Most hospitalized ill patients have a wasting syndrome, especially kwashiorkor and cachexia which both are characterized by hypercatabolic status of endogenously lean body mass (LBM) and visceral proteins including albumin (ALB) pre-albumin, retinol binding protein, and transferrin, owing to protein hyper-catabolism which is inexorably hastened by the systemic inflammation response syndrome (SIRS) and chronic hyper-catabolic ststus [1,2]. Cachexia is primarily characterized by dysregulation in protein, fat, and carbohydrate metabolism that is ultimately resulted in severe LBM wasting, branched chain amino acids (BCAAs) depletion, ALB and other body's protein hypercatabolism [3,4]. Consequently, hypoalbuminemia is a pronounced finding in hospitalized patients and independently predicts an increased risk of post-surgical infections, increased hospital LOS and mortality [5,6]. However, ALB, among other proteins, is a negative acute phase reactant and is profoundly influenced by vascular permeability and thus cannot be used to attest to the nutritional status of the acutely ill unless it is matched to CRP in a more predictive CRP:ALB ratio [7]. In the critical care setting, muscle wasting secondary to immobility, inflammation, anorexia and drugs such as corticosteroids and neuromuscular blockers, termed critical illness myopathy (CIM) or intensive care unit-acquired weakness (ICUAW), delays weaning from mechanical ventilation and is associated with poor clinical outcomes [8-10].

Whey protein (WP) has the best protein quality attributed to its high digestibility and absorbability rate. In addition, WP has an excellent source of BCAAs in which every 25 g WP is composed of 3 g leucine: comprising 12% leucine and 26% total BCCA by weight, yielding a Leucine: 

Isoleucine: Valine ratio of approximately 4:1:1, respectively. Leucine is uniquely characterized by its anabolic effect rather than the anticatabolic effect and has been proven beneficial in mitigating protein wasting in critically ill patients [11,12].                To mitigate the certain erosion of protein and its subsequent complications: measures must be taken to either reduce catabolism, stimulate anabolism, or both. The role of WP in stimulating protein anabolism has been well established [13]. WP is particularly superior to other proteins such as casein due to its unique characteristics. Additionally, WP has a shorter gastrointestinal transit time than casein, and is hydrolyzed at a faster rate; enabling its absorption and more readily spiking postprandial serum amino acid concentration [14]. The aim of this study is to evaluate the clinical impacts differences between two protein formulas; BCAAs enriched Protein Formula (Formula I) and Standard Protein Formula (Formula II) regarding biochemical and major clinical imapcts.

A retrospective analysis will be conducted in our King Hussein Medical Hospital (KHMH) for patients who were admitted between Jan 2019 and Jan 2021 and who were their baseline demographics, diagnostics, and anthropometrics could be obtained or assessed from our institutional electronic health record (Hakeem) or admitted patient's kardex. Patients will be excluded if they discharged or died before completed at least 1 week after admission and if the patient had at least 2 consecutive diarrhea episodes. All patient’s continuous variables will be analyzed by using the independent samples T-test to express the Means±SDs and Mean differences±SEMs for cachectic c hospitalized patients who were on Formula I (Group I) and cachectic hospitalized patients who were on Formula II (Group II). One sample T-test will be used to express Means±SDs for total cachectic cohort. All, Group I, and Group II categorical data will be expressed as numbers with percentages by using the Chi square test. Statistical analyses were performed using IBM SPSS version. 25 (IBM Corp., Armonk, NY, USA) and p-values ≤0.05 were considered statistically significant. 

There was no significant difference in age between the two studied groups. Group I demonstrated a significantly shorter LOS and lower overall 28-day mortality compared with Group II, with Mean±SD of (9.80±1.79 days vs. 12.00±2.33 days) and Mean percentage of (20.97% vs. 13.33%), respectively. There was no significant difference regarding gastrointestinal symptoms, including diarrhea, between the two groups. Furthermore, no significant differences in baseline Gastric residual volumes (GRV) nor in GRVs measured one week after admission were observed, however, the percent changes in GRV were significantly lower in Group I with Mean±SD 17.0%±6.98% in Group I vs. 20.4%±3.77% in Group II. 

The nutritional indices of total calorie input (TCI) and protein density (PD) were (1042.0±183.9 Cal/day vs. 1148.7±202.4 Cal/day) and (4.39±0.49 g/100Cal/day vs. 4.37±0.64 g/100Cal/day) in Group I vs. Group II, respectively. The primary outcomes; %∆CRP and %∆ALB were significantly higher in Group I (133.8%±24.26% vs. 113.2%±18.55%) (35.3%±4.64% vs. 28.3%±5.49%) for Group I vs. Group II. However, the difference in the Mean±SD of %∆CRP:ALB ratio was not significant (73.4%±22.31%vs. 66.5%±16.78%) for Group I vs. Group II. 

CRP was significantly higher in Group I both at baseline and after one week (11.57±1.67 mg/dl and 26.78±2.77mg/dl) vs. (9.30±1.75 mg/dl and 19.77±3.60 mg/dl) for Group II. Regarding ALB, Group II had significantly higher ALBs than Group I both at baseline (2.43±0.09 g/dl vs. 2.58±0.14 g/dl) and after one week (3.28±0.01 g/dl vs. 3.30±0.04 g/dl) for Means±SDs of Group I vs. Group II, respectively. The ALB must be seen considering the significantly higher Mean±SD of human albumin (H.ALB) administered intravenously in Group II at 20.00±0.00 g/day for Group II vs. 9.00±3.05 g/day in Group I. 

