Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury.

OBJECTIVES: We have sought to develop an automated methodology for the continuous updating of optimal cerebral perfusion pressure (CPPopt) for patients after severe traumatic head injury, using continuous monitoring of cerebrovascular pressure reactivity. We then validated the CPPopt algorithm by determining the association between outcome and the deviation of actual CPP from CPPopt. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: A total of 327 traumatic head-injury patients admitted between 2003 and 2009 with continuous monitoring of arterial blood pressure and intracranial pressure. MEASUREMENTS AND MAIN RESULTS: Arterial blood pressure, intracranial pressure, and CPP were continuously recorded, and pressure reactivity index was calculated online. Outcome was assessed at 6 months. An automated curve fitting method was applied to determine CPP at the minimum value for pressure reactivity index (CPPopt). A time trend of CPPopt was created using a moving 4-hr window, updated every minute. Identification of CPPopt was, on average, feasible during 55% of the whole recording period. Patient outcome correlated with the continuously updated difference between median CPP and CPPopt (chi-square=45, p<.001; outcome dichotomized into fatal and nonfatal). Mortality was associated with relative "hypoperfusion" (CPP<CPPopt), severe disability with "hyperperfusion" (CPP>CPPopt), and favorable outcome was associated with smaller deviations of CPP from the individualized CPPopt. While deviations from global target CPP values of 60 mm Hg and 70 mm Hg were also related to outcome, these relationships were less robust. CONCLUSIONS: Real-time CPPopt could be identified during the recording time of majority of the patients. Patients with a median CPP close to CPPopt were more likely to have a favorable outcome than those in whom median CPP was widely different from CPPopt. Deviations from individualized CPPopt were more predictive of outcome than deviations from a common target CPP. CPP management to optimize cerebrovascular pressure reactivity should be the subject of future clinical trial in severe traumatic head-injury patients.

Caveolin expression changes in the neurovascular unit after juvenile traumatic brain injury: signs of blood-brain barrier healing?

Traumatic brain injury (TBI) is one of the major causes of death and disability in pediatrics, and results in a complex cascade of events including the disruption of the blood-brain barrier (BBB). A controlled-cortical impact on post-natal 17 day-old rats induced BBB disruption by IgG extravasation from 1 to 3 days after injury and returned to normal at day 7. In parallel, we characterized the expression of three caveolin isoforms, cav-1, cav-2 and cav-3. While cav-1 and cav-2 are expressed on endothelial cells, both cav-1 and cav-3 were found to be present on reactive astrocytes, in vivo and in vitro. Following TBI, cav-1 expression was increased in blood vessels at 1 and 7 days in the perilesional cortex. An increase of vascular cav-2 expression was observed 7 days after TBI. In contrast, astrocytic cav-3 expression decreased 3 and 7 days after TBI. Activation of eNOS (via its phosphorylation) was detected 1 day after TBI and phospho-eNOS was detected both in association with blood vessels and with astrocytes. The molecular changes involving caveolins occurring in endothelial cells following juvenile-TBI might participate, independently of eNOS activation, to a mechanism of BBB repair while, they might subserve other undefined roles in astrocytes.

Effect of n-3 fatty acids on markers of brain injury and incidence of sepsis-associated delirium in septic patients.

BACKGROUND: Data regarding immunomodulatory effects of parenteral n-3 fatty acids in sepsis are conflicting. In this study, the effect of administration of parenteral n-3 fatty acids on markers of brain injury, incidence of sepsis-associated delirium, and inflammatory mediators in septic patients was investigated. METHODS: Fifty patients with sepsis were randomized to receive either 2 ml/kg/day of a lipid emulsion containing highly refined fish oil (equivalent to n-3 fatty acids 0.12 mg/kg/day) during 7 days after admission to the intensive care unit or standard treatment. Markers of brain injury and inflammatory mediators were measured on days 1, 2, 3 and 7. Assessment for sepsis-associated delirium was performed daily. The primary outcome was the difference in S-100β from baseline to peak level between both the intervention and the control group, compared by t-test. Changes of all markers over time were explored in both groups, fitting a generalized estimating equations model. RESULTS: Mean difference in change of S-100β from baseline to peak level was 0.34 (95% CI: -0.18-0.85) between the intervention and control group, respectively (P = 0.19). We found no difference in plasma levels of S-100β, neuron-specific enolase, interleukin (IL)-6, IL-8, IL-10, and C-reactive protein between groups over time. Incidence of sepsis-associated delirium was 75% in the intervention and 71% in the control groups (risk difference 4%, 95% CI -24-31%, P = 0.796). CONCLUSION: Administration of n-3 fatty acids did not affect markers of brain injury, incidence of sepsis-associated delirium, and inflammatory mediators in septic patients.

