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Background: Patients with kidney failure are at risk for lethal complications from hyperkalemia. Resuscitation, medications, and hemodialysis are used to mitigate increased potassium (K+) levels in circulating blood; however, these approaches may not always be readily available or effective, especially in a resource limited environment. We tested a sorbent cartridge (KC, K+ontrol CytoSorbents Medical Inc., Monmouth Junction, New Jersey) which contains a resin adsorber for K+. The objective of this study was to test the utility of KC in an ex vivo circulation system. We hypothesized that KC reduces K+ levels in extracorporeal circulation of donor swine whole blood infused with KCl. Methods: A six-hour circulation study was carried out using KC, a NxStage (NxStage Medical, Inc., Lawrence, MA) membrane, blood bag containing heparinized whole blood with KCl infusion, 3/16-inch ID tubing, a peristaltic pump, and flow sensors. The NxStage permeate line was connected back to the main circuit in the Control group (n = 6), creating a recirculation loop. For KC group (n = 6), KC was added to the recirculation loop, and a continuous infusion of KCl at 10 mEq/hour was administered for two hours. Blood samples were acquired at baseline and every hour for 6 h. Results: In the control group, K+ levels remained at ∼9 mmol/L; 9.1 ± 0.4 mmol/L at 6 h. In the KC group, significant decreases in K+ at hour 1 (4.3 ± 0.3 mmol/L) and were sustained for the experiment duration equilibrating at 4.6 ± 0.4 mmol/L after 6 h (p = 0.042). Main loop blood flow was maintained under 400 mL/min; recirculation loop flow varied between 60 and 70 mL/min in the control group and 45–55 mL/min in the KC group. Decreases in recirculation loop flow in KC group required 7% increase of pump RPM. Conclusions: During ex-vivo extracorporeal circulation using donor swine blood, KC removed approximately 50% of K+, normalizing circulating levels. [ABSTRACT FROM AUTHOR]

Introduction: Clot formation, infection, and biofouling are unfortunate but frequent complications associated with the use of blood-contacting medical devices. The challenge of blood-foreign surface interactions is exacerbated during medical device applications involving substantial blood contact area and extended duration of use, such as extracorporeal life support (ECLS). We investigated a novel surface modification, a liquid-impregnated surface (LIS), designed to minimize protein adsorption and thrombus development on medical plastics. Methods: The hemocompatibility and efficacy of LIS was investigated first in a low-shear model with LIS applied to the lumen of blood incubation vials and exposed to human whole blood. Additionally, LIS was evaluated in a 6 h ex vivo circulation model with swine blood using full-scale ECLS circuit tubing and centrifugal pumps with clinically relevant flow rate (1.5 L/min) and shear conditions for extracorporeal carbon dioxide removal. Results: Under low-shear, LIS preserved fibrinogen concentration in blood relative to control polymers (+40 ± 6 mg/dL vs polyvinyl chloride, p <.0001), suggesting protein adsorption was minimized. A fibrinogen adhesion assay demonstrated a dramatic reduction in protein adsorption under low shear (87% decrease vs polyvinyl chloride, p =.01). Thrombus deposition and platelet adhesion visualized by scanning electron microscopy were drastically reduced. During the 6 h ex vivo circulation, platelets in blood exposed to LIS tubing did not become significantly activated or procoagulant, as occurred with control tubing; and again, thrombus deposition was visually reduced. Conclusions: A LIS coating demonstrated potential to reduce thrombus formation on medical devices. Further testing is needed specialized to clinical setting and duration of use for specific medical target applications. [ABSTRACT FROM AUTHOR]

