INTRODUCTION:

Sepsis is a life-threatening condition associated with a dysregulated host response to infection¹. It is commonly indicates the final pathway to death caused by many infection disease^1,2. The further complications appear due to late recognition or not getting proper treatment. The complications, multiple organ failure and septic shock, have been the major caused of healthcare problem. Sepsis has been known around the world as killer condition of people annually²^,3.

The recent study shows prevalence of sepsis worldwide reached 48.9 million cases which counted as 20% of all global deaths in 2017^1,2^,4. In the United States, sepsis affects 300 million people and becomes the tenth most common cause of death⁵. A study about sepsis severity at a provincial hospital in North Sulawesi of Indonesia, with a total of 35 sepsis patients in a year, four patients was diagnosed with severe sepsis while two patients diagnosed with septic shocked. However, only twelve patients (34.3%) survived⁶. Another study about sepsis management at a provincial hospital in East Java, Indonesia, reported clinical improvement in patient whose completed 3-6 hours sepsis bundle precisely according to Surviving Sepsis Campaign (SSC) 2016. However, patients death is still found⁷.

Sepsis can affect multiple organ disruption such as small intestine (ileum and jejunum), skeletal muscle, liver, and lung. The effects of severe sepsis have been recorded in a study by isolated live Pseudomonas aeruginosa from the patient and transferred the bacteria via i.v catheter to pigs. Eighteen hours later, these effect leads to the specific metabolism condition, in particular: linoleic acid metabolism changes in the liver and ileum, valine or leucine or isoleucine metabolism changes in the lung and ileum, and arginine or proline metabolism changes in the liver, jejunum and skeletal^8-11.

Furthermore, sepsis is a leading cause of multiple organ failure and frequently occurring in patients with critical illness who must stay in the intensive care unit (ICU)¹². In sepsis patients generally difficult to determine with certainty the nutritional needs. Thus, it will be physicians’ responsibility to initiate artificial nutrition for them¹².

Malnutrition could increase mortality in critically ill patients. Amount 50% of 68 patients in the ICU that have been found in Egypt, are malnourished. They classified malnutrition as mildly-moderately malnourished (14.7%) and severely malnourished (35.3%). It showed that 55.9% mortality occurs in malnourished patients. The study demonstrated that the length of stay (LOS) in ICU are between 2 until 28 days, with average LOS is 10 days. Likelihood prevalence of mortality are found 2 times higher in malnourished groups then well-nourished groups. The increasing of mortality associated with high prevalence malnutrition of patients in the medical ICU¹³.

Another study including eight countries in the Latin America also demonstrated high prevalent of malnutrition in critically ill patients, which attain to over 70% patients that classified as moderate and severe malnutrition. Almost half of admission (47.3%) were from surgical patients. Duration of LOS were between 28 days until 63 days. The lack of caloric intake target are occured in about 40% critically ill patients that have been treated¹⁴.

Based on ASPEN/AND criteria, 54% malnutrition patients were found from 98 patients who stay in the Intermediate Care Unit (IMC) and ICU at Northern Virginia, showed higher LOS and hospitalization cost. Hospital costs in malnutrition patients reach almost 45% higher than well-nutrition patients. Comorbidities, hospital LOS, and cost significantly worse in malnutrition patients. The study also showed increasing of mortality trends in patients with sepsis¹⁵.

In contrary, another review about association of malnutrition and clinical outcomes in the ICU showed in study at Singapore. They found the small prevalence of malnutrition. Totally 260 patients are included in the study, which there are only 21.6% patients in moderate malnourished and 1.6% patients are severe malnourished has been found. Differences of malnutrition prevalence might be caused by countries status which is in developed or developing countries, and also the type of ICU such as medical or surgical ICU¹⁶.

Immunonutrients are nutrients that have the ability to alter the immune system's cellular functions. Specific or combination nutrients are widely utilized as a therapeutic. Immunonutrients have the functions of repairing the barrier and immune function, enhancing wound healing, and reducing hyperinflammation¹⁷. Generally, immunonutrient recognized as inflammatory response modulatory in infection or injury, and also beneficial to improving clinical outcome. Mechanism of immunonutrient as a modulatory in immune function and tissue repair depending on influence of the genetic, metabolic, or environment¹⁸.

