Abstract
-
Background
- Critically ill patients with muscle wasting experience prolonged intensive care unit (ICU) stays, delayed weaning, and higher mortality. Trauma-induced stress disrupts protein metabolism, leading to immunosuppression and muscle loss. This study evaluates whether high-protein intake through enteral nutrition preserves muscle mass and improves clinical outcomes compared to standard protein intake.
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Methods
- In our multicenter research, 102 critically ill, mechanically ventilated patients (age, 39±7; female, 51; body mass index, 30.3±1.8 kg/m2) were assigned randomly to receive either a high-protein (2.2 g/kg BW/day) or standard (1.5 g/kg BW/day) diet. Enteral nutrition was individualized based on energy expenditure. Ultrasound measured whether the rectus femoris muscle cross-sectional area (RFM-9 CSA) and pennation angle correlated with dietary intake. The data are presented as mean±standard deviation.
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Results
- Protein intake was 1.8±0.2 vs. 1.2±0.4 g/kg/day in high-protein and standard groups, respectively. In the intervention and standard groups, the baseline RFM-CSA and Pennation angle were 11.43±0.87 mm vs. 11.3±0.91 mm and 9.1±0.58 mm vs. 8.91±1.04 mm (P>0.05). Days 5, 10, and 20 showed significant variations in RFM-CSA and pennation angle (P<0.001). The intervention group experienced a shorter ICU length of stay (47.0±19.5 vs. 56.3±26.9 days, P=0.001) and a shorter period of mechanical ventilation (33±3.5 vs. 33±2.3 days, P=0.001).
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Conclusions
- Early high protein intake significantly preserves muscle mass, reducing the duration of stay in the ICU and the need for mechanical ventilation.
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Key Words: enteral nutrition; rectus femoris; traumatic brain injury; ultrasound
INTRODUCTION
Globally, traumatic brain injuries (TBIs) are a leading cause of disability and death, with millions of new cases reported each year, highlighting their significant impact on healthcare systems and resulting in considerable disability and socioeconomic burdens [1]. The Glasgow Coma Scale (GCS) is a widely used clinical tool for assessing TBI severity, showing correlations with permanent disability rates of 10%–100% and mortality rates ranging from 20% to 30%. The economic burden of TBIs is substantial, exceeding $80 billion in the United States alone [2,3].
TBI's primary and secondary mechanisms involve mechanical damage to the central nervous system, leading to cerebral edema, inflammation, excitotoxicity, ischemia, and immunosuppression. These injuries induce a hypermetabolic and hypercatabolic state in patients, increasing caloric expenditure and protein breakdown [4]. In TBI patients, muscle atrophy—especially in the rectus femoris (RF) —frequently occurs due to dysregulated protein metabolism, which disrupts the balance between synthesis and degradation [5]. Various imaging modalities can noninvasively assess skeletal muscle mass, with ultrasound gaining attention for its cost-effectiveness and portability [6].
Muscle architecture, size, and quality can all be measured by ultrasound imaging. Crucial elements of muscle architecture, muscle fascicle length and pennation angle, are essential for understanding muscular function and biomechanical efficiency [7]. Anatomical cross-sectional area (CSA) and muscle thickness are important factors determining muscular strength capacity. Echo intensity, a noninvasive measure of muscle quality, offers insights into tissue composition and serves as a biomarker for evaluating muscle health status [8].
To control the hypermetabolism of TBI patients and avoid consequences like infections, muscular atrophy, and hyperglycemia, nutritional supplementation is essential [5]. Historically, nitrogen balance (NB) studies have been used to estimate adequate protein intake [8], however, recent research emphasizes functional outcomes such as muscle mass and strength [9]. Early enteral feeding is recommended, with close monitoring of nutritional status using biomarkers such as pre-albumin and albumin [10].
Consistent with current European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines, early enteral nutrition within 48 hours is prioritized in critically ill patients to counteract catabolic muscle loss [8,11-13]. According to various observational studies [14-17], ESPEN [18] advise a daily intake of 1.3 g of protein per kilogram of body weight. While, according to the American Society for Parenteral and Enteral Nutrition (ASPEN) [19], protein targets of 1.2–2.0 g/kg/day are widely recommended. Randomized controlled trials (RCTs) [20-22] evaluating high protein intake have shown variable results on clinical outcomes such as mortality, intensive care unit (ICU) stay, and metabolic status. This variability likely stems from methodological heterogeneity in patient populations, delivery methods, and nutritional protocols, emphasizing the need for standardized, targeted research in this area.