Neuroprotection in acute brain injury: an up-to-date review.

Neuroprotective strategies that limit secondary tissue loss and/or improve functional outcomes have been identified in multiple animal models of ischemic, hemorrhagic, traumatic and nontraumatic cerebral lesions. However, use of these potential interventions in human randomized controlled studies has generally given disappointing results. In this paper, we summarize the current status in terms of neuroprotective strategies, both in the immediate and later stages of acute brain injury in adults. We also review potential new strategies and highlight areas for future research.

Normobaric Hyperoxia is Associated with Increased Cerebral Excitotoxicity After Severe Traumatic Brain Injury.

BACKGROUND: Normobaric oxygen therapy is frequently applied in neurocritical care, however, whether supplemental FiO2 has beneficial cerebral effects is still controversial. We examined in patients with severe traumatic brain injury (TBI) the effect of incremental FiO2 on cerebral excitotoxicity, quantified by cerebral microdialysis (CMD) glutamate. METHODS: This was a retrospective analysis of a database of severe TBI patients monitored with CMD and brain tissue oxygen (PbtO2). The relationship of FiO2-categorized into four separate ranges (<40, 41-60, 61-80, and >80 %)-with CMD glutamate was examined using ANOVA with Tukey's post hoc test. RESULTS: A total of 1,130 CMD samples from 36 patients-monitored for a median of 4 days-were examined. After adjusting for brain (PbtO2, intracranial pressure, cerebral perfusion pressure, lactate/pyruvate ratio, Marshall CT score) and systemic (PaCO2, PaO2, hemoglobin, APACHE score) covariates, high FiO2 was associated with a progressive increase in CMD glutamate [8.8 (95 % confidence interval 7.4-10.2) µmol/L at FiO2 < 40 % vs. 12.8 (10.9-14.7) µmol/L at 41-60 % FiO2, 19.3 (15.6-23) µmol/L at 61-80 % FiO2, and 22.6 (16.7-28.5) µmol/L at FiO2 > 80 %; multivariate-adjusted p < 0.05]. The threshold of FiO2-related increase in CMD glutamate was lower for samples with normal versus low PbtO2 < 20 mmHg (FiO2 > 40 % vs. FiO2 > 60 %). Hyperoxia (PaO2 > 150 mmHg) was also associated with increased CMD glutamate (adjusted p < 0.001). CONCLUSIONS: Incremental normobaric FiO2 levels were associated with increased cerebral excitotoxicity in patients with severe TBI, independent from PbtO2 and other important cerebral and systemic determinants. These data suggest that supra-normal oxygen may aggravate secondary brain damage after severe TBI.

BAPNE method and N eurorehabilitation in patients with severe acquired brain injury

The use of body percussion through BAPNE method in neurorehabilitation offers the possibility of studying the development of motor skills, attention, coordination, memory and social interaction of patients with neurological diseases. The experimental protocol was carried out on 52 patients with severe acquired brain injury. Patients were selected for the cut - off scores in the standard neuropsychologic al tests of sustained attention , divided and alert ; at least one emisoma intact, cut -off scores in the standard for procedural and semantic memory ; eye sight , hearing and speech intact. The first group of patients has supported the protocol BAPNE tougher with the traditional rehabilitation activities . The control group continued to perform exclusively the cognitive and neuromotor rehabilitation according to traditional protocols. At 6 months after administration of the protocol is expected to re-test to assess if present , the maintenance of the effects of rehabilitation obtained. Experimentation is carried out for 10 weeks following the protocol of BAPNE method in the Roboris Foundation of Rome.

Neuroenergetic Response to Prolonged Cerebral Glucose Depletion after Severe Brain Injury and the Role of Lactate.

Lactate may represent a supplemental fuel for the brain. We examined cerebral lactate metabolism during prolonged brain glucose depletion (GD) in acute brain injury (ABI) patients monitored with cerebral microdialysis (CMD). Sixty episodes of GD (defined as spontaneous decreases of CMD glucose from normal to low [<1.0 mmol/L] for at least 2 h) were identified among 26 patients. During GD, we found a significant increase of CMD lactate (from 4±2.3 to 5.4±2.9 mmol/L), pyruvate (126.9±65.1 to 172.3±74.1 μmol/L), and lactate/pyruvate ratio (LPR; 27±6 to 35±9; all, p<0.005), while brain oxygen and blood lactate remained normal. Dynamics of lactate and glucose supply during GD were further studied by analyzing the relationships between blood and CMD samples. There was a strong correlation between blood and brain lactate when LPR was normal (r=0.56; p<0.0001), while an inverse correlation (r=-0.11; p=0.04) was observed at elevated LPR >25. The correlation between blood and brain glucose also decreased from r=0.62 to r=0.45. These findings in ABI patients suggest increased cerebral lactate delivery in the absence of brain hypoxia when glucose availability is limited and support the concept that lactate acts as alternative fuel.

