Investigating the Relationship between Bleeding, Clotting, and Coagulopathy During Automated Partial REBOA Strategies in a Highly Lethal Porcine Hemorrhage Model.

BACKGROUND: Death due to hemorrhagic shock, particularly, non-compressible truncal hemorrhage (NCTH), remains one of the leading causes of potentially preventable deaths. Automated partial and intermittent resuscitative endovascular balloon occlusion of the aorta (i.e., pREBOA and iREBOA, respectively) are lifesaving endovascular strategies aimed to achieve quick hemostatic control while mitigating distal ischemia. In iREBOA, the balloon is titrated from full occlusion to no occlusion intermittently whereas in pREBOA, a partial occlusion is maintained. Therefore, these two interventions impose different hemodynamic conditions, which may impact coagulation and the endothelial glycocalyx layer (EGL). In this study, we aimed to characterize the clotting kinetics and coagulopathy associated with iREBOA and pREBOA, using thromboelastography (TEG). We hypothesized that iREBOA would be associated with a more hypercoagulopathic response compared to pREBOA due to more oscillatory flow. METHODS: Yorkshire swine (n = 8/group) were subjected to an uncontrolled hemorrhage by liver transection, followed by 90 minutes of automated partial REBOA (pREBOA), intermittent REBOA (iREBOA), or no balloon support (Control). Hemodynamic parameters were continuously recorded, and blood samples were serially collected during the experiment (i.e., 8 key time points: baseline (BL), T0, T10, T30, T60, T90, T120, T210 minutes). Citrated kaolin heparinase (CKH) assays were run on a TEG 5000 (Haemonetics, Niles, IL). General linear mixed models were employed to compare differences in TEG parameters between groups and over time using STATA (v17; College Station, TX), while adjusting for sex and weight. RESULTS: As expected, iREBOA was associated with more oscillations in proximal pressure (and greater magnitudes of peak pressure) because of the intermittent periods of full aortic occlusion and complete balloon deflation, compared to pREBOA. Despite these differences in acute hemodynamics, there were no significant differences in any of the TEG parameters between iREBOA and pREBOA groups. However, animals in both groups experienced a significant reduction in clotting times (R-time: p < 0.001; K-time: p < 0.001) and clot strength (MA: p = 0.01; G: p = 0.02) over the duration of the experiment. CONCLUSIONS: Despite observing acute differences in peak proximal pressures between iREBOA and pREBOA groups, we did not observe any significant differences in TEG parameters between iREBOA and pREBOA. The changes in TEG profiles were significant over time, indicating that a severe hemorrhage followed by both pREBOA and iREBOA can result in faster clotting reaction times (i.e., R-times). Nevertheless, when considering the significant reduction in transfusion requirements and more stable hemodynamic response in the pREBOA group, there may be some evidence favoring pREBOA usage over iREBOA.

MAN VERSUS MACHINE: PROVIDER DIRECTED VERSUS PRECISION AUTOMATED CRITICAL CARE MANAGEMENT IN A PORCINE MODEL OF DISTRIBUTIVE SHOCK.

ABSTRACT: Background: Critical care management of shock is a labor-intensive process. Precision Automated Critical Care Management (PACC-MAN) is an automated closed-loop system incorporating physiologic and hemodynamic inputs to deliver interventions while avoiding excessive fluid or vasopressor administration. To understand PACC-MAN efficacy, we compared PACC-MAN to provider-directed management (PDM). We hypothesized that PACC-MAN would achieve equivalent resuscitation outcomes to PDM while maintaining normotension with lower fluid and vasopressor requirements. Methods : Twelve swine underwent 30% controlled hemorrhage over 30 min, followed by 45 min of aortic occlusion to generate a vasoplegic shock state, transfusion to euvolemia, and randomization to PACC-MAN or PDM for 4.25 h. Primary outcomes were total crystalloid volume, vasopressor administration, total time spent at hypotension (mean arterial blood pressure <60 mm Hg), and total number of interventions. Results : Weight-based fluid volumes were similar between PACC-MAN and PDM; median and IQR are reported (73.1 mL/kg [59.0-78.7] vs. 87.1 mL/kg [79.4-91.8], P = 0.07). There was no statistical difference in cumulative norepinephrine (PACC-MAN: 33.4 µg/kg [27.1-44.6] vs. PDM: 7.5 [3.3-24.2] µg/kg, P = 0.09). The median percentage of time spent at hypotension was equivalent (PACC-MAN: 6.2% [3.6-7.4] and PDM: 3.1% [1.3-6.6], P = 0.23). Urine outputs were similar between PACC-MAN and PDM (14.0 mL/kg vs. 21.5 mL/kg, P = 0.13). Conclusion : Automated resuscitation achieves equivalent resuscitation outcomes to direct human intervention in this shock model. This study provides the first translational experience with the PACC-MAN system versus PDM.

