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Ann Thorac Surg 2009;88:1993-1998. doi:10.1016/j.athoracsur.2009.06.038
© 2009 The Society of Thoracic Surgeons
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New Technology

A Feasibility and Safety Study of Bronchoscopic Thermal Vapor Ablation: A Novel Emphysema Therapy

Gregory I. Snell, MDa,*, Peter Hopkins, MBBSb, Glen Westall, PhDa, Lynda Holsworth, BNursa, Anne Carle, RNb, Trevor J. Williams, MDa

a Alfred Hospital and Monash University, Melbourne, Australia
b Prince Charles Hospital, Brisbane, Australia

Accepted for publication June 12, 2009.

* Address correspondence to Dr Snell, Alfred Hospital, 5th Flr, Commercial Rd, Melbourne, NSW 3004, Australia (Email: g.snell{at}alfred.org.au).


   Abstract
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Purpose: This study reports the feasibility and safety of novel second-generation bronchoscopic lung volume reduction (LVR) technology, independent of collateral ventilation.

Description: Eleven patients with severe heterogeneous emphysema underwent unilateral bronchoscopic application of vapor thermal energy (mean 4.9 cal/g alveolar tissue; range, 3 to 7.5) with bronchial thermal vapor ablation (BTVA) aiming to induce a controlled inflammatory airway and parenchymal response with resultant LVR.

Evaluation: Nine women and 2 men, with a mean age of 61 years, forced expiratory volume in 1 second (FEV1) of 0.77 ± 0.17 L (32% predicted), residual volume (RV) of 4.1 ± 0.9 L (219% predicted), and gas transfer of 7.8 ± 2.2 (34% predicted), underwent unilateral upper lobe treatments. Serious adverse events in 5 included probable bacterial pneumonia and exacerbations of airways disease in 2. Although no important FEV1 or RV changes occurred during 6 months of follow-up, gas transfer improved, 16% to 9.0% ± 2.1% (38% predicted), the Medical Research Council Dyspnoea Score improved from 2.6 to 2.1, and the St. George Respiratory Questionnaire Total Score improved from 64.4 at baseline to 49.1.

Conclusions: These preliminary data on unilateral BTVA therapy confirm feasibility, an acceptable safety profile, and the potential for efficacy.


   Introduction
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Surgical lung volume reduction (LVR) is now an established palliative therapy for selected patients with severe emphysema, with the potential to provide symptomatic benefit when other treatment options have been exhausted [1]. A number of randomized studies have demonstrated that lung function, exercise capacity, and quality of life improve with surgical LVR [1, 2]. Despite the most careful case selection, however, significant morbidity and death have inevitably been observed [1, 2].

A number of approaches have subsequently been developed that aim to achieve LVR but minimize morbidity and death. Attempts at bronchoscopic LVR (BLVR) using a variety of prostheses, valves, stents, and glues have been widely trialed, and there is real potential to achieve a satisfactory safety profile and useful efficacy [3–5]. In a recent large animal model of emphysema, BLVR was achieved by inducing an inflammatory response in airways and lung parenchyma by the bronchoscopic introduction of heated water vapor (steam) into segmental airways [6].

The current study describes an assessment of the new technology of bronchial thermal vapor ablation (BTVA) BLVR procedures (Uptake Medical Corporation, Seattle, WA) in patients, with the aim of establishing the feasibility and safety of the BTVA procedure for LVR in patients with heterogeneous emphysema This simple approach has the theoretic advantages of avoiding surgical chest incursion, avoiding the implantation of foreign-body prostheses, and is independent of the presence of interlobar collateral ventilation, which is a particular problem for airway valves and plugs [7].


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Patient Selection Criteria
Eleven patients on optimal medical management for severe heterogeneous upper lobe emphysema underwent unilateral upper lobe BLVR. All patients were assessed according to standard acceptance criteria for surgical LVR and BLVR [1–3]. Key inclusion and exclusion criteria are outlined in Table 1. The study was approved by Alfred Hospital and Prince Charles Hospital Institutional Ethics Committees.


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  		Table 1 Key Study Inclusion and Exclusion Criteria
 
Device Description
The Uptake Medical BTVA treatment system consists of a multiuse generator with a fiberoptic bronchoscopic catheter attachment that is used to deliver heated water vapor (steam) to a target lobar segment. The vapor generator is an electronically controlled pressure vessel that generates and delivers precise amounts of steam, with the flow and pressure settings determining the dose of steam (Fig 1). The nonreusable 2-mm vapor catheter comprises a flexible shaft and distal occlusion balloon.


