"THE MANTLE" bundle for minimizing cerebral hypoxia in severe traumatic brain injury.

To ensure neuronal survival after severe traumatic brain injury, oxygen supply is essential. Cerebral tissue oxygenation represents the balance between oxygen supply and consumption, largely reflecting the adequacy of cerebral perfusion. Multiple physiological parameters determine the oxygen delivered to the brain, including blood pressure, hemoglobin level, systemic oxygenation, microcirculation and many factors are involved in the delivery of oxygen to its final recipient, through the respiratory chain. Brain tissue hypoxia occurs when the supply of oxygen is not adequate or when for some reasons it cannot be used at the cellular level. The causes of hypoxia are variable and can be analyzed pathophysiologically following "the oxygen route." The current trend is precision medicine, individualized and therapeutically directed to the pathophysiology of specific brain damage; however, this requires the availability of multimodal monitoring. For this purpose, we developed the acronym "THE MANTLE," a bundle of therapeutical interventions, which covers and protects the brain, optimizing the components of the oxygen transport system from ambient air to the mitochondria.

Relation of RhoA in Peripheral Blood Mononuclear Cells With Severity of Aneurysmal Subarachnoid Hemorrhage and Vasospasm.

BACKGROUND AND PURPOSE: Rho-kinase, an effector of RhoA, is associated with various cardiovascular diseases in circulating blood cells. However, the role of RhoA/Rho-kinase in peripheral blood mononuclear cells from patients with spontaneous aneurysmal subarachnoid hemorrhage (aSAH) has not yet been studied in relation to the severity of this disease. Therefore, we analyzed the expression and activity of RhoA as a possible biomarker in aSAH. METHODS: Twenty-four patients with aSAH and 15 healthy subjects were examined. Peripheral blood mononuclear cells were collected, and RhoA activity and expression were determined by RhoA activation assay kit (G-LISA) and enzyme-linked immunosorbent assay tests, respectively. The severity of aSAH was determined from the World Federation of Neurological Surgeon scale, and vasospasm was evaluated using clinical symptoms, arteriography, and sonography. RESULTS: RhoA expression was significantly increased in peripheral blood mononuclear cells from patients on days 0, 2, and 4 after aSAH versus healthy subjects (P=0.036, 0.010, and 0.018, respectively, by U Mann-Whitney analysis). There was a significant correlation between RhoA expression and injury severity on days 2 and 4 (Spearman test, day 2: r=0.682, n=14, P=0.007; day 4: r=0.721, n=14, P=0.004). No significant correlation was observed on day 0 (day 0: r=0.131, n=6, P=0.805). Active RhoA was not significantly different in patients and healthy subjects on days 0, 2, and 4 (P=0.243, 0.222, and 0.600, respectively) nor did it increase significantly on days 0 and 2 in patients with vasospasm versus patients without vasospasm (P=0.064 and 0.519, respectively). In contrast, active RhoA was significantly higher on day 4 in patients who developed vasospasm versus patients without vasospasm (P=0.028). CONCLUSIONS: Our preliminary results indicate that RhoA expression and activity in peripheral blood mononuclear cells might be related with aSAH severity and cerebral vasospasm. RhoA is a potential biomarker of the risks associated with aSAH.

IMPACT Score for Traumatic Brain Injury: Validation of the Prognostic Tool in a Spanish Cohort.

BACKGROUND: The aim of this work was to validate the IMPACT (International Mission for Prognosis and Analysis of Clinical Trials in TBI) model in a Spanish cohort of patients with moderate-severe TBI (traumatic brain injury). SETTING: Two level I neurotrauma centers. PARTICIPANTS: Patients admitted to these hospitals between 2011 and 2014 with a diagnosis of TBI and a Glasgow Coma Scale score of 12 or less. DESIGN: Prospective observational study. MAIN MEASURES: We collected prospectively the clinical variables included in the IMPACT models. Outcome evaluation was prospectively done at 6-month follow-up according to the Glasgow Outcome Scale. RESULTS: A total of 290 patients were included in the study. Forty-seven patients (16.2%) died within 6 months post-TBI, and 74 patients (25.5%) had an unfavorable outcome. The Hosmer-Lemeshow test revealed that there was no difference between observed and predicted outcomes; hence, the 3 models displayed adequate calibration for predicting 6-month mortality or unfavorable outcome. The receiver operating characteristic curve indicated that the 3 models (Core, Extended, and Lab) could accurately discriminate between favorable and unfavorable outcomes, as well as between survival and mortality (P < .001). CONCLUSION: The IMPACT model validates prediction of 6-month outcomes in a Spanish population of moderate-severe TBI. IMPACT Lab model is the one that presents a higher discriminative capacity. These results encourage the implementation of the IMPACT model as a prognostic tool in the management of patients with TBI.

