C.Hayes_TBI Annotated Bib_Final Draft

Chelsea Hayes12/5/2014

Traumatic Brain Injury: Metabolic Perspective

The metabolic response to acute traumatic brain injury (TBI) involves a myriad of undesirable

corporeal and cerebral alterations. Some of those alterations include a modified immune function,

severely disrupted, unchecked metabolism, and a hypercatabolic state. A number of critical pathways,

hormones and inflammatory mediators contribute to this deranged metabolic picture, leading to shifts

in fuel sources and nutrition demands. Based on the supporting studies in the following ten annotated

bibliographies (nine controlled experimental and one review study), this overview identifies four main

pathways affected by acute TBI, which include: glycolysis, gluconeogenesis, glycogenolysis and

proteolysis. These pathways and their regulatory influences can be further understood by their roles in

and effects on specific tissues.

In the brain, the primary injury induces the release of cytokines, most commonly TNF-alpha, IL-

1, and IL-6, as part of the immediate inflammatory response. This severe local inflammation and direct

disruption of the mitochondrial membrane result in a demand for energy to repair the damaged area.

Hyperglycolysis ensues, followed by suppressed cerebral glucose uptake and increased net lactate

uptake, along with a massive outpour of counter-regulatory hormones like cortisol, glucagon and the

catecholamines (1, 2). The degradation of brain glycogen attempts to attend to the emergency energy

need for local tissue repair, while peripheral carbohydrate stores are mobilized via lactate to hepatic and

renal gluconeogenesis to support brain glucose (1). Endogenous fueling of the brain post TBI shifts to the

mobilization of total body glycogen reserves and the production of lactate, which is thought to act as a

brain fuel through the astrocyte-neuron lactate shuttle (3).

In the heart, hypermetabolism is attributed to the increase in levels of catabolic hormones and

cytokines known to elevate cardiac output and induce tachycardia and mild hypertension. The

downstream effects of this include increased oxygen consumption and caloric requirements (4).

In the liver and kidney, catecholamines and glucagon stimulate the breakdown of glycogen into

glucose (5). They also stimulate glucagon secretion and inhibit insulin secretion after injury, which has

been linked to a hyperglycemic response (5). When the supply of oxygen is limited, pyruvate is reduced

to lactate. The increased lactate levels and subsequent acidosis is thought to contribute to secondary

neuronal damage (5). However, studies have found that nutritive needs are supported by large,

coordinated increases in lactate shuttling throughout the body, largely regulated by gluconeogenesis.

Gluconeogenesis in the liver and kidneys is the main lactate clearance pathway; thus blood glucose

elevations following TBI are mostly due to lactate mobilization from body glycogen reserves (1).

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Within 24 hours following injury, hepatic glycogen stores are rapidly depleted through

glycogenolysis. This rapid glycogen depletion in the liver prompts gluconeogenesis in the kidneys and

liver to become the primary energy provider for the brain, blood cells, and bone barrow (6). The liver

also utilizes glycolysis as a source of intermediates mainly from amino acid breakdown in skeletal muscle

and fatty acid breakdown in adipose tissue (proteolysis and lipolysis, respectively). Ultimately, whole-

body catabolism ensues, characterized by a marked increase in protein turnover (2). The amino acid

depletion by way of proteolysis leads to a negative nitrogen balance and enhanced whole body protein

breakdown continually stimulated by inflammation and the sympathetic nervous system (2). It is

important to note that because TBI results in a stressed-starvation state as opposed to a nonstressed-

starvation state, glucose requirements are much higher and the breakdown of skeletal muscle proteins

are the primary carbon-skeleton source for gluconeogenesis to make glucose. In fact, the adaptation to

the use of ketone bodies may not occur (6).

This profound hypercatabolic response with an excessive metabolic state often leads to severe

malnutrition, especially protein calories, and it is often suggested that TBI patients receive around two

times (2.0g/kg/d) the normal recommended amount of protein intake. Moreover, specialized enteral

diets with both higher protein content and immune-enhancing supplements may be beneficial to

maintain anabolism and reduce complications (7).

Accordingly, the Nutrition Risk Screening 2002 tool should be utilized to identify patients at risk

for malnourishment and appropriate nutrition protocols should be implemented. Appropriate protocols

for early nutrition and reduced likelihood of nutrition-related complications include guidelines for

determining energy expenditure, changes in REE and protein needs, preferred routes and timing of

enteral feeding, and measures for monitoring tolerance and nutrition adequacy (7).