Figure 1
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  		Fig 1. Uptake Medical bronchial thermal vapor ablation generator and catheter (Uptake Medical Corporation, Seattle, WA).

 
Dosing Rationale
The system was initially examined in a series of seven preclinical dose-ranging studies in 71 animals, including 30 treated with papain to produce a model of emphysema [6]. On the basis of the risk/benefit profile from this work, a conservative unilateral dose of 5 cal/g of lung tissue was chosen for this human study. The tissue weight for each segmental target was interpolated from chest computed tomography (CT)-derived density and volume analysis (VIDA Diagnostics Inc, Iowa City, IA) [8], and this was correlated with vapor generator output data to derive the specific treatment time for each segment.


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Procedure Description
Anesthesia was according to local standard techniques using a large (size 9 or 10) single-lumen endotracheal tube or laryngeal mask. Two operators performed the procedure, one controlled the fiberoptic bronchoscope (Olympus BF type 1T180, Tokyo, Japan) and the other controlled and manipulated the catheter system and handpiece. The vapor catheter was then introduced into the target segmental airway, the occlusion balloon was inflated (0.5 to 1.5 mL) to create a seal, and the desired dose of steam was delivered. Subsequent segments were treated after a mandatory 5-minute wait until all lobar segments selected for treatment had been dealt with.

All patients received postoperative prophylactic antibiotics, inhaled bronchodilators, and supplemental oxygen as determined by arterial oxygen saturations.

Study End Points
The primary end point was to assess all adverse events secondary to the BTVA treatment procedure during 6 months of follow-up. Serious adverse events (SAEs) were defined as fatal or life-threatening events, an event requiring unexpected hospitalization, or an event resulting in permanent disability. The secondary end point was to consider preliminary indicators of efficacy by radiologic criteria, improvements in quality-of-life, pulmonary function testing, or 6-minute walk (6MW) distance.

Follow-Up
A chest roentgenogram, arterial blood gas analysis, a blood panel, and an electrocardiogram (ECG) were performed postoperatively. Subsequent clinical evaluation and blood work followed at weekly intervals for the first 3 weeks. The clinical evaluation at week 4, and then at 3 and 6 months after the procedure included Medical Research Council (MRC) Dyspnoea Scale and the St George Respiratory Questionnaire (SGRQ), pulmonary function testing, and gas transfer factor (diffusion capacity of the lung for carbon monoxide [DLCO]), arterial blood gases, 6MW distance, and CT chest scanning. At 6 months, bronchoscopy and ECG were performed.

Statistical Analysis
This small safety study was generally not powered to detect statistical differences in efficacy end points, although for interest, t test comparisons have been included in Table 2. Data are presented as mean (range) to summarize responses. Pearson correlation coefficients are used to demonstrate correlations.


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  		Table 2 Respiratory Function Test Outcomes
 

   Clinical Experience
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Patient demographics and base line characteristics are outlined in Table 3.


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  		Table 3 Patient Demographics and Baseline Characteristics
 
Procedure
The procedure itself was safe, technically feasible, and well tolerated. The mean total procedure time was 22 minutes (range, 16 to 31 minutes) to treat unilaterally 9 right upper lobes and 2 left upper lobes (32 treatments, targeting 33 segments in total). The BTVA-treated areas represented a mean of 27% (range, 21% to 41%) of the total lung volume as calculated from the chest CT. The mean dose of vapor delivered was 4.9 cal/g (range, 3.0 to 7.5 cal/g) taking a mean treatment time of 4.6 seconds (range, 3 to 8 seconds). The mean length of hospital stay was 1.7 days (range, 1 to 5 days).

Adverse Events
No intraoperative adverse events were noted. Nonserious postprocedural events, consistent with the anticipated effects of anesthesia and bronchoscopy, were noted in 10 of 11 patients. The commonest included nausea, cough, mild to moderate hemoptysis, and transient fatigue. Seven exacerbations of chronic obstructive pulmonary disease (COPD) were reported in 4 patients. Three were judged infectious and 4 noninfectious by the investigators. Two bouts of pneumonitis were reported, one probable infection-based pneumonitis on day 6 and one noninfectious inflammatory pneumonitis on day 4. There were five SAE, all requiring hospitalization for a mean of 4.6 days (range, 2 to 8 days), comprising COPD exacerbations in 2 patients, and pneumonitis, anxiety, and atrial tachycardia in 1 patient each. All nonserious and SAE resolved without sequelae.

