Intravenous Autologous Bone Marrow-derived Mesenchymal Stromal Cells Delay Acute Respiratory Distress Syndrome in Swine.

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 × 106 white blood cells and a mean of 56.6 × 106 platelets per dose), allogeneic MSCs (n = 10; 6.1 × 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.

Heart transplantation from donation after circulatory death: Impact on waitlist time and transplant rate.

The effect of using donation after circulatory death (DCD) hearts on waitlist outcomes has not been substantiated. We retrospectively analyzed 184 heart transplant (HT) candidates at our institution from 2019 to 2021. Patients were stratified into 2 observation periods centered on September 12, 2020, when the adult DCD HT program officially began. The primary outcome was a comparison of transplant rate between period 1 (pre-DCD) and period 2 (post-DCD). Secondary outcomes included waitlist time-to-transplant, waitlist mortality rate, independent predictors of incidence of HT, and posttransplant outcomes. A total of 165 HTs (n = 92 in period 1 and n = 73 in period 2) were performed. The median waitlist time-to-transplant decreased from 47.5 to 19 days in periods 1 and 2, respectively (P = .004). The transplant rate increased from 181 per 100 patient-years in period 1 to 579 per 100 patient-years in period 2 (incidence rate ratio, 1.87; 95% CI, 1.04-3.38; P = .038). There were no statistical differences in waitlist mortality rate (P = .566) and 1-year survival (P = .699) between the 2 periods. DCD HTs (n = 36) contributed to 49.3% of overall HT activity in period 2. We concluded that utilization of DCD hearts significantly reduced waitlist time and increased transplant rate. Short-term posttransplant outcomes were comparable between the pre-DCD and post-DCD periods.

Regional blood acidification inhibits coagulation during extracorporeal carbon dioxide removal (ECCO2 R).

BACKGROUND: Consumption of platelets and coagulation factors during extracorporeal carbon dioxide removal (ECCO2 R) increases bleeding complications and associated mortality. Regional infusion of lactic acid enhances ECCO2 R by shifting the chemical equilibrium from bicarbonate to carbon dioxide. Our goal was to test if regional blood acidification during ECCO2 R inhibits platelet function and coagulation. METHODS: An ECCO2 R 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 ECCO2 R with no recirculation compared to five sheep that received ECCO2 R 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 ECCO2 R. This is the first report of a simple method that may enhance effective anticoagulation for ECCO2 R.

Adjunct Use of Continuous Renal Replacement Therapy with Extracorporeal Membrane Oxygenation Achieves Negative Fluid Balance and Enhances Oxygenation Which Improves Survival in Critically Ill Patients without Kidney Failure.

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.

In vitro hemocompatibility screening of a slippery liquid impregnated surface coating for extracorporeal organ support applications.

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.

Dynamics of appearance and decay of gaseous microemboli during in vitro extracorporeal circulation.

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.

K+ontrol rapidly and efficiently reduces potassium in donor blood during ex vivo circulation.

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.

Assessment of spontaneous breathing during pressure controlled ventilation with superimposed spontaneous breathing using respiratory flow signal analysis.

Integrating spontaneous breathing into mechanical ventilation (MV) can speed up liberation from it and reduce its invasiveness. On the other hand, inadequate and asynchronous spontaneous breathing has the potential to aggravate lung injury. During use of airway-pressure-release-ventilation (APRV), the assisted breaths are difficult to measure. We developed an algorithm to differentiate the breaths in a setting of lung injury in spontaneously breathing ewes. We hypothesized that differentiation of breaths into spontaneous, mechanical and assisted is feasible using a specially developed for this purpose algorithm. Ventilation parameters were recorded by software that integrated ventilator output variables. The flow signal, measured by the EVITA® XL (Lübeck, Germany), was measured every 2 ms by a custom Java-based computerized algorithm (Breath-Sep). By integrating the flow signal, tidal volume (VT) of each breath was calculated. By using the flow curve the algorithm separated the different breaths and numbered them for each time point. Breaths were separated into mechanical, assisted and spontaneous. Bland Altman analysis was used to compare parameters. Comparing the values calculated by Breath-Sep with the data from the EVITA® using Bland-Altman analyses showed a mean bias of - 2.85% and 95% limits of agreement from - 25.76 to 20.06% for MVtotal. For respiratory rate (RR) RRset a bias of 0.84% with a SD of 1.21% and 95% limits of agreement from - 1.53 to 3.21% were found. In the cluster analysis of the 25th highest breaths of each group RRtotal was higher using the EVITA®. In the mechanical subgroup the values for RRspont and MVspont the EVITA® showed higher values compared to Breath-Sep. We developed a computerized method for respiratory flow-curve based differentiation of breathing cycle components during mechanical ventilation with superimposed spontaneous breathing. Further studies in humans and optimizing of this technique is necessary to allow for real-time use at the bedside.