This research examines whether high-protein enteral feeding, compared to standard protocols, preserves the mass of the RF muscle in ICU mechanically ventilated patients with TBIs. The goal of the study is to determine the best nutritional therapies to maintain muscle mass and enhance clinical outcomes in this patient population by comparing these feeding practices.
MATERIALS AND METHODS
From February 2019 to May 2023, a prospective, randomized, double-blind, controlled study was conducted at a critical care unit in Egypt and the United States. The Institutional Review Board of Tufts Medical Center examined and approved this study protocol (No. STUDY00003291) and clinical trial registration (No. NCT06012201). Written informed consent was obtained from all patients’ surrogates.
Participants
Adults aged 18 to 50 years who were admitted to the ICU within 24 hours following severe TBI—defined by a GCS score of ≤8 and an Injury Severity Score (ISS) >15—were eligible for inclusion. To ensure sufficient exposure to the nutritional intervention, participants were required to have an anticipated ICU stay of at least four days from the time of enrollment. Additional inclusion criteria included mechanical ventilation (MV) for more than 48 hours, a Modified Nutrition Risk in Critically Ill (mNUTRIC) score of 0–4 (low nutritional risk), no prior history of chronic illnesses, and adequate baseline nutritional status.
To minimize clinical heterogeneity and reduce potential confounding, we deliberately limited the study population to patients with a mNUTRIC score of 0–4. Patients with higher scores (≥5) were excluded due to their increased likelihood of comorbidities and systemic inflammation, which may independently contribute to muscle wasting and adversely affect clinical outcomes—thereby complicating interpretation of the specific effects of protein provision.
Exclusion criteria included pregnancy, active vascular insufficiency or trauma involving the lower extremities, pre-existing neuromuscular disorders, prolonged immobility before ICU admission, and major comorbidities such as chronic renal, hepatic, or cardiac disease; diabetes mellitus; and chronic obstructive pulmonary disease. Additional exclusions were obesity (body mass index [BMI] ≥35 kg/m2), active malignancy, immunocompromised states, recent use of high-dose corticosteroids (e.g., prednisone ≥40 mg/day for ≥14 days or ≥10 mg/day for ≥28 days) [23] and/or neuromuscular blocking agents, acute respiratory distress syndrome, sepsis, and multiorgan failure patients.
Study Procedures
Following informed consent acquisition, all pertinent information was systematically recorded using structured data collection forms. Participant demographics, such as age (years), sex, body weight, BMI, and mNUTRIC score, were recorded on these assessments. During the 24 hours following ICU admission, a comprehensive nutritional evaluation was conducted for each patient using a mNUTRIC risk assessment tool to confirm eligibility. A computer-generated randomization sequence was used to randomly assign eligible participants to one of two groups, and the envelopes were sealed and opaque. These envelopes contained allocations to either standard or high-protein nutritional regimens. An independent investigator, not involved in subsequent study procedures, accessed the allocation details to maintain blinding. Study diets were prepared and labeled as formula A or B by a nurse with no other involvement in the trial to ensure impartiality. Group 1 (standard formula): patients in this group received protein at a dose of 1.5 gm/kg/day, reflecting our institution’s standard ICU nutrition protocol, and group 2 (high-protein formula): patients in this group received protein at a dose of 2.2 g/kg/day, as defined by the study protocol. All patients received daily standardized physiotherapy, including passive limb mobilization and respiratory physiotherapy, per our ICU protocol. Ambulation was not feasible due to the neurological status and MV.
Outcomes
The primary outcome was the change in RF muscle CSA over 20 days, assessed by serial ultrasound. Secondary outcomes included muscle quality parameters such as pennation angle and echogenicity (via the Heckmatt scale), biochemical markers including serum albumin, total protein, and blood urea nitrogen (BUN); NB; nutritional adequacy based on daily and cumulative protein and caloric intake; and clinical outcomes including duration of MV, length of ICU stay, ventilator-associated pneumonia (VAP), and ICU mortality rate.
