5-Year Survival after Endobronchial Coil Implantation: Secondary Analysis of the First Randomised Controlled Trial, RESET.

BACKGROUND: Lung volume reduction surgery is a proven treatment for emphysematous patients with hyperinflation, but the precarious health of candidates has prompted development of less invasive approaches. Bronchoscopic implanted endobronchial coils, shape-memory nitinol filaments, shrink emphysematous lung tissue to restore elastic recoil and to tether airways to maintain patency. Studies have demonstrated an acceptable safety profile and improvements in lung function, exercise capacity, and quality of life out to 3 years. Volume reduction is key. However, data for longer-term survival are limited. OBJECTIVE: The aim of this study was to establish the 5-year overall and transplant-free survivals of subjects whose procedure in the first randomized controlled trial, RESET, achieved clinically meaningful reduction in residual volume (RV). METHODS: Patients and their primary care doctors were contacted to confirm vital status and history of additional interventions. Death certificates were acquired via the General Registry Office. Survival time was calculated for responders achieving a reduction of ≥10% in RV compared to non-responders. RESULTS: 39 patients completed the planned bilateral sequential treatments. Six patients received unilateral implants. At 5 years, 22 patients had died. The overall survivals at 1, 2, 3, 4 and 5 years were 88.9, 88.9, 77.8, 64.4 and 50.6%, respectively. Two patients underwent lung transplantation at 52 and 59 months and were alive at 5 years. The transplant-free (TF) survivals at 1, 2, 3, 4 and 5 years were 88.9, 88.9, 77.8, 64.4 and 46.7%, respectively. Volume reduction responders (n = 18) at 3 months had a 5-year TF survival of 66.7% compared to 36.4% for non-responders (n = 22; p = 0.07). Higher baseline inspiratory capacity (HR 0.13, 95% CI 0.02-0.73; p = 0.02) and partial pressure of oxygen (pO2) (HR 0.57, 95% CI 0.38-0.86; p < 0.01) values were predictive of survival for the entire cohort and were not influenced by age. CONCLUSIONS: Endobronchial coil implantation appears to confer a 5-year survival advantage for those who achieved a 10% reduction in RV at 3 months. Ongoing trials are designed to clarify the mechanisms of action of coils and to refine patient selection.

Protocol of a Randomized Controlled Study of the PneumRx Endobronchial Coil System versus Standard-of-Care Medical Management in the Treatment of Subjects with Severe Emphysema (ELEVATE).

BACKGROUND: The PneumRx endobronchial coil system for patients with severe emphysema has been shown to improve quality of life, exercise capacity, and pulmonary function in patients with emphysema. A post hoc analysis of the RENEW trial has identified patient characteristics and lobar selection methods associated with improved outcomes, which have to be confirmed prospectively. METHODS: The ELEVATE trial is a prospective, multicenter, open label, randomized (2:1), controlled trial comparing outcomes in patients treated with endobronchial coils (treatment) to a medically managed control group (control). The trial aims to enroll 210 patients (140 in the treatment group and 70 in the control group) with severe emphysema. Control patients will be eligible to crossover to coil treatment after 6 months of follow-up. The co-primary effectiveness endpoints are percent change in forced expiratory volume in 1 s and quality of life measured by change in St. George's Respiratory Questionnaire from baseline to 6 months. Secondary objectives are determination of responder rates of clinical endpoints and mean change in other functional and physiologic endpoints. All patients will be followed for 24 months after initial treatment. Adverse events will be collected on an ongoing basis throughout the trial. DISCUSSION: The primary objective of the ELEVATE trial is to prospectively confirm the safety and effectiveness profile of the coil system for the treatment of severe emphysema in consideration of the findings of previous randomized controlled trials. Secondary objectives are the determination of responder rates in all clinical endpoints and mean change in physiologic endpoints.

Predictors of Response to Endobronchial Coil Therapy in Patients With Advanced Emphysema.

BACKGROUND: The Lung Volume Reduction Coil Treatment in Patients With Emphysema (RENEW) trial reported improvements in quality of life, pulmonary function, and exercise performance following endobronchial coil treatment. OBJECTIVES: The purpose of this post hoc analysis was to identify baseline predictors, including quantitative CT measures, that identify patients most likely to significantly benefit from endobronchial coil therapy. METHODS: Quantitative CT analysis by an independent radiology laboratory and a qualitative evaluation by five blinded experts of the baseline thoracic CT imaging were performed. Univariate and multivariate logistic regression analyses were performed to elucidate characteristics associated with clinical response. RESULTS: In total, 125 patients underwent coil treatment and had evaluable 12-month follow-up results. Of these, 78 patients received treatment of lobes with the highest emphysematous destruction determined by quantitative CT analysis (quantitative visual match [QVM]+), and 47 received treatment in at least one lobe that was not the most destroyed (QVM-). From the 78 patients with QVM+ treatment, a subgroup of 50 patients (64%) was identified with baseline residual volume > 200% predicted, emphysema score > 20% low attenuation area, and absence of airway disease. In this subgroup, greater lobar residual volume reduction in the treated lobes was achieved, which was associated with significant mean ± SE improvement in FEV1 (15.2 ± 3.1%), St. George's Respiratory Questionnaire (-12 ± 2 points), and residual volume (-0.57 ± 0.13 L). DISCUSSION: This post hoc analysis found that both significant hyperinflation (residual volume ≥ 200% predicted) and CT analysis are critical for patient selection and treatment planning for endobronchial coil therapy. Quantitative CT analysis is important to identify optimal lobar treatment and to exclude patients with insufficient emphysema (< 20% low attenuation area), whereas visual assessment identifies patients with signs of airway disease associated with worse outcomes. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01608490; URL: www.clinicaltrials.gov.

