INTRODUCTION:

Traumatic Brain Injury (TBI) is an insult to the brain caused by an impact of fall or accident, internal damage caused by gunshot or surgical intervention and loss of oxygen. TBI may not be visible but can cause enduring physical, emotional, intellectual and social changes for the survivor.

It is estimated that nearly 1.5 to 2 million people are injured and one in million succumb to death every year in India. According to WHO by 2020, TBI will be considered as the third largest killer in developing world.1Patients with head trauma presents an important metabolic alteration that trigger increased protein energy expenditure as compared to patients without brain injury. It is observed in patient with head injury that the protein catabolism reaches a range of 14-25g nitrogen/day, which is much higher than a normal fasting individual (3-5 g of nitrogen/day). It’s also found that patients with neurological conditions associated with use of sedatives, steroids, barbiturates and muscle relaxing drugs postpones the use of nutrients which increases the complication of acute malnutrition, infection and longer hospitalization.2,3 In a developing country like India every other patient admitted with head injury are already malnourished and metabolic responses to injury, weight loss, negative nitrogen balance and immune dysfunctions make management of patient more critical and needs highly complex care with adequate nutritional support. Thus, early initiation of enteral nutrition therapy may minimize acute malnutrition and guarantee survival of these patients.4

Enteral nutrition lessens the catabolic responses to trauma and decreases the incidence of abdominal infection, possibly due to enhancing mucosal barrier and reducing bacterial translocation.5 It has been reported that early initiation of enteral nutrition acts as infection reducing factor,6 decreases the occurrence of sepsis and effectively reduces inflammatory responses which is an essential necessity of mechanical ventilation and hospitalization.7,8,9 Enteral nutrition consist of specific nutrients such as Glutamine, Arginine, Omega-3 fatty acids, glycine, probiotics, symbiotic and nucleotides which yields promising results but an ideal enteral nutrition has not yet been developed.

Among the above mentioned nutrients glutamine alone or associated with other components enhances the immunity and reduces infections and hospital stay. Trauma patients in common experience increased proteolysis and concomitant translocation of peripheral amino acids to visceral organs, in these circumstances, muscles mostly release the amino acid called glutamine. Although abundantly available in plasma, glutamine consumption is accelerated, especially in stress, resulting in a negative balance. During acute post-operative period the plasma glutamine concentration reduces up to 50%.10 Considering the above, normal routine feed which is being routinely provided to the TBI patients in ICU can be supplemented with glutamine enriched feed to benefit the patient by improving better nutritional status, reduction of infection complications in turn reducing hospital stay. It was recorded that intravenous glutamine in clinically relevant doses leaves cerebral glutamate unaffected.11

This opens up the possibility of evaluating the effects of glutamine supplementation upon outcome of neurosurgical ICU patients. Since glutamine enriched feed have a number of advantages over normal routine feed, and also because no such studies are so far conducted in Indian setting among head injury patients. The investigator believed that the results of this study can change the nursing practices carried out on TBI patients in clinical settings and planned a double-blinded randomized trial to evaluate the benefits of glutamine enriched feed over normal routine feed in patient with traumatic brain injury.

METHODS:

Trial Design:

In TC3 Intensive Care Unit (ICU) and TC5 ward of Jai Prakash Narayan Apex Trauma Centre (JPNATC), AIIMS, we randomized patients admitted with traumatic brain injury (TBI) in a double-blind, randomized control trial comparing the clinical consequences of glutamine enriched feed versus normal routine feed (normal standard practice) between June and November 2013. Quantitative evaluative approach was used for the study. The trail was registered at the Clinical Trial Registry-India (CTRI) and the registration number is CTRI/2014/02/004399.

Study Population:

We assessed the eligibility of all patients admitted with TBI to either TC3 ICU or TC5 ward of JPNATC, AIIMS. Patients aged between 18 and 60 years, with GCS score of 5 to 12, and with Body Mass Index (BMI) of 17 to 30 were enrolled in the study. We excluded patients with signs of systemic infections at the time of admission, multiple organ system dysfunction, immune suppressive conditions such as HIV and Tuberculosis, cancer, chronic obstructive pulmonary disease (COPD), renal failure or hepatic dysfunction, previous organ transplantation, pregnancy, indication of total parenteral nutrition (TPN), chronic alcoholics and or smokers, and with associated trauma such as contusion, extremity fracture, chest or intra-abdominal injuries. Patient fulfilling above criteria was approached and enrolled in the study after obtaining well informed written consent. Patient who were already enrolled in other research studies were excluded even if they fulfilled all other criteria for this trial.

