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.

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.

Effects of a hemoglobin-based oxygen carrier (HBOC-201) and derivatives with altered oxygen affinity and viscosity on systemic and microcirculatory variables in a top-load rat model.

The effects of a polymerized bovine hemoglobin-based oxygen carrier (HBOC) and two derivatives on arteriolar vasoactivity and tissue oxygen tension were explored by administering HBOC in a dose-response fashion to normovolemic rats. The effect of oxygen affinity (P50) and viscosity was also explored, where the P50 and viscosity of the parent compound (HBOC-201) and its modifications (MP50 and LP50A) were as follows: 40mmHg and 3.0cP (HBOC-20l); 18mmHg and 4.4cP (MP50); and 17mmHg and 12.1cP (LP50A). Anesthetized male Sprague-Dawley rats (N=32) were randomized to receive one of the HBOC solutions, and were administered four infusions that increased in concentration for each dose (2, 22, 230 and 780mg/kg, IV). Data were compared to rats receiving an equivalent volume for each of the four infusions (0.4, 0.4, 3.8, 13.1ml/kg, IV) of iso-oncotic 5.9% human serum albumin (HSA). Increasing doses of either HBOC solutions or HSA were associated with increasing MAP. Doses 3 and 4 of HBOC-201, MP50 and HSA produced significant increases in MAP, whereas similar increases began at a lower dose (Dose 2) with LP50A. There were no significant changes in arteriolar diameters at any dose for any group. Interstitial partial pressure of oxygen (ISF PO2) remained unchanged for HBOC-201, MP50 and HSA, but LP50A caused a significant decrease in ISF PO2 compared to baseline after Doses 3 and 4. In conclusion, there was no evidence that HBOC-201 would perform better with increased oxygen affinity (40 to 18mmHg) or viscosity (3.0 to 4.4cP).

Pre-hospital resuscitation with HBOC-201 and rFVIIa compared to HBOC-201 alone in uncontrolled hemorrhagic shock in swine.

In a previous dose escalation study our group found that combining 90µg/kg rFVIIa with HBOC-201 reduced blood loss and improved physiologic parameters compared to HBOC alone. In this follow-up study in a swine liver injury model, we found that while there were no adverse hematology effects and trends observed in the previous study were confirmed, statistical significance could not be reached. Additional pre-clinical studies are indicated to identify optimal components of a multifunctional blood substitute for clinical use in trauma.

Dose response of sodium nitrite on vasoactivity associated with HBOC-201 in a swine model of controlled hemorrhage.

Sodium nitrite (NaNO(2)) was evaluated in a 55% EBV hemorrhage swine model to mitigate the increased blood pressure due to HBOC-201. Animals were resuscitated by three 10 ml/kg infusions of either HBOC-201 or Hextend with and without NaNO(2). All vital signs, coagulation and blood chemistry were measured for 2 hr. HBOC-201-vasoconstriction was attenuated only after the first 10.8 µmol/kg NaNO(2) infusion. Complete abolition was obtained with the highest 3 NaNO(2) dose, but side effects were observed. There was no reduction in platelet function due to NaNO(2). NaNO(2) ability to reduce HBOC-201 vasoactivity was transient and 10.8 µmol/kg NaNO(2) seems an acceptable dose for further investigation.

When blood is not an option: factors affecting survival after the use of a hemoglobin-based oxygen carrier in 54 patients with life-threatening anemia.

