-
Seminars in Respiratory and Critical... Oct 2023While static mechanical forces govern resting lung volumes, dynamic forces determine tidal breathing, airflow, and changes in airflow and lung volume during normal and...
While static mechanical forces govern resting lung volumes, dynamic forces determine tidal breathing, airflow, and changes in airflow and lung volume during normal and abnormal breathing. This section will examine the mechanisms, measurement methodology, and interpretation of the dynamic changes in airflow and lung volume that occur in health and disease. We will first examine how the total work of breathing can be described by the parameters of the equation of motion, which determine the pressure required to move air into and out of the lung. This will include a detailed description of airflow characteristics and airway resistance. Next, we will review the changes in pressure and flow that determine maximal forced inspiration and expiration, which result in the maximal flow-volume loop and the clinically important forced expired volume in 1 second. We will also assess the mechanisms and interpretation of bronchodilator responsiveness, dynamic hyperinflation, and airways hyperresponsiveness.
Topics: Humans; Lung; Bronchodilator Agents
PubMed: 37429331
DOI: 10.1055/s-0043-1770058 -
Methodist DeBakey Cardiovascular Journal 2023Vasoplegia is a condition characterized by persistent low systemic vascular resistance despite a normal or high cardiac index, resulting in profound and uncontrolled... (Review)
Review
Vasoplegia is a condition characterized by persistent low systemic vascular resistance despite a normal or high cardiac index, resulting in profound and uncontrolled vasodilation. Vasoplegia may occur due to various conditions, including cardiac failure, sepsis, and post-cardiac surgery. In the cardiac cohort, multiple risk factors for vasoplegia have been identified. Several factors contribute to the pathophysiology of this condition, and various mechanisms have been proposed, including nitric oxide, adenosine, prostanoids, endothelins, the renin-angiotensin-aldosterone system, and hydrogen sulfide. Early identification and prompt management of vasoplegia is crucial to prevent development of shock. This review expands upon the different vasopressors used in management of vasoplegia, including catecholamines such as norepinephrine, dopamine, epinephrine, phenylephrine, and other agents including vasopressin, methylene blue, angiotensin II, hydroxocobalamin, vitamin C, thiamine, and corticosteroids (ie, hydrocortisone). It also emphasizes the importance of conducting further research and making advancements in treatment regimens for vasoplegia.
Topics: Humans; Vasoplegia; Epinephrine; Norepinephrine; Phenylephrine; Sepsis
PubMed: 37547893
DOI: 10.14797/mdcvj.1245 -
American Journal of Respiratory and... Aug 2023Ensifentrine is a novel, selective, dual phosphodiesterase (PDE)3 and PDE4 inhibitor with bronchodilator and antiinflammatory effects. Replicate phase III trials of... (Randomized Controlled Trial)
Randomized Controlled Trial
Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-controlled, Multicenter Phase III Trials (the ENHANCE Trials).
UNLABELLED
Ensifentrine is a novel, selective, dual phosphodiesterase (PDE)3 and PDE4 inhibitor with bronchodilator and antiinflammatory effects. Replicate phase III trials of nebulized ensifentrine were conducted (ENHANCE-1 and ENHANCE-2) to assess these effects in patients with chronic obstructive pulmonary disease (COPD). To evaluate the efficacy of ensifentrine compared with placebo for lung function, symptoms, quality of life, and exacerbations in patients with COPD. These phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled trials were conducted between September 2020 and December 2022 at 250 research centers and pulmonology practices in 17 countries. Patients aged 40-80 years with moderate to severe symptomatic COPD were enrolled. Totals of 760 (ENHANCE-1) and 789 (ENHANCE-2) patients were randomized and treated, with 69% and 55% receiving concomitant long-acting muscarinic antagonists or long-acting β-agonists, respectively. Post-bronchodilator FEV percentage predicted values were 52% and 51% of predicted normal. Ensifentrine treatment significantly improved average FEV area under the curve at 0-12 hours versus placebo (ENHANCE-1, 87 ml [95% confidence interval, 55, 119]; ENHANCE-2, 94 ml [65, 124]; both < 0.001). Ensifentrine treatment significantly improved symptoms (Evaluating Respiratory Symptoms) and quality of life (St. George's Respiratory Questionnaire) versus placebo at Week 24 in ENHANCE-1 but not in ENHANCE-2. Ensifentrine treatment reduced the rate of moderate or severe exacerbations versus placebo over 24 weeks (ENHANCE-1, rate ratio, 0.64 [0.40, 1.00]; = 0.050; ENHANCE-2, rate ratio, 0.57 [0.38, 0.87]; = 0.009) and increased time to first exacerbation (ENHANCE-1, hazard ratio, 0.62 [0.39, 0.97]; = 0.038; ENHANCE-2, hazard ratio, 0.58 [0.38, 0.87]; = 0.009). Adverse event rates were similar to those for placebo. Ensifentrine significantly improved lung function in both trials, with results supporting exacerbation rate and risk reduction in a broad COPD population and in addition to other classes of maintenance therapies. Clinical trial registered with www.
