Oral Nutrition Supplements in Enhanced Recovery After Surgery (ERAS): The Pandora’s Box for Prehabilitation Practice in Enhanced Recovery After Surgery (ERAS):

Background: Malnutrition is present in 25 to 54% of hospitalized patients upon admission and it has a direct association with increased morbidity, mortality, length of stay (LOS), increased readmissions, and cost of care. The high level of insulin will block the lipolysis and the usage of FAs as the primary fuel (insulin inhibits ketogenesis). Therefore, the body will shift towards gluconeogenesis and use amino acids as the main fuel. This process will lead to protein and skeletal muscle wasting and increase the risk of malnutrition and other postoperative complications. Prehabilitation includes the process of improving the patient’s overall condition before surgery to keep a higher level of the patient’s functional body capacity during surgery and also inhibit postoperative consequences including complications caused by metabolic stress. One of the best practical methods of prehabilitation is the Enhanced Recovery After Surgery (ERAS) protocol. ERAS is a multi-professional model to educate patients and improve their physical and nutritional status prior to surgery. The ERAS protocol mainly targets the inflammatory responses and hormonal changes during metabolic stress. This can alter the metabolism leading to suppression of protein-sparing resulting in a decrease in protein wasting. The ERAS program was initially started at CRMC as a pilot quality improvement project in 2017. Furthermore, there is no standardized protocol for ERAS, especially on Oral Nutrition Supplementation (ONS). To date, there is sufficient data to support the benefits of oral nutrition supplementation for patients undergoing metabolic stress. Nonetheless, there is not enough evidence regarding the effectiveness of any specific product over others for improving the patients’ nutritional status prior to surgery and the patients’ overall survival and complications post surgery. Materials and Methods: In this review paper we sought to compare some of the most common nutritional supplements and their ingredients used for ERAS programs in the United States by focusing on the cell signaling effect they may have on metabolism, protein sparing, some elective amino acids, insulin resistance, and glycemic index. Results: The main results revealed that an optimal oral nutrition supplementation should provide an opportunity to trigger the cell signaling pathways that would increase the transcriptional level of endogenous protein synthase while other ingredients would provide further benefits. Despite several review articles and clinical trials and clinical outcome measurements, there is very limited metabolic research on prehabilitation biochemical mechanisms and cell signaling responses pathways. There is an absolute need for mechanistic studies that will help to select the most appropriate formulas. Pandora’s