Cerebral Lactate Metabolism After Traumatic Brain Injury.

Cerebral energy dysfunction has emerged as an important determinant of prognosis following traumatic brain injury (TBI). A number of studies using cerebral microdialysis, positron emission tomography, and jugular bulb oximetry to explore cerebral metabolism in patients with TBI have demonstrated a critical decrease in the availability of the main energy substrate of brain cells (i.e., glucose). Energy dysfunction induces adaptations of cerebral metabolism that include the utilization of alternative energy resources that the brain constitutively has, such as lactate. Two decades of experimental and human investigations have convincingly shown that lactate stands as a major actor of cerebral metabolism. Glutamate-induced activation of glycolysis stimulates lactate production from glucose in astrocytes, with subsequent lactate transfer to neurons (astrocyte-neuron lactate shuttle). Lactate is not only used as an extra energy substrate but also acts as a signaling molecule and regulator of systemic and brain glucose use in the cerebral circulation. In animal models of brain injury (e.g., TBI, stroke), supplementation with exogenous lactate exerts significant neuroprotection. Here, we summarize the main clinical studies showing the pivotal role of lactate and cerebral lactate metabolism after TBI. We also review pilot interventional studies that examined exogenous lactate supplementation in patients with TBI and found hypertonic lactate infusions had several beneficial properties on the injured brain, including decrease of brain edema, improvement of neuroenergetics via a "cerebral glucose-sparing effect," and increase of cerebral blood flow. Hypertonic lactate represents a promising area of therapeutic investigation; however, larger studies are needed to further examine mechanisms of action and impact on outcome.

Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury.

Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy.

Circulating progenitor cells during exercise, muscle electro-stimulation and intermittent hypobaric hypoxia in patients with traumatic brain injury. A pilot study

BACKGROUND: Circulating progenitor cells (CPC) treatments may have great potential for the recovery of neurons and brain function. OBJECTIVE: To increase and maintain CPC with a program of exercise, muscle electro-stimulation (ME) and/or intermittent-hypobaric-hypoxia (IHH), and also to study the possible improvement in physical or psychological functioning of participants with Traumatic Brain Injury (TBI). METHODS: Twenty-one participants. Four groups: exercise and ME group (EEG), cycling group (CyG), IHH and ME group (HEG) and control group (CG). Psychological and physical stress tests were carried out. CPC were measured in blood several times during the protocol. RESULTS: Psychological tests did not change. In the physical stress tests the VO2 uptake increased in the EEG and the CyG, and the maximal tolerated workload increased in the HEG. CPC levels increased in the last three weeks in EEG, but not in CyG, CG and HEG. CONCLUSIONS: CPC levels increased in the last three weeks of the EEG program, but not in the other groups and we did not detect performed psychological test changes in any group. The detected aerobic capacity or workload improvement must be beneficial for the patients who have suffered TBI, but exercise type and the mechanisms involved are not clear.

Apolipoprotein E and Recovery from Traumatic Brain Injury

The outcome from traumatic brain injury (TBI) is variable and only partly explained by known prognostic factors. This is especially true for predicting long-term outcome. Genetic factors may influence the brain`s susceptibility to injury or capacity for repair and regeneration. To examine the association of apolipoproteinE (apoE) genotype with long-term outcome, hippocampal volumes and general brain atrophy, we determined the apoE genotype from 61 TBI patients who had been injured over on average 31 years earlier. The long-term outcome was evaluated with repeated neuropsychological testing and by applying various measures of everyday functioning and quality of life. Magnetic resonance imaging (MRI) based volumetric analyses of the hippocampus and lateral ventricles were performed. In the prospective study, the purpose was to examine the association between apoE genotype and visibility of traumatic brain lesions during the first year after TBI and the ability of apoE genotype, the Glasgow Coma Score (GCS), MRI findings and duration of posttraumatic amnesia (PTA) to predict the one-year outcome. Thirty-three patients with TBI were studied and the outcome was evaluated with the Head Injury Symptom Checklist (HISC) and the Glasgow Outcome Scale extended version (GOS-E) scores one year after the injury. MRI and apoE genotyping were carried out. After three decades, neither hippocampal nor lateral ventricle volumes differed significantly in those patients with the apoE ε4 allele vs those without this allele, but the TBI patients with the apoE ε4 allele showed significantly poorer general cognitive level than those without this allele. This decline was wholly accounted for by a subgroup of patients who had developed incident or clinical dementia. In the prospective study the apoE genotype was not associated with visible MRI changes or outcome. The duration of PTA and acute MRI were the best predictors of one-year outcome in TBI. A portion of the TBI patients with the apoE ε4 allele seem to be at risk of long-term cognitive decline. This association may involve mechanisms other than those responsible for the development of brain atrophy. The early MRI and PTA have an important role in assessing the injury severity and prognosis.