BACKGROUND: In consenting Jehovah's Witness patients and others for whom blood is contraindicated or not available, hemoglobin-based oxygen carrier (HBOC)-201 may enable survival in acutely anemic patients while underlying conditions are treated. METHODS: Survival factors were identified in a multicenter, unblinded series of severely anemic "compassionate use" patients receiving available standard treatment plus consultant-supported HBOC-201 administration by novice users. Predictors of outcome were sought and compared between survivors and nonsurvivors. A compound variable, hemoglobin-duration deficit product was used to describe the interactive clinical effects of severity and duration of anemia. Mortality,correlations between patient characteristics, and survival to hospital discharge were determined from patient records. RESULTS: Fifty-four patients (median age 50 years) with life-threatening anemia (median hemoglobin concentration at time of request = 4 g/dL) received 60 to 300 g HBOC-201.Twenty-three patients (41.8%) were discharged. Intraoperative blood loss (45%), malignancy(18%), and acute hemolysis (13%) were the prevailing reasons for anemia. Time from onset of anemia (< or = 8 g/dL) to HBOC-201 infusion was shorter for survivors than nonsurvivors (3.2 vs 4.4 days, P = 0.027). Mean hemoglobin levels before HBOC-201 infusion in survivors and nonsurvivors were 4.5 and 3.8 g/dL, respectively (P = 0.120). No serious adverse event was attributed to HBOC-201. The hemoglobin-duration deficit product separated survivors from nonsurvivors. Cancer and renal disease were associated with nonsurvival. CONCLUSION: Earlier, compared with later, administration by inexperienced users of HBOC-201 to patients with anemia was associated with improved chances of survival of acutely bleeding and hemolyzing patients. Survival was more likely if the duration and magnitude of low hemoglobin was minimized before treatment with HBOC-201.

Treatment of Swine Closed Head Injury with Perfluorocarbon NVX-428.

Pre-hospital treatment of traumatic brain injury (TBI) with co-existing polytrauma is complicated by requirements for intravenous fluid volume vs. hypotensive resuscitation. A low volume, small particle-size-oxygen-carrier perfluorocarbon emulsion NVX-428 (dodecafluoropentane emulsion; 2% w/v) could improve brain tissue with minimal additional fluid volume. This study examined whether the oxygen-carrier NVX-428 shows safety and efficacy for pre-hospital treatment of TBI. Anesthetized swine underwent fluid percussion injury TBI and received 1 mL/kg IV NVX-428 (TBI-NVX) at 15 min (T15) or normal saline (no-treatment) (TBI-NON). Similarly, uninjured swine received NVX-428 (SHAM-NVX) or normal saline (SHAM-NON). Animals were monitored and measurements were taken for physiological and neurological parameters before euthanasia at the six-hour mark (T360). Histopathological analysis was performed on paraffin embedded tissues. Physiological, biochemical and blood gas parameters were not different, with the exception of a significant but transient increase in mean pulmonary artery pressure observed in the TBI-experimental group immediately after drug administration. There were no initial differences in brain oxygenation at baseline, but over time oxygen decreased ~50% in both TBI groups. Histological brain injury scores were similar between TBI-NVX and TBI-NON, although a number of subcategories (spongiosis-ischemic/dead neurons-hemorrhage-edema) in TBI-NVX had a tendency for lower scores. The cerebellum showed significantly lower spongiosis and ischemic/dead neuron injury scores and a lower number of Fluoro-Jade-B-positive cerebellar-Purkinje-cells after NVX-428 treatment compared to controls. NVX-428 may assist in mitigating secondary cellular brain damage.

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.

Regional blood flow after serial normovolemic exchange transfusion with HBOC-201 (Hemopure) in anesthetized swine.

BACKGROUND: This study determined individual organ blood flows and global hemodynamic, oxygen delivery and consumption parameters after normovolemic exchange transfusions with the hemoglobin based oxygen carrier (HBOC)-201 in a lightly anesthetized swine model. METHODS: The exchange transfusions were performed as a stepped reduction in blood volume to attain volume exchanges of 10%, 30%, and 50% with a 1:1 replacement with HBOC-201 (n = 8) or oncotically matched 5.9% human serum albumin (HSA, n = 8). Four additional animals served as time controls. RESULTS: There was no change in the regional blood flows in 8 of 9 organs (brain, heart, kidney, liver, pancreas, gall bladder, small intestines, large intestines, and skeletal muscle) after HBOC-201 compared with controls; only skeletal muscle blood flow decreased. In contrast, with HSA, blood flow increased 150% to 200% of baseline in all organs except muscle where blood flow was unchanged. HBOC-201 effectively restored oxygen delivery after these exchanges. The mean arterial pressure increases in the HBOC-201 group were within 15% to 20% of baseline during the initial 10% exchange and similar to controls during subsequent exchanges. Although peak pulmonary arterial pressure increases in the HBOC-201 group were 10 mm Hg to 15 mm Hg above baseline, cardiac index was unchanged. There were no differences in global oxygen consumption, consistent with unchanged regional blood flow and suggests intact physiologic coupling of oxygen delivery and consumption that was unimpaired by local vasoconstriction. This is in contrast to significant changes of increased cardiac index, decreased arterial pressure, decreased oxygen content, and increased oxygen extraction ratio to maintain normal oxygen consumption in the HSA group. CONCLUSION: Although the use of HBOC-201 caused alterations in systemic (minimal) and pulmonary (modest) pressures, these changes had no consequence on regional organ blood flow.

