|Year : 2017 | Volume
| Issue : 1 | Page : 60-67
Intravenous glutamine supplementation improves gut mucosal function in burn patients: a randomized controlled trial
Yasser A Salem, Heba A Labib, Mohammad A.S Algendy
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Web Publication||3-Aug-2018|
Yasser A Salem
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, 11371
Source of Support: None, Conflict of Interest: None
Background Glutamine supplementation in burned adults was found to improve the overall immune functions and gut integrity, and shortens overall hospital stay after burn injury with better clinical outcome. Glutamine depletion jeopardizes the functional integrity of the gut and leads to immunosuppression. Enteral intolerance is a clinical sign of defective gut mucosal integrity and is considered as a major complication along the course of treatment of burned patients. It is associated with the development of sepsis and increased mortality. We aimed in this study to find out whether intravenous glutamine supplementation will improve tolerance to enteral feeding and eventually clinical outcome of burn patients.
Patients and methods Sixty critically ill burn patients were included in this study. They were randomly allocated into two groups. Group A received intravenous glutamine, and group B received placebo. Both groups were assessed as regards inflammatory and nutritional markers. Tolerance to enteral nutrition was observed and compared between the two groups, in addition to development of bacteremia.
Results Group A patients were found to be more tolerant to enteral feeding compared with group B patients, with a statistically significant drop in enteral feeding intolerance rate in group A (P=0.048). As regards nutritional markers, a drop in serum transferrin and serum prealbumin with statistical significance was noticed among group B patients compared with group A patients after day 7, whereas no difference of statistical significance was noticed in serum albumin values. Positivity of blood culture for gram-negative organisms was less frequent among patients in group A, with high statistical significance.
Conclusion Early use of intravenous glutamine in severely burned patients might provide a gut mucosal protective value reflected on its function. This was evident with improvement in enteral feeding intolerance, in addition to improvement in the barrier function of the gut mucosa that limits bacterial translocation.
Keywords: burn patients, feeding, glutamine, gram-negative bacteremia, tolerance
|How to cite this article:|
Salem YA, Labib HA, Algendy MA. Intravenous glutamine supplementation improves gut mucosal function in burn patients: a randomized controlled trial. Ain-Shams J Anaesthesiol 2017;10:60-7
|How to cite this URL:|
Salem YA, Labib HA, Algendy MA. Intravenous glutamine supplementation improves gut mucosal function in burn patients: a randomized controlled trial. Ain-Shams J Anaesthesiol [serial online] 2017 [cited 2018 Dec 17];10:60-7. Available from: http://www.asja.eg.net/text.asp?2017/10/1/60/238453
| Introduction|| |
Despite improvements in prevention, burn injury continues to represent a major threat to the health and welfare of people worldwide in all age groups. Nutrition therapy and adequate supply is considered an integral part of standard patient care, especially in burn patients. Over the past two decades, specific nutrients have been added to nutritional formulas in an attempt to modulate the inflammatory or immune response and affect the clinical outcomes. ‘Immunonutrition’ or ‘immune-enhancing diets’ are some of the terms that have been used to describe these products .
Glutamine is normally the most abundant amino acid in the body, constituting about 25% of the plasma amino acids and 60% of the muscle-free amino acids . Glutamine is considered as one of the immunonutrients. It is involved in a wide variety of metabolic and synthetic biochemical processes and supports rapidly proliferating cells, such as lymphocytes and enterocytes .
In conditions of excessive organ/tissue demand of glutamine during episodes of postburn catabolic stress situations, skeletal muscles export large amounts of glutamine into the blood, and glutamine-using tissues markedly increase glutamine uptake. This effect was proven by demonstration of maintenance of glutamine production in sepsis and multiorgan failure patients ,. If stress persists, glutamine use exceeds endogenous production. This will lead to exhaustion of skeletal muscles and plasma glutamine stores. Provision of conventional glutamine-free nutrition or standard tube feedings (which typically contain low amounts of glutamine) may not adequately support the glutamine requirements during a serious illness. Glutamine depletion is demonstrated to be an independent predictor of mortality in a group of ICU patients with a cutoff plasma glutamine concentration of 420 μmol/l .
Low plasma and tissue levels of glutamine in the critically ill suggest that demand may exceed endogenous supply . That is why glutamine became a ‘conditionally essential’ amino acid in burn patients. A relative deficiency of glutamine could compromise recovery, resulting in prolonged illness and an increase in late mortality, morbidity, and consequently hospital costs .
Severe systemic tissue injury (as in burn injury) will lead to mucosal atrophy and can alter the intestinal tract mucosal immunity. As a result, microbial colonization occurs with associated entry of luminal toxins and gram-negative bacteria directly into the portal circulation, a condition defined as bacterial translocation .
