J.J. Egea-Guerrero

Oxidative Stress in Traumatic Brain Injury

Traumatic brain injury (TBI) is a major healthcare concern, constituting a major cause of death and disability throughout the world. Among the factors leading to TBI outcome are biochemical cascades which occur in response to primary and secondary injury. These mechanisms generate oxidative stress, an imbalance between oxidant and antioxidant agents that can result in neural dysfunction and death. After TBI, an assembly of oxidative stress markers (carbonylated proteins, lipid peroxides, reactive oxygen and reactive nitrogen species) are produced in the brain, while antioxidant defense enzymes decrease (GSH, ratio GSH/GSSG, GPx, GR, GST, G-6PD, SOD, CAT). This imbalance is directly related to the pathogenesis of TBI. Therefore, the development of antioxidant strategies is of primary interest in ongoing efforts to optimize brain injury treatment. The success of any drug intervention strategy relies, in part, on knowledge of the optimal dosage and therapeutic window for its administration. But while the enzymes involved in oxidative stress have been identified, the temporal course of this imbalance following TBI has yet to be determined. This would explain why most antioxidant strategies developed to treat patients with TBI have failed.

Role of early cell-free DNA levels decrease as a predictive marker of fatal outcome after severe traumatic brain injury.

INTRODUCTION Circulating cell-free DNA levels are increased after trauma injury. This increase is higher since the first hours after trauma and may be related with primary outcome. A sensitive and reliable biomarker for patients at higher risk is needed to identify these patients to initiate early intervention. In this way, circulating DNA may be a possible biological marker after severe TBI. MATERIALS AND METHODS We investigated DNA plasma concentrations after severe traumatic brain injury and during the next 96 h in the Intensive Care Unit (ICU) by real time PCR. 65 patients suffering severe TBI were included in the study. RESULTS Cell-free DNA levels were considerably higher in patients samples compared with voluntary control ones. After the following four days we observed a 51% decrease during the first 24h and a 71% fall from 48 h. TBI population was stratified for the primary outcome (survivors/non-survivor) and DNA levels decrease ratio was calculated for the first 48 h. A higher decrease in the survivors from 0 h to 24h compared with the non-survivors was found. A cut-off point of 1.95 ratio was established for the detection of the highest proportions of patients after the TBI that will not survive after the injury with a sensitivity of 70% and specificity of 66%. CONCLUSIONS In summary we showed that severe TBI is associated with elevated cf-DNA levels and we propose that cf-DNA decrease during the first 24h may predict patient outcome.

Accuracy of the S100β protein as a marker of brain damage in traumatic brain injury.

Introduction: This study tested the hypothesis that S100β is a useful screening tool for detecting intracranial lesion (IL) in patients with a normal level of consciousness after traumatic brain injury (TBI). Methods: One hundred and forty-three post-TBI patients without a decrease in consciousness (GCS = 15) and with at least one neurological symptom (e.g. transitory loss of consciousness, amnesia, headache, dizziness or vomiting) were prospectively included. A blood sample was drawn at 6-hours post-TBI. A routine CT scan was obtained within 24 hours post-injury. Diagnostic properties of S100β for IL prediction in CT scan findings were tested using ROC-analysis. Results: A total of 15 patients (10.5%) had IL. Serum levels were significantly higher in these patients. Significant differences were found between S100β levels and CT scan findings (p = 0.007). ROC-analysis showed that S100β is a useful tool for detecting the presence of IL in CT scans (p = 0.007). In this series, the best cut-off for S100β is 0.130 µg L−1, with 100% sensitivity and 32.81% specificity. Conclusion: Within the first 6 hours post-TBI, serum S100β seems to be an effective biochemical indicator of IL in patients without a decrease in consciousness. These results indicate that higher S100β cut-off values substantially improve the clinical relevance of this protein.

Role of S100B protein in urine and serum as an early predictor of mortality after severe traumatic brain injury in adults

S100B is a calcium-binding protein released into the blood from astroglial cells due to brain injury. Some authors have described a correlation between S100B serum concentration and severity of brain damage. There is not much information about the accuracy of urinary S100B for predicting outcome after severe traumatic brain injury (TBI). 55 patients with severe TBI were included in the study. Blood and urine samples were drawn to determine S100B levels on admission and on the subsequent 24, 48, 72 and 96 h. S100B concentrations (serum and urine) were significantly higher in patients who were dead a month after the accident compared to survivors. ROC-analysis showed that S100B at 24h post-severe TBI is a useful tool for predicting mortality (serum: AUC 0.958, urine: AUC 0.778). The best cut-offs for S100B were 0.461 μg/L and 0.025 μg/L (serum and urine respectively), with a sensitivity of 90% for both measurements and a specificity of 88.4% (serum) and 62.8% (urine). We can state that the determination of S100B levels both in urine and serum acts as a sensitive and an effective biomarker for the early prediction of mortality after severe TBI.

