Improving ECMO therapy: Monitoring oxygenator functionality and identifying key indicators, factors, and considerations for changeout.

INTRODUCTION: The optimal timing for extracorporeal membrane oxygenation (ECMO) circuit change-out is crucial for the successful management of patients with severe cardiopulmonary failure. This comprehensive review examines the various factors that influence the timing of oxygenator replacement in the ECMO circuit. By considering these factors, clinicians can make informed decisions to ensure timely and effective change-out, enhancing patient outcomes and optimizing the delivery of ECMO therapy. METHODOLOGY: A thorough search of relevant studies on ECMO circuits and oxygenator change-out was conducted using multiple scholarly databases and relevant keywords. Studies published between 2017 and 2023 were included, resulting in 40 studies that met the inclusion criteria. DISCUSSION: Thrombosis within the membrane oxygenator and its impact on dysfunction were identified as significant contributors, highlighting the importance of monitoring coagulation parameters and gas exchange. Several factors, including fibrinogen levels, pre and post-membrane blood gases, plasma-free hemoglobin, D-dimers, platelet function, flows and pressures, and anticoagulation strategy, were found to be important considerations when determining the need for an oxygenator or circuit change-out. The involvement of a multidisciplinary team and thorough preparation were also highlighted as crucial aspects of this process. CONCLUSION: In conclusion, managing circuit change-outs in ECMO therapy requires considering factors such as fibrinogen levels, blood gases, plasma-free hemoglobin, D-dimers, platelet function, flows, pressures, and anticoagulation strategy. Monitoring these parameters allows for early detection of issues, timely interventions, and optimized ECMO therapy. Standardized protocols, personalized anticoagulation approaches, and non-invasive monitoring techniques can improve the safety and effectiveness of circuit change-outs. Further research and collaboration are needed to advance ECMO management and enhance patient outcomes.

Advocating for an open communication culture in perfusion and cardiothoracic community: a call to action.

This article advocates for an open communication culture in the perfusion and cardiothoracic community to enhance patient safety during surgery. All team members, including nurses, anesthesiologists, and perfusionists, should actively contribute their insights. Empowering perfusionists to voice concerns without fear of repercussions is crucial. Involvement in debriefs, root cause analyses and data management systems aids continuous improvement. A robust speak-up culture prevents unsafe practices and elevates perfusion care standards, leading to better patient outcomes.

Effect of Tezepelumab on Lung Function in Patients With Severe, Uncontrolled Asthma in the Phase 3 NAVIGATOR Study.

INTRODUCTION: Severe asthma is associated with airway inflammation and airway obstruction. In the phase 3 NAVIGATOR study, tezepelumab treatment significantly improved pre-bronchodilator forced expiratory volume in 1 s (FEV1) compared with placebo in patients with severe, uncontrolled asthma. This analysis assessed the effect of tezepelumab versus placebo on additional lung function parameters in patients from NAVIGATOR. METHODS: NAVIGATOR was a multicenter, randomized, double-blind, placebo-controlled study. Patients (12-80 years old) receiving medium- or high-dose inhaled corticosteroids and at least one additional controller medication, with or without oral corticosteroids, were randomized 1:1 to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Changes from baseline to week 52 in pre-bronchodilator FEV1, post-bronchodilator FEV1, forced vital capacity (FVC), pre-bronchodilator FEV1/FVC ratio, pre-bronchodilator forced expiratory flow between 25 and 75% of vital capacity (FEF25-75), and morning and evening peak expiratory flow (PEF) were assessed. RESULTS: Tezepelumab treatment improved all evaluated lung function parameters over 52 weeks compared with placebo [least-squares mean difference (95% confidence interval): pre-bronchodilator FEV1, 0.13 (0.08, 0.18) L; post-bronchodilator FEV1, 0.12 (0.07, 0.16) L; FVC, 0.13 (0.07, 0.19) L; FEV1/FVC ratio, 2.06% (1.22%, 2.90%); FEF25-75, 0.13 (0.07, 0.19) L/s; morning PEF, 16.6 (8.1, 25.1) L/min; and evening PEF, 14.9 (6.3, 23.4) L/min]. Improvements were observed as early as weeks 1-2 and were maintained over 52 weeks. Greater improvements in lung function compared with placebo were observed in patients with a disease duration of less than 20 years, those with baseline post-bronchodilator FEV1 reversibility of at least 20%, and in patients with a baseline post-bronchodilator FEV1/FVC ratio of less than 0.7. CONCLUSION: These findings further support the benefits of tezepelumab treatment in improving airflow limitation in patients with severe, uncontrolled asthma. CLINICAL TRIAL REGISTRATION: NAVIGATOR (NCT03347279).

