Impact of mepolizumab in patients with high-burden severe asthma within a managed care population.

OBJECTIVE: To evaluate the real-world impact of mepolizumab on the incidence of asthma exacerbations, oral corticosteroid (OCS) use and asthma exacerbation-related costs in patients with high-burden severe asthma. METHODS: This was a retrospective study of the MarketScan Commercial and Medicare Databases in patients with high-burden severe asthma (≥80th percentile of total healthcare expenditure and/or significant comorbidity burden). Patients were ≥12 years of age upon mepolizumab initiation (index date November 1, 2015-December 31, 2018) and had ≥2 mepolizumab administrations during the 6 months post-index. Asthma exacerbation frequency (primary outcome), use of OCS (secondary outcome), and asthma exacerbation-related costs (exploratory outcome) were assessed during the 12 months pre-index (baseline) and post-index (follow-up). RESULTS: In total, 281 patients were analyzed. Mepolizumab significantly reduced the proportion of patients with any asthma exacerbation (P < 0.001) or exacerbations requiring hospitalization (P = 0.004) in the follow-up versus baseline period. The mean number of exacerbations decreased from 2.5 to 1.5 events/patient/year (relative reduction: 40.0%; P < 0.001). The proportion of patients with ≥1 OCS claim also decreased significantly from 94.0% to 81.9% (relative reduction: 12.9%; P < 0.001), corresponding to a decrease from 6.6 to 4.7 claims/person/year (P < 0.001). Of the 264 patients with ≥1 OCS claim during baseline, 191 (72.3%) showed a decrease in mean daily OCS use by ≥50% in 117 patients (61.3%). Total asthma exacerbation-related costs were significantly lower after mepolizumab was initiated (P < 0.001). CONCLUSIONS: Mepolizumab reduced exacerbation frequency, OCS use and asthma exacerbation-related costs in patients with high-cost severe asthma. Mepolizumab provides real-world benefits to patients, healthcare systems and payers.

Once-daily single-inhaler versus twice-daily multiple-inhaler triple therapy in patients with COPD: lung function and health status results from two replicate randomized controlled trials.

BACKGROUND: The comparative efficacy of inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist (ICS/LAMA/LABA) triple therapy administered via single or multiple inhalers in patients with chronic obstructive pulmonary disease (COPD) has not been evaluated comprehensively. We conducted two replicate trials comparing single- with multiple-inhaler ICS/LAMA/LABA combination in COPD. METHODS: 207608 and 207609 were Phase IV, 12-week, randomized, double-blind, triple-dummy non-inferiority trials comparing once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg via Ellipta inhaler, with twice-daily budesonide/formoterol (BUD/FOR) 400/12 µg via metered-dose inhaler plus once-daily tiotropium (TIO) 18 µg via HandiHaler. Patients had symptomatic COPD and forced expiratory volume in 1 s (FEV1) < 50% predicted, or FEV1 < 80% predicted and ≥ 2 moderate or 1 severe exacerbations in the prior year. The primary endpoint in both trials was weighted mean change from baseline (wmCFB) in 0-24-h FEV1 at Week 12. Secondary endpoints included CFB in trough FEV1 at Day 84 and 85. Other endpoints included serial FEV1 and health status outcomes at Week 12. Safety was evaluated descriptively. RESULTS: The modified per-protocol population included 720 and 711 patients in studies 207608 and 207609 (intent-to-treat population: 728 and 732). FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 (Study 207608 treatment difference [95% confidence interval]: 15 mL [- 13, 43]; Study 207609: 11 mL [- 20, 41]). FF/UMEC/VI improved trough FEV1 CFB versus BUD/FOR+TIO at Day 84 and 85 (Day 85 treatment difference: Study 207608: 38 mL [10, 66]; Study 207609: 51 mL [21, 82]) and FEV1 at 12 and 24 h post-morning dose at Week 12 in both studies. No treatment differences were seen in health status outcomes. Safety profiles were similar between treatments; pneumonia occurred in 7 (< 1%) patients with FF/UMEC/VI and 9 (1%) patients with BUD/FOR+TIO, across both studies. CONCLUSIONS: FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 in patients with COPD. Greater improvements in trough and serial FEV1 measurements at Week 12 with FF/UMEC/VI versus BUD/FOR+TIO, together with similar health status improvements and safety outcomes including the incidence of pneumonia, suggest that once-daily single-inhaler FF/UMEC/VI triple therapy is a viable option for patients looking to simplify their treatment regimen. TRIAL REGISTRATION: GSK (207608/207609; NCT03478683/NCT03478696).