The nutrient that has been known potentially important as a component of immunonutrient for example a glutamine and arginine^17,19,20.In addition to providing calories, administration of GAC maybe have additional positive effects.¹²^,²¹ GAC supplementation might be plays favorable role in mechanism of immune defense, inflammatory respons, gut barrier function, and tissue oxygenation^18,22,23.

Glutamine and arginine amino acids have both roles on growth, tissue repair, cell renewal and collagen synthesis²⁴. Glutamine is the most abundant amino acid but its storage is immediately depleted from muscles in catabolic stages such as trauma, sepsis and burn. For this reason glutamine is defined as conditionally essential. Arginine has also roles in nitrogen metabolism, creatine and polyamine synthesis and is the major substrate for nitric oxide synthesis. Thus, it has an important role on immune response. Arginine is not an essential amino acid for healthy subjects, but in stress phases such as sepsis, it might be essential^25,26. Low plasma arginine levels and increased arginine requirement which could not be met by endogenous synthesis in septic patients are related with worsening prognosis²⁷^,²⁸.

Nutritional supplementation is defined as the provision of parenteral or enteral. Parenteral nutrition administered via inravenous to the bloodstream. While enteral route administered by oral ingestion or via tube into the gastrointestinal tract²⁹. In sepsis patient, early administration of full enteral nutrition is more recommended than early parenteral nutrition or parenteral combined with enteral feeding. Majority in critically ill patients, practically and safely to use enteral route instead of parenteral route. The beneficial effects of enteral route are well documented in nomeourus randomized controlled trial, involving a variety of patient populations in critically illness, and the most consistence effect is reduction in infectious morbidity and ICU LOS³⁰.

This review aims to determine the advantages of GAC administration as immunonutrient for sepsis patients.

Pathophysiology of Sepsis:

The molecular pathobiology and immunology of sepsis has experienced a transformation which led to the new understanding about the complexity interplay both host and infectious agent³¹^,³². Sepsis definition not only as a process of immune disorder or response of systemic inflammation, but also includes the alteration of multiple organs function³³. As depicted in Figure 1, on the molecular and levels of cellular, sepsis pathogenesis is highly complex, including the disruption in response of inflammation, coagulopathy, immune dysfunction, mitochondrial breakdown, and another process of pathophysiological that eventually leads to organ disfunctional^32,33. The proinflammatory mediators (TNF-α and IL-1) consider as caused several symptoms occurring in sepsis: hypotension, induction of other proinflammatory cytokines, leucocytosis, coagulation and fibrinolysis simultaneous activation and fever³²^,³⁴^,³⁵.

Fig 1. The complex pathogenesis of sepsis³³

It is known that a well-balanced microbiota is essential to maintain enteric and systemic immune homeostasis. Disruption of the integrity of the intestinal microbiota potentially increases susceptibility to sepsis³⁶. Intestine plays main role to maintain homeostasis in order to inhibit sepsis spread and expansion. Spesifically, alteration function of gut barrier induce the viable bacteria and antigens to leave the gut and enter the systemic system which known as translocation bactery that represent gut origin sepsis. This conditions can lead to the worsening of sepsis, cytokine-mediated SIRS onset, MODS, and death³⁷.

Micro-circulatory alteration will disrupted intestinal barrier integrity in critically ill patient. Furthermore, translocation bacteria and endotoxins happened and got into mesenteric lymph nodes and portal vein system, which further reach to the circulation systemic. Consequently, a systemic inflammatory response is promoted, further induces functional destructive and structural alterations. Several evidence used intestinal permeability measurement to defined gut barrier failure. Intestinal permeability significantly increased in crtically ill patients which related to the worsening of systemic inflammatory response syndrome (SIRS), sepsis, and multiple organs dysfunction (MODS)³⁸.

Worsening of MODS was associated with gut permeability enhancement and dysfunctional of barrier intestine. It is recognized that intestinal immuno-logical system defense activated by intestinal submucosa that has been accesed by gut microbes and or their products. Danger-associated molecular patterns (DAMPs) and intestinal injury released in the mesenteric lymphatics by intestinal pro-inflammatory response, which further brought to the lung and the systemic circulation. Intestine becomes key pro-inflammatory organ which encourage defective impact even in distant organs exceed DAMPs release, with translocation bacteria systemic unneeded³⁸.

DAMPs is a substance which is produced from the debris of host cells breakdown through irreversible stimulation, with role as inflammation induction. Another factor of inflammation induction namely pathogen associated molecular pattern (PAMPs). PAMPs could be shaped as a microba (pathogen bacteria) or substance which is released by pathogen while presence within the host, for example lipopolysaccharide (LPS)³⁹.