Cognitive Functions After Traumatic Brain Injury. A 30-year Follow-up Study

Many cognitive deficits after TBI (traumatic brain injury) are well known, such as memory and concentration problems, as well as reduced information-processing speed. What happens to patients and cognitive functioning after immediate recovery is poorly known. Cognitive functioning is flexible and may be influenced by genetic, psychological and environmental factors decades after TBI. The general aim of this thesis was to describe the long-term cognitive course after TBI, to find variables that may contribute to it, and how the cognitive functions after TBI are associated with specific medical factors and reduced survival. The original study group consisted of 192 patients with TBI who were originally assessed with the Mild Deterioration Battery (MDB) on average two years after the injury, during the years 1966 – 1972. During a 30-year follow-up, we studied the risks for reduced survival, and the mortality of the patients was compared with the general population using the Standardized Mortality Ratio (SMR). Sixty-one patients were re-assessed during 1998-2000. These patients were evaluated with the MDB, computerized testing, and with various other neuropsychological methods for attention and executive functions. Apolipoprotein-E (ApoE) genotyping and magnetic resonance imaging (MRI) based on volumetric analysis of the hippocampus and lateral ventricles were performed. Depressive symptoms were evaluated with the short form of the Beck depression inventory. The cognitive performance at follow-up was compared with a control group that was similar to the study group in regard to age and education. The cognitive outcome of the patients with TBI varied after three decades. The majority of the patients showed a decline in their cognitive level, the rest either improved or stayed at the same level. Male gender and higher age at injury were significant risk factors for the decline. Whereas most cognitive domains declined during the follow-up, semantic memory behaved in the opposite way, showing recovery after TBI. In the follow-up assessment, the memory decline and impairments in the set-shifting domain of executive functions were associated with MRI-volumetric measures, whereas reduction in information-processing speed was not associated with the MRI measures. The presence of local contusions was only weakly associated with cognitive functions. Only few cognitive methods for attention were capable of discriminating TBI patients with and without depressive symptoms. On the other hand, most complex attentional tests were sensitive enough to discriminate TBI patients (non-depressive) from controls. This means that complex attention functions, mediated by the frontal lobes, are relatively independent of depressive symptoms post-TBI. The presence of ApoE4 was associated with different kinds of memory processes including verbal and visual episodic memory, semantic memory and verbal working memory, depending on the length of time since TBI. Many other cognitive processes were not affected by the presence of ApoE4. Age at injury and poor vocational outcome were independent risk factors for reduced survival in the multivariate analysis. Late mortality was higher among younger subjects (age < 40 years at death) compared with the general population which should be borne in mind when assessing the need for rehabilitation services and long-term follow-up after TBI.

Evaluation of prognostic factors of decompressive craniectomy in the treatment of severe traumatic brain injury

OBJECTIVE: to determine predictive factors for prognosis of decompressive craniectomy in patients with severe traumatic brain injury (TBI), describing epidemiological findings and the major complications of this procedure.METHODS: we conducted a retrospective study based on analysis of clinical and neurological outcome, using the extended Glasgow outcome in 56 consecutive patients diagnosed with severe TBI scale treated in the emergency department from February 2004 to July 2012. The variables assessed were age, mechanism of injury, presence of pupillary changes, Glasgow coma scale (GCS) score on admission, CT scan findings (volume, type and association of intracranial lesions, deviation from the midline structures and classification in the scale of Marshall and Rotterdam).RESULTS: we observed that 96.4% of patients underwent unilateral decompressive craniectomy (DC) with expansion duraplasty, and the remainder to bilateral DC, 53.6% of cases being on the right 42.9% on the left, and 3.6% bilaterally, with predominance of the fourth decade of life and males (83.9%). Complications were described as transcalvarial herniation (17.9%), increased volume of brain contusions (16.1%) higroma (16.1%), hydrocephalus (10.7%), swelling of the contralateral lesions (5.3%) and CSF leak (3.6%).CONCLUSION: among the factors studied, only the presence of mydriasis with absence of pupillary reflex, scoring 4 and 5 in the Glasgow Coma Scale, association of intracranial lesions and diversion of midline structures (DML) exceeding 15mm correlated statistically as predictors of poor prognosis.