Targeted lung denervation in sheep: durability of denervation and long-term histologic effects on bronchial wall and peribronchial structures.

BACKGROUND: Targeted lung denervation (TLD), a novel bronchoscopic procedure which attenuates pulmonary nerve input to the lung to reduce the clinical consequences of neural hyperactivity, may be an important emerging treatment for COPD. While procedural safety and impact on clinical outcomes have recently been reported, the mechanism of action has not been reported. We explored the long-term pathologic and histopathologic effects in a sheep model of ablation of bronchial branches of the vagus nerve using a novel dual-cooled radiofrequency ablation catheter. METHODS: Nineteen sheep underwent circumferential ablation of both main bronchi with simultaneous balloon surface cooling using a targeted lung denervation system (Nuvaira, Inc., USA). Animals were followed over an extended time course (30, 365, and 640 days post procedure). At each time point, lung denervation (axonal staining in bronchial nerves), and effect on peribronchial structures near the treatment site (histopathology of bronchial epithelium, bronchial cartilage, smooth muscle, alveolar parenchyma, and esophagus) were quantified. One way analysis of variance (ANOVA) was performed to reveal differences between group means on normal data. Non-parametric analysis using Kruskal-Wallis Test was employed on non-normal data sets. RESULTS: No adverse clinical effects were observed in any sheep. Nerve axon staining distal to the ablation site was decreased by 60% at 30 days after TLD and efferent axon staining was decreased by >70% at 365 and 640 days. All treated airways exhibited 100% epithelial integrity. Effect on peribronchial structures was strictly limited to lung tissue immediately adjacent to the ablation site. Tissue structure 1 cm proximal and distal to the treatment area remained normal, and the pulmonary veins, pulmonary arteries, and esophagus were unaffected. CONCLUSIONS: The denervation of efferent axons induced by TLD therapy is durable and likely a contributing mechanism through which targeted lung denervation impacts clinical outcomes. Further, long term lung denervation did not alter the anatomy of the bronchioles or lung, as evaluated from both a gross and histologic perspective.

Respiratory Sinus Arrhythmia Attenuation via Targeted Lung Denervation in Sheep and Humans.

BACKGROUND: Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung. Parasympathetic input to the heart originating from the lungs contributes to respiratory sinus arrhythmia (RSA) and disruption of pulmonary nerves via TLD may impact RSA. OBJECTIVE: The aim of this study was to assess the potential of TLD to affect RSA in sheep and humans. METHODS: TLD was performed in 5 sheep and 9 humans using a novel lung denervation system (Nu-vaira Inc., Minneapolis, MN, USA) with an electrocardiogram collected before and after the procedure. Frequency domain analysis of heart rate variability was performed in 5 sheep and 6 humans with presence of RSA approximated as high-frequency power (HF power). RESULTS: HF power decreased in 3 of 5 sheep with 1 animal reaching less than 7% of its baseline HF power 30 days after TLD. The average treatment location was more distal in the remaining 2 animals, which did not exhibit RSA attenuation, suggesting diminished denervation. HF power decreased in 5 of 6 humans, with 3 subjects reaching less than 50% of their baseline HF power 90 days after TLD. CONCLUSIONS: TLD appeared to attenuate RSA in both sheep and human cohorts of this sub-study. Further confirmation in humans is necessary to allow for RSA attenuation to be used as a marker of successful lung denervation via TLD.

Physiologic and histopathologic effects of targeted lung denervation in an animal model.

Parasympathetic efferent innervation of the lung is the primary source of lung acetylcholine. Inhaled long-acting anticholinergics improve lung function and symptoms in patients with chronic obstructive pulmonary disease. Targeted lung denervation (TLD), a bronchoscopic procedure intended to disrupt pulmonary parasympathetic inputs, is an experimental treatment for chronic obstructive pulmonary disease. The physiologic and histologic effects of TLD have not previously been assessed. Eleven sheep and two dogs underwent circumferential ablation of the main bronchi with simultaneous balloon surface cooling using a lung denervation system (Nuvaira, Inc., Minneapolis, MN). Changes in pulmonary air flow resistance were monitored before and following TLD. Four animals were assessed for the presence or abolishment of the sensory axon-mediated Hering-Breuer reflex before and following TLD. Six sheep were histologically evaluated 30 days post-TLD for the extent of lung denervation (axonal staining) and effect on peribronchial structures near the treatment site. No adverse clinical effects were seen in any treated animals. TLD produced a ~30% reduction in pulmonary resistance and abolished the sensory-mediated Hering-Breuer reflex. Axonal staining was consistently decreased 60% at 30 days after TLD. All treated airways exhibited 100% epithelial integrity. Damage to other peribronchial structures was minimal. Tissue 1 cm proximal and distal to the treatment was normal, and the esophagus and periesophageal vagus nerve branches were unaffected. TLD treatment effectively denervates the lung while protecting the bronchial epithelium and minimizing effects on peribronchial structures. NEW & NOTEWORTHY The feasibility of targeted lung denervation, a new minimally invasive therapy for obstructive lung disease, has been demonstrated in humans with preliminary clinical studies demonstrating improvement in symptoms, pulmonary function, and exercise capacity in patients with chronic obstructive pulmonary disease. This preclinical animal study demonstrates the ability of targeted lung denervation to disrupt vagal inputs to the lung and details its physiologic and histopathologic effects.