Invasive Mechanical Ventilation.

Invasive mechanical ventilation is a potentially lifesaving intervention for acutely ill patients. The goal of this review is to provide a concise, clinically focused overview of basic invasive mechanical ventilation for the many clinicians who care for mechanically ventilated patients. Attention is given to how common ventilator modes differ in delivering a mechanical breath, evaluation of respiratory system mechanics, how to approach acute changes in airway pressure, and the diagnosis of auto-positive end-expiratory pressure. Waveform interpretation is emphasized throughout the review.

Complications of thoracentesis: incidence, risk factors, and strategies for prevention.

PURPOSE OF REVIEW: Although thoracentesis is generally considered safe, procedural complications are associated with increased morbidity, mortality, and healthcare costs. In this article, we review the risk factors and prevention of the most common complications of thoracentesis including pneumothorax, bleeding (chest wall hematoma and hemothorax), and re-expansion pulmonary edema. RECENT FINDINGS: Recent data support the importance of operator expertise and the use of ultrasound in reducing the risk of iatrogenic pneumothorax. Although coagulopathy or thrombocytopenia and the use of anticoagulant or antiplatelet medications have traditionally been viewed as contraindications to thoracentesis, new evidence suggests that patients may be able to safely undergo thoracentesis without treating their bleeding risk. Re-expansion pulmonary edema, a rare complication of thoracentesis, is felt to result in part from the generation of excessively negative pleural pressure. When and how to monitor changes in pleural pressure during thoracentesis remains a focus of ongoing study. SUMMARY: Major complications of thoracentesis are uncommon. Clinician awareness of risk factors for procedural complications and familiarity with strategies that improve outcomes are essential components for safely performing thoracentesis.

Targeting Asthma Remission as the Next Therapeutic Step Toward Improving Disease Control.

The long-term goal of asthma management is to achieve disease control, comprising the assessment of 2 main domains: (1) symptom control and (2) future risk of adverse outcomes. Decades of progress in asthma management have correlated with increasingly ambitious disease control targets. Moreover, the introduction of precision medicines, such as biologics, has further expanded the limits of what can be achieved in terms of disease control. It is now believed that clinical remission, a term rarely associated with asthma, may be an achievable treatment goal. An expert framework published in 2020 took the first step toward developing a commonly accepted definition of clinical remission in asthma. However, there remains a widespread discussion about the clinical parameters and thresholds that should be included in a standardized definition of clinical remission. This review aims to discuss on-treatment clinical remission as an aspirational outcome in asthma management, drawing on experiences from other chronic diseases where remission has long been a goal. We also highlight the integral role of shared decision-making between patients and health care professionals and the need for a common understanding of the individual patient journey to remission as foundational elements in reducing disease burden and improving outcomes for patients with asthma.

Real-world association between systemic corticosteroid exposure and complications in US patients with severe asthma.

BACKGROUND: Systemic corticosteroid (SCS) use remains widespread among patients with severe asthma, despite associated complications. OBJECTIVE: Evaluate the association between cumulative SCS exposure and SCS-related complications in severe asthma. METHODS: This retrospective, longitudinal study used claims data from the Optum Clinformatics Data Mart database (GSK ID: 214469). Eligible patients (≥ 12 years old) had an asthma diagnosis and were divided into two cohorts: SCS use and non/burst-SCS use. Patients in the SCS use cohort had a claim for a daily prednisone-equivalent dose ≥ 5 mg SCS following ≥ 6 months of continuous SCS use; those in the non/burst-SCS cohort had no evidence of continuous SCS use and had a non-SCS controller/rescue medication initiation claim. For each cohort, the date of the qualifying claim was the index date. SCS users were further stratified by SCS use during each quarter of follow-up: low (≤ 6 mg/day), medium (> 6-12 mg/day), high (> 12 mg/day), and continuous high (≥ 20 mg/day for 90 days). SCS-related complications were evaluated in the quarter following SCS exposure. The adjusted odds ratios (OR) of experiencing SCS-related complications during follow-up in each of the SCS use groups versus the non/burst SCS cohort were calculated using generalized estimating equations models. RESULTS: SCS and non/burst-SCS use cohorts included 7473 and 89,281 patients (mean follow-up: 24.6 and 24.2 months), respectively. Compared with the non/burst-SCS use cohort, medium, high, and continuous high SCS use was associated with greater odds of any SCS-related complication (adjusted OR [95% confidence interval]: 1.30 [1.21, 1.39], 1.49 [1.35, 1.64] and 1.63 [1.40, 1.89], respectively) including increased acute gastrointestinal, cardiovascular, and immune system-related complications, and chronic cardiovascular, metabolic/endocrine, central nervous system, bone-/muscle-related, ophthalmologic, and hematologic/oncologic complications. Low-dose SCS use was also associated with significantly increased odds of acute gastrointestinal and immune system-related complications, and chronic bone-/muscle-related and hematologic/oncologic complications versus the non/burst-SCS use cohort. CONCLUSION: SCS use, even at low doses, is associated with increased risk of SCS-related complications among patients with severe asthma.