Nutritional Support
Nutritional support was administered via a nasogastric tube. For patients with skull base fractures or craniofacial trauma, an orogastric tube was inserted once hemodynamic stability and adequate resuscitation were achieved, typically within 24 hours of admission. Caloric requirements for each participant were calculated using indirect calorimetry and met with a high-energy enteral formula (1.5 kcal/ml, containing 5.6 g of protein per 100 ml). To achieve the designated protein intake based on group allocation, supplemental protein was integrated into the regimen using an enteral protein additive (32 g of protein per 100 g of supplement powder), adjusted as needed to meet individualized targets. Participants who failed to meet the full caloric target (100%) within seven days of nutritional intervention were excluded from further participation. A very low rate of enteral feeding (10–20 ml/hr) was started and gradually escalated by 25 ml increments every 6 hours until prescribed caloric and protein objectives were attained. Individuals exhibiting elevated gastric residual volumes (≥500 ml) within the first 24 hours of feeding were administered intravenous prokinetic agents (e.g., metoclopramide, erythromycin), concurrently reducing the feeding rate temporarily. If intolerance persisted beyond 72 hours, as evidenced by clinical indicators such as abdominal distension, emesis, or sustained high residuals, these individuals were excluded from the final analysis. Additionally, subjects who were completely contraindicated for enteral feeding were not included. Upon regaining consciousness, participants were encouraged to transition to oral intake, supplemented with standardized oral nutritional formulas to maintain protocol-defined caloric and protein delivery targets: group 1 (1.5 g/kg/day) and group 2 (2.2 g/kg/day).
Assessment of RF Muscle
Upon admission, all enrolled patients received endotracheal intubation, MV, and sedation on the first day. Subsequent imaging assessments were restricted to individuals remaining intubated and ventilated. Ultrasound evaluations of skeletal muscles were conducted to obtain both quantitative metrics and qualitative observations. Ultrasound imaging of the RF muscle was performed serially, starting at baseline (≤24 hours after injury) and repeated on days 5, 10, 15, and 20 to assess temporal dynamics. A SonoScape SSI-6000 ultrasound system, equipped with a 2–5 MHz linear transducer, was employed for all assessments. Standardized parameters (depth, gain, focus) were maintained for RF imaging. To limit compression-related artifacts, a generous gel application ensured acoustic coupling. The transducer was positioned three-fifths of the way from the anterior superior iliac spine to the superior patellar border, at a 90° angle to the muscle's long axis (15 cm proximal to the patella). Measurement sites were demarcated with permanent ink to ensure longitudinal consistency and reproducibility. Quantitative analysis included CSA calculations, derived from the perimeter contour of the muscle in frozen ultrasound images (Figure 1). The RF's pennation angle was further quantified through longitudinal ultrasound imaging, which revealed a near-parallel alignment of muscle fibers relative to their fascial plane. This angle was determined by analyzing fiber orientation in relation to the fascia, as visualized in the longitudinal plane of the ultrasound scans (Figure 2). Ultrasound-derived muscle echogenicity was categorized using the Heckmatt Scale, where elevated grades correlate histologically with muscle fiber degradation and loss of tissue integrity.
Measurements and Monitoring
The participant data that were meticulously documented included age, sex, body weight, BMI, mNUTRIC score, and ISS. Quantitative ultrasonographic metrics comprised pennation angle and RF CSA, assessed at baseline (day 0) and longitudinally on days 5, 10, 15, and 20 following nutritional intervention initiation. Qualitative evaluation of muscle architecture included echogenicity grading via the Heckmatt Scale, measured at identical intervals. Serum biomarkers (albumin, total protein) and metabolic parameters (BUN, NB) were analyzed at baseline and days 5, 10, 15, and 20. A widely utilized approach for assessing NB in clinical settings was calculated using the standard formula:
NB (g/day)=[protein intake (g/day)/6.25]–[urinary urea nitrogen (g/day)+4].
The constant 4 g accounts for non-urinary nitrogen losses (e.g., fecal, integumentary, and insensible) [19]. Clinical outcomes compared across research cohorts included length of stay in the ICU and duration of MV, VAP, and ICU mortality rate.
Statistical analysis
REDCap, a safe web-based platform housed within our hospital and intended to make research data capture easier, was used for data administration and collection. IBM SPSS Statistics version 25 (IBM Corp.) was used to conduct the statistical analysis. Baseline demographic and clinical characteristics were summarized using descriptive statistics: categorical variables were expressed as counts (percentages) and analyzed using chi-square tests, while continuous variables were evaluated using parametric (Student t-test) or nonparametric (Mann-Whitney U-test) methods following normality assessment with the Shapiro-Wilk test. Data that were regularly distributed were reported using mean±standard deviation (SD), whereas nonparametric data were reported using median (interquartile range). Data distributions were displayed using histograms. The two-tailed significance level of P<0.05 was applied to each statistical comparison.
RESULTS
Participants
We enrolled 102 patients diagnosed with head trauma who were subsequently admitted to the ICU for this prospective study. The patient flow is presented in Figure 3. The demographic data of the studied groups, shown in Table 1, indicated no significant differences in any of the characteristics of the study subjects between group 1 and group 2.