Outcomes among Patients Treated with Renal Replacement Therapy during Extracorporeal Membrane Oxygenation: A Single-Center Retrospective Study.

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.

Therapeutic potential of products derived from mesenchymal stem/stromal cells in pulmonary disease.

Multipotent mesenchymal stem/stromal cells (MSCs) possess robust self-renewal characteristics and the ability to differentiate into tissue-specific cells. Their therapeutic potential appears promising as evident from their efficacy in several animal models of pulmonary disorders as well as early-phase clinical trials of acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). Such therapeutic efficacy might be attributed to MSC-derived products (the "secretome"), namely conditioned media (CM) and extracellular vesicles (EVs), which have been shown to play pivotal roles in the regenerative function of MSCs. Importantly, the EVs secreted by MSCs can transfer a variety of bioactive factors to modulate the function of recipient cells via various mechanisms, including ligand-receptor interactions, direct membrane fusion, endocytosis, or phagocytosis.Herein, we review the current state-of-the-science of MSC-derived CM and EVs as potential therapeutic agents in lung diseases. We suggest that the MSC-derived secretome might be an appropriate therapeutic agent for treating aggressive pulmonary disorders because of biological and logistical advantages over live cell therapy. Nonetheless, further studies are warranted to elucidate the safety and efficacy of these components in combating pulmonary diseases.

Reciprocal Risk of Acute Kidney Injury and Acute Respiratory Distress Syndrome in Critically Ill Burn Patients.

OBJECTIVE: To evaluate the association between acute respiratory distress syndrome and acute kidney injury with respect to their contributions to mortality in critically ill patients. DESIGN: Retrospective analysis of consecutive adult burn patients requiring mechanical ventilation. SETTING: A 16-bed burn ICU at tertiary military teaching hospital. PATIENTS: Adult patients more than 18 years old requiring mechanical ventilation during their initial admission to our burn ICU from January 1, 2003, to December 31, 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total 830 patients were included, of whom 48.2% had acute kidney injury (n = 400). These patients had a 73% increased risk of developing acute respiratory distress syndrome after controlling for age, gender, total body surface area burned, and inhalation injury (hazard ratio, 1.73; 95% CI, 1.18-2.54; p = 0.005). In a reciprocal multivariate analysis, acute respiratory distress syndrome (n = 299; 36%) demonstrated a strong trend toward developing acute kidney injury (hazard ratio, 1.39; 95% CI, 0.99-1.95; p = 0.05). There was a 24% overall in-hospital mortality (n = 198). After adjusting for the aforementioned confounders, both acute kidney injury (hazard ratio, 3.73; 95% CI, 2.39-5.82; p < 0.001) and acute respiratory distress syndrome (hazard ratio, 2.16; 95% CI, 1.58-2.94; p < 0.001) significantly contributed to mortality. Age, total body surface area burned, and inhalation injury were also significantly associated with increased mortality. CONCLUSIONS: Acute kidney injury increases the risk of acute respiratory distress syndrome in mechanically ventilated burn patients, whereas acute respiratory distress syndrome similarly demonstrates a strong trend toward the development of acute kidney injury. Acute kidney injury and acute respiratory distress syndrome are both independent risks for subsequent death. Future research should look at this interplay for possible early interventions.

Extracorporeal Carbon Dioxide Removal Enhanced by Lactic Acid Infusion in Spontaneously Breathing Conscious Sheep.

