Endovascular Perfusion Augmentation After Resuscitative Endovascular Balloon Occlusion of the Aorta Improves Renal Perfusion and Decreases Vasopressors.

INTRODUCTION: Resuscitative endovascular balloon occlusion of the aorta (REBOA) causes a severe ischemia-reperfusion injury. Endovascular Perfusion Augmentation for Critical Care (EPACC) has emerged as a hemodynamic/mechanical adjunct to vasopressors and crystalloid for the treatment of post-REBOA ischemia-reperfusion injury. The objective of the study is to examine the impact of EPACC as a tool for a wean from complete REBOA compared to standard resuscitation techniques. METHODS: Nine swine underwent anesthesia and then a controlled 30% blood volume hemorrhage with 30 min of supraceliac total aortic occlusion to create an ischemia-reperfusion injury. Animals were randomized to standardized critical care (SCC) or 90 min of EPACC followed by SCC. The critical care phase lasted 270 min after injury. Hemodynamic markers and laboratory values of ischemia were recorded. RESULTS: During the first 90 min the intervention phase SCC spent 60% (54%-73%) and EPACC spent 91% (88%-92%) of the time avoiding proximal hypotension (<60 mm Hg), P = 0.03. There was also a statistically significant decrease in cumulative norepinephrine dose at the end of the experiment between SCC (80.89 mcg/kg) versus EPACC (22.03 mcg/kg), P = 0.03. Renal artery flow during EPACC was similar compared to SCC during EPACC, P = 0.19. But during the last hour of the experiment (after removal of aortic balloon) the renal artery flow in EPACC (2.9 mL/kg/min) was statistically significantly increased compared to SCC (1.57 mL/min/kg), P = 0.03. There was a statistically significant decrease in terminal creatinine in the EPACC (1.7 mg/dL) compared to SCC (2.1 mg/dL), P = 0.03. CONCLUSIONS: The 90 min of EPACC as a weaning adjunct in the setting of a severe ischemia-reperfusion injury after complete supraceliac REBOA provides improved renal flow with improvement in terminal creatinine compared to SCC with stabilized proximal hemodynamics and decreased vasopressor dose.

Zone 3 REBOA does not provide hemodynamic benefits during nontraumatic cardiac arrest.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) may be a novel intervention to improve cardiopulmonary resuscitation (CPR) quality during cardiac arrest. Zone 1 supraceliac aortic occlusion improves coronary and cerebral blood flow. It is unknown if Zone 3 occlusion distal to the renal arteries offers a similar physiologic benefit while maintaining blood flow to organs above the point of occlusion. METHODS: Fifteen swine were anesthetized, instrumented, and placed into ventricular fibrillation. Mechanical CPR was immediately initiated. After 5 min of CPR, Zone 1 REBOA, Zone 3 REBOA, or no intervention (control) was initiated. Hemodynamic variables were continuously recorded for 30 min. RESULTS: There were no significant differences between groups before REBOA deployment. Once REBOA was deployed, Zone 1 animals had statistically greater diastolic blood pressure compared to control (median [IQR]: 19.9 mmHg [9.5-20.5] vs 3.9 mmHg [2.4-4.8], p = .006). There were no differences in diastolic blood pressure between Zone 1 and Zone 3 (8.6 mmHg [5.1-13.1], p = .10) or between Zone 3 and control (p = .10). There were no significant differences in systolic blood pressure, cerebral blood flow, or time to return of spontaneous circulation (ROSC) between groups. CONCLUSION: In our swine model of cardiac arrest, Zone 1 REBOA improved diastolic blood pressure when compared to control. Zone 3 does not offer a hemodynamic benefit when compared to no occlusion. Unlike prior studies, immediate use of REBOA after arrest did not result in an increase in ROSC rate, suggesting REBOA may be more beneficial in patients with prolonged no-flow time. INSTITUTIONAL PROTOCOL NUMBER: FDG20180024A.

The Association of Glasgow Coma Scale Score With Clinically Important Traumatic Brain Injuries in Children.

