INTRODUCTION:

Multiple traumas are very risky not only at the onset of the attack but also it leads to impairment in the immunological system but also leads to metabolic dysfunction. Major trauma is characterised by alteration and depression of the immune response along with increased infections, sepsis, multiple organ failure and also death. In fact, many critically ill patients die due to serious infectious complications.

The role and effectiveness of glutamine supplementation in critically ill patients has been extensively studied and debated in literature for at least the 15 years [1]. A number of systematic reviews and Meta analyses have shed light on this interesting topic. The critically ill patient population is haemodynamically and immunologically different from the surgical population. [2] Furthermore, the critically ill patient population is clinically heterogeneous, hence results from one subgroup of patients cannot be generalised to the whole population, even in nutrition support interventions. Many of the studies that have investigated the effect of intravenous or enteral glutamine supplementation includes multiple trauma patients with other critically ill patients as one population group and have utilised many different outcome measures,[3] not all of which are likely to be of clinical relevance.

The standard approach for this study is the meta-analysis approach, but the heterogeneity of this approach has decreased the usefulness of the approach and also the extensive studies done in this category has made it difficult to pool all the effects, hence we decided to do a narrative review. Therefore, the purpose of this narrative review was to focus on the trials conducted specifically to investigate the effect of glutamine or glutamine dipeptide as a single pharmaco nutrient. It is to critically appraise, and synthesize randomised clinical trial data evaluating the effect of enteral immuno nutrients in critically ill patients.

Search strategy and selection criteria:

The patient group in this review represents the critically ill patients with multiple trauma that require enteral or parenteral nutrition support. Pub Med and EMBASE from 1990 to 2011 were searched and was used to identify trials that evaluated enteral and parenteral glutamine supplementation in trauma patients. Search terms included “glutamine”, “alanylglutamine” “Trauma”, “injury” or “head injury”. Papers that were written in English were only used for the review. [4,5] Search Parameters were limited to human clinical trials. Studies which had only glutamine supplementation were only used for the trial. If the trials were conducted with glutamine supplementations along with other immune nutrients then those trials were excluded. Also any kind of safety trials were also excluded. Additional articles were identified through searching the bibliography of practice guidelines, systematic reviews and meta-analyses of glutamine supplementation in critically ill patients.

BACKGROUND:

Immune and metabolic response to trauma and injury:

Multiple trauma and severe injury evoke reproducible immune and metabolic responses that

Correlate with the extent and duration of the injury. The immune (inflammatory) response starts within minutes and is characterized by increased release of pro-inflammatory cytokines. Alternatively, if the anti-inflammatory mediators predominate, this results in compensatory anti-inflammatory response syndrome. [6] In parallel, there is a concurrent production of anti-inflammatory cytokines. This response is required to restore homeostasis as soon as possible. In uncomplicated trauma and injury, there is an equilibrium between the pro and anti-inflammatory cytokines. However, if the pro-inflammatory mediators predominate, this results in a systemic inflammatory response syndrome. An imbalance between systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome,

The severity of the trauma and stress will lead to infectious complications and also increased multiple organ failure rate. [7] In conjunction, there is an escalated production of catabolic and counter-regulatory hormones. These neuroendocrine changes trigger the metabolic response that is characterised by hyper metabolism, insulin resistance associated with hyperglycaemia, increased fat breakdown (lipolysis) and accelerated protein catabolism (proteolysis). [8,9,10] Proteolysis, which may reach up to 16%, is mainly derived from the skeletal muscle and can last for up to 21 days. The synthesis of protein in the muscle also rises but it does not equal the proteolysis. In critically ill patient s, protein catabolism is elevated despite aggressive nutritional support and increased protein intake. Although muscle catabolism is important for providing substrates for acute phase protein synthesis and gluconeogenesisin the liver, severe and prolonged depletion of lean body mass has deleterious effects such as irreversible muscle wastage, impaired wound healing and delayed recovery from illness. Protein catabolism is also associated with the release of glutamine from the skeletal muscle and this result in a marked and prolonged depletion of glutamine levels in plasma and the skeletal muscle. [11]

Glutamine metabolism during stress and critical illness:

Protein energy malnutrition” a major problem in the management of post-operative patients was long recognized by Hiram, an American surgeon way back in 1936, as he observed that weight loss was as significant predictor of surgical risk among his patients suffering from peptic ulcer disease.[14] According to “gut origin of sepsis” hypothesis the leaky gut is an essential factor in developing septic complications with the concept of bacterial translocation as demonstrated in vitro and in vivo studies. In addition, nutritional depletion is associated with increased intestinal permeability and a decrease in villous height. Post-operative nutritional supplementation has been known to improve the quality of life, nutritional status, and morbidity of patients. Hence, “malnutrition matters” and “nutrition is the cutting edge in surgery.”[12, 13] Enteral nutrition has been known to bring about reduction in infectious complications in post major abdominal surgery. Previous systematic reviews and meta-analysis have suggested that immune nutrition in critically ill have been associated with reduced hospital stay, infection rate, and inflammatory response.[15] Any catabolic stressful condition results in 50% loss of glutamine from the muscles and it is of utmost importance to deliver adequate amounts of glutamine to maintain the integrity of intestinal mucosa, to preserve the muscle glutamine pool and to improve overall nitrogen economy during conditions of stress.

Glutamine is the most abundant amino acid in the body and is synthesised in sufficient amounts under normal physiological conditions, and therefore has been considered as a non-essential amino acid for decades. It is involved in a wide range of metabolic and biochemical processes in the body.

Glutamine is known to be a precursor of protein synthesis and the mucosal and the immune cells in the body utilize this particular immunonutrient as an energy source in almost all the tissues. Furthermore, glutamine is involved in a large number of metabolic pathways. One of the major procedures which result in severe depletion of glutamine from the skeletal muscles, bringing about muscle loss immunosuppression thus resulting in increased risk for post-operative infection and sepsis is surgery. [16]

These functions are summarised in Table 1. As the preferred fuel for enterocytes, it has been suggested that glutamine may have a role in reducing bacterial translocation across the gastrointestinal tract and thus reduce the risk of infections and sepsis.[17] In fact, enteral glutamine administration has been associated with reduced intestinal permeability and bacterial translocation in some animal studies. Also, some clinical trials showed that glutamine supplementation maintained gastrointestinal structure in critically ill patients and was associated with reduced intestinal permeability. However, other trials could not reproduce this finding.

Table 1:

Glutamine functions in the human body:

· Fuel for immune cells (lymphocytes and macrophages)

· Arginine synthesis in the kidney (being a precursor for citrulline)Fuel for enterocytes

· Glutathione synthesis (antioxidant defence)

· Enhance heat shock protein expression (prevent apoptosis)

· Enhance insulin sensitivity

· Nitrogen transport

· Acid-base homeostasis

· Gluconeogenesis

Under catabolic conditions, such as critical illness, glutamine is released from the skeletal muscle in large quantities. Although glutamine synthesis is not impaired during critical illness, plasma and intramuscular glutamine levels are severely depleted in conditions such as major surgery, burn injury and multiple trauma because of increased demand. Therefore, glutamine has been proposed as an essential amino acid in these situations.

Clinical trials of glutamine supplementation in multiple trauma patients:

A number of trials have been conducted to investigate the effect of glutamine supplementation in a homogeneous group of multiple trauma patients. Table 2 and 3 summarise the trials of enteral and parenteral glutamine supplementation in traumapatients, which are subsequently discussed.

Clinical trials of enteral glutamine supplementation in multiple trauma patients:

The use of glutamine supplementation in people following enteral nutrition after surgery is a controversial topic. Research indicates that initiation of early enteral nutrition (i.e. within the first 24–48 hours following intensive care unit admission) in critically ill patients, including trauma patients, is recommended when the gastrointestinal tract is functioning as it is associated with decreased infectious morbidity, hospital length of-stay and improved overall clinical outcome. Therefore, the concept of enteral glutamine supplementation in multiple trauma patients is attractive and advocated when enteral nutrition is required. However, it has been documented that the systemic bioavailability of glutamine through the enteral route is lower than the parenteral route.

Also, glucose turnover, oxidation and recycling were not significantly different between the two groups. The same trial attempted to see the effect of glutamine supplementation on hypoaminoacidaemia, which results in increased in nonessential amino acids in the intracellular pool. However, it was reported that total essential amino acids concentration was significantly increased in both groups, while the nonessential amino acids concentration was increased significantly only in the control group. This increase was explained by the added amino acids to the control formula to make it is nitrogenous. [19] Plasma glutamine level was not influenced by supplementation.