DAMPs or PAMPs were detected by innate immune systems which activated through pattern recognition receptor (PRR) mediation. Consequently, increasing genetic expression-related inflammation occurred³³. Complicated interaction of the immune system and other host systems with infection of DAMPs or PAMPs, will generate clinical manifestation of sepsis³⁷.

The pathophysiological mechanisms found that the gut has a main role in sepsis onset and distribution in several periods. However, further investigation the intestinal microbiota roles in sepsis and effective therapies that beneficial to improve sepsis survival are still needed³⁷.

Sepsis is one of the critical illness may induce endothelial tight junction (TJ) disruption through mechanical, excessive inflammation or ischemic. Inflammation stimulation may lead to the active disassembly of endothelial TJs, as is presumed to occur in capillary leak associated with septic shock. Serum ZO-1, occludin, and zonulin are all elevated in sepsis however, ZO-1 best stratified sepsis severity and degree of organ dysfunction⁴⁰. The ZO-1 outperformed other TJ markers may reflect the concomitant organ epithelial injury which occurs in multiple organ dysfunction syndrome. Similarly, in Dengue fever, serum levels correlated with the amount of plasma leakage, demonstrating its specificity as a biomarker of vascular barrier dysfunction. A number of clinical factors may initiate destabilization of epithelial and endothelial barriers in critical illness, such as overwhelming or unrelenting stimulation from inflammatory (i.e., cytokines), hypoxic-ischemic or traumatic insults (i.e., damage associated molecular patterns)⁴¹.

The Effect of Nutrition in Sepsis:

Due to limited literature and research paper about this particular topic, we aim to give this review of the advantages of choosing enteral nutrition (EN) for sepsis patients. Sepsis patients in the ICU experience gastric emptying which tend to impaired and slow. This condition impacts on a large gastric residual volume, thus the use of enteral feeding is stopped for patients. On the other side, the initiation of early parental nutrition within 48 hours for patients who are just admitted to the ICU have been recommended by European guidelines⁴². Providing the adequate intake for instituting EN in early stage could preserve gut mucosa integrity³³. The rational of this treatment is that the lower risk of infection is on EN rather than parenteral nutrition. Besides, as every patient has different energy requirement, the physicians should estimate every patients needs based on a daily basis by measuring oxygen consumption and carbon dioxide production⁴³.

Enteral nutrition is possibly producing non-nutritional benefits for over a week just after the patient’s admission to the ICU which leads to the several gastrointestinal responses, namely: keeping the integrity of gut, supporting the variety of the microbiome, continuing outcome secretory IgA (sIgA) and gut-associated lymphoid tissue (GALT), mucosa-associated lymphoid tissue (MALT), stimulating T-regulatory cells and Th2 anti-inflammatory lymphocytes⁴⁴. A total of 70–80% immune cells are present in the intestine⁴⁵. Intestinal mucosal defense against enteric toxins and pathogenic microorganism occur by sIgA roles, through the various of gut antigen in the luminal intestine such as dietary components, self-antigen and microbiota⁴⁶. According to a study, in critically ill condition the nutrition risk used as a score to define the benefits of nutrition therapy, with high score is highly likely to decrease the probability of mortality^45,46. Moreover, studies related to immune-modulating macronutrients, micronutrients, combination of them for feeding either enteral or parenteral way proved the outcome of patients in the ICU⁴⁴. A meta-analysis study showed that enteral nutrition in general ICU beneficial to reducing infection, LOS, and days of ventilation mechanical usage¹⁸.

Consideration for Choosing Glutamine:

Glutamine has been classified as a nonessential amino acid, but it’s also the most abundant one. It has been used to treat critical ill patient, although the clinical benefits are still unclear. On the contrary, this amino acid has been connected with decrease of mortality rate and hospitalization for several patients conditions, example can be seen in severe burn patients⁴⁷. It because glutamine is the principal oxidative fuel for rapidly proliferating cells, such as those in the gastrointestinal tract and immune system. The gut integrity may be preserved, when administered from the parenteral side of the intestinal epithelial cell. The main immune actions of glutamine are improving tissue protection, immunological modulation, glutathione-antioxidant capacity preservation, and cellular metabolism preservation after injury^34,48. Recent study describe that glutamine supplementation beneficial to alleviate gut failure or support gut function recovery³⁷.