Introduction
Major surgeries may cause several metabolic derangements in patients' bodies known as metabolic stress. In this situation, The Basal metabolic Rate (BMR) will increase, and the body will go through several hormonal changes including a higher insulin level.
Subsequently, these hormonal imbalances will trigger changes in metabolic pathways [1,2]. In healthy individuals, when the protein or glucose intake is high, insulin, an anabolic hormone, is secreted by the beta cells of the pancreas. It would stimulate glycogenesis and the uptake of glucose into muscles (for fuel) and fat cells (for storage as triglyceride) via Glucose Transporter 4 receptor (GLU4).
However, in metabolic stress situations, cells develop insulin resistance based on stress, which continues for up to three weeks even after uncomplicated, moderate surgery. Likewise, common perioperative experiences like nothing per mouth (NPO) status, pain, and bed rest can also contribute to a reduced sensitivity to insulin as well [3][4][5]. In situations such as starvation, the drop of glucose level will cause a reduction in insulin levels and result in a condition known as glucose repression [6].
Glucose repression includes a cascade of genes and protein expression changes to switch to alternative fuels for different cells. Please see Figure 1 for more details [7-9]. However; in metabolic stress, as mentioned above, the insulin level is very high, and it will block the lipolysis and beta-oxidation, resulting in decreased usage of FA as the primary fuel (the presence of insulin inhibits ketogenesis). Therefore the body will shift to gluconeogenesis and will use Amino Acids as the main fuel [7,10,11]. This shift to gluconeogenesis would initially affect the muscles by increasing the whole body and tissue-specific protein turnover which would consequently increase the free amino acid pool circulating in the body. Secondly, it would decrease the uptake of amino acids into the skeletal muscle as well [11]. Furthermore, metabolic stress also will cause a cascade of inflammatory responses. The liver would retain amino acids to synthesize acute phase proteins like Tumor necrosis factor (TNF-alpha), C-Reactive Protein (CRP), and Interleukins to send signals to the immune system, which will result in the sparing of body proteins as well [2,12]. The scientific outcomes of this negative protein balance can cause skeletal muscle wasting, respiratory impairment, fatigue, higher risk of malnutrition, and diminished mTOR signaling and muscle protein synthesis [1,2,12].
This condition would increase the risk of complications by six-folds and severe infection by ten folds especially in major surgeries and large burn wounds [13].
Although a well-nourished adolescent patient might not experience a severe form of these consequences during metabolic stress, this condition may cause serious complications known as 'catabolic crisis' in malnourished or elderly patients. For this reason, the patient's health conditions prior to surgery including obesity, metabolic syndrome, diabetes, and low insulin sensitivity could impact the adverse outcomes after major surgeries [3,11,14].
Prehabilitation includes improving the patient's overall condition before surgery to keep a higher level of functional capacity during and immediately after surgery. It also aims at decreasing postoperative deleterious consequences such as complications caused by metabolic stress and postoperative catabolism [15,11].
The use of prehabilitation is increasing in hospital settings for high-risk patients, since evidence has shown better postoperative outcomes, only minor infections, shorter length of stay, fewer readmissions, and a dramatic decrease in narcotic pain medication requirement. Several smallrandomized trials have demonstrated that multimodal prehabilitation enhances pre-and postoperative functional capacity in elective surgical patients. One of the best practical methods of prehabilitation is Enhanced Recovery After Surgery (ERAS) [11, [16][17][18].
ERAS is a multi-professional model to educate patients and improve their physical and nutritional status prior to surgery. ERAS is designed to reduce complications, hospital length of stay (LOS), and overall elective surgery setting costs. Since its introduction by Kehlet in the 1990s, ERAS has shown several benefits in patients undergoing elective surgeries including colorectal, gynecological and urological surgery [19][20][21][22]. ERAS protocol mainly focuses on the inflammatory responses and hormonal changes during metabolic stress. This effort includes medical optimization, psychological support, physical exercise, and nutritional support. These interventions are provided by a multidisciplinary team consisting of physicians, nurses, geriatricians, physiotherapists, nutritionists, and psychologists [11, 23,24]. Other than commercial recommendations, there is no globally accepted protocol for ERAS for oral nutrition supplements (ONS). The primary effect of ONS in ERAS is unclear, and some of the perioperative supplements might have limited efficiency on postoperative outcomes, if the preoperative risk factors are not addressed properly [3,[25][26][27].
As described by Gündoğdu, currently there are three main categories of ONS available for ERAS. They are generally utilized to prepare patients for major surgeries depending on the patient's malnutrition status and health condition [28].

1.
Oral carbohydrate supplementation: It is administered for metabolic preparation mainly via increasing insulin sensitivity.

2.
High protein supplementation: It is used for severely malnourished patients with or without metabolic stress risk DOI: 10.26717/BJSTR.2021. 38.006099 to reduce the complications after surgery. This group would benefit the ONS more than well-nourished patients.

3.
Immunonutrition supplementation: It is utilized to improve the immune system and gastrointestinal barrier.
In this review paper we sought to compare some of the most common nutritional supplements and their ingredients used for ERAS programs in the US by focusing on the cell signaling effect that they may have on metabolism, protein sparing, some elective amino acids, insulin resistance, and glycemic index.  [23,27,28]. Previous studies also have shown consumption of these carbohydrate rich drinks could improve enterocytes function after surgery. In addition, preoperative carbohydrate loading was an independent predictor of positive clinical outcomes in patients undergoing colorectal surgery [29]. Maltodextrin is a small polysaccharide and a by-product of hydrolyzing starches. According to the FDA, maltodextrin is a GRAS (Generally Recognized as Safe) food additive. From a Glycemic Index (GI) standpoint, maltodextrin is categorized as high GI, even higher than sucrose. Therefore, maltodextrin consumption could result in a significant increase in blood sugar levels [30]. Furthermore, all of the mentioned sugar substitutes, including maltodextrin, fructose, sucralose, and acesulfame potassium can alter the gut microbiome and affect the balance of gut bacteria and cause insulin resistance in the long term [31,32]. However, since the usage of these supplements is limited to the day of surgery, the probability of that aforementioned problem, in the long run, is low. Likewise, Chromium (Cr) is a trace mineral that can improve insulin sensitivity 7 and exists in Impact Advanced Recovery® (Nestlé) 33mcg and Ensure® Surgery (Abbott) 12mcg.

