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Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a lifesaving maneuver for the management of lethal torso hemorrhage. However, its prolonged use leads to distal organ ischemia–reperfusion injury (IRI) and systemic inflammatory response syndrome (SIRS). The objective of this study is to investigate the blood-based biomarkers of IRI and SIRS and the efficacy of direct intestinal cooling in the prevention of IRI and SIRS. A rat lethal hemorrhage model was produced by bleeding 50% of the total blood volume. A balloon catheter was inserted into the aorta for the implementation of REBOA. A novel TransRectal Intra-Colon (TRIC) device was placed in the descending colon and activated from 10 min after the bleeding to maintain the intra-colon temperature at 37 °C (TRIC37°C group) or 12 °C (TRIC12°C group) for 270 min. The upper body temperature was maintained at as close to 37 °C as possible in both groups. Blood samples were collected before hemorrhage and after REBOA. The organ injury biomarkers and inflammatory cytokines were evaluated by ELISA method. Blood based organ injury biomarkers (endotoxin, creatinine, AST, FABP1/L-FABP, cardiac troponin I, and FABP2/I-FABP) were all drastically increased in TRIC37°C group after REBOA. TRIC12°C significantly downregulated these increased organ injury biomarkers. Plasma levels of pro-inflammatory cytokines TNF-α, IL-1b, and IL-17F were also drastically increased in TRIC37°C group after REBOA. TRIC12°C significantly downregulated the pro-inflammatory cytokines. In contrast, TRIC12°C significantly upregulated the levels of anti-inflammatory cytokines IL-4 and IL-10 after REBOA. Amazingly, the mortality rate was 100% in TRIC37°C group whereas 0% in TRIC12°C group after REBOA. Directly cooling the intestine offered exceptional protection of the abdominal organs from IRI and SIRS, switched from a harmful pro-inflammatory to a reparative anti-inflammatory response, and mitigated mortality in the rat model of REBOA management of lethal hemorrhage. [ABSTRACT FROM AUTHOR]

Introduction: Extracorporeal membrane oxygenation circuit performance can be compromised by oxygenator thrombosis. Stagnant blood flow in the oxygenator can increase the risk of thrombus formation. To minimize thrombogenic potential, computational fluid dynamics is frequently applied for identification of stagnant flow conditions. We investigate the use of computed tomography angiography to identify flow patterns associated with thrombus formation. Methods: A computed tomography angiography was performed on a Quadrox D oxygenator, and video densitometric parameters associated with flow stagnation were measured from the acquired videos. Computational fluid dynamics analysis of the same oxygenator was performed to establish computational fluid dynamics–based flow characteristics. Forty-one Quadrox D oxygenators were sectioned following completion of clinical use. Section images were analyzed with software to determine oxygenator clot burden. Linear regression was used to correlate clot burden to computed tomography angiography and computational fluid dynamics–based flow characteristics. Results: Clot burden from the explanted oxygenators demonstrated a well-defined pattern, with the largest clot burden at the corner opposite the blood inlet and outlet. The regression model predicted clot burden by region of interest as a function of time to first opacification on computed tomography angiography (R2 = 0.55). The explanted oxygenator clot burden map agreed well with the computed tomography angiography predicted clot burden map. The computational fluid dynamics parameter of residence time, when summed in the Z-direction, was partially predictive of clot burden (R2 = 0.35). Conclusion: In the studied oxygenator, clot burden follows a pattern consistent with clinical observations. Computed tomography angiography–based flow analysis provides a useful adjunct to computational fluid dynamics–based flow analysis in understanding oxygenator thrombus formation. [ABSTRACT FROM AUTHOR]