Impact of Mepolizumab on Exacerbations in the US Medicare Population.

BACKGROUND: Asthma is a common chronic respiratory disorder associated with significant disease and economic burden. Mepolizumab is an anti-IL-5 mAb approved for use as an add-on treatment in patients with severe eosinophilic asthma. OBJECTIVE: To assess the impact of mepolizumab initiation on asthma exacerbation frequency, oral corticosteroid (OCS) use, and asthma exacerbation-related costs in a US Medicare population. METHODS: This was a retrospective cohort study of mepolizumab claims from patients with asthma in the Centers for Medicare and Medicaid Services Medicare database carried out between January 2016 and December 2018. The index date (first claim for mepolizumab) was required to occur between January and December 2017. The baseline and follow-up periods were the 12 months before and 12 months after the index, respectively. Outcomes included changes in the proportion of patients experiencing exacerbations (primary), OCS use (secondary), and asthma exacerbation-related costs during the baseline and follow-up periods. RESULTS: The study identified 1,278 patients (mean age, 67.9 years; 65% female) with one or more prescription or administration claim for mepolizumab who were eligible for study inclusion. There was a significant relative reduction in the proportion of patients with an asthma exacerbation (27%; P < .0001) in the follow-up versus baseline period. Similarly, a lower proportion of patients received OCS for asthma (16% relative reduction; P < .0001), fewer patients were chronic OCS users (5 mg/day or more; 48% relative reduction; P < .0001), and there was a significant decrease in asthma exacerbation-related costs (total reduction, $888; P = .0002) during the follow-up versus the baseline period. CONCLUSION: Mepolizumab reduced exacerbations, OCS use, and exacerbation-related healthcare costs in a US Medicare population, confirming its benefits in this specific population with severe asthma.

The Association Between Age at Diagnosis and Disease Characteristics and Damage in Patients With ANCA-Associated Vasculitis.

OBJECTIVE: This study examined the relationship between age at diagnosis and disease characteristics and damage in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Analysis of a prospective longitudinal cohort of patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA) in the Vasculitis Clinical Research Consortium (2013-2021). Disease cohorts were divided by age at diagnosis (years): children (<18), young adults (18-40), middle-aged adults (41-65), and older adults (>65). Data included demographics, ANCA type, clinical characteristics, Vasculitis Damage Index (VDI) scores, ANCA Vasculitis Index of Damage (AVID) scores, and novel disease-specific and non-disease-specific damage scores built from VDI and AVID items. RESULTS: Analysis included data from 1020 patients with GPA/MPA and 357 with EGPA. Female predominance in GPA/MPA decreased with age at diagnosis. AAV in childhood was more often GPA and proteinase 3-ANCA positive. Children with GPA/MPA experienced more subglottic stenosis and alveolar hemorrhage; children and young adults with EGPA experienced more alveolar hemorrhage, need for intubation, and gastrointestinal involvement. Older adults (GPA/MPA) had more neurologic manifestations. After adjusting for disease duration, medications, tobacco, and ANCA, all damage scores increased with age at diagnosis for GPA/MPA (P < 0.001) except the disease-specific damage score, which did not differ (P = 0.44). For EGPA, VDI scores increased with age at diagnosis (P < 0.009), whereas all other scores were not significantly different. CONCLUSION: Age at diagnosis is associated with clinical characteristics in AAV. Although VDI and AVID scores increase with age at diagnosis, this is driven by non-disease-specific damage items.

Pressure modes of invasive mechanical ventilation.