More information on the metabolic effects of TBI described above can be found in the following

annotated bibliographies, which include: two randomized controlled laboratory studies that explore

glucose metabolism in head-injured rats, two clinical studies that investigate the role of lactate

metabolism in TBI patients, one randomized controlled laboratory study that assesses the altered

nutritional state in brain-injured rats, two randomized controlled laboratory studies on TBI rats that

consider treatments to improve dysimmunity, and two randomized controlled laboratory studies and

one review study that evaluate nutritional support in TBI.

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References:

1. Glenn TC, Martin NA, McArthur DL, et al. Endogenous nutritive support following traumatic brain injury: peripheral lactate production for glucose supply via gluconeogenesis. J. Neurotrauma 2014.

2. Moinard C, Neveux N, Royo N, et al. Characterization of the alteration of nutritional state in brain injury induced by fluid percussion in rats. Intensive Care Med. 2005;31(2):281-288.

3. Jalloh I, Carpenter KLH, Grice P, et al. Glycolysis and the pentose phosphate pathway after human traumatic brain injury: microdialysis studies using 1,2-C glucose. J. Cereb. Blood Flow Metab. 2014.

4. Yanko JR, Nurse AP, Hospital AG, Mitcho K, Manager TP, Hospital AG. Acute Care Management of Severe Traumatic Brain Injuries. 2001;23(4):1-23.

5. Ly L, Dq C. A correlation study of the expression of resistin and glycometabolism in muscle tissue after traumatic brain injury in rats. 2014;17(3):125-129.

6. Pepe JL, Barba CA. The metabolic response to acute traumatic brain injury and implications for nutritional support. J. Head Trauma Rehabil. 1999;14(5):462-474.

7. Vizzini A, Aranda-Michel J. Nutritional support in head injury. Nutrition 2011;27(2):129-32.

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Glenn TC, Martin NA, McArthur DL, et al. Endogenous nutritive support following traumatic brain injury: peripheral lactate production for glucose supply via gluconeogenesis. J. Neurotrauma 2014. doi:10.1089/neu.2014.3482.

12 non-penetrating moderate to severe head-injured males aged 16 or older and 6 healthy, non-

smoking, weight-stable, 28±8.22 year old females were enrolled in this controlled clinical trial to study

the metabolic fates of glucose and lactate in patients suffering from TBI, using two stable, non-

radioactive isotope tracers. The relationships among lactatemia, glycemia and cerebral substrate supply

and metabolism in TBI-suffering individuals were also explored in this study. Head-injured patients with

a terminal illness, severe neurologic illness, or an acute complete spinal cord injury were excluded along

with control subjects that were taking medications, had abnormal lung function or were diseased and/or

injured.

Cerebral blood was monitored daily to assess brain metabolism, while stable non-radioactive D2-glucose

and 3-13C lactate isotope tracers were infused 2-10 days after ICU admission for 90 minutes. Arterial

and jugular blood samples were collected prior to isotope infusions and every hour for 3 hours following

infusion to measure the patients’ background isotope glucose and lactate enrichments. Blood lactate

concentrations and enrichments and blood glucose concentrations and enrichments were determined

for final evaluation in whole body metabolism calculations. Metabolic data was only taken from 0-5 days

post-injury and not all studies were completed due to the patients’ clinical status.

2 groups were compared:

6 healthy controls receiving infused glucose and lactate isotope tracers

12 moderate to severe head injured males receiving infused glucose and lactate isotope tracers

Both populations showed significant cerebral net glucose uptake from low jugular bulb glucose

concentrations compared to arterial values; however, the increase in body glucose rates of appearance

and disappearance post TBI were not significantly different. 71% higher lactate appearance and disposal

rates in TBI patients were observed. The glucose rates of appearance and disappearance post TBI from

GNG significantly increased to 67.1% due to greater hepatic and renal conversion of lactate to glucose

compared to controls. Therefore, the role of lactate as a gluconeogenic precursor is markedly elevated

following TBI. Accordingly, these findings suggest that lactate is a major contributor to hepatic and renal

glucose production post TBI, and since lactate flux rates were 40% greater than glucose flux rates,

lactate is a more important carbohydrate-derived carbon source than glucose overall.

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Charrueau C, Belabed L, Besson V, Chaumeil J, Cynober L, Moinard C. Metabolic response and nutritional support in head injury: evidence for resistance to renutrition. J Neurotrauma. 2009; 26: 1-10. doi: 10.1089/neu.2008.0737.

