Females are less likely to receive best medical therapy for stroke prevention before and after carotid revascularization than males.

BACKGROUND: Current professional guidelines recommend best medical therapy (BMT) with statin agents and antiplatelet therapy for primary and secondary stroke prevention in patients with carotid artery stenosis. We aimed to assess the association of patient sex with preoperative BMT in patients undergoing carotid revascularization. METHODS: We performed a retrospective review of Vascular Quality Initiative patients who underwent carotid endarterectomy or carotid artery stenting between January 2003 and February 2022. Multivariable logistic regression models were used to assess the association of patient sex with preoperative BMT after adjusting for sociodemographic, comorbidity, and disease severity characteristics. In-hospital outcomes were assessed by sex and preoperative BMT status. RESULTS: Of 214,008 patients who underwent carotid revascularization, 38.7% (n = 82,855) were female and 61.3% (n = 131,153) were male. Overall, 77.2% (n = 63,922) of females were on preoperative BMT, compared with 80.4% (n = 105,375) of males (P < .001). After adjusting for baseline differences, females had 11% lower odds of being on BMT compared with males (adjusted odds ratio, 0.89; 95% confidence interval, 0.86-0.91). Postoperatively, females had 18% lower odds of being prescribed BMT than males (adjusted odds ratio, 0.82; 95% confidence interval, 0.79-0.84). In-hospital stroke (1.20% vs 1.51%), death (0.37% vs 0.66%), and stroke/death (1.46% vs 1.98%) were all significantly lower for patients on BMT (all P < .001). CONCLUSIONS: There is a significant discrepancy in the proportion of females versus males receiving preoperative BMT for stroke prevention before carotid artery revascularization. In-hospital outcomes are worse in patients without BMT, highlighting the importance of raising awareness and implementing targeted interventions to improve preoperative adherence to stroke prevention guidelines.

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.

Simulated Aeromedical Evacuation in a Polytrauma Rat Model.

BACKGROUND: Hemorrhage and traumatic brain injury can be lethal if left unattended. The transportation of severely wounded combat casualties from the battlefield to higher level of care via aeromedical evacuation (AE) may result in unintended complications. This could become a serious concern at the time of evacuation of mass casualties or for prolonged field care scenarios with limited resources.METHODS: Following instrumentation (t1), anesthetized Sprague-Dawley rats were injured or not [75-kPa blast and 30% estimated blood-volume controlled hemorrhage] (t2). After 15 min, all rats were resuscitated with saline. During the simulated 3-h evacuation, 8000 ft (2440 m) vs. sea-level heart rate, temperature, and oxygenation (Spo2) were continuously recorded. One group of rats was euthanized immediately after evacuation (t3) and another after a 72-h recovery period (t4). Hematology and metabolic levels were measured at t1, t2, t3, and t4.RESULTS: Survival was 100% in control-uninjured animals, 83% in injured animals under normobaria, and significantly reduced to 50% under hypobaria. This AE setting resulted in significantly lower hemodynamics, thermoregulation, and oxygenation parameters in the animals under hypobaria than those under normobaria. The initial lower mean arterial pressure (MAP) with the reduced oxygen level before AE were critical factors for the survival of injured animals. We observed a general increase of white blood cells and platelet ability to aggregate at t4 in all experimental groups.CONCLUSION: Physiological parameters were affected during aeromedical evacuation in all groups. This was worsened for injured animals with MAP less than 60 mmHg associated with low Spo2 in a simulated aeromedical evacuation. This represented a high risk of mortality for severely polytraumatized animals.Arnaud F, Pappas G, Maudlin-Jeronimo E, Goforth C. Simulated aeromedical evacuation in a polytrauma rat model. Aerosp Med Hum Perform. 2019; 90(12):1016-1025.

Effect of acute restraint stress in a polytrauma rat model.

INTRODUCTION: A stressful environment may contribute to poor outcomes after TBI. The current study evaluates the impact of acute stress in a polytrauma rat model. METHODS: Rats were stressed by a 45-minute immobilization period before instrumentation under ketamine (t1). Polytrauma was produced by blast overpressure and controlled hemorrhage (t2). Rats were euthanized immediately after a 3 h simulated Medevac-transport time (t3) or after 72 h post-trauma (t4). Corticosterone, ACTH, and ACTH receptor gene expression were measured at these time points. Physiological parameters were monitored throughout the study. RESULTS: HR was higher in stressed compared to unstressed animals at t1. Corticosterone and ACTH levels were similar for all conditions at t1 and t2; ACTH and corticosterone became elevated in all groups at t3 and at t4, respectively. The ACTH receptor gene expression trended towards higher values at t4 for the stressed animals whether being injured or not. Survival after injury was 83% in both unstressed and stressed animals. CONCLUSION: Overall, corticosterone was not significantly affected following acute stress in ketamine-anesthetized rats. Early mortality was primarily due to polytrauma and change in the animal's biochemical parameters appeared at t4 post trauma. The findings indicate that ketamine-anesthesia and/or surgery may have overshadowed the effect of the initial stress.

