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Clinical Investigations: BRONCHOSCOPY |

A Prospective Feasibility Study of Bronchial Thermoplasty in the Human Airway* FREE TO VIEW

John D. Miller, MD; Gerard Cox, MB; Lydia Vincic, MD; Charles M. Lombard, MD; Bryan E. Loomas; Christopher J. Danek, PhD
Author and Funding Information

*From the Division of Thoracic Surgery (Drs. Miller, Cox, and Vincic), St. Joseph’s Healthcare, Hamilton, ON, Canada; Department of Pathology (Dr. Lombard), El Camino Hospital, Palo Alto CA; (Broncus Technologies (Mr. Loomas), Mountain View, CA; and Asthmatx Inc. (Dr. Danek), Mountain View, CA.

Correspondence to: John D. Miller, MD, Head, Division of Thoracic Surgery, St. Joseph’s Healthcare, 50 Charlton Ave East, Hamilton, ON, Canada L8N 4A6; e-mail: jmiller@mcmaster.ca



Chest. 2005;127(6):1999-2006. doi:10.1378/chest.127.6.1999
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Published online

Background: Bronchial thermoplasty is a novel procedure being developed as a potential treatment for asthma. Experience with animal studies has enabled development of appropriate reliable equipment, definition of therapeutic parameters, and descriptions of tissue effects of treatment.

Study objectives: This study was undertaken to assess the feasibility and general safety of the application of bronchial thermoplasty in the human airway, and to determine if the reduction in airway smooth muscle seen in animal studies could be replicated.

Design: A prospective study.

Setting: Academic thoracic surgery center.

Participants: Nine patients scheduled to undergo lung resection for suspected or proven lung cancer.

Interventions: Bronchial thermoplasty was performed during routine preoperative bronchoscopy up to 3 weeks prior to prescheduled lung resection. Treatment was limited to areas of the segmental bronchi within the lobe that was to be removed. Treated airways were inspected via bronchoscopy at the time of thoracotomy, and were examined histologically following surgical resection.

Results: There were no adverse clinical effects of the procedure, including no new symptoms and no unscheduled visits for medical care. Treated sites exhibited slight redness and edema of the mucosa within 2 weeks of treatment, and appeared normal at later time points. There was narrowing (visually estimated at 25 to 50%) in four airways in two subjects examined at 5 days and 13 days after treatment, with excess mucus in two of these airways. There was no bronchoscopic evidence of scarring in any of the airways examined. Histologic examination showed a reduction in airway smooth muscle, and the extent of the treatment effect was confined to the airway wall and the immediate peribronchial region.

Conclusion: Application of bronchial thermoplasty to the human airway appears to be well tolerated. Treatment resulted in significant reduction of smooth muscle mass in the airways. Bronchial thermoplasty may provide therapeutic benefit in disease states such as asthma.

Figures in this Article

Asthma is an often debilitating chronic disease characterized by airway inflammation, bronchial hyperresponsiveness (excessive bronchoconstriction in response to stimuli), and excessive mucus production.1Many of the symptoms, and frequently the mortality of asthma, are due to airway narrowing caused by these factors.2Contraction of airway smooth muscle (ASM) almost always contributes to the airway narrowing that occurs during exacerbations of asthma and is a primary target of therapy with long- and short-acting bronchodilator drugs.3 The recognition of the role of inflammation in the pathogenesis of asthma has led to major advances in asthma control through development and use of anti-inflammatory medications, especially corticosteroids.3 However, despite the proven benefits of currently available medications, there are at least two needs that are not addressed: our ability to reduce the severity of bronchial hyperresponsiveness in certain patients is quite limited,34 and occasionally excessive airway narrowing occurs that is not responsive to conventional medications.3 Thus, a therapy that reduces the potential for bronchoconstriction should mitigate one of the major mechanisms of airflow obstruction during asthma exacerbations.