Trends in Protein and Caloric Requirements
Group 2 demonstrated significantly higher protein intake (mean difference, 53.2–57.8 g/day; P<0.001) and caloric delivery (Δ243-421 kcal/day from day 5 onward, P<0.001) than group 1, indicating fundamentally distinct nutritional requirements. This protein-calorie dissociation—where group 2 maintained 44% higher protein intake while simultaneously achieving 13%–18% greater caloric delivery (Table 2).
Changes in CSA
Significant reductions in the CSA of the RF muscle were observed in group 1 throughout the observation period, with the most notable decrease by day 20 (P<0.01); comparatively, group 2 exhibited a less pronounced decline. In group 1 (standard-protein), the area declined from 11±0.8 cm² at baseline to 10.7±0.6 cm² on day 20 (P<0.001), while in group 2 (high-protein), it decreased from 11.3±0.8 cm² to 11±0.7 cm² (P<0.001). Although both groups experienced muscle loss, group 1 showed a significantly lower CSA than group 2 on days 10 (P=0.04), 15 (P=0.03), and 20 (P=0.01) (Figure 4, Table 3).
Changes in Pennation Angle
A significant decrease in the pennation angle of the RF muscle was observed in group 1; the reduction was observed from 8.9°±0.9° at baseline to 8.4°±0.9° by day 20 (P=0.02). In group 2, high protein intake also led to a decline from 9.1°±0.5° to 8.9°±0.6° (P=0.004). Comparative analysis revealed that while both groups experienced reductions, group 1 had a significantly lower pennation angle than group 2 on days 10 (P=0.002), 15 (P=0.01), and 20 (P=0.01) (Figure 5, Table 3).
Change in Muscle Echogenicity
The muscle echogenicity was measured in groups 1 and 2 over 20 days using the Heckmatt scale. While both groups had comparable scores at baseline (day 0), significant differences emerged by day 5, with group 1 showing increased echogenicity (median score of 3) compared to group 2 (median score of 2, P=0.011), a trend that persisted through day 20, where group 1 maintained a median score of 2 while group 2 decreased to 1 (P<0.001) (Table 3).
Change in Biomedical Markers
Concerning biochemical markers, measured over 20 days in groups 1 and 2, no significant differences in BUN were observed across all time points (P>0.05), while the levels of serum albumin were comparable until day 15, when group 2 exhibited a significant increase (P=0.01). Total protein levels showed no significant differences until day 20, where group 2 demonstrated a marked increase (P<0.001), and NB was significantly higher in group 2 on days 15 and 20 (P=0.05, P=0.04) (Table 4).
Change in Clinical Outcomes
Both the duration of MV and ICU stay were significantly reduced in the high-protein group; however, no statistically significant differences were observed in VAP or ICU mortality. Specifically, patients receiving high-protein nutrition had a shorter duration of MV (30±3.5 days) compared to those in the standard-protein group (30.0±3.5 days) compared to those in the standard-protein group (33.0±2.5 days), and their ICU length of stay was also shorter (47.0±19.5 days vs. 56.3±26.9) (Table 5, Figure 6).
DISCUSSION
This RCT demonstrates that early high-protein enteral nutrition (2.2 g/kg/day) significantly preserved muscle mass in critically ill TBI patients compared to standard protein intake (1.5 g/kg/day). The high-protein group exhibited superior rectus femoris cross-sectional area at days 10, 15, and 20 (all P<0.05), alongside better-maintained pennation angle (days 10, 15, and 20; P<0.01) and favorable muscle echogenicity patterns. These structural advantages were paralleled by metabolic improvements, including significantly more positive NB at days 15-20 (P<0.05) and higher serum albumin at day 15 (P=0.04), consistent with accelerated transition from catabolic to anabolic metabolism. Clinically, the intervention reduced MV duration by 3 days (30.0±3.5 vs. 33±2.3 days) and ICU length of stay by 9.3 days (47.0±19.5 vs. 56.3±26.9 days, P=0.001), without a clinically significant effect on VAP incidence or ICU mortality.
Despite extensive investigation through RCTs, the clinical benefits of elevated protein intake (>1.2 g/kg/day) in critical care are equivocal [24-26]. Evaluating clinical outcomes, including morbidity, mortality, length of hospital stay, and metabolic parameters (NB, urinary urea excretion, creatinine, amino acid profiles, and glomerular filtration rate), has yielded inconsistent conclusions. This variability likely reflects methodological heterogeneity across trials—particularly differences in patient cohorts, nutritional protocol standardization, caloric adequacy, and feeding routes (enteral vs. parenteral). A systematic review of RCTs on ICU nutrition trials (1966–2015) reinforced this ambiguity, reporting no mortality reduction despite significant variations in protein delivery [27]. Consequently, optimal protein dosing during critical illness remains poorly defined in current guidelines [28].