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.

Infusion of solutions of pre-irradiated components in rats.

INTRODUCTION: The objective of this study was to conduct a 14-day toxicology assessment for intravenous solutions prepared from irradiated resuscitation fluid components and sterile water. METHODS: Healthy Sprague Dawley rats (7-10/group) were instrumented and randomized to receive one of the following Field IntraVenous Resuscitation (FIVR) or commercial fluids; Normal Saline (NS), Lactated Ringer's, 5% Dextrose in NS. Daily clinical observation, chemistry and hematology on days 1,7,14, and urinalysis on day 14 were evaluated for equivalence using a two sample t-test (p<0.05). A board-certified pathologist evaluated organ histopathology on day 14. RESULTS: Equivalence was established for all observation parameters, lactate, sodium, liver enzymes, creatinine, WBC and differential, and urinalysis values. Lack of equivalence for hemoglobin (p=0.055), pH (p=0.0955), glucose (p=0.0889), Alanine-Aminotransferase (p=0.1938), albumin (p=0.1311), and weight (p=0.0555, p=0.1896), was deemed not clinically relevant due to means within physiologically normal ranges. Common microscopic findings randomly distributed among animals of all groups were endocarditis/myocarditis and pulmonary lesions. DISCUSSION: These findings are consistent with complications due to long-term catheter use and suggest no clinically relevant differences in end-organ toxicity between animals infused with FIVR versus commercial fluids.

Endovascular Cooling Method for Hypothermia in Injured Swine.

We evaluated an endovascular cooling method to modulate core temperature in trauma swine models with and without fluid support. Anesthetized swine (N = 80) were uninjured (SHAM) or injured through a bone fracture plus soft tissue injury or an uncontrolled hemorrhage and then subdivided to target body temperatures of 38°C (normothermia) or 33°C (hypothermia) by using a Thermogard endovascular cooling device (Zoll Medical). Temperature regulation began simultaneously at onset of injury (T0). Body temperatures were recorded from a rectal probe (Rec Temp) and from a central pulmonary artery catheter (PA Temp). At T15, swine received 500 mL IV Hextend over 30 minutes or no treatment (NONE) with continued monitoring until 3 hours from injury. Hypothermia was attained in 105 ± 39 minutes, at a cooling rate of -0.061°C ± 0.007°C/min for NONE injury groups. Postinjury Hextend administration resulted in faster cooling (-0.080°C ± 0.006°C/min); target temperature was reached in 83 ± 11 minutes (p < 0.05). During active cooling, body temperature measured by the PA Temp was significantly cooler than the Rec Temp due to the probe's closer proximity to the blood-cooling catheter balloons (p < 0.05). This difference was smaller in SHAM and fluid-supported injury groups (1.1°C ± 0.4°C) versus injured NONE groups (2.1°C ± 0.3°C). Target temperatures were correctly maintained thereafter in all groups. In normothermia groups, there was a small initial transient overshoot to maintain 38°C. Despite the noticeable difference between PA Temp and Rec Temp until target temperature was attained, this endovascular method can safely induce moderate hypothermia in anesthetized swine. However, likely due to their compromised hemodynamic state, cooling in hypovolemic and/or injured patients will be different from those without injury or those that also received fluids.

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.

Effects of the Oxygen-Carrying Solution OxyVita C on the Cerebral Microcirculation and Systemic Blood Pressures in Healthy Rats.

