Semi-elemental versus polymeric formula for enteral nutrition in brain-injured critically ill patients: a randomized trial.

BACKGROUND: The properties of semi-elemental enteral nutrition might theoretically improve gastrointestinal tolerance in brain-injured patients, known to suffer gastroparesis. The purpose of this study was to compare the efficacy and tolerance of a semi-elemental versus a polymeric formula for enteral nutrition (EN) in brain-injured critically ill patients. METHODS: Prospective, randomized study including brain-injured adult patients [Glasgow Coma Scale (GCS) ≤ 8] with an expected duration of mechanical ventilation > 48 h. INTERVENTION: an enteral semi-elemental (SE group) or polymeric (P group) formula. EN was started within 36 h after admission to the intensive care unit and was delivered according to a standardized nurse-driven protocol. The primary endpoint was the percentage of patients who received both 60% of the daily energy goal at 3 days and 100% of the daily energy goal at 5 days after inclusion. Tolerance of EN was assessed by the rate of gastroparesis, vomiting and diarrhea. RESULTS: Respectively, 100 and 95 patients were analyzed in the SE and P groups: Age (57[44-65] versus 55[40-65] years) and GCS (6[3-7] versus 5[3-7]) did not differ between groups. The percentage of patients achieving the primary endpoint was similar (46% and 48%, respectively; relative risk (RR) [95% confidence interval (CI)] = 1.05 (0.78-1.42); p = 0.73). The mean daily energy intake was, respectively, 20.2 ± 6.3 versus 21.0 ± 6.5 kcal/kg/day (p = 0.42). Protein intakes were 1.3 ± 0.4 versus 1.1 ± 0.3 g/kg/day (p < 0.0001). Respectively, 18% versus 12% patients presented gastroparesis (p = 0.21), and 16% versus 8% patients suffered from diarrhea (p = 0.11). No patient presented vomiting in either group. CONCLUSION: Semi-elemental compared to polymeric formula did not improve daily energy intake or gastrointestinal tolerance of enteral nutrition. TRIAL REGISTRATION: EudraCT/ID-RCB 2012-A00078-35 (registered January 17, 2012).

The immunomodulatory mechanism of brain injury induced by hyperhomocysteinemia in spontaneously hypertensive rats.

BACKGROUND: Elevated plasma homocysteine (Hcy) concentration is considered as the diagnostic criteria of Hyperhomocysteinemia (HHcy), which is associated with the inflammatory response and blood-brain barrier disruption. Previous studies have proposed that HHcy with hypertension was associated with the brain injury by enhancing the cerebrovascular permeability, however, the immune mechanism remains obscure. The purpose of the study is to explore the immunomodulatory mechanism of brain injury in spontaneously hypertensive rats (SHRs) induced by HHcy. MATERIALS AND METHODS: Sixty SHRs were randomly assigned to three groups: SHR-C (control group), SHR-M (methionine group) and SHR-T (treatment group). Physical examination of body weight, systolic blood pressure (SBP) and plasma Hcy content was measured every 4 weeks. Besides, T-helper cell 17 and regulatory T cells (Treg)-related inflammatory cytokines (interleukin [IL]-6, IL-17, IL-10, and transforming growth factor beta [TGF-ß]) and genes (RORγt and FoxP3) were detected by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction , Western blot, and immunohistochemistry. RESULTS: High methionine diet could cause weight loss, SBP rising, and plasma Hcy content significantly elevated. IL-16 and IL-17A levels in peripheral blood and in brain tissue both lifted, while IL-10 and TGF-ß levels dropped; RORγt expression raised in brain, nevertheless, FoxP3 levels were the opposite. After the intervention with vitamin B6, B12, and folic acid in SHR-T group, these trends would be eased or completely changed. Furthermore, brain tissue slices showed that IL-17-positive cells tended to decrease, and IL-10-positive cells increased in SHR-T group, which was reversed in SHR-M group. CONCLUSIONS: HHcy may promote inflammation that can lead to brain lesions and down-regulate immune response to protect the brain.

The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury.