A respiratory correlated image guided surgery method: quantitative accuracy results in swine and human cadaver environments.

BACKGROUND: Intervention on small targets in the lung is difficult, leading our team to develop a highly accurate respiratory correlated image guided surgery (RCIGS) system. METHODS: Simulated point source targets were implanted into ex vivo porcine and human cadaver lungs attached to a ventilator. The RCIGS system was utilized to guide intervention in the presence of respiratory motion using a commercially available electromagnetic tracking solution. After intervention, the lungs were imaged to determine the target registration error between the target and needle. RESULTS: The system tumor position modeling had sub-mm accuracy. The mean intervention error for 12 porcine targets was 3.8 mm. The mean target registration error on four targets in a human cadaver was 4.0 mm at a mean depth of 9 cm. CONCLUSIONS: The system provides an accuracy for intervention on targets of less than 1 cm in diameter at depths of up to 10 cm. A system of this accuracy outperforms current clinical standards.

The correlation of tissue motion within the lung: implications on fiducial based treatments.

In radiation therapy many motion management and alignment techniques rely on the accuracy of an internal fiducial acting as a surrogate for target motion within the lung. Although fiducials are routinely used as surrogates for tumor motion, the extent to which varying spatial locations in the lung move similarly to other locations has yet to be quantitatively analyzed. In an attempt to analyze the motion correlation throughout the lung, ten primary lung cancer patients underwent IRB-approved 4DCT scans in the supine position. Deformable registration produced motion vectors for each voxel between exhalation and inhalation. Modeling was performed for each vector and all surrounding vectors within the lung in order to determine the mean 3D Euclidean distance necessary for an implanted fiducial to correlate with surrounding tissue motion to within 3 mm (left lower: 1.7 cm, left upper: 2.1 cm, right lower 1.6 cm, and right upper 2.9 cm). No general implantation rule of where to position a fiducial with respect to the tumor was found as the motion is highly patient and lobe specific. Correlation maps are presented showcasing spatial anisotropy of the motion of tissue surrounding the tumor.

Safety of investigative bronchoscopy in the Severe Asthma Research Program.

BACKGROUND: Investigative bronchoscopy was performed in a subset of participants in the Severe Asthma Research Program to gain insights into the pathobiology of severe disease. We evaluated the safety aspects of this procedure in this cohort with specific focus on patients with severe asthma. OBJECTIVE: To evaluate prospectively changes in lung function and the frequency of adverse events related to investigative bronchoscopy. METHODS: Bronchoscopy was performed by using a common manual of procedures. A subset of very severe asthma was defined by severe airflow obstruction, chronic oral corticosteroid use, and recent asthma exacerbations. Subjects were monitored for changes in lung function and contacted by telephone for 3 days after the procedure. RESULTS: A total of 436 subjects underwent bronchoscopy (97 normal, 196 not severe, 102 severe, and 41 very severe asthma). Nine subjects were evaluated in hospital settings after bronchoscopy; 7 of these were respiratory-related events. Recent emergency department visits, chronic oral corticosteroid use, and a history of pneumonia were more frequent in subjects who had asthma exacerbations after bronchoscopy. The fall in FEV1 after bronchoscopy was similar in the severe and milder asthma groups. Prebronchodilator FEV1 was the strongest predictor of change in FEV1 after bronchoscopy with larger decreases observed in subjects with better lung function. CONCLUSION: Bronchoscopy in subjects with severe asthma was well tolerated. Asthma exacerbations were rare, and reduction in pulmonary function after the procedure was similar to that in subjects with less severe asthma. With proper precautions, investigative bronchoscopy can be performed safely in severe asthma.

Bronchial thermoplasty: a novel technique in the treatment of severe asthma.

New therapies are needed for patients with severe persistent asthma who cannot achieve control with current therapy of inhaled corticosteroids and long-acting beta(2)-agonists. Bronchial thermoplasty is a novel intervention for asthma that delivers controlled thermal energy to the airway wall during a series of bronchoscopies, resulting in a prolonged reduction in airway smooth muscle mass. We review the method of performing bronchial thermoplasty with the Alair System, how to appropriately select and manage patients undergoing bronchial thermoplasty, and the clinical experience to date with this treatment. Randomized, controlled clinical trials with bronchial thermoplasty in subjects with severe asthma have resulted in improvements in overall asthma control as demonstrated by significant improvement in quality of life, asthma symptoms, severe exacerbations requiring corticosteroids, days lost from work/school/other daily activities due to asthma, and healthcare utilization.

Bronchoscopic implantation of a novel wireless electromagnetic transponder in the canine lung: a feasibility study.