The use of hemoglobin-based oxygen carriers (HBOC) as oxygen delivering therapies during hypoxic states has been hindered by vasoconstrictive side effects caused by depletion of nitric oxide (NO). OxyVita C is a promising oxygen-carrying solution that consists of a zero-linked hemoglobin polymer with a high molecular weight (~17 MDa). The large molecular weight is believed to prevent extravasation and limit NO scavenging and vasoconstriction. The aim of this study was to assess vasoactive effects of OxyVita C on systemic blood pressures and cerebral pial arteriole diameters. Anesthetized healthy rats received four intravenous (IV) infusions of an increasing dose of OxyVita C (2, 25, 50, 100 mg/kg) and hemodynamic parameters and pial arteriolar diameters were measured pre- and post-infusion. Normal saline was used as a volume-matched control. Systemic blood pressures increased (P ≤ 0.05) with increasing doses of OxyVita C, but not with saline. There was no vasoconstriction in small (<50 µm) and medium-sized (50-100 µm) pial arterioles in the OxyVita C group. In contrast, small and medium-sized pial arterioles vasoconstricted in the control group. Compared to saline, OxyVita C showed no cerebral vasoconstriction after any of the four doses evaluated in this rat model despite increases in blood pressure.

Effects of perfluorocarbon dodecafluoropentane (NVX-108) on cerebral microvasculature in the healthy rat.

NVX-108, a dodecafluoropentane-based perfluorocarbon (PFC) emulsion, has therapeutic potential as an oxygen- carrying fluid for emergency medical treatment for traumatic brain injury (TBI) and hemorrhagic shock. Potential cerebral vasoactive properties were assessed by directly measuring pial arteriolar vessel diameters before and after a 30 minute intravenous (IV) infusion of 1.0 ml/kg (high dose [H]) or 0.25 ml/kg (low dose [L]) NVX-108 compared to 2.0 ml/kg Saline (control) in healthy anesthetized rats (N = 6/group). Results showed that post-infusion vessel diameters for small (< 50 µm) and medium (50-100 µm)-sized pial arterioles were significantly (p < 0.05) narrower after only the NVX- 108 H infusion although this vasoconstriction was not statistically significant when analyzed as a percentage change in these vessels. Pial arteriolar vessel diameters were not significantly different for mean value or percentage change after either NVX-108 L or Saline infusions. There were no significant post-infusion changes from baseline in systolic, mean or diastolic blood pressures after any of the treatments although post-infusion blood pressure was statistically higher in the NVX-108 L group compared to NVX-108 H and Saline groups. Arterial blood gases, methemoglob in and lactate were not different from baseline or among groups. No adverse events were observed at either dose of NVX-108. In conclusion, neither 0.25 nor 1.0 ml/kg NVX-108 caused vasoconstriction in cerebral pial arterioles of healthy rats nor resulted in blood pressure changes; the compound should be considered for further investigation for TBI therapy.

Effects of N-acetyl-L-cysteine and hyaluronic acid on HBOC-201-induced systemic and cerebral vasoconstriction in the rat.

Hemoglobin-based oxygen carrier-201 (HBOC) was developed as a resuscitative fluid but concerns exist over potentially adverse vasoconstriction. This study evaluated whether concurrent IV (intra venous) N-acetyl-L-cysteine (NAC) or hyaluronic acid (HA) would attenuate HBOC-associated vasoconstriction, assessed by systemic blood pressures and cerebral pial microvasculature, when administered to healthy, anesthetized rats. Rats (8-9/group) received a 30 min infusion of 3 ml/kg HBOC, HBOC plus 600 mg/kg NAC (HBOC/NAC), HBOC plus 1.5 mg/kg HA (HBOC/HA) or 3 ml/kg Albumin. Mean (MAP) and systolic (SBP) blood pressures, blood chemistries and cerebral pial vessel diameters were measured at baseline, end of infusion, and intermittently for an additional 90 min. HBOC caused immediate and sustained increases in SBP and MAP (35.3 ± 3.6 and 29.1 ± 2.5 mm Hg peak increases above baseline, respectively; mean ± SEM) and immediate but progressive vasoconstriction (11 µm maximum reduction) in medium-sized (50-100 µm) pial arterioles. When NAC was co-administered, blood pressure changes were attenuated and vessel changes were abolished. Similar trends were noted with co-administration of HA but were not statistically different from HBOC-alone. Small-sized (< 50 µm) pial vessels and blood parameters showed no differences from baseline or among groups. No adverse clinical signs were observed. We demonstrated that it is possible for adjuvant drugs to reduce the vasoconstriction associated with HBOC-201. Coinfusion of the anti-oxidant NAC mitigated HBOC-201-associated increases in blood pressures and vasoconstriction in medium-sized cerebral pial vessels. The drag-reducing polymer HA may be more effective at a higher dose as a similar but non-significant trend was observed.