The postinjury period of glucose metabolic depression is accompanied by adenosine triphosphate decreases, increased flux of glucose through the pentose phosphate pathway, free radical production, activation of poly-ADP ribose polymerase via DNA damage, and inhibition of glyceraldehyde dehydrogenase (a key glycolytic enzyme) via depletion of the cytosolic NAD pool. Under these post-brain injury conditions of impaired glycolytic metabolism, glucose becomes a less favorable energy substrate. Ketone bodies are the only known natural alternative substrate to glucose for cerebral energy metabolism. While it has been demonstrated that other fuels (pyruvate, lactate, and acetyl-L-carnitine) can be metabolized by the brain, ketones are the only endogenous fuel that can contribute significantly to cerebral metabolism. Preclinical studies employing both pre- and postinjury implementation of the ketogenic diet have demonstrated improved structural and functional outcome in traumatic brain injury (TBI) models, mild TBI/concussion models, and spinal cord injury. Further clinical studies are required to determine the optimal method to induce cerebral ketone metabolism in the postinjury brain, and to validate the neuroprotective benefits of ketogenic therapy in humans.

Nutritional intake, body mass index, and activity in postacute traumatic brain injury: a preliminary study.

PURPOSE: In the United States, traumatic brain injury (TBI) remains a serious health problem contributing to lifelong disability. Little has been written about nutrition problems experienced postrehabilitation discharge. Our objective was to describe the nutrition and weight management characteristics of TBI survivors after discharge from rehabilitation and to identify characteristics of individuals at risk for weight control issues. METHOD/DESIGN: Twenty-six TBI survivors admitted to a freestanding rehabilitation hospital were followed for 1 year postdischarge. Data on height, weight, disability rating, diet and activity were collected at admission, 3, 6, 9 and 12 months after discharge. FINDINGS: Approximately 30% of the participants showed an increasing body mass index from discharge to 1-year follow up. Two patients had more complete long-term data and are highlighted. CONCLUSION/CLINICAL RELEVANCE: The case studies provide insight into the need for rehabilitation nurses to provide nutrition education to TBI survivors that will accommodate changes in lifestyle and activity after discharge.

Traumatic brain injury in children: acute care management.

The care of the pediatric patient with a severe traumatic brain injury (TBI) is an all-encompassing nursing challenge. Nursing vigilance is required to maintain a physiological balance that protects the injured brain. From the time a child and family first enter the hospital, they are met with the risk of potential death and an uncertain future. The family is subjected to an influx of complex medical and nursing terminology and interventions. Nurses need to understand the complexities of TBI and the modalities of treatment, as well as provide patients and families with support throughout all phases of care.

Nutritional Interventions in Children with Brain Injuries: A Systematic Review.

BACKGROUND: Brain injury has several consequences throughout life, its increased incidence has caused great public concern. The aim was identifying the main nutritional therapies recommended for children with brain injuries. METHODS: A systematic review was carried out using the terms in the search strategy: "Brain Injuries", "Nutrition Therapy", and "Child" and their synonyms, from database inception up to August 2020. The search was conducted in the following databases: MEDLINE, EMBASE, Scopus, Cochrane library, LILACS, and grey literature. Two reviewers independently selected the included studies, according to the eligibility criteria and extracted data from the included articles. RESULTS: A total of 1196 studies resulted from electronic searches, and out of these, 27 studies were read in full and eight studies were included. For early enteral nutritional support (<48 h), results suggest benefit in increasing survival rates. Type of dietary protein seems to be related to decreasing gastric emptying by 40%. The use of fibers seems to reduce gastrointestinal discomfort and increase stool frequency. CONCLUSIONS: The evidence mapped was extracted from small studies analyzing different outcomes, so any decision making should be analyzed considering the context. We present the direction of the effect, but the magnitude is still unclear.

A randomized controlled trial investigating the impact of maternal dietary supplementation with pomegranate juice on brain injury in infants with IUGR.