Improving the precision of shock resuscitation by predicting fluid responsiveness with machine learning and arterial blood pressure waveform data.

Fluid bolus therapy (FBT) is fundamental to the management of circulatory shock in critical care but balancing the benefits and toxicities of FBT has proven challenging in individual patients. Improved predictors of the hemodynamic response to a fluid bolus, commonly referred to as a fluid challenge, are needed to limit non-beneficial fluid administration and to enable automated clinical decision support and patient-specific precision critical care management. In this study we retrospectively analyzed data from 394 fluid boluses from 58 pigs subjected to either hemorrhagic or distributive shock. All animals had continuous blood pressure and cardiac output monitored throughout the study. Using this data, we developed a machine learning (ML) model to predict the hemodynamic response to a fluid challenge using only arterial blood pressure waveform data as the input. A Random Forest binary classifier referred to as the ML fluid responsiveness algorithm (MLFRA) was trained to detect fluid responsiveness (FR), defined as a ≥ 15% change in cardiac stroke volume after a fluid challenge. We then compared its performance to pulse pressure variation, a commonly used metric of FR. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC), confusion matrix metrics, and calibration curves plotting predicted probabilities against observed outcomes. Across multiple train/test splits and feature selection methods designed to assess performance in the setting of small sample size conditions typical of large animal experiments, the MLFRA achieved an average AUROC, recall (sensitivity), specificity, and precision of 0.82, 0.86, 0.62. and 0.76, respectively. In the same datasets, pulse pressure variation had an AUROC, recall, specificity, and precision of 0.73, 0.91, 0.49, and 0.71, respectively. The MLFRA was generally well-calibrated across its range of predicted probabilities and appeared to perform equally well across physiologic conditions. These results suggest that ML, using only inputs from arterial blood pressure monitoring, may substantially improve the accuracy of predicting FR compared to the use of pulse pressure variation. If generalizable, these methods may enable more effective, automated precision management of critically ill patients with circulatory shock.

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.

Positron Emission Tomography-Computed Tomography Imaging of Selective Lobar Delivery of Stem Cells in Ex Vivo Lung Model of Mechanical Ventilation.

Introduction: The delivery of cell therapies may be an important frontier to treat different respiratory diseases in the near future. However, the cell size, delivery conditions, cell viability, and effect in the pulmonary function are critical factors. We performed a proof-of-concept experiment using ex vivo lungs and novel subglottic airway device that allows for selective lobar isolation and administration of drugs and biologics in liquid solution deep into the lung tissues, while simultaneously ventilating the rest of the lung lobes. Methods: We used radiolabeled cells and positron emission tomography-computed tomography (PET-CT) imaging to demonstrate the feasibility of high-yield cell delivery to a specifically targeted lobe. This study proposes an alternative delivery method of live cells labeled with radioactive isotope into the lung parenchyma and tracks the cell delivery using PET-CT imaging. The technique combines selective lobar isolation and lobar infusion to carry large particles distal to the trachea, subtending bronchial segments and reaching alveoli in targeted regions. Results: The solution with cells and carrier achieved a complete and homogeneous lobar distribution. An increase in tissue density was shown on the computed tomography (CT) scan, and the PET-CT imaging demonstrated retention of the activity at central, peripheral lung parenchyma, and pleural surface. The increase in CT density and metabolic activity of the isotope was restricted to the desired lobe only without leak to other lobes. Conclusion: The selective lobe delivery is targeted and imaging-guided by bronchoscopy and CT to a specific diseased lobe during mechanical ventilation. The feasibility of high-yield cell delivery demonstrated in this study will lead to the development of potential novel therapies that contribute to lung health.

Hardware and software implementation of POCT1-A for integration of point of care testing in research.