To identify the need for specific nutritional support in head injury (HI) patients by testing if conventional

nutritional support in HI patients restores nutritional status, the standard enteral nutrition of 7 healthy

and 14 gastrostomy HI (fluid percussion-induced) male Sprague-Dawley rats were evaluated in this

randomized controlled laboratory trial.

The rats were separated into three groups—an adlibitum fed group, a standard chow diet HI group

(receiving NaCl 0.9% at a constant rate by the enteral route), and a standard enteral HI group (receiving

enteral nutrition of 290kcal/kg/day and 3.29g N/Kg/day at a constant rate). All rats were housed in

metabolic cages and assessed over a 4 day period for anorexia, body weight loss and muscular atrophy

via the following measurements: body and organ weight, food and energy intake, 3-methylhistidine

(MH)/creatine ratio, amino acid concentration, tissue protein, and albumin and fibrogen concentrations.


7 Adlibitum fed standard chow diet healthy rats (AL control group)

8 Gastrostomy HI with free access to standard chow diet rats (HI experimental group)

6 Gastrostomy HI rats receiving the standard polymeric enteral diet (HI-EN experimental group)

Significant decreases in body and organ weights were not mediated by enteral nutrition. In conclusion,

due to nutritionally unimproved significant increases in muscular atrophy and significant decreases in

nitrogen balance in the HI-EN group compared to the HI and AL groups, standard enteral nutrition is

ineffective in restoring HI-associated nutritional alterations and reductions in intestinal mass.

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Body weight variation between day 0 and day 4 inthe following groups: rats fed ad libitum (AL), head-injuredrats (HI), and HI rats fed the standard enteral nutrition (HIEN).The results are expressed in g. Values are expressed mean standard error of the mean (SEM). Analysis of variance

0.05 versus AL

FIG. 2. Cumulated nitrogen balance from day 0 to day 4 in the following groups: rats fed ad libitum (AL), head-injured rats (HI), and HI rats fed the standard enteral nutrition (HIEN). The results are expressed in g. Values are expressed as mean_standard error of the mean (SEM). Analysis of variance (ANOVA)þDuncan test: *p<0.05 versus AL; **p<0.05 versus AL and HI.


Moinard C, Neveux N, Royo N, et al. Characterization of the alteration of nutritional state in brain injury induced by fluid percussion in rats. Intensive Care Med. 2005;31(2):281-288. doi:10.1007/s00134-004-2489-9.

24 male Wistar rats were used in this randomized controlled laboratory study to characterize their

hypercatabolism level and to evaluate their nutritional status after moderate severity fluid percussion

TBI.

Rats were allowed to acclimatize and then were randomized into three groups of eight and examined for

10 days in environmentally-controlled metabolic cages following TBI.

Their body weight, food intake, and urine volume were assessed daily. Their glutamine and arginine

concentrations in plasma and tissues were also measured.


TBI group (n = 8)

Healthy pair-fed (PF) group (n = 8)

Healthy, ad libitum fed (AL) control group (n = 8)

TBI induced severe anorexia, revealing a 78% decline in food intake. Additionally, TBI induced a decrease

in whole body weight starting on day one. The TBI induced-anorexia reduced the hepatic protein

content by -47% and increased muscular proteolysis to 50% in the first two days of TBI. In conclusion,

the above findings support that TBI impairs nutritional status through its association with prolonged

anorexia and its enhancement of proteolysis, distal intestinal atrophy, and altered renal function.

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Ly L, Dq C. A correlation study of the expression of resistin and glycometabolism in muscle tissue after traumatic brain injury in rats. 2014;17(3):125-129. doi:10.3760/cma.j.issn.1008-1275.2014.03.001.

Few studies explore the relationship between resistin (RSTN) and hyperglycemia after TBI. Thus, this

study sought to evaluate the muscular RSTN expression in TBI rates and its relationship with

glycometabolism to characterize the role it plays in hyperglycemic post-TBI rats. 78 clean SD male rats

(300-350g) were the chosen subjects in this randomized controlled correlation study.

All rats were randomly divided into a sham operation group (bone window procedure), a traumatic

group (fluid percussion), and a RSTN antibody injection group (fluid percussion and RSTN antibody

injection). Six rats were respectively sacrificed every 12, 24 and 72 hours and 1, 2 and 4 weeks after

venous blood collection. Thereafter, the right hind leg skeletal muscle tissue in all rats was sampled and

stored.

