Histopathological Evidence of Multiple Organ Damage After Simulated Aeromedical Evacuation in a Swine Acute Lung Injury Model.

INTRODUCTION: Rapid aeromedical evacuation (AE) is standard of care in current conflicts. However, not much is known about possible effects of hypobaric conditions. We investigated possible effects of hypobaria on organ damage in a swine model of acute lung injury. METHODS: Lung injury was induced in anesthetized swine via intravenous oleic acid infusion. After a stabilization phase, animals were subjected to a 4 hour simulated AE at 8000 feet (HYPO). Control animals were kept at normobaria. After euthanasia and necropsy, organ damage was assessed by combined scores for hemorrhage, inflammation, edema, necrosis, and microatelectasis. RESULTS: Hemodynamic, neurological, or hematologic measurements were similar prior to transport. Hemodynamic instability became apparent during the last 2 hours of transport in the HYPO group. Histological injury scores in the HYPO group were higher for all organs (lung, kidney, liver, pancreas, and adrenal glands) except the brain, with the largest difference in the lungs (P < 0.001). CONCLUSIONS: Swine with mild acute lung injury subjected to a 4 hour simulated AE showed more injury to most organs and, in particular, to the lungs compared with ground transport. This may exacerbate otherwise subclinical pathology and, eventually, manifest as abnormalities in gas exchange or possibly end-organ function.

N-acetylcysteine Amide Ameliorates Blast-Induced Changes in Blood-Brain Barrier Integrity in Rats.

Traumatic brain injury resulting from exposure to blast overpressure (BOP) is associated with neuropathology including impairment of the blood-brain barrier (BBB). This study examined the effects of repeated exposure to primary BOP and post-blast treatment with an antioxidant, N-acetylcysteine amide (NACA) on the integrity of BBB. Anesthetized rats were exposed to three 110 kPa BOPs separated by 0.5 h. BBB integrity was examined in vivo via a cranial window allowing imaging of pial microcirculation by intravital microscopy. Tetramethylrhodamine isothiocyanate Dextran (TRITC-Dextran, mw = 40 kDa or 150 kDa) was injected intravenously 2.5 h after the first BOP exposure and the leakage of TRITC-Dextran from pial microvessels into the brain parenchyma was assessed. The animals were randomized into 6 groups (n = 5/group): four groups received 40 kDa TRITC-Dextran (BOP-40, sham-40, BOP-40 NACA, and sham-40 NACA), and two groups received 150 kDa TRITC-Dextran (BOP-150 and sham-150). NACA treated groups were administered NACA 2 h after the first BOP exposure. The rate of TRITC-Dextran leakage was significantly higher in BOP-40 than in sham-40 group. NACA treatment significantly reduced TRITC-Dextran leakage in BOP-40 NACA group and sham-40 NACA group presented the least amount of leakage. The rate of leakage in BOP-150 and sham-150 groups was comparable to sham-40 NACA and thus these groups were not assessed for the effects of NACA. Collectively, these data suggest that BBB integrity is compromised following BOP exposure and that NACA treatment at a single dose may significantly protect against blast-induced BBB breakdown.

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.

Affective profiling for anxiety-like behavior in a rodent model of mTBI.

Mild traumatic brain injury is a common outcome of blast exposure, and current literature indicates high rates of comorbid posttraumatic stress disorder (PTSD) in military personnel. Blast-exposed rats display PTSD-like behavior, suggesting relationships may exist between PTSD and blast exposure. Other studies demonstrate the roles of stathmin and corticosterone associated with fear- and anxiety-like behaviors in rodent models. Furthermore, studies have observed ranges of responses to both physical and psychological trauma in animal populations (Elder 2012, Ritov 2016). This study exposed rodents to repeated blast overpressure (BOP) and analyzed behavioral responses and molecular variables at 3 weeks and 6 months after exposure. We applied a modified version of a previously reported behavioral profiling approach that separates "affected" and "unaffected" rats based on the presence of anxiety-like behaviors (Ritov, 2016). We report that "affected" 3 week animals showed higher plasma corticosterone and amygdalar stathmin levels, while "affected" 6 month animals had lower prefrontal cortex stathmin. Higher corticosterone also paralleled anxiety behavior in "affected" 3 week animals, which was not observed in 6 month animals, indicating possible negative feedback loop mechanisms. Elevated levels of amygdalar stathmin correlated with anxiety behaviors in "affected" 3 week and 6 month animals, indicating sustained molecular changes. We conclude that this unique analysis may provide more information about response to blast. This type of analysis should also be considered when treating clinical populations, since individual differences may affect behavioral and long-term outcomes. Future studies should elucidate relationships of stress and fear responses in the context of BOP.

