Exploring blood-brain barrier hyperpermeability and potential biomarkers in traumatic brain injury.

Blood-brain barrier breakdown and associated vascular hyperpermeability leads to vasogenic edema in traumatic brain injury (TBI). Tight junctions maintain blood-brain barrier integrity; their disruption in TBI holds significant promise for diagnosis and treatment. A controlled cortical impactor was used for TBI in mouse studies. Blood was collected 1 h after injury and sent for antibody microarray analysis. Twenty human subjects with radiographic evidence of TBI were enrolled and blood collected within 48 h of admission. Control subjects were individuals with nontrauma diagnoses. The subjects were matched by age and gender. Enzyme-linked immunosorbent assays were performed on each TBI and control sample for tight junction-associated proteins (TJPs), inflammatory markers, and S100ß. Plasma was used to conduct in vitro monolayer permeability studies with human brain endothelial cells. S100ß and the TJP occludin were significantly elevated in TBI plasma in both the murine and human studies. Monolayer permeability studies showed increased hyperpermeability in TBI groups. Plasma from TBI subjects increases microvascular hyperpermeability in vitro. TJPs in the blood may be a potential biomarker for TBI.

Quetiapine protects the blood-brain barrier in traumatic brain injury.

BACKGROUND: The integrity of the blood-brain barrier (BBB) is paramount in limiting vasogenic edema following traumatic brain injury (TBI). The purpose of this study was to ascertain if quetiapine, an atypical antipsychotic commonly used in trauma/critical care for delirium, protects the BBB and attenuates hyperpermeability in TBI. METHODS: The effect of quetiapine on hyperpermeability was examined through molecular modeling, cellular models in vitro and small animal models in vivo. Molecular docking was performed with AutoDock Vina to matrix metalloproteinase-9. Rat brain microvascular endothelial cells (BMECs) were pretreated with quetiapine (20 µM; 1 hour) followed by an inflammatory activator (20 µg/mL chitosan; 2 hours) and compared to controls. Immunofluorescence localization for tight junction proteins zonula occludens-1 and adherens junction protein ß-catenin was performed. Human BMECs were grown as a monolayer and pretreated with quetiapine (20 µM; 1 hour) followed by chitosan (20 µg/mL; 2 hours), and transendothelial electrical resistance was measured. C57BL/6 mice (n = 5/group) underwent mild to moderate TBI (controlled cortical impactor) or sham craniotomy. The treatment group was given 10 mg/kg quetiapine intravenously 10 minutes after TBI. The difference in fluorescence intensity between intravascular and interstitium (ΔI) represented BBB hyperpermeability. A matrix metalloproteinase-9 activity assay was performed in brain tissue from animals in the experimental groups ex vivo. RESULTS: In silico studies showed quetiapine thermodynamically favorable binding to MMP-9. Junctional localization of zonula occludens-1 and ß-catenin showed retained integrity in quetiapine-treated cells as compared with the chitosan group in rat BMECs. Quetiapine attenuated monolayer permeability compared with chitosan group (p < 0.05) in human BMECs. In the animal studies, there was a significant decrease in BBB hyperpermeability and MMP-9 activity when compared between the TBI and TBI plus quetiapine groups (p < 0.05). CONCLUSION: Quetiapine treatment may have novel anti-inflammatory properties to provide protection to the BBB by preserving tight junction integrity. LEVEL OF EVIDENCE: level IV.

Correlation between capnography and arterial carbon dioxide before, during, and after severe chest injury in swine.

The relationship between end-tidal carbon dioxide (EtCO(2)) and arterial carbon dioxide (PaCO(2))-if better defined-could facilitate the difficult task of ventilation in prehospital trauma patients. We aimed to study the PaCO(2)-EtCO(2) relationship before, during, and after chest trauma, hemorrhage, and resuscitation in swine. Twenty-four swine were intubated, anesthetized, and monitored in an animal intensive care unit during three phases: phase 1 (day 1, healthy animals); phase 2 (day 2, injury), which consisted of blunt chest trauma, hemorrhage, and resuscitation; and phase 3 (day 2, after injury). "Respiratory maneuvers" (changes in respiratory rate and tidal volume [TV], intended to vary the PaCO(2) over a range of 25 to 85 mmHg, were performed during phases 1 and 3. End-tidal CO(2) and PaCO(2) were recorded after each respiratory maneuver and analyzed using linear regression. During phase 1, PaCO(2) and EtCO(2) were strongly correlated (r(2) = 0.97, P < 0.01). During phase 2, animals developed decreased oxygenation (PaO(2):FiO(2) [fraction of inspired oxygen] ratio <200) and hypotension (mean arterial pressure, 20-50 mmHg); the PaCO(2)-EtCO(2) relationship deteriorated (r(2) = 0.25, P < 0.0001). During phase 3, oxygenation, hemodynamics, and the PaCO(2)-EtCO(2) relationship recovered (r(2) = 0.92, P < 0.01). End-tidal CO(2) closely correlates to PaCO(2) in healthy animals and after injury/resuscitation across a wide range of respiratory rates and tidal volumes. Once oxygenation and hemodynamics are restored, EtCO(2) can be used to predict PaCO(2) following chest trauma/hemorrhage and should be considered for patient monitoring. This work demonstrated that EtCO(2) alone can reliably be used to estimate PaCO(2) in uninjured subjects and in those subjects who have been resuscitated from severe injury. Immediately after blunt chest injury, the correlation between EtCO(2) and PaCO(2) is temporarily unstable. Under these circumstances (with abnormal oxygenation and/or hemodynamics), greater caution and other monitoring tools may be required.