Glutamine also reduces the inflammatory response in human intestine, stimulates intestinal protein synthesis, normalizes microbial colonization patterns within the gastrointestinal tract, increases lymphocyte counts within the lamina propria and Peyer’s patches, decreases the production of proinflammatory factors, and, as it is utilized primarily by the enterocytes and gut-associated lymphoid tissue, it increases the production of IgA . Glutamine is utilized in rapidly dividing cells in the splanchnic area. Quantitatively, most glutamine is oxidized, but the availability of glutamine in surplus is important for the de-novo synthesis of nucleotides and necessary for cell division and protein synthesis . Glutamine may support antioxidant defenses through glutathione, which itself may be a limiting factor in ICU patients with multiorgan failure. The possible predictive value of glutathione status has not been investigated in ICU patients . The whole previous pathway consequently may improve and maintain gut barrier mechanisms. It may also protect the structural and functional integrity of intestinal mucosa and augment cellular immune functions, especially during stressful conditions. More knowledge about the regulation of the endogenous production of glutamine is needed to outline better guidelines for glutamine supplementation in the future.
Combining both enteral and parenteral route for glutamine supply is advocated. The ESPEN guidelines for enteral nutrition recommend addition of glutamine to standard enteral formula in burn and trauma patients (grade A recommendation) . Meanwhile, in parenteral nutrition for ICU patients, a balanced amino acid mixture is recommended (grade B recommendation) with addition of 0.2–0.4 g/kg/day of l-glutamine (grade A recommendation) .
The availability of glutamine in cell cultures was found to be necessary for the expression of heat shock proteins (HSPs). Furthermore, glutamine supplementation enhances the expression of HSPs in in-vitro and in-vivo studies . It has been suggested that glutamine deficiency renders the cells incapable of an adequate HSP response . Moreover, glutamine supplementation increases serum and tissue HSP-70 expression in experimental models of sepsis. Glutamine-supplemented patients demonstrated significantly higher (3.7-fold) serum HSP-70 concentrations compared with non-glutamine-supplemented patients . Glutamine appears to regulate protein turnover, increase half-life of long-lived proteins, and enhances HSP-70 and HSP-25 expressions. A high level of HSP ameliorates systemic inflammatory response. Thereby, it protects against acute lung injury and reduces end-organ injury and overall mortality.
| Patients and methods|| |
This study was designed to evaluate the effect of intravenous glutamine supplementation on tolerance to enteral nutrition as an outcome of gastrointestinal mucosal function in burn patients. The clinical outcome, metabolic status, and development of bacteremia (especially gram-negative bacteremia) were considered as an indirect indicator of enteral feeding intolerance. Intolerance will cause decreased caloric and protein intake and eventually accelerate the catabolic effect of burn injury.
This study was conducted at the Intensive Care Burn Unit of Aldemerdash Hospital during the period from July 2014 to January 2015.
After approval by ethical committee and informed consent from all participants or their legal custodians if the condition of the patient can not permit to provide consent, 60 critically ill burn patients (recently burned, with a delay not more than 24 h) were included in this study. Patients between 20 and 60 years and total burn surface area percentage (TBSA %) ranging between 25 and 50% were selected. The following categories were excluded to avoid bias:
- Pregnant females.
- Delay of fluid resuscitation for more than 24 h.
- Patients with polytrauma.
- Unable to tolerate enteral nutrition within 72 h after injury (e.g. patient refusal or postburn gastric ileus).
- History of significant hepatic impairment (patients with Child B, C) and/or severe renal impairment (AKIN III or more).
- Diabetes mellitus, chronic immunosuppression, and cancer patients (i.e. medical problems predisposing to infection and poor wound healing).
- Not expected to be admitted in the ICU more than 48 h.
- Previous cardiopulmonary resuscitation.
- Drug sensitivity to any components of intravenous glutamine.
- Patients with inborn errors of amino acid metabolism (e.g. phenylketonurea).
- Patients in whom parenteral nutrition was prescribed before admission or have absolute contraindication to enteral nutrition (e.g. diffuse peritonitis, intestinal obstruction, gastrointestinal ischemia, or risk for aspiration).
Patients were randomly allocated into two groups. Group A (n=30) included patients who received the maximum dose of intravenous alanyl-glutamine (0.5 g/kg body weight/day; 2.5 ml/kg body weight; i.e. 0.35 g l-glutamine/kg body weight/day by means of continuous infusion) through a dedicated lumen by means of central venous access until discharge from the ICU, death, or for a maximum duration of 3 weeks. The intravenous infusion was initiated after completion of the first 24 h of fluid resuscitation and establishment of enteral nutrition. Patients who failed to fulfill either condition or both were excluded. In group B (n=30), alanyl-glutamine was replaced with Ringer’s acetate solution with the same volume, rate, and method of administration. Randomization was performed through computer-generated random numbers.