Bronchial thermoplasty (Alair System; Asthmatx; Mountain View, CA) is designed to reduce the contractile capacity of ASM, and thus airway hyperresponsiveness, by delivering controlled, therapeutic radiofrequency energy to the airway.5This delivery of radiofrequency energy coagulates bronchial tissue and reduces the amount of ASM in the airway wall. Therapeutic radiofrequency energy is widely used in a number of medical technologies, such as surgical diathermy or in the treatment of cardiac conduction defects.6High-energy radiofrequency technology has been employed in the lung as an ablative treatment for cancer.7 However, to our knowledge, the effect of the low-energy, controlled radiofrequency treatment presented here on the airway wall has not been studied in humans.

Extensive in vivo preclinical studies5 using a canine model have been conducted defining treatment parameters that enable the procedure to be performed safely; treatment resulted in significant reduction of airway responsiveness to local methacholine challenge using a dose of methacholine chloride solution shown to produce intense bronchoconstriction of untreated airways. Examination of tissue sections obtained at time points between 1 week and 3 years following treatment showed persistent reduction in the amount of ASM that correlated with observations of reduced responsiveness to local methacholine challenge at those sites. The objectives of this study were as follows: (1) to determine the safety of the bronchial thermoplasty in humans over the short term, (2) to examine the histologic effects of bronchial thermoplasty in the human airway, and (3) to determine if bronchial thermoplasty reduces ASM in the human airway as was observed in the canine model.

The protocol for this clinical study was approved by the Research Ethics Board of St. Joseph’s Healthcare, Hamilton, ON, and the Medical Devices Bureau, Therapeutic Products Division, of Health Canada. Informed consent was obtained from all subjects prior to their participation in the study.

Study Subjects

Subjects were recruited from patients referred to the Division of Thoracic Surgery, at St. Joseph’s Healthcare, Hamilton. Bronchial thermoplasty was performed during routine preoperative bronchoscopy in patients who were scheduled to undergo lung resection for suspected or proven lung cancer.

The Alair System

The instrumentation consists of a uniquely designed bronchial catheter (Alair Catheter Model ATS 2–5X1; Asthmatx, Inc.) and a radiofrequency generator (Alair Generator Model 115X1; Asthmatx, Inc.), along with a commercially available return electrode pad. The catheter fits through the 2-mm working channel of a standard 5-mm fiberoptic bronchoscope and has an expandable four-electrode basket with heating and temperature-sensing elements for feedback control at the distal end. The generator delivers 460 kHz, low-power, monopolar radiofrequency energy to the airway wall, using active feedback to maintain the target treatment temperature for 10 s. The generator is equipped with multiple pulmonary-specific algorithms to ensure precise energy delivery.8Figure 1 shows a bronchoscopic view of the deployed device in an airway.

Application of Bronchial Thermoplasty

Bronchial thermoplasty was performed during bronchoscopy on spontaneously breathing patients approximately 1 to 3 weeks prior to scheduled surgery. Patients received standard local anesthetic and sedative medications. Treatment was targeted to visually accessible airways in areas of the lung that were to be removed at surgery. Airways > 1 cm from known tumor sites or any visualized abnormality and the planned excision margin were targeted for treatment. This limited the number of sites available for treatment. Once a target site was chosen, the treatment catheter was advanced and the basket expanded so that the electrodes came in contact with the airway wall. The device was activated in carefully noted locations that could later be identified in the resected specimen. Each activation administered radiofrequency energy through a stationary catheter, and repeated adjacent deployments of the device were performed to achieve contiguous treatment over the length of targeted airway segments. The location of each treated segment was mapped using a diagram of the airway tree, and this was recorded along with observations of the appearance of the airway wall immediately following treatment.

All treated subjects were assessed at an office visit between the treatment and their scheduled surgery. All treated airways were observed bronchoscopically by one of the authors (J.D.M.) and videotaped immediately prior to surgical resection. All bronchoscopic observations, including presence of mucus, appearance of the epithelial lining, and airway caliber, along with any other remarkable findings were recorded.