Most enterally administered glutamine is utilised and oxidised by the splanchnic organs. Furthermore, before consideringglutamine supplementation via the enteral route, it is important to recognise that most enteraltrials failed to reach the target prescribed dose due to delayed feeding, feeding intolerance and interruption of feeding due to extubation or surgery. One of the early trials that have been conducted to investigate the effect of enteral glutamine supplementation in 30 trauma patients by Long et al found that there were no significant differences in outcomes including nitrogen balance, protein synthesis and breakdown, and muscle proteolysis between the glutamine supplemented and the control groups. These results suggested that a short period of glutamine provision (i.e. three days) has no effect on nutritional or metabolic outcomes and a longer period is required. The authors explained the negative results by altered glutamine absorption in critically ill patients and glutamine being mostly oxidised by the gut and liver.

On the other hand, Houdik et al showed that enteral glutamine supplementation significantly increased plasma glutamine concentration, whichwas associated with an increased plasma arginine concentration suggesting that enteral glutamine stimulated renal production of arginine. Mortality as a primary outcome was investigated in one of the largest trials of enteral glutamine supplementation in trauma patients. The in-hospital mortality rate was higher in the treatment group compared with the control group, but the results were not significant (P=0.09), particularly after controlling for age and severity of illness (P ≤0.11). This trial suggested that enteral glutamine might have negative effects with a trend toward increased mortality. [20]

The authors theorised that enteral administration of glutamine makes it available to the bacteria in thegastrointestinal tract. The effect of enteral glutamine supplementation on infectious morbidity was investigated in two main trials. Houdijk and colleagues reported that glutamine-enriched enteral feed resulted in a significant decrease in pneumonia (17 vs 45%; P <0.02), bacteraemia (7 vs 42%; P <0.005) and sepsis (4 vs 26%; P <0.02). Gram-negative bacteraemia occurred in 54% of the cases of bacteraemia in the control patients and was not reported in any of the glutamine supplemented patients, suggesting that glutamine might prevent bacterial translocation from the gut. In contrast, Schulman et al found that enteral glutamine had no significant effect on reducing infectious complications and the use ofantibiotics. In both trials there were no significant differences in mechanical ventilation days, intensive care unit and hospital length-of-stay between the supplemented and the control groups. In an attempt to explain the relationship between the reduction in infectious morbidity by enteral glutamine supplementation and endocrine responses.

Houdijk et al reported in a subsequent paper that enteral glutamine had no influence on metabolic and endocrine changes in trauma patients. Hyperglycaemia was sustained in both glutamine and control groups, and plasma levels of stress hormones (cortisol and glucagon) increased to high normal levels in both groups, but this was not significant. Growth hormone levels were within the normal range and did not differ between groups. In both groups there was a significant increase in α1-antitrypsin levels and the inflammatory marker C-reactive protein. [21, 22, 23] It was concluded that the reduction in infectious complications by glutamine supplementation was not related to the changes in the metabolic and hormonalresponses. In a pilot study, 20 patients with severe trauma were randomised to receive enteral glutamine or an isonitrogenous placebo during the first 24 hours of resuscitation, before even starting enteral feeding for ten days.

The supplementation was given as a bolus two to three times daily, dissociated from enteral feed as a pharmacological dose. The study demonstratedthat glutamine was well-tolerated during resuscitation with no adverse events. It was reported that the glutamine group had significantly fewer instances of high gastric output (5 vs 23, P=0.01) and abdominal distension (3 vs 12; P=0.021).

These results suggested that enteral glutamine can be safely given during active shock resuscitation and enhances gastrointestinal tolerance. However, this was a pilot study and a larger trial is required to investigate the effect of enteral glutamine administered to haemodynamically unstable patients on other clinical outcomes.

Table 2-Trials of enteral glutamine supplementation in trauma patients

Study	Design	Route	Commencement and duration
Houdijk et al 1998, 199965,69	DB RCT, n=72 (60 received feeding ≥5 d)	EN (NJ)	Within 48 h of trauma and until tolerating oral feeding (study period 15 d)
Long et al 1995, 1996	DB RCT, n=30	EN (NG)	Approximately 24 h after admission; 3 d
Boelenes et al 2002	DB RCT, n=108	EN (NJ)	Within 48 h of trauma and until tolerating oral feeding (pts fed at least 5 d enterally were included in results; study period 15 d)
Schulman et al 2005, 2006	Sequential rotating assignment, unblind, n=185 (175 trauma)	EN (NJ) and some converted to PEG	EN continued until oral diet was tolerated or TPN was required
Brantley et al 200083 (Abstract	RCT unblended (not mentioned in abstract), n=70	EN	7 d
McQuiggan et al	Pilot, unblinded RCT, n=20	EN (NG)	Start during the first 24 h of resuscitation; 10 d

Table 2 Continue…..