OBJECTIVE: An accurate understanding of the incidence of clinically important traumatic brain injuries (ciTBIs) based on presenting Glasgow Coma Scale (GCS) scores in pediatric patients is required to formulate a pretest probability of disease to guide testing and treatment. Our objective was to determine the prevalence of ciTBI and neurosurgical intervention for each GCS score (range 3-15) in children presenting after blunt head trauma. METHODS: This was a secondary analysis of prospectively collected observational data from 25 pediatric emergency departments in the Pediatric Emergency Care Applied Research Network. Patients younger than 18 years with nontrivial blunt head injury were included. RESULTS: A total of 43,379 children with complete GCS scores were included in the analysis. Seven hundred sixty-three children had ciTBIs (1.8%) and 200 underwent neurosurgery (0.5%). Children with GCS scores of 4 had the highest incidence of ciTBI (21/22, 95.5%) and neurosurgical intervention (16/22, 72.2%). A nearly linear decrease in the prevalence of ciTBI from a GCS score of 4 to a score of 15 was observed (R = 0.92). Of 1341 children, 107 (8.0%) presenting with GCS scores of 14 were found to have ciTBIs and 17 (1.3%) underwent neurosurgical intervention. CONCLUSIONS: A nearly linear relationship exists between the initial GCS score and ciTBI in children with blunt head trauma. The highest prevalence of ciTBI and neurosurgical intervention occurred in children with GCS scores of 4. Children presenting with GCS scores of 14 had a nonnegligible prevalence of ciTBI. These findings are critical to providers caring for children with blunt head trauma to accurately formulate pretest probabilities of ciTBI.

Early intramuscular adrenaline administration is associated with improved survival from out-of-hospital cardiac arrest.

BACKGROUND: Early administration of adrenaline is associated with improved survival after out-of-hospital cardiac arrest (OHCA). Delays in vascular access may impact the timely delivery of adrenaline. Novel methods for administering adrenaline before vascular access may enhance survival. The objective of this study was to determine whether an initial intramuscular (IM) adrenaline dose followed by standard IV/IO adrenaline is associated with improved survival after OHCA. METHODS STUDY DESIGN: We conducted a before-and-after study of the implementation of an early, first-dose IM adrenaline EMS protocol for adult OHCAs. The pre-intervention period took place between January 2010 and October 2019. The post-intervention period was between November 2019 and May 2024. SETTING: Single-center urban, two-tiered EMS agency. PARTICIPANTS: Adult, nontraumatic OHCA meeting criteria for adrenaline use. INTERVENTION: Single dose (5 mg) IM adrenaline. All other care, including subsequent IV or IO adrenaline, followed international guidelines. MAIN OUTCOMES AND MEASURES: The primary outcome was survival to hospital discharge. Secondary outcomes were time from EMS arrival to the first dose of adrenaline, survival to hospital admission, and favorable neurologic function at discharge. RESULTS: Among 1405 OHCAs, 420 (29.9%) received IM adrenaline and 985 (70.1%) received usual care. Fifty-two patients received the first dose of adrenaline through the IV or IO route within the post-intervention period and were included in the standard care group analysis. Age was younger and bystander CPR was higher in the IM adrenaline group. All other characteristics were similar between IM and standard care cohorts. Time to adrenaline administration was faster for the IM cohort [(median 4.3 min (IQR 3.0-6.0) vs. 7.8 min (IQR 5.8-10.4)]. Compared with standard care, IM adrenaline was associated with improved survival to hospital admission (37.1% vs. 31.6%; aOR 1.37, 95% CI 1.06-1.77), hospital survival (11.0% vs 7.0%; aOR 1.73, 95% CI 1.10-2.71) and favorable neurologic status at hospital discharge (9.8% vs 6.2%; aOR 1.72, 95% CI 1.07-2.76). CONCLUSION: In this single-center before-and-after implementation study, an initial IM dose of adrenaline as an adjunct to standard care was associated with improved survival to hospital admission, survival to hospital discharge, and functional survival. A randomized controlled trial is needed to fully assess the potential benefit of IM adrenaline delivery in OHCA.

Investigating the variability in pressure-volume relationships during hemorrhage and aortic occlusion.