Tezepelumab reduces exacerbations across all seasons in patients with severe, uncontrolled asthma (NAVIGATOR).

BACKGROUND: Asthma exacerbation frequencies vary throughout the year owing to seasonal triggers. Tezepelumab is a human monoclonal antibody that targets thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab significantly reduced the annualized asthma exacerbation rate (AAER) vs placebo in patients with severe, uncontrolled asthma. OBJECTIVE: To evaluate the effect of tezepelumab on asthma exacerbations across all seasons in NAVIGATOR patients (post hoc). METHODS: NAVIGATOR was a multicenter, randomized, double-blind, placebo-controlled study. Patients (12-80 years old) were randomized 1:1 to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. AAER over 52 weeks was assessed by season. Data from patients in the Southern Hemisphere were transformed to align with Northern Hemisphere seasons. RESULTS: Tezepelumab reduced the AAER vs placebo by 63% (95% confidence interval [CI], 52-72) in winter, 46% (95% CI, 26-61) in spring, 62% (95% CI, 48-73) in summer, and 54% (95% CI, 41-64) in fall. In matched climates, during the spring allergy season (March 1 to June 15) and ragweed allergy season (September), tezepelumab reduced the AAER vs placebo in patients with seasonal allergy by 59% (95% CI, 29-77) and 70% (95% CI, 33-87), respectively. In patients with perennial allergy and in those with seasonal allergy, tezepelumab reduced the AAER vs placebo across all seasons. CONCLUSION: Tezepelumab reduced exacerbations across all seasons vs placebo in patients with severe, uncontrolled asthma, including patients with seasonal and perennial allergies. These data further support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03347279 (https://clinicaltrials.gov/ct2/show/NCT03347279).

Effect of tezepelumab on healthcare utilization in patients with severe, uncontrolled asthma: The NAVIGATOR study.

BACKGROUND: Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study, tezepelumab reduced exacerbations and improved lung function, asthma control, and health-related quality of life compared with placebo in patients with severe, uncontrolled asthma. However, little is known about the impact of tezepelumab on healthcare utilization (HCU) in these patients. OBJECTIVE: To evaluate to what extent tezepelumab reduces patients' HCU. METHODS: In NAVIGATOR, patients were randomized to receive subcutaneous tezepelumab 210 mg or placebo, every 4 weeks for 52 weeks. For this analysis, the main outcomes of interest were asthma-related HCU. A blinded, systematic analysis of the symptoms and HCU recorded in the investigator-reported narratives describing exacerbation-related hospitalizations was also conducted; the narratives included blinded ratings of event intensity, recorded as mild, moderate, or severe. RESULTS: Recipients of tezepelumab (n = 528) required fewer asthma-related unscheduled specialist visits (tezepelumab, 285 events; placebo, 406 events), telephone calls with a healthcare provider (tezepelumab, 234; placebo, 599), ambulance transports (tezepelumab, 5; placebo, 22), emergency department visits (without subsequent hospitalization; tezepelumab, 16; placebo, 37), hospitalizations (tezepelumab, 14; placebo, 78), and intensive care days (tezepelumab, 0; placebo, 31) than did recipients of placebo (n = 531). Among patients with asthma exacerbation-related hospitalizations, 38% of those hospitalized and receiving tezepelumab (5/13) had an event rated as severe, compared with 82% of those hospitalized and receiving placebo (32/39). CONCLUSION: Tezepelumab substantially reduced HCU across all outcomes measured compared with placebo, in addition to the severity of asthma exacerbations requiring hospitalization. Tezepelumab can reduce the overall burden of disease of severe, uncontrolled asthma. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home), identifier: NCT03347279.

Efficacy of Biologics in Severe, Uncontrolled Asthma Stratified by Blood Eosinophil Count: A Systematic Review.