Intervention-gln

Intervention-control

Main outcomes

Gln-enriched EN provides 30.5 g Gln/ 100 g protein, n= 35

Isocaloric, isonitrogenous feed, n=37

Mean plasma levels of Gln, citrolline and arginine ↑↑

in Gln group

Mean serum levels of TNF-receptors ↓↓ in Gln group

↓↓ pneumonia (17 vs 45%; P <0.02), ↓↓ bacteraemia

(7 vs 42%; P <0.005),

↓↓ sepsis (3 vs 26%; P <0.02) in Gln group

No gram-negative bacteraemia in Gln group vs 54%

in control group.

ND ICU or hospital length-of-stay, mechanical

Ventilation days.

Glucose levels above normal fasting levels in both

groups

Plasma levels of stress hormones (cortisol and

glucagon) ↑ to high normal levels in both groups

(P=NS)

Growth hormone levels were in normal range

throughout study and ND between groups

α1-antitrypsin ↑↑ on day 2; P <0.05, days 3, 7 and 10;

P <0.01 vs baseline in both groups

CRP ↑↑ and reached peak levels on day 3 (P <0.05

vs baseline) in both groups

Gln-enriched EN, mean intake 0.35 g Gln/kg/d, n=16

Isonitrogenous, is caloric EN, n=14

ND NB, protein turnover, synthesis and breakdown

ND glucose turnover, oxidation and recycling

ND plasma Gln levels

EAA conc. ↑↑ in both groups

NEAA ↑↑ in control group

Gln-enriched EN;

provides 30.5 g Gln/

100 g protein, n=28

Isocaloric, isonitrogenous EN

(control), n=27

Age-matched

healthy people,

n=53

On day 1 HLA-DR expression much lower in Gln

and control groups compared to healthy volunteers

group

HLA-DR expression ↑↑ on day 5 (P <0.05), day 9 (P

<0.05) and day 14 (P <0.05) in Gln group compared

with day 1 but did not restore normal values

FcγRI/CD64 expression in monocytes in Gln and

control groups = expression in healthy volunteers

0.6 g/kg/d Gln

+ Standard EN

(Group 2), n=59

0.6 g/kg/d Gln +

Immune-modulated

EN (Group 3),

n=62

Isocaloric,

isonitrogenous

standard EN feed

(Group 1), n=64

ND mean number of infections, incidence of

infections, antibiotic use between groups

ND mechanical ventilation days, ICU and hospital

length-of-stay

In-hospital mortality was 6.3% (Group 1) vs 16.9%

(Group 2; P=0.09) and 16.1% (Group 3; P=0.09)

ND in-hospital mortality between groups (after

controlling for age and severity of illness, P ≤0.11)

0.5 g/ kg Gln +

supplemented EN

formula, n=32

Isocaloric,

isonitrogenous

formula, n= 38

Prealbumin ↑↑ in Gln group on day 7

NB balance better in Gln group (NS)

ND infections, total costs, ICU and hospital length of-

Stay

0.5 g/kg/d

glutamine(boluses

2–3 times daily

(NG) + immune enhancing

EN (NJ)

which started on

post-injury day 1,

n=10

0.5 g/kg/d

isonitrogenous

whey protein

+ immune enhancing,

n=10

Gln well tolerated during resuscitation, no adverse

events

Gln group had ↓↓ instances of high gastric output

(5 vs 23; P=0.01), abdominal distension (3 vs 12;

P=0.021) and total instances of intolerance (8 vs 42;

P=0.011)

ND in CRP on day 4 between groups

Total UUN ↑↑ in Gln group vs control (P=0.012)

Gln=glutamine, DB=double-blind, RCT=randomised clinical trial, EN=enteral nutrition, NG=nasogastric, h=hours, d=days, ND=no significant difference, NB=nitrogen balance,

EAA=essential amino acid, NEAA=non-essential amino acid, ↑↑=significant increase, NJ=nasojejunal, TNF=tumour necrosis factor, ↓↓=significant decrease, ICU=intensive care unit,

