Cerebral autoregulation in traumatic brain injury: ultra-low-frequency pressure reactivity index and intracranial pressure across age groups.

BACKGROUND: The ultra-low-frequency pressure reactivity index (UL-PRx) has been established as a surrogate method for bedside estimation of cerebral autoregulation (CA). Although this index has been shown to be a predictor of outcome in adult and pediatric patients with traumatic brain injury (TBI), a comprehensive evaluation of low sampling rate data collection (0.0033 Hz averaged over 5 min) on cerebrovascular reactivity has never been performed. OBJECTIVE: To evaluate the performance and predictive power of the UL-PRx for 12-month outcome measures, alongside all International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) models and in different age groups. To investigate the potential for optimal cerebral perfusion pressure (CPPopt). METHODS: Demographic data, IMPACT variables, in-hospital mortality, and Glasgow Outcome Scale Extended (GOSE) at 12 months were extracted. Filtering and processing of the time series and creation of the indices (cerebral intracranial pressure (ICP), cerebral perfusion pressure (CPP), UL-PRx, and deltaCPPopt (ΔCPPopt and CPPopt-CPP)) were performed using an in-house algorithm. Physiological parameters were assessed as follows: mean index value, % time above threshold, and mean hourly dose above threshold. RESULTS: A total of 263 TBI patients were included: pediatric (17.5% aged ≤ 16 y) and adult (60.5% aged > 16 and < 70 y and 22.0% ≥ 70 y, respectively) patients. In-hospital and 12-month mortality were 25.9% and 32.7%, respectively, and 60.0% of patients had an unfavorable outcome at 12 months (GOSE). On univariate analysis, ICP, CPP, UL-PRx, and ΔCPPopt were associated with 12-month outcomes. The cutoff of ~ 20-22 for mean ICP and of ~ 0.30 for mean UL-PRx were confirmed in all age groups, except in patients older than 70 years. Mean UL-PRx remained significantly associated with 12-month outcomes even after adjustment for IMPACT models. This association was confirmed in all age groups. UL-PRx resulted associate with CPPopt. CONCLUSIONS: The study highlights UL-PRx as a tool for assessing CA and valuable outcome predictor for TBI patients. The results emphasize the potential clinical utility of the UL-PRx and its adaptability across different age groups, even after adjustment for IMPACT models. Furthermore, the correlation between UL-PRx and CPPopt suggests the potential for more targeted treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05043545, principal investigator Paolo Gritti, date of registration 2021.08.21.

The Effect of Positive Pressure Ventilation on Acute Kidney Injury in COVID-19 Patients with Acute Respiratory Distress Syndrome: An Observational Study.

INTRODUCTION: Acute kidney injury (AKI) is frequent in critically ill COVID-19 patients and is associated with a higher mortality risk. By increasing intrathoracic pressure, positive pressure ventilation (PPV) may reduce renal perfusion pressure by reducing venous return to the heart or by increasing renal venous congestion. This study's aim was to evaluate the association between AKI and haemodynamic and ventilatory parameters in COVID-19 patients with ARDS. METHODS: This is a single-centre retrospective observational study. Consecutive patients diagnosed with COVID-19 who met ARDS criteria and required invasive mechanical ventilation were enrolled. The relationship between respiratory and haemodynamic parameters influenced by PPV and AKI development was evaluated. AKI was defined according to KDIGO criteria. AKI recovery was evaluated a month after ICU admission and patients were classified as "recovered," if serum creatinine (sCr) value returned to baseline, or as having "acute kidney disease" (AKD), if criteria for AKI stage 1 or greater persisted. The 6-month all-cause mortality was collected. RESULTS: A total of 144 patients were included in the analysis. AKI occurred in 69 (48%) patients and 26 (18%) required renal replacement therapy. In a multivariate logistic regression analysis, sex, hypertension, cumulative dose of furosemide, fluid balance, and plateau pressure were independently associated with AKI. Mortality at 6 months was 50% in the AKI group and 32% in the non-AKI group (p = 0.03). Among 36 patients who developed AKI and were discharged alive from the hospital, 56% had a full renal recovery after a month, while 14%, 6%, and 14% were classified as having an AKD of stage 0, 2, and 3, respectively. CONCLUSIONS: In our cohort, AKI was independently associated with multiple variables, including high plateau pressure, suggesting a possible role of PPV on AKI development. Further studies are needed to clarify the role of mechanical ventilation on renal function.

