Next-Generation REBOA (Resuscitative Endovascular Balloon Occlusion of the Aorta) Device Precisely Achieves Targeted Regional Optimization in a Porcine Model of Hemorrhagic Shock.

INTRODUCTION: Limitations such as time-dependent distal ischemia have slowed the adoption of resuscitative endovascular balloon occlusion of the aorta (REBOA) for noncompressible hemorrhage. Next-generation REBOA technologies may allow for controlled partial flow, known as targeted regional optimization, to reduce distal ischemia. We aimed to characterize the efficacy of one such catheter in a porcine model of lethal hemorrhagic shock. METHODS: Noncompressible hemorrhage from an iliac injury was induced in anesthetized swine (Sus scrofa) (70-90 kg), targeting 30% total blood volume. Animals were then randomized to partial aortic occlusion (PO) with targeted distal mean arterial pressure (MAP) of 35-40 mm of mercury (mm Hg) and complete aortic occlusion (CO) (n = 8 per group) for 90 min. All groups were then resuscitated during a two-h critical care (CC) phase, with flow rate and MAP recorded continuously at the distal infrarenal aorta and proximal carotid artery, and analyzed with two-way repeated measures analysis of variance with S-N-K post-hoc test. RESULTS: During aortic occlusion, MAP distal to the balloon was consistently maintained at 35.8 ± 0.3 mm Hg in the PO group compared to 27.1 ± 0.3 mm Hg in the CO group (P < 0.05), which also corresponded to higher flow rates (202.9 ± 4.8 mL/min PO versus 25.9 ± 0.8 mL/min CO; P < 0.05). MAP proximal to the balloon was significantly higher with CO versus PO (109.2 ± 2.3 mm Hg versus 85.2 ± 2.3 mm Hg; P < 0.05). During the CC phase, distal aortic flow and MAP were not significantly different between groups. However, creatinine returned to baseline levels by the end of the study in the PO group, but not the CO group. One animal died in the CO group, whereas none died in the PO group. CONCLUSIONS: This is the first examination of the next-generation pREBOA-PRO in a porcine model of lethal hemorrhagic shock. We show technical feasibility of this technique to precisely achieve targeted regional optimization without device failure or complication. The ability to titrate balloon inflation and thus distal flow/pressure may extend the therapeutic window of REBOA by mitigating distal ischemia.

Targeted Regional Optimization: Increasing the Therapeutic Window for Endovascular Aortic Occlusion In Traumatic Hemorrhage.

ABSTRACT: Resuscitative endovascular balloon occlusion of the aorta (REBOA) allows for effective temporization of exsanguination from non-compressible hemorrhage (NCTH) below the diaphragm. However, the therapeutic window for aortic occlusion is time-limited given the ischemia-reperfusion injury generated. Significant effort has been put into translational research to develop new strategies to alleviate the ischemia-reperfusion injury and extend the application of endoaortic occlusion. Targeted regional optimization (TRO) is a partial REBOA strategy to augment proximal aortic and cerebral blood flow while targeting minimal threshold of distal perfusion beyond the zone of partial aortic occlusion. The objective of TRO is to reduce the degree of ischemia caused by complete aortic occlusion while providing control of distal hemorrhage. This review provides a synopsis of the concept of TRO, pre-clinical, translational experiences with TRO and early clinical outcomes. Early results from TRO strategies are promising; however, further studies are needed prior to large-scale implementation into clinical practice.

A multi-registry analysis of military and civilian penetrating cervical carotid artery injury.