Validation of S100B use in a cohort of Spanish patients with mild traumatic brain injury: a multicentre study.

INTRODUCTION: The aim of this study was to validate the S100B protein as a diagnostic tool for ruling out the presence of intracranial lesion (IL) after mild traumatic brain injury (mTBI). Subjects with a Glasgow Coma Scale (GCS) score of 15 and at least one neurological symptom post-trauma were selected from a large Spanish cohort. METHODS: A number of 260 patients with mTBI were enrolled. Blood samples were extracted within 6 h and CT scan performed within 24 h post-injury. Blood samples were also drawn from 18 healthy subjects. RESULTS: CT scan revealed the presence of IL in 22 patients (8.5%). Patients with mTBI had higher S100B serum levels (p = 0.008) than the healthy subjects (p < 0.001). The ROC analysis of S100B discriminated between patients with and without IL (AUC: 0.671; 95%CI: 0.574-0.769; p = 0.008). The multivariate analysis identified male gender (OR: 5.39; 95%CI: 1.45-20.10; p = 0.012), age > 65 (OR: 2.97; 95%CI: 1.04-8.44; p = 0.041) and S100B level >0.10 µg/L (OR: 7.93; 95%CI: 1.03-60.76; p = 0.046) as independent risk factors for IL in patients with mTBI. CONCLUSION: Measurement of S100B within 6 h of mTBI accurately predicts risk of IL in patients with a GCS score of 15 and at least one neurological symptom.

Comparison of two competitive enzyme immunoassay kits for quantification of plasma Urotensin-II in rats.

Changes in Urotensin-II (U-II) concentration, a potent vasoconstrictor peptide, have been detected in various pathologies, but it has been impossible to define a normality range. We aimed to analyze the concordance and interchangeability between two enzyme immunoassay methods developed by Phoenix Pharmaceuticals, Inc. to measure U-II plasma concentration in rats: ELISA and fluorescent EIA. Assays resulted positively correlated (r = 0.850; p < 0.01). There was a significant difference between assays values (p < 0.001). The analysis of agreement (Bland and Altman plot) stated that the mean of the differences was 2.055 (SD ± 0.588). Hence, we concluded that the two U-II assays were correlated but not interchangeable.

Effects of Red Blood Cell Transfusion on Long-Term Disability of Patients with Traumatic Brain Injury.

BACKGROUND: This 3-year prospective study examined the association between red blood cell transfusion (RBCT) and 1-year neurocognitive and disability levels in 309 patients with traumatic brain injury (TBI) admitted to the neurological intensive care unit (NICU). METHODS: Using a telephone interview-based survey, functional outcomes were assessed by the Glasgow Outcome Scale (GOS), Rancho Los Amigos Levels of Cognitive Functioning Scale (RLCFS), and Disability Rating Scale (DRS) and dichotomized as favorable and unfavorable (dependent variable). The adjusted influence of RBCT on unfavorable results was assessed by conventional logistic regression, controlling for illness severity and propensity score (introduced as a continuous variable and by propensity score-matched patients). RESULTS: Overall, 164 (53 %) patients received ≥1 unit of RBCT during their NICU stay. One year postinjury, transfused patients exhibited significantly higher unfavorable GOS (46.0 vs. 22.0 %), RLCFS (37.4 vs. 15.4 %), and DRS (39.6 vs. 18.7 %) scores than nontransfused patients. Although transfused patients were more severely ill upon admission, their adjusted odds ratios (95 % confidence intervals) for unfavorable GOS, RLCFS, and DRS scores were 2.5 (1.2-5.1), 3.0 (1.4-6.3), and 2.3 (1.1-4.8), respectively. These odds ratios remained largely unmodified when the calculated propensity score was incorporated as an independent continuous variable into the multivariate analysis. Furthermore, in 76 pairs of propensity score-matched patients, the rate of an unfavorable RLCFS score at the 1-year (but not 6-month) follow-up was significantly higher in transfused than nontransfused patients [3.0 (1.1-8.2)]. CONCLUSION: Our results strongly suggest an independent association between RBCT and unfavorable long-term functional outcomes of patients with TBI.

Gender influences cerebral oxygenation after red blood cell transfusion in patients with severe traumatic brain injury.