Low-level blast exposure disrupts gliovascular and neurovascular connections and induces a chronic vascular pathology in rat brain.

Much concern exists over the role of blast-induced traumatic brain injury (TBI) in the chronic cognitive and mental health problems that develop in veterans and active duty military personnel. The brain vasculature is particularly sensitive to blast injury. The aim of this study was to characterize the evolving molecular and histologic alterations in the neurovascular unit induced by three repetitive low-energy blast exposures (3 × 74.5 kPa) in a rat model mimicking human mild TBI or subclinical blast exposure. High-resolution two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry of purified brain vascular fractions from blast-exposed animals 6 weeks post-exposure showed decreased levels of vascular-associated glial fibrillary acidic protein (GFAP) and several neuronal intermediate filament proteins (α-internexin and the low, middle, and high molecular weight neurofilament subunits). Loss of these proteins suggested that blast exposure disrupts gliovascular and neurovascular interactions. Electron microscopy confirmed blast-induced effects on perivascular astrocytes including swelling and degeneration of astrocytic endfeet in the brain cortical vasculature. Because the astrocyte is a major sensor of neuronal activity and regulator of cerebral blood flow, structural disruption of gliovascular integrity within the neurovascular unit should impair cerebral autoregulation. Disrupted neurovascular connections to pial and parenchymal blood vessels might also affect brain circulation. Blast exposures also induced structural and functional alterations in the arterial smooth muscle layer. Interestingly, by 8 months after blast exposure, GFAP and neuronal intermediate filament expression had recovered to control levels in isolated brain vascular fractions. However, despite this recovery, a widespread vascular pathology was still apparent at 10 months after blast exposure histologically and on micro-computed tomography scanning. Thus, low-level blast exposure disrupts gliovascular and neurovascular connections while inducing a chronic vascular pathology.

Blast-induced "PTSD": Evidence from an animal model.

A striking observation among veterans returning from the recent conflicts in Iraq and Afghanistan has been the co-occurrence of blast-related mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). PTSD and mTBI might coexist due to additive effects of independent psychological and physical traumas experienced in a war zone. Alternatively blast injury might induce PTSD-related traits or damage brain structures that mediate responses to psychological stressors, increasing the likelihood that PTSD will develop following a subsequent psychological stressor. Rats exposed to repetitive low-level blasts consisting of three 74.5 kPa exposures delivered once daily for three consecutive days develop a variety of anxiety and PTSD-related behavioral traits that are present for at least 9 months after blast exposure. A single predator scent challenge delivered 8 months after the last blast exposure induces additional anxiety-related changes that are still present 45 days later. Because the blast injuries occur under general anesthesia, it appears that blast exposure in the absence of a psychological stressor can induce chronic PTSD-related traits. The reaction to a predator scent challenge delivered many months after blast exposure suggests that blast exposure in addition sensitizes the brain to react abnormally to subsequent psychological stressors. The development of PTSD-related behavioral traits in the absence of a psychological stressor suggests the existence of blast-induced "PTSD". Findings that PTSD-related behavioral traits can be reversed by BCI-838, a group II metabotropic glutamate receptor antagonist offers insight into pathogenesis and possible treatment options for blast-related brain injury. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".

Hypobaria during long-range flight resulted in significantly increased histopathological evidence of lung and brain damage in a swine model.