Evaluation and application of ultra-low-frequency pressure reactivity index in pediatric traumatic brain injury patients.

PURPOSE: While clinical practice suggests that knowing the cerebral autoregulation (CA) status of traumatic brain injury (TBI) patients is crucial in assessing the best treatment, evidence in pediatric TBI (pTBI) is limited. The pressure reactivity index (PRx) is a surrogate method for the continuous estimation of CA in adults; however, calculations require continuous, high-resolution monitoring data. We evaluate an ultra-low-frequency pressure reactivity index (UL-PRx), based on data sampled at ∼5-min periods, and test its association with 6-month mortality and unfavorable outcome in a cohort of pTBI patients. METHODS: Data derived from pTBI patients (0-18 years) requiring intracranial pressure (ICP) monitoring were retrospectively collected and processed in MATLAB using an in-house algorithm. RESULTS: Data on 47 pTBI patients were included. UL-PRx mean values, ICP, cerebral perfusion pressure (CPP), and derived indices showed significant association with 6-month mortality and unfavorable outcome. A value of UL-PRx of 0.30 was identified as the threshold to better discriminate both surviving vs deceased patients (AUC: 0.90), and favorable vs unfavorable outcomes (AUC: 0.70) at 6 months. At multivariate analysis, mean UL-PRx and % time with ICP > 20 mmHg, remained significantly associated with 6-month mortality and unfavorable outcome, even when adjusted for International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT)-Core variables. In six patients undergoing secondary decompressive craniectomy, no significant changes in UL-PRx were found after surgery. CONCLUSIONS: UL-PRx is associated with a 6-month outcome even if adjusted for IMPACT-Core. Its application in pediatric intensive care unit could be useful to evaluate CA and offer possible prognostic and therapeutic implications in pTBI patients. CLINICALTRIALS: GOV: NCT05043545, September 14, 2021, retrospectively registered.

Characterization of compliance phenotypes in COVID-19 acute respiratory distress syndrome.

BACKGROUND: Coronavirus disease 2019-associated acute respiratory distress syndrome (COVID-19 ARDS) seems to differ from the "classic ARDS", showing initial significant hypoxemia in the face of relatively preserved compliance and evolving later in a scenario of poorly compliant lungs. We tested the hypothesis that in patients with COVID-19 ARDS, the initial value of static compliance of respiratory system (Crs) (1) depends on the previous duration of the disease (i.e., the fewer days of illness, the higher the Crs and vice versa) and (2) identifies different lung patterns of time evolution and response to prone positioning. METHODS: This was a single-center prospective observational study. We enrolled consecutive mechanically ventilated patients with a diagnosis of COVID-19 who met ARDS criteria, admitted to intensive care unit (ICU). Patients were divided in four groups based on quartiles of initial Crs. Relationship between Crs and the previous duration of the disease was evaluated. Respiratory parameters collected once a day and during prone positioning were compared between groups. RESULTS: We evaluated 110 mechanically ventilated patients with a diagnosis of COVID-19 who met ARDS criteria admitted to our ICUs. Patients were divided in groups based on quartiles of initial Crs. The median initial Crs was 41 (32-47) ml/cmH2O. No association was found between the previous duration of the disease and the initial Crs. The Crs did not change significantly over time within each quartile. Positive end-expiratory pressure (PEEP) and driving pressure were respectively lower and greater in patients with lower Crs. Prone positioning significantly improved PaO2/FiO2 in the 4 groups, however it increased the Crs significantly only in patients in lower quartile of Crs. CONCLUSIONS: In our cohort, the initial Crs is not dependent on the previous duration of COVID-19 disease. Prone positioning improves oxygenation irrespective to initial Crs, but it ameliorates respiratory mechanics only in patients with lower Crs.