The roles of the large membrane surface of the oxygenator and the high mechanical shear stress (HMSS) of the pump in the extracorporeal membrane oxygenation (ECMO) circuit were examined under a pediatric support setting. A clinical centrifugal pump and a pediatric oxygenator were used to construct the ECMO circuit. An identical circuit without the oxygenator was constructed for comparison. Fresh human blood was circulated in the two circuits for 4 hours under the identical pump speed and flow. Blood samples were collected hourly for blood damage assessment, including platelet activation, generation of platelet‐derived microparticles (PDMP), losses of key platelet hemostasis receptors (glycoprotein (GP) Ibα (GPIbα) and GPVI), and high molecular weight multimers (HMWM) of von Willebrand factor (VWF) and plasma free hemoglobin (PFH). Platelet adhesion on fibrinogen, VWF, and collagen was further examined. The levels of platelet activation and generation of PDMP and PFH exhibited an increasing trend with circulation time while the expression levels of GPIbα and GPVI receptors on the platelet surface decreased. Correspondingly, the platelets in the blood samples exhibited increased adhesion capacity to fibrinogen and decreased adhesion capacities on VWF and collagen with circulation time. Loss of HMWM of VWF occurred in both circuits. No statistically significant differences were found in all the measured parameters for blood damage and platelet adhesion function between the two circuits. The results indicate that HMSS from the pump played a dominant role in blood damage associated with ECMO and the impact of the large surface of the oxygenator on blood damage was insignificant. [ABSTRACT FROM AUTHOR]

Extracorporeal membrane oxygenation (ECMO) has become a mainstay of therapy for patients suffering from severe respiratory failure. Ambulatory ECMO systems aim to provide long‐term out‐of‐hospital respiratory support. As a patient's activity level changes, the required level of ECMO support varies with oxygen consumption and metabolic fluctuations. To compensate for such changes, an autoregulatory ECMO system (AR‐ECMO) has been developed and its performance was evaluated as a proof of concept in an acute ovine model. The AR‐ECMO system consists of a regular ECMO circuit and an electromechanical control system. A custom fuzzy logic control algorithm was implemented to adjust the blood flow and sweep gas flow of the ECMO circuit to meet the varying respiratory demand by utilizing two noninvasive sensors for venous oxyhemoglobin saturation and the oxygenator exhaust gas CO2 concentration. Disturbance responses of the AR‐ECMO to induced acute respiratory distress were assessed for six hours in four juvenile sheep cannulated with a veno‐pulmonary artery ECMO configuration, including acute ventilator shutoff, ventilator step change (off‐on‐off), and forced desaturation. All sheep survived for the study duration. The AR‐ECMO system was able to respond and maintain stable hemodynamics and physiological blood gas contents (SpO2 = 96.3 % ± 4.29, pH 7.44 ± 0.09, pCO2 = 38.9 ± 9.9 mm Hg, and pO2 =237.9 ± 123.6 mm Hg) during simulated respiratory distress. Acceptable correlation between oxygenator exhaust gas CO2 and oxygenator outlet pCO2 were observed (R2 = 0.84). In summary, the AR‐ECMO system successfully maintained physiologic control of peripheral oxygenation and carbon dioxide over the study period, utilizing only measurements taken directly from the ECMO circuit. The range of system response necessitates an adaptable system in the setting of variable metabolic demands. The ability of this system to respond to significant disturbances in ventilator support is encouraging. Future work to evaluate our AR‐ECMO system in long‐term, awake animal studies is necessary for further refinement. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the impact of the nonphysiological shear stress (NPSS) on platelet hemostatic function relevant to thrombosis and bleeding in mechanically assisted circulation. Fresh human blood was circulated for four hours in in vitro circulatory flow loops with a CentriMag blood pump operated under a flow rate of 4.5 L/min against three pressure heads (70 mm Hg, 150 mm Hg, and 350 mm Hg) at 2100, 2800, and 4000 rpm, respectively. Hourly blood samples from the CentriMag pump‐assisted circulation loops were collected and analyzed for glycoprotein (GP) IIb/IIIa activation and receptor shedding of GPVI and GPIbα on the platelet surface with flow cytometry. Adhesion of platelets to fibrinogen, collagen, and von Willebrand factor (VWF) of the collected blood samples was quantified with fluorescent microscopy. In parallel, mechanical shear stress fields within the CentriMag pump operated under the three conditions were assessed by computational fluid dynamics (CFD) analysis. The experimental results showed that levels of platelet GPIIb/IIIa activation and platelet receptor shedding (GPVI and GPIbα) in the blood increased with increasing the circulation time. The levels of platelet activation and loss of platelet receptors GPVI and GPIbα were consistently higher with higher pressure heads at each increasing hour in the CentriMag pump‐assisted circulation. The platelet adhesion on fibrinogen increased with increasing the circulation time for all three CentriMag operating conditions and was correlated well with the level of platelet activation. In contrast, the platelet adhesion on collagen and VWF decreased with increasing the circulation time under all the three conditions and was correlated well with the loss of the receptors GPVI and GPIbα on the platelet surface, respectively. The CFD results showed that levels of shear stresses inside the CentriMag pump under all three operating conditions exceeded the maximum level of shear stress in the normal physiological circulation and were strongly dependent on the pump operating condition. The level of platelet activation and loss of key platelet adhesion receptors (GPVI and GPIbα) were correlated with the level of NPSS generated by the CentriMag pump, respectively. In summary, the level of NPSS associated with pump operating condition is a critical determinant of platelet dysfunction in mechanically assisted circulation. [ABSTRACT FROM AUTHOR]