PURPOSE: The success of targeted radiation therapy for lung cancer treatment is limited by tumor motion during breathing. A real-time, objective, nonionizing, electromagnetic localization system using implanted electromagnetic transponders has been developed (Beacon electromagnetic transponder, Calypso Medical Technologies, Inc., Seattle, WA). We evaluated the feasibility and fixation of electromagnetic transponders bronchoscopically implanted in small airways of canine lungs and compared to results using gold markers. METHODS AND MATERIALS: After approval of the Animal Studies Committee, five mongrel dogs were anesthetized, intubated, and ventilated. Three transponders were inserted into the tip of a plastic catheter, passed through the working channel of a flexible bronchoscope, and implanted into small airways of a single lobe using fluoroscopic guidance. This procedure was repeated for three spherical gold markers in the opposite lung. One, 7, 14, 28, and 60 days postimplantation imaging was used to assess implant fixation. RESULTS: Successful bronchoscopic implantation was possible for 15 of 15 transponders and 12 of 15 gold markers; 3 markers were deposited in the pleural space. Fixation at 1 day was 15 of 15 for transponders and 12 of 12 for gold markers. Fixation at 60 days was 6 of 15 for transponders and 7 of 12 for gold markers, p value = 0.45. CONCLUSIONS: Bronchoscopic implantation of both transponders and gold markers into the canine lung is feasible, but fixation rates are low. If fixation rates can be improved, implantable electromagnetic transponders may allow improved radiation therapy for lung cancer by providing real-time continuous target tracking. Developmental work is under way to improve the fixation rates and to reduce sensitivity to implantation technique.

Fiducial-based translational localization accuracy of electromagnetic tracking system and on-board kilovoltage imaging system.

PURPOSE: The Calypso medical four-dimensional localization system uses AC electromagnetics, which do not require ionizing radiation, for accurate, real-time tumor tracking. This investigation compared the static and dynamic tracking accuracy of this system to that of an on-board imaging kilovoltage X-ray system for concurrent use of the two systems. METHODS AND MATERIALS: The localization accuracies of a kilovoltage imaging system and a continuous electromagnetic tracking system were compared. Using an in-house developed four-dimensional stage, quality-assurance fixture containing three radiofrequency transponders was positioned at a series of static locations and then moved through the ellipsoidal and nonuniform continuous paths. The transponder positions were tracked concurrently by the Calypso system. For static localization, the transponders were localized using portal images and digitally reconstructed radiographs by commercial matching software. For dynamic localization, the transponders were fluoroscopically imaged, and their positions were determined retrospectively using custom-written image processing programs. The localization data sets were synchronized with and compared to the known quality assurance fixture positions. The experiment was repeated to retrospectively track three transponders implanted in a canine lung. RESULTS: The root mean square error of the on-board imaging and Calypso systems was 0.1 cm and 0.0 cm, respectively, for static localization, 0.22 mm and 0.33 mm for dynamic phantom positioning, and 0.42 mm for the canine study. CONCLUSION: The results showed that both localization systems provide submillimeter accuracy. The Calypso and on-board imaging tracking systems offer distinct sets of advantages and, given their compatibility, patients could benefit from the complementary nature of the two systems when used concurrently.

Successful bronchoscopic balloon dilation of nonmalignant tracheobronchial obstruction without fluoroscopy.

OBJECTIVE: To evaluate the safety and efficacy of bronchoscopic balloon dilation (BBD) without fluoroscopy for relief of tracheobronchial obstruction. METHODS: We performed a retrospective study of all adult patients who underwent BBD without fluoroscopy at the Tulane University Hospital and Clinic between July 1, 1997, and June 30, 2002. RESULTS: Twenty-four patients (mean [+/- SD] age, 58 +/- 14 years; 80% men) underwent 59 BBD procedures without fluoroscopy for the following conditions: iatrogenic tracheal stenosis (80%); saber-sheath trachea (4%); bronchial stenosis resulting from lung transplantation (4%); sarcoidosis (4%); Wegener granulomatosis (4%); and idiopathic stenosis (4%). All BBD procedures were performed via a rigid bronchoscope (61%) or a flexible bronchoscope (39%) without fluoroscopy. BBD was often combined with mechanical debridement (64%), stent placement (47%), or laser photoresection (19%), although in 26% of cases BBD was the only intervention. During the 59 procedures, 71 different balloon catheters were deployed a total of 112 times (deployment was defined as any use of balloon dilation in a different location, for a different purpose, or to a different inflation diameter). These 112 deployments were performed for primary dilation (49%), dilation prior to stent placement (28%), and stent seating (22%). Improvement in stenosis was achieved immediately postprocedure in all 59 procedures (100%). One balloon ruptured during inflation without clinically significant effect, and no other complications occurred. CONCLUSION: BBD without fluoroscopy for the relief of nonmalignant tracheobronchial obstruction can be safely performed through a rigid or flexible bronchoscope. It can be used alone or as an adjunct to other therapeutic modalities. In this series, 100% of airway obstructions were improved, and there were no clinically significant complications. BBD of a tracheobronchial obstruction without fluoroscopy is safe, efficacious, and cost-effective.