Coagulopathy and COVID-19.

SARS-CoV-2 infection is associated with frequent thrombotic events, at the micro and macro-vascular level, due to the perpetuation of a state of hypercoagulability. The so-called 'COVID-19 associated coagulopathy' (CAC) represents a key aspect in the genesis of organ damage from SARS-CoV-2. The main coagulative alterations described in the literature are represented by high levels of D-dimer and fibrinogen. Although CAC has some common features with disseminated intravascular coagulation and sepsis-induced coagulopathy, there are important differences between these clinical pictures and the phenotype of CAC is unique. The pathogenesis of CAC is complex and is affected by the strong interconnection between the inflammatory system and coagulation, in the phenomenon of immunothrombosis and thrombo-inflammation. Several mechanisms come into play, such as inflammatory cytokines, neutrophils, the complement system as well as an alteration of the fibrinolytic system. Finally, an altered platelet function and especially endothelial dysfunction also play a central role in the pathophysiology of CAC. Heparin has several potential effects in CAC, in fact in addition to the anticoagulant effect, it could have a direct antiviral effect and anti-inflammatory properties. The high incidence of thrombo-embolic phenomena despite the use of antithrombotic prophylaxis have led some experts to recommend the use of anticoagulant doses of heparin, but at present the optimal anticoagulant regimen remains to be determined.

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.

Mannose-binding lectin is expressed after clinical and experimental traumatic brain injury and its deletion is protective.

OBJECTIVE: Mannose-binding lectin protein is the activator of the lectin complement pathway. Goals were (1) to investigate mannose-binding lectin expression after human and experimental traumatic brain injury induced by controlled cortical impact and (2) to evaluate whether mannose-binding lectin deletion is associated with reduced sequelae after controlled cortical impact. DESIGN: Translational research, combining a human/experimental observational study and a prospective experimental study. SETTING: University hospital/research laboratory. PATIENTS AND SUBJECTS: Brain-injured patients, C57Bl/6 mice, and mannose-binding lectin-A and mannose-binding lectin-C double-knockout (-/-) mice. INTERVENTIONS: Using anti-human mannose-binding lectin antibody, we evaluated mannose-binding lectin expression in tissue samples from six patients who underwent surgery for a cerebral contusion. Immunohistochemistry was also performed on tissues obtained from mice at 30 minutes; 6, 12, 24, 48, and 96 hours; and 1 week after controlled cortical impact using anti-mouse mannose-binding lectin-A and mannose-binding lectin-C antibodies. We evaluated the effects of mannose-binding lectin deletion in wild-type and mannose-binding lectin-A and mannose-binding lectin-C double-knockout mice. Functional outcome was evaluated using the neuroscore and beam walk tests for 4 weeks postinjury (n = 11). Histological injury was evaluated by comparing neuronal cell counts in the cortex adjacent to the contusion (n = 11). MEASUREMENTS AND MAIN RESULTS: Following human traumatic brain injury, we observed mannose-binding lectin-positive immunostaining in the injured cortex as early as few hours and up to 5 days postinjury. Similarly in mice, we observed mannose-binding lectin-C-positive immunoreactivity in the injured cortex beginning 30 minutes and persisting up to 1 week postinjury. The extent of mannose-binding lectin-A expression was lower when compared with that of mannose-binding lectin-C. We observed attenuated sensorimotor deficits in mannose-binding lectin (-/-) mice compared with wild-type mice at 2-4 weeks postinjury. Furthermore, we observed reduced cortical cell loss at 5 weeks postinjury in mannose-binding lectin (-/-) mice compared with wild-type mice. CONCLUSIONS: Mannose-binding lectin expression was documented after traumatic brain injury. The reduced sequelae associated with mannose-binding lectin absence suggest that mannose-binding lectin modulation might be a potential target after traumatic brain injury.