Critically ill patients are prone to rapid skeletal muscle wasting, driven by acute inflammation, hormonal dysregulation, immobility, and neural injury, as well as compounding factors like infection, inadequate nutrition, and certain medications [29]. A meta-analysis has shown daily muscle loss ranging from 6% to 12.5% during the first week of the ICU stay [30], with ultrasound-based studies reporting a 17.7% reduction in rectus femoris cross-sectional area within the first 10 days, predominantly in the initial week [31]. This early muscle loss is strongly associated with prolonged ICU stays and long-term functional disability [32]. Emerging evidence suggests that higher protein intake may attenuate this decline, as seen in trials demonstrating reduced loss of quadriceps muscle layer thickness [33,34] and improved outcomes in critically ill populations [35-38]. In that regard, our studies align with the targeted full energy and enteral delivery in critically ill patients: a pilot randomized controlled trial (FEED Trial) which reported that patients receiving 1.5 g/kg/day of protein had less quadriceps muscle layer thickness loss and lower malnutrition rates at ICU discharge compared to those receiving 1.0 g/kg/day [36]. In another study [37], patients receiving 1.5 g/kg/day or 0.8 g/kg/day of protein showed greater femoral muscle loss in the lower-protein group. Similarly, our study observed muscle mass decline in both groups; however, the reduction was less pronounced, likely due to higher protein delivery in our protocol. In line with these findings, our study observed reductions in rectus femoris cross-sectional area and pennation angle over 20 days in both groups, though the decline was less pronounced in the high-protein group—suggesting a potential muscle-preserving effect. Specifically, the standard-protein group showed a 2.82% decrease in CSA and 5.17% in pennation angle, while the high-protein group experienced smaller reductions of 2.48% and 2.41%, respectively.
In contrast, some studies [12,39] reported no significant reduction in RF muscle loss with higher protein intake. Differences in protein dose and timing may explain this discrepancy. Prior trials often compared lower protein levels, potentially limiting anabolic effects. Moreover, interventions in late-phase critical illness, as in this study [12], may be less effective than early-phase strategies. Our findings support the importance of early, adequately dosed protein delivery during the acute phase of critical illness to mitigate muscle wasting.
Ultrasound assessments in our study revealed progressive morphological changes in skeletal muscle, including adipose infiltration, fiber loss, and fibrotic remodeling. Temporal increases in echogenicity, initially associated with edema, later reflected structural degeneration and disorganization, suggesting reduced muscle fiber density and impaired architecture. These changes may underlie functional decline, as echogenicity has been correlated with muscle strength and performance [40]. Unlike edema, fibrotic tissue alters the bone-muscle interface on ultrasound, providing a distinct signature of structural damage [28,41]. Comparative studies have shown moderate agreement between ultrasound echogenicity and computed tomography (CT)-based muscle density, with ultrasound demonstrating a stronger association with muscle torque, highlighting its potential as a functional biomarker [41,42]. These findings underscore the value of bedside ultrasonography not only for quantifying muscle mass but also for evaluating tissue quality and predicting functional outcomes. Compared to CT or magnetic resonance imaging, ultrasound offers a noninvasive, cost-effective, and repeatable tool that may enhance early detection of ICU-acquired weakness and guide individualized nutritional and rehabilitative strategies [42,43].
In our study, muscle echogenicity was assessed using the Heckmatt Scale, a semiquantitative grading system previously applied in critically ill populations, as described by Grimm et al. [44]. The scale evaluates echogenicity based on the degree of bone signal attenuation, with higher grades indicating more severe muscle pathology [45]. While our study relied on the semiquantitative Heckmatt Scale to assess muscle echogenicity—a practical and accessible bedside tool—it is subject to interobserver variability and lacks the objectivity of quantitative grayscale analysis. Nevertheless, its clinical utility remains relevant, particularly in resource-limited settings [45]. Notably, our findings contrast with prior studies [37,46] that also utilized ultrasound-based assessments of muscle quality and size but reported no significant differences between protein intake groups over 5 [37] or 20 days [46], potentially reflecting differences in study design, population, or protein dosing strategies.
In addition to imaging findings, our study demonstrated that NB was significantly more favorable in the high-protein group at days 15 and 20, supporting prior evidence that higher protein intake enhances nitrogen retention in critically ill patients [37]. These findings align with prior research suggesting that improved NB is associated with reduced all-cause mortality, although not necessarily with initial NB levels [47]. This highlights the importance of monitoring NB as a dynamic marker of protein metabolism over time, rather than relying solely on baseline values.