Pressure modes of invasive mechanical ventilation generate a tidal breath by delivering pressure over time. Pressure control ventilation (PC) is the prototypical pressure mode and is patient- or time-triggered, pressure-limited, and time-cycled. Other pressure modes include pressure support ventilation (PSV), pressure-regulated volume control (PRVC, also known as volume control plus [VC+]), airway pressure release ventilation (APRV), and biphasic ventilation (also known as BiLevel). Despite their complexity, modern ventilators respond to patient effort and respiratory system mechanics in a fairly predictable fashion. No single mode has consistently demonstrated superiority in clinical trials; however, empiric management with a pressure mode may achieve the goals of patient-ventilator synchrony, effective respiratory system support, adequate gas exchange, and limited ventilator-induced lung injury.

Single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus tiotropium monotherapy in patients with COPD.

Chronic obstructive pulmonary disease (COPD) treatment guidelines do not currently include recommendations for escalation directly from monotherapy to triple therapy. This 12-week, double-blind, double-dummy study randomized 800 symptomatic moderate-to-very-severe COPD patients receiving tiotropium (TIO) for ≥3 months to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg via ELLIPTA (n = 400) or TIO 18 mcg via HandiHaler (n = 400) plus matched placebo. Study endpoints included change from baseline in trough forced expiratory volume in 1 s (FEV1) at Days 85 (primary), 28 and 84 (secondary), health status (St George's Respiratory Questionnaire [SGRQ] and COPD Assessment Test [CAT]) and safety. FF/UMEC/VI significantly improved trough FEV1 at all timepoints (Day 85 treatment difference [95% CI] 95 mL [62-128]; P < 0.001), and significantly improved SGRQ and CAT versus TIO. Treatment safety profiles were similar. Once-daily single-inhaler FF/UMEC/VI significantly improved lung function and health status versus once-daily TIO in symptomatic moderate-to-very-severe COPD patients, with a similar safety profile.

Online learning versus simulation for teaching principles of mechanical ventilation to nurse practitioner students.

Patient simulation is increasingly used in the education of healthcare providers, yet few studies have compared simulation to other teaching modalities. The purpose of this study was to determine differences in knowledge acquisition and student satisfaction between two methods of teaching the principles of mechanical ventilation to advanced practice nursing (APN) students: high-fidelity patient simulation (including face-to-face instruction) versus an online, narrated PowerPoint presentation. Twenty APN students were randomized to either the simulation or online teaching method in this pre/posttest study. Measures included a 12-item knowledge questionnaire and a 5-item satisfaction survey. Both groups had significant improvement in knowledge scores from pretest to posttest, but knowledge scores were not significantly different at posttest between groups. Student satisfaction with their learning method was significantly higher in the simulation group. Students choosing to participate in the alternative teaching method after study completion preferred the simulation to the online method.

Current evidence for COPD management with dual long-acting muscarinic antagonist/long-acting ß2-agonist bronchodilators.

Long-acting inhaled bronchodilator medications are recommended as initial maintenance therapy for many patients with COPD. These medications include long-acting muscarinic antagonists (LAMA) and long-acting ß2-agonists (LABA). Combinations of long-acting bronchodilator agents (LAMA/LABA) and inhaled corticosteroids combined with LABA (ICS/LABA) are also used as initial or follow-up therapy in patients with more severe symptoms or at risk of COPD exacerbations. This review summarizes the position of LAMA/LABA combinations in treatment recommendations, and the evidence supporting their placement relative to LAMA monotherapy and ICS/LABA combination therapy, as well as differences within the LAMA/LABA class. Most studies show that LAMA/LABA treatment leads to greater improvements in lung function and symptoms than LAMA monotherapy or ICS/LABA treatment. There are fewer studies comparing the impact of different medication classes on patients' risk of exacerbations; however, the available evidence suggests that LAMA/LABA treatment and LAMA monotherapy lead to a similar reduction in exacerbation risk, while the effect of LAMA/LABA compared with ICS/LABA remains unclear. The incidence of adverse events is similar with LAMA/LABA and LAMA alone. There is a lower risk of pneumonia with LAMA/LABA compared with ICS/LABA. This evidence supports the use of LAMA/LABA combinations as an initial maintenance therapy option for symptomatic patients with low exacerbation risk and severe breathlessness or patients with severe symptoms who are at risk of exacerbations, and as follow-up treatment in patients with uncontrolled symptoms or exacerbations on bronchodilator monotherapy.

Basic invasive mechanical ventilation.