BACKGROUND: Aeromedical evacuation to definitive care is standard in current military conflicts. However, there is minimal knowledge on the effects of hypobaria (HYPO) on either the flight crew or patients. The effects of HYPO were investigated using healthy swine. METHODS: Anesthetized Yorkshire swine underwent a simulated 4 h "transport" to an altitude of 2,441 m (8,000 feet.; HYPO, N = 6) or at normobaric conditions (NORMO, N = 6). Physiologic and biochemical data were collected. Organ damage was assessed for hemorrhage, inflammation, edema, necrosis, and for lungs only, microatelectasis. RESULTS: All parameters were similar prior to and after "transport" with no significant effects of HYPO on hemodynamic, neurologic, or oxygen transport parameters, nor on blood gas, chemistry, or complete blood count data. However, the overall Lung Injury Score was significantly worse in the HYPO than the NORMO group (10.78 ± 1.22 vs. 2.31 ± 0.71, respectively) with more edema/fibrin/hemorrhage in the subpleural, interlobular and alveolar space, more congestion in alveolar septa, and evidence of microatelectasis (vs. no microatelectasis in the NORMO group). There was also increased severity of pulmonary neutrophilic (1.69 ± 0.20 vs. 0.19 ± 0.13) and histiocytic inflammation (1.83 ± 0.23 vs. 0.47 ± 0.17) for HYPO versus NORMO, respectively. On the other hand, there was increased renal inflammation in NORMO compared with HYPO (1.00 ± 0.13 vs. 0.33 ± 0.17, respectively). There were no histopathological differences in brain (whole or individual regions), liver, pancreas, or adrenals. CONCLUSION: Hypobaria, itself, may have an adverse effect on the respiratory system, even in healthy individuals, and this may be superimposed on combat casualties where there may be preexisting lung injury. The additional effects of anesthesia and controlled ventilation on these results are unknown, and further studies are indicated using awake models to better characterize the mechanisms for this pathology and the factors that influence its severity.

Corrigendum: Repeated Low Intensity Blast Exposure Is Associated With Damaged Endothelial Glycocalyx and Downstream Behavioral Deficits.

[This corrects the article DOI: 10.3389/fnbeh.2017.00104.].

PTSD-Related Behavioral Traits in a Rat Model of Blast-Induced mTBI Are Reversed by the mGluR2/3 Receptor Antagonist BCI-838.

Battlefield blast exposure related to improvised explosive devices (IEDs) has become the most common cause of traumatic brain injury (TBI) in the recent conflicts in Iraq and Afghanistan. Mental health problems are common after TBI. A striking feature in the most recent veterans has been the frequency with which mild TBI (mTBI) and posttraumatic stress disorder (PTSD) have appeared together, in contrast to the classical situations in which the presence of mTBI has excluded the diagnosis of PTSD. However, treatment of PTSD-related symptoms that follow blast injury has become a significant problem. BCI-838 (MGS0210) is a Group II metabotropic glutamate receptor (mGluR2/3) antagonist prodrug, and its active metabolite BCI-632 (MGS0039) has proneurogenic, procognitive, and antidepressant activities in animal models. In humans, BCI-838 is currently in clinical trials for refractory depression and suicidality. The aim of the current study was to determine whether BCI-838 could modify the anxiety response and reverse PTSD-related behaviors in rats exposed to a series of low-level blast exposures designed to mimic a human mTBI or subclinical blast exposure. BCI-838 treatment reversed PTSD-related behavioral traits improving anxiety and fear-related behaviors as well as long-term recognition memory. Treatment with BCI-838 also increased neurogenesis in the dentate gyrus (DG) of blast-exposed rats. The safety profile of BCI-838 together with the therapeutic activities reported here, make BCI-838 a promising drug for the treatment of former battlefield Warfighters suffering from PTSD-related symptoms following blast-induced mTBI.

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.

Lack of chronic neuroinflammation in the absence of focal hemorrhage in a rat model of low-energy blast-induced TBI.

Blast-related traumatic brain injury (TBI) has been a common cause of injury in the recent conflicts in Iraq and Afghanistan. Blast waves can damage blood vessels, neurons, and glial cells within the brain. Acutely, depending on the blast energy, blast wave duration, and number of exposures, blast waves disrupt the blood-brain barrier, triggering microglial activation and neuroinflammation. Recently, there has been much interest in the role that ongoing neuroinflammation may play in the chronic effects of TBI. Here, we investigated whether chronic neuroinflammation is present in a rat model of repetitive low-energy blast exposure. Six weeks after three 74.5-kPa blast exposures, and in the absence of hemorrhage, no significant alteration in the level of microglia activation was found. At 6 weeks after blast exposure, plasma levels of fractalkine, interleukin-1ß, lipopolysaccharide-inducible CXC chemokine, macrophage inflammatory protein 1α, and vascular endothelial growth factor were decreased. However, no differences in cytokine levels were detected between blast-exposed and control rats at 40 weeks. In brain, isolated changes were seen in levels of selected cytokines at 6 weeks following blast exposure, but none of these changes was found in both hemispheres or at 40 weeks after blast exposure. Notably, one animal with a focal hemorrhagic tear showed chronic microglial activation around the lesion 16 weeks post-blast exposure. These findings suggest that focal hemorrhage can trigger chronic focal neuroinflammation following blast-induced TBI, but that in the absence of hemorrhage, chronic neuroinflammation is not a general feature of low-level blast injury.