INTRODUCTION: Randomized controlled trials (RCTs) of biologics in patients with severe, uncontrolled asthma have shown differential results by baseline blood eosinophil count (BEC). In the absence of head-to-head trials, we describe the effects of biologics on annualized asthma exacerbation rate (AAER) by baseline BEC in placebo-controlled RCTs. Exacerbations associated with hospitalization or an emergency room visit, pre-bronchodilator forced expiratory volume in 1 s, Asthma Control Questionnaire score, and Asthma Quality of Life Questionnaire score were also summarized. METHODS: MEDLINE (via PubMed) was searched for RCTs of biologics in patients with severe, uncontrolled asthma and with AAER reduction as a primary or secondary endpoint. AAER ratios and change from baseline in other outcomes versus placebo were compared across baseline BEC subgroups. Analysis was limited to US Food and Drug Administration-approved biologics. RESULTS: In patients with baseline BEC ≥ 300 cells/µL, AAER reduction was demonstrated with all biologics, and other outcomes were generally improved. In patients with BEC 0 to < 300 cells/µL, consistent AAER reduction was demonstrated only with tezepelumab; improvements in other outcomes were inconsistent across biologics. In patients with BEC 150 to < 300 cells/µL, consistent AAER reduction was demonstrated with tezepelumab and dupilumab (300 mg dose only), and in those with BEC 0 to < 150 cells/µL, AAER reduction was demonstrated only with tezepelumab. CONCLUSION: The efficacy of all biologics in reducing AAER in patients with severe asthma increases with higher baseline BEC, with varying profiles across individual biologics likely due to differing mechanisms of action.

Efficacy of Tezepelumab in Severe, Uncontrolled Asthma: Pooled Analysis of the PATHWAY and NAVIGATOR Clinical Trials.

Rationale: Tezepelumab reduced exacerbations in patients with severe, uncontrolled asthma across a range of baseline blood eosinophil counts and fractional exhaled nitric oxide levels, and irrespective of allergy status, in the phase 2b PATHWAY (Study to Evaluate the Efficacy and Safety of MEDI9929 [AMG 157] in Adult Subjects With Inadequately Controlled, Severe Asthma; NCT02054130) and phase 3 NAVIGATOR (Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; NCT03347279) trials. Objectives: To examine the efficacy and safety of tezepelumab in additional clinically relevant subgroups using pooled data from PATHWAY and NAVIGATOR. Methods: PATHWAY and NAVIGATOR were randomized, double-blind, placebo-controlled trials with similar designs. This pooled analysis included patients with severe, uncontrolled asthma (PATHWAY, 18-75 years old; NAVIGATOR, 12-80 years old) who received tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. The annualized asthma exacerbation rate over 52 weeks and secondary outcomes were calculated in the overall population and in subgroups defined by inflammatory biomarker levels or clinical characteristics. Measurements and Main Results: Overall, 1,334 patients were included (tezepelumab, n = 665; placebo, n = 669). Tezepelumab reduced the annualized asthma exacerbation rate versus placebo by 60% (rate ratio, 0.40 [95% confidence interval, 0.34-0.48]) in the overall population, and clinically meaningful reductions in exacerbations were observed in tezepelumab-treated patients with type 2-high and type 2-low disease by multiple definitions. Tezepelumab reduced exacerbation-related hospitalization or emergency department visits and improved secondary outcomes compared with placebo overall and across subgroups. The incidence of adverse events was similar between treatment groups. Conclusions: Tezepelumab resulted in clinically meaningful reductions in exacerbations and improvements in other outcomes in patients with severe, uncontrolled asthma, across clinically relevant subgroups. Clinical trials registered with www.clinicaltrials.gov (NCT02054130 [PATHWAY], NCT03347279 [NAVIGATOR]).

Number of patient-reported asthma triggers predicts uncontrolled disease among specialist-treated patients with severe asthma.

BACKGROUND: Patients with severe asthma (SA) experience a high disease burden, often precipitated by exposure to disease triggers. OBJECTIVE: To evaluate the prevalence and effects of patient-reported triggers on asthma disease burden in a cohort of subspecialist-treated patients with SA in the United States. METHODS: CHRONICLE is an observational study of adults with SA receiving biologics or maintenance systemic corticosteroids or whose disease is uncontrolled on high-dosage inhaled corticosteroids and additional controllers. Data were analyzed for patients enrolled between February 2018 and February 2021. This analysis evaluated patient-reported triggers from a 17-category survey and associations with multiple measures of disease burden. RESULTS: Among 2793 enrolled patients, 1434 (51%) completed the trigger questionnaire. The median trigger number per patient was 8 (interquartile range, 5-10). The most frequent triggers were weather or air changes, viral infections, seasonal allergies, perennial allergies, and exercise. Patients reporting more triggers experienced more poorly controlled disease, worse quality of life, and reduced work productivity. The annualized rates of exacerbations and asthma hospitalizations increased by 7% and 17%, respectively, for each additional trigger (both P < .001). For all measures, trigger number was a stronger predictor of disease burden than blood eosinophil count. CONCLUSION: Among US specialist-treated patients with SA, asthma trigger number was positively and significantly associated with greater uncontrolled disease burden across multiple measures, which highlights the importance of understanding patient-reported triggers in SA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Blocking endothelial lipase with monoclonal antibody MEDI5884 durably increases high density lipoprotein in nonhuman primates and in a phase 1 trial.