While BUN and total protein levels were numerically higher in the high-protein group, these differences were not statistically significant, consistent with earlier reports showing limited changes in traditional metabolic markers despite increased protein delivery [47]. In contrast, serum albumin levels did not differ significantly between groups early in the ICU course but showed a significant increase by day 15 in the high-protein group, likely reflecting the transition from the catabolic to the anabolic phase of illness. Nevertheless, albumin and prealbumin remain negative acute-phase reactant; albumin is more influenced by systemic inflammation than nutritional intake during the early stages of critical illness [48]. Several retrospective studies have similarly reported poor correlation between serum albumin levels and protein intake in ICU patients, further reinforcing their limited reliability as nutritional biomarkers [47]. Taken together, these findings suggest that while NB may serve as a sensitive marker of protein metabolism, traditional biomarkers such as albumin and prealbumin have limited utility for assessing nutritional adequacy during the acute phase of critical illness. In this context, our findings support the emerging consensus that NB offers greater sensitivity than serum proteins for assessing the metabolic response to nutritional interventions in critically ill patients. Although one study suggested that adequate protein intake may mitigate the mortality risk associated with hypoalbuminemia, the inconsistency in serum protein responses across studies underscores their limited utility in guiding nutritional adequacy during the ICU stay [10,47].
Interestingly, a significant rise in albumin was also observed on day 20 in the high-protein group, possibly indicating ongoing anabolic recovery. This observation is consistent with studies showing that higher protein intake (>1.2 g/kg/day) is associated with lower 28- and 90-day mortality and with greater ΔBUN, though ΔBUN itself did not correlate with outcomes [48]. Our results also align with research demonstrating minimal changes in protein-related biomarkers during critical illness, despite elevated intake [49]. In contrast, studies in healthy individuals receiving very high protein loads (e.g., 2.4 g/kg/day) have reported marked increases in BUN, likely attributable to the higher absolute protein burden rather than catabolic stress [8].
Taken together, our results reinforce the notion that traditional serum biomarkers such as albumin and BUN have limited responsiveness to protein intake during the acute phase of critical illness. Instead, NB appears to be a more robust and dynamic marker of protein metabolism, particularly when interpreting the effectiveness of nutrition support in ICU patients.
Previous research on ICU patients has recorded alterations in muscle structure, which have been linked to prolonged ICU stays [28,49]. Our study indicated that high-protein enteral feeding was associated with a reduced length of MV compared to the standard protein intake group, as well as a shorter ICU stay. This, being concordant with another study [50], suggests that high-protein, enteral feeding may contribute to the above-stated benefits in critically ill patients. In contrast, some similar studies’ results that show no significant differences between high and regular protein intake groups concerning, among others, ICU/hospital/long-term mortality, ICU/hospital length of stay, and MV length could be explained through a lack of accounting for disease severity and energy provision, which would in turn lead to an underestimation of the beneficial effect of a higher protein intake [40], two meta-analyses [51,52] was also unable to find any significant differences concerning these endpoints.
Furthermore, in contrast to our results, in the effect of higher protein dosing in critically ill patients with high nutritional risk: an organized, multicentre, pragmatic, registry-based randomized trial (EFFORT trial) [53], similarly to this study, the effects of high-dose protein administration in critically ill patients were evaluated by comparing a higher intake (≥2.2 g/kg/day) to a standard dose (≤1.2 g/kg/day). While not only finding no significant reduction in hospital discharge time, it suggested poorer outcomes in patients with acute kidney injury and severe organ dysfunction in the high-protein intake group. These findings were attributed to variations in patient characteristics across the study population. Also, the recent protein provision in critical illness (PRECISe trial) [48], a large multicenter RCT, found that higher protein intake (2.0 g/kg/day) in mechanically ventilated ICU patients did not improve outcomes compared to standard intake (1.3 g/kg/day). The study reported no benefit in quality of life and a possible signal of harm, including a 47% posterior probability of increased 60-day mortality. These findings highlight the need for individualized protein targets, particularly during the early phase of critical illness.
Also, while the total caloric intake in our study exceeded 3,000 kcal/day, this was primarily driven by the need to meet the high-protein target (2.2 g/kg/day) using a protein-enriched enteral formula, rather than by deliberate overfeeding of non-protein calories. Energy requirements were individually tailored and guided by indirect calorimetry, the gold standard for metabolic assessment in critical illness. The absence of metabolic complications may be attributed to the preserved physiological resilience of our cohort, who were previously healthy, young patients with isolated TBI. These findings align with another report [54] that high-protein intakes up to 30 kcal/kg/day are generally well tolerated in metabolically stable ICU populations, without adverse effects on renal function or nitrogen handling.