Repeated Low Intensity Blast Exposure Is Associated with Damaged Endothelial Glycocalyx and Downstream Behavioral Deficits.

Current clinical research into mild traumatic brain injury (mTBI) has focused on white matter changes as identified by advanced MRI based imaging techniques. However, perivascular tau accumulation in the brains of individuals diagnosed with mTBI suggests that the vasculature plays a key role in the pathology. This study used a rat model to examine whether the endothelial glycocalyx, a layer of the vasculature responsible for sensing luminal shear forces, is damaged by exposure to repeated low intensity blast, and whether this layer is associated with observed behavioral deficits. The blast exposure used consisted of 12, 40 kPa blast exposures conducted with a minimum of 24 h between blasts. We found that repeated blast exposure reduced glycocalyx length and density in various brain regions indicating damage. This blast exposure paradigm was associated with a mild performance decrement in the Morris water maze (MWM) which assesses learning and memory. Administration of hyaluronidase, an enzyme that binds to and degrades hyaluronan (a major structural component of the glycocalyx) prior to blast exposure reduced the observed behavioral deficits and induced a thickening of the glycocalyx layer. Taken together these findings demonstrate that the endothelial glycocalyx degradation following repeated blast is associated with behavioral decrements which can be prevented by treatment with hyaluronidase.

Protective Effect of N-Acetylcysteine Amide on Blast-Induced Increase in Intracranial Pressure in Rats.

Blast-induced traumatic brain injury is associated with acute and possibly chronic elevation of intracranial pressure (ICP). The outcome after TBI is dependent on the progression of complex processes which are mediated by oxidative stress. So far, no effective pharmacological protection against TBI exists. In this study, rats were exposed to a single or repetitive blast overpressure (BOP) at moderate intensities of 72 or 110 kPa in a compressed air-driven shock tube. The degree and duration of the increase in ICP were proportional to the intensity and frequency of the blast exposure(s). In most cases, a single dose of antioxidant N-acetylcysteine amide (NACA) (500 mg/kg) administered intravenously 2 h after exposure to BOP significantly attenuated blast-induced increase in ICP. A single dose of NACA was not effective in improving the outcome in the group of animals that were subjected to repetitive blast exposures at 110 kPa on the same day. In this group, two treatments with NACA at 2 and 4 h post-BOP exposure resulted in significant attenuation of elevated ICP. Treatment with NACA prior to BOP exposure completely prevented the elevation of ICP. The findings indicate that oxidative stress plays an important role in blast-induced elevated ICP as treatment with NACA-ameliorated ICP increase, which is frequently related to poor functional recovery after TBI.

Cerebral Vasoactivity and Oxygenation with Oxygen Carrier M101 in Rats.

The severity of traumatic brain injury (TBI) may be reduced if oxygen can be rapidly provided to the injured brain. This study evaluated if the oxygen-carrier M101 causes vasoconstricton of pial vasculature in healthy rats (Experiment 1) and if M101 improves brain tissue oxygen (PbtO2) in rats with controlled cortical impact (CCI)-TBI (Experiment 2). M101 (12.5 mL/kg intravenous [IV] over 2 h) caused a mild (9 mm Hg) increase in the mean arterial blood pressure (MAP) of healthy rats without constriction of cerebral pial arterioles. M101 (12 mL/kg IV over 1 h) caused a modest (27 mm Hg) increase in MAP (peak, 123 ± 5 mm Hg [mean ± standard error of the mean]) of CCI-TBI rats and restored PbtO2 to near pre-injury levels. In both M101 and untreated control (NON) groups, PbtO2 was ∼30 ± 2 mm Hg pre-injury and decreased (p ≤ 0.05) to ∼16 ± 2 mm Hg 15 min after CCI. In NON, PbtO2 remained ∼50% of baseline but M101 administration resulted in a sustained increase in PbtO2 (peak, 25 ± 5 mm Hg), which was not significantly different from pre-injury until the end of the study, when it decreased again below pre-injury (but was still higher than NON). Histopathology showed no differences between groups. In conclusion, M101 increased systemic blood pressures without concurrent cerebral pial vasoconstriction (in healthy rats) and restored PbtO2 to 86% of pre-injury for at least 80 min when given soon after CCI-TBI. M101 should be evaluated in a clinically-relevant large animal model for pre-hospital treatment of TBI.

Effects of Exposure to Blast Overpressure on Intracranial Pressure and Blood-Brain Barrier Permeability in a Rat Model.