Changes of the GPR17 receptor, a new target for neurorepair, in neurons and glial cells in patients with traumatic brain injury.

Unveiling the mechanisms participating in the damage and repair of traumatic brain injury (TBI) is fundamental to develop new therapies. The P2Y-like GPR17 receptor has recently emerged as a sensor of damage and a key actor in lesion remodeling/repair in the rodent brain, but its role in humans is totally unknown. Here, we characterized GPR17 expression in brain specimens from seven intensive care unit TBI patients undergoing neurosurgery for contusion removal and from 28 autoptic TBI cases (and 10 control subjects of matched age and gender) of two university hospitals. In both neurosurgery and autoptic samples, GPR17 expression was strong inside the contused core and progressively declined distally according to a spatio-temporal gradient. Inside and around the core, GPR17 labeled dying neurons, reactive astrocytes, and activated microglia/macrophages. In peri-contused parenchyma, GPR17 decorated oligodendrocyte precursor cells (OPCs) some of which had proliferated, indicating re-myelination attempts. In autoptic cases, GPR17 expression positively correlated with death for intracranial complications and negatively correlated with patients' post-traumatic survival. Data indicate lesion-specific sequential involvement of GPR17 in the (a) death of irreversibly damaged neurons, (b) activation of microglia/macrophages remodeling the lesion, and (c) activation/proliferation of multipotent parenchymal progenitors (both reactive astrocytes and OPCs) starting repair processes. Data validate GPR17 as a target for neurorepair and are particularly relevant to setting up new therapies for TBI patients.

Clinical frailty scale as a predictor of outcome in elderly patients affected by moderate or severe traumatic brain injury.

Background: Older age is a well-known risk factor for unfavorable outcome in traumatic brain injury (TBI). However, many older people with TBI respond well to aggressive treatments, suggesting that chronological age and TBI severity alone may be inadequate prognostic markers. Frailty is an age-related homeostatic imbalance of loss of physiologic and cognitive reserve resulting in both limitation in autonomy of activities of daily living and vulnerability to adverse events. We hypothesized that frailty would be associated with 6-month adverse functional outcome in older people affected by moderate or severe TBI. Methods: This was a single-center prospective observational study. We enrolled consecutive patients aged ≥65 years after TBI with Glasgow Coma Scale ≤13 and admitted to our Neurosurgical Intensive Care Unit. Frailty was evaluated by Clinical Frailty Scale (CFS). Relationships between TBI severity, frailty and extended Glasgow Outcome Scale (GOSE) at 6-month were evaluated. Results: Sixty patients were studied, 65% were males, their age was 76 years (IQR 70-80) and their admission GCS was 8 (IQR 6-11) with a GCS motor score of 5 (IQR 4-5). Twenty eight were vulnerable-frail (defined as CFS ≥ 4). Vulnerable-frail patients showed greater 6-month mortality and unfavorable outcome compared to non-frail [87% vs. 30% OR and 95% CI: 15.7 (3.9-55.2), p < 0.0001 and 92% vs. 51% OR and 95% CI: 9.9 (2.1-46.3), p = 0.002]. In univariate analysis patients with unfavorable outcome were more frequently male and vulnerable-frail, had a higher prevalence of pre-existing neurodegenerative disease, abnormal pupil, lower GCS and had worst CT scan characteristics. At multivariate analysis, only CFS ≥ 4 and traumatic subarachnoid hemorrhage remained associated to 6-month outcome. Conclusion: Frailty was associated with 6 month-outcome, suggesting that the pre-injury functional status could represent an additional indicator to stratify patient's severity and to predict outcome.

Evaluation and Application of Ultra-Low-Resolution Pressure Reactivity Index in Moderate or Severe Traumatic Brain Injury.