Introduction: The pressure-volume (P-V) relationships of the left ventricle are the classical benchmark for studying cardiac mechanics and pumping function. Perturbations in the P-V relationship (or P-V loop) can be informative and guide the management of heart failure, hypovolemia, and aortic occlusion. Traditionally, P-V loop analyses have been limited to a single-beat P-V loop or an average of consecutive P-V loops (e.g., 10 cardiac cycles). While there are several algorithms to obtain single-beat estimations of the end-systolic and end-diastolic pressure-volume relations (i.e., ESPVR and EDPVR, respectively), there remains a need to better evaluate the variations in P-V relationships longitudinally over time. This is particularly important when studying acute and transient hemodynamic and cardiac events, such as active hemorrhage or aortic occlusion. In this study, we aim to investigate the variability in P-V relationships during hemorrhagic shock and aortic occlusion, by leveraging on a previously published porcine hemorrhage model. Methods: Briefly, swine were instrumented with a P-V catheter in the left ventricle of the heart and underwent a 25% total blood volume hemorrhage over 30 min, followed by either Zone 1 complete aortic occlusion (i.e., REBOA), Zone 1 endovascular variable aortic control (EVAC), or no occlusion as a control, for 45 min. Preload-independent metrics of cardiac performance were obtained at predetermined time points by performing inferior vena cava occlusion during a ventilatory pause. Continuous P-V loop data and other hemodynamic flow and pressure measurements were collected in real-time using a multi-channel data acquisition system. Results: We developed a custom algorithm to quantify the time-dependent variance in both load-dependent and independent cardiac parameters from each P-V loop. As expected, all pigs displayed a significant decrease in the end-systolic pressures and volumes (i.e., ESP, ESV) after hemorrhage. The variability in response to hemorrhage was consistent across all three groups. However, upon introduction of REBOA, we observed significantly high levels of variability in both load-dependent and independent cardiac metrics such as ESP, ESV, and the slope of ESPVR (Ees). For instance, pigs receiving REBOA experienced a 342% increase in ESP from hemorrhage, while pigs receiving EVAC experienced only a 188% increase. The level of variability within the EVAC group was consistently less than that of the REBOA group, which suggests that the EVAC group may be more supportive of maintaining healthier cardiac performance than complete occlusion with REBOA. Discussion: In conclusion, we successfully developed a novel algorithm to reliably quantify the single-beat and longitudinal P-V relations during hemorrhage and aortic occlusion. As expected, hemorrhage resulted in smaller P-V loops, reflective of decreased preload and afterload conditions; however, the cardiac output and heart rate were preserved. The use of REBOA and EVAC for 44 min resulted in the restoration of baseline afterload and preload conditions, but often REBOA exceeded baseline pressure conditions to an alarming level. The level of variability in response to REBOA was significant and could be potentially associated to cardiac injury. By quantifying each P-V loop, we were able to capture the variability in all P-V loops, including those that were irregular in shape and believe that this can help us identify critical time points associated with declining cardiac performance during hemorrhage and REBOA use.

Real-Time Monitoring and Modulation of Blood Pressure in a Rabbit Model of Ischemic Stroke.

Control of blood pressure, in terms of both absolute values and its variability, affects outcomes in ischemic stroke patients. However, it remains challenging to identify the mechanisms that lead to poor outcomes or evaluate measures by which these effects can be mitigated because of the prohibitive limitations inherent to human data. In such cases, animal models can be utilized to conduct rigorous and reproducible evaluations of diseases. Here we report refinement of a previously described model of ischemic stroke in rabbits that is augmented with continuous blood pressure recording to assess the impacts of modulation on blood pressure. Under general anesthesia, femoral arteries are exposed through surgical cutdowns to place arterial sheaths bilaterally. Under fluoroscopic visualization and roadmap guidance, a microcatheter is advanced into an artery of the posterior circulation of the brain. An angiogram is performed by injecting the contralateral vertebral artery to confirm occlusion of the target artery. With the occlusive catheter remaining in position for a fixed duration, blood pressure is continuously recorded to allow for tight titration of blood pressure manipulations, whether through mechanical or pharmacological means. At the completion of the occlusion interval, the microcatheter is removed, and the animal is maintained under general anesthesia for a prescribed length of reperfusion. For acute studies, the animal is then euthanized and decapitated. The brain is harvested and processed to measure the infarct volume under light microscopy and further assessed with various histopathological stains or spatial transcriptomic analysis. This protocol provides a reproducible model that can be utilized for more thorough preclinical studies on the effects of blood pressure parameters during ischemic stroke. It also facilitates effective preclinical evaluation of novel neuroprotective interventions that might improve care for ischemic stroke patients.

Precision Automated Critical Care Management: Closed-loop critical care for the treatment of distributive shock in a swine model of ischemia-reperfusion.