BACKGROUND: Important differences with respect to gender exist in the prognosis and mortality of traumatic brain injury (TBI) patients. The objective of this study was to assess the role of gender as an independent factor in cerebral oxygenation variations following red blood cell transfusion (RBCT). METHODS: This retrospective analysis of a prospective study was conducted on patients with severe TBI. Hemoglobin levels were measured at baseline and 6 h after transfusion. Brain tissue oxygen pressure (PbrO(2)), cerebral perfusion pressure (CPP), intracranial pressure (ICP), and mean arterial pressure (MAP) were measured at baseline, at the end of RBCT and at 1, 2, 3, 4, 5, and 6 h after transfusion. After the patients were stratified into two groups according to gender, the effect of RBCT on PbrO(2) (cerebral oxygenation) was analyzed using a multivariate analysis of variance with repeated measures (MANOVA). The MANOVA was repeated after adjusting for all covariables with baseline differences between groups. RESULTS: At baseline, we found differences in age (P = 0.01), weight (P = 0.03), MAP (P = 0.01), ISS (P = 0.05), and CCP (P = 0.01) between the groups. After adjusting for these co-variables, we observed that gender and age were related to the increase in PbrO(2) (P = 0.05 and P = 0.04, respectively). CONCLUSIONS: Our results suggest that the effect of RBCT on cerebral oxygenation, as measured by PbrO(2), is greater in women than in men.

The Infrascanner, a handheld device for screening in situ for the presence of brain haematomas.

PURPOSE: Early identification and treatment of intracranial haematomas in patients sustaining traumatic brain injury is fundamental to successful treatment. This pilot study evaluates the Infrascanner as a handheld medical screening tool for detection, in situ, of brain haematomas in patients with head injury. METHODS: This study included 35 TBI patients aged 17-76 (M = 47.6), admitted to the neurosurgical intensive care unit and observation unit of a University Hospital in a Level 1 trauma centre. The Infrascanner NIRS device uses near infrared light measurements to calculate optical density in brain regions. RESULTS: Results show Infrascanner sensitivity at 89.5% and specificity at 81.2%. PPV was 85% and NPV 86.7%. The device detected 90% of extra-axial, 88.9% of intra-axial and 93.3% of non-surgical haematomas (less than 25 mL). PPV for this classification was 82.3%; 87.5% sensitivity was found when the Infrascanner exam was performed within 12 hours post-trauma, whereas after 12 hours post-trauma, exams had 90.1% sensitivity. CONCLUSIONS: This study demonstrates that the Infrascanner is useful in initial examinations and screenings of patients with head injury as an adjunct to a CT scan or when it is not available and may allow earlier treatment and reduce secondary injury caused by present and delayed haematomas.

The prognostic value of the temporal course of S100beta protein in post-acute severe brain injury: A prospective and observational study.

PRIMARY OBJECTIVE: To study the predictive capacity of early S100beta samples for long-term outcome prediction after severe TBI. METHODS AND PROCEDURES: Eighty-seven patients with severe TBI were studied. Clinical and CT scan were taken at admission. S100beta concentration was quantified at admission and 24, 48 and 72 hours post-TBI (days 0, 1, 2 and 3). Outcome was assessed 12 months after discharge using Glasgow Outcome Score (GOS). RESULTS: Significant negative correlations were found between 1-year GOS and S100beta concentrations on days 1-3, but not on day 0. Deceased patients showed higher S100beta concentration than survivors on days 1-3. Good (GOS = 4-5) vs poor outcome (GOS = 1-3) differed significantly on day 3. Death outcome was independently predicted by day 2 (>2.37 microg l(-1)), day 3 (>1.41 microg l(-1)) samples and absence of pupillary reaction. Poor outcome was predicted independently only by pupillary reaction and the 72-hour sample (>1.1 microg l(-1)), but this predictive model was less satisfactory than the predictive model for death. CONCLUSIONS: A temporal profile of S100beta release from admission to 72 hours post-TBI is strongly recommended for use in identifying patients at risk of developing a worse outcome. The S100beta protein might be an early biomarker for predicting long-term outcome in patients with acute severe TBI.

International consensus on the monitoring of cerebral oxygen tissue pressure in neurocritical patients. / Consenso internacional sobre la monitorización de la presión tisular cerebral de oxígeno en pacientes neurocríticos.