Point of care testing (POCT) is increasingly utilized in clinical medicine. Small, portable testing devices can now deliver reliable and accurate diagnostic results during a patient encounter. With these increases in POCT, the issue of data and results management quickly emerges. Results need to be cataloged accurately and efficiently while the providers/support staff are simultaneously managing patient encounters. The integration of electronic medical records (EMR) as data repositories requires that point of care testing data imports automatically into the EMR. POCT1-A was developed as a standard communication language for POCT device manufacturers to streamline automatic data import integration. While all modern POCT devices are built with this connectivity, the systems that provide the integration layer are often proprietary and require a fee for service. In the research environment, there is not enough throughput to justify the practical investment in these data management architectures. Moreover, researcher needs are different and unique compared to data management systems for clinicians. To meet this need, we developed a novel hardware and software connectivity solution using commercially available components to automate data management from a point-of-care blood biochemical analyzer during a critical care study in the preclinical research environment.

Development of a computational fluid dynamic model to investigate the hemodynamic impact of REBOA.

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a lifesaving intervention for major truncal hemorrhage. Balloon-tipped arterial catheters are inserted via the femoral artery to create a temporary occlusion of the aorta, which minimizes the rate of internal bleeding until definitive surgery can be conducted. There is growing concern over the resultant hypoperfusion and potential damage to tissues and organs downstream of REBOA. To better understand the acute hemodynamic changes imposed by REBOA, we developed a three-dimensional computational fluid dynamic (CFD) model under normal, hemorrhage, and aortic occlusion conditions. The goal was to characterize the acute hemodynamic changes and identify regions within the aortic vascular tree susceptible to abnormal flow and shear stress. Methods: Hemodynamic data from established porcine hemorrhage models were used to build a CFD model. Swine underwent 20% controlled hemorrhage and were randomized to receive a full or partial aortic occlusion. Using CT scans, we generated a pig-specific aortic geometry and imposed physiologically relevant inlet flow and outlet pressure boundary conditions to match in vivo data. By assuming non-Newtonian fluid properties, pressure, velocity, and shear stresses were quantified over a cardiac cycle. Results: We observed a significant rise in blood pressure (∼147 mmHg) proximal to REBOA, which resulted in increased flow and shear stress within the ascending aorta. Specifically, we observed high levels of shear stress within the subclavian arteries (22.75 Pa). Alternatively, at the site of full REBOA, wall shear stress was low (0.04 ± 9.07E-4 Pa), but flow oscillations were high (oscillatory shear index of 0.31). Comparatively, partial REBOA elevated shear levels to 84.14 ± 19.50 Pa and reduced flow oscillations. Our numerical simulations were congruent within 5% of averaged porcine experimental data over a cardiac cycle. Conclusion: This CFD model is the first to our knowledge to quantify the acute hemodynamic changes imposed by REBOA. We identified areas of low shear stress near the site of occlusion and high shear stress in the subclavian arteries. Future studies are needed to determine the optimal design parameters of endovascular hemorrhage control devices that can minimize flow perturbations and areas of high shear.

Near-Infrared Spectroscopy for Determination of Cardiac Output Augmentation in a Swine Model of Ischemia-Reperfusion Injury.

CONTEXT: Near infrared spectroscopy (NIRS) is a noninvasive tool for assessing local oxygen balance. In circulatory shock, the microcirculatory environment as measured by NIRS during resuscitation may provide additional diagnostic tools of value to the critical care physician. HYPOTHESIS: To assess whether a relative increase in peripheral NIRS was correlated with a clinically relevant increase in cardiac output following a fluid bolus in a swine model of shock. METHODS AND MODELS: Nine healthy young adult swine with median weight 80 kg (interquartile range, 75-83 kg) were anesthetized and surgically instrumented. They underwent a controlled hemorrhage of 20% of their blood volume followed by partial or complete aortic occlusion to create a variable ischemia-reperfusion injury. Next, the animals underwent four 500-mL plasmalyte boluses over 9 minutes each followed by a 6-minute pause. The animal then underwent a 25% mixed auto/homologous blood transfusion followed by four more 500 mL plasmalyte boluses over 9 minutes. Finally, the animals underwent a 25% mixed auto/homologous blood transfusion followed by an additional four rounds of 500-mL plasmalyte boluses over 9 minutes. Left thoracic limb NIRS, descending thoracic aortic flow (dAF), arterial blood pressure (MAP), central venous pressure (CVP), and mixed central venous oxygen saturation (Svo2) were measured continuously for comparison. RESULTS: The area under the receiver operating curve for an increase in dAF of 10% in response to a 500 mL bolus based on a percent increase in the proximal NIRS was 0.82 with 95% CI, 0.72-0.91; Svo2, 0.86 with 95% CI, 0.78-0.95; MAP, 0.75 with 95% CI, 0.65-0.85 and CVP, 0.64 with 95% CI, 0.53-0.76. INTERPRETATION AND CONCLUSIONS: A dynamic relative increase in NIRS in response to a crystalloid challenge has moderate discriminatory power for cardiac output augmentation during shock in a swine model of ischemia-reperfusion injury. NIRS performed as well as invasive measurements (Svo2 and MAP) and better than CVP.