BACKGROUND: Goal-directed blood pressure management in the intensive care unit can improve trauma outcomes but is labor-intensive. Automated critical care systems can deliver scaled interventions to avoid excessive fluid or vasopressor administration. We compared a first-generation automated drug and fluid delivery platform, Precision Automated Critical Care Management (PACC-MAN), to a more refined algorithm, incorporating additional physiologic inputs and therapeutics. We hypothesized that the enhanced algorithm would achieve equivalent resuscitation endpoints with less crystalloid utilization in the setting of distributive shock. METHODS: Twelve swine underwent 30% hemorrhage and 30 minutes of aortic occlusion to induce an ischemia-reperfusion injury and distributive shock state. Next, animals were transfused to euvolemia and randomized into a standardized critical care (SCC) of PACC-MAN or an enhanced version (SCC+) for 4.25 hours. SCC+ incorporated lactate and urine output to assess global response to resuscitation and added vasopressin as an adjunct to norepinephrine at certain thresholds. Primary and secondary outcomes were decreased crystalloid administration and time at goal blood pressure, respectively. RESULTS: Weight-based fluid bolus volume was lower in SCC+ compared with SCC (26.9 mL/kg vs. 67.5 mL/kg, p = 0.02). Cumulative norepinephrine dose required was not significantly different (SCC+: 26.9 µg/kg vs. SCC: 13.76 µg/kg, p = 0.24). Three of 6 animals (50%) in SCC+ triggered vasopressin as an adjunct. Percent time spent between 60 mm Hg and 70 mm Hg, terminal creatinine and lactate, and weight-adjusted cumulative urine output were equivalent. CONCLUSION: Refinement of the PACC-MAN algorithm decreased crystalloid administration without sacrificing time in normotension, reducing urine output, increasing vasopressor support, or elevating biomarkers of organ damage. Iterative improvements in automated critical care systems to achieve target hemodynamics in a distributive-shock model are feasible.

Automated partial resuscitative endovascular balloon occlusion of the aorta reduces blood loss and hypotension in a highly lethal porcine liver injury model.

BACKGROUND: Partial and intermittent resuscitative endovascular balloon occlusion of the aorta (pREBOA and iREBOA, respectively) are lifesaving techniques designed to extend therapeutic duration, mitigate ischemia, and bridge patients to definitive hemorrhage control. We hypothesized that automated pREBOA balloon titration compared with automated iREBOA would reduce blood loss and hypotensive episodes over a 90-minute intervention phase compared with iREBOA in an uncontrolled liver hemorrhage swine model. METHODS: Twenty-four pigs underwent an uncontrolled hemorrhage by liver transection and were randomized to automated pREBOA (n = 8), iREBOA (n = 8), or control (n = 8). Once hemorrhagic shock criteria were met, controls had the REBOA catheter removed and received transfusions only for hypotension. The REBOA groups received 90 minutes of either iREBOA or pREBOA therapy. Surgical hemostasis was obtained, hemorrhage volume was quantified, and animals were transfused to euvolemia and then underwent 1.5 hours of automated critical care. RESULTS: The control group had significantly higher mortality rate (5 of 8) compared with no deaths in both REBOA groups, demonstrating that the liver injury is highly lethal ( p = 0.03). During the intervention phase, animals in the iREBOA group spent a greater proportion of time in hypotension than the pREBOA group (20.7% [16.2-24.8%] vs. 0.76% [0.43-1.14%]; p < 0.001). The iREBOA group required significantly more transfusions than pREBOA (21.0 [20.0-24.9] mL/kg vs. 12.1 [9.5-13.9] mL/kg; p = 0.01). At surgical hemostasis, iREBOA had significantly higher hemorrhage volumes compared with pREBOA (39.2 [29.7-44.95] mL/kg vs. 24.7 [21.6-30.8] mL/kg; p = 0.04). CONCLUSION: Partial REBOA animals spent significantly less time at hypotension and had decreased transfusions and blood loss. Both pREBOA and iREBOA prevented immediate death compared with controls. Further refinement of automated pREBOA is necessary, and controller algorithms may serve as vital control inputs for automated transfusion. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells.

The directed differentiation of forebrain neuronal types from human embryonic stem cells (hESCs) has not been achieved. Here, we show that hESCs differentiate to telencephalic progenitors with a predominantly dorsal identity in a chemically defined medium without known morphogens. This is attributed to endogenous Wnt signaling, which upregulates the truncated form of GLI3, a repressor of sonic hedgehog (SHH). A high concentration of SHH, or the inhibition of Wnt by dickkopf 1 (DKK1) together with a low concentration of SHH, almost completely converts the primitive dorsal precursors to ventral progenitors, which is partially achieved through both downregulation of the truncated GLI3 and upregulation of full-length GLI3 expression. These dorsal and ventral telencephalic progenitors differentiate to functional glutamatergic and GABAergic neurons, respectively. Thus, although hESCs generate dorsal telencephalic cells, as opposed to ventral progenitors in other vertebrates, in the absence of exogenous morphogens, human cells use a similar molecular mechanism to control the dorsal versus ventral fate. The coordination of Wnt and SHH signaling through GLI3 represents a novel mechanism that regulates ventral-dorsal patterning in the development of forebrain neuronal subtypes.