Study Intervention:

Patients with TBI and who fulfilled inclusion criteria were randomly assigned to receive either interventional group or control group. Subjects in both interventional and control group were started on enteral feed within 24-48 hours after the time of admission as ordered by the physician and the patients in the interventional group were supplemented with 20g of glutamine per day for 10 days along with the normal routine feed for head injury patients.

Randomization:

Following eligibility screening of patients, research assistant (third party) randomly assigned eligible patients with TBI into either interventional group or control group. The groups were named as A and B as known to investigator but the investigator was blinded about the type of treatment the groups received. The addition of glutamine was only known by the dietician or the corresponding people from the dietetics department and the third party who was doing the randomization. Details regarding type of diet provided to group A or B was obtained by the research assistant from dietician and was assigned to respective group just before analysis of data. So study investigators, research assistant, and patient were blinded to treatment allocation.

Study Outcomes:

The primary outcome was compound outcome comprised of biophysiological parameters of nutritional status (hemoglobin, serum protein, serum albumin), anthropometric measurements (mid arm circumference MAC, triceps skin fold thickness and mid arm muscle circumference), infections complications (TLC and culture reports) and parameters related to prognosis (The number of days on hospitalization, on ventilator and on ICU. Patients in both groups were assessed for hemoglobin, serum protein, serum albumin, mid arm circumference, triceps skin fold thickness and mid arm muscle circumference on the day of initiation of feeding (0 day), 5^th day and 10^th day. All the study subjects were assessed for infectious complications (Total Leucocyte Count, Fever and Culture studies specific to any signs of infection as identified by the treating doctor if there is fever>100F or TLC >10000/mm³) on day 1, day 3, day 5 and day 10. The number of days on ventilator, number of days of hospitalization and ICU stay were calculated from patient records at discharge.

Sample Size and Statistical Analysis:

Thirty patients with TBA who were screened for eligibility were randomly assigned to interventional group (n₁-15) and control group. Baseline characteristics of patients in two groups were reported using frequency distributions and descriptive statistics including measures of central tendencies and dispersion. Outcome variables of interventional and control group were compared using independent ‘t’ test. Changes within the groups were compared using paired sample‘t’ test. Chi-Square/Fisher’s Exact test was used to compare the categorical variables of interventional and control groups. All the hypotheses were tested at 0.05 (two-tailed) level of significance. Statistical Package for Social Sciences (SPSS) version 19.0 was used for statistical analysis.

RESULTS:

Study population:

Nine out of 15 subjects in the interventional group were males where as 11 out of 15 participants in control group were males, however there was no significant difference (p=0.07) between the groups in terms of gender distribution. Table No. 2.0 compares the baseline characteristics of patients between interventional and control group. Independent sample ‘t’ test was used to compare the parameters which are measured in continuous scale. There was no significant difference between interventional and control group patients at baseline (0 day) in terms of age, hemoglobin (Hb), serumb albumin, serum protein, Mid Arm Muscle Circumference (MAMC), Glascow Coma Scale (GCS) and Body Mass Index (BMI).

Table No. 2: Baseline characteristics of the study subjects

Variables	(Mean±SD)		p value
Variables	Interventional Group(n₁=15)	Control Group(n₂=15)	p value
Age	40.20 ± 12.02	39.27 ± 12.03	0.833
Hb (g/dl)	11.94 ± 01.45	12.13 ± 01.46	0.718
S. Albumin (g/dl)	03.27 ± 00.53	03.4 ± 00.51	0.488
S. Protein (g/dl)	05.45 ± 00.59	05.67 ± 0.49	0.291
MAMC(cm)	22.09 ± 01.69	22.67 ± 02.13	0.417
GCS	7.73 ± 02.25	08.27 ± 02.63	0.556
BMI	22.54±1.44	22.86 ± 01.41	0.538

Note: Hb: Hemoglobin; MAMC: Mid Arm Muscle Circumference; GCS: Glasgow Coma Scale; BMI: Body Mass Index

Parameters of Nutritional status:

Haemoglobin:

Mixed model repeated measures ANOVA was used to test the hypothesis that there will be difference in Hb level between patients who received glutamine enriched feed and who received routine feed. Analysis showed that there was significant difference in Hb levels of subjects across four measurements (day 1, 3, 5 and 10) between interventional and control group (F=17.25; p<0.001). Greenhouse-Geisser adjustment was used as the Mauchly’s sphericity test showed violation of assumption of sphericity. Pair wise comparison of Hb level across four levels of data collection between interventional and control group is illustrated in Figure No. 2. There was no statistically significant difference in Hb level on day 1 (p=0.752) and day 3 (0.658) of treatment between two groups. But the Hb level of the subjects in both the groups has significantly decreased from day 1 to day 3 of treatment (p=0.017 in interventional group and p<0.001 in control group). There was a significant increase in Hb level of subjects from day 3 and day 5 of treatment in interventional group (p<0.001) while no significant changes found in Hb level of control group (p=1.0). The same trend continued between day 5 and day 10 as there was significant increase in Hb of interventional group (p=0.001) while no significant changes in control group (p=1.0). Analyses of Hb level of day 5 and day 10 showed that the mean Hb of interventional group was significantly higher than that of control group. Though subjects in both the groups showed an initial decline in Hb, positive changes in Hb level of subjects received glutamine were evident from day 5 of initiation of feed while no evidence of positive improvement in Hb level of subjects received routine feed at any stage.

Figure No.2: Hemoglobin level of patients on 0, 3^rd, 5^th and 10^th day of assessment in groups received routine feed and with glutamine supplement

Serum Protein, albumin and MAMC

Table No. 3: Comparison of Serum protein, serum albumin and MAMC between control and interventional group patients on dat 3, 5 and 10 (n=30)

Nutritional status indicator (Mean ± SD)	Group	Baseline (Mean ± SD)	3^rd day(Mean ± SD)	5^th day (Mean ± SD)	10^th day (Mean ± SD)
			p value	p value	p value
S. Protein (g/dl)	Control group (n=15)	5.67±0.49	5.2±0.56	5±0.53	4.67±0.62
			0.004*	0.001*	0.001*
	Interventional group (n=15)	5.45±0.59	5.2±0.59	5.67±0.32	6.01±0.39
			0.038*	0.110	0.011*
S. Albumin (g/dl)	Control group (n=15)	3.4±0.51	3.2±0.56	3±0.65	2.87±0.74
			0.082	0.009*	0.006*
	Interventional group (n=15)	3.27±0.53	3.4±0.55	3.5±0.54	3.9±0.52
			0.027*	0.148	0.001*
MAMC(cm)	Control group (n=15)	22.67±2.13		23±2.33	22.73±2.02
				0.055	0.774
	Interventional group (n=15)	22.09±1.69		22.13±1.82	22.13±1.82
				0.691	0.691

^*Significant level p<0.05, paired t test

Table no.3 and Figure no. 3 shows that there was a significant decline in mean serum protein level of patients in control group from day 0 to day 3, day 0 to day 5 and day 0 to day 10. In patients who received glutamine feed, the mean serum protein level of patients was significantly higher on day 3 and day 10 than that of day 0. However, there was no difference between day 0 and day 5 in terms of serum protein level. It can be interpreted that there was significant decline in protein level of patient who received routine feed where as the serum protein level patients who received glutamine feeding showed significant increase from day 0 to day 10. It is inferred that the serum protein level of patients who received glutamine feeding has significantly increased while there was decline in serum protein level of patients who received routine feeding.

Figure No.3: Serum protein level of patients on 0, 3^rd, 5^th and 10^th day of assessment in groups received routine feed and with glutamine supplement

Figure No.4: Serum albumin level of patients on 0, 3^rd, 5^th and 10^th day of assessment in groups received routine feed and with glutamine supplement

Table no.3 and Figure no. 4 shows that there was a significant difference between day 0 and day 3 in terms of serum albumin level of patients who received routine feeding. There was significant decline in mean serum albumin level of patients in control group from day 0 to day 5 and from day 0 to day 10. In patients who received glutamine feed, the mean serum albumin level of patients was significantly higher on day 3 and day 10 than that of day 0. However, there was no difference between day 0 and day 5 in terms of serum albumin level. It can be interpreted that there was significant decline in protein level of patient who received routine feed where as the serum albumin level patients who received glutamine feeding showed significant increase from day 0 to day 10. It is inferred that the serum albumin level of patients who received glutamine feeding has significantly increased while there was decline in serum protein level of patients who received routine feeding. In patients of both control and interventional group, there was no statistically significant change in the nutritional status in terms of MAMC on 5th day or 10^th day when compared with the baseline parameter.