S100B Protein May Detect Brain Death Development after Severe Traumatic Brain Injury

Despite improvements in the process of organ donation and transplants, the number of organ donors is progressively declining in developed countries. Therefore, the early detection of patients at risk for brain death (BD) is a priority for transplant teams seeking more efficient identification of potential donors. In the extensive literature on S100B as a biomarker for traumatic brain injury (TBI), no evidence appears to exist on its prognostic capacity as a predictor of BD after severe TBI. The objective of this study is to assess the value of including acute S100B levels in standard clinical data as an early screening tool for BD after severe TBI. This prospective study included patients with severe TBI (Glasgow Coma Scale score [GCS] ≤ 8) admitted to our Neurocritical Care Unit over a 30 month period. We collected the following clinical variables: age, gender, GCS score, pupillary alterations at admission, hypotension and pre-hospital desaturation, CT scan results, isolated TBI or other related injuries, Injury Severity Score (ISS), serum S100B levels at admission and 24 h post-admission, and a final diagnosis regarding BD. Of the 140 patients studied, 11.4% developed BD and showed significantly higher S100B concentrations (p<0.001). Multivariate analysis showed that bilateral unresponsive mydriasis at admission and serum S100B at 24 h post-admission had odds ratios (ORs) of 21.35 (p=0.005) and 4.9 (p=0.010), respectively. The same analysis on patients with photomotor reflex in one pupil at admission left only the 24 h S100B sample in the model (OR=15.5; p=0.009). Receiver operating characteristics (ROC) curve analysis on this group showed the highest area under the curve (AUC) (0.86; p=0.001) for 24 h S100B determinations. The cut off was set at 0.372 μg/L (85.7% sensitivity, 79.3% specificity, positive predictive value [PPV]=18.7% and negative predictive value [NPV]=98.9%). This study shows that pupillary responsiveness at admission, as well as 24 h serum S100B levels, could serve as screening tools for the early detection of patients at risk for BD after severe TBI.

Clinical Variables and Neuromonitoring Information (Intracranial Pressure and Brain Tissue Oxygenation) as Predictors of Brain-Death Development After Severe Traumatic Brain Injury

BACKGROUND AND PURPOSE The aim of this study was to ascertain the role of clinical variables and neuromonitoring data as predictors of brain death (BD) after severe traumatic brain injury (TBI). PATIENTS AND METHODS This prospective observational study involved severe TBI patients admitted to the intensive care unit between October 2009 and May 2011. The following variables were recorded: gender, age, reference Glasgow Coma Scale after resuscitation, pupillary reactivity, prehospital hypotension and desaturation, injury severity score, computed tomography (CT) findings, intracranial hypertension, and low brain tissue oxygenation (Pti02) levels (<16 mm Hg), as well as the final result of BD. RESULTS Among 61 patients (86.9% males) who met the inclusion criteria, the average age was 37.69 ± 16.44 years. Traffic accidents were the main cause of TBI (62.3%). The patients at risk of progressing to BD (14.8% of the entire cohort) were those with a mass lesion on CT (odds ratio [OR] 33.6; 95% confidence interval [CI]: 3.75-300.30; P = .002), altered pupillary reaction at admission (OR 25.5; 95% CI: 2.27-285.65; P = .009), as well low Pti02 levels on admission (OR 20.41; 95% CI: 3.52-118.33; P < .001) and during the first 24 hours of neuromonitoring (OR 20; 95% CI: 2.90-137.83; P < .001). Multivariate logistic regression showed that a low Pti02 level on admission was the best independent predictor for BD (OR 20.41; 95% CI: 3.53-118.33; P = .001). CONCLUSIONS Clinical variables and neuromonitoring information may identify TBI patients at risk of deterioration to BD.

Biomarkers of vasospasm development and outcome in aneurysmal subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage (SAH) is a neurologic emergency caused by a brain aneurysm burst, resulting in a bleeding into the subarachnoid space. Its incidence is estimated between 4 and 28/10,000 inhabitants and it is the main cause of sudden death from stroke. The prognosis of patients with SAH is directly related to neurological status on admission, to the magnitude of the initial bleeding, as well as to the development of cerebral vasospasm (CVS). Numerous researchers have studied the role of different biomarkers in CVS development. These biomarkers form part of the metabolic cascade that is triggered as a result of the SAH. Hence, among these metabolites we found biomarkers of oxidative stress, inflammation biomarkers, indicators of brain damage, and markers of vascular pathology. However, to the author knowledge, none of these biomarkers has been demonstrated as a useful tool for predicting neither CVS development nor outcome after SAH. In order to reach success on future researches, firstly it should be stated which pathophysiological process is mainly responsible for CVS development. Once this process has been determined, the temporal course of this pathophysiologic cascade should be characterized, and then, perform further studies on biomarkers already analyzed, as well as on new biomarkers not yet studied in the SAH pathology, focusing attention on the temporal course of the diverse metabolites and the sampling time for its quantification.