Dodecafluoropentane Emulsion (DDFPE) as a Resuscitation Fluid for Treatment of Hemorrhagic Shock and Traumatic Brain Injury: A Review.

Dodecafluoropentane emulsion (DDFPe) is a novel nanotechnology for oxygen delivery with therapeutic potential for hemorrhagic shock and/or traumatic brain injury (TBI). DDFPe demonstrates efficacy at smaller doses than previously tested perfluorocarbon oxygen therapeutics. This smaller dose potentially eliminates toxicities exhibited by previous oxygen therapeutics, whereas anti-inflammatory properties of DDFPe may alleviate damage from ischemia reperfusion injury. This minireview summarizes our progress in developing a battlefield-ready product to prevent combat death due to hemorrhagic shock and/or TBI. Preclinical studies, for both indications, show promising effects of DDFPe as a resuscitation fluid. DDFPe may become a part of the toolkit for tactical healthcare professionals in battlefield and domestic emergency medicine.

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.

Hitachi Hemolytic Index correlates with HBOC-201 concentrations: impact on suppression of analyte results.

OBJECTIVES: To determine the feasibility of laboratories to use an instrument's Hemolytic Index (HI) to determine if a test result would be accurate in the presence of hemoglobin-based oxygen carrier HBOC-201. DESIGN AND METHODS: HI values from the Roche Hitachi Modular P800 for samples containing HBOC-201 were determined. HI limits for 24 tests determined by addition of RBC lysate hemoglobin to serum and the instrument manufacturer's HI limits were compared to HI limits for reporting the same tests determined by adding HBOC-201 to plasma. RESULTS: There is a linear relationship (R(2)=0.99) between the HI value on the Modular P800 and HBOC-201 concentrations. Twenty-one of 24 HI limits for reporting results as determined by the manufacturer or adding RBC lysate to serum were more conservative or equal to the limit determined by HBOC-201 interference testing. HBOC-201 interference testing was more conservative for albumin, creatinine, and uric acid. CONCLUSION: For most analytes, the Modular P800 HI provides an accurate, conservative and automated method to determine whether laboratory results should be reported or suppressed when samples contain HBOC-201.

Determination of methemoglobin and hemoglobin levels in small volume samples.

Background/aims Hemoglobin-based oxygen carriers (HBOCs) have been previously studied as resuscitation fluids. Due to HBOCs specific molecular conformation, hemoglobin (Hb) and methemoglobin (MetHb) determination is not always possible with automated apparatus. A practical technique was designed that allows simultaneous reading of MetHb and Hb in small volume samples. Methods A spectrophotometric method for measuring low levels of MetHb and Hb from limited volume samples was developed using a 96-well-plate by downsizing the Evelyn-Malloy and Drabkin methods. Either blood or buffer samples were spiked with one of five HBOCs (HBOC-201, M101, MP4CO-NP, Sanguinate and Oxyvita C). After treatment with cyanides, the samples were read at 540, 630, and 680 nm, and Hb and MetHb results were compared to certificate-of-analysis. Results Hb levels ranging from 0.2 to 2.8 g/dl were detected accurately with the 96-well-plate method with HBOC-201. Similarly, this method accurately measured Hb from either plasma or buffer samples containing any of the HBOCs. The MetHb plasma samples with HBOC-201 were also in agreement with ABL results (R = 0.99719). MetHb from all HBOCs in buffer measured with this method was comparable to reference but the accuracy was compromised for HBOCs in blood. Conclusions A useful 96-well-plate method of measuring HBOCs' Hb was designed for small-volume plasma samples. It was accurate for measuring MetHb from samples, that contained M101, MP4CO-NP, Sanguinate, and Oxyvita C diluted in buffer. This well-plate method allows reading of batch samples, multiple replicates, and using small volumes to accommodate limited animal blood collection which would not be otherwise detected by automated instrumentation.