As a multicenter RCT with rigorous ESPEN protocol adherence, this study benefits from methodological consistency across sites and minimizes confounding through exclusion of patients with significant comorbidities. Standardized ultrasound assessments by a trained operator strengthen muscle architecture evaluation, building upon validated techniques. We acknowledge important limitations. Patients with high nutritional risk (mNUTRIC ≥5) were excluded to enhance cohort homogeneity and isolate protein effects. While this improved internal validity, it limits generalizability to the most severely catabolic patients who might derive differential benefits. The 20-day assessment window precludes evaluation of long-term functional recovery. Though RF evaluation provides practical bedside assessment, multi-muscle analysis would offer more comprehensive insight. While the Heckmatt scale enabled efficient echogenicity assessment, its semi-quantitative nature introduces potential interobserver variability compared to quantitative grayscale analysis. Finally, unmeasured fluid status variations could influence ultrasound metrics.
This multicenter randomized trial supports the role of high-protein enteral nutrition in preserving muscle integrity and improving clinical outcomes in critically ill TBI patients. Guided by ESPEN recommendations, targeted protein delivery was associated with better muscle architecture and reduced ICU and ventilation durations, highlighting its value in ICU nutrition strategies.
KEY MESSAGES
• High-protein intake helps preserve muscle mass, enhances muscle quality, and speeds up recovery in critically ill patients.
• Despite some trends in serum protein levels, biochemical markers alone may not reliably reflect nutritional adequacy during the acute phase of critical illness.
• Enhanced nutrition shortens intensive care unit stays and ventilation time, improving cost-effectiveness and patient outcomes.
NOTES
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CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.
-
FUNDING
None.
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ACKNOWLEDGMENTS
The study was part of the PhD thesis of one of the authors (HE), which was defended on June 9, 2024 at Tanta University.
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AUTHOR CONTRIBUTIONS
Conceptualization: HE. Methodology: HE, PS. Formal analysis: HE, PS, MA. Data curation: HE. Visualization: HE, PS, MB, MA. Project administration: HE, PS, MB. Writing - original draft: HE. Writing - review & editing: HE, MF. All authors read and agreed to the published version of the manuscript.
Figure 1.Cross-sectional area of the rectus femoris muscle. Dotted lines indicate the surface of the rectus femoris muscle, while arrows point to the same muscle surface for clarity. RFCSA: rectus femoris cross-sectional area.
Figure 2.Pennation angle (PA) of the rectus femoris muscle. RF: rectus femoris.
Figure 3.Flowchart of patient recruitment and allocation to study.
Figure 4.Comparison between groups 1 (standard formula) and 2 (high-protein formula) as regards the effects of protein intake on rectus femoris muscle cross-sectional area on days 0, 5, 10, 15, and 20 in intensive care unit (ICU). a) Statistically significant.
Figure 5.Comparison between groups 1 (standard formula) and 2 (high-protein formula) as regards the effects of protein intake on rectus femoris muscle pennation angle on days 0, 5, 10, 15, and 20 in intensive care unit (ICU). a) Statistically significant.
Figure 6.Secondary clinical outcomes in group 1 (standard formula) vs. group 2 (high-protein formula). ICU: intensive care unit; VAP: ventilator-associated pneumonia. a) Statistically significant.