Essential Ingredients used in the Majority of ONS
Zinc: Zinc is the essential element for the function of more than 100 metalloenzymes, including those used for protein synthesis.
It is mainly stored in muscles and bones [7]. There are several established functions for zinc, including improving the healing process for wounds, tissue repair and regeneration, and production of DNA and RNA. It is also part of the enzymes and proteins that repair skin cells and enhance their proliferation [33,34]. Metabolic stress may cause a reduction in the serum zinc concentration, which negatively affects its anti-inflammatory and wound-healing properties [35]. Therefore it is recommended to incorporate zinc into the ERAS ONS, with the cautionary note that a higher intake of zinc (more than 40 mg/day) may suppress the immune system [36,37]. The two examples of main ERAS ONS used in the US are Impact Advanced Recovery® (Nestlé) and Ensure® Surgery (Abbott). Both of these supplements contain 5mg zinc/bottle, and the recommended intake is two bottles/day for at least five days prior to surgery which renders both of them safe from a zinc toxicity standpoint.
Omega -3 Fatty Acids Supplementation: As mentioned above Ensure® Surgery (Abbott) and Impact Advanced Recovery® pro-inflammatory cytokines [38]. The meaningful clinical effects of omega-3 for prehabilitation ONS in reducing mortality and a patients' overall outcomes have been observed by a combination of omega-3 with high protein supplementation. These improvements were independent of the omega-3 fatty acids type (ALA vs. EPA & DHA) [18,39] and were not seen if offered individually, even in the form of DHA and EPA [40,41].
Nucleotides: Purine, pyrimidine bases, ribose, and phosphoric acid are needed to synthesize deoxynucleic acid (DNA), ribonucleic acid (RNA), and ATP. They are required for cell growth, proliferation, and differentiation. Therefore, they play a vital role in rapidly dividing cells, including lymphocytes and enterocytes, and the maintenance and restoration of the immune response [42]. Akyuz emphasizes supplementation with nucleotide as part of an immune nutrition supplement (including omega-3 fatty acids, arginine, and nucleotides) that can protect the enterocytes against chemotherapy damage [43]. Although the body can synthesize these nucleotides during metabolic stress, their formation would be altered because of the hormonal and metabolic changes [44]. The only commercially available ONS in the US with nucleotides is Impact Advanced Recovery® (Nestlé), with 430mg dietary nucleotides.

High Protein Supplementation:
As mentioned before, the metabolic stress of major surgeries stimulates a catabolic state which increases gluconeogenesis and causes a higher need for proteins in general. It has been shown that patients going through uncomplicated elective surgery usually lose ∼2 kg total lean mass within the first six weeks after surgery [45][46][47]. Although required protein intakes for patients undergoing major surgeries are not gr/kg/day for during metabolic stress [48,49]. A study by Gillis emphasizes that 30% of patients undergoing colorectal surgery are malnourished and are not meeting their protein need via their diet intake alone [50]. Another study conducted by Yeung compared ERAS protocols with conventional care regarding protein intake and showed that even though ERAS patients consume more protein (mainly via ONS), neither ERAS nor conventional care patients meet the required protein intake [47]. Well-nourished patients with a functional digestive system can initiate their oral intake 24 hours after surgery to achieve most of their dietary needs. However, any delay to restarting oral intake is connected to the higher rate of infections and lower survival rate [29,51]. Several meta-analyses emphasize an increased risk of vomiting and postoperative aspiration related to early oral intake as well [29]. These results very well establish the importance of high protein supplementation prior to surgery to meet the patient's requirements. There are many different ONS in several forms (liquid, powder) to provide different amino acids for gluconeogenesis caused by metabolic stress and prevent the body from going through muscle wasting and malnutrition due to metabolic stress. Several studies have shown the effectiveness of different amino acids and high protein supplements. However, these types of supplementations seem to be more effective in malnourished patients undergoing major surgeries or critically ill patients [25,47,52,53].