Excised (treated and untreated) tissue from each patient was examined histologically. Lung specimens from the first two subjects were dissected prior to fixation, and tissue blocks were fixed in a solution of 10% formalin. Subsequent specimens were fixed by distension with 10% formalin solution to facilitate dissection. Two- to 3-millimeter-thick sections of treated airways were obtained serially along the length of the excised segment, and the orientation of tissue slices was preserved. Samples were also obtained proximal and distal to the treated areas, and slides were prepared with hematoxylin-eosin stain. Observations of the airway wall and surrounding tissue were recorded, with special attention to the epithelium, mucus glands and ducts, ASM, and cartilage.

A total of nine patients gave consent for their participation in the study between January and May 2000. Of these, eight patients were treated. Patient 4–07 was not treated because the geometry of airways in right upper lobe made it difficult to place the bronchoscope and catheter at the targeted sites. The treated patients included four male and four female white patients ranging in age from 52 to 78 years (mean age, 65 ± 8.3 years SD). Pertinent patient demographics are shown in Table 1 .

All bronchoscopies, including treatment with bronchial thermoplasty, were completed in < 12 min. A total of 12 activations at 55°C were performed in two patients, and 41 activations at 65°C were performed in six patients. The number of activations or treatment sites in the airways ranged from three to nine per patient. All patients tolerated the procedure well. All airways remained patent, and there were no adverse consequences as a result of treatment. All treated subjects proceeded with their surgery as scheduled. The time between bronchial thermoplasty and surgical resection ranged from 5 to 20 days. During this period, there were no occurrences of hemoptysis or clinical symptoms of excessive bronchial irritation following treatment. There were no instances of respiratory tract infection following treatment and no requirement for additional medications (ie, antibiotics, bronchodilators, anti-inflammatory medications) or supplemental oxygen. There were no additional or unscheduled visits of any study subject to health-care providers as a result of treatment. Table 2 summarizes the perioperative bronchoscopic observations on all treated patients.

All airways treated at 55°C appeared normal, and there were no remarkable observations. One patient (patient 4–05) treated at 65°C and viewed at the earliest time interval (5 days after treatment) had narrowing of three airways (visually estimated as a reduction in airway diameter of 25 to 50%) with retained mucus in two treated airways and narrowing alone in one other airway. One patient (patient 4–09) treated at 65°C and examined 13 days after treatment had possible narrowing and erythema of one treated airway. One subject (patient 4–04) treated at 65°C and examined 20 days after treatment had linear blanching in three airways. The airways of the remaining three patients treated at 65°C and viewed from 9 to 20 days after treatment had no remarkable observations.

Histology

Taking serial sections of treated airways 2- to 3-mm thick provided adequate sampling of the airways to observe the effect of treatment; this was confirmed by examining sections at 250-μm intervals in select tissue blocks. Sections for histologic review included areas of untreated tissue since samples were taken proximal and distal to the treated areas. Sections from treated areas revealed changes that were consistent with recent tissue injury. These findings were anticipated given our previous observations on the effects of bronchial thermoplasty on airways in animals.5 In the animal studies, there was a significant reduction in the amount of smooth muscle present in the airway wall. ASM changes were estimated as the percentage of the overall airway circumference occupied by “altered ASM,” which refers to changes to the native smooth muscle, including atrophy, necrosis, fibroblastic replacement, and/or absence of ASM. Table 3 summarizes the primary histologic findings seen in lung tissue sections from each patient.

The changes observed in airways treated at a setting of 55°C were subtle. Only focal amounts of altered smooth muscle were noted in these sections, occupying up to 5% of the airway circumference. The epithelium was largely normal (ranging from 68% normal for one patient to 98% in the other patient) and showed some minor signs of regeneration (< 2%). There were focal observations of metaplasia in the mucus ducts and glands in 4 of the 14 sections observed at this temperature. All perichondral vessels and cartilage appeared normal, and there were no observations of pneumonitis or focal necrosis in the immediate parenchymal region of any of these 14 sections.