↑=increased, NS=not significant, CRP=C-reactive protein, HLA-DR=human leukocyte antigen DR, FcγRI/CD64=Fc receptor, PEG=percutaneous endoscopic gastrostomy, TPN=total

Parenteral nutrition, UUN=urinary urea nitrogen

Table 3-Trials of parenteral glutamine supplementation in trauma patients

STUDY	DESIGN	ROUTE	COMMENCEMENT AND DURATION
Bakalar et al	Pilot, unblended RCT, n=40	IV	Started 24 h after injury for 7 d
Yang et al 2007	RCT	IV	Started within 24 h for 2 w TPN started on day 3 after injury, EN gradually replaced TPN in the first week
Eroglu 2009	DB RCT, n=40	IV	7 d
Perezéz-Bárcena 2010	SB RCT, n=43	IV	5 d

Table 3 Continue…

INTERVENTION-CONTROL

MAIN OUTCOMES

Isocaloric,

isonitronegous

amino acids

control + PN

or EN, n=20

ND protein breakdown between groups

ND SOFA score

Energy expenditure ↓ in Gln group

Insulin-mediated glucose disposal ↑↑ in Gln group at day 4

(P=0.044) and day 8 (P <0.001)

Endogenous insulin secretion was ↑↑ in control group on day 8

Gln group had a better insulin sensitivity (statistically significant)

Standard

nutritional

therapy, n=23

Mortality rate in first 2 w and ICU length-of-stay ↓↓ in Gln group

ND GCS between groups

Patients with lung infection and alimentary tract haemorrhage↓↓

in Gln group

ND urinary tract infection between groups

Total serum protein and total lymphocyte count ↑↑ in Gln group

Control

(normal saline)

+ standard

EN, n=20

Total plasma glutathione levels ↑↑ in Gln group on days 7 and 10

ND CRP, prealbumin, glucose levels between groups

ND SOFA score

ND infections, ICU length-of-stay between groups

ND 1 m mortality rate between group

Isonitrogenous,

isocaloric TPN,

n=20

TLR4 levels were not different between groups before treatment

(glutamine supplemented TPN doesn’t improve the expression or

the functionality of TLRs in peripheral blood monocytes)

Gln=glutamine, RCT=randomised clinical trial, IV=intravenous, h=hours, d=days, PN=parenteral nutrition, EN=enteral nutrition, ND=no significance difference, SOFA=sequential

Organ failure assessment, ↓=decrease, ↑↑=significant increase, w=weeks, TPN=total parenteral nutrition, ICU=intensive care unit, ↓↓=significant decrease, GCS=Glasgow Coma Score,

DB=double-blind, CRP=C-reactive protein, m=month, SB=single-blind, TLR=toll-like receptor.

Limitation of glutamine trials in multiple trauma patients:

Like other nutritional interventions, there are limitations in the existing trials of glutamine supplementation in trauma patients that make recommendations inconclusive. These are as follows:

· Some trials used a mixture of immunonutrients concurrently as an intervention, which makes it impossible to make a clear judgment about the exact beneficial effect of each nutrient.

· Other trials used a historical group as a control.

· In enteral feeding it is often difficult to deliver the supplemented feed effectively due to feeding intolerance, which is present in many critically ill patients.

· The quality of many trials was low and did not meet the CONSORT (consolidated standards of reporting trials) guidelines in terms of random allocation concealment, blinding of assessors or care-givers and presenting results in an intention to- treat analysis.

· Most trials had a small number of subjects and were not sufficiently powered to investigate major clinical outcomes such as mortality.

· The doses varied between trials which makes clear comparison between trials problematic.

· The period of supplementation was very short in some trials (e.g. three to seven days).

CONCLUSION:

There are many evidences that glutamine supplementation must be used in patients with multiple trauma but at the same time well-designed multi centre trials are very important to impart any sort of greater clinical evidences. The trials have been conducted only among limited number of patients hence the conclusions are not made clearly. The use of glutamine as an enteral supplementation is very difficult as well as uncertain; hence future trials must focus more on the use of glutamine intravenously.

ACKNOWLEDGEMENT:

The authors are thankful to vels university (VISTAS) and its management for providing research facilities and encouragement.

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Received on 27.04.2017 Modified on 24.05.2017

Research J. Pharm. and Tech. 2017; 10(8): 2801-2808.

DOI: 10.5958/0974-360X.2017.00496.6