CT Scan Outcomes
Overall, little overt volume reduction was seen in the targeted segments, with only 3 of 11 showing macroscopic change at 6 months. Chest CT-derived volume analyses [8] noted a change in target lobar volume from 1497 mL (range, 819 to 2004 mL) at baseline to 1235 mL (range, 409 to 2001 mL) at 6 months, a mean decrease of 16% (range, –75% to 1%; Fig 2). The best example of CT volume loss is shown in Figure 3. The extent of the volume loss in the BTVA target area correlated with the improvement in SGRQ (r = 0.83). Although there were overall no significant changes in CT-calculated total lung volume, the nontreated adjacent upper lobe remained of similar volume (2% increase, range, –11% to 13%) and the nontreated adjacent lower lobe increased in volume by 24% (range, 1% to 141%).


Figure 2
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  		Fig 2. Individual changes in treated lobar volume, comparing baseline (0 months), 3 months, and 6 months in 11 patients.

 

Figure 3
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  		Fig 3. Chest computed tomography transverse slice example of left-sided unilateral bronchial thermal vapor ablation demonstrates loss of the target left upper lobe volume at (A) baseline, (B) 3 months, and (C) 6 months.

 
Narrowed or occluded segmental or subsegmental airways were seen in all patients, with changes evident in 31 of 33 segmental airways treated.

Bronchoscopic Outcomes
Review bronchoscopy at 6 months showed no airway inflammatory changes or granulation tissue. Nine of 33 treated segmental airways were noted to have localized pallor and 14 had at least some visible tapering obstruction of a main segmental or subsegmental airway.

MRC Dyspnoea Score and SGRQ Scores
Overall, compared with baseline, there were potentially clinically relevant improvements in the MRC Dyspnoea Score from 2.6 to 2.1 at 6 months. The SGRQ Scores mirrored this with a Total Score improvement (decrease in score) from 64.4 (range, 37 to 84) at baseline to 49.1 (range, 32 to 64) at 6 months (Fig 4), a mean fall of 15.3 units. The SGRQ Impact Score, Activity Score, and Symptom Score, all contributed to the overall Total Score result with changes of –16.3 (range, –53 to 3), –21.0 (range, –72 to 22), and –10.1 (range, –43 to 30), respectively.


Figure 4
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  		Fig 4. Individual changes in St. George Respiratory Questionnaire Total Sccores comparing baseline (0 months) and 6 months.

 
Respiratory Function Test Outcomes
Overall, compared with the baseline measurements, there were no dramatic apparent differences in FEV1, forced vital capacity (FVC), residual volume (RV), and 6MW distance at 6 months (Table 2). However, there were individuals who did respond and others who did not (Fig 5). DLCO showed a potentially clinically significant 16% improvement from 7.7 (range, 4.5 to 10.5) to 9.0 (range, 5.1 to 12.1; p = 0.01). The extent of the improvement in DLCO correlated with the improvement in SGRQ (r = 0.43).


Figure 5
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  		Fig 5. Individual forced expiratory volume in 1 second (FEV1), residual volume (RV), and diffusion capacity of the lung for carbon monoxide (DLCO) results at baseline (0 months) and at 1, 3, and 6 months in 11 patients.

 

   Comment
Top
 Abstract
 Introduction
 Technology
 Technique
 Clinical Experience
 Comment
Disclosures and Freedom of...
 Footnotes
 References
 
This assessment demonstrates the technical feasibility and safety of applying thermal energy unilaterally to targeted segmental airways in patients with severe heterogeneous emphysema. The inflammatory response induced by the steam has effects on the proximal airways and distal lung parenchyma. The adverse effects reflected this, with relatively minor airway-predominant COPD exacerbations and two potentially more important bouts of pneumonitis. CT scan analyses demonstrated loss of volume in the target treated lobe and narrowing or obstruction of treated airways. Efficacy was evident in terms of improved quality of life and an improvement in gas transfer. As such, this study extends the previously published BLVR experience with valves, stents, and glues [3–5], providing a platform for subsequent therapeutic approaches using this novel technology.