In contrast, histologic changes were more noticeable in airways treated at 65°C. Most notably, there was a reduction in the ASM in sites treated at 65°C. While there was considerable variation among patients, on average approximately 50% of the circumference of the treated airway contained altered ASM (range, 16 to 71%). Epithelium was entirely normal in three patients (patients 4–06, 4–03, and 4–04), while in three other patients (patients 4–05, 4–08, and 4–09) there was variable amounts of sloughing (2 to 11%) and regenerative epithelium (14 to 65%). The sections of airways examined from the patient with the shortest follow-up (5 days) showed necrosis of mucus ducts and glands. All of the other sections exhibited metaplasia of the mucus ducts and glands. Three airway sections in two patients (patients 4–08 and 4–09) showed signs of thrombosis in the perichondral vessels. These vessels were 0.2 mm and 0.4 mm in diameter, respectively. Mild focal necrotic cartilage was seen in 14 of 64 sections (22%). Eleven of 64 sections (17%) exhibited new cartilage growth along the perichondrium, consistent with regenerative change.

Noninfectious pneumonitis in the peribronchial region was an expected inflammatory response to the delivery of therapeutic energy to the lungs. This pneumonitis was characterized histologically by a patchy accumulation of inflammatory cells, primarily lymphocytes in interstitial spaces and by variable numbers of fibroblasts. Pneumonitis was observed in 17 of 64 sections (27%) examined from six subjects treated at 65°C. Focal necrosis, which refers to heat-induced coagulative necrosis of parenchymal tissues, was noted in 16 of the 64 sections (25%) examined. There was no histologic evidence of infectious pneumonia in any patient. Any evidence of pneumonitis or focal necrosis in the parenchyma is listed in Table 3. Representative histologic findings seen at 20 days after treatment are shown in Figure 2 .

This study reports the first deployment in humans of the Alair System, a novel device for performing bronchial thermoplasty that involves the delivery of mild, controlled heat to the airway wall. The delivery of radiofrequency energy to the airway wall reduces the amount of ASM. We hypothesize that such a physical approach could be an effective treatment for asthma if it results in a diminished potential for airway narrowing due to bronchoconstriction.5Radiofrequency energy has been safely and effectively used in a variety of medical and surgical applications.67

The components of the Alair System and the parameters for treatment were developed and refined through extensive preclinical studies.5 One of the most important elements of the system is the target temperature and the duration of activations. Based on canine studies,5 the lower temperature of 55°C was expected to result in minor changes to the airway wall in this study, while the higher temperature of 65°C was expected to cause significant reduction in ASM. It was important to examine if the human airway wall would respond in similar fashion to the canine airway in terms of the extent of tissue effects of treatment, and the rate of resolution of changes.

The design of the study presented here allowed the examination of the effects of bronchial thermoplasty at intervals ranging from 5 to 20 days after treatment. Since treatment was confined to areas of the lung that were scheduled to be removed, the patients were not at risk for longer-term complications if there were unexpected or exaggerated effects of treatment in the human airway.

The eight patients treated with bronchial thermoplasty had no adverse events. There was no need to increase or change their medical therapy. In all cases, the planned surgery was carried out when scheduled, and there were no delays to operative management. The duration of the bronchoscopic procedure during which bronchial thermoplasty was performed in a limited area of the lung was longer by approximately 5 min than a routine procedure.

Since bronchial thermoplasty involves the application of controlled heat via a metal device contacting the airway wall, it is inevitable that the epithelial lining will be injured to some degree. The tissue reaction following thermal injury involves epithelial changes as well as variable amounts of edema and mucus accumulation, which may cause a temporary reduction in airway caliber. The observed changes of airway narrowing, mucus, and erythema seen here were milder than the observations from preclinical canine studies.5 In these animal studies, airway surface changes resolved between the first and sixth weeks after treatment (assessed by bronchoscopic examinations). Based on this experience, and the observation that the longer the interval between treatment and scheduled surgery, the less remarkable the airway abnormalities, it is likely that the superficial changes would have resolved had longer follow-up been available.