CLINICALTRIALS
gov and EudraCT (ENHANCE-1, www.
CLINICALTRIALS
gov identifier NCT04535986, EudraCT identifier 2020-002086-34; ENHANCE-2, www.
CLINICALTRIALS
gov identifier NCT04542057, EudraCT identifier 2020-002069-32).
Topics: Humans; Bronchodilator Agents; Double-Blind Method; Forced Expiratory Volume; Phosphoric Diester Hydrolases; Pulmonary Disease, Chronic Obstructive; Quality of Life; Adult; Middle Aged; Aged; Aged, 80 and over
PubMed: 37364283
DOI: 10.1164/rccm.202306-0944OC -
European Respiratory Review : An... Jun 2023Bronchiectasis is a common progressive respiratory disease with recognisable radiological abnormalities and a clinical syndrome of cough, sputum production and recurrent...
Bronchiectasis is a common progressive respiratory disease with recognisable radiological abnormalities and a clinical syndrome of cough, sputum production and recurrent respiratory infections. Inflammatory cell infiltration into the lung, in particular neutrophils, is central to the pathophysiology of bronchiectasis. Herein we explore the roles and relationships between infection, inflammation and mucociliary clearance dysfunction in the establishment and progression of bronchiectasis. Microbial and host-mediated damage are important processes underpinning bronchiectasis and the relative contribution of proteases, cytokines and inflammatory mediators to the propagation of inflammation is presented. We also discuss the emerging concept of inflammatory endotypes, defined by the presence of neutrophilic and eosinophilic inflammation, and explore the role of inflammation as a treatable trait. Current treatment for bronchiectasis focuses on treatment of underlying causes, enhancing mucociliary clearance, controlling infection and preventing and treating complications. Data on airway clearance approaches exercise and mucoactive drugs, pharmacotherapy with macrolides to decrease exacerbations and the usefulness of inhaled antibiotics and bronchodilators are discussed, finishing with a look to the future where new therapies targeting host-mediated immune dysfunction hold promise.
Topics: Humans; Adult; Bronchiectasis; Inflammation; Cough; Anti-Bacterial Agents; Macrolides
PubMed: 37286220
DOI: 10.1183/16000617.0015-2023 -
JAMA Internal Medicine Jul 2023Clinical guidelines on chronic obstructive pulmonary disease (COPD) recommend inhalers containing long-acting muscarinic antagonists (LAMAs) and long-acting β-agonists...
IMPORTANCE
Clinical guidelines on chronic obstructive pulmonary disease (COPD) recommend inhalers containing long-acting muscarinic antagonists (LAMAs) and long-acting β-agonists (LABAs) over inhalers containing inhaled corticosteroids (ICSs) and LABAs. However, data from randomized clinical trials comparing these combination inhalers (LAMA-LABAs vs ICS-LABAs) have been conflicting and raised concerns of generalizability.
OBJECTIVE
To assess whether LAMA-LABA therapy is associated with reduced COPD exacerbations and pneumonia hospitalizations compared with ICS-LABA therapy in routine clinical practice.
DESIGN, SETTING, AND PARTICIPANTS
This was a 1:1 propensity score-matched cohort study using Optum's Clinformatics Data Mart, a large commercial insurance-claims database. Patients must have had a diagnosis of COPD and filled a new prescription for a combination LAMA-LABA or ICS-LABA inhaler between January 1, 2014, and December 31, 2019. Patients younger than 40 years were excluded, as were those with a prior diagnosis of asthma. The current analysis was performed from February 2021 to March 2023.
EXPOSURES
Combination LAMA-LABA inhalers (aclidinium-formoterol, glycopyrronium-formoterol, glycopyrronium-indacaterol, tiotropium-olodaterol, or umeclidinium-vilanterol) and combination ICS-LABA inhalers (budesonide-formoterol, fluticasone-salmeterol, fluticasone-vilanterol, or mometasone-formoterol).