BACKGROUND: The pressure reactivity index (PRx) has emerged as a surrogate method for the continuous bedside estimation of cerebral autoregulation and a predictor of unfavorable outcome after traumatic brain injury (TBI). However, calculation of PRx require continuous high-resolution monitoring currently limited to specialized intensive care units. The aim of this study was to evaluate a new index, the ultra-low-frequency PRx (UL-PRx) sampled at ∼0.0033 Hz at ∼5 minutes periods, and to investigate its association with outcome. METHODS: Demographic data, admission Glasgow coma scale, in-hospital mortality and Glasgow outcome scale extended at 12 months were extracted from electronic records. The filtering and preparation of time series of intracranial pressure (ICP), mean arterial pressure and cerebral perfusion pressure (CPP), and calculation of the indices (UL-PRx, Δ-optimal CPP), were performed in MATLAB using an in-house algorithm. RESULTS: A total of 164 TBI patients were included in the study; in-hospital and 12-month mortality was 29.3% and 38.4%, respectively, and 64% of patients had poor neurological outcome at 12 months. On univariate analysis, ICP, CPP, UL-PRx, and ΔCPPopt were associated with 12-month mortality. After adjusting for age, Glasgow coma scale, ICP and CPP, mean UL-PRx and UL-PRx thresholds of 0 and +0.25 remained associated with 12-month mortality. Similar findings were obtained for in-hospital mortality. For mean UL-PRx, the area under the receiver operating characteristic curves for in-hospital and 12-month mortality were 0.78 (95% confidence interval [CI]: 0.69-0.87; P <0.001) and 0.70 (95% CI: 0.61-0.79; P <0.001), respectively, and 0.65 (95% CI: 0.57-0.74; P =0.001) for 12-month neurological outcome. CONCLUSIONS: Our findings indicate that ultra-low-frequency sampling might provide sufficient resolution to derive information about the state of cerebrovascular autoregulation and prediction of 12-month outcome in TBI patients.

MRI evidence of olfactory system alterations in patients with COVID-19 and neurological symptoms.

BACKGROUND AND OBJECTIVE: Despite olfactory disorders being among the most common neurological complications of coronavirus disease 2019 (COVID-19), their pathogenesis has not been fully elucidated yet. Brain MR imaging is a consolidated method for evaluating olfactory system's morphological modification, but a few quantitative studies have been published so far. The aim of the study was to provide MRI evidence of olfactory system alterations in patients with COVID-19 and neurological symptoms, including olfactory dysfunction. METHODS: 196 COVID-19 patients (median age: 53 years, 56% females) and 39 controls (median age 55 years, 49% females) were included in this cross-sectional observational study; 78 of the patients reported olfactory loss as the only neurological symptom. MRI processing was performed by ad-hoc semi-automatic processing procedures. Olfactory bulb (OB) volume was measured on T2-weighted MRI based on manual tracing and normalized to the brain volume. Olfactory tract (OT) median signal intensity was quantified on fluid attenuated inversion recovery (FLAIR) sequences, after preliminary intensity normalization. RESULTS: COVID-19 patients showed significantly lower left, right and total OB volumes than controls (p < 0.05). Age-related OB atrophy was found in the control but not in the patient population. No significant difference was found between patients with olfactory disorders and other neurological symptoms. Several outliers with abnormally high OT FLAIR signal intensity were found in the patient group. CONCLUSIONS: Brain MRI findings demonstrated OB damage in COVID-19 patients with neurological complications. Future longitudinal studies are needed to clarify the transient or permanent nature of OB atrophy in COVID-19 pathology.

Brain diffusion alterations in patients with COVID-19 pathology and neurological manifestations.