RSTN gene (Retn) expression via real-time PCR, RSTN expression via western blot, total blood glucose

and serum insulin via ELISA, and calculation of insulin sensitivity check index were assessed.

Comparisons were made among three groups:

Sham operation group (n=6)

Traumatic group (n=36)

RSTN antibody injection group (n=36)

RSTN gene expression, RSTN protein expression, and blood glucose and serum insulin levels were

significantly increased (P<0.05) in the traumatic group and RSTN group when compared to the sham

operation group at each time point. While the blood glucose and serum insulin levels were increased in

the two TBI groups, the Q value was much lower in the RSTN group at each interval. Comparison of

muscle tissue Retn expression and insulin sensitivity (Q value) in the traumatic group revealed a strong

negative correlation (-0.978). In conclusion, serum RSTN is higher in skeletal muscle tissue of rats post

TBI, but insulin sensitivity is lower, suggesting stronger insulin resistance. After RSTN antibody injection,

insulin resistance was improved and blood glucose level was significantly decreased in the RSTN group

further suggesting that RSTN is involved in insulin resistance. Further investigation is required before a

direct causality between RSTN and hyperglycemia can be made.

Figure 1. Relationship between Q value and Retn expression.

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SI D, LI J, LIU J, et al. Progesterone protects blood-brain barrier function and improves neurological outcome following traumatic brain injury in rats. Experimental and Therapeutic Medicine 2014;8(3):1010-1014. doi:10.3892/etm.2014.1840.

90 adult male Sprague-Dawley rats were studied to explore the effect of progesterone on the expression

of prostaglandin E2, cyclooxygenase-2 (COX-2), nuclear factor KB and tumor necrosis factor-α in the

brain, BBB permeability, cerebral edema, and neurological outcome after TBI.

Rats were randomly assigned to one of three groups:

A sham-operated group (SHAM; n = 30)

A TBI group (TBI; n = 30)

A progesterone treatment group (TBI-PROG; n = 30)

TBI was induced via the weight drop method in the TBI groups, while the sham group underwent skull

fenestration absent of brain injury. The TBI-PROG group received 16mg/ kg progesterone injections (IP)

at 6 and 12 hours post-injury. All rats were sacrificed 24 hours after TBI and COX-2 and NF-kB

expression, PGE2 and TNF-α, BBB permeability, brain water content and neurological outcome were

measured via respective immunohistochemistry, ELISA, detection of EB dye extravasation and

determination of brain water content and modified neurological severity score (mNSS).

Immunohistochemical analysis revealed significant decreases in COX-2 and NF-kB expression levels in

the cortex of the TBI-PROG group compared to the TBI group. Progesterone treatment also showed

decreases in the PGE2 and TNF- α (4.5 and 1.2ng/g), BBB permeability (8.3μg/g), and brain water

content (78.4%) when compared to the SHAM (respectively 2.3ng/g, 0.6ng/g, 3.2μg/g and 74.3%) and

TBI (7.1ng/g, 1.7ng/g, 14.6μg/g, 82.6%) groups. Progesterone also increased (lower score =

improvement) neurological outcome (TBI-PROG 10.5 versus TBI group 14.8 mNSSs) following TBI.

Accordingly, progesterone treatment inhibits the inflammatory response, reduces the BBB dysregulation

and brain edema, and improves neurological function post-TBI.

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Figure 1. Immunohistochemical analysis of COX-2 and NF-κB in the cortex of rats in the SHAM, TBI and TBI-PROG groups. Immunohistochemistry of (A-C) COX-2 and (D-F) NF-κB expression. (A,D) The SHAM group showed few positive cells, (B,E) The TBI group showed strongly stained positive cells, and (C,F) the TBI-PROG group showed fewer positive cells compared with the TBI group (scale bar, 50 μm; magnification, x400). (G) Administration of progesterone significantly inhibited the TBI-induced upregulation of COX-2 and NF-κB expression in the cortex (n=6/group); *P<0.05, compared with the SHAM group; #P<0.05, compared with the TBI group. COX-2, cyclooxygenase 2; NF-κB, nuclear factor κB; TBI, traumatic brain injury, PROG, progesterone.


Jalloh I, Carpenter KLH, Grice P, et al. Glycolysis and the pentose phosphate pathway after human traumatic brain injury: microdialysis studies using 1,2-C glucose. J. Cereb. Blood Flow Metab. 2014. doi:10.1038/jcbfm.2014.177.