Rationale: Early post injury mitigation strategies in ARDS are in short supply. Treatments with allogeneic stromal cells are administered after ARDS develops, require specialized expertise and equipment, and to date have shown limited benefit. Objectives: Assess the efficacy of immediate post injury intravenous administration of autologous or allogeneic bone marrow-derived mesenchymal stromal cells (MSCs) for the treatment of acute respiratory distress syndrome (ARDS) due to smoke inhalation and burns. Methods: Yorkshire swine (n = 32, 44.3 ± 0.5 kg) underwent intravenous anesthesia, placement of lines, severe smoke inhalation, and 40% total body surface area flame burns, followed by 72 hours of around-the-clock ICU care. Mechanical ventilation, fluids, pressors, bronchoscopic cast removal, daily lung computed tomography scans, and arterial blood assays were performed. After injury and 24 and 48 hours later, animals were randomized to receive autologous concentrated bone marrow aspirate (n = 10; 3 x 106 white blood cells and a mean of 56.6 x 106 platelets per dose), allogeneic MSCs (n = 10; 6.1 x 106 MSCs per dose) harvested from healthy donor swine, or no treatment in injured control animals (n = 12). Measurements and Main Results: The intravenous administration of MSCs after injury and at 24 and 48 hours delayed the onset of ARDS in swine treated with autologous MSCs (48 ± 10 h) versus control animals (14 ± 2 h) (P = 0.004), reduced ARDS severity at 24 (P < 0.001) and 48 (P = 0.003) hours, and demonstrated visibly diminished consolidation on computed tomography (not significant). Mortality at 72 hours was 1 in 10 (10%) in the autologous group, 5 in 10 (50%) in the allogeneic group, and 6 in 12 (50%) in injured control animals (not significant). Both autologous and allogeneic MSCs suppressed systemic concentrations of TNF-α (tumor necrosis factor-α). Conclusions: The intravenous administration of three doses of freshly processed autologous bone marrow-derived MSCs delays ARDS development and reduces its severity in swine. Bedside retrieval and administration of autologous MSCs in swine is feasible and may be a viable injury mitigation strategy for ARDS. [ABSTRACT FROM AUTHOR]

Recent global events such as COVID‐19 pandemic amid rising rates of chronic lung diseases highlight the need for safer, simpler, and more available treatments for respiratory failure, with increasing interest in extracorporeal membrane oxygenation (ECMO). A key factor limiting use of this technology is the complexity of the blood circuit, resulting in clotting and bleeding and necessitating treatment in specialized care centers. Microfluidic oxygenators represent a promising potential solution, but have not reached the scale or performance required for comparison with conventional hollow fiber membrane oxygenators (HFMOs). Here the development and demonstration of the first microfluidic respiratory assist device at a clinical scale is reported, demonstrating efficient oxygen transfer at blood flow rates of 750 mL min⁻1, the highest ever reported for a microfluidic device. The central innovation of this technology is a fully 3D branching network of blood channels mimicking key features of the physiological microcirculation by avoiding anomalous blood flows that lead to thrombus formation and blood damage in conventional oxygenators. Low, stable blood pressure drop, low hemolysis, and consistent oxygen transfer, in 24‐hour pilot large animal experiments are demonstrated – a key step toward translation of this technology to the clinic for treatment of a range of lung diseases. [ABSTRACT FROM AUTHOR]

Numerous biomaterials have been developed for application in blood‐contacting medical devices to prevent thrombosis; however, few materials have been applied to full‐scale devices and evaluated for hemocompatibility under clinical blood flow conditions. We applied a dual‐action slippery liquid‐infused (LI) nitric oxide (NO)‐releasing material modification (LINO) to full‐scale blood circulation tubing for extracorporeal lung support and evaluated the tubing ex vivo using swine whole blood circulated for 6 h at a clinically relevant flow. LINO tubing was compared to unmodified tubing (CTRL) and isolated LI and NO‐releasing modifications (n = 9/group). The primary objective was to evaluate safety and blood compatibility of this approach, prior to progression to in vivo testing of efficacy in animal models. The secondary objective was to evaluate coagulation outcomes relevant to hemocompatibility. No untoward effects of the coating, such as elevated methemoglobin fraction, were observed. Additionally, LINO delayed platelet loss until 6 h versus the reduction in platelet count in CTRL at 3 h. At 6 h, LINO significantly reduced the concentration of platelets in an activated P‐selectin expressing state versus CTRL (32 ± 1% decrease, p =.02). Blood clot deposition was significantly reduced on LINO blood pumps (p =.007) and numerically reduced on tubing versus CTRL. Following blood exposure, LINO tubing continued to produce a measurable NO‐flux (0.20 ± 0.06 × 10−10 mol cm−2 min−1). LINO is a potential solution to reduce circuit‐related bleeding and clotting during extracorporeal organ support, pending future extended testing in vivo using full‐scale extracorporeal lung support devices. [ABSTRACT FROM AUTHOR]