Single Amino Acid Supplements
Arginine: Arginine (ARG) is commonly categorized as a nonessential amino acid, but it becomes conditionally essential in situations like metabolic stress [54]. The main site for arginine metabolism is the liver and kidney. The kidney can convert citrulline to arginine, then some of this endogenous arginine would be transported into the blood to be used by other organs. Please see Figure 2 for more details [55]. There are several known functions for ARG, but the most important one is the production of Nitric Oxide (NO). Since its discovery in 1987, many biological roles have been established for NO. It is a critical molecule in vascular dilation, neurotransmission, acute and chronic inflammation, and the immune system [56]. Different cells, including macrophages and neutrophils, use ARG to make NO [57]. It also has been suggested that the presence of NO generated from the ARG-NO pathway facilitates the shift of a wound from the acute inflammatory phase to the proliferative phase of wound healing [35,38]. ARG supplementation may increase NO production in different cells, including immune cells and endothelial cells.58 Another by-product of the ARG-Urea pathway in Ornithine. Ornithine can be converted to L-proline, a substrate for collagen synthesis, and polyamines, stimulating cellular proliferation [58].
Interestingly, supplementation with L-citrulline increases levels of circulating L-arginine more than supplementing with ARG itself [59,60] In a normal situation, around half of the consumed ARG would be entered into the portal vein and the other half will be directly used by enterocytes or will be degraded [35]. ARG supplementation is generally safe when the consumed amount is 20 grams or less per day, but it could trigger gastrointestinal symptoms at quantities as low as 5 grams per day [61]. L-citrulline is claimed to be one of the ingredients in CF(Preop)® but there is no information about the quantity in the nutrition facts about this ingredient. Studies have shown that major surgical procedures can diminish circulating ARG due to more ARG breakdown for NO synthases and less endogenous ARG production [62]. The two main ERAS ONS used in the US are Impact Advanced Recovery® (Nestlé) and Ensure®® Surgery (Abbott). Both of these supplements contain  [63,64]. Also, by blocking the activity of NFκB and STATE proteins GLN acts as an anti-inflammatory marker [65][66]. Several studies also have confirmed the effect of GLN on cell differentiation regulation, mucin formation, and nucleotide synthesis stimulation [67][68][69]. However, the best effect of GLN supplementation happens when it has been combined with other amino acids, especially BCAA and/or HMB [70]. For example, a clinical trial has compared two different ONS containing GLN (Free GLN vs. GLN-Alanine) and showed both of these ONS had the same effect on promoting neovascularization and improving skin flap survival in rats [71]. The     Alanine: Alanine is a nonessential amino acid. During metabolic stress, when the body shifts to gluconeogenesis for energy production, alanine is the primary fuel. This would increase the importance of alanine supplementation during metabolic stress to provide the amino acid precursor for gluconeogenesis and protect the body's protein and skeletal muscles. This can decrease muscle wasting and protein malnutrition [52,72]. The main concern with using alanine supplementation is that it would cause a slight increase in circulating alanine aminotransferase concentration which may interfere with liver function tests [73]. Neither Ensure® that HMB can interact with the mTOR complex-1 pathway to promote muscle protein synthesis [7, [74][75]. Please see Figure 1 for more details. Supplementation with HMB has been studied in elderly patients and athletes. HMB has been used in several overthe-counter products and supplements to improve muscle function and increase lean body mass [76][77][78]. He X and Stancliffe R, in two different studies, stated that the effect of HMB is by increasing gene expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), which is a master regulator of mitochondrial metabolism 74 and mTOR complex-1 pathway, which control the protein biogenesis [7, [79][80].

Most common ONS in the US for ERAS protocol with GLN is Impact
Although Tokunaga has shown that Leucine can promote p70α phosphorylation via the mTOR complex-1 pathway by serving as a mitochondrial fuel 9, further studies have clarified that this effect is not directly via Leucine and is mainly through its metabolite HMB [80]. As shown in Figure 1, HMB's effect on reducing the muscle protein degradation and improving the muscle mass is independent of ARG and GLN [70]. Hsieh has further explained that HMB supplementation might have anti-inflammatory effects and improve pulmonary function in COPD patients in an intensive care unit setting. The evidence indicates a lower level of CRP and ventilator modes improvement [81]. It can also decrease apoptosis and increase cell proliferation and has been used safely in patients with malnutrition, cancer, chronic disease, sepsis, and HIV [82].
In healthy individuals, only 5% of Leucine would be converted to HMB. Therefore the increased requirements for HMB due to metabolic stress cannot be met by a regular diet, Leucine, or high protein supplementations [83]. Despite all of these essential functions on protein synthase and mitochondrial biogenesis, HMB is not one of the ingredients in the majority of ERAS ONS. Only Ensure® Enlive (Abbott) contains HMB, while this supplement is only recommended for postoperative care by the company.

Summary
In this paper, we sought to introduce the most commonly used oral nutrition supplements in the prehabilitation protocols in the US that are commercially available. Additionally, we have tried to further analyze supplements and explain their major ingredients Table 1. summarizes the findings. The biochemical characteristics of these active ingredients and their effect at the molecular and cellular level are explained in detail as well. To our knowledge, this is the first review paper that gathers and collectively compares different types of ONS. Based on this review, we hypothesize that an optimal oral nutrition supplementation should provide an opportunity to trigger the cell signaling pathways that would increase the transcriptional level of endogenous protein synthase while other ingredients would provide further benefits. We hope that this detailed understanding of these ONS and their ingredients will help the providers in determining the proper supplementation for their patients, based on their individualized and complex needs. Also, we hope that this paper could pique some interest in designing human trials to better understand the mechanisms of function, proper dosage, and optimal formulations for future types of nutrition supplementation.