Automated aortic endovascular balloon volume titration prevents re-arrest immediately after return of spontaneous circulation in a swine model of nontraumatic cardiac arrest.

Objectives: Endovascular aortic occlusion as an adjunct to cardiopulmonary resuscitation (CPR) for non-traumatic cardiac arrest is gaining interest. In a recent clinical trial, return of spontaneous circulation (ROSC) was achieved despite prolonged no-flow times. However, 66% of patients re-arrested upon balloon deflation. We aimed to determine if automated titration of endovascular balloon volume following ROSC can augment diastolic blood pressure (DBP) to prevent re-arrest. Methods: Twenty swine were anesthetized and placed into ventricular fibrillation (VF). Following 7 minutes of no-flow VF and 5 minutes of mechanical CPR, animals were subjected to complete aortic occlusion to adjunct CPR. Upon ROSC, the balloon was either deflated steadily over 5 minutes (control) or underwent automated, dynamic adjustments to maintain a DBP of 60 mmHg (Endovascular Variable Aortic Control, EVAC). Results: ROSC was obtained in ten animals (5 EVAC, 5 REBOA). Sixty percent (3/5) of control animals rearrested while none of the EVAC animals rearrested (p = 0.038). Animals in the EVAC group spent a significantly higher proportion of the post-ROSC period with a DBP > 60 mmHg [median (IQR)] [control 79.7 (72.5-86.0)%; EVAC 97.7 (90.8-99.7)%, p = 0.047]. The EVAC group had a statistically significant reduction in arterial lactate concentration [7.98 (7.4-8.16) mmol/L] compared to control [9.93 (8.86-10.45) mmol/L, p = 0.047]. There were no statistical differences between the two groups in the amount of adrenaline (epinephrine) required. Conclusion: In our swine model of cardiac arrest, automated aortic endovascular balloon titration improved DBP and prevented re-arrest in the first 20 minutes after ROSC.

The physiology of aortic flow and pressures during partial resuscitative endovascular balloon occlusion of the aorta in a swine model of hemorrhagic shock.

BACKGROUND: Partial resuscitative endovascular balloon occlusion of the aorta (REBOA) has shown promise as a method to extend REBOA, but there lacks a standard definition of the technique. The purpose of this study was to investigate the relationships between distal and proximal mean arterial pressure (MAP) and distal aortic flow past a REBOA catheter. We hypothesize that a relationship between distal aortic flow and distal MAP in Zone 1 partial REBOA (pREBOA) is conserved and that there is no apparent relationship between aortic flow and proximal MAP. METHODS: A retrospective data analysis of swine was performed. Cohort 1 underwent 20% controlled hemorrhage and then randomized to aortic flow of 400 mL/min or complete occlusion for 20 minutes (n = 11). Cohort 2 underwent 30% controlled hemorrhage followed by complete aortic occlusion for 30 minutes (n = 29). Then, they all underwent REBOA wean in a similar stepwise fashion. Blood pressure was collected from above (proximal) and below (distal) the REBOA balloon. Aortic flow was measured using a surgically implanted supraceliac aortic perivascular flow probe. The time period of balloon wean was taken as the time point of interest. RESULTS: A linear relationship between distal MAP and aortic flow was observed ( R2 value, 0.80), while no apparent relationship appeared between proximal MAP and aortic flow ( R2 value, 0.29). The repeated-measures correlation coefficient for distal MAP (0.94; 95% confidence interval, 0.94-0.94) was greater than proximal MAP (-0.73; 95% confidence interval, -0.74 to -0.72). CONCLUSION: The relationship between MAP and flow will be a component of next-generation pREBOA control inputs. This study provides evidence that pREBOA techniques should rely on distal rather than proximal MAP for control of distal aortic flow. These data could inform future inquiry into optimal flow rates and parameters based on distal MAP in both translational and clinical contexts.

Paramedic rhythm interpretation misclassification is associated with poor survival from out-of-hospital cardiac arrest.