Animal studies have demonstrated the therapeutic potential of polyphenol-rich pomegranate juice. We recently reported altered white matter microstructure and functional connectivity in the infant brain following in utero pomegranate juice exposure in pregnancies with intrauterine growth restriction (IUGR). This double-blind exploratory randomized controlled trial further investigates the impact of maternal pomegranate juice intake on brain structure and injury in a second cohort of IUGR pregnancies diagnosed at 24-34 weeks' gestation. Ninety-nine mothers and their eligible fetuses (n = 103) were recruited from Brigham and Women's Hospital and randomly assigned to 8 oz pomegranate (n = 56) or placebo (n = 47) juice to be consumed daily from enrollment to delivery. A subset of participants underwent fetal echocardiogram after 2 weeks on juice with no evidence of ductal constriction. 57 infants (n = 26 pomegranate, n = 31 placebo) underwent term-equivalent MRI for assessment of brain injury, volumes and white matter diffusion. No significant group differences were found in brain volumes or white matter microstructure; however, infants whose mothers consumed pomegranate juice demonstrated lower risk for brain injury, including any white or cortical grey matter injury compared to placebo. These preliminary findings suggest pomegranate juice may be a safe in utero neuroprotectant in pregnancies with known IUGR warranting continued investigation.Clinical trial registration: NCT04394910, https://clinicaltrials.gov/ct2/show/NCT04394910 , Registered May 20, 2020, initial participant enrollment January 16, 2016.

Free radical damage to cerebral cortex in Alzheimer's disease, microvascular brain injury, and smoking.

Evidence supports a pathogenic role for free radical injury to brain in Alzheimer's disease; however, clinical trial results are only mildly encouraging. Examining brains from The Adult Changes in Thought study offers a unique perspective. Selectively increased free radical damage to cerebral cortex was associated with Alzheimer's disease, microvascular brain injury, and current smoking, but not with antioxidant supplement usage. Our results support suppression of free radical injury to brain as a therapeutic target for Alzheimer's disease and microvascular brain injury; however, future clinical trials should consider other antioxidants or doses than those identified in our study.

Inducing ketogenesis via an enteral formulation in patients with acute brain injury:a phase II study.

Objective: Although extensively studied in children, the safety and tolerability of ketone supplementation in adults is unclear, particularly in the acute brain injury population. The purpose of this study was to examine the feasibility and safety of inducing ketosis using an enteric ketogenic formulation and determine its impact on intracranial and cerebral perfusion pressures and metabolic parameters.Methods: Prospective interventional Phase II trial of ventilated critically ill patients with acute brain injury administered a ketogenic feed over a 6 day period.Results: 20 patients were recruited, 5 females and 15 males, 3 with stroke, 2 with subarachnoid haemorrhage and 15 with traumatic brain injury. Feeds were well tolerated with 19 patients completing study. There was a significant increase in both plasma beta-hydroxybutyrate and acetoacetate from 0.24± 0.31 mmol/l and 0.19 ± 0.16 mmol/l to 0.61 ± 0.53 mmol/l (p =0.0005) and 0.52 ± 0.40 mmol/l (p<0.0001) respectively over the 6 day period. Total daily Ketocal® caloric intake was positively correlated with plasma beta-hydroxybutyrate concentrations (p=0.0011). There was no significant correlation between the cerebral hypertension and cerebral hypoperfusion indices and plasma ketone concentrations. In 95% of patients there were no clinically significant changes in acid/base status over the 6 days with pH remaining within normal range.Conclusion: In patients with acute brain injury, an enterally administered ketogenic formulation increased plasma ketone concentrations, was well tolerated, did not impact on cerebral hemodynamics and can be safely administered.Clinical trial registered at the Australian New Zealand Clinical Trials Registry (ACTRN12616000332426)Abbreviations: BHB: betahydroxybutyrate; AcAc: acetoacetate; ABI: acute brain injury; TBI: traumatic brain injury; CSF: cerebrospinal fluid; SAH: subarachnoid injury; CVA: cerebrovascular accidents; ICP: intracranial pressure; CPP: cerebral perfusion pressure; ICU: intensive care unit; EVD: external ventricular device; CHI: cerebral hypoperfusion index; IHI: intracranial hypertension index; GCS: Glasgow Coma Scale.

The protective effect of the ketogenic diet on traumatic brain injury-induced cell death in juvenile rats.