In a meta-analysis evaluating four randomised controlled trials with glutamine has shown that high prevalences of infectious complications are caused by intestinal permeability, colonic apoptosis and decreased sIgA function, abnormal lymphocytes and macrophage functions and glutamine supplementation might reverse all these effects. In another study on rats evaluating the effects of glutamine on intestinal functions has shown that decreasing amino acid concentration due to endotoxemia is related with enterocyte dysfunction, thus oral or enteral glutamine supplementation could not be as effective as parenteral glutamine administration due to impaired intestinal capacity⁴⁹. Differently, a study investigating intraabdominal sepsis model in rats has shown that enteral glutamine supplementation decreases bacterial translocation and increases mucosal thickness and antioxidant levels⁵⁰.

A study used meta-analysis method found that glutamine supplementation may be linked to a lower rate of infection complication in patients of surgery particularly when it administered through parenteral route with high doses³⁴. A study used meta-analysis reported that parenteral glutamine supplementation was associated with a significant reduction in hospital mortality and length of stay⁵¹^,⁵². A recent study found a reduction in the frequency of nosocomial pneumonia and urinary tract infection, after critically ill patients were administrated parenteral alanyl- glutamine dipeptide in first three days after admission in the ICU³⁴.

Depletion of glutamine during sepsis can be severe and last longer than the widespread protein depletion associated with injury-induced hyper catabolism³⁴. In septic patients, EN supplemented with glutamine and antioxidants has been demonstrated to repair numerous organ failure indices when compared to a standard enteral diet⁵¹. Furthermore, the benefit could have come from other immunomodulating medicines rather than glutamine alone⁵². A study on rats showed that parenteral glutamine with protein energy deficiency for four weeks reduced inflammation and protected organs from sepsis-related organ damage⁵³.

In addition, other amino acids (arginine, leucine, glutamate, glycine) and glutamine were able to limit barrier disruption induced by MTX in Caco-2 cells compared with other tested amino acids. Citrulline also showed a trend but difference did not reach significance. The results are in accordance with previous study showing that glutamine was able to modulate TJs protein expression and localization during glutamine deprivation in Caco-2 cells⁴¹.

Low glutamine levels were thought to be a result of muscle wasting, because when muscle mass is lost, glutamine production may not be able to keep up with the increased glutamine demands of immune cells, hepatocytes, and enterocytes. Low glutamine levels have been linked to a poor prognosis in patients with severe illnesses. Supplementing glutamine would improve patient outcomes⁴². Glutamine may establish intestinal mitogenic pathways through nucleus signaling at 10mM concentrations. Any nutrient with such a critical function might affect the metabolism of cell, however glutamine was the first discovered as adequate amino acid to activate the intestinal cell signaling-related kinases that phosphorylated downstream targets (within minutes). This indicates that glutamine may act as a gut “primitive hormone”, because it boosted the effectiveness the infusion of nutrition and cell signaling. Severe stress models, such as multiorgan system failure, endotoxemia, skin burns, weaning, and cancer, were used to test glutamine’s efficacy. Furthermore, results from rodent and pig models have proven quite similar. Glutamine therapy significantly reduced mortality caused by lipopolysaccharide^53-56.

Enterocytes require exogenous administration of glutamine as a primary metabolic fuel in stressful situation such as systemic illness or intestinal injury. A study about glutamine administration in non-surgical rat model demonstrated improvement in jejunal morphometric measurements, mainly increase in villus height, but none in ileum. According to those study, jejunal enterocyte is transformed by glutamine absorption in the proximal small intestine. Differences in glutamine response could means that jejunum is more sensitive than ileum⁵⁷.

Glutamine affects gut microbiota through different mechanism, including NF-κB and PI3K-Akt pathways to reduce firmicutes ratio to bacteriodetes, decrease the intestinal colonies (Eimera lesions) and translocation of bacteria, increase production of sIgA and IgA+ cell in the luminal intestine, and also decreasing asparagine levels. Dietary of glutamine supplementation increased secretory IgA in the jejunum and ileum, also number of IgA+ plasma cell in the rat intestinal⁵⁸. Meanwhile, another study showed that glutamine supplementation significantly increases secretory IgA concentration in the ileum than jejunum⁵⁹.