To evaluate glycolysis and the pentose phosphate pathways (PPP) as routes of glucose metabolism in

the brains of TBI patients, 15 male and female severe TBI patients aged 16-59 years, 8 male and female

macroscopically normal brain patients undergoing surgery for benign tumors aged 59-73 years, and 9

male and female patients undergoing surgery for acoustic neuroma resection aged 20-61 years were

enrolled in this controlled clinical trial.

To measure and analyze lactate labeling patterns, 1,2- C2❑13 glucose was perfused into the severe TBI

patients’ brains, the cranial opening at the end of the normal brain subjects’ neurological procedure and

into the quadriceps of the muscle subjects. Glucose, lactate, pyruvate, glutamate, and glycerol

microdialysates were assessed hourly in the TBI patients, while these microdialysates were respectively

assessed at 4 and 2 hour intervals in the normal brain and muscle subjects. All TBI patients, 2 normal

brain subjects, and 5 muscle subjects were evaluated for a baseline period.

Comparisons were made among 4 groups post-CCI:

Severe TBI patients (median age 27 years old) receiving 1,2-C2-glucose perfusion

Macroscopically normal-appearing brain patients

A non-CNS tissue (quadriceps muscle) comparison group

Plain, unsupplemented perfusion fluid without 1,2-13C2 glucose group

Microdialysate glucose concentrations significantly increased between the baseline and the 1.2-13C2

glucose perfusion period for all groups (TBI: 1.0-3.8mmol/L; 1.9-3.9mmol/L; 2.8-5.3mmol/L). The ratio of

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Figure 1. Simplified schematic of steps

in glycolysis and the pentose phosphate pathway (PPP) showing 13C labeling patterns resulting from1,2-13C2 glucose substrate. Red fills indicate 13C atoms. Glc-6-P, glucose-6-phosphate; 6PGL, 6 phosphogluconolactone; F6P, fructose-6-phosphate; G3P, glyceraldehyde-3-phosphate; PYR, pyruvate. Figure originally published in Carpenter et al34 under a Creative Commons Attribution License.


PPP-derived 3-13C lactate to glycolytic 2,3-13C lactate was a median 6.7% in the normal brain and 4.9%

in the TBI brain. Showing that microdialysis 1,2-13C2 glucose infusion results in 13C-labeling in lactate in

produced microdialysates enables the comparison of lactate-derived glycolysis to that of lactate-derived

PPP. This study found that glycolytic lactate production was significantly greater in the TBI brain than in

the normal brain and that PPP-derived lactate production was not significantly different between the

two. Further studies are needed to explore the roles of PPP and glycolysis after TBI.

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Xing G, Ren M, Watson WD, et al. Traumatic brain injury-induced expression and phosphorylation of pyruvate dehydrogenase: a mechanism of dysregulated glucose metabolism. Neurosci. Lett. 2009;454(1):38-42. doi:10.1016/j.neulet.2009.01.047.

48 male Sprague-Dawley rats were studied in this randomized controlled laboratory trial to determine

the relevance of PDHE1α’s mRNA and protein expression (PDHE1α1) and phosphorylated PHDE1 α

protein (p- PDHE1α1) in PDH activity and glucose metabolism after induction of controlled cortical

impact (CCI).

Using PDHEα1 mRNA and protein expression and phosphorylated PDHE1α protein as dependent

variables in PDH activity and glucose metabolism, 48 healthy male Sprague-Dawley rats were randomly

assigned to either a naïve control, craniotomy, or controlled cortical impact traumatic brain injury group.

Brain samples were collected at 4 and 24 hours and 3 and 7 days post CCI in all groups (n = 4 for each

group and time point) and were treated with specific antibodies against each protein to allow for

visualization of immunoreactive bands in western blots. Additionally, real-time PCR determination of

PDHE1a1 mRNA and western blotting determination of p-PDHE1a1 protein and PDHE1a1 protein in

naïve control, craniotomy and contralateral CCI and ipsilateral CCI groups were analyzed.