Table 1.Demographic data in the two groups
|
Variable |
Group 1 (n=49) |
Group 2 (n=53) |
P-value |
|
Age (yr) |
39±7 |
40±6 |
0.22 |
|
Sex |
|
|
|
|
Male |
28 (57.1) |
23 (43.4) |
0.08 |
|
Female |
21 (42.9) |
30 (56.6) |
0.09 |
|
Weight (kg) |
79.00±5.32 |
78.00±5.25 |
0.18 |
|
BMI (kg/m2) |
30.45±1.79 |
30.05±1.77 |
0.13 |
|
mNUTRIC score |
3 (2–3) |
3 (2–3) |
0.42 |
|
ISS |
21 (20–23) |
20 (18–23) |
0.09 |
Table 2.Comparison between groups 1 and 2 as regards the protein and caloric intake on days 0, 5, 10, 15, and 20
|
Variable |
Baseline |
5 day |
10 day |
15 day |
20 day |
|
Protein intake (g/day) |
|
|
|
|
|
|
Group 1 |
118.5±8.0 |
121.1±8.2 |
118±7.9 |
115±7.7 |
113.3±7.6 |
|
Group 2 |
171.7±11.6 |
176±11.9 |
173.7±11.7 |
172±11.9 |
171.1±11.5 |
|
P-value |
<0.001 |
|
Caloric intake (kcal/day) |
|
|
|
|
|
|
Group 1 |
3,649.8±245.9 |
3,956.2±266.6 |
3,633.1±244.8 |
3,220.3±216.8 |
3,172.0±213.7 |
|
Group 2 |
3,605.3±242.9 |
4,199.4±282.9 |
3,908.0±263.3 |
3,720.4±250.7 |
3,592.9±242.1 |
|
P-value |
<0.001 |
Table 3.Comparison between groups 1 and 2 as regards the effects of protein intake on rectus femoris muscle outcomes on days 0, 5, 10, 15, and 20
|
Variable |
Group 1 |
Group 2 |
P-value |
|
Cross-sectional area (cm2) |
|
|
Day 0 |
11.00±0.76 |
11.29±0.81 |
0.08 |
|
Day 5 |
10.70±0.72 |
10.90±0.84 |
0.34 |
|
Day 10 |
10.40±0.71 |
10.60±0.79 |
0.04 |
|
Day 15 |
10.50±0.68 |
10.78±0.79 |
0.03 |
|
Day 20 |
10.69±0.66 |
11.01±0.75 |
0.01 |
|
Pennation angle (°) |
|
|
|
|
Day 0 |
8.90±0.90 |
9.10±0.50 |
0.09 |
|
Day 5 |
8.56±0.93 |
8.79±0.55 |
0.06 |
|
Day 10 |
8.16±0.94 |
8.59±0.56 |
0.002 |
|
Day 15 |
8.32±0.93 |
8.71±0.57 |
0.01 |
|
Day 20 |
8.40±0.90 |
8.90±0.60 |
0.01 |
|
Echogenicity |
|
|
|
|
Day 0 |
1 (1–2) |
1 (1–2) |
0.72 |
|
Day 5 |
3 (2–3) |
2 (2–3) |
0.011 |
|
Day 10 |
3 (2–3) |
2 (2–3) |
< 0.001 |
|
Day 15 |
2 (1–3) |
2 (1–2) |
0.002 |
|
Day 20 |
2 (1–3) |
1 (1–2) |
< 0.001 |
Table 4.Laboratory data
|
Variable |
Day 0 |
Day 5 |
Day 10 |
Day 15 |
Day 20 |
|
Blood urea nitrogen (mg/dl) |
|
|
Group 1 |
13 (12–15) |
19 (18–21) |
22 (20–27) |
25 (22–28) |
27 (24–30) |
|
Group 2 |
14 (13–15) |
20 (19–22) |
24 (22–27) |
22 (21–25) |
30 (25–35) |
|
P-value |
0.08 |
0.14 |
0.08 |
0.05 |
0.05 |
|
Serum albumin (gm/dl) |
|
|
Group 1 |
4.45±0.58 |
3.69±0.50 |
3.79±0.53 |
3.90±0.54 |
4.10±0.57 |
|
Group 2 |
4.40±0.49 |
3.80±0.51 |
3.96±0.50 |
4.20±0.51 |
4.30±0.50 |
|
P-value |
0.52 |
0.28 |
0.11 |
0.01 |
0.09 |
|
Total protein (gm) |
|
|
Group 1 |
4.9 (4.1–5.6) |
5.1 (4.5–5.4) |
5.5 (4.9-6.4) |
5.8 (5.4–6.2) |
6.0 (5.7–6.2) |
|
Group 2 |
5.2 (4.8–5.5) |
5.3 (4.9–5.5) |
5.6 (5.1-5.9) |
6.0 (5.7–6.4) |
6.7 (6.3–6.9) |
|
P-value |
0.10 |
0.16 |
0.61 |
0.06 |
<0.001 |
|
Nitrogen balance (g) |
|
|
Group 1 |
11 (9–14) |
18 (14–18) |
21 (19–33) |
26 (19–38) |
25 (20–43) |
|
Group 2 |
12 (10–15) |
19 (14–24) |
25 (20–28) |
22 (17–26) |
29 (20–35) |
|
P-value |
0.06 |
0.06 |
0.05 |
0.05 |
0.04 |
Table 5.The secondary clinical outcomes
|
Outcome |
Group 1 |
Group 2 |
P-value |
|
Mechanical ventilation (day) |
33.0±2.3 |
30.0±3.5 |
0.001 |
|
ICU length of stay (day) |
56.3±26.9 |
47.0±19.5 |
0.001 |
|
VAP incidence (%) |
17.0±2.9 |
21.0±3.2 |
0.45 |
|
ICU mortality (%) |
11.8±1.9 |
13.7±2.4 |
0.60 |
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