Continuous monitoring of cerebral oxygenation and its application to the management of the severe neurological patient is a challenge for the management of patients with acute critical brain damage. Although several techniques have been described for monitoring brain, brain tissue oxygen monitoring provides relevant information about oxygen levels of brain tissue. However, the development of this technique has been associated with the need to answer not only some technical aspects of it as well as the meaning of the changes of the cerebral oxygenation in the neurocritical patient. The consensus document responds to various questions related to the monitoring of cerebral oxygenation by means of a cerebral oxygen tissue pressure sensor. For this purpose, a list of questions was prepared and a reviewed of the medical literature was made. The quality of the evidence and the degree of recommendation was evaluated using the GRADE methodology.

Brain Injury Biomarker Behavior in Spontaneous Intracerebral Hemorrhage.

BACKGROUND: S100B and neuron-specific enolase (NSE) have been widely studied in diverse neurocritical pathologies, being recognized as the most promising biomarkers for brain injury assessment. However, their role in intracerebral hemorrhage (ICH) has not been widely analyzed. METHODS: This was an observational prospective cohort study of patients with ICH admitted to a neurocritical care unit. Blood samples were collected on admission and at 24 hours, 48 hours, and 72 hours. Patient outcomes were assessed at 6 months after the event. RESULTS: Thirty-six patients with ICH were included in the study. The mortality rate was 36%. Nonsurvivors had higher S100B values than survivors at admission, 24 hours, and 48 hours (P < 0.05). Likewise, S100B levels were higher in patients with poor outcomes (modified Rankin Scale [mRS] score >4) compared with those with good outcome (mRS score ≤3) in the 24-hour, 48-hour, and 72-hour samples. Receiver operating characteristic (ROC) curve analysis showed that S100B at admission, 24 hours, and 48 hours can discriminate between patients who survive and those who die as a consequence of ICH. The 48-hour sample (area under the ROC curve, 0.817; P = 0.003) reached the best values for sensitivity (75%) and specificity (80%); cutoff, 0.250 µg/L. For 6-month functional outcome, S100B protein could differentiate between groups at 24, 48, and 72 hours. The S100B 24-hour sample had the best values for sensitivity (82.6%) and specificity (72.7%), with a cutoff of 0.202 µg/L. We found no clear relationship between NSE values and clinical characteristics. CONCLUSIONS: S100B protein acts as early predictor of mortality and functional outcome in patients with ICH. This biomarker measurement can provide additional information beyond clinical and radiologic findings to guide physicians in the management of these patients.

Impact of age of transfused blood on cerebral oxygenation in male patients with severe traumatic brain injury.

OBJECTIVE: Prolonged erythrocyte storage time might reduce the efficacy of transfusion. In this study, the effects of transfusion of erythrocytes with four different storage periods (<10 days, n = 18; 10-14 days, n = 15; 15-19 days, n = 17; and >19 days, n = 16 patients) on brain tissue oxygen tension (PtiO2) in stable male patients with severe traumatic brain injury were investigated during a 24-hr follow-up period. DESIGN: Prospective, observational study. SETTING: Neurotrauma critical care unit of a university hospital. PATIENTS: Sixty-six male, nonbleeding, hemodynamically stable anemic patients (hemoglobin <95 g/L) with Glasgow Coma Scale score <9. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PtiO2, cerebral perfusion pressure, mean arterial pressure, intracranial pressure, peripheral oxygen saturation, CO2 pressure at the end of expiration, and intracerebral temperature were recorded in all patients at baseline, immediately after the completion of transfusion, and 1, 2, 3, 4, 5, 6, 12, and 24 hrs posttransfusion. All four groups were homogeneous with respect to multiple baseline variables, except for storage time of transfused erythrocytes (p < .0001). There was a significant short-lasting (3-4 hrs) increase in PtiO2 values after transfusion of erythrocytes stored for <10 days, 10-14 days, or 15-19 days, compared with those at baseline. In contrast, no significant changes in PtiO2 were observed after transfusion of erythrocytes stored >19 days. CONCLUSIONS: Transfusion of erythrocytes increased cerebral oxygenation in patients with severe traumatic brain injury, except in those transfused with erythrocytes stored >19 days.

The hemodynamics of cognitive control: the level of concentration of oxygenated hemoglobin in the superior prefrontal cortex varies as a function of performance in a modified Stroop task.