Comparisons were made among 4 groups post-CCI:

PDHE1α1 protein and mRNA and p- PDHE1α1 in naïve controls (n = 16)

PDHE1α1 protein and mRNA and p- PDHE1α1 in craniotomy (n = 16)

PDHE1α1 protein and mRNA and p- PDHE1α1 in contralateral and ipsilateral sides of brain in CCI

(n = 16)

At 4h, 24 h, 3, and 7 days post-CCI PDHE1α1 protein significantly decreased ipsilateral to CCI

(respectively 62%, 75%, 57% and 39%) and contralateral to CCI (77%, 78%m, 78% and 36%) when

compared to naïve controls (100%). Additionally, at 4h, 24h, 3d and 7d, p- PDHE1α1 protein decreased

significantly ipsilateral (31%, 102%, 64%, and 14%) and contralateral (35%, 74%, 60%, and 20%) to CCI

with like reductions in PDHE1α1 and p- PDHE1α1 protein found in the craniotomy CCI group. In

conclusion, PDHE1α1 expression and phosphorylation post-TBI may play an important role in altered

PDH activity and glucose metabolism in the brain. Future research is still needed, however.

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Fig. 1. (A) Western blotting of p-PDHE1_1 and PDHE1_1 protein in the homogenates of rat brain samples collected at 4 h, 24 h, 3- and 7-day post-CCI. Forty micrograms of total protein of rat brain hemisphere tissue extract were resolved on SDS-PAGE gel and incubated with the specific primary antibodies against each protein. N, naïve control; S, craniotomy (sham CCI); C, contralateral CCI hemisphere; I, ipsilateral CCI hemisphere. (B). Real-time PCR determination of PDHE1_1 mRNA (a) and semi-quantitative determination of western blotting p-PDHE1_1 protein (b) and PDHE1_1 protein (c) in the homogenates of the naïve control, craniotomy, contralateral CCI and ipsilateral CCI hemisphere. PDHE1_1 mRNA increased moderately in the CCI group at 4 h and 24 h post-CCI, increased significantly in the contralateral CCI but decreased significantly in the ipsilateral CCI at 3 days post-CC; p-PDHE1_1 and PDHE1_1 protein, and PDHE1_1:p-PDHE1_1 ratio (d) reduced significantly in ipsilateral and contralateral CCI at 4 h, 24 h, 3 and 7 days post-CCI when compared with the naïve group (=C). (*) p < 0.05; (**) p < 0.01, (+) P < 0.09, versus the naïve group, respectively.


Belabed L, Charrueau C, Besson V, et al. Impairment of lymphocyte function in head-injured rats: effects of standard and immune-enhancing diets for enteral nutrition. Clin. Nutr. 2006;25(5):832-41. doi:10.1016/j.clnu.2006.02.003.

In order to explore the effects of HI on lymphocyte function and to ascertain the effects of an enteral

immune-enhancing diet (IED) compared to standard enteral nutrition, 25 male Srague-Dawley rats were

studied in this randomized controlled laboratory experiment.

Animals underwent a 6 day acclimatization period, followed by an overnight fast. They were randomized

into 4 groups, an AL fed group and three other groups that underwent gastronomy on day 7. Post-

gastronomy, rats were allowed a 6 day recovery period in metabolic cages. Thereafter, HI was induced

by way of fluid percussion and rats were separated into a control group and two experimental groups.

The enteral nutrition diet groups were infused 24h/24h (290kcal/kg/d and 3.29g of N/kg/d) at a constant

rate over a 4 day period until 2 hours prior to being sacrificed.

Their plasma fibrinogen and albumin, thymus, white blood cells, and lymphocyte receptor expression

and densities were evaluated.


Standard chow diet ad libitum fed healthy group (AL; n = 7)

HI control group receiving a constant rate of 0.9% NaCl via the enteral route along with free

access to the standard chow diet (HI; n = 6)

Experimental group receiving the enteral standard diet Sondalis HP (HIS; n = 6)

Experimental group receiving the enteral IED Crucial (HIC; n=6)

A significant increase in plasma fibrinogen was noted in the HI group (6.2g/l) versus the AL group

(2.6g/l), but not in the HIS (4.5g/l) and HIC (5.0g/l) versus AL group. The HI group (16.6g/l) also showed

hypoalbuminemia, which was corrected in the HIC group (20.4g/l) compared to the AL group (25.6g/l).

HI induced an uncorrected significant thymus atrophy (296mg) compared to the AL group (552mg),

although this atrophy was not exhibited in the HIC group (386mg). A significant increase in white blood

cell count was observed in the HI (12.3 103/mm2) versus AL (5.5 103/mm2) group. CD25 receptor density

in the blood, spleen and mesenteric lymph nodes in the AL group showed a marked increase after Con A

stimulation versus the HI group. Lymphocytes in Peyer patches showed a significant increase in CD25

receptor density after stimulation only in the HIC group.