BACKGROUND AND OBJECTIVE: COVID-19 neurological manifestations have been progressively recognized. Among available MRI techniques, diffusion weighted imaging (DWI) shows promise to study microstructure, inflammation, and edema. Previous DWI studies reported alterations in brain diffusivity in COVID-19 patients, as assessed by morphologic evaluation of brain DWI scans only. The aim of this study was to assess and quantify brain diffusion alterations in COVID-19 patients with neurological manifestations. METHODS: 215 COVID-19 patients with neurological manifestations (olfactory and/or other neurological disorders) and 36 normal controls were compared and studied with DWI and T1-weighted MRI scans. MRI scans were processed by a semi-automatic processing procedure specifically developed for the purpose of this study, and the Apparent Diffusion Coefficient (ADC) was quantified in different brain tissues and individual white matter (WM) and gray matter (GM) regions. Differences in ADC values were assessed between COVID-19 patients and normal controls, as well as in the COVID-19 patient population grouped by hospitalization and neurological symptoms. RESULTS: Among COVID-19 patients (median [IQR] = 52 [42 - 60] years of age, 58 % females), 91 were hospitalized and 26 needed intensive care. 84 patients had hyposmia/ageusia only, while 131 ones showed other neurological disorders. COVID-19 patients showed significantly increased ADC values in the WM and in several GM regions (p < 0.001). ADC values were significantly correlated with MRI time from disease onset (p < 0.05). Hospitalized patients showed significantly higher ADC alteration than non-hospitalized patients in all brain tissues; similarly, COVID-19 patients with neurological disorders showed significantly higher ADC values than those with olfactory loss only. ADC alteration was highest in patients with cognitive or memory disorder and in those with encephalitis or meningitis. ADC values were neither associated with the duration of hospitalization nor with the need for intensive care. CONCLUSION: Current findings suggest DWI potential as a non-invasive marker of neuroinflammation in COVID-19, and the transient nature of the same. Future longitudinal studies are needed to confirm our findings.

Cerebral Microbleeds Assessment and Quantification in COVID-19 Patients With Neurological Manifestations.

It is increasingly acknowledged that Coronavirus Disease 2019 (COVID-19) can have neurological manifestations, and cerebral microbleeds (CMBs) have been observed in this setting. The aim of this study was to characterize CMBs patterns on susceptibility-weighted imaging (SWI) in hospitalized patients with COVID-19 with neurological manifestations. CMBs volume was quantified and correlated with clinical and laboratory parameters. The study included patients who were hospitalized due to COVID-19, exhibited neurological manifestations, and underwent a brain MRI between March and May 2020. Neurological, clinical, and biochemical variables were reported. The MRI was acquired using a 3T scanner, with a standardized protocol including SWI. Patients were divided based on radiological evidence of CMBs or their absence. The CMBs burden was also assessed with a semi-automatic SWI processing procedure specifically developed for the purpose of this study. Odds ratios (OR) for CMBs were calculated using age, sex, clinical, and laboratory data by logistic regression analysis. Of the 1,760 patients with COVID-19 admitted to the ASST Papa Giovanni XXIII Hospital between 1 March and 31 May 2020, 116 exhibited neurological symptoms requiring neuroimaging evaluation. Of these, 63 patients underwent brain MRI and were therefore included in the study. A total of 14 patients had radiological evidence of CMBs (CMBs+ group). CMBs+ patients had a higher prevalence of CSF inflammation (p = 0.020), a higher white blood cell count (p = 0.020), and lower lymphocytes (p = 0.010); the D-dimer (p = 0.026), LDH (p = 0.004), procalcitonin (p = 0.002), and CRP concentration (p < 0.001) were higher than in the CMBs- group. In multivariable logistic regression analysis, CRP (OR = 1.16, p = 0.011) indicated an association with CMBs. Estimated CMBs volume was higher in females than in males and decreased with age (Rho = -0.38; p = 0.18); it was positively associated with CRP (Rho = 0.36; p = 0.22), and negatively associated with lymphocytes (Rho = -0.52; p = 0.07). CMBs are a frequent imaging finding in hospitalized patients with COVID-19 with neurological manifestations and seem to be related to pro-inflammatory status.

Human umbilical cord blood mesenchymal stem cells protect mice brain after trauma.