BACKGROUND: Early recognition and rapid defibrillation of shockable rhythms is strongly associated with survival in out of hospital cardiac arrest (OHCA). Little is known about the accuracy of paramedic rhythm interpretation and its impact on survival. We hypothesized that inaccurate paramedic interpretation of initial rhythm would be associated with worse survival. METHODS: This is a retrospective cohort analysis of prospectively collected OHCA data over a nine-year period within a single, urban, fire-based EMS system that utilizes manual defibrillators equipped with rhythm-filtering technology. We compared paramedic-documented initial rhythm with a reference standard of post-event physician interpretation to estimate sensitivity and specificity of paramedic identification of and shock delivery to shockable rhythms. We assessed the association between misclassification of initial rhythm and neurologically intact survival to hospital discharge using multivariable logistic regression. RESULTS: A total of 863 OHCA cases were available for analysis with 1,756 shocks delivered during 542 (63%) resuscitation attempts. Eleven percent of shocks were delivered to pulseless electrical activity (PEA). Sensitivity and specificity for paramedic initial rhythm interpretation were 176/197 (0.89, 95% CI 0.84-0.93) and 463/504 (0.92, 95% CI 0.89-0.94) respectively. No patient survived to hospital discharge when paramedics misclassified the initial rhythm. CONCLUSIONS: Paramedics achieved high sensitivity for shock delivery to shockable rhythms, but with an 11% shock delivery rate to PEA. Misclassification of initial rhythm was associated with poor survival. Technologies that assist in rhythm identification during CPR, rapid shock delivery, and minimal hands-off time may improve outcomes.

Endovascular Perfusion Augmentation for Critical Care Decreases Vasopressor Requirements while Maintaining Renal Perfusion.

BACKGROUND: Ischemia reperfusion injury causes a profound hyperdynamic distributive shock. Endovascular perfusion augmentation for critical care (EPACC) has emerged as a hemodynamic adjunct to vasopressors and crystalloid. The objective of this study was to examine varying levels of mechanical support for the treatment of ischemiareperfusion injury in swine. METHODS: Fifteen swine underwent anesthesia and then a controlled 30% blood volume hemorrhage followed by 30 min of supra-celiac aortic occlusion to create an ischemia-reperfusion injury Animals were randomized to standardized critical care (SCC), EPACC with low threshold (EPACC-Low), and EPACC with high threshold (EPACC-High). The intervention phase lasted 270 min after injury Hemodynamic markers and laboratory values of ischemia were recorded. RESULTS: During the intervention phase, SCC spent 82.4% of the time avoiding proximal hypotension (>60 mm Hg), while EPACC-Low spent 97.6% and EPACC-High spent 99.5% of the time avoiding proximal hypotension, P  < 0.001. Renal artery flow was statistically increased in EPACC-Low compared with SCC (2.29 mL/min/kg vs. 1.77 mL/ min/kg, P  < 0.001), while renal flow for EPACC-High was statistically decreased compared with SCC (1.25 mL/min/kg vs. 1.77 mL/min/kg, P  < 0.001). EPACC animals required less intravenous norepinephrine, (EPACC-Low: 16.23mcg/kg and EPACC-High: 13.72 mcg/kg), compared with SCC (59.45 mcg/kg), P = 0.049 and P = 0.013 respectively. CONCLUSIONS: Compared with SCC, EPACC-High and EPACC-Low had decreased norepinephrine requirements with decreased frequency of proximal hypotension. EPACC-Low paradoxically had increased renal perfusion despite having a mechanical resistor in the aorta proximal to the renal arteries. This is the first description of low volume mechanical hemodynamic support in the setting of profound shock from ischemia-reperfusion injury in swine demonstrating stabilized proximal hemodynamics and augmented distal perfusion.

Maintaining Zone 1 Occlusion is a Dynamic Process: The Effects of Proximal Pressure and Blood Transfusion During REBOA.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) provides hemodynamic support to patients with non-compressible truncal hemorrhage. As cardiac output increases due to aortic occlusion (AO), aortic diameter will increase as a function of compliance, potentially causing unintended flow around the balloon. MATERIALS AND METHODS: Swine (N = 10) were instrumented to collect proximal mean arterial blood pressure (pMAP), distal MAP (dMAP), balloon pressure (bP), balloon volume (bV), and distal aortic flow (Qaorta). A 7-Fr automated REBOA catheter was positioned in Zone 1. At T0, animals underwent 30% total blood volume hemorrhage over 30 min followed by balloon inflation to complete AO. Automated balloon inflation occurred from T30-T60 when Qaorta was detected. Period of interest was T55-T60, while the balloon actively worked to maintain AO during transfusion of shed blood. RESULTS: Median weight of the cohort was 73.75 [IQR:71.58-74.45] kg. During T40-T55 and T55-T60, median pMAP was 88.95 [IQR:76.80-109.92] and 108.13 [IQR:99.13-119.51] mmHg, P = 0.07. Median Qaorta during T40-T55, and T55-T60 was 0.81 [IQR:0.41-0.96], and 1.53 [IQR:1.07-1.96] mL/kg/min, P = 0.06. Median number of balloon inflations during T40-T55 was 0.00 [IQR:0.00-0.75] and increased during active transfusion to 10.00 [IQR:5.25-14.00], P = 0.001. DISCUSSION: In clinical practice, following initial establishment of AO, progressive balloon inflations are required to maintain AO in response to intrinsic and transfusion-mediated increases in cardiac output, blood pressure, and aortic diameter.