Invasive mechanical ventilation is a lifesaving intervention for patients with respiratory failure. The most commonly used modes of mechanical ventilation are assist-control, synchronized intermittent mandatory ventilation, and pressure support ventilation. When employed as a diagnostic tool, the ventilator provides data on the static compliance of the respiratory system and airway resistance. The clinical scenario and the data obtained from the ventilator allow the clinician to provide effective and safe invasive mechanical ventilation through manipulation of the ventilator settings. While life-sustaining in many circumstances, mechanical ventilation may also be toxic and should be withdrawn when clinically appropriate.

Chugging in patients on veno-venous extracorporeal membrane oxygenation: An under-recognized driver of intravenous fluid administration in patients with acute respiratory distress syndrome?

BACKGROUND: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is increasingly utilized in the management of severe acute respiratory distress syndrome (ARDS). Providers who care for patients on VV-ECMO should be familiar with common circuit complications. OBJECTIVES: To provide an example of a common complication, circuit "chugging," and suggest a management algorithm which aims to avoid excessive fluid administration to patients with ARDS. METHODS: We use a clinical case to illustrate chugging and discuss potential management strategies. RESULTS: Our patient received frequent boluses of albumin for intermittent circuit chugging contributing to a net positive fluid balance of roughly 6 liters 4 days after cannulation. CONCLUSIONS: Chugging is a common complication for patients on VV ECMO. A thoughtful approach to management may help limit potentially harmful fluid administration for patients with ARDS.

Description and Early Outcomes of a Comprehensive Curriculum Redesign at the Northwestern University Feinberg School of Medicine.

In 2012, the Northwestern University Feinberg School of Medicine launched a redesigned curriculum addressing the four primary recommendations in the 2010 Carnegie Foundation for the Advancement of Teaching report on reforming medical education. This new curriculum provides a more standardized evaluation of students' competency achievement through a robust portfolio review process coupled with standard evaluations of medical knowledge and clinical skills. It individualizes learning processes through curriculum flexibility, enabling students to take electives earlier and complete clerkships in their preferred order. The new curriculum is integrated both horizontally and vertically, combining disciplines within organ-based modules and deliberately linking elements (science in medicine, clinical medicine, health and society, professional development) and threads (medical decision making, quality and safety, teamwork and leadership, lifestyle medicine, advocacy and equity) across the three phases that replaced the traditional four-year timeline. It encourages students to conduct research in an area of interest and commit to lifelong learning and self-improvement. The curriculum formalizes the process of professional identity formation and requires students to reflect on their experiences with the informal and hidden curricula, which strongly shape their identities.The authors describe the new curriculum structure, explain their approach to each Carnegie report recommendation, describe early outcomes and challenges, and propose areas for further work. Early data from the first cohort to progress through the curriculum show unchanged United States Medical Licensing Examination Step 1 and 2 scores, enhanced student research engagement and career exploration, and improved student confidence in the patient care and professional development domains.

Predicting extubation failure after successful completion of a spontaneous breathing trial.

OBJECTIVE: To derive a clinical prediction rule that uses bedside clinical variables to predict extubation failure (reintubation within 48 h) after a successful spontaneous breathing trial. METHODS: This prospective observational cohort study was performed at the Northwestern Memorial Hospital in Chicago, Illinois, which is a large tertiary-care university hospital. Among 673 consecutive patients who received mechanical ventilation during a 15-month period, 122 were ventilated for at least 2 days and did not undergo withdrawal of support or tracheostomy. These patients were followed after extubation to identify those who were reintubated within 48 h (extubation failure). We used logistic regression analysis to identify variables that predict reintubation, and we used bootstrap resampling to internally validate the predictors and adjust for overoptimism. RESULTS: Sixteen (13%) of the 122 patients required reintubation within 48 h. Three clinical variables predicted reintubation: moderate to copious endotracheal secretions (p = 0.001), Glasgow Coma Scale score < or =10 (p = 0.004), and hypercapnia (P(aCO(2)) > or = 44 mm Hg) during the spontaneous breathing trial (p = 0.001). Using logistic regression and bootstrap resampling to adjust for overfitting, we derived a clinical prediction rule that combined those 3 clinical variables (area under the receiver operating characteristic curve 0.87, 95% confidence interval 0.74-0.94). CONCLUSIONS: With our clinical prediction rule that incorporates an assessment of mental status, endotracheal secretions, and pre-extubation P(aCO(2)), clinicians can predict who will fail extubation despite a successful spontaneous breathing trial.