Tidal stretches differently regulate the contractile and cytoskeletal elements in intact airways.

Recent reports suggest that tidal stretches do not cause significant and sustainable dilation of constricted intact airways ex vivo. To better understand the underlying mechanisms, we aimed to map the physiological stretch-induced molecular changes related to cytoskeletal (CSK) structure and contractile force generation through integrin receptors. Using ultrasound, we measured airway constriction in isolated intact airways during 90 minutes of static transmural pressure (Ptm) of 7.5 cmH2O or dynamic variations between Ptm of 5 and 10 cmH20 mimicking breathing. Integrin and focal adhesion kinase activity increased during Ptm oscillations which was further amplified during constriction. While Ptm oscillations reduced ß-actin and F-actin formation implying lower CSK stiffness, it did not affect tubulin. However, constriction was amplified when the microtubule structure was disassembled. Without constriction, α-smooth muscle actin (ASMA) level was higher and smooth muscle myosin heavy chain 2 was lower during Ptm oscillations. Alternatively, during constriction, overall molecular motor activity was enhanced by Ptm oscillations, but ASMA level became lower. Thus, ASMA and motor protein levels change in opposite directions due to stretch and contraction maintaining similar airway constriction levels during static and dynamic Ptm. We conclude that physiological Ptm variations affect cellular processes in intact airways with constriction determined by the balance among contractile and CSK molecules and structure.

A mechanical design principle for tissue structure and function in the airway tree.

With every breath, the dynamically changing mechanical pressures must work in unison with the cells and soft tissue structures of the lung to permit air to efficiently traverse the airway tree and undergo gas exchange in the alveoli. The influence of mechanics on cell and tissue function is becoming apparent, raising the question: how does the airway tree co-exist within its mechanical environment to maintain normal cell function throughout its branching structure of diminishing dimensions? We introduce a new mechanical design principle for the conducting airway tree in which mechanotransduction at the level of cells is driven to orchestrate airway wall structural changes that can best maintain a preferred mechanical microenvironment. To support this principle, we report in vitro radius-transmural pressure relations for a range of airway radii obtained from healthy bovine lungs and model the data using a strain energy function together with a thick-walled cylinder description. From this framework, we estimate circumferential stresses and incremental Young's moduli throughout the airway tree. Our results indicate that the conducting airways consistently operate within a preferred mechanical homeostatic state, termed mechanical homeostasis, that is characterized by a narrow range of circumferential stresses and Young's moduli. This mechanical homeostatic state is maintained for all airways throughout the tree via airway wall dimensional and mechanical relationships. As a consequence, cells within the airway walls throughout the airway tree experience similar oscillatory strains during breathing that are much smaller than previously thought. Finally, we discuss the potential implications of how the maintenance of mechanical homeostasis, while facilitating healthy tissue-level alterations necessary for maturation, may lead to airway wall structural changes capable of chronic asthma.

Airway resistance at maximum inhalation as a marker of asthma and airway hyperresponsiveness.

BACKGROUND: Asthmatics exhibit reduced airway dilation at maximal inspiration, likely due to structural differences in airway walls and/or functional differences in airway smooth muscle, factors that may also increase airway responsiveness to bronchoconstricting stimuli. The goal of this study was to test the hypothesis that the minimal airway resistance achievable during a maximal inspiration (R(min)) is abnormally elevated in subjects with airway hyperresponsiveness. METHODS: The R(min) was measured in 34 nonasthmatic and 35 asthmatic subjects using forced oscillations at 8 Hz. R(min) and spirometric indices were measured before and after bronchodilation (albuterol) and bronchoconstriction (methacholine). A preliminary study of 84 healthy subjects first established height dependence of baseline R(min) values. RESULTS: Asthmatics had a higher baseline R(min) % predicted than nonasthmatic subjects (134 ± 33 vs. 109 ± 19 % predicted, p = 0.0004). Sensitivity-specificity analysis using receiver operating characteristic curves indicated that baseline R(min) was able to identify subjects with airway hyperresponsiveness (PC20 < 16 mg/mL) better than most spirometric indices (Area under curve = 0.85, 0.78, and 0.87 for R(min) % predicted, FEV1 % predicted, and FEF25-75 % predicted, respectively). Also, 80% of the subjects with baseline R(min) < 100% predicted did not have airway hyperresponsiveness while 100% of subjects with R(min) > 145% predicted had hyperresponsive airways, regardless of clinical classification as asthmatic or nonasthmatic. CONCLUSIONS: These findings suggest that baseline R(min), a measurement that is easier to perform than spirometry, performs as well as or better than standard spirometric indices in distinguishing subjects with airway hyperresponsiveness from those without hyperresponsive airways. The relationship of baseline R(min) to asthma and airway hyperresponsiveness likely reflects a causal relation between conditions that stiffen airway walls and hyperresponsiveness. In conjunction with symptom history, R(min) could provide a clinically useful tool for assessing asthma and monitoring response to treatment.