Glutamine also increasing the expression of IL-1 and IL-2. Metabolism of glutamine will produce substrates for hepato-gluconeogenesis and nucleotide synthesis at enterocyte, limphocyte, and neutrophil. As the precursor of ornithin, glutamine will stimulate ornithin proliferation through polyamine synthesis⁶⁰.

Recent study shows optimal benefit of glutamine when administered at 0.5 grams per kilograms body weight per day for longer than 5 days⁶¹. Further studies will be necessary to determine whether an increased glutamine contact duration with the intestines is needed or specific binary or pancreatic products existance to reap glutamine beneficial effect⁵⁷. Additional information from more solid randomized studies is needed to better understand the benefits and drawbacks of glutamine and other protein dietary supplementation in critically ill septic patients.

Consideration for Choosing Arginine:

The macrophages play some major roles, both as antimicrobial effector and as immunoregulatory cells. There are two phenotypes of macrophages. The M1 either for killing or fighting and the M2 for healing or fixing. The M1 macrophage role is producing nitric oxide (NO) and citruline through arginine metabolism. Meanwhile, M2 macrophage transformed arginine into urea and ornithine⁶².

The macrophage uses arginine as a precursor to produce nitric oxide with activity of nitric oxide synthetase. In theory, arginine supplementation could injure a critically ill septic patient who is hemodynamically unstable by boosting nitric oxide production, leading to increased hemodynamic instability and organ failure. Clinical experiments using arginine given to septic patients, in contrast, found no exacerbation of shock^63,64.

Enhancement of nitric oxide level with aggravating vasodilatation has been linked to death risk augmentation in septic patients receiving arginine supplementation with unstable hemodynamic. On the contrary, other studies have found that dietary with high concentration of arginine reduce the presence of bacteria in the blood and septic patient mortality in the ICU. Further research is needed before making any recommendations about dietary supplementation of arginine uses and safety³⁴.

Arginine as a conditionally necessary amino acid, is critical key to inhibit malfunction of T-lymphocyte after physical injury, and have a role in regeneration of connective tissue, even is a precursor for the synthesis of nitric oxide as key signalling molecule. Lack of arginine develops quickly after physical injury (but not after sepsis) and is related with inadequate dietary intake as well as the development of arginase 1, an arginine depletion enzyme. Recent studies have found a significant reduction in complication of infections linked with dietary supplementation of arginine during surgery, but no overall effect on mortality⁶⁵.

In septic patient, arginine may help by enhancing tissue perfusion, lowering protein catabolism, and boosting cardiac output⁶⁴. However, the outcome improvements were limited to patients with a moderate severity of disease, limiting the generalizability of these findings to all critically sick sepsis patients. Furthermore, the benefit may not have come from arginine alone, but rather from other immunomodulating drugs¹².

Multiple investigations in septic patients found no deleterious hemodynamic alteration in response to parenteral arginine infusion, casting doubt on the dangers of giving arginine in sepsis state. In elective surgery patients, formulations of arginine or fish oil might be yet useful. Three short studies in immune-modulating nutrition of various components revealed improved outcomes in severe acute pancreatitis, but the limited amount involved were such that just one study approached significance, and a meta-analysis was negative^34,35,66,42.

In patients who will undergo surgery for head and neck cancer, L-arginine given by enteral route lowered infection cases and the duration of staying in the hospital, unfortunately infection rates do not considerably show any reduction. Supplementing with L-arginine resulted in considerable diastolic blood pressure reductions, but not significant systolic blood pressure decreases⁵⁵.

Arginine was reported to modulate the production of IL-6, TNF-α, and NO in rats with severe inflammation, according to a previous study. The arginine supplementation enterally with 2% dosage of total energy during 7 days has significant reduction in translocation of bacteria due to intestinal obstruction in the blood, mesentric lymph node, liver, spleen, and lungs^53,54. Dietary of arginine supplementation 0.4% increase sIgA in the luminal intestine and number of IgA+ plasma cells, also mRNA expression including IL-5, IL-6 and IL-13 in the ileum. Arginine supplementation might promote sIgA through cytokine. Gut microbiota might be important in sIgA by arginine supplementation in the rat intestine⁴⁶. In contrast, another study found that supplementation of arginine has a small effect in sIgA concentration in the luminal intestine in the jejunum and ileum⁵⁹. Arginine beneficially stimulate IL-10 which has anti-inflammatory effect. Hydrolize by arginase enzyme, arginine will change into ornithine and become polyamine, glutamate, and proline, and all of these have functional effect on cell proliferation and tissue repairing⁶².

