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.

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.

Prevalence and reversibility of pulmonary dysfunction in refractory systemic lupus: improvement correlates with disease remission following hematopoietic stem cell transplantation.

AIM: To report the prevalence and reversibility of pulmonary function test (PFT) abnormalities among systemic lupus erythematosus (SLE) patients, refractory to therapy, undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Thirty-four SLE patients received 200 mg/kg cyclophosphamide and 90 mg/kg equine antithymocyte globulin followed by HSCT. PFTs were performed prior to, at 6 months, and yearly following HSCT. RESULTS: The prevalence of significant PFT abnormalities was high (97%). Low FEV(1) and FVC occurred in 26 of 34 patients (76%). A significant abnormality in diffusion capacity of the lung for carbon monoxide (Dlco) occurred in 26 of 32 individuals able to complete Dlco testing (81%). Dlco 18 months after HSCT. Five of 28 patients had a normal entry FVC; for each, the FVC remains normal. Of the 23 patients with an abnormal baseline FVC, 18 have improved, 15 completely and 3 partially. Eight of these 18 patients also have improved Dlco. The two patients with a diagnosis of SLS and one patient with SLE-related pulmonary hypertension improved in both parameters. Only 5 of 23 patients with an abnormal FVC did not improve. Each of these five patients retained active lupus in spite of HSCT. CONCLUSION: The prevalence of lung impairment among SLE patients requiring long-term immune suppression is high. Following HSCT, pulmonary impairments can improve, which is sustained if disease control is sustained.

Adult toxicology in critical care: part I: general approach to the intoxicated patient.

Intensivists are confronted with poisoned patients on a routine basis, with clinical scenarios ranging from known drug overdose or toxic exposure, illicit drug use, suicide attempt, or accidental exposure. In addition, drug toxicity can also manifest in hospitalized patients from inappropriate dosing and drug interactions. In this review article, we describe the epidemiology of poisoning in the United States, review physical examination findings and laboratory data that may aid the intensivist in recognizing a toxidrome (symptom complex of specific poisoning) or specific poisoning, and describe a rational and systematic approach to the poisoned patient. It is important to recognize that there is a paucity of evidence-based information on the management of poisoned patient. However, the most current recommendations by the American Academy of Clinical Toxicology and European Association of Poisons Centers and Clinical Toxicologists will be reviewed. Specific poisonings will be reviewed in the second section of these review articles.

Oropharyngeal deglutition in stable COPD.

STUDY OBJECTIVES: The aim of this study was to examine deglutition in stable patients with COPD and lung hyperinflation. DESIGN: Twenty consecutive, eligible COPD patients with an FEV(1) < or = 65% of predicted and a total lung capacity > or = 120% of predicted were enrolled prospectively. INTERVENTION: Patients received a detailed videofluoroscopic evaluation of oropharyngeal swallowing and were compared to 20 age-matched and sex-matched historical control subjects. SETTING: An outpatient pulmonary clinic at a Veterans Affairs Medical Center. MEASUREMENTS AND RESULTS: The mean total lung capacity, functional residual capacity, and residual volume for the patients were 128% of predicted, 168% of predicted, and 218% of predicted, respectively. The mean FEV(1) was 39% of predicted. There was no evidence of tracheal aspiration in either group. The laryngeal position at rest measured relative to the cervical vertebrae was not different between groups. The maximal laryngeal elevation during swallowing was significantly lower in patients with COPD (p < 0.001). Patients with COPD exhibited more frequent use of spontaneous protective swallowing maneuvers such as longer duration of airway closure and earlier laryngeal closure relative to the cricopharyngeal opening than did control subjects (p < 0.05). CONCLUSIONS: We conclude that hyperinflated patients with COPD have an altered swallowing physiology. We suspect that the protective alterations in swallowing physiology (swallow maneuvers) may reduce the risk of aspiration. However, these swallowing maneuvers may not be useful during an exacerbation and may require further research.

First-year residents outperform third-year residents after simulation-based education in critical care medicine.

INTRODUCTION: Previous research shows that gaps exist in internal medicine residents' critical care knowledge and skills. The purpose of this study was to compare the bedside critical care competency of first-year residents who received a simulation-based educational intervention plus clinical training with third-year residents who received clinical training alone. METHODS: During their first 3 months of residency, a group of first-year residents completed a simulation-based educational intervention. A group of traditionally trained third-year residents who did not receive simulation-based training served as a comparison group. Both groups were evaluated using a 20-item clinical skills assessment at the bedside of a patient receiving mechanical ventilation at the end of their medical intensive care unit rotation. Scores on the skills assessment were compared between groups. RESULTS: Simulator-trained first-year residents (n = 40) scored significantly higher compared with traditionally trained third-year residents (n = 27) on the bedside assessment (91.3% [95% confidence interval, 88.2%-94.3%] vs. 80.9% [95% confidence interval, 76.8%-85.0%]; P < 0.001). CONCLUSIONS: First-year residents who completed a simulation-based educational intervention demonstrated higher clinical competency compared with third-year residents who did not undergo simulation training. Critical care competency cannot be assumed after clinical intensive care unit rotations; simulation-based curricula can help ensure residents are proficient to care for critically ill patients.