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.

Closed-loop automated critical care as proof-of-concept study for resuscitation in a swine model of ischemia-reperfusion injury.

BACKGROUND: Volume expansion and vasopressors for the treatment of shock is an intensive process that requires frequent assessments and adjustments. Strict blood pressure goals in multiple physiologic states of shock (traumatic brain injury, sepsis, and hemorrhagic) have been associated with improved outcomes. The availability of continuous physiologic data is amenable to closed-loop automated critical care to improve goal-directed resuscitation. METHODS: Five adult swine were anesthetized and subjected to a controlled 30% estimated total blood volume hemorrhage followed by 30 min of complete supra-celiac aortic occlusion and then autotransfusion back to euvolemia with removal of aortic balloon. The animals underwent closed-loop critical care for 255 min after removal of the endovascular aortic balloon. The closed-loop critical care algorithm used proximal aortic pressure and central venous pressure as physiologic input data. The algorithm had the option to provide programmatic control of pumps for titration of vasopressors and weight-based crystalloid boluses (5 ml/kg) to maintain a mean arterial pressure between 60 and 70 mmHg. RESULTS: During the 255 min of critical care the animals experienced hypotension (< 60 mmHg) 15.3% (interquartile range: 8.6-16.9%), hypertension (> 70 mmHg) 7.7% (interquartile range: 6.7-9.4%), and normotension (60-70 mmHg) 76.9% (interquartile range: 76.5-81.2%) of the time. Excluding the first 60 min of the critical care phase the animals experienced hypotension 1.0% (interquartile range: 0.5-6.7%) of the time. Median intervention rate was 8.47 interventions per hour (interquartile range: 7.8-9.2 interventions per hour). The proportion of interventions was 61.5% (interquartile range: 61.1-66.7%) weight-based crystalloid boluses and 38.5% (interquartile range: 33.3-38.9%) titration of vasopressors. CONCLUSION: This autonomous critical care platform uses critical care adjuncts in an ischemia-reperfusion injury model, utilizing goal-directed closed-loop critical care algorithm and device actuation. This description highlights the potential for this approach to deliver nuanced critical care in the ICU environment, thereby optimizing resuscitative efforts and expanding capabilities through cognitive offloading. Future efforts will focus on optimizing this platform through comparative studies of inputs, therapies, and comparison to manual critical care.

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.

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.

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.

Timing of adding blood to prime affects inflammatory response to neonatal cardiopulmonary bypass.

Complications from systemic inflammation are reported in neonates following exposure to cardiopulmonary bypass. Although the use of asanguinous primes can reduce these complications, in neonates, this can result in significant haemodilution, requiring addition of blood. This study investigates whether the addition of blood after institution of bypass alters the inflammatory response compared with a blood prime. Neonatal swine were randomised into four groups: blood prime, blood after bypass but before cooling, blood after cooling but before low flow, and blood after re-warming. All groups were placed on central bypass, cooled, underwent low flow, and then re-warmed for a total bypass time of 2 hours. Although haematocrit values between groups varied throughout bypass, all groups ended with a similar value. Although they spent time with a lower haematocrit, asanguinous prime groups did not have elevated lactate levels at the end of bypass compared with blood prime. Asanguinous primes released less tumour necrosis factor α than blood primes (p=0.023). Asanguinous primes with blood added on bypass produced less interleukin 10 and tumour necrosis factor α (p=0.006, 0.019). Animals receiving blood while cool also showed less interleukin 10 and tumour necrosis factor α production than those that received blood warm (p=0.026, 0.033). Asanguinous primes exhibited less oedema than blood primes, with the least body weight gain noted in the end cool group (p=0.011). This study suggests that using an asanguinous prime for neonates being cooled to deep hypothermia is practical, and the later addition of blood reduces inflammation.

Characterization of CD133 Antibody-Directed Recellularized Heart Valves.