Exposure to blast overpressure (BOP) activates a cascade of pathological processes including changes in intracranial pressure (ICP) and blood-brain barrier (BBB) permeability resulting in traumatic brain injury (TBI). In this study the effect of single and multiple exposures at two intensities of BOP on changes in ICP and BBB permeability in Sprague-Dawley rats was evaluated. Animals were exposed to a single or three repetitive (separated by 0.5 h) BOPs at 72 kPa or 110 kPa. ICP was monitored continuously via telemetry for 6 days after exposure to BOP. The alteration in the permeability of BBB was determined by extravasation of Evans Blue (EB) into brain parenchyma. A significant increase in ICP was observed in all groups except the single 72 kPa BOP group. At the same time a marked increase in BBB permeability was also seen in various parts of the brain. The extent of ICP increase as well as BBB permeability change was dependent on intensity and frequency of blast.

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.

The Emulsified PFC Oxycyte® Improved Oxygen Content and Lung Injury Score in a Swine Model of Oleic Acid Lung Injury (OALI).

PURPOSE: Perfluorocarbons (PFCs) can transport 50 times more oxygen than human plasma. Their properties may be advantageous in preservation of tissue viability in oxygen-deprived states, such as in acute lung injury. We hypothesized that an intravenous dose of the PFC emulsion Oxycyte® would improve tissue oxygenation and thereby mitigate the effects of acute lung injury. METHODS: Intravenous oleic acid (OA) was used to induce lung injury in anesthetized and instrumented Yorkshire swine assigned to three experimental groups: (1) PFC post-OA received Oxycyte® (5 ml/kg) 45 min after oleic acid-induced lung injury (OALI); (2) PFC pre-OA received Oxycyte® 45 min before OALI; and (3) Controls which received equivalent dose of normal saline. Animals were observed for 3 h after OALI began, and then euthanized. RESULTS: The median survival times for PFC post-OA, PFC pre-OA, and control were 240, 87.5, and 240 min, respectively (p = 0.001). Mean arterial pressure and mean pulmonary arterial pressure were both higher in the PFC post-OA (p < 0.001 for both parameters). Oxygen content was significantly different between PFC post-OA and the control (p = 0.001). Histopathological grading of lung injury indicated that edema and congestion was significantly less severe in the PFC post-OA compared to control (p = 0.001). CONCLUSION: The intravenous PFC Oxycyte® improves blood oxygen content and lung histology when used as a treatment after OALI, while Oxycyte® used prior to OALI was associated with increased mortality. Further exploration in other injury models is indicated.

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.

Brain hypoxia is exacerbated in hypobaria during aeromedical evacuation in swine with traumatic brain injury.

BACKGROUND: There is inadequate information on the physiologic effects of aeromedical evacuation on wounded war fighters with traumatic brain injury (TBI). At altitudes of 8,000 ft, the inspired oxygen is lower than standard sea level values. In troops experiencing TBI, this reduced oxygen may worsen or cause secondary brain injury. We tested the hypothesis that the effects of prolonged aeromedical evacuation on critical neurophysiologic parameters (i.e., brain oxygenation [PbtO2]) of swine with a fluid percussion injury/TBI would be detrimental compared with ground (normobaric) transport. METHODS: Yorkshire swine underwent fluid percussion injury/TBI with pretransport stabilization before being randomized to a 4-hour aeromedical transport at simulated flight altitude of 8,000 ft (HYPO, n = 8) or normobaric ground transport (NORMO, n = 8). Physiologic measurements (i.e., PbtO2, cerebral perfusion pressure, intracranial pressure, regional cerebral blood flow, mean arterial blood pressure, and oxygen transport variables) were analyzed. RESULTS: Survival was equivalent between groups. Measurements were similar in both groups at all phases up to and including onset of flight. During the flight, PbtO2, cerebral perfusion pressure, and mean arterial blood pressure were significantly lower in the HYPO than in the NORMO group. At the end of flight, regional cerebral blood flow was lower in the HYPO than in the NORMO group. Other parameters such as intracranial pressure, cardiac output, and mean pulmonary artery pressure were not significantly different between the two groups. CONCLUSION: A 4-hour aeromedical evacuation at a simulated flight altitude of 8,000 ft caused a notable reduction in neurophysiologic parameters compared with normobaric conditions in this TBI swine model. Results suggest that hypobaric conditions exacerbate cerebral hypoxia and may worsen TBI in casualties already in critical condition.

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.