Cardiovascular disease (CVD) is the leading global cause of death, and treatments that further reduce CV risk remain an unmet medical need. Epidemiological studies have consistently identified low high-density lipoprotein cholesterol (HDL-C) as an independent risk factor for CVD, making HDL elevation a potential clinical target for improved CVD resolution. Endothelial lipase (EL) is a circulating enzyme that regulates HDL turnover by hydrolyzing HDL phospholipids and driving HDL particle clearance. Using MEDI5884, a first-in-class, EL-neutralizing, monoclonal antibody, we tested the hypothesis that pharmacological inhibition of EL would increase HDL-C by enhancing HDL stability. In nonhuman primates, MEDI5884 treatment resulted in lasting, dose-dependent elevations in HDL-C and circulating phospholipids, confirming the mechanism of EL action. We then showed that a favorable lipoprotein profile of elevated HDL-C and reduced low-density lipoprotein cholesterol (LDL-C) could be achieved by combining MEDI5884 with a PCSK9 inhibitor. Last, when tested in healthy human volunteers, MEDI5884 not only raised HDL-C but also increased HDL particle numbers and average HDL size while enhancing HDL functionality, reinforcing EL neutralization as a viable clinical approach aimed at reducing CV risk.

Blood eosinophil count group shifts and kinetics in severe eosinophilic asthma.

BACKGROUND: Blood eosinophil count (BEC) measurements are a noninvasive, relatively reliable surrogate marker for eosinophilic airway inflammation. Single measurements of peripheral BEC greater than or equal to 150 cells/µL predict the response to anti-eosinophil therapies for patients with characteristics of severe eosinophilic asthma. OBJECTIVE: To describe how BECs shift over time for patients with severe, uncontrolled asthma receiving placebo in 2 large, randomized, placebo-controlled clinical trials of benralizumab (SIROCCO and CALIMA). METHODS: Our analysis included all adult patients who were randomized to placebo in the SIROCCO and CALIMA phase III benralizumab studies. Patients were categorized into baseline BEC groups of less than 150 cells/µL, greater than or equal to 150 cells/µL but less than 300 cells/µL, and greater than or equal to 300 cells/µL. The timing of the initial shift from baseline to a different group was evaluated at weeks 4, 8, 24, and 40 and at the end of treatment. Baseline characteristics, including oral corticosteroid use, were described based on the presence or absence of a BEC group shift. RESULTS: Of the 734 evaluable patients, 65% (n = 474) shifted BEC groups during the study, and most patients (86% [n = 410]) shifted by week 24. Patients who started in the less than 150 cells/µL group tended to shift groups earlier, with 59% shifting by week 4 compared with 38% to 55% for other groups in the same time frame. Patients who shifted BEC groups vs those who did not tend to have lower BECs, more oral corticosteroid use, and less incidence of nasal polyps or past polypectomy. CONCLUSION: A single BEC measurement, particularly when low, may be inadequate to help establish a phenotype of severe eosinophilic asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers NCT01928771 (SIROCCO trial) and NCT01914757 (CALIMA trial).

Clinical evaluation of the Sorin Synthesis oxygenator with integrated arterial filter.

The use of arterial line filters has long been a standard of practice in the field of cardiopulmonary bypass. Sorin Biomedica has designed an adult hollow-fiber oxygenator that not only incorporates their Mimesys biomimicry coating technology but also has a 40-micron arterial filter as an integrated component of this unique membrane oxygenator. We did a prospective, randomized clinical trial of 54 Synthesis coated oxygenators and compared them with 54 uncoated Monolyth Pro oxygenators, the latter of which incorporated an external arterial line filter with a standard bypass loop There were few statistically significant differences found between the Synthesis group and the Monolyth group with regard to pressure differentials, hemodynamic resistance, and platelet drop. The Synthesis oxygenator did require less priming volume, but the amount was not significant. Platelet counts with the Phosphorylcholine coated Synthesis oxygenators, using crystalloid perfusates, was similar to our previously published data on platelet protection and Albumin perfusates. We conclude that the Sorin Synthesis oxygenator appears to have better flow characteristics than the Monolyth oxygenator, with the potential for lower priming volumes. The most clinically significant benefit comes from the elimination of the arterial filter bypass loop and the avoidance of inverting the arterial filter during priming.