The PI3K/Akt signaling pathway has been implicated in playing an important role in platelet activation during hemostasis and thrombosis involving platelet‐matrix interaction and platelet aggregation. Its role in non‐physiological shear stress (NPSS)‐induced platelet activation relevant to high‐shear blood contacting medical devices (BCMDs) is unclear. In the context of blood cells flowing in BCMDs, platelets are subjected to NPSS (>100 Pa) with very short exposure time (<1 s). In this study, we investigated whether NPSS with short exposure time induces platelet activation through the PI3K/Akt signaling pathway. Healthy donor blood treated with or without PI3K inhibitor was subjected to NPSS (150 Pa) with short exposure time (0.5 s). Platelet activation indicated by the surface P‐selectin expression and activated glycoprotein (GP) IIb/IIIa was quantified using flow cytometry. The phosphorylation of Akt, activation of the PI3K signaling, was characterized by western blotting. Changes in adhesion behavior of NPSS‐sheared platelets on fibrinogen, collagen, and von Willebrand factor (vWF) were quantified with fluorescent microscopy by perfusing the NPSS‐sheared and PI3K inhibitor‐treated blood through fibrinogen, collagen, and vWF‐coated microcapillary tubes. The results showed that the PI3K/Akt signaling was involved with both NPSS‐induced platelet activation and platelet‐matrix interaction. NPSS‐sheared platelets exhibited exacerbated platelet adhesion on fibrinogen, but had diminished platelet adhesion on collagen and vWF. The inhibition of PI3K signaling reduced P‐selectin expression and GPIIb/IIIa activation with suppressed Akt phosphorylation and abolished NPSS‐enhanced platelet adhesion on fibrinogen in NPSS‐sheared blood. The inhibition of PI3K signaling can attenuate the adhesion of unsheared platelets (baseline) on collagen and vWF, while had no impact on adhesion of NPSS‐sheared platelets on collagen and vWF. This study confirmed the important role of PI3K/Akt signaling pathway in NPSS‐induced platelet activation. The finding of this study suggests that blocking PI3K/Akt signaling pathway could be a potential method to treat thrombosis in patients implanted with BCMDs. [ABSTRACT FROM AUTHOR]

Non-surgical bleeding (NSB) is the most common clinical complication in heart failure (HF) patients supported by continuous-flow left ventricular assist devices (CF-LVADs). In this study, oxidative stress and alteration of signal pathways leading to platelet apoptosis were investigated. Thirty-one HF patients supported by CF-LVADs were divided into bleeder ( n = 12) and non-bleeder ( n = 19) groups. Multiple blood samples were collected at pre-implant (baseline) and weekly up to 1-month post-implant. A single blood sample was collected from healthy subjects (reference). Production of reactive oxygen species (ROS) in platelets, total antioxidant capacity (TAC), oxidized low-density lipoproteins (oxLDL), expression of Bcl-2 and Bcl-xL, Bax and release of cytochrome c ( Cyt.c), platelet mitochondrial membrane potential (Δ ψ ), activation of caspases, gelsolin cleavage and platelet apoptosis were examined. Significantly elevated ROS, oxLDL and depleted TAC were evident in the bleeder group compared to non-bleeder group ( p < 0.05). Platelet pro-survival proteins (Bcl-2, Bcl-xL) were significantly reduced in the bleeder group in comparison to the non-bleeder group ( p < 0.05). Translocation of Bax into platelet mitochondria membrane and subsequent release of Cyt.c were more prevalent in the bleeder group. Platelet mitochondrial damage, activation of caspases, gelsolin cleavage, and ultimate platelet apoptosis in the bleeder group were observed. Oxidative stress and activation of both intrinsic and extrinsic pathways of platelet apoptosis may be linked to NSB in CF-LVAD patients. Additionally, biomarkers of oxidative stress, examination of pro-survivals and pro-apoptotic proteins in platelets, mitochondrial damage, caspase activation, and platelet apoptosis may be used to help identify HF patients at high risk of NSB post-implant. [ABSTRACT FROM AUTHOR]

Aim: We sought to quantify the location and volume of thrombus in used hollow-fiber membrane oxygenators and correlate the volume of thrombus with patient demographics, flow characteristics and anticoagulation parameters. Methods: Hollow-fiber membrane oxygenators (Quadrox D, Maquet, Rastatt, Germany) were collected after clinical use in ECMO circuits and divided into sections. Each section was digitally imaged and analyzed using ImageJ software. The location and total volume (cm³) of thrombus was calculated for different sections. In an effort to predict thrombus formation, we correlated thrombus volume with possible aggravating and mitigating variables. Results: We collected 41 oxygenators from 27 patients. Twenty-seven (66%) were configured in the veno-venous mode and 14 (34%) in the veno-arterial mode. The median duration of use was 131 hours (interquartile range 61-214 hours). Eighteen (44%) were removed when the patient recovered, six (15%) were removed after withdrawal of care and seventeen (41%) were exchanged. The median volume of thrombus was 11.4 cm3 (interquartile range 2.2-44.5 cm³). Conclusions: A multivariable linear regression model suggested that the combination of median flow, configuration of ECMO and visible thrombus partially predicted internal thrombus volume (adjusted R²=0.39). [ABSTRACT FROM AUTHOR]

Respiratory failure is one of the major causes of mortality and morbidity all over the world. Therapeutic options to treat respiratory failure remain limited. The objective of this study was to evaluate the gas transfer performance of a newly developed miniature portable integrated pediatric pump-lung device (PediPL) with small membrane surface for respiratory support in an acute ovine respiratory failure model. The respiratory failure was created in six adult sheep using intravenous anesthesia and reduced mechanical ventilation at 2 breaths/min. The PediPL device was surgically implanted and evaluated for respiratory support in a venovenous configuration between the right atrium and pulmonary artery. The hemodynamics and respiratory status of the animals during support with the device gas transfer performance of the PediPL were studied for 4 h. The animals exhibited respiratory failure 30 min after mechanical ventilation was reduced to 2 breaths/min, indicated by low oxygen partial pressure, low oxygen saturation, and elevated carbon dioxide in arterial blood. The failure was reversed by establishing respiratory support with the PediPL after 30 min. The rates of O2 transfer and CO2 removal of the PediPL were 86.8 and 139.1 mL/min, respectively. The results demonstrated that the PediPL (miniature integrated pump-oxygenator) has the potential to provide respiratory support as a novel treatment for both hypoxia and hypercarbia. The compact size of the PediPL could allow portability and potentially be used in many emergency settings to rescue patients suffering acute lung injury. [ABSTRACT FROM AUTHOR]