BACKGROUND: The ketogenic diet (the KD) is an effective treatment for intractable epilepsy, especially in the paediatric population, and a growing number of studies have shown the neuroprotective role of the KD. However, few studies focused on the neuroprotective effects of the KD in traumatic brain injury (TBI). The present study aimed to investigate the effects of the KD on TBI. METHODS AND PROCEDURES: Male Sprague-Dawley rats (n = 60) were randomly divided into four groups according to the diet fed (the KD vs normal diet) and whether brain was injured or not. TBI was produced using Feeney weight drop model. Brain oedema was estimated by wet/dry weight ratio; Bax and Bcl-2 mRNA levels were determined by RealTime-PCR; Bax and Bcl-2 protein levels were detected by Western blot. Furthermore, cellular apoptosis in the penumbra area was examined using terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) method. MAIN OUTCOMES AND RESULTS: The results indicated that both Bax mRNA and protein levels were significantly elevated 72 hours after TBI and decreased by KD administration. Neither TBI nor the KD affected Bcl-2 mRNA and protein levels. KD administration also reduced brain oedema and cellular apoptosis. CONCLUSION: These results suggest that the KD might be a useful treatment for children suffering from the consequences of TBI.

Nutrient pattern analysis in critically ill patients using Omics technology (NAChO) - Study protocol for a prospective observational study.

INTRODUCTION: Intensive care unit-acquired weakness (ICU-AW) is often observed in critically ill patients with prolonged intensive care unit (ICU) stay. We hypothesized that evolving metabolic abnormalities during prolonged ICU stay are reflected by changing nutrient patterns in blood, urine and skeletal muscle, and that these patterns differ in patients with/without ICU-AW and between patients with/without sepsis. METHODS: In a prospective single-center observational trial, we aim to recruit 100 critically ill patients (ICU length of stay ≥ 5 days) with severe sepsis/septic shock ("sepsis group", n = 50) or severe head trauma/intracerebral hemorrhage ("CNS group", n = 50). Patients will be sub-grouped for presence or absence of ICU-AW as determined by the Medical Research Council sum score. Blood and urine samples will be collected and subjected to comprehensive nutrient analysis at different time points by targeted quantitative mass spectrometric methods. In addition, changes in muscular tissue (biopsy, when available), muscular architecture (ultrasound), electrophysiology, body composition analyses (bioimpedance, cerebral magnetic resonance imaging), along with clinical status will be assessed. Patients will be followed-up for 180 and 360 days including assessment of quality of life. DISCUSSION: Key objective of this trial is to assess changes in nutrient pattern in blood and urine over time in critically ill patients with/without ICU-AW by using quantitative nutrient analysis techniques. Peer-reviewed published NAChO data will allow for a better understanding of metabolic changes in critically ill patients on standard liquid enteral nutrition and will likely open up new avenues for future therapeutic and nutritional interventions.

Dietary choline supplementation improves behavioral, histological, and neurochemical outcomes in a rat model of traumatic brain injury.

Novel pharmacological approaches that safely and effectively lessen the degree of neurological impairment following traumatic brain injury (TBI) are sorely needed. Non-invasive approaches that could be used over an extended periods of time might be particularly useful. Previous studies from our lab have hypothesized that TBI-induced decreases in hippocampal and cortical alpha7 neuronal nicotinic cholinergic receptor (nAChR) expression might contribute to cognitive impairment that follows brain injury. The purpose of this study was to determine whether the low-potency, but selective alpha7 nAChR agonist choline might be a useful treatment for improvement of neurological outcome in a rat model of TBI. Male Sprague-Dawley rats were exposed to control or choline-supplemented diets for 2 weeks prior to experimental brain injury (1.5-mm cortical contusion injury) and throughout the recovery phase. Dietary choline supplementation resulted in a modest degree of improvement in spatial memory as assessed in the Morris water maze test. In addition, choline treatment resulted in significant cortical tissue sparing, reduced brain inflammation, and normalized some TBI-induced deficits in nAChR expression. The results of this study suggest that alpha7 nAChR agonists may be useful drugs to enhance recovery following brain injury.

Diet, ketones, and neurotrauma.

The annual incidence of traumatic brain injury far exceeds the rates of any other disease in the United States, yet progress toward age-relevant therapies, attention to patients needs, and research funding have all been minimal. Cerebral metabolism of glucose has been shown to be altered after head injury, and increasing cerebral metabolism of alternative substrates (ketones) has been shown to be neuroprotective in several models of traumatic brain injury. This altered dietary approach may have tremendous therapeutic potential for both the pediatric and adult head-injured populations.