CD133mAb conjugation (CD133-C) hastens in vivo recellularization of decellularized porcine heart valve scaffolds when placed in the pulmonary position of sheep. We now characterize this early cellularization process 4 h, 3, 7, 14, 30, or 90 days post-implantation. Quantitative immunohistochemistry identified cell types as well as changes in cell markers and developmental cues. CD133(+)/CD31(-) cells adhered to the leaflet surface of CD133-C leaflets by 3 days and transitioned to native leaflet-like CD133(-)/CD31(+) cells by 30 days. Leaflet interstitium became increasingly populated with both alpha-smooth muscle actin (αSMA) and vimentin(+) cells from 14 to 90 days post-implantation. Wnt3a, and beta-catenin proteins were expressed at early (3-14 days) but not later (30-90 days) time points. In contrast, matrix metalloproteinase-2 and periostin proteins were increasingly expressed over 90 days. Thus, early development of CD133-C constructs includes a fairly rapid transition from a precursor cell adhesion/migration/transdifferentiation phenotype to a more mature cell/native valve-like matrix metabolism phenotype.

Mechanical tissue resuscitation (MTR): a nonpharmacological approach to treatment of acute myocardial infarction.

BACKGROUND AND AIM: Myocardial ischemia-reperfusion injury is known to trigger an inflammatory response involving edema, apoptosis, and neutrophil activation/accumulation. Recently, mechanical tissue resuscitation (MTR) was described as a potent cardioprotective strategy for reduction of myocardial ischemia-reperfusion injury. Here, we further describe the protective actions of MTR and begin to define its therapeutic window. METHODS: A left ventricular, free-wall ischemic area was created in anesthetized swine for 85 minutes and then reperfused for three hours. Animals were randomized to two groups: (1) untreated controls (Control) and (2) application of MTR that was delayed 90 minutes after the initiation of reperfusion (D90). Hemodynamics and regional myocardial blood flow were assessed at multiple time points. Infarct size and neutrophil accumulation were assessed following the reperfusion period. In separate cohorts, the effect of MTR on myocardial interstitial water (MRI imaging) and blood flow was examined. RESULTS: Both groups had similar areas at risk (AAR), hemodynamics, and arterial blood gas values. MTR, even when delayed 90 minutes into reperfusion (D90, 29.2 ± 5.0% of AAR), reduced infarct size significantly compared to Controls (51.9 ± 2.7%, p = 0.006). This protection was associated with a 33% decrease in neutrophil accumulation (p = 0.047). Improvements in blood flow and interstitial water were also observed. Moreover, we demonstrated that the therapeutic window for MTR lasts for at least 90 minutes following reperfusion. CONCLUSIONS: This study confirms our previous observations that MTR is an effective therapeutic approach to reducing reperfusion injury with a clinically useful treatment window.

Mechanical tissue resuscitation protects against myocardial ischemia-reperfusion injury.

BACKGROUND AND AIM: Reperfusion injury is a complex inflammatory response involving numerous mechanisms and pathways. Mechanical tissue resuscitation is a newly described therapeutic strategy that reduces reperfusion injury. This study further investigates potential mechanisms for the protective effects of mechanical tissue resuscitation while utilizing a bio-absorbable matrix. METHODS: Anesthetized swine were subjected to 80 minutes of coronary ischemia and three hours of reperfusion. An absorbable matrix was used to cover the ischemic-reperfused myocardium and apply the mechanical tissue resuscitation (-50 mmHg) throughout reperfusion. Infarct size, myocardial blood flow (microspheres), apoptosis, edema, and hemodynamics were analyzed. RESULTS: Both control and treated groups displayed similar hemodynamics and physiologic parameters. Mechanical tissue resuscitation significantly reduced early infarct size (16.6 ± 3.8% vs. 27.3 ± 2.5% of area at risk, p < 0.05). This reduction of infarct size was accompanied by reduced edema formation in both epicardial (27% reduction) and endocardial (58% reduction) samples. Histological examination of both epicardial and endocardial tissues also revealed a reduction in apoptosis (80% and 44% reductions) in MTR-treated hearts. CONCLUSIONS: Treatment with mechanical tissue resuscitation during reperfusion reduces both early cell death and the delayed, programmed cell death after ischemia-reperfusion. This cardioprotection is also associated with a significant reduction in interstitial water. Additional cardioprotection may be derived from mechanical tissue resuscitation-induced increased blood flow. Mechanical tissue resuscitation, particularly with a resorbable device, is a straightforward and efficacious mechanical strategy for decreasing cardiomyocyte death following myocardial infarction as an adjunctive therapy to surgical revascularization.