As seen in preclinical studies with the canine model,5 the changes observed in human airways treated at a setting of 55°C were subtle, with very limited evidence of the anticipated injury to smooth muscle. Treatments at a higher temperature (65°C) resulted in more of the desired tissue effect. While there was considerable variation among sites in this group, on average, the ASM was altered over approximately 50% of the circumference of the airway. This finding was consistent with our previous observations in dogs, where bronchial thermoplasty resulted in a significant reduction in the amount of smooth muscle present in the airway wall as early as 1 week after treatment, with no evidence of ASM regeneration at any point during the 3-year study period.5

Over the follow-up period of 5 to 20 days, a clear picture of epithelial repair was observed. Epithelial sloughing occurs after treatment, followed by regeneration and a return to normal respiratory epithelium. The epithelium in airway sections obtained with longer healing periods was intact and normal.

It is tempting to speculate that causing injury to mucus glands and ducts could prove beneficial to patients whose condition includes chronic overproduction of unnecessary mucus. However, although reduction in mucus glands was seen in this study, preclinical studies5 in dogs have shown postprocedure regeneration of mucus glands and ducts and return to normal appearance over an extended period. Thus, it seems unlikely that bronchial thermoplasty will cause a substantial persistent reduction of glandular elements.

The changes seen in this study in response to treatment were limited to the airway wall, its vessels, and a shallow parenchymal region adjacent to the airway. In particular, any observations of pneumonitis or coagulative necrosis of alveolar tissue were focal and limited to immediate peribronchial areas. These changes are similar to those seen in the canine model over a similar time period and, as in that model, would be expected to resolve at later time points without complications. Cartilage in treated sections was predominantly normal; any changes to cartilage observed were focal and often accompanied by signs of early regeneration. The limited effect of bronchial thermoplasty on cartilage, along with the discontinuous structure of the cartilage plates in the airways treated, makes adverse clinical consequences (such as bronchomalacia) from changes to cartilage unlikely. Earlier studies5 in dogs with longer follow-up showed similar focal changes of cartilage accompanied by regenerative cartilage, without adverse clinical consequence.

In the present study, only a limited amount of the airways were targeted for treatment. The experience with patient 4–07 is informative, as the lesion requiring resection was situated in the right upper lobe and only two subsegmental airways were suitable for deploying the treatment catheter. However, the geometry of the airways in the targeted section made placement of the bronchoscope and catheter difficult so the treatment could not be carried out.

While the patients treated in this study tolerated the procedure well, and showed the desired changes to ASM, they did not have asthma. It is possible that the airways of asthma patients would respond differently to treatment. Examining this question requires the study of bronchial thermoplasty in asthma patients. Furthermore, if bronchial thermoplasty were implemented as a treatment for asthma, then considerably more of the bronchial tree would need to be targeted. The logistics of such an intervention, especially the extent of treatment needed to affect ASM and thereby improve airflow, and the amount of airway that may be treated during a single bronchoscopic procedure, require further study.

ASM plays a central role in the major features of asthma, including airflow obstruction, chronic airway inflammation, and airway hyperresponsiveness, via its contractile function and release of various inflammatory mediators.911 Reduction in the amount of ASM is expected to be the primary mechanism for reducing future bronchoconstriction as a result of diminished natural variation in airway caliber and decreased responsiveness to bronchoconstricting stimuli. However, it is possible that other changes such as loss of continuity of muscle bands, stiffening of the airway wall as a result of limited fibrosis, or increased tethering by peribronchial parenchyma also contribute to reducing bronchoconstriction. It remains to be seen whether bronchial thermoplasty in humans will lead to sustained reduced airway responsiveness, as was documented in the canine studies. Additionally, it has yet to be determined whether this treatment effect could also help to reverse the hypertrophy and hyperplasia of ASM, and resulting thickening of airway walls, which are hallmarks of the extensive airway remodeling found in chronic asthma. Further studies in patients with asthma will be needed to answer these questions and to evaluate whether any clinically relevant improvements in airflow or attenuation of bronchoconstriction will result from bronchial thermoplasty.