The Association of Modifiable Postresuscitation Management and Annual Case Volume With Survival After Extracorporeal Cardiopulmonary Resuscitation.

It is not know if hospital-level extracorporeal cardiopulmonary resuscitation (ECPR) case volume, or postcannulation clinical management associate with survival outcomes. OBJECTIVES: To describe variation in postresuscitation management practices, and annual hospital-level case volume, for patients who receive ECPR and to determine associations between these management practices and hospital survival. DESIGN: Observational cohort study using case-mix adjusted survival analysis. SETTING AND PARTICIPANTS: Adult patients greater than or equal to 18 years old who received ECPR from the Extracorporeal Life Support Organization Registry from 2008 to 2019. MAIN OUTCOMES AND MEASURES: Generalized estimating equation logistic regression was used to determine factors associated with hospital survival, accounting for clustering by center. Factors analyzed included specific clinical management interventions after starting extracorporeal membrane oxygenation (ECMO) including coronary angiography, mechanical unloading of the left ventricle on ECMO (with additional placement of a peripheral ventricular assist device, intra-aortic balloon pump, or surgical vent), placement of an arterial perfusion catheter distal to the arterial return cannula (to mitigate leg ischemia); potentially modifiable on-ECMO hemodynamics (arterial pulsatility, mean arterial pressure, ECMO flow); plus hospital-level annual case volume for adult ECPR. RESULTS: Case-mix adjusted patient-level management practices varied widely across individual hospitals. We analyzed 7,488 adults (29% survival); median age 55 (interquartile range, 44-64), 68% of whom were male. Adjusted hospital survival on ECMO was associated with mechanical unloading of the left ventricle (odds ratio [OR], 1.3; 95% CI, 1.08-1.55; p = 0.005), performance of coronary angiography (OR, 1.34; 95% CI, 1.11- 1.61; p = 0.002), and placement of an arterial perfusion catheter distal to the return cannula (OR, 1.39; 95% CI, 1.05-1.84; p = 0.022). Survival varied by 44% across hospitals after case-mix adjustment and was higher at centers that perform more than 12 ECPR cases/yr (OR, 1.23; 95% CI, 1.04-1.45; p = 0.015) versus medium- and low-volume centers. CONCLUSIONS AND RELEVANCE: Modifiable ECMO management strategies and annual case volume vary across hospitals, appear to be associated with survival and should be the focus of future research to test if these hypothesis-generating associations are causal in nature.

Functional control of transplantable human ESC-derived neurons via optogenetic targeting.

Current methods to examine and regulate the functional integration and plasticity of human ESC (hESC)-derived neurons are cumbersome and technically challenging. Here, we engineered hESCs and their derivatives to express the light-gated channelrhodopsin-2 (ChR2) protein to overcome these deficiencies. Optogenetic targeting of hESC-derived neurons with ChR2 linked to the mCherry fluorophore allowed reliable cell tracking as well as light-induced spiking at physiological frequencies. Optically induced excitatory and inhibitory postsynaptic currents could be elicited in either ChR2(+) or ChR2(-) neurons in vitro and in acute brain slices taken from transplanted severe combined immunodeficient (SCID) mice. Furthermore, we created a clonal hESC line that expresses ChR2-mCherry under the control of the synapsin-1 promoter. On neuronal differentiation, ChR2-mCherry expression was restricted to neurons and was stably expressed for at least 6 months, providing more predictable light-induced currents than transient infections. This pluripotent cell line will allow both in vitro and in vivo analysis of functional development as well as the integration capacity of neuronal populations for cell-replacement strategies.

Effects of Extended Lower Extremity Cooling Following Zone 3 REBOA in a Porcine Hemorrhage Model.