INTRODUCTION: Penetrating cervical carotid artery injury is an uncommon but high-stake scenario associated with stroke and death. The objective of this study was to characterize and compare penetrating carotid injury in the military and civilian setting, as well as provide considerations for management. METHODS: Cohorts with penetrating cervical carotid artery injury from the Department of Defense Trauma Registry (2002-2015) and the American Association for the Surgery of Trauma Prospective Observation Vascular Injury Treatment Registry (2012-2018) were analyzed. A least absolute shrinkage and selection operator multivariate analysis using random forest-based imputation was performed to identify risk factors affecting stroke and mortality. RESULTS: There were a total of 157 patients included in the study, of which 56 (35.7%) were military and 101 (64.3%) were civilian. The military cohort was more likely to have been managed with open surgery (87.5% vs. 44.6%, p < 0.001) and to have had any procedure to restore or maintain flow to the brain (71.4% vs. 35.6%, p < 0.001), while the civilian cohort was more likely to undergo nonoperative management (45.5% vs. 12.5%, p < 0.001). Stroke rate was higher within the military cohort (41.1% vs. 13.9%, p < 0.001); however, mortality did not differ between the groups (12.5% vs. 17.8%, p = 0.52). On multivariate analysis, predictors for stroke were presence of a battle injury (log odds, 2.1; p < 0.001) and internal or common carotid artery ligation (log odds 1.5, p = 0.009). For mortality outcome, protective factors included a high Glasgow Coma Scale on admission (log odds, -0.21 per point; p < 0.001). Increased admission Injury Severity Score was a predictor of mortality (log odds, 0.05 per point; p = 0.005). CONCLUSION: The stroke rate was higher in the military cohort, possibly reflecting complexity of injury; however, there was no difference in mortality between military and civilian patients. For significant injuries, concerted efforts should be made at carotid reconstruction to reduce the occurrence of stroke. LEVEL OF EVIDENCE: Retrospective cohort analysis, level III.

Temporary intravascular shunt use improves early limb salvage after extremity vascular injury.

OBJECTIVE: The use of temporary intravascular shunts (TIVSs) allow for restoration of distal perfusion and reduce ischemic time in the setting of arterial injury. As a damage control method, adjunct shunts restore perfusion during treatment of life-threatening injuries, or when patients require evacuation to a higher level of care. Single-center reports and case series have demonstrate that TIVS use can extend the opportunity for limb salvage. However, few multi-institutional studies on the topic have been reported. The objective of the present study was to characterize TIVS use through a multi-institutional registry and define its effects on early limb salvage. METHODS: Data from the Prospective Observation Vascular Injury Treatment registry was analyzed. Civilian patients aged ≥18 years who had sustained an extremity vascular injury from September 2012 to November 2018 were included. Patients who had a TIVS used in the management of vascular injury were included in the TIVS group and those who had received treatment without a TIVS served as the control group. An unadjusted comparison of the groups was conducted to evaluate the differences in the baseline and outcome characteristics. Double robust estimation combining logistic regression with propensity score matching was used to evaluate the effect of TIVS usage on the primary end point of limb salvage. RESULTS: TIVS use was identified in 78 patients from 24 trauma centers. The control group included 613 patients. Unmatched analysis demonstrated that the TIVS group was more severely injured (mean ± standard deviation injury severity score, 18.83 ± 11.76 for TIVS vs 14.93 ± 10.46 for control; P = .002) and had more severely mangled extremities (mean ± standard deviation abbreviated injury scale, extremity, score 3.23 ± 0.80 for TIVS vs 2.95 ± 0.87 for control; P = .008). Logistic regression demonstrated that propensity-matched control patients had a three times greater likelihood of amputation compared with the TIVS patients (odds ratio, 3.6; 95% confidence interval, 1.2-11.1; P = .026). Concomitant nerve injury and orthopedic fracture were associated with a greater risk of amputation. The median follow-up for the TIVS group was 12 days (interquartile range, 4-25 days) compared with 9 days (interquartile range, 4-18 days) for the control group. CONCLUSIONS: To the best of our knowledge, the present study is the first multicenter, matched-cohort study to characterize early limb salvage as a function of TIVS use in the setting of extremity vascular injury. Shunts expedite limb perfusion and resulted in lower rates of amputation during the early phase of care. The use of TIVS should be one part of a more aggressive approach to restore perfusion in the most injured patients and ischemic limbs.