We have demonstrated that bronchial thermoplasty is well tolerated in humans. There were no clinically significant adverse events associated with this treatment, either acutely or during follow-up periods of up to 20 days. There were no unexpected findings at histology, and the anticipated potentially beneficial effect of this treatment to reduce the amount of ASM in the bronchial wall was observed. These observations provide a strong impetus for further studies of bronchial thermoplasty as a novel therapy to treat human asthma.

Abbreviation: ASM = airway smooth muscle

Support was provided by Asthmatx, Inc. (formerly a part of Broncus Technologies, Inc.).

Figure Jump LinkFigure 1. Bronchoscopic visualization of the Alair System device placed in the airway immediately prior to bronchial thermoplasty.Grahic Jump Location
Table Graphic Jump Location
Table 1. Patient Baseline Demographics, Diagnosis, and Procedure Performed*
* 

RLL = right lower lobe; LLL = left lower lobe; RUL = right upper lobe; PVD = peripheral vascular disease; IHD = ischemic heart disease; CABG = coronary artery bypass grafting; GERD = gastroesophageal reflux disease; TB = tuberculosis; MI = myocardial infarction; M = male; F = female.

Table Graphic Jump Location
Table 2. Perioperative Bronchoscopic Observations by Treatment Temperature, Listed According to Length of Follow-up*
* 

NRO = no remarkable observation. See Table 1 for expansion of abbreviations.

 

Visually estimated as 25 to 50% reduction in airway diameter.

Table Graphic Jump Location
Table 3. Primary Histological Findings by Treatment Temperature, Listed According to Length of Follow-up
* 

Sampling by serial sectioning at 2- to 3-mm intervals.

 

Number of sections listed is for all sections with the finding noted anywhere on the section. Where findings are indicated as something other than “normal,” the amount of the abnormal finding on the section was variable, but typically was focal and limited so that these sections usually contained primarily normal findings.

Figure Jump LinkFigure 2. Representative section of an airway from patient 4–04 resected 20 days after treatment with bronchial thermoplasty at 65°C. Left: An airway in cross-section stained with hematoxylin-eosin. Right: Trichrome-stained section at higher magnification. ASM is largely absent to the left of the arrow. (Magnification: left panel, 40×; right panel, 400×.)Grahic Jump Location
 Global Initiative for Asthma. Global strategy for asthma management and prevention 2002 report. 2002; ,.:1 -7 National Institutes of Health National Heart, Lung, and Blood Institute. Bethesda, MD:.
 
 Global Initiative for Asthma. Global strategy for asthma management and prevention 2002 report. 2002; ,.:16 -18 National Institutes of Health, National Heart, Lung, and Blood Institute. Bethesda, MD:.
 
 Global Initiative for Asthma. Global strategy for asthma management and prevention 2002 report. 2002; ,.:102 -119 National Institutes of Health, National Heart, Lung, and Blood Institute. Bethesda, MD:.
 
ERS Task Force.. Difficult/therapy-resistant asthma.Eur Respir J1999;13,1198-1208. [PubMed]
 
Danek, CJ, Lombard, CM, Dungworth, DL, et al Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs.J Appl Physiol2004;97,1946-1953. [CrossRef] [PubMed]
 
Manolis, AS, Vassilikos, V, Maounis, TN, et al Radiofrequency ablation in pediatric and adult patients: comparative results.J Interv Card Electrophysiol2001;5,443-453. [CrossRef] [PubMed]
 
Bhatia, P Radiofrequency ablation of lung cancer [abstract]. Thorax. 2003;;58 ,.:771. [CrossRef]
 
Cox, G, Miller, J, Mitzner, W, et al Invited perspective: radiofrequency ablation of airway smooth muscle for sustained treatment of asthma; rationale and preliminary investigations.Eur Respir J2004;24,659-663. [CrossRef] [PubMed]
 
National Asthma Education and Prevention Program... Expert panel report 2: guidelines for the diagnosis and management of asthma. 1997; National Institutes of Health. Bethesda, MD: publication No. 97–4051.
 