Lack of arginine can disturb ornithine productions, which further affects M2 macrophage polarization⁶⁷. M2 macrophage role is releasing the IL-10 anti-inflammatory cytokine⁶⁸. IL-10 inhibit the pro-inflammatory cytokine namely NF-κB⁶⁹. Inability of IL-10 to inhibit NFκB, causes the increase of TNF-α and IL-8 pro-inflammatory cytokine production^70,39.

In subgroup analysis of subjects receiving a critical amount of nutrition, the experimental diet significantly reduced the duration of mechanical ventilation and length of hospital stay. However, the conclusion that this subgroup analysis demonstrated benefit has been questioned, because of a trend toward increased mortality⁷¹.

Table 2. Advantages and disadvantages of arginine use in sepsis patient

Advantages	Disadvantages
Arginine as a precursor to produce nitric oxide	Probability caused harmful within higher doses in critically-ill patients with shock sepsis
Showing beneficial effect in reduce bacteremia and septic patient mortality
Necessary for preventing T lymphocyte malfunction
Arginine treatment enhancing tissue perfusion, and boosting cardiac output.
Reduced whole-body protein breakdown without altering hemodynamic parameters.
Safe for enteral and parenteral route

The Glutamine and Arginine Combination:

As mentioned above, glutamine and arginine independently have role on growth, tissue recovery, regeneration cell and reduce bacteria translocation. Glutamine is a non-essential amino acid, but has been found to be abundant in the human body. These retention is immediately decreased in catabolic phase (such as sepsis, trauma and burn), making it conditionally essential⁴⁷.Arginine is another conditionally essential amino acids. It has been found worsening prognosis in sepsic patients related to the lack of arginine plasma levels and arginine requirement which could be met by endogenous synthesis^63,64.

Respectively, glutamine and arginine in sepsis studies have almost equal of advantages, disadvantages, and no effect. Different studies, such as animal and human model, are performed but the result still varies. While study about their combination is a lot more minimal. Other studies reported that combination of arginine and glutamine supplementation has positive impact to inhibit sepsis, meanwhile its usage in enteral route is still unknown⁷².

Study in healthy newborn rats, arginine reduced the beneficial effects of glutamine on oxidative stress⁷³. In contrast, either during gut derived sepsis in mice, in colonic mucosa of Crohn’s patients or in IgE-activated mast cells combined glutamine and arginine had enhanced protective effects compared with arginine or glutamine alone. These discrepancies between studies may be due to the different metabolic pathways involved in the model^74,75.

Other animal model study that administered glutamine and arginine supplementation enterally with sepsis induced by lipopolysacharide (LPS) found positive results. It evaluated the effect of enteral administration of glutamin arginine respectively and also GAC group between control, by blood and tissue analysis. Glutamine group and arginine group respectively are given 500 milligrams per kilograms body weight per day meanwhile GAC group is given 250 milligrams per kilograms body weight per day of glutamine and 250 milligrams per kilograms body weight per day of arginine containing suspension by orogastric route. The parameters of inflammation and sepsis included CRP, TNF-α, IL-1β, and IL-6 levels, while aspartate transaminase (AST) and alanine transaminase (ALT) were observed as indicators of organ damage. Other parameters are also evaluated, such as abscesses, hepatocyte damage, Kupffer cell proliferation and portal inflammation⁷².

A similar study of glutamine and arginine combination on rat models with lower dosage found similar but better results. Administered of 300 milligrams per kilograms bodyweight per day of glutamine and arginine supplementation and a combination of 150 milligrams per kilograms body weight per day for glutamine and 150 milligrams per kilograms body weight per day arginine respectively are compared. The mRNA TNF-α, IL-β, IL-6, and IL-10 levels were evaluated in the jejunum and ileum. They found that both in the jejunum and ileum, the abundance of TNF-α and IL-1β mRNA significantly decreased in GAC group. Meanwhile in the ileum, GAC significantly decreased IL-10⁵². From those two conducted studies, GAC group showed similar result in decreasing pro-inflammatory factors^72,76.

GAC group showed that TNF-α significantly low, however glutamine group presented high levels of TNF-α and IL-6, while there’s no significant difference in IL-1β, CRP and IL-6 levels^72,76. We could not compare IL-1β levels between groups because we have found 250 pg/ml in all groups which was the maximum level that could be analysed in those concentrations. In order to determine significant results, the samples should have been analysed at more diluted concentrations.