Intravenous tranexamic acid for hyperacute primary intracerebral hemorrhage: Protocol for a randomized, placebo-controlled trial:

Rationale Outcome after intracerebral hemorrhage remains poor. Tranexamic acid is easy to administer, readily available, inexpensive, and effective in other hemorrhagic conditions. Aim This randomized trial aims to test the hypothesis that intravenous tranexamic acid given within 8 h of spontaneous intracerebral hemorrhage reduces death or dependency. Design Phase III prospective double-blind randomized placebo-controlled trial. Participants within 8 h of spontaneous intracerebral hemorrhage are randomized to receive either intravenous tranexamic acid 1 g 10 min bolus followed by 1 g 8 h infusion, or placebo. Sample size estimates A trial of 2000 participants (300 from start-up phase and 1700 from main phase) will have 90% power to detect an ordinal shift of the modified Rankin Scale with odds ratio 0.79. Study outcomes The primary outcome is death or dependency measured by ordinal shift analysis of the 7 level mRS at day 90. Secondary outcomes are neurological impairment at day 7 and disability, quality of life, cognition, and mood at day 90. Safety outcomes are death, serious adverse events, thromboembolic events, and seizures. Cost outcomes are length of stay in hospital, readmission, and institutionalization. Discussion This pragmatic trial is assessing efficacy of tranexamic acid after spontaneous intracerebral hemorrhage. Recruitment started in 2013; as of 15th January 2016 1355 participants have been enrolled, from 95 centers in seven countries. Recruitment is due to end in 2017. TICH-2 Trial is registered as ISRCTN93732214.

S100B and Neuron-Specific Enolase as mortality predictors in patients with severe traumatic brain injury

Objective: To determine temporal profile and prognostic ability of S100B protein and neuron-specific enolase (NSE) for prediction of short/long-term mortality in patients suffering from severe traumatic brain injury (sTBI). Methods: Ninety-nine patients with sTBI were included in the study. Blood samples were drawn on admission and on subsequent 24, 48, 72, and 96 h. Results: 15.2% of patients died in NeuroCritical Care Unit, and 19.2% died within 6 months of the accident. S100B concentrations were significantly higher in patients who died compared to survivors. NSE levels were different between groups just at 48 h. In the survival group, S100B levels decreased from 1st to 5th sample (p < 0.001); NSE just from 1st to 3rd (p < 0.001) and then stabilized. Values of S100B and NSE in non-survival patients did not significantly vary over the four days post sTBI. ROC-analysis showed that all S100B samples were useful tools for predicting mortality, the best the 72 h sample (AUC 0.848 for discharge mortality, 0.855 for six-month mortality). NSE ROC-analysis indicated that just the 48-h sample predicted mortality (AUC 0.733 for discharge mortality, 0.720 for six-month mortality). Conclusion: S100B protein showed higher prognostic capacity than NSE to predict short/long-term mortality in sTBI patients.

Modelo experimental de lesión cerebral tipo masa en rata: expresión del daño cerebral mediante enolasa neuroespecífica y proteína S100B

OBJECTIVE To determine whether a model of transient mass-type brain damage (MTBD) in the rat produces early release of neurospecific enolase (NSE) and protein S100B in peripheral blood, as an expression of the induced brain injury. DESIGN An experimental study with a control group. SETTING Experimental operating room of the Institute of Biomedicine (IBiS) of Virgen del Rocío University Hospital (Seville, Spain). PARTICIPANTS Fourteen adult Wistar rats. INTERVENTIONS Blood was sampled at baseline, followed by: MTBD group, a trephine perforation was used to insert and inflate the balloon of a catheter at a rate of 500 μl/20 sec, followed by 4 blood extractions every 20 min. Control group, the same procedure as before was carried out, though without trephine perforation. PRIMARY STUDY VARIABLES Weight, early mortality, serum NSE and S100B concentration. RESULTS Differences in NSE and S100B concentration were observed over time within the MTBD group (P<.001), though not so in the control group. With the exception of the baseline determination, differences were observed between the two groups in terms of the mean NSE and S100B values. Following MTBD, NSE and S100B progressively increased at all measurement timepoints, with r=0.765; P=.001 and r=0.628; P=.001, respectively. In contrast, the control group showed no such correlation for either biomarker. CONCLUSIONS Serum NSE and S100B concentrations offer an early indication of brain injury affecting the gray and white matter in an experimental model of mass-type MTBD in the rat.