OBJECTIVE: To investigate whether human umbilical cord blood mesenchymal stem cells, a novel source of progenitors with multilineage potential: 1) decrease traumatic brain injury sequelae and restore brain function; 2) are able to survive and home to the lesioned region; and 3) induce relevant changes in the environment in which they are infused. DESIGN: Prospective experimental study. SETTING: Research laboratory. SUBJECTS: Male C57Bl/6 mice. INTERVENTIONS: Mice were subjected to controlled cortical impact/sham brain injury. At 24 hrs postinjury, human umbilical cord blood mesenchymal stem cells (150,000/5 µL) or phosphate-buffered saline (control group) were infused intracerebroventricularly contralateral to the injured side. Immunosuppression was achieved by cyclosporine A (10 mg/kg intraperitoneally). MEASUREMENTS AND MAIN RESULTS: After controlled cortical impact, human umbilical cord blood mesenchymal stem cell transplantation induced an early and long-lasting improvement in sensorimotor functions assessed by neuroscore and beam walk tests. One month postinjury, human umbilical cord blood mesenchymal stem cell mice showed attenuated learning dysfunction at the Morris water maze and reduced contusion volume compared with controls. Hoechst positive human umbilical cord blood mesenchymal stem cells homed to lesioned tissue as early as 1 wk after injury in 67% of mice and survived in the injured brain up to 5 wks. By 3 days postinjury, cell infusion significantly increased brain-derived neurotrophic factor concentration into the lesioned tissue, restoring its expression close to the levels observed in sham operated mice. By 7 days postinjury, controlled cortical impact human umbilical cord blood mesenchymal stem cell mice showed a nonphagocytic activation of microglia/macrophages as shown by a selective rise (260%) in CD11b staining (a marker of microglia/macrophage activation/recruitment) associated with a decrease (58%) in CD68 (a marker of active phagocytosis). Thirty-five days postinjury, controlled cortical impact human umbilical cord blood mesenchymal stem cell mice showed a decrease of glial fibrillary acidic protein positivity in the scar region compared with control mice. CONCLUSIONS: These findings indicate that human umbilical cord blood mesenchymal stem cells stimulate the injured brain and evoke trophic events, microglia/macrophage phenotypical switch, and glial scar inhibitory effects that remodel the brain and lead to significant improvement of neurologic outcome.

Early management of patients with aneurysmal subarachnoid hemorrhage in a hospital without neurosurgical/neuroendovascular facilities: a consensus and clinical recommendations of the Italian Society of Anesthesia and Intensive Care (SIAARTI).

BACKGROUND: The immediate management of subarachnoid hemorrhage (SAH) patients in hospitals without neurosurgical/neurointerventional facilities and their transfer to a specialized center is challenging and not well covered in existing guidelines. To address these issues, we created a consensus of experts endorsed by the Italian Society of Anesthesia and Intensive Care (SIAARTI) to provide clinical guidance. METHODS: A multidisciplinary consensus panel composed by 19 physicians selected for their established clinical and scientific expertise in the acute management of SAH patients with different specializations (anesthesia/intensive care, neurosurgery and interventional neuroradiology) was created. A modified Delphi approach was adopted. RESULTS: A total of 14 statements have been discussed. Consensus was reached on 11 strong recommendations and 2 weak recommendations. In one case, where consensus could not be agreed upon, no recommendation could be provided. CONCLUSIONS: Management of SAH in a non-specialized setting and early transfer are difficult and may have a critical impact on outcome. Clinical advice, based on multidisciplinary consensus, might be helpful. Our recommendations cover most, but not all, topics of clinical relevance.

c-Jun N-terminal kinase pathway activation in human and experimental cerebral contusion.