Estimation of TBSA % was carried out according to Lund and Browder chart. Weight, height, and BMI were identified on admission. Patients with BMI below 18.5 kg/m2 were considered malnourished .
All patients in both groups were initially resuscitated using the Parkland formula. Enteral nutrition was started 8–12 h after burn injury, starting with clear water for 8 h in ascending volumes and, if tolerated, starting semisolids for another 4 h and then establishing full enteral nutrition according to ESPEN clinical guidelines through oral dietary intake. Patients whose oral intake did not meet the estimated caloric requirements were given additional tube feedings. Estimation of daily protein requirement was calculated as 1.5 g/kg/day. Estimation of daily caloric requirement was based on Curreri formula for adult patients (25 kcal/kg actual BW+40 kcal/%TBSA) .
Supplemental intravenous glutamine or control solutions were not taken into account in calculating caloric or protein intake goals. All patients were cared for by the staff of surgeons and intensivists at the burn ICU and thereby benefited from standardized care procedures, including early surgical excision and grafting if needed, and medical treatment. The wounds were treated with occlusive dressings. Excisions were performed as deemed necessary in the early postburn period. Recalculation of nutritional requirements occurred on a routine basis (every week) as wound size and thus metabolism changes with skin grafting and re-epithelialization.
Intolerance to enteral nutrition was assessed with the occurrence of abdominal distension detected with abdominal radiography, increase in abdominal girth by more than 2 cm, diarrhea more than five motions of loose stool, or vomiting more than twice daily for 2 successive days.
Serum transferrin, serum prealbumin, and serum albumin were measured as nutritional catabolic parameters in addition to nitrogen balance (NB) calculated as follows: NB=[total protein intake (g/day)/6.25]−(UUN+4 g) .
Serum C-reactive protein was measured every other day as inflammatory parameter together with complete blood picture. Blood culture and wound culture were collected on the third day and whenever indicated according to burn ICU protocol. Blood samples were collected on days 1, 7, and 14 for analysis of transferrin, prealbumin, and albumin as nutritional markers.
NB, blood culture, wound culture, and urine cultures were collected on days 1, 7, and 14. In addition, ICU stay and hospital stay were recorded. Tolerance to enteral nutrition was considered as primary endpoint, and serum transferrin was considered as secondary endpoint.
Data were collected, coded, tabulated, and then analyzed using SPSS v12.0 computer software (SPSS Inc., Chicago, IL, USA) for windows statistical package. Numerical variables were presented as mean and SD, whereas categorical variables were presented as number of cases and percent. Between-group comparisons of numerical variables were made using the unpaired Student t-test or Mann–Whitney’s test, whereas those of categorical variables were made using Fisher’ exact test or the χ2-square test, as appropriate. Within-group comparisons of numerical variables were made using the paired t-test. Any difference with P-value less than 0.05 was considered statistically significant. According to a pilot study in our unit, it was calculated that a sample size of 56 achieves 80% power to detect a 50% in patients who will tolerate enteral nutrition using a two-sided binomial test with a significance level of less than 0.05. Sixty patients were included to compensate for any unmeasured parameters. As regards serum transferrin as a secondary endpoint, Epi Info 7 was used to calculate sample size with estimated power more than 0.8 after considering serum transferrin level.
| Results|| |
Both groups A and B were found to be comparable as regards age, sex, percentage of TBSA, and history of malnutrition ([Table 1]).
Comparison between group A and group B as regards nutritional markers (serum transferrin, serum prealbumin, and serum albumin levels) showed a statistically significant difference between group A and group B in serum transferrin level after 7 and 14 days. Similarly, there was a statistically significant difference in serum prealbumin level after 7 and 14 days. Nevertheless, there was no difference of statistical significance in serum albumin level ([Table 2], [Figure 1] and [Figure 2]).
|Table 2 Comparison between group A and group B as regards nutritional markers|
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Comparison between group A and group B as regards C-reactive protein showed a statistically significant difference between the two groups after 7 and 14 days ([Table 3] and [Figure 3]).
|Figure 3 C-reactive protein level in both groups compared with each other.|
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Group A and group B were compared as regards blood culture results. There was a statistically significant difference between the two groups on day 14 (P<0.05) as regards negativity of blood culture, with group A being more negative compared with group B. However, comparison of results of positive blood cultures between the two groups revealed a statistically significant drop in gram-negative bacteremia in group A, whereas there was no statistically significant difference between group A and group B as regards gram-positive bacteremia ([Table 4] and [Figure 4]).
Comparison between group A and group B as regards tolerance to enteral feeding showed that there was a statistically significant difference, with group A patients being more tolerant to enteral feeding compared with patients in group B ([Table 5] and [Figure 5]).