Normalization of hemoglobin-based oxygen carrier-201 induced vasoconstriction: targeting nitric oxide and endothelin.

Hemoglobin-based oxygen carrier (HBOC)-201 is a cell-free modified hemoglobin solution potentially facilitating oxygen uptake and delivery in cardiovascular disorders and hemorrhagic shock. Clinical use has been hampered by vasoconstriction in the systemic and pulmonary beds. Therefore, we aimed to 1) determine the possibility of counteracting HBOC-201-induced pressor effects with either adenosine (ADO) or nitroglycerin (NTG); 2) assess the potential roles of nitric oxide (NO) scavenging, reactive oxygen species (ROS), and endothelin (ET) in mediating the observed vasoconstriction; and 3) compare these effects in resting and exercising swine. Chronically instrumented swine were studied at rest and during exercise after administration of HBOC-201 alone or in combination with ADO. The role of NO was assessed by supplementation with NTG or administration of the eNOS inhibitor Nω-nitro-l-arginine. Alternative vasoactive pathways were investigated via intravenous administration of the ETA/ETB receptor blocker tezosentan or a mixture of ROS scavengers. The systemic and to a lesser extent the pulmonary pressor effects of HBOC-201 could be counteracted by ADO; however, dosage titration was very important to avoid systemic hypotension. Similarly, supplementation of NO with NTG negated the pressor effects but also required titration of the dose. The pressor response to HBOC-201 was reduced after eNOS inhibition and abolished by simultaneous ETA/ETB receptor blockade, while ROS scavenging had no effect. In conclusion, the pressor response to HBOC-201 is mediated by vasoconstriction due to NO scavenging and production of ET. Further research should explore the effect of longer-acting ET receptor blockers to counteract the side effect of hemoglobin-based oxygen carriers.NEW & NOTEWORTHY Hemoglobin-based oxygen carrier (HBOC)-201 can disrupt hemodynamic homeostasis, mimicking some aspects of endothelial dysfunction, resulting in elevated systemic and pulmonary blood pressures. HBOC-201-induced vasoconstriction is mediated by scavenging nitric oxide (NO) and by upregulating endothelin (ET) production. Pressor effects can be prevented by adjuvant treatment with NO donors or direct vasodilators, such as nitroglycerin or adenosine, but dosages must be carefully monitored to avoid hypotension. However, hemodynamic normalization is more easily achieved via administration of an ET receptor blocker.

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.

In vitro alteration of hematological parameters and blood viscosity by the perfluorocarbon: Oxycyte.

UNLABELLED: While perfluorocarbons (PFCs) may be useful in some clinical situations, previous studies have shown that interferences with chemistry analytes can occur with blood samples containing PFCs. This in vitro study focused on how the PFC Oxycyte may affect hematology measurements in blood samples. Swine blood diluted with Oxycyte or saline (Controls) were analyzed for Hemoglobin (Hb), Mean Corpuscular Volume (MCV),Hematocrit (Hct) and Fluorocrit (Fct) using a HemaVet, ABL-735 (ABL), or microhematocrit. Ancillary tests (blood viscosity, electrolytes, cell counts, and red blood cell morphology) were performed secondarily. Increasing Oxycyte resulted in increases in MCV, Hct, and visible cell shape change and morphology vs. CONTROLS: Effects correlated with lower sodium in Oxycyte samples vs. CONTROLS: With increasing Oxycyte, Hb became higher than Controls or became unpredictable depending on the instrument (HemaVet or ABL, respectively). Fct was smaller than predicted and likely represented the heaviest components of Oxycyte. At ≥50 % Oxycyte, RBC hemolysis rendered further measurements impractical. Viscosity first increased then decreased with increasing Oxycyte, peaking at ~40 % Oxycyte. Hct, MCV, Hb, and RBC morphology may be affected by Oxycyte. These observations correlated with lower sodium and increasing Oxycyte, causing hemolysis at high Oxycyte concentrations. These changes were due to alterations in the blood samples in vitro and this should be considered when interpreting hematology parameters from in vivo 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.

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.