Additionally, the baseline BUN was significantly higher in Group I vs. Group II with 14.06±3.48 mg/dl vs. 11.12±2.59 mg/dl. After at least one week, the BUN in Group I remained significantly higher than Group II with Mean±SD of 14.57±0.32 mg/dl vs. 12.31±2.37 mg/dl. Finally, the Means differences±SEMs for Group I vs. Group II of %∆ ALB, %∆ CRP, %∆ CRP:ALB ratio, and Overall Hospital LOS were 6.95%±1.29%, 20.64%±5.51%, 6.93%±5.04%, and -2.20±0.53 days, respectively. Demographics, admission diagnostics and wards, anthropometrics, nutritional indices and follow-up comparison data of the study’s cachectic hospitalized patients are summarized in (Table 1,2). 

Table 1: Demographics, Admission Diagnostics and Wards, Tolerance Rates, and Mortalities of The Study’s Cachectic Hospitalized Patients

Data were presented as number (percentage) by using the Chi Square test, Group I: Cachectic hospitalized patients who received BCAAs enriched WP formula (Formula I), Group II: Cachectic hospitalized patients who received standard WP formula (Formula II), S: Significant (p-value <0.05), GI: Gastrointestinal, NS: Non-significant (p-value >0.05), Sx: Symptoms, N: Number of Study’s Hospitalized Patients, Dx: Diagnosis

Table 2: Anthropometrics and Nutritional Indices and Follow-Up Comparison Data of The Study’s Cachectic Hospitalized Patients

Data were presented as Mean±SD and Mean difference±SEM by using the Independent T-test, Group I: Cachectic hospitalized patients who received BCAAs enriched WP formula (Formula I), Group II: Cachectic hospitalized patients who received standard WP formula (Formula II), Yrs: Years. N: Number of study’s hospitalized patients, BW: Actual body weight, ALB: Albumin level, BMI: Body mass index, Cal: Calories, K: Serum corrected potassium level, 1: baseline at admission, H.ALB: Human albumin, PO₄: Serum phosphate level, 2: 1 week after admission, PD: Protein density, BUN: Blood urea nitrogen, %∆: Percentage of Changes, CRP: C-reactive protein, TCI: Total calorie input, S: Significant (P-Value <0.05), CRP: ALB: CRP to ALB ratio, GRV: Gastric residual volume, NS: Non-significant (p-value >0.05), Mg: Total corrected serum magnesium level, LOS: Length of stay day [5].

The present retrospective study of 62 cachexic hypoalbuminemic patients investigated the effect of WP with two different percentages of BCAAs on protein metabolism. During critical illness, major changes in protein metabolism occur: A shift in the prioritization of protein synthesis takes place in the liver, favoring the synthesis of positive acute phase reactants at the expense of negative phase reactants such as ALB [15]. Cachexia accompanies an array of diseases, the exact mechanism remains unclear, however, cytokines appear to play a pivotal role in the pathophysiology of cachexia. 

Cytokines negatively affect protein synthesis at a nuclear level. Leading to loss of the major loss of muscle mass associated with increased mortality [16]. To ameliorate the catabolism occurring to adapt to the increased demand associated with a critical illness, Protein must be provided exogenously to spare the structural and visceral proteins from catabolism [17]. To further support the provision of protein in critically ill patients, an observational cohort study of 113 ICU patients, Allingstrup et al concluded that higher protein administration reduced overall 28-day mortality [18]. 

WP administration has been proven efficacious in stimulating protein anabolism.WP’s anabolic effects may be attributed to its high BCAAs content and specifically the Leucine content [19]. In 1992 Nair et al. reported the positive effect of leucine, a BCAA, on stimulating anabolism in the resting skeletal muscle [20]. Stimulation of protein anabolism by leucine was later explained by its stimulation of mTOR signalling [21]. Leucine stimulates protein anabolism in a “dose-dependent” manner, to the extent that the leucine content of a meal has been proposed to measure a meal’s capacity to stimulate muscle protein synthesis [22]. in this study, we sought to examine the effect of the content of BCAAs on protein anabolism. 

Patients who received BCAAs enriched WP formula (Group I) had significantly higher %∆ ALB despite the higher %∆ CRP, which reflects hyper catabolism, indicating a positive shift in protein metabolism favoring anabolism. This was further indicated by the significantly lower percentage changes in blood urea nitrogen (%∆BUN) in Group I compared with Group II with Mean difference±SEM of -4.44%±6.36%. In summary, BCAAs enriched WP formula was superior to standard WP formula in stimulating ALB synthesis and LBM anabolism/catabolism ratio in cachexic hospitalized hypoalbuminemic patients. This study is limited by its retrospective design and its use of single-center data. However, our center is an experienced and high-volume unit, so our data may be useful to other centers. A larger, multisite prospective study is required to establish the effect of BCAA dose on stimulating protein synthesis.

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