Mannose binding lectin deficiency attenuates neurobehavioral deficits following experimental traumatic brain injury

Introduction: Mannose binding lectin (MBL) is the activator of the lectin complement pathway. After cerebral ischemia it has been shown that MBL could be a mediator of secondary brain damage, in contrast after traumatic brain injury (TBI) there are data suggesting that it could be linked to neuroprotection. We tested the hypothesis that MBL is involved in the pathophysiology of TBI. We 1) characterized the temporal activation of MBL and 2) the effects of its inhibition in a model of experimental TBI. Methods: 1) Male C57/Bl6 mice were subjected to intraperitoneal anesthesia (Pentobarbital, 65 mg/kg) followed by the controlled cortical impact brain injury model of experimental TBI (injury parameters: velocity of 5 meter/second and 1 mm depth of deformation). MBL immunostaining was evaluated at various time points after TBI: 30 minutes, 1, 6, 12, 24, 48, 96 hours and 1 week using anti MBL-A and MBL-C antibodies (n=3). 2) The effects of MBL inhibition were evaluated by comparing functional and histologic outcomes in C57/Bl6 mice (WT) and in MBL knock-out (-/-) mice. Functional outcome was tested using the Composite Neuroscore and Beam Walk test weekly up to 4 weeks postinjury (n = 11). Histologic outcome was evaluated by calculating the contusion volume at 4 weeks postinjury (n = 6). Sham-operated mice received identical anesthesia without brain injury. Results: We observed a robust MBL positive immunostaining in the injured cerebral cortex starting at 30 minutes postinjury and up to 1 week, suggestive of an activation of this pathway following TBI. MBL was observed both at endothelial and tissue level. Consistently, injured WT and MBL (-/-) mice showed neurological motor deficits up to 4 weeks postinjury when compared to their sham controls. Notably, MBL (-/-) mice showed attenuated behavioral deficits when compared to their WT counterpart at 2-4 weeks postinjury (p < 0.01 for both Neuroscore and Beam Walk test). In contrast we observed similar contusion volumes at 4 weeks postinjury (WT = 15.6 \ub1 3.2 cm3 and MBL KO = 13.9 \ub1 3.2 cm3, p = 0.3). Conclusions: We observed that 1) MBL deposition and/or synthesis is increased following TBI; 2) MBL deficiency is associated with functional neuroprotection, suggesting that MBL modulation might be a potential therapeutic target after TBI

Chronic impact of traumatic brain injury on outcome and quality of life : a narrative review

Traditionally seen as a sudden, brutal event with short-term impairment, traumatic brain injury (TBI) may cause persistent, sometimes life-long, consequences. While mortality after TBI has been reduced, a high proportion of severe TBI survivors require prolonged rehabilitation and may suffer long-term physical, cognitive, and psychological disorders. Additionally, chronic consequences have been identified not only after severe TBI but also in a proportion of cases previously classified as moderate or mild. This burden affects the daily life of survivors and their families; it also has relevant social and economic costs. Outcome evaluation is difficult for several reasons: co-existing extra-cranial injuries (spinal cord damage, for instance) may affect independence and quality of life outside the pure TBI effects; scales may not capture subtle, but important, changes; co-operation from patients may be impossible in the most severe cases. Several instruments have been developed for capturing specific aspects, from generic health status to specific cognitive functions. Even simple instruments, however, have demonstrated variable inter-rater agreement. The possible links between structural traumatic brain damage and functional impairment have been explored both experimentally and in the clinical setting with advanced neuro-imaging techniques. We briefly report on some fundamental findings, which may also offer potential targets for future therapies. Better understanding of damage mechanisms and new approaches to neuroprotection-restoration may offer better outcomes for the millions of survivors of TBI

Intracranial pressure dynamics in patients with acute brain damage

The time pattern of intracranial pressure (ICP) during pressure-volume index (PVI) tests was analyzed in 20 patients with severe acute brain damage by means of a simple mathematical model. In most cases, a satisfactory fitting between model response and patient data was achieved by adjusting only four parameters: the cerebrospinal fluid (CSF) outflow resistance, the intracranial elastance coefficient, and the gain and time constant of cerebral autoregulation. The correlation between the parameter estimates was also analyzed to elucidate the main mechanisms responsible for ICP changes in each patient. Starting from information on the estimated parameter values and their correlation, the patients were classified into two main classes: those with weak autoregulation (8 of 20 patients) and those with strong autoregulation (12 of 20 patients). In the first group of patients, ICP mainly reflects CSF circulation and passive cerebral blood volume changes. In the second group, ICP exhibits paradoxical responses attributable to active changes in cerebral blood volume. Moreover, in two patients of the second group, the time constant of autoregulation is significantly increased (>40 s). The correlation between the parameter estimates was significantly different in the two groups of patients, suggesting the existence of different mechanisms responsible for ICP changes. Moreover, analysis of the correlation between the parameter estimates might give information on the directions of parameter changes that have a greater impact on ICP