Conjugated Linoleic Acid (CLA) inhibits new vessel growth in the mammalian brain.

Conjugated Linoleic Acid (CLA) is fatty acid found endogenously in food sources that prevents new tumor development and reduces the growth of existing tumors in laboratory animals. CLA exerts its anti-carcinogenic effect by reducing VEGF and bFGF serum levels and by blocking flk-1 receptors, thereby inhibiting vascular growth critical to tumor growth and survival. Although the ability of CLA to inhibit angiogenesis in the peripheral nervous system is well characterized, it remains unknown whether CLA also affects vascular morphology in the central nervous system. Therefore, in the present study, exercising and sedentary animals received either standard rat chow or a specially formulated diet consisting of 0.5% CLA for 24 days. The brains were then examined to determine the extent of vascular growth in the cerebellum, a region known to exhibit robust exercise-induced angiogenesis. Our results indicate that CLA administration significantly reduces angiogenesis in the cerebellum. This study is the first to demonstrate the anti-angiogenic effect of CLA in the brain, and suggests that CLA be explored as a therapeutic treatment for cancer and tumors in the brain.

Magnesium dietary manipulation and recovery of function following controlled cortical damage in the rat.

Previous research has shown that dietary magnesium (Mg2+) deficiency prior to injury worsens recovery of function and that systemic administration of Mg2+ pre or post-injury significantly improves functional recovery. The purpose of the present study was to determine if manipulations in dietary Mg2+ would alter functional recovery following unilateral cortical injuries. Two weeks prior to injury, rats were placed on a customized diet enriched with Mg2+, deficient in Mg2+, or on a standard Mg2+ diet. Rats were then prepared with unilateral cortical contusion injuries (CCI) of the sensorimotor cortex. Two days following CCI, rats were tested on a battery of sensorimotor (vibrissae-forelimb placing and bilateral tactile adhesive removal tests), as well as the acquisition of reference memory in the Morris water maze. Serum analysis for Mg2+ prior to injury showed a diet-dependent modulation in levels. The Mg(2+)-enriched diet showed significantly higher levels of serum Mg2+ compared to the normal diet and the Mg(2+)-deficient diet showed significantly lower levels compared to the Mg(2+)-normal diet. On the placing and tactile removal tests Mg2+ deficiency significantly worsened recovery compared to the Mg(2+)-enriched and Mg(2+-)normal diet conditions. There were no statistically significant differences between the Mg(2+)-normal and Mg(2+)-enriched diets on the sensorimotor tests. On the acquisition of reference memory there were no significant difference between diet conditions; however, the Mg(2+)-deficient diet showed a trend toward impaired performance compared to the other diet conditions. The Mg(2+)-deficient diet resulted in a larger lesion cavity compared to the other diet conditions. These findings suggest that dietary Mg2+ modulates recovery of function.

Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity.

Cerebral metabolism of ketones after traumatic brain injury (TBI) improves neuropathology and behavior in an age-dependent manner. Neuroprotection is attributed to improved cellular energetics, although other properties contribute to the beneficial effects. Oxidative stress is responsible for mitochondrial dysfunction after TBI. Ketones decrease oxidative stress, increase antioxidants and scavenge free radicals. It is hypothesized that ketogenic diet (KD) will decrease post-TBI oxidative stress and improve mitochondria. Postnatal day 35 (PND35) male rats were given sham or controlled cortical impact (CCI) injury and placed on standard (STD) or KD. Ipsilateral cortex homogenates and mitochondria were assayed for markers of oxidative stress, antioxidant expression and mitochondrial function. Oxidative stress was significantly increased at 6 and 24 h post-injury and attenuated by KD while inducing protein expression of antioxidants, NAD(P)H dehydrogenase quinone 1 (NQO1) and superoxide dismutase (SOD1/2). Complex I activity was inhibited in STD and KD groups at 6 h and normalized by 24 h. KD significantly improved Complex II-III activity that was reduced in STD at 6 h. Activity remained reduced at 24 h in STD and unchanged in KD animals. These results strongly suggest that ketones improve post-TBI cerebral metabolism by providing alternative substrates and through antioxidant properties, preventing oxidative stress-mediated mitochondrial dysfunction.