INTRODUCTION: External cooling of ischemic limbs has been shown to have a significant protective benefit for durations up to 4 hours. MATERIALS AND METHODS: It was hypothesized that this benefit could be extended to 8 hours. Six swine were anesthetized and instrumented, then underwent a 25% total blood volume hemorrhage. Animals were randomized to hypothermia or normothermia followed by 8 hours of Zone 3 resuscitative endovascular balloon occlusion of the aorta, then resuscitation with shed blood, warming, and 3 hours of critical care. Physiologic parameters were continuously recorded, and laboratory specimens were obtained at regular intervals. RESULTS: There were no significant differences between groups at baseline. There were no significant differences between creatine kinase in the hypothermia group when compared to the normothermia group (median [IQR] = 15,206 U/mL [12,476-19,987] vs 23,027 U/mL [18,745-26,843]); P = 0.13) at the end of the study. Similarly, serum myoglobin was also not significantly different in the hypothermia group after 8 hours (7,345 ng/mL [5,082-10,732] vs 5,126 ng/mL [4,720-5,298]; P = 0.28). No histologic differences were observed in hind limb skeletal muscle. CONCLUSION: While external cooling during prolonged Zone 3 resuscitative endovascular balloon occlusion of the aorta appears to decrease ischemic muscle injury, this benefit appears to be time dependent. As the ischemic time approaches 8 hours, the benefit from hypothermia decreases.

The use of resuscitative endovascular balloon occlusion of the aorta (REBOA) for non-traumatic cardiac arrest: A review.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) has been proposed as a novel approach to managing non-traumatic cardiac arrest (NTCA). During cardiac arrest, cardiac output ceases and perfusion of vital organs is compromised. Traditional advanced cardiac life support (ACLS) measures and cardiopulmonary resuscitation are often unable to achieve return of spontaneous circulation (ROSC). During insertion of REBOA a balloon-tipped catheter is placed into the femoral artery and advanced in a retrograde manner into the aorta while the patient is undergoing cardiopulmonary resuscitation (CPR). The balloon is then inflated to fully occlude the aorta. The literature surrounding the use of aortic occlusion in non-traumatic cardiac arrest is limited to animal studies, case reports and one recent non-controlled feasibility trial. In both human and animal studies, preliminary data show that REBOA may improve coronary and cerebral perfusion pressures and key physiologic parameters during cardiac arrest resuscitation, and animal data have demonstrated improved rates of ROSC. Multiple questions remain before REBOA can be considered as an adjunct to ACLS. If demonstrated to be effective clinically, REBOA represents a potentially cost-effective and generalizable intervention that may improve quality of life for patients with non-traumatic cardiac arrest.

Reperfusion repercussions: A review of the metabolic derangements following resuscitative endovascular balloon occlusion of the aorta.

BACKGROUND: Current resuscitative endovascular balloon occlusion of the aorta (REBOA) literature focuses on improving outcomes through careful patient selection, diligent catheter placement, and expeditious definitive hemorrhage control. However, the detection and treatment of post-REBOA ischemia-reperfusion injury (IRI) remains an area for potential improvement. Herein, we provide a review of the metabolic derangements that we have encountered while managing post-REBOA IRI in past swine experiments. We also provide data-driven clinical recommendations to facilitate resuscitation post-REBOA deflation that may be translatable to humans. METHODS: We retrospectively reviewed the laboratory data from 25 swine across three varying hemorrhagic shock models that were subjected to complete REBOA of either 45 minutes, 60 minutes, or 90 minutes. In each model the balloon was deflated gradually following definitive hemorrhage control. Animals were then subjected to whole blood transfusion and critical care with frequent electrolyte monitoring and treatment of derangements as necessary. RESULTS: Plasma lactate peaked and pH nadired long after balloon deflation in all swine in the 45-minute, 60-minute, and 90-minute occlusion models (onset of peak lactate, 32.9 ± 6.35 minutes, 38.8 ± 10.55 minutes, and 49.5 ± 6.5 minutes; pH nadir, 4.3 ± 0.72 minutes, 26.9 ± 12.32 minutes, and 42 ± 7.45 minutes after balloon deflation in the 45-, 60-, and 90-minute occlusion models, respectively). All models displayed persistent hypoglycemia for more than an hour following reperfusion (92.1 ± 105.5 minutes, 125 ± 114.9 minutes, and 96 ± 97.8 minutes after balloon deflation in the 45-, 60-, and 90-minute occlusion groups, respectively). Hypocalcemia and hyperkalemia occurred in all three groups, with some animals requiring treatment more than an hour after reperfusion. CONCLUSION: Metabolic derangements resulting from REBOA use are common and may worsen long after reperfusion despite resuscitation. Vigilance is required to detect and proactively manage REBOA-associated IRI. Maintaining a readily available "deflation kit" of pharmacological agents needed to treat common post-REBOA electrolyte abnormalities may facilitate management. LEVEL OF EVIDENCE: Level V.