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Thus, this model indeed characterized hypercatabolism via fibrinogen and albumin changes. Due to the

thymus atrophy, it also characterized a reorganization of lymphocytes to the lymphoid organ and GI

tract. Additionally, its model of HI dysimmunity revealed that Crucial helped reduce thymus atrophy.

Finally, following HI in rats, EN appeared to efficiently restore blood lymphocyte stimulation capacity,

while the IED formula provided added benefits to attune lymphocyte stimulation capacity in the PPs and

limit thymus atrophy; although, further research remains concerning the deeper mechanism.

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Figure 1 Study design.


Moinard C, Delpierre E, Loi C, et al. An oligomeric diet limits the response to injury in traumatic brain-injured rats. J. Neurotrauma 2013;30(11):975-980. doi:10.1089/neu.2012.2707.

To assess the effectiveness of an oligomeric formula improving nutritional status by restoring intestinal

balance in rats with TBI, 26 male Sprague-Dawley rats were selected for study in this randomized

controlled laboratory trial.

All 26 rats acclimatized in metabolic cages for a week and then were randomized into three groups:

Healthy rats fed a standard polymeric enteral nutrition (control group; n = 8)

TBI rats fed the polymeric diet (TBIP; n = 9)

TBI rats fed the oligomeric diet (TBIO; n = 9)

All groups underwent gastronomy on day 7 after fasting for 12 hours. Proceeding a 7 day recovery

period, the non-control group received fluid percussion, inducing TBI. 4 hours post TBI (Day 0), enteral

nutrition was introduced. The day following TBI, the enteral nutrition flow rate was increased to

290kcal/g/d and 2.3gN/kg/d infused at a constant rate for 4 days. Rats were weighed daily starting at

Day 0 and ending on Day 4, when they were sacrificed.

Blood samples were taken and various tissues were removed with organ weights, amino acid

concentrations in plasma and muscles, tissue protein content, intestinal morphometry and

enterbacterial translocation and dissemination being secondarily analyzed.

Results showed that significant decreases in body weight were induced by TBI and were reduced by the

oligomeric diet (TBIP versus TBIO). Moreover, the oligomeric formula appeared to attenuate thymus

weight loss after TBI (TBIP at 0.30g versus control at 0.46g). Tissue protein content showed no significant

difference in any groups compared. Glutamine concentration was the only significant difference found

between groups for plasma and amino acid concentrations, revealing improvement by the oligomeric

diet (Control group plasma 591μmol/L and TBIP 615μmol/L versus TBIO 688μmol/L). While intestinal

morphometry showed no significant changes, enterobacterial translocation in the mesenteric lymph

nodes and dissemination in the spleen and liver of the TBI groups were noted, but were not altered by

the enteral diet. Overall, the oligomeric diet reduced thymus atrophy induced by TBI and showed

promise in being potentially beneficial for restoring glutamine stores; however, further research is

necessary to substantiate these promising results.

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FIG. 1. Body weight variation between day 0 and day 4. Variation in total body weight in control rats, traumatic brain injury + standard polymeric diet rats (TBIP), and traumatic brain injury + oligomeric diet rats (TBIO). Results are given as means – standard error of the mean (analysis of variance + Newman-Keuls test). *p < 0.05 vs.control; ¤ p < 0.05 vs. TBIP.


Vizzini A, Aranda-Michel J. Nutritional support in head injury. Nutrition 2011;27(2):129-32.

This review explored the role of nutritional support in the recovery of patients sustaining a head-injury,

and was separated into eight discrete discussion parts:

Hypermetabolism and hypercatabolsim: Head injury results in a complex cascade of metabolic

alterations. An increase in the levels of cytokines and the counter-regulatory hormones such as cortisol,

glucagon, norepinephrine and epinephrine contribute to this altered metabolism. These counter-

regulatory hormones stimulate an increase in heart rate, cardiac output, oxygen consumption,

glycogenolysis and gluconeogenesis, which all play a role in the development of total body metabolic

derangements, including hyperglycemia and hypercatabolism. Hypercatabolism causes the degredation

of skeletal muscle proteins and an increase in urinary nitrogen secretion, resulting in a severe negative

nitrogen balance (>30g/d) and often malnutrition. Further complications may arise as a consequence of

the malnutrition such as hyperglycemia, difficulty with wound healing, increased risk for infection, and

multiple organ failure.

