Exposure to Blast Overpressure Impairs Cerebral Microvascular Responses and Alters Vascular and Astrocytic Structure.

Exposure to blast overpressure may result in cerebrovascular impairment, including cerebral vasospasm. The mechanisms contributing to this vascular response are unclear. The aim of this study was to evaluate the relationship between blast and functional alterations of the cerebral microcirculation and to investigate potential underlying changes in vascular microstructure. Cerebrovascular responses were assessed in sham- and blast-exposed male rats at multiple time points from 2 h through 28 days after a single 130-kPa (18.9-psi) exposure. Pial microcirculation was assessed through a cranial window created in the parietal bone of anesthetized rats. Pial arteriolar reactivity was evaluated in vivo using hypercapnia, barium chloride, and serotonin. We found that exposure to blast leads to impairment of arteriolar reactivity >24 h after blast exposure, suggesting delayed injury mechanisms that are not simply attributed to direct mechanical deformation. Observed vascular impairment included a reduction in hypercapnia-induced vasodilation, increase in barium-induced constriction, and reversal of the serotonin effect from constriction to dilation. A reduction in vascular smooth muscle contractile proteins consistent with vascular wall proliferation was observed, as well as delayed reduction in nitric oxide synthase and increase in endothelin-1 B receptors, mainly in astrocytes. Collectively, the data show that exposure to blast results in delayed and prolonged alterations in cerebrovascular reactivity that are associated with changes in the microarchitecture of the vessel wall and astrocytes. These changes may contribute to long-term pathologies involving dysfunction of the neurovascular unit, including cerebral vasospasm.

Brain oxygenation with a non-vasoactive perfluorocarbon emulsion in a rat model of traumatic brain injury.

OBJECTIVE: The aim of this study was to assess, in two experiments, the safety and efficacy of the PFC emulsion Oxycyte as an oxygen therapeutic for TBI to test the hypothesis that early administration of this oxygen-carrying fluid post-TBI would improve brain tissue oxygenation (Pbt O2 ). METHODS: The first experiment assessed the effects of Oxycyte on cerebral vasoactivity in healthy, uninjured rats using intravital microscopy. The second experiment investigated the effect of Oxycyte on cerebral Pbt O2 using the PQM in TBI model. Animals in the Oxycyte group received a single injection of Oxycyte (6 mL/kg) shortly after TBI, while NON animals received no treatment. RESULTS: Oxycyte did not cause vasoconstriction in small- (<50 µm) or medium- (50-100 µm) sized pial arterioles nor did it cause a significant change in blood pressure. Treatment with Oxycyte while breathing 100% O2 did not improve Pbt O2 . However, in rats ventilated with ~40% O2 , Pbt O2 improved to near pre-TBI values within 105 minutes after Oxycyte injection. CONCLUSIONS: Although Oxycyte did not cause cerebral vasoconstriction, its use at the dose tested while breathing 100% O2 did not improve Pbt O2 following TBI. However, Oxycyte treatment while breathing a lower enriched oxygen concentration may improve Pbt O2 after TBI.

Cerebral Microvascular and Systemic Effects Following Intravenous Administration of the Perfluorocarbon Emulsion Perftoran.

Oxygen-carrying perfluorocarbon (PFC) fluids have the potential to increase tissue oxygenation during hypoxic states and to reduce ischemic cell death. Regulatory approval of oxygen therapeutics was halted due to concerns over vasoconstrictive side effects. The goal of this study was to assess the potential vasoactive properties of Perftoran by measuring brain pial arteriolar diameters in a healthy rat model. Perftoran, crystalloid (saline) or colloid (Hextend) solutions were administered as four sequential 30 min intravenous (IV) infusions, thus allowing an evaluation of cumulative dose-dependent effects. There were no overall changes in diameters of small-sized (<50 µm) pial arterioles within the Perftoran group, while both saline and Hextend groups exhibited vasoconstriction. Medium-sized arterioles (50-100 µm) showed minor (~8-9%) vasoconstriction within saline and Hextend groups and only ~5% vasoconstriction within the Perftoran group. For small- and medium-sized pial arterioles, the mean percent change in vessel diameters was not different among the groups. Although there was a tendency for arterial blood pressures to increase with Perftoran, pressures were not different from the other two groups. These data show that Perftoran, when administered to healthy anesthetized rats, does not cause additional vasoconstriction in cerebral pial arterioles or increase systemic blood pressure compared with saline or Hextend.

Sanguinate's effect on pial arterioles in healthy rats and cerebral oxygen tension after controlled cortical impact.

Sanguinate, a polyethylene glycol-conjugated carboxyhemoglobin, was investigated for cerebral vasoactivity in healthy male Sprague-Dawley rats (Study 1) and for its ability to increase brain tissue oxygen pressure (PbtO2) after controlled cortical impact (CCI) - traumatic brain injury (TBI) (Study 2). In both studies ketamine-acepromazine anesthetized rats were ventilated with 40% O2. In Study 1, a cranial window was used to measure the diameters of medium - (50-100µm) and small-sized (<50µm) pial arterioles before and after four serial infusions of Sanguinate (8mL/kg/h, cumulative 16mL/kg IV), volume-matched Hextend, or normal saline. In Study 2, PbtO2 was measured using a phosphorescence quenching method before TBI, 15min after TBI (T15) and then every 10min thereafter for 155min. At T15, rats received either 8mL/kg IV Sanguinate (40mL/kg/h) or no treatment (saline, 4mL/kg/h). Results showed: 1) in healthy rats, percentage changes in pial arteriole diameter were the same among the groups, 2) in TBI rats, PbtO2 decreased from 36.5±3.9mmHg to 19.8±3.0mmHg at T15 in both groups after TBI and did not recover in either group for the rest of the study, and 3) MAP increased 16±4mmHg and 36±5mmHg after Sanguinate in healthy and TBI rats, respectively, while MAP was unchanged in control groups. In conclusion, Sanguinate did not cause vasoconstriction in the cerebral pial arterioles of healthy rats but it also did not acutely increase PbtO2 when administered after TBI. Sanguinate was associated with an increase in MAP in both studies.

Perfluorocarbon NVX-108 increased cerebral oxygen tension after traumatic brain injury in rats.

BACKGROUND: Hypoxia is a critical secondary injury mechanism in traumatic brain injury (TBI), and early intervention to alleviate post-TBI hypoxia may be beneficial. NVX-108, a dodecafluoropentane perfluorocarbon, was screened for its ability to increase brain tissue oxygen tension (PbtO2) when administered soon after TBI. METHODS: Ketamine-acepromazine anesthetized rats ventilated with 40% oxygen underwent moderate controlled cortical impact (CCI)-TBI at time 0 (T0). Rats received either no treatment (NON, n=8) or 0.5 ml/kg intravenous (IV) NVX-108 (NVX, n=9) at T15 (15 min after TBI) and T75. RESULTS: Baseline cortical PbtO2 was 28±3 mm Hg and CCI-TBI resulted in a 46±6% reduction in PbtO2 at T15 (P<0.001). Significant differences in time-group interactions (P=0.013) were found when comparing either absolute or percentage change of PbtO2 to post-injury (mixed-model ANOVA) suggesting that administration of NVX-108 increased PbtO2 above injury levels while it remained depressed in the NON group. Specifically in the NVX group, PbtO2 increased to a peak 143% of T15 (P=0.02) 60 min after completion of NVX-108 injection (T135). Systemic blood pressure was not different between the groups. CONCLUSION: NVX-108 caused an increase in PbtO2 following CCI-TBI in rats and should be evaluated further as a possible immediate treatment for TBI.