The purpose of this study was to establish the relationship between the hemodynamic response of prefrontal cortex (PFC) and individual differences in cognitive control, as measured by a color-word interference task. Twenty-five healthy volunteers were observed through functional near infrared spectroscopy (fNIRS) while performing a modified Stroop paradigm. Mean concentration levels of oxygenated hemoglobin (oxy-Hb) were correlated with behavioral performance in the conflict task. Those with shorter reaction times had higher levels of oxy-Hb concentration in superior dorsolateral PFC. Our results are the first to show a positive correlation between behavioral performance and oxy-Hb levels in superior dorsolateral PFC in a cognitive conflict task. These results suggest that the availability of oxygen in the superior PFC, possibly linked to an increase in metabolism, may be related to attention level and effectiveness of cognitive control.

Rapid and simplified synthesis of [18F]Fluoromisonidazole and its use in PET imaging in an experimental model of subarachnoid hemorrhage.

Cerebral damage secondary to the vasospasm due to subarachnoid hemorrhage (SAH) is an important cause of morbid-mortality. We propose the use of the PET tracer [18F]Fluoromisonidazole to visualize the hypoxia due to the vasospasm. On the other hand [18F]Fluoromisonidazole synthesis process was optimized, avoiding HPLC purification using SPE cartridges instead, and reducing some synthesis steps. [18F]Fluoromisonidazole in vitro stability was tested for ten hours, and in vivo PET/CT images showed higher cerebral uptake in hemorrhagic animals than in control rats.

Hyperventilation Therapy for Control of Posttraumatic Intracranial Hypertension.

During traumatic brain injury, intracranial hypertension (ICH) can become a life-threatening condition if it is not managed quickly and adequately. Physicians use therapeutic hyperventilation to reduce elevated intracranial pressure (ICP) by manipulating autoregulatory functions connected to cerebrovascular CO2 reactivity. Inducing hypocapnia via hyperventilation reduces the partial pressure of arterial carbon dioxide (PaCO2), which incites vasoconstriction in the cerebral resistance arterioles. This constriction decrease cerebral blood flow, which reduces cerebral blood volume and, ultimately, decreases the patient's ICP. The effects of therapeutic hyperventilation (HV) are transient, but the risks accompanying these changes in cerebral and systemic physiology must be carefully considered before the treatment can be deemed advisable. The most prominent criticism of this approach is the cited possibility of developing cerebral ischemia and tissue hypoxia. While it is true that certain measures, such as cerebral oxygenation monitoring, are needed to mitigate these dangerous conditions, using available evidence of potential poor outcomes associated with HV as justification to dismiss the implementation of therapeutic HV is debatable and remains a controversial subject among physicians. This review highlights various issues surrounding the use of HV as a means of controlling posttraumatic ICH, including indications for treatment, potential risks, and benefits, and a discussion of what techniques can be implemented to avoid adverse complications.

Red Blood Cell Transfusion Guided by Near Infrared Spectroscopy in Neurocritically Ill Patients with Moderate or Severe Anemia: A Randomized, Controlled Trial.

In neurocritically ill patients (NCPs), the use of hemoglobin level as the sole indicator for red blood cell transfusion (RBCT) can result in under- or over-transfusion. This randomized controlled trial was conducted to ascertain whether a transcranial oxygen saturation (rSO2) threshold, as measured by near-infrared spectroscopy, reduces RBCT requirements in anemic NCPs (closed traumatic brain injury, subarachnoid, or intracerebral hemorrhage), compared with a hemoglobin threshold alone. Patients with hemoglobin 70-100 g/L received RBCTs to attain an rSO2 > 60% (rSO2 arm) or to maintain hemoglobin between 85 and 100 g/L (hemoglobin arm). A total of 102 NCPs (51 in each group) were included in the intention-to-treat analysis, and 97 were included in the per-protocol analysis (51 and 46, respectively). Compared with those from the hemoglobin arm, patients in rSO2 arm received fewer RBC units (1.0 ± 0.1 vs. 1.5 ± 1.4 units/patient; p < 0.05) and showed lower hemoglobin levels while in protocol. There were no differences between the study arms regarding the percentage of transfused patents (59% vs. 71%; relative risk 0.83 [95% CI 0.62-1.11]), stay on neurocritical care unit (21 vs. 20 days), unfavorable Glasgow Outcome Scale scores on hospital discharge (57% vs. 71%), in-hospital mortality (6% vs. 10%), or 1 year mortality (24% vs. 24%). Among NCPs with hemoglobin concentrations of 70-85 g/L, withholding transfusion until rSO2 is <60% may result in reduced RBCs requirements compared with routinely transfusing to attain a hemoglobin level >85 g/L. Further studies are required to confirm this finding and its possible impact on clinically significant outcomes.