James, AL, Paré, PD, Hogg, JC The mechanics of airway narrowing in asthma.Am Rev Respir Dis1989;139,242-246. [CrossRef] [PubMed]
 
Johnson, SR, Knox, AJ Synthetic functions of airway smooth muscle in asthma.Trends Pharmacol Sci1997;18,288-292. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Bronchoscopic visualization of the Alair System device placed in the airway immediately prior to bronchial thermoplasty.Grahic Jump Location
Figure Jump LinkFigure 2. Representative section of an airway from patient 4–04 resected 20 days after treatment with bronchial thermoplasty at 65°C. Left: An airway in cross-section stained with hematoxylin-eosin. Right: Trichrome-stained section at higher magnification. ASM is largely absent to the left of the arrow. (Magnification: left panel, 40×; right panel, 400×.)Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Patient Baseline Demographics, Diagnosis, and Procedure Performed*
* 

RLL = right lower lobe; LLL = left lower lobe; RUL = right upper lobe; PVD = peripheral vascular disease; IHD = ischemic heart disease; CABG = coronary artery bypass grafting; GERD = gastroesophageal reflux disease; TB = tuberculosis; MI = myocardial infarction; M = male; F = female.

Table Graphic Jump Location
Table 2. Perioperative Bronchoscopic Observations by Treatment Temperature, Listed According to Length of Follow-up*
* 

NRO = no remarkable observation. See Table 1 for expansion of abbreviations.

 

Visually estimated as 25 to 50% reduction in airway diameter.

Table Graphic Jump Location
Table 3. Primary Histological Findings by Treatment Temperature, Listed According to Length of Follow-up
* 

Sampling by serial sectioning at 2- to 3-mm intervals.

 

Number of sections listed is for all sections with the finding noted anywhere on the section. Where findings are indicated as something other than “normal,” the amount of the abnormal finding on the section was variable, but typically was focal and limited so that these sections usually contained primarily normal findings.

References

 Global Initiative for Asthma. Global strategy for asthma management and prevention 2002 report. 2002; ,.:1 -7 National Institutes of Health National Heart, Lung, and Blood Institute. Bethesda, MD:.
 
 Global Initiative for Asthma. Global strategy for asthma management and prevention 2002 report. 2002; ,.:16 -18 National Institutes of Health, National Heart, Lung, and Blood Institute. Bethesda, MD:.
 
 Global Initiative for Asthma. Global strategy for asthma management and prevention 2002 report. 2002; ,.:102 -119 National Institutes of Health, National Heart, Lung, and Blood Institute. Bethesda, MD:.
 
ERS Task Force.. Difficult/therapy-resistant asthma.Eur Respir J1999;13,1198-1208. [PubMed]
 
Danek, CJ, Lombard, CM, Dungworth, DL, et al Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs.J Appl Physiol2004;97,1946-1953. [CrossRef] [PubMed]
 
Manolis, AS, Vassilikos, V, Maounis, TN, et al Radiofrequency ablation in pediatric and adult patients: comparative results.J Interv Card Electrophysiol2001;5,443-453. [CrossRef] [PubMed]
 
Bhatia, P Radiofrequency ablation of lung cancer [abstract]. Thorax. 2003;;58 ,.:771. [CrossRef]
 
Cox, G, Miller, J, Mitzner, W, et al Invited perspective: radiofrequency ablation of airway smooth muscle for sustained treatment of asthma; rationale and preliminary investigations.Eur Respir J2004;24,659-663. [CrossRef] [PubMed]
 
National Asthma Education and Prevention Program... Expert panel report 2: guidelines for the diagnosis and management of asthma. 1997; National Institutes of Health. Bethesda, MD: publication No. 97–4051.
 
James, AL, Paré, PD, Hogg, JC The mechanics of airway narrowing in asthma.Am Rev Respir Dis1989;139,242-246. [CrossRef] [PubMed]
 
Johnson, SR, Knox, AJ Synthetic functions of airway smooth muscle in asthma.Trends Pharmacol Sci1997;18,288-292. [PubMed]
 
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