Introduction: Fluid overload in extracorporeal membrane oxygenation (ECMO) patients has been associated with increased mortality. Patients receiving ECMO and continuous renal replacement therapy (CRRT) who achieve a negative fluid balance have improved survival. Limited data exist on the use of CRRT solely for fluid management in ECMO patients. Methods: We performed a single-center retrospective review of 19 adult ECMO patients without significant renal dysfunction who received CRRT for fluid management. These patients were compared to a cohort of propensity-matched controls. Results: After 72 h, the treatment group had a fluid balance of −3840 mL versus + 425 mL (p ≤ 0.05). This lower fluid balance correlated with survival to discharge (odds ratio 2.54, 95% confidence interval 1.10–5.87). Improvement in the ratio of arterial oxygen content to fraction of inspired oxygen was also significantly higher in the CRRT group (102.4 vs. 0.7, p ≤ 0.05). We did not observe any significant difference in renal outcomes. Conclusions: The use of CRRT for fluid management is effective and, when resulting in negative fluid balance, improves survival in adult ECMO patients without significant renal dysfunction. [ABSTRACT FROM AUTHOR]

Purpose Bicaval dual-lumen catheters allow for single-site cannulation venovenous extracorporeal gas exchange and facilitate early mobilization of patients. Using these catheters blood is drained from the superior and inferior venae cavae, pumped through a respiratory membrane, and returned into the right atrium. The insertion of these catheters is challenging as their correct positioning is fundamental to reduce recirculation and avoid severe complications. We describe here a new technique for the positioning of bicaval dual-lumen catheters. Materials and methods The right internal jugular vein was percutaneously cannulated in nine sheep. The distance between skin and tricuspid valve was measured from the point of pressure change in the waveform of a Swan-Ganz catheter being retracted from the right ventricle into the right atrium. The atrium-tricuspid valve-ventricle axis was determined by observing the fluctuations of the tip of the Swan-Ganz entering the ventricle during fluoroscopy. A bicaval dual-lumen catheter was placed on the basis of these evaluations and connected to an extracorporeal respiratory support system. Results The position of the catheter was verified at necropsy approximately 18 h after insertion. In all cases the catheter was correctly placed, with the central port situated in front of the tricuspid valve. Conclusions The described technique may help to position bicaval dual-lumen catheters for venovenous extracorporeal gas exchange without the use of transesophageal echocardiography or contrast media during fluoroscopy., Author(s): Thomas Langer [sup.1] [sup.2] [sup.4] , Vittoria Vecchi [sup.1] [sup.3] [sup.4] , Slava M. Belenkiy [sup.1] , Leopoldo C. Cancio [sup.1] , Luciano Gattinoni [sup.2] , Andriy I. Batchinsky [...]

Background: Consumption of platelets and coagulation factors during extracorporeal carbon dioxide removal (ECCO2R) increases bleeding complications and associated mortality. Regional infusion of lactic acid enhances ECCO2R by shifting the chemical equilibrium from bicarbonate to carbon dioxide. Our goal was to test if regional blood acidification during ECCO2R inhibits platelet function and coagulation. Methods: An ECCO2R system containing a hemofilter circulated blood at 0.25 L/min in eight healthy ewes (Ovis aries) for 36 h. Three of the sheep received ECCO2R with no recirculation compared to five sheep that received ECCO2R plus 12 h of regional blood acidification via the hemofilter, placed upstream from the oxygenator, into which 4.4 M lactic acid was infused. Blood gases, platelet count and function, thromboelastography, coagulation‐factor activity, and von Willebrand factor activity (vWF:Ag) were measured at baseline, at start of lactic acid infusion, and after 36 h of extracorporeal circulation. Results: Twelve hours of regional acid infusion significantly inhibited platelet aggregation response to adenosine diphosphate; vWF; and platelet expression of P‐selectin compared to control. It also significantly reduced consumption of fibrinogen and of coagulation factors V, VII, IX, compared to control. Conclusions: Regional acidification reduces platelet activation and vitamin‐K‐dependent coagulation‐factor consumption during ECCO2R. This is the first report of a simple method that may enhance effective anticoagulation for ECCO2R. [ABSTRACT FROM AUTHOR]