There was no significant distinction levels of AST and ALT in all groups, but these parameters were highest in control and lowest in GAC. The abscess is found in one rat in GAC group, with grade III abscess, on the other hand hepatocyte damage was not found in the GAC. Grade I Kupffer cell proliferation is found on all group. Portal inflammation is found on 2 rats in in GAC group⁷².

Another rats study that evaluated parenteral effect on administration of glutamine in the intestine function found that the concentration of amino acid are decreased due to endotoxemia, which related with enterocyte disfunction. Due to impared intestinal capacity, thus enteral administration could not be as effective as parenteral route. These results are different to another study also on rats evaluating enteral glutamine administration on sepsis model, which found decreases in translocation of bacteria and increases antioxidant levels and thickness of mucosa. This mixed result is similar to the first study, where only TNF-α levels is found to be significantly lower in GAC group but glutamine group showed highest levels of TNF-α and IL-6⁷².

Oral supplementation with glutamine, arginine or their combination enhanced villus length either in jejunum or ileum and showed synergistic effects on intestinal integrity and anti-inflammatory cytokines activity. As mentioned above, there is a conflict that if the decrease in TNF-α levels was due to the use of combination of these amino acids or due to the dose that have used for these amino acids^64,72.

Current findings show that glutamine supplementation at 500 milligrams per kilogram of body weight per day is advantageous, with the optimal dose ranging between 142-428 milligrams per kilogram of body weight per day. The maximum tolerable dose for glutamine supplementation in the absence of complications is 501 mg/kg/day. This findings show that arginine administered at a dose 14-570 milligrams per kilogram of body weight per day is well tolerated⁷². In another study investigating the effects of arginine doses on inflammation it has been shown that a dose of 5000 mg/kg/ day arginine supplementation has a significant anti-inflammatory effect on peritoneal macrophages with no adverse effects⁷².

However, potential risk associated with these combinations has not yet been determined. Further information from more comprehensive randomized studies are required to better understand the benefits and drawbacks of arginine and glutamine supplementation in critically ill septic patients.

Table 3: Advantages and disadvantages of GAC use in sepsis patient

Advantages	Disadvantages
Oral supplmentation of GAC had beneficial effects to improved villus height in jejunum and ileum and intestinal mucosa	The exact beneficial dose for GAC supplementation in sepsis treatment still varies greatly
GAC supplementation decreases pro-inflammatory factor especially TNF-α	Not all inflammatory factors can be reduced by taking GAC supplementation

CONCLUSION:

Metabolic changes during sepsis indicate that combinations arginine and glutamine could be considered as an essential amino acid in sepsis and that sepsis could be an arginine-deficient state. Combination arginine and glutamine supplementation could subsequently be advantageous in sepsis by enhancing microcirculation and protein anabolism. For immuno function, the combination of glutamine and arginine could decrease pro inflammatory factors and in contrary increase the anti-inflammatory factor. As the use of both glutamine and arginine for patients with sepsis showed favorable outcome in some conditions, it is suggested for physicians to be cautious and attentive when maintaining the doses, indication, and starting time of these supplementation. However, further research for arginine and glutamine proper doses and when to start the supplementation in human is required.

ACKNOWLEDGEMENT:

We thanked the administrative staff of the Department of Anesthesiology and Reanimation of Dr. Soetomo General Hospital - Faculty of Medicine Universitas Airlangga for support and help. We also thanked the Faculty of Medicine, Universitas Airlangga for providing a journal consultation through the journal clinics.

INTEREST OF CONFLICT:

The author(s) declares no conflict of interest.

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Received on 18.11.2022 Modified on 27.01.2023

Research J. Pharm. and Tech 2023; 16(11):5544-5553.

DOI: 10.52711/0974-360X.2023.00897

Advantages	Disadvantages
Re-accommodating conditional deficiency to decrease mortality	Inconclusive and probability caused harmful within higher doses
Showing beneficial effect in jejunum	Less showing positive effect in ileum
Recommended for oral administered source
Glutamine treatment decline the lipopolysaccharide induced mortality
Glutamine is necessary for tight junction stabilization
reduces inflammation and protects organs from sepsis-related organ damage
decreases bacterial translocation and increases mucosal thickness and antioxidant levels