MAIN OUTCOME
The primary effectiveness outcome was first moderate or severe COPD exacerbation, and the primary safety outcome was first pneumonia hospitalization. Propensity score matching was used to control for confounding between the 2 groups. Logistic regression analysis was used to estimate propensity scores. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models stratified on matched pairs.
RESULTS
Among 137 833 patients (mean [SD] age, 70.2 [9.9] years; 69 530 [50.4%] female) (107 004 new ICS-LABA users and 30 829 new LAMA-LABA users), 30 216 matched pairs were identified for the primary analysis. Compared with ICS-LABA use, LAMA-LABA use was associated with an 8% reduction in the rate of first moderate or severe COPD exacerbation (HR, 0.92; 95% CI, 0.89-0.96) and a 20% reduction in the rate of first pneumonia hospitalization (HR, 0.80; 95% CI, 0.75-0.86). These findings were robust across a range of prespecified subgroup and sensitivity analyses.
CONCLUSION
In this cohort study, LAMA-LABA therapy was associated with improved clinical outcomes compared with ICS-LABA therapy, suggesting that LAMA-LABA therapy should be preferred for patients with COPD.
Topics: Humans; Female; Aged; Male; Glycopyrrolate; Cohort Studies; Adrenergic beta-2 Receptor Agonists; Administration, Inhalation; Fluticasone; Adrenal Cortex Hormones; Nebulizers and Vaporizers; Muscarinic Antagonists; Formoterol Fumarate; Pulmonary Disease, Chronic Obstructive; Pneumonia; Bronchodilator Agents; Drug Therapy, Combination
PubMed: 37213116
DOI: 10.1001/jamainternmed.2023.1245 -
Chest Sep 2023In the phase 3 MANDALA trial, as-needed albuterol-budesonide pressurized metered-dose inhaler significantly reduced severe exacerbation risk vs as-needed albuterol in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the phase 3 MANDALA trial, as-needed albuterol-budesonide pressurized metered-dose inhaler significantly reduced severe exacerbation risk vs as-needed albuterol in patients with moderate-to-severe asthma receiving inhaled corticosteroid-containing maintenance therapy. This study (DENALI) was conducted to address the US Food and Drug Administration combination rule, which requires a combination product to demonstrate that each component contributes to its efficacy.
RESEARCH QUESTION
Do both albuterol and budesonide contribute to the efficacy of the albuterol-budesonide combination pressurized metered-dose inhaler in patients with asthma?
STUDY DESIGN AND METHODS
This phase 3 double-blind trial randomized patients aged ≥ 12 years with mild-to-moderate asthma 1:1:1:1:1 to four-times-daily albuterol-budesonide 180/160 μg or 180/80 μg, albuterol 180 μg, budesonide 160 μg, or placebo for 12 weeks. Dual-primary efficacy end points included change from baseline in FEV area under the curve from 0 to 6 h (FEV AUC) over 12 weeks (assessing albuterol effect) and trough FEV at week 12 (assessing budesonide effect).
RESULTS
Of 1,001 patients randomized, 989 were ≥ 12 years old and evaluable for efficacy. Change from baseline in FEV AUC over 12 weeks was greater with albuterol-budesonide 180/160 μg vs budesonide 160 μg (least-squares mean [LSM] difference, 80.7 [95% CI, 28.4-132.9] mL; P = .003). Change in trough FEV at week 12 was greater with albuterol-budesonide 180/160 and 180/80 μg vs albuterol 180 μg (LSM difference, 132.8 [95% CI, 63.6-201.9] mL and 120.8 [95% CI, 51.5-190.1] mL, respectively; both P < .001). Day 1 time to onset and duration of bronchodilation with albuterol-budesonide were similar to those with albuterol. The albuterol-budesonide adverse event profile was similar to that of the monocomponents.
INTERPRETATION
Both monocomponents contributed to albuterol-budesonide lung function efficacy. Albuterol-budesonide was well tolerated, even at regular, relatively high daily doses for 12 weeks, with no new safety findings, supporting its use as a novel rescue therapy.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov; No.: NCT03847896; URL: www.
CLINICALTRIALS
gov.
Topics: Humans; Child; Budesonide; Formoterol Fumarate; Metered Dose Inhalers; Administration, Inhalation; Asthma; Albuterol; Double-Blind Method; Bronchodilator Agents; Treatment Outcome
PubMed: 37003355
DOI: 10.1016/j.chest.2023.03.035