BACKGROUND: The authors studied the effects on membrane lung carbon dioxide extraction (VCO2ML), spontaneous ventilation, and energy expenditure (EE) of an innovative extracorporeal carbon dioxide removal (ECCO2R) technique enhanced by acidification (acid load carbon dioxide removal [ALCO2R]) via lactic acid. METHODS: Six spontaneously breathing healthy ewes were connected to an extracorporeal circuit with blood flow 250 ml/min and gas flow 10 l/min. Sheep underwent two randomly ordered experimental sequences, each consisting of two 12-h alternating phases of ALCO2R and ECCO2R. During ALCO2R, lactic acid (1.5 mEq/min) was infused before the membrane lung. Caloric intake was not controlled, and animals were freely fed. VCO2ML, natural lung carbon dioxide extraction, total carbon dioxide production, and minute ventilation were recorded. Oxygen consumption and EE were calculated. RESULTS: ALCO2R enhanced VCO2ML by 48% relative to ECCO2R (55.3 ± 3.1 vs. 37.2 ± 3.2 ml/min; P less than 0.001). During ALCO2R, minute ventilation and natural lung carbon dioxide extraction were not affected (7.88 ± 2.00 vs. 7.51 ± 1.89 l/min, P = 0.146; 167.9 ± 41.6 vs. 159.6 ± 51.8 ml/min, P = 0.063), whereas total carbon dioxide production, oxygen consumption, and EE rose by 12% each (223.53 ± 42.68 vs. 196.64 ± 50.92 ml/min, 215.3 ± 96.9 vs. 189.1 ± 89.0 ml/min, 67.5 ± 24.0 vs. 60.3 ± 20.1 kcal/h; P less than 0.001). CONCLUSIONS: ALCO2R was effective in enhancing VCO2ML. However, lactic acid caused a rise in EE that made ALCO2R no different from standard ECCO2R with respect to ventilation. The authors suggest coupling lactic acid-enhanced ALCO2R with active measures to control metabolism.

"Awake" extracorporeal membrane oxygenation (ECMO): pathophysiology, technical considerations, and clinical pioneering.

Venovenous extracorporeal membrane oxygenation (vv-ECMO) has been classically employed as a rescue therapy for patients with respiratory failure not treatable with conventional mechanical ventilation alone. In recent years, however, the timing of ECMO initiation has been readdressed and ECMO is often started earlier in the time course of respiratory failure. Furthermore, some centers are starting to use ECMO as a first line of treatment, i.e., as an alternative to invasive mechanical ventilation in awake, non-intubated, spontaneously breathing patients with respiratory failure ("awake" ECMO). There is a strong rationale for this type of respiratory support as it avoids several side effects related to sedation, intubation, and mechanical ventilation. However, the complexity of the patient-ECMO interactions, the difficulties related to respiratory monitoring, and the management of an awake patient on extracorporeal support together pose a major challenge for the intensive care unit staff. Here, we review the use of vv-ECMO in awake, spontaneously breathing patients with respiratory failure, highlighting the pros and cons of this approach, analyzing the pathophysiology of patient-ECMO interactions, detailing some of the technical aspects, and summarizing the initial clinical experience gained over the past years.

Update on the role of extracorporeal CO2 removal as an adjunct to mechanical ventilation in ARDS.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2015 and co-published as a series in Critical Care. Other articles in the series can be found online at http://ccforum.com/series/annualupdate2015. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.

Extracorporeal gas exchange and spontaneous breathing for the treatment of acute respiratory distress syndrome: an alternative to mechanical ventilation?*.

OBJECTIVES: Venovenous extracorporeal gas exchange is increasingly used in awake, spontaneously breathing patients as a bridge to lung transplantation. Limited data are available on a similar use of extracorporeal gas exchange in patients with acute respiratory distress syndrome. The aim of this study was to investigate the use of extracorporeal gas exchange in awake, spontaneously breathing sheep with healthy lungs and with acute respiratory distress syndrome and describe the interactions between the native lung (healthy and diseased) and the artificial lung (extracorporeal gas exchange) in this setting. DESIGN: Laboratory investigation. SETTING: Animal ICU of a governmental laboratory. SUBJECTS: Eleven awake, spontaneously breathing sheep on extracorporeal gas exchange. INTERVENTIONS: Sheep were studied before (healthy lungs) and after the induction of acute respiratory distress syndrome via IV injection of oleic acid. Six gas flow settings (1-10 L/min), resulting in different amounts of extracorporeal CO2 removal (20-100% of total CO2 production), were tested in each animal before and after the injury. MEASUREMENTS AND MAIN RESULTS: Respiratory variables and gas exchange were measured for every gas flow setting. Both healthy and injured sheep reduced minute ventilation according to the amount of extracorporeal CO2 removal, up to complete apnea. However, compared with healthy sheep, sheep with acute respiratory distress syndrome presented significantly increased esophageal pressure variations (25 ± 9 vs 6 ± 3 cm H2O; p < 0.001), which could be reduced only with very high amounts of CO2 removal (> 80% of total CO2 production). CONCLUSIONS: Spontaneous ventilation of both healthy sheep and sheep with acute respiratory distress syndrome can be controlled via extracorporeal gas exchange. If this holds true in humans, extracorporeal gas exchange could be used in awake, spontaneously breathing patients with acute respiratory distress syndrome to support gas exchange. A deeper understanding of the pathophysiology of spontaneous breathing during acute respiratory distress syndrome is however warranted in order to be able to propose extracorporeal gas exchange as a safe and valuable alternative to mechanical ventilation for the treatment of patients with acute respiratory distress syndrome.