Consistent with the prior animal work [6], the inflammatory response in humans generated by the vapor therapy appears to have several phases, with an initial airway response manifest by bronchoscopically visible airway blanching and immediate postoperative chest roentgenogram changes likely representing mild alveolar edema. Between day 7 and day 14, these effects typically contributed to mild nonspecific airway symptoms. Beyond day 14, healing processes saw the inflammatory response and any related symptoms settle. Ultimately, 42% of treated segmental airways were least partially occluded bronchoscopically and 94% were at least partially occluded on CT at 6 months. There was also some volume loss in the treated lobe in 9 of 11 patients (Fig 2 and 3) at the 6-month CT scan analyses.

Although most other BLVR techniques do not create this inflammatory milieu up-front, a major strength of the BTVA approach is that this targeted response does rapidly settle and it is an initially sterilizing therapy, with the absence of a retained foreign body.

The BTVA procedure described here shows efficacy in the form of improved MRC Dyspnoea Score and SGRQ quality-of-life scores as well as some potentially useful trends in lung function (Fig 4, Table 3). The mean change in SGRQ of 15.3 units is beyond that described for other BLVR techniques (ranging, –1.2 to –11.0 units [3–5]) and parallels the 14.4-unit change seen in the National Emphysema Treatment Trial surgical LVR study [9]. The improvement in DLCO represents improved efficiency in gas exchange either by a reduction in dead space ventilation or net recruitment of functional alveolar capillary membrane. This latter effect has been seen in BLVR and surgical LVR previously [3, 10]. The absence of improvements in overall lung function indicators may at least partially reflect the problems of a unilateral approach to a more extensive problem. The overall lack of change in CT lung volume, despite a reduction in the volume of the treated lung, is explained by the expansion of the adjacent nontreated lower lobes.

As a phase I study, the current report describes a conservative unilateral low-dose (5 cal thermal vapor energy/g tissue) approach to BLVR. The technique could potentially be applied bilaterally, as either a single procedure or staged procedure of individual lobes or even segments.

In conclusion, thermal energy can feasibly and safely be applied to human emphysematous lung with the potential for LVR and subsequent improvement in quality of life. The flexibility of the staging and variability of the dosing regimen holds promise and justifies further human clinical trials of this simple, second-generation BLVR technology.


   Disclosures and Freedom of Investigation
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Financial, technical, and equipment support was provided from the sponsor Uptake Medical Corp, Seattle, Washington, to undertake this study. The authors had full control of the study design, methods used, outcome parameters, data analysis and the production of this report.


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Disclaimer The Society of Thoracic Surgeons, the Southern Thoracic Surgical Association, and The Annals of Thoracic Surgery neither endorse nor discourage use of the new technology described in this article.


   References
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  1. Stirling GR, Babidge WJ, Peacock MJ, et al. Lung volume reduction surgery in emphysema: a systematic review Ann Thorac Surg 2001;72:641-648.[Abstract/Free Full Text]
  2. Geddes D, Davies M, Koyama H, et al. Effect of lung-volume-reduction surgery in patients with severe emphysema N Engl J Med 2000;343:239-245.[Medline]
  3. Snell GI, Holsworth L, Borrill ZL, et al. The potential for bronchoscopic lung volume reduction using bronchial prostheses: a pilot study Chest 2003;124:1073-1080.[Abstract/Free Full Text]
  4. Cardoso PFG, Snell GI, Hopkins P, et al. Clinical application of airway bypass utilizing paclitaxel-eluting stents: early results J Thorac Cardiovasc Surg 2007;134:974-978.[Abstract/Free Full Text]
  5. Ingenito EP, Wood DE, Utz JP. Bronchoscopic lung volume reduction in severe emphysema Proc Am Thorac Soc 2008;5:454-460.[Abstract/Free Full Text]
  6. Emery MJ, Couteil LL, Coad JB, et al. Lung volume reduction(LVR) by bronchoscopic thermal vapour ablation (BTVA)(abstract) Chest 2007;132:439b.
  7. Higuchi T, Reed A, Oto T, et al. Relation of interlobar collaterals to radiological heterogeneity in severe emphysema Thorax 2006;61:409-413.[Abstract/Free Full Text]
  8. Tschirren J, Hoffman EA, McLennan G, et al. Medical imaging IEEE Trans 2005;24:1529-1539.
  9. National Emphysema Treatment Trial