Neuro-Link, a computer-assisted database for head injury in intensive care

Reliable information is vital for clinical trials, so we developed a database, for head trauma victims admitted to neuro-intensive care units (NICU). This database, first step in a sequential project, comprises 176 selected fields mainly focused on the early post-traumatic phase and has a user-friendly computerized interface. The software was tested for a trimester in 18 Italian neuro-intensive care units. The paper describes the main features of the database, the results of a three months' data collection test, its limitations and its potential improvements. A description of the database fields and a brief summary of the 282 patients included so far are also presented

Metformin increases skeletal muscle lactate production in pigs: a microdialysis study

Introduction Lactic acidosis during metformin intoxication is mainly attributed to impaired hepatic lactate clearance [1]. The aim of this present work was to clarify whether metformin at high dose also increases skeletal muscle lactate production. Methods Reverse microdialysis was used in six healthy, sedated and mechanically ventilated pigs, equipped with two skeletal muscle catheters (CMA Microdialysis AB, Sweden). Following a baseline recording, a continuous infusion of saline (control) or metformin diluted in saline (1 mol/l) began. Outfl ow lactate concentration was measured every 3 hours, up to 12 hours. Results Data are presented as the mean and standard deviation in Figure 1. The interaction between infusion (saline vs. metformin) and time was statistically signifi cant (P = 0.02; two-way repeated-measures ANOVA). Conclusions In skeletal muscle, a high dose of metformin increases interstitial lactate levels, a fi nding consistent with local lactate overproduction. Reference 1. Lalau JD: Drug Saf 2010, 33:727-740

Accuracy of intracranial pressure monitoring : systematic review and meta-analysis

Introduction: Intracranial pressure (ICP) measurement is used to tailor interventions and to assist in formulating the prognosis for traumatic brain injury patients. Accurate data are therefore essential. The aim of this study was to verify the accuracy of ICP monitoring systems on the basis of a literature review. Methods: A PubMed search was conducted from 1982 to 2014, plus additional references from the selected papers. Accuracy was defined as the degree of correspondence between the pressure read by the catheter and a reference "real" ICP measurement. Studies comparing simultaneous readings from at least two catheters were included. Drift was defined as the loss of accuracy over the monitoring period. Meta-analyses of data from the studies were used to estimate the overall mean difference between simultaneous ICP measurements and their variability. Individual studies were weighted using both a fixed and a random effects model. Results: Of 163 articles screened, 83 compared two intracranial catheters: 64 reported accuracy and 37 drift(some reported both). Of these, 10 and 17, respectively, fulfilled the inclusion criteria for accuracy and zero drift analysis. The combined mean differences between probes were 1.5mmHg (95% confidence interval (CI) 0.7-2.3) with the random effects model and 1.6mmHg (95% CI 1.3-1.9) with the fixed effects model. The reported mean drift over a long observation period was 0.75mmHg. No relation was found with the duration of monitoring or differences between various probes. Conclusions: This study confirms that the average error between ICP measures is clinically negligible. The random effects model, however, indicates that a high percentage of readings may vary over a wide range, with clinical implications both for future comparison studies and for daily care

Brain oxygen tension, oxygen supply, and oxygen consumption during arterial hyperoxia in a model of progressive cerebral ischemia

We investigated the changes in brain oxygen tension (ptiO(2)) after ventilation with pure O-2 in order to (1) clarify the pathophysiology of O-2 exchange in the cerebral microcirculation; and (2) investigate the relationship between brain O-2 tension, O-2 delivery, and consumption in steady-state conditions during stepwise cerebral blood flow (CBF) reductions. A swine model was developed to reduce CBF in three stable steps: (1) baseline (CBF 100%), (2) CBF of 50-60% of baseline, and (3) CBF of (30% of baseline. CBF was reduced by infusing saline into the left lateral ventricle through a catheter connected with an infusion pump. At each step, hyperoxia was tested by increasing the inspired oxygen fraction up to 100%, PtiO(2) reflected the CBF reductions, since it was respectively 27.95 ( +/-10.15), 14.77 (+/-3.58), and 3.45 (+/-2.89) mm Hg during the three CBF steps. Hyperoxia was followed by an increase in ptiO(2), although the increase was significantly lower when hyperoxia was applied during progressive ischemia. O-2 supply to the brain did not change during hyperoxia. Arteriovenous oxygen difference (AVDO(2)) decreased during the phases of intact CBF and moderate impairment, but not during the phase of severe CBF reduction. In conclusion, ptiO(2) reductions closely reflect the imbalance between oxygen delivery and demand; this implies a link between low ptiO(2) and defective O-2 supply due to impaired CBF. However, this relation is not necessarily reciprocal, since manipulating brain oxygen tension does not always influence brain oxygen delivery, as in the case of ventilation with pure oxygen