Reliable real-time calculation of heart-rate complexity in critically ill patients using multiple noisy waveform sources.

Heart-rate complexity (HRC) has been proposed as a new vital sign for critical care medicine. The purpose of this research was to develop a reliable method for determining HRC continuously in real time in critically ill patients using multiple waveform channels that also compensates for noisy and unreliable data. Using simultaneously acquired electrocardiogram (Leads I, II, V) and arterial blood pressure waveforms sampled at 360 Hz from 250 patients (over 375 h of patient data), we evaluated a new data fusion framework for computing HRC in real time. The framework employs two algorithms as well as signal quality indices. HRC was calculated (via the method of sample entropy), and equivalence tests were then performed. Bland-Altman plots and box plots of differences between mean HRC values were also obtained. Finally, HRC differences were analyzed by paired t tests. The gold standard for obtaining true means was manual verification of R waves and subsequent entropy calculations. Equivalence tests between mean HRC values derived from manually verified sequences and those derived from automatically detected peaks showed that the "Fusion" values were the least statistically different from the gold standard. Furthermore, the fusion of waveform sources produced better error density distributions than those derived from individual waveforms. The data fusion framework was shown to provide in real-time a reliable continuously streamed HRC value, derived from multiple waveforms in the presence of noise and artifacts. This approach will be validated and tested for assessment of HRC in critically ill patients.

First 24-Hour-Long Intensive Care Unit Testing of a Clinical-Scale Microfluidic Oxygenator in Swine: A Safety and Feasibility Study.

Microfluidic membrane oxygenators are designed to mimic branching vasculature of the native lung during extracorporeal lung support. To date, scaling of such devices to achieve clinically relevant blood flow and lung support has been a limitation. We evaluated a novel multilayer microfluidic blood oxygenator (BLOx) capable of supporting 750-800 ml/min blood flow versus a standard hollow fiber membrane oxygenator (HFMO) in vivo during veno-venous extracorporeal life support for 24 hours in anesthetized, mechanically ventilated uninjured swine (n = 3/group). The objective was to assess feasibility, safety, and biocompatibility. Circuits remained patent and operated with stable pressures throughout 24 hours. No group differences in vital signs or evidence of end-organ damage occurred. No change in plasma free hemoglobin and von Willebrand factor multimer size distribution were observed. Platelet count decreased in BLOx at 6 hours (37% dec, P = 0.03), but not in HFMO; however, thrombin generation potential was elevated in HFMO (596 ± 81 nM·min) versus BLOx (323 ± 39 nM·min) at 24 hours ( P = 0.04). Other coagulation and inflammatory mediator results were unremarkable. BLOx required higher mechanical ventilator settings and showed lower gas transfer efficiency versus HFMO, but the stable device performance indicates that this technology is ready for further performance scaling and testing in lung injury models and during longer use conditions.

Digital twin mathematical models suggest individualized hemorrhagic shock resuscitation strategies.

BACKGROUND: Optimizing resuscitation to reduce inflammation and organ dysfunction following human trauma-associated hemorrhagic shock is a major clinical hurdle. This is limited by the short duration of pre-clinical studies and the sparsity of early data in the clinical setting. METHODS: We sought to bridge this gap by linking preclinical data in a porcine model with clinical data from patients from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study via a three-compartment ordinary differential equation model of inflammation and coagulation. RESULTS: The mathematical model accurately predicts physiologic, inflammatory, and laboratory measures in both the porcine model and patients, as well as the outcome and time of death in the PROMMTT cohort. Model simulation suggests that resuscitation with plasma and red blood cells outperformed resuscitation with crystalloid or plasma alone, and that earlier plasma resuscitation reduced injury severity and increased survival time. CONCLUSIONS: This workflow may serve as a translational bridge from pre-clinical to clinical studies in trauma-associated hemorrhagic shock and other complex disease settings.

Research to improve survival in patients with severe bleeding after major trauma presents many challenges. Here, we created a computer model to simulate the effects of severe bleeding. We refined this model using data from existing animal studies to ensure our simulations were accurate. We also used patient data to further refine the simulations to accurately predict which patients would live and which would not. We studied the effects of different treatment protocols on these simulated patients and show that treatment with plasma (the fluid portion of blood that helps form blood clots) and red blood cells jointly, gave better results than treatment with intravenous fluid or plasma alone. Early treatment with plasma reduced injury severity and increased survival time. This modelling approach may improve our ability to evaluate new treatments for trauma-associated bleeding and other acute conditions.