The recent emergence of microfluidic extracorporeal lung support technologies presents an opportunity to achieve high gas transfer efficiency and improved hemocompatibility relative to the current standard of care in extracorporeal membrane oxygenation (ECMO). However, a critical challenge in the field is the ability to scale these devices to clinically relevant blood flow rates, in part because the typically very low blood flow in a single layer of a microfluidic oxygenator device requires stacking of a logistically challenging number of layers. We have developed biomimetic microfluidic oxygenators for the past decade and report here on the development of a high-flow (30 mL/min) single-layer prototype, scalable to larger structures via stacking and assembly with blood distribution manifolds. Microfluidic oxygenators were designed with biomimetic in-layer blood distribution manifolds and arrays of parallel transfer channels, and were fabricated using high precision machined durable metal master molds and microreplication with silicone films, resulting in large area gas transfer devices. Oxygen transfer was evaluated by flowing 100% O2 at 100 mL/min and blood at 0–30 mL/min while monitoring increases in O2 partial pressures in the blood. This design resulted in an oxygen saturation increase from 65% to 95% at 20 mL/min and operation up to 30 mL/min in multiple devices, the highest value yet recorded in a single layer microfluidic device. In addition to evaluation of the device for blood oxygenation, a 6-h in vitro hemocompatibility test was conducted on devices (n = 5) at a 25 mL/min blood flow rate with heparinized swine donor blood against control circuits (n = 3). Initial hemocompatibility results indicate that this technology has the potential to benefit future applications in extracorporeal lung support technologies for acute lung injury.

Extracorporeal membrane oxygenation (ECMO) has been advancing rapidly due to a combination of rising rates of acute and chronic lung diseases as well as significant improvements in the safety and efficacy of this therapeutic modality. However, the complexity of the ECMO blood circuit, and challenges with regard to clotting and bleeding, remain as barriers to further expansion of the technology. Recent advances in microfluidic fabrication techniques, devices, and systems present an opportunity to develop new solutions stemming from the ability to precisely maintain critical dimensions such as gas transfer membrane thickness and blood channel geometries, and to control levels of fluid shear within narrow ranges throughout the cartridge. Here, we present a physiologically inspired multilayer microfluidic oxygenator device that mimics physiologic blood flow patterns not only within individual layers but throughout a stacked device. Multiple layers of this microchannel device are integrated with a three-dimensional physiologically inspired distribution manifold that ensures smooth flow throughout the entire stacked device, including the critical entry and exit regions. We then demonstrate blood flows up to 200 ml/min in a multilayer device, with oxygen transfer rates capable of saturating venous blood, the highest of any microfluidic oxygenator, and a maximum blood flow rate of 480 ml/min in an eight-layer device, higher than any yet reported in a microfluidic device. Hemocompatibility and large animal studies utilizing these prototype devices are planned. Supplemental Visual Abstract, http://links.lww.com/ASAIO/A769 .

OBJECTIVES:To perform a systematic review and meta-analysis to generate estimates of mortality in patients with COVID-19 that required hospitalization, ICU admission, and organ support.DATA SOURCES: A systematic search of PubMed, Embase, and the Cochrane databases was conducted up to December 31, 2021.STUDY SELECTION: Previously peer-reviewed observational studies that reported ICU, mechanical ventilation (MV), renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO)-related mortality among greater than or equal to 100 individual patients.DATA EXTRACTION: Random-effects meta-analysis was used to generate pooled estimates of case fatality rates (CFRs) for in-hospital, ICU, MV, RRT, and ECMO-related mortality. ICU-related mortality was additionally analyzed by the study country of origin. Sensitivity analyses of CFR were assessed based on completeness of follow-up data, by year, and when only studies judged to be of high quality were included.

Background Accurate accounting of coronavirus disease 2019 (COVID-19) critical care outcomes has important implications for health care delivery. Research Question We aimed to determine critical care and organ support outcomes of intensive care unit (ICU) COVID-19 patients and whether they varied depending on the completeness of study follow-up or admission time period. Study Design and Methods We conducted a systematic review and meta-analysis of reports describing ICU, mechanical ventilation (MV), renal replacement therapy (RRT), and extracorporeal membrane oxygenation (ECMO) mortality. A search was conducted using PubMed, Embase, and Cochrane databases. We included English language observational studies of COVID-19 patients, reporting ICU admission, MV, and ICU case fatality, published from December 1, 2019 to December 31, 2020. We excluded reports of less than 5 ICU patients and pediatric populations. Study characteristics, patient demographics, and outcomes were extracted from each article. Subgroup meta-analyses were performed based on the admission end date and the completeness of data. Results Of 6,778 generated articles, 145 were retained for inclusion (n = 60,357 patients). Case fatality rates across all studies were 34.0% (95% CI = 30.7%, 37.5%, P < 0.001) for ICU deaths, 47.9% (95% CI = 41.6%, 54.2%, P < 0.001) for MV deaths, 58.7% (95% CI = 50.0%, 67.2%, P < 0.001) for RRT deaths, and 43.3% (95% CI = 31.4%, 55.4%, P < 0.001) for extracorporeal membrane oxygenation deaths. There was no statistically significant difference in ICU and organ support outcomes between studies with complete follow-up versus studies without complete follow-up. Case fatality rates for ICU, MV, and RRT deaths were significantly higher in studies with patients admitted before April 31st 2020. Interpretation Coronavirus disease 2019 critical care outcomes have significantly improved since the start of the pandemic. Intensive care unit outcomes should be evaluated contextually (study quality, data completeness, and time) for the most accurate reporting and to effectively guide mortality predictions.

A perfluorocarbon (PFC) investigated for treatment of traumatic brain injury (TBI) delivers oxygen to support brain function, but causes transient thrombocytopenia. TBI can cause acute inflammation with resulting thrombocytopenia; an interaction between the PFC effects and TBI inflammation might exacerbate thrombocytopenia. Therefore, PFC effects on platelet (PLT) function and hemostasis in a lipopolysaccharide (LPS) model of inflammation in the baboon were studied. Animals were randomized to receive saline ±LPS, and ± one of two doses of PFC. PLT count, transmission electron microscopy, and microparticle populations were quantified at baseline (BL) and at 2, 24, 48, 72, and 96 hours; hemostatic parameters for aggregometry and for blood clotting were measured at baseline (BL) and days 3 and 4. Injection of vehicle and LPS caused thrombocytopenia within hours; PFCs caused delayed thrombocytopenia beginning 48 hours post-infusion. LPS+PFC produced a more prolonged PLT decline and decreased clot strength. LPS+PFC increased ADP-stimulated aggregation, but PFC alone did not. Microparticle abundance was greatest in the LPS+PFC groups. LPS+PFC caused diffuse microvascular hemorrhage and death in 2 of 5 baboons in the low dose LPS-PFC group and 2 of 2 in the high dose LPS-PFC group. Necropsy and histology suggested death was caused by shock associated with hemorrhage in multiple organs. Abnormal morphology of platelets and red blood cells were notable for PFC inclusions. In summary, PFC infusion caused clinically significant thrombocytopenia and exacerbated LPS-induced platelet activation. The interaction between these effects resulted in decreased hemostatic capacity, diffuse bleeding, shock and death.

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Background: Significant clinical similarities have been observed between the recently described ‘Long-Haul’ COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, “brain-fog”, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms. Methods/Design: A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction. A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction. Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights. Discussion: Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade. Trial registration:ClinicalTrials.gov, ID:NCT05481177 Registered on 29 July 2022.