Lactoferrin during lactation reduces lipopolysaccharide-induced brain injury.

Lactoferrin (Lf), component of maternal milk, has antioxidant, anti-inflammatory and antimicrobial properties. Neuroprotective effects of Lf on the immature brain have been recently shown in rodent models of intrauterine growth restriction and cerebral hypoxia/ischemia. Here we postulated that Lf could also have beneficial effects on preterm inflammatory brain injury. Lf was supplemented in maternal food during lactation and lipopolysaccharide (LPS) was injected in subcortical white matter of rat pups at postnatal day 3 (P3). Effect of maternal Lf supplementation was investigated 24 h (P4), 4 (P7), or 21 days (P24) after LPS injection mainly on the striatum. Lateral ventricle and brain structures volumes were quantified. Microstructure was evaluated by diffusion tensor imaging, neurite orientation dispersion and density imaging as well as electron microscopy. Neurochemical profile was measured by (1) H-magnetic resonance spectroscopy. GFAP protein, proinflammatory cytokines mRNA expression microglial activation were assessed. Lf displayed neuroprotective effects as shown by reduced LPS-induced ventriculomegaly, brain tissue loss, and microstructural modifications, including myelination deficit. (1) H-MRS neurochemical profile was less altered through an antioxidant action of Lf. Despite the lack of effect on LPS-induced proinflammatory cytokines genes expression and on reactive gliosis, microglia was less activated under Lf treatment. In conclusion, Lf supplemented in food during lactation attenuated acute and long-term cerebral LPS-induced alterations. This provides a new evidence for a promising use of Lf as a preventive neuroprotective approach in preterm encephalopathy. © 2016 BioFactors, 42(3):323-336, 2016.

Safety and Tolerability of Enteral Protein Supplementation for Infants With Brain Injury.

BACKGROUND: We hypothesized that enteral protein supplementation in infants with brain injury would be safe and well tolerated and improve growth. MATERIALS AND METHODS: Twenty-five infants with perinatal brain injury were randomized to a high-protein (4 g/kg/d) or standard-protein diet and followed for 12 months. RESULTS: The whey protein powder was well tolerated by 9 of the 13 infants in the high-protein group, and no adverse events related to the supplement were seen. The protein group had higher serum urea nitrogen at 10 and 30 days after study initiation but no difference in bicarbonate levels at either time point. Infants in the protein group maintained their weight z score from birth to 3 months of age, while infants in the standard group had a significant decrease in their weight z score over the same time period. CONCLUSION: These results suggest that enteral protein supplementation may reduce growth failure in infants with brain injury.

Ketogenic diet in a patient with congenital hyperinsulinism: a novel approach to prevent brain damage.

BACKGROUND: Congenital hyperinsulinism (CHI) is the most frequent cause of hypoglycemia in children. In addition to increased peripheral glucose utilization, dysregulated insulin secretion induces profound hypoglycemia and neuroglycopenia by inhibiting glycogenolysis, gluconeogenesis and lipolysis. This results in the shortage of all cerebral energy substrates (glucose, lactate and ketones), and can lead to severe neurological sequelae. Patients with CHI unresponsive to medical treatment can be subjected to near-total pancreatectomy with increased risk of secondary diabetes. Ketogenic diet (KD), by reproducing a fasting-like condition in which body fuel mainly derives from beta-oxidation, is intended to provide alternative cerebral substrates such ketone bodies. We took advantage of known protective effect of KD on neuronal damage associated with GLUT1 deficiency, a disorder of impaired glucose transport across the blood-brain barrier, and administered KD in a patient with drug-unresponsive CHI, with the aim of providing to neurons an energy source alternative to glucose. METHODS: A child with drug-resistant, long-standing CHI caused by a spontaneous GCK activating mutation (p.Val455Met) suffered from epilepsy and showed neurodevelopmental abnormalities. After attempting various therapeutic regimes without success, near-total pancreatectomy was suggested to parents, who asked for other options. Therefore, we proposed KD in combination with insulin-suppressing drugs. RESULTS: We administered KD for 2 years. Soon after the first six months, the patient was free of epileptic crises, presented normalization of EEG, and showed a marked recover in psychological development and quality of life. CONCLUSIONS: KD could represent an effective treatment to support brain function in selected cases of CHI.