Introduction: Extracorporeal life support (ECLS) patients are at risk for complications caused by gaseous microemboli (GME). GMEs can cause hypoxia, inflammation, coagulation, and end-organ damage. The objective of this in vitro study was to assess dynamics of GME formation during circulation of whole blood or a glycerol blood surrogate. We hypothesized that there is no difference in GME counts and sizes between whole blood and the glycerol blood surrogate and that the membrane lung reduces GME counts over time. Methods: A circulation platform was developed using the Cardiohelp ECLS system to run either donor blood or glycerol solution. We conducted 10 repetitions consisting of three phases of ultrasound GME detection using the EDAC™ Quantifier (Luna Innovations, Charlottesville, VA, USA) for each group. Phases were 3-minute recordings at the initiation of 2 L/min flow (Phase 1), post-injection of a GME suspension (Phase 2), and 10 minutes after injection (Phase 3). The number and size of GME pre- and post-ML were recorded separately and binned based on diameter ranges. Results: In Phase 1, GME count in blood was higher than in glycerol. In Phase 2, there was a large increase in GME counts; however, most GME were reduced post-membrane in both groups. In Phase 3, there was a significant decrease in GME counts compared to Phase 2. GME > 100 μm in glycerol decreased post membrane. Conclusions: We demonstrated GME formation and decay dynamics during in vitro circulation in an ECLS system with blood and glycerol. GME counts were higher in blood, likely due to varying rheological properties. There were decreases in GME levels post membrane in both groups after GME injection, with the membrane lung effectively trapping the GME, and additional reduction 10 minutes after GME injection. [ABSTRACT FROM AUTHOR]

Background: In this review, we assess the state of Resuscitative Endovascular Occlusion of the Aorta (REBOA) today with respect to out-of-hospital (OOH) vs. inhospital (H) use in blunt and penetrating trauma, as well as discuss areas of promising research that may be key in further advancement of REBOA applications. Methods: To analyze the trends in REBOA use, we conducted a review of the literature and identified articles with human or animal data that fit the respective inclusion and exclusion criteria. In separate tables, we compiled data extracted from selected articles in categories including injury type, zone and duration of REBOA, setting in which REBOA was performed, sample size, age, sex and outcome. Based on these tables as well as more detailed review of some key cases of REBOA usage, we assessed the current state of REBOA as well as coagulation and histological disturbances associated with its usage. All statistical tests were 2-sided using an alpha=0.05 for significance. Analysis was done using SAS 9.5 (Cary, NC). Tests for significance was done with a t-test for continuous data and a Chi Square Test for categorical data. Results: In a total of 44 cases performed outside of a hospital in both military and civilian settings, the overall survival was found to be 88.6%, significantly higher than the 50.4% survival calculated from 1,807 cases of REBOA performed within a hospital (p<.0001). We observe from human data a propensity to use Zone I in penetrating trauma and Zone III in blunt injuries. We observe lower final metabolic markers in animal studies with shorter REBOA time and longer follow-up times. Conclusions: Further research related to human use of REBOA must be focused on earlier initiation of REBOA after injury which may depend on development of rapid vascular access devices and techniques more so than on any new improvements in REBOA. Future animal studies should provide detailed multisystem organ assessment to accurately define organ injury and metabolic burden associated with REBOA application. Overall, animal studies must involve realistic models of injury with severe clinical scenarios approximating human trauma and exsanguination, especially with long-term follow-up after injury. [ABSTRACT FROM AUTHOR]