Energy expenditure: Massive increases to around 40-200% in resting energy expenditure (REE) beyond

that of a non-injured person are noted in head-injured patients. The metabolic rate in head-injured

patients may be attenuated by up to 12-32% if given paralyzing agents, sedatives, or barbiturates;

however, steroid administration and feeding does not follow this same pattern, and thus appears to be

ineffective. To predict REE, the gold standard indirect calorimetry is often the measurement of choice.

Although, due to the high variability in metabolic rates post-TBI, energy needs for individual patients

should not be assessed through predictive equations. Because TBI patients often experience a 15% per

week weight loss due to muscle wasting, the supply of sufficient calories is critical, with caution to

overfeeding.

Protein requirements: Hypercatabolism results in greater urinary nitrogen (UNN) secretion, making the

provision of sufficient protein essential. Protein requirements for head-injured persons generally range

from 2.0-2.5g/kg/d with the Management of Severe Traumatic Brain injury guidelines suggesting 15-20%

of total calories as nitrogen calories. However, nitrogen imbalance usually persists for up to 2-3 weeks

after the injury. The UNN measurement has been helpful in determining the true catabolism of an

individual, excluding those with renal failure or undergoing dialysis, to provide personalized protein

supplementation. While protein supplementation will not decrease hypercatabolism, it can secure

protein replacement to maintain anabolism. Some studies suggest IGF-1 hormone therapy to improve

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nitrogen utilization, but it is not recommended due to its association with increases in morbidity and

mortality in critically ill patients.

Specific nutrients: Because zinc is essential for many processes in the body and because patients with

TBI have been known to have increased zinc urinary excretion and decreased serum zinc levels, zinc

supplementation is often provided. However, optimal zinc supplementation dosing is still unclear.

Vitamin E and C and magnesium are also under consideration as beneficial TBI supplements.

Additionally, arginine, glutamine, nucleic acid, omega-3 fatty acids, and antioxidants are used as

supplements in immune-modulating enteral formulas in trauma patients and critically ill patients.

Glutamine supplementation is still being explored as researchers speculate it plays a role in

hemodynamic instability in severely septic patients. To provide 0.3-0.5g/kg/d glutamine given in two to

three divided doses, recommendations suggest adding standard dosing of glutamine powder to non-

glutamine supplemented enteral formulas for trauma patients.

Nutrition support (timing of feeding): Enteral nutrition provided within 24-72 hours of injury have shown

to be beneficial in a plethora of studies. Infection rates and overall complications can be improved by

early, adequate nutritional intervention, which may even improve Glasgow Outcome Scores at 3

months. Recommendations include providing >50-60% of goal calories via enteral nutrition within the

first week of hospitalization to decrease cognitive recovery time, as well as, attaining full caloric

replacement within 7 days post TBI.

Nutrition Support (Route of feeding): Enteral nutrition is now the preferred method of feeding due to

improved early enteral access procedures. If enteral access or nutrition goals are not achieved within 48-

72 hours after the injury, parenteral nutrition may be necessary. Short-term (< 4 weeks) enteral feeding

requires nasogastric or nasoenteric tubes, whereas long-term enteral feeding requires gastronomy or

jejunostomy tubes (>4 weeks). Enteral feeding comes with the potential for complications such as

diarrhea, delayed gastric emptying, abdominal distention, aspiration, and pneumonitis. SCCM and SPEN

guidelines recommend gastric and small bowel feeding for ICU patients. Across the board, enteral

nutrition should be delivered continuously (20 mL/h, increasing by 10-20mL/h every 6-8 hours) with a

controlled pump to improve tolerance, reduce the potential for infections and promptly achieve

nutritional goals.

Monitoring nutritional status: REE should be measured regularly or whenever changes in a patient’s

metabolic demand are affected, according the ASPEN guidelines. UNN measurements should be taken

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on TBI patients, excluding those undergoing dialysis, once or twice per week until protein balance has

been reached. Prealbumin, albumin and CRP may be monitored weekly for reflection of nutritional

status if inflammatory markers are stable. Monitoring of electrolytes, like potassium and phosphorus,

may be relevant nutrition status indicators in TBI patients as well.

Clinical practice: The Nutrition Risk Screening 2002 tool should be utilized to identify patients at risk for

malnourishment and appropriate nutrition protocols should be implemented. Appropriate protocols for

early nutrition and reduced likelihood of nutrition-related complications include guidelines for

determining energy expenditure, changes in REE and protein needs, preferred routes and timing of

enteral feeding, and measures for monitoring tolerance and nutrition adequacy.

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