The c-Jun N-terminal kinase (JNK) pathway is involved in cell stress and apoptosis. We tested the hypothesis that this pathway plays a role in traumatic brain injury (TBI) by assessing JNK activation in human brain tissues and in brains of mice subjected to controlled cortical impact brain injury. We also assessed the effects of specific inhibition of the JNK pathway by the cell-permeable JNK inhibitor peptide, D-JNKI1, on neurobehavioral function and posttraumatic cell loss in mice. The inhibitor was administered intraperitoneally 10 minutes after injury. The JNK pathway showed robust activation both in human contusion specimens and in injured cortex and hippocampi of TBI-injured mice, 1, 4, and 48 hours after injury. D-JNKI1 treatment significantly improved motor performance at 48 hours and 7 days after injury and reduced the contusion volume compared with saline treatment; the numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were significantly decreased in the hippocampi of injured mice 48 hours after treatment. Thus, because the JNK pathway is activated after human and experimental TBI and the inhibitor peptide D-JNKI1 affords significant neuroprotection and amelioration of neurobehavioral deficits after experimental TBI, therapeutic targeting of the JNK activation pathway may hold promise for future clinical applications.

C1-inhibitor attenuates neurobehavioral deficits and reduces contusion volume after controlled cortical impact brain injury in mice.

OBJECTIVE: The aim of the study was to evaluate the effects of C1-inhibitor (C1-INH), an endogenous inhibitor of complement and kinin systems, on neurobehavioral and histological outcome following controlled cortical impact brain injury. DESIGN: Experimental prospective randomized study in mice. SETTING: Experimental laboratory. SUBJECTS: Male C57Bl/6 mice (n = 81). INTERVENTIONS: Mice were subjected to controlled cortical impact brain injury followed by an intravenous bolus of either C1-INH (15 U either at 10 minutes or 1 hour postinjury) or saline (equal volume, 150 microl at 10 minutes postinjury). Sham-operated mice received identical surgery and saline injection without brain injury. Neurological motor function was evaluated weekly for 4 weeks using the Composite Neuroscore. Cognitive function was evaluated at 4 weeks postinjury using the Morris Water Maze. Histological outcome was performed by measuring the contusion volume at 1 week and 4 weeks postinjury. MEASUREMENTS AND MAIN RESULTS: Brain-injured mice receiving C1-INH at 10 minutes postinjury showed attenuated motor deficits, cognitive dysfunction and reduced contusion volume compared to brain-injured mice receiving saline. Mice receiving C1-INH at 1 hour postinjury showed reduced motor deficits compared to brain-injured mice receiving saline, but no significantly different cognitive and histological outcome. Immunohistochemical analysis showed that 20 minutes after infusion, C1-INH was localised on endothelial cells and in brain tissue surrounding brain capillaries of the injured hemisphere. CONCLUSION: Our results show that post-traumatic administration of C1-INH attenuates neuro-behavioral deficits and histological damage associated with traumatic brain injury.

Human brain trauma severity is associated with lectin complement pathway activation.

We explored the involvement of the lectin pathway of complement in post-traumatic brain injury (TBI) pathophysiology in humans. Brain samples were obtained from 28 patients who had undergone therapeutic contusion removal, within 12 h (early) or from >12 h until five days (late) from injury, and from five non-TBI patients. Imaging analysis indicated that lectin pathway initiator molecules (MBL, ficolin-1, ficolin-2 and ficolin-3), the key enzymes MASP-2 and MASP-3, and the downstream complement components (C3 fragments and TCC) were present inside and outside brain vessels in all contusions. Only ficolin-1 was found in the parenchyma of non-TBI tissues. Immunoassays in brain homogenates showed that MBL, ficolin-2 and ficolin-3 increased in TBI compared to non-TBI (2.0, 2.2 and 6.0-times) samples. MASP-2 increased with subarachnoid hemorrhage and abnormal pupil reactivity, two indicators of structural and functional damage. C3 fragments and TCC increased, respectively, by 3.5 - and 4.0-fold in TBI compared to non-TBI tissue and significantly correlated with MBL, ficolin-2, ficolin-3, MASP-2 and MASP-3 levels in the homogenates. In conclusion, we show for the first time the direct presence of lectin pathway components in human cerebral contusions and their association with injury severity, suggesting a central role for the lectin pathway in the post-traumatic pathophysiology of human TBI.