A New Pressure-Regulated, Partial Resuscitative Endovascular Balloon Occlusion of the Aorta Device Achieves Targeted Distal Perfusion.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) reduces blood loss and improves hemodynamics. Complete occlusion results in distal ischemia, limiting its use for prolonged care. This study evaluated two next-generation partial REBOA (pREBOA) catheters and their ability to achieve targeted distal aortic flow. MATERIALS AND METHODS: Swine underwent hemorrhagic shock, complete aortic occlusion, controlled continuous balloon deflation, and targeted distal perfusion (TDP; 300-mL/min) phases. They were randomized into three groups (n = 6/group), one managed with the current ER-REBOA (ER), and two with the new pREBOA technologies: a bilobed (BL) device and a semicompliant pREBOA-PRO (PRP). Hemodynamics including flow rates and mean arterial pressures at the carotid artery and infrarenal aorta were recorded. RESULTS: Hemodynamics were comparable between groups during hemorrhage and complete occlusion phases. During the controlled continuous balloon deflation phase, the distal aortic flow rate strongly correlated with percent balloon volume in BL and PRP groups, suggesting a precise control of distal perfusion. The slope of flow-balloon-volume curves was greater in the ER group than BL and PRP groups, indicating the change in distal aortic flow rate was more sensitive to the balloon volume (less titratable) when using ER. During the TDP phase, variation in distal aortic flow and mean arterial pressure with respect to the target flow was lower in ER and PRP groups, than the BL group. CONCLUSIONS: Pressure-regulated occlusion using the next-generation pREBOA catheters is more controlled than the first-generation ER-REBOA catheter and allow for targeted and precise distal perfusion.

Toward the development of a sensitive, pre-clinical screen for neurological diseases from spontaneous neural coordination in juvenile and young-adult C57BK6 mice.

Spontaneous Frequency Bursts (SFBs) are a newly discovered form of long-distance neural coordination. They have several distinctive properties, including near-simultaneity of occurrence (+/-25-50 ms) across distant brain regions and high within- and across-site coherence in multiple low and high frequency bands, presumably requiring high axonal, dendritic and vascular integrity. We examined whether SFBs occurred in young and young-adult C57BK6 mice with properties similar to those seen in rats. We found that across the entorhinal and piriform cortices, SFBs occur robustly in young and young-adult mice under light anesthesia, and that their rate of occurrence dropped sharply as anesthetic levels increased, as in rats. Moreover, murine SFBs showed high cross-site coherence in multiple frequency bands, including those that require exquisite action potential timing to be maintained across long distances. We discuss our findings in light of SFBs potential as a pre-clinical biomarker for diseases affecting action potential firing and local field potential coherence, especially in high frequency ranges (20-30 Hz and beyond).

Induction of microglial reactive oxygen species production by the organochlorinated pesticide dieldrin.

Exposure to pesticides has been speculated to contribute to the development of sporadic Parkinson's disease (PD) characterized by a progressive degeneration of the nigrostriatal dopaminergic pathway. Activation of brain microglia that produce various neurotoxic factors including cytokines and reactive oxygen species (ROS) has been increasingly associated with dopaminergic neurodegeneration induced by various toxicants. Dieldrin, a highly persistent organochlorinated pesticide found enriched in the substantia nigra of some postmortem PD brains, has been shown to be toxic to dopamine neurons. In this study, we set out to determine the effect of dieldrin on the production of ROS and the underlying mechanism of action in murine microglia. Treatment of microglial cells with 0.1 nM to 1 microM dieldrin for 24 h resulted in a concentration-dependent generation of ROS. The dieldrin-induced microglial ROS generation was time-dependent in that significant ROS production was observed in cells 12-24 h, but not 6 h after dieldrin treatment. Furthermore, the dieldrin-induced microglial ROS generation was significantly reduced by inhibitors of NADPH oxidase, gene transcription and protein synthesis. In addition to immortalized microglial cells, dieldrin induced a concentration-dependent ROS generation in primary microglia, but not in primary astroglia. These results demonstrate that nanomolar concentrations of dieldrin can stimulate microglia to produce ROS that may contribute to the degeneration of dopamine neurons known to be vulnerable to oxidative damage. These findings provide important information on the potential role of microglia in dieldrin-induced neurodegeneration in relevance to the development of idiopathic PD.