Length of stay in hospital, ventilator and ICU

Table No.4: Comparison of selected clinical characteristics between control and interventional groups

Variables Days(Mean ±SD)	Interventional group(n₁=15)	Control group(n₂=15)	p value
Mechanical ventilation	7.07 ± 5.22	12.13 ±8.48	0.059
ICU stay	11.60 ± 5.48	18.20 ± 9.14	0.023*
Hospital stay	22.13 ± 6.21	32.73 ± 13.83	0.011*

*Significant level p<0.05, Chi-Square test

Table no.4 reveals that, the mean number of days on mechanical ventilator was 7.07 days for the interventional group and 12.13 days for the control group, the mean number of days of ICU stay was 11.60 days for the interventional group and 18.20 days for the control group, the mean number of days of hospital stay was 22.13 days for the interventional group and 2.73 days for the control group. There was statistically significant reduction in the number of days of ICU stay (p=0.023) and number of days of hospital stay (p=0.011) for interventional group at discharge/death when compared to the control group. But there was no statistically significant change (p=0.059) in the number of days on mechanical ventilation between the two study groups.

DISCUSSION:

The present study showed a statistically significant improvement in the nutritional status of the patients who received glutamine enriched feed when compared with the patients who received normal routine feed at 5^th day and 10^th day after starting the feed. The improvement of the nutritional status was in terms of hemoglobin, serum protein and serum albumin. Comparison of the findings is not possible since no studies have been conducted in head injury patients to find out nutritional status difference in terms of hemoglobin, serum protein and serum albumin, after giving glutamine enriched feed. There was no change in the nutritional status between two groups on the basis of anthropometric measurements on post treatment day 10. This is contradictory to the finding of the study done by Zeng J et al (2009)12 who found that values of arm circumference and arm mid circumference of patients in glutamine group were obviously higher than those of control group (p< 0.01) on post-treatment day 14. No change in anthropometric measurements could have been due to the short term follow up period in the present study. An immune enriched diet has many possible beneficial effects and are described in the literature.^5-7 Glutamine is used as a source of energy for cells of the intestinal epithelium and immune system. Mainly because of the immune enhancing effects, glutamine seems to be able to decrease the occurrence of bacterial translocation and inflammatory response, thus reducing the possibility of Systemic Inflammatory Response and sepsis. This can result in reduced number of days on mechanical ventilator and thus hospital stay.^9,
17 The present study also showed a trend towards reduction in the length of hospital stay in the patients getting glutamine enriched feed (22.13 days) when compared to the patients getting normal routine feed (32.73 days) which is supported by the findings of the study done on head injury patients by Zeng J et al (2009).¹² Also similar findings were seen in studies done with glutamine enriched feed on different patient groups by Garrel D et al (2003),13 Novak F et al (2002),¹⁴Goeters C et al (2002).¹⁵

In the present study there was no statistically significant difference in the number of days on mechanical ventilator between the patients getting glutamine enriched feed and the patients getting normal routine feed .This is contradictory to the finding of the study done by Falcão de Arruda IS et al (2004)²in which the number of days on mechanical ventilation for control group was 14 (3–53) compared with 7 (1–15) days in glutamine group (p=0.04). Contradiction in the result might have occurred due different setting or changes in the ICU protocols for keeping the patient on mechanical ventilator. Even though not statistically significant, there was an apparent reduction in the number of days on mechanical ventilator in the interventional group when compared to the control group.

Traumatic brain injury patients usually stay longer time in ICU because of many other causes other than head injury like presence of infectious complications, acute malnutrition and sepsis.^16,17 Weight loss, negative nitrogen balance and impaired immune system response to the injured patients increase their susceptibility to infectious diseases and longer ICU stay.¹⁴ In this study also we compared the days of ICU stay in both interventional and control group and it was found that there is a significant reduction in number of days of ICU stay for patients in the interventional group (11.60 days) when compared to the patients in the control group (18.20 days). This finding is supported by the study done by Falcão de Arruda IS et al (2004)² in head injury patients who found that the number of days of critical care unit stay was 22 (7–57) days in control group when compared with 10 (5–20) days in glutamine group (p<0.01). Similar findings was also reported in the studies done by Goeters C et al (2002)¹⁵, Oudemans-van Straaten HM et al (2001)18 in different patient groups.