Finally, comparison between group A and group B showed that group A patients had shorter ICU stay compared with group B with statistical significance, whereas there was no difference in hospital stay of statistical significance between the two groups ([Table 6]).
| Discussion|| |
Glutamine is quantitatively the most important fuel for intestinal tissue and has a well-established role in contribution to the integrity of the intestinal mucosa .
Most of the de-novo glutamine synthesis takes place in skeletal muscle and then exported to the splanchnic area where it will be utilized by enterocytes and immune cells ,. There is no alteration of glutamine production in severely burned patients, whereas the production is relatively insufficient to keep up the plasma concentration . Moreover, intravenous glutamine supplementation results in a uniform uptake of glutamine across the splanchnic area, similar to what happens with the endogenously produced glutamine. There is a feeling among investigators and opinion leaders that enteral nutrition is superior to parenteral nutrition in the management of critically ill patients, including major burns. This is probably true for infectious complications, but no studies or meta-analyses demonstrate a mortality difference ,,,. Paradoxically, the meta-analysis that demonstrates a difference does so in favor of parenteral nutrition . In the existing scoring systems for outcomes, there is no marker for gastrointestinal function. This is largely related to the absence of a suitable surrogate parameter for scoring . However, there is solid information that successful enteral feeding is a predictor for a favorable outcome in patients with a similar mortality risk, as estimated from the conventional scoring systems as it is considered as a secondary indicator of gastrointestinal tract function ,.
Based on the previous data, we considered the improvement in serum nutritional markers with relatively short half-life (transferrin and prealbumin), among patients who received intravenous glutamine ([Table 2], [Figure 1] and [Figure 2]) as a sign of healthy gut mucosal absorptive function that led to less catabolic effect proved by higher serum levels of these markers, especially as no parenteral nutrition was administered. The nonsignificant results as regards serum albumin (relatively longer half-life) on day 14 indicate more prolonged follow-up to gain a significant difference.
Enteral nutrition tolerance is often limited in case of small bowl bacterial overgrowth (SBBOG). This is mostly secondary to symptoms associated with intestinal malabsorption, which renders the patient dependent on parenteral nutrition. The administration of parenteral nutrition requires a central venous catheter and hence increases the risk for catheter-related blood stream infection (CRBSI) . It has been hypothesized that SBBOG can be a potential source of bacteria contributing to CRBSI ,. Bacterial translocation has been noted in animal models, but data supporting its occurrence in humans is limited . CRBSI is mostly gram-positive in nature, whereas SBBOG is mostly gram-negative in nature. Subsequently, in our study, we considered that gram-negative bacteremia was mostly due to bacterial translocation, whereas gram-positive bacteremia was mostly due to catheter-related infections. Statistically significant limitation of gram-negative bacteremia among patients in group A was interpreted as an indicative of more protective intestinal mucosal barrier ([Table 4] and [Figure 4]). Collectively, intravenous glutamine may improve both absorptive and protective functions of gastrointestinal mucosal function.
There is an extensive literature about the essential role of glutamine in a number of experimental systems including whole animals. Cell division demands an increase in nucleotide synthesis, and glutamine is a main precursor for this type of synthesis. Cell culture media usually contain a much higher free glutamine concentration than does human plasma, and lowering of glutamine concentration in cell culture media is associated with a lower rate of cell division . Many cultured cells prefer glutamine over glucose as their main energy source, and imposing stressful events to the cell culture is reported to enhance the preference for glutamine over glucose as an energy substrate. In tissues and whole animals, it is the rapidly replicating cells that seem to be particularly dependent on glutamine availability . Enterocytes in the gastrointestinal tract and immune-competent cells are reported to be particularly sensitive to glutamine depletion. Histological changes and bacterial translocation in the gut occur when there is glutamine shortage, and provision of glutamine can reverse this effect . Clinical overall effect of all previous data has not be evaluated, something that we tried to evaluate by comparing enteral feeding tolerance between the two groups. Lack of numerical or objective parameters that reflect enteral feeding tolerance made it a difficult task to perform. Therefore, we adopted multiple symptoms and signs with specific definitions trying to be more objective in the identification of enteral feeding intolerance. Tolerance to enteral feeding was markedly improved with the use of intravenous glutamine supplement, as shown in [Table 5] and [Figure 5]. Combining these data as regards improvement in absorptive and barrier function of the gut plus more tolerance to enteral feeding can provide acceptable clinical evidence that intravenous glutamine improves gut mucosal function in severely burned adults.
| Conclusion|| |
The use of intravenous glutamine in severely burned patients improves gut mucosal function. It improves both absorptive and barrier functions. A more objective way is needed to verify suggested improvements in enteral feeding tolerance with specific surrogate endpoint. Follow-up of patients for a longer period of time in addition to a larger sample size will provide more clear evidence about the therapeutic effect of glutamine in the management of burn patients.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]