Intracranial pressure after subarachnoid hemorrhage

Objectives: To describe mean intracranial pressure after aneurysmal subarachnoid hemorrhage, to identify clinical factors associated with increased mean intracranial pressure, and to explore the relationship between mean intracranial pressure and outcome. Design: Analysis of a prospectively collected observational database. Setting: Neuroscience ICU of an academic hospital. Patients: One hundred sixteen patients with subarachnoid hemorrhage and intracranial pressure monitoring. Interventions: None. Measurements and Main Results: Episodes of intracranial pressure greater than 20 mm Hg lasting at least 5 minutes and the mean intracranial pressure for every 12-hour interval were analyzed. The highest mean intracranial pressure was analyzed in relation to demographic characteristics, acute neurologic status, initial radiological findings, aneurysm treatment, clinical vasospasm, and ischemic lesion. Mortality and 6-month outcome (evaluated using a dichotomized Glasgow Outcome Scale) were also introduced in multivariable logistic models. Eighty-one percent of patients had at least one episode of high intracranial pressure and 36% had a highest mean intracranial pressure more than 20 mm Hg. The number of patients with high intracranial pressure peaked 3 days after subarachnoid hemorrhage and declined after day 7. Highest mean intracranial pressure greater than 20 mm Hg was significantly associated with initial neurologic status, aneurysmal rebleeding, amount of blood on CT scan, and ischemic lesion within 72 hours from subarachnoid hemorrhage. Patients with highest mean intracranial pressure greater than 20 mm Hg had significantly higher mortality. When death, vegetative state, and severe disability at 6 months were pooled, however, intracranial pressure was not an independent predictor of unfavorable outcome. Conclusions: High intracranial pressure is a common complication in the first week after subarachnoid hemorrhage in severe cases admitted to ICU. Mean intracranial pressure is associated with the severity of early brain injury and with mortality

Evaluation of the relationship between slow-waves of intracranial pressure, mean arterial pressure and brain tissue oxygen in TBI: a CENTER-TBI exploratory analysis.

Brain tissue oxygen (PbtO2) monitoring in traumatic brain injury (TBI) has demonstrated strong associations with global outcome. Additionally, PbtO2 signals have been used to derive indices thought to be associated with cerebrovascular reactivity in TBI. However, their true relationship to slow-wave vasogenic fluctuations associated with cerebral autoregulation remains unclear. The goal of this study was to investigate the relationship between slow-wave fluctuations of intracranial pressure (ICP), mean arterial pressure (MAP) and PbtO2 over time. Using the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) high resolution ICU sub-study cohort, we evaluated those patients with recorded high-frequency digital intra-parenchymal ICP and PbtO2 monitoring data of a minimum of 6 h in duration. Digital physiologic signals were processed for ICP, MAP, and PbtO2 slow-waves using a moving average filter to decimate the high-frequency signal. The first 5 days of recording were analyzed. The relationship between ICP, MAP and PbtO2 slow-waves over time were assessed using autoregressive integrative moving average (ARIMA) and vector autoregressive integrative moving average (VARIMA) modelling, as well as Granger causality testing. A total of 47 patients were included. The ARIMA structure of ICP and MAP were similar in time, where PbtO2 displayed different optimal structure. VARIMA modelling and IRF plots confirmed the strong directional relationship between MAP and ICP, demonstrating an ICP response to MAP impulse. PbtO2 slow-waves, however, failed to demonstrate a definite response to ICP and MAP slow-wave impulses. These results raise questions as to the utility of PbtO2 in the derivation of cerebrovascular reactivity measures in TBI. There is a reproducible relationship between slow-wave fluctuations of ICP and MAP, as demonstrated across various time-series analytic techniques. PbtO2 does not appear to reliably respond in time to slow-wave fluctuations in MAP, as demonstrated on various VARIMA models across all patients. These findings suggest that PbtO2 should not be utilized in the derivation of cerebrovascular reactivity metrics in TBI, as it does not appear to be responsive to changes in MAP in the slow-waves. These findings corroborate previous results regarding PbtO2 based cerebrovascular reactivity indices.</p