Limited sample size made it impossible to do subgroup analysis and the long term effect of the intervention was not studied.

CONCLUSIONS:

The benefits of glutamine enriched feed in traumatic brain injury patients are well established with the findings of the present study. Routine administration of glutamine enriched feed can be safely done and it can result in better clinical outcome for the traumatic brain injury patients compared with those who are getting normal routine feed which lacks in glutamine.

REFERENCES:

1. Gururaj G. Epidemiology of traumatic brain injuries: Indian scenario. Neurol Res. 2002 Jan;24(1):24–

2. Falcão de Arruda IS, de Aguilar-Nascimento JE. Benefits of early enteral nutrition with glutamine and probiotics in brain injury patients. Clin Sci. 2004 Mar;106(3):287–92.

3. Darbar A. Nutritional requirements in severe head injury. Nutrition. 2001 Jan;17(1):71–2.

4. Young B, Ott L, Phillips R, McClain C. Metabolic management of the patient with head injury. Neurosurg Clin N Am. 1991 Apr;2(2):301–20.

5. Houdijk AP, Rijnsburger ER, Jansen J, Wesdorp RI, Weiss JK, McCamish MA, et al. Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet. 1998 ;352(9130):772–6.

6. O’Flaherty L, Bouchier-Hayes DJ. Immunonutrition and surgical practice. Proc Nutr Soc. 1999 Nov;58(4):831–7.

7. Kudsk KA. Early enteral nutrition in surgical patients. Nutrition. 1998 ;14(6):541–4.

8. Kudsk KA, Minard G, Croce MA, Brown RO, Lowrey TS, Pritchard FE, et al. A randomized trial of is nitrogenous enteral diets after severe trauma. An immune-enhancing diet reduces septic complications. Ann Surg. 1996 Oct;224(4):531–540; discussion 540–543.

9. Moore FA, Moore EE, Kudsk KA, Brown RO, Bower RH, Koruda MJ, et al. Clinical benefits of an immune-enhancing diet for early postinjury enteral feeding. J Trauma. 1994 Oct;37(4):607–15.

10. Greig JE, Keast D, Garcia-Webb P, Crawford P. Inter-relationships between glutamine and other biochemical and immunological changes after major vascular surgery. Br J Biomed Sci. 1996 Jun;53(2):116–21.

11. Berg A, Bellander BM, Wanecek M, Gamrin L, Elving A, Rooyackers O, et al. Intravenous glutamine supplementation to head trauma patients leaves cerebral glutamate concentration unaffected. Intensive Care Med. 2006 Nov;32(11):1741–6.

12. Zeng J, Zhao X, Huang Q, Wang E. [Effects of glutamine-enriched enteral nutrition on nutritional status and prognosis of patients with severe head injury]. Zhonghua Shao Shang Za Zhi. 2009 Oct;25(5):335–8.

13. Garrel D, Patenaude J, Nedelec B, Samson L, Dorais J, Champoux J, et al. Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine supplements: a prospective, controlled, randomized clinical trial. Crit Care Med. 2003 Oct;31(10):2444–9.

14. Novak F, Heyland DK, Avenell A, Drover JW, Su X. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med. 2002 Sep;30(9):2022–9.

15. Goeters C, Wenn A, Mertes N, Wempe C, Van Aken H, Stehle P, et al. Parenteral L-alanyl-L-glutamine improves 6-month outcome in critically ill patients. Crit Care Med. 2002 Sep;30(9):2032–7.

16. Wilmore DW, Smith RJ, O’Dwyer ST, Jacobs DO, Ziegler TR, Wang XD. The gut: a central organ after surgical stress. Surgery. 1988 Nov;104(5):917–23.

17. MacLaren R. Intolerance to intragastric enteral nutrition in critically ill patients: complications and management. Pharmacotherapy. 2000 Dec;20(12):1486–98.

18. Oudemans-van Straaten HM, Bosman RJ, Treskes M, van der Spoel HJ, Zandstra DF. Plasma glutamine depletion and patient outcome in acute ICU admissions. Intensive Care Med. 2001 Jan;27(1):84–90.

Received on 21.04.2016 Modified on 15.05.2016

Asian J. Nur. Edu. and Research.2016; 6(4): 485-490.

DOI: 10.5958/2349-2996.2016.00091.4