Tidal stretches do not modulate responsiveness of intact airways in vitro.

Studies on isolated tracheal airway smooth muscle (ASM) strips have shown that length/force fluctuations, similar to those likely occurring during breathing, will mitigate ASM contractility. These studies conjecture that, solely by reducing length oscillations on a healthy, intact airway, one can create airway hyperresponsiveness, but this has never been explicitly tested. The intact airway has additional complexities of geometry and structure that may impact its relevance to isolated ASM strips. We examined the role of transmural pressure (Ptm) fluctuations of physiological amplitudes on the responsiveness of an intact airway. We developed an integrated system utilizing ultrasound imaging to provide real-time measurements of luminal radius and wall thickness over the full length of an intact airway (generation 10 and below) during Ptm oscillations. First, airway constriction dynamics to cumulative acetylcholine (ACh) doses (10(-7) to 10(-3) M) were measured during static and dynamic Ptm protocols. Regardless of the breathing pattern, the Ptm oscillation protocols were ineffective in reducing the net level of constriction for any ACh dose, compared with the static control (P = 0.225-0.793). Next, Ptm oscillations of increasing peak-to-peak amplitude were applied subsequent to constricting intact airways under static conditions (5.0-cmH(2)O Ptm) with a moderate ACh dose (10(-5) M). Peak-to-peak Ptm oscillations < or = 5.0 cmH(2)O resulted in no statistically significant bronchodilatory response (P = 0.429 and 0.490). Larger oscillations (10 cmH(2)O, peak to peak) produced modest dilation of 4.3% (P = 0.009). The lack of modulation of airway responsiveness by Ptm oscillations in intact, healthy airways suggests that ASM level mechanisms alone may not be the sole determinant of airway responsiveness.

Maintenance of airway caliber in isolated airways by deep inspiration and tidal strains.

Deep inspirations (DIs) are large periodic breathing maneuvers that regulate airway caliber and prevent airway obstruction in vivo. This study characterized the intrinsic response of the intact airway to DI, isolated from parenchymal attachments and other in vivo interactions. Porcine isolated bronchial segments were constricted with carbachol and subjected to transmural pressures of 5-10 cmH2O at 0.25 Hz (tidal breathing) interspersed with single DIs of amplitude 5-20 cmH2O, 5-30 cmH2O, or 5-40 cmH2O (6-s duration) or DI of amplitude 5-30 cmH2O (30-s duration). Tidal breathing was ceased after DI in a subset of airways and in control airways in which no DI was performed. Luminal cross-sectional area was measured using a fiber-optic endoscope. Bronchodilation by DI was amplitude dependent; 5-20 cmH2O DIs produced less dilation than 5-30 cmH2O and 5-40 cmH2O DIs (P=0.003 and 0.012, respectively). Effects of DI duration were not significant (P=0.182). Renarrowing after DI followed a monoexponential decay function to pre-DI airway caliber with time constants between 27.4+/-4.3 and 36.3+/-6.9 s. However, when tidal breathing was ceased after DI, further bronchoconstriction occurred within 30s. This response was identical in both the presence and absence of DI (P=0.919). We conclude that the normal bronchodilatory response to DI occurs as a result of the direct mechanical effects of DI on activated ASM in the airway wall. Further bronchoconstriction occurs by altering the airway wall stress following DI, demonstrating the importance of continual transient strains in maintaining airway caliber.

Respiratory impedance measurements for assessment of lung mechanics: focus on asthma.

This review discusses the history and current state of the art of the forced oscillation technique (FOT) to measure respiratory impedance. We focus on how the FOT and its interaction with models have emerged as a powerful method to extract out not only clinically relevant information, but also to advance insight on the mechanisms and structures responsible for human lung diseases, especially asthma. We will first provide a short history of FOT for basic clinical assessment either directly from the data or in concert with lumped element models to extract out specific effective properties. We then spend several sections on the more exciting recent advances of FOT to probe the relative importance of tissue versus airway changes in disease, the impact of the disease on heterogeneous lung function, and the relative importance of small airways via synthesis of FOT with imaging. Most recently, the FOT approach has been able to directly probe airway caliber in humans and the distinct airway properties of asthmatics that seem to be required for airway hyperresponsiveness. We introduce and discuss the mechanism and clinical implications of this approach, which may be substantial for treatment assessment. Finally, we highlight important future directions for the FOT, particularly its use to probe specific lung components (e.g., isolated airways, isolated airway smooth muscle, etc.) and relate such data to the whole lung. The intent is to substantially advance an integrated understanding of structure-function relationships in the lung.