Background and objective: Resuscitative Endovascular Balloon Occlusion of Aorta (REBOA) has emerged as a potential life-saving maneuver for the management of non-compressible torso hemorrhage in trauma patients. Complete REBOA (cREBOA) is inherently associated with the burden of ischemia reperfusion injury (IRI) and organ dysfunction. However, the distal organ inflammation and its association with organ injury have been little investigated. This study was conducted to assess these adverse effects of cREBOA following massive hemorrhage in swine. Methods: Spontaneously breathing and consciously sedated Sinclair pigs were subjected to exponential hemorrhage of 65% total blood volume over 60 minutes. Animals were randomized into 3 groups (n = 7): (1) Positive control (PC) received immediate transfusion of shed blood after hemorrhage, (2) 30min-cREBOA (A30) received Zone 1 cREBOA for 30 minutes, and (3) 60min-cREBOA (A60) given Zone 1 cREBOA for 60 minutes. The A30 and A60 groups were followed by resuscitation with shed blood post-cREBOA and observed for 4h. Metabolic and hemodynamic effects, coagulation parameters, inflammatory and end organ consequences were monitored and assessed. Results: Compared with 30min-cREBOA, 60min-cREBOA resulted in (1) increased IL-6, TNF-α, and IL-1β in distal organs (kidney, jejunum, and liver) (p < 0.05) and decreased reduced glutathione in kidney and liver (p < 0.05), (2) leukopenia, neutropenia, and coagulopathy (p < 0.05), (3) blood pressure decline (p < 0.05), (4) metabolic acidosis and hyperkalemia (p < 0.05), and (5) histological injury of kidney and jejunum (p < 0.05) as well as higher levels of creatinine, AST, and ALT (p < 0.05). Conclusion: 30min-cREBOA seems to be a feasible and effective adjunct in supporting central perfusion during severe hemorrhage. However, prolonged cREBOA (60min) adverse effects such as distal organ inflammation and injury must be taken into serious consideration. [ABSTRACT FROM AUTHOR]

Background: Extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) are modalities used in critically ill patients suffering organ failure and metabolic derangements. Although the effects of CRRT have been extensively studied, the impact of simultaneous CRRT and ECMO is less well described. The purpose of this study is to evaluate the incidence and the impact of CRRT on outcomes of patients receiving ECMO. Methods: A single center, retrospective chart review was conducted for patients receiving ECMO therapy over a 6-year period. Patients who underwent combined ECMO and CRRT were compared to those who underwent ECMO alone. Intergroup -statistical comparisons were performed using Wilcoxon/Kruskal-Wallis and chi-square tests. Logistic regression was performed to identify independent risk factors for mortality. Results: The demographic and clinical data of 92 patients who underwent ECMO at our center were reviewed including primary diagnosis, indications for and mode of ECMO support, illness severity, oxygenation index, vasopressor requirement, and presence of acute kidney injury. In those patients that required ECMO with CRRT, we reviewed urine output prior to initiation, modality used, prescribed dose, net fluid balance after 72 h, requirement of renal replacement therapy (RRT) at discharge, and use of diuretics prior to RRT initiation. Our primary endpoint was survival to hospital discharge. During the study period, 48 patients required the combination of ECMO with CRRT. Twenty-nine of these patients survived to hospital discharge. Of the 29 survivors, 6 were dialysis dependent at hospital discharge. The mortality rate was 39.5% with combined ECMO/CRRT compared to 31.4% among those receiving ECMO alone (p = 0.074). Of those receiving combined therapy, nonsurvivors were more likely to have a significantly positive net fluid balance at 72 h (p = 0.001). A multivariate linear regression analysis showed net positive fluid balance and increased age were independently associated with mortality. Conclusions: Use of CRRT is prevalent among patients undergoing ECMO, with over 50% of our patient population receiving combination therapy. Fluid balance appears to be an important variable associated with outcomes in this cohort. Rates of renal recovery and overall survival were higher compared to previously published reports among those requiring combined ECMO/CRRT. [ABSTRACT FROM AUTHOR]

