anticatabolic effects. Rather, our conclusions were explicitly limited to the primary outcome—reduced muscle loss in lower-limb weight-bearing muscles during the first week of ICU stay with high-protein, normocaloric nutrition (1.5 gm/kg/day protein; 25 kcal/kg/day energy intake).

We concur that future investigations, particularly large-scale randomized trials incorporating diverse ICU populations, various muscle groups, and standardized imaging protocols, are necessary to optimize protein dosing strategies. We appreciate the opportunity to clarify these methodological and clinical aspects, and we hope our response enriches ongoing discourse in critical care nutrition.

Orcid

Vetriselvan Parasuraman https://orcid.org/0009-0001-3338-5838

Bikash Ranjan Ray https://orcid.org/0000-0003-1461-1518

Puneet Khanna https://orcid.org/0000-0002-9243-9963

Rahul K Anand https://orcid.org/0000-0002-7852-1231

Rakupathy Shanmugam https://orcid.org/0000-0001-7174-6932