Hemocompatible materials for extracorporeal life support (ECLS) technology are investigated to mitigate thrombotic complications associated with this therapy. A promising solution is an omniphobic bilayer coating, tethered liquid perfluorocarbon (TLP), which utilizes an immobilized tether to anchor a mobile, liquid surface lubricant that prevents adhesion of blood components to the substrate. In this study, we investigated the effects of TLP on real‐time clot formation using thromboelastography (TEG). TLP was applied to TEG cups, utilizing perfluorodecalin (PFD) or FluorLube63 as the liquid layer, and compared to uncoated cups. Human blood (n = 10) was added to cups; and TEG parameters (R, K, α‐angle, MA, LY30, LY60) and adherent thrombus weight were assessed. TLP decreased clot amplification (α‐angle), clot strength (MA), and adherent clot weight (p <.0001). These effects were greater with FluorLube63 versus PFD (α‐angle p <.0001; MA p =.0019; clot weight p <.0001). Reaction time (R) was longer in TLP‐coated cups versus control cups with liquid lubricant added (p =.0377). Percent fibrinolysis (LY30 and LY60) was greater in the TLP versus controls at LY30 (p <.0001), and in FluoroLube63 versus controls at LY60 (p =.0021). TLP significantly altered clot formation, exerting antithrombogenic effects. This reduction in surface thrombogenicity supports TLP as a candidate for improved biocompatibility of ECLS materials, pending further validation with exposure to shear stress. [ABSTRACT FROM AUTHOR]

BACKGROUND: Portable noninvasive Heart Rate Complexity (HRC) and Compensatory Reserve Measurement (CRM) monitors have been developed to triage supine combat casualties. Neither monitor has been tested in upright individuals during physical exercise. This study tests the hypothesis that exercise evokes proportional changes in HRC and CRM. METHODS: Two instruments monitored volunteers (9 civilian and 11 soldiers) from the Army Trauma Training Department (ATTD) before, during, and following physical exercise. One recorded heart rate (HR, bpm), cardiac output (CO, L · min-1), heart rate variability (HRV, root mean square of successive differences, ms), and HRC (Sample Entropy, unitless). The other recorded HR, pulse oximetry (Spo2, %), and CRM (%). RESULTS: Baseline HR, CO, HRV, HRC, and CRM averaged 72 ± 1 bpm, 5.6 ± 1.2 L · min-1, 48 ± 24 ms, 1.9 ± 0.5, and 85 ± 10% in seated individuals. Exercise evoked peak HR and CO at > 200% of baseline, while HRC and CRM were simultaneously decreased to minimums that were ≤ 50% of baseline (all P < 0.001). HRV changes were variable and unreliable. Spo2 remained consistently above 95%. During a 60 min recovery, HR and CRM returned to baseline on parallel tracks (t1/2=11 ± 8 and 18 ± 14 min), whereas HRC recovery was slower than either CRM or HR (t1/2=40 ± 18 min, both P < 0.05). DISCUSSION: Exercise evoked qualitatively similar changes in CRM and HRC. CRM recovered incrementally faster than HRC, suggesting that vasodilation, muscle pump, and respiration compensate faster than cardiac autonomic control in young, healthy volunteers. Both HRC and CRM appear to provide reliable, objective, and noninvasive metrics of human performance in upright exercising individuals. [ABSTRACT FROM AUTHOR]

Aim: In this study, we aimed at identifying the optimal conditions for isolation, processing and expansion of mesenchymal stem cells (MSCs). Methods: Porcine bone marrow was obtained from either small- or large-volume bone marrow aspirate (BMA). Next, three BMA processing methods were compared. Finally, the best condition was selected from various culture parameters, including basal media, supplementation and seeding density. Results: Our results demonstrate that a small-volume BMA and direct plating yields significantly higher concentration of MSCs. Basal media supplementation with 10% platelet lysate and seeding density of 1000 cells/cm2 can generate large numbers of multipotent MSCs with augmented function and low population doublings. Conclusion: This work provides guidance for preparation of robust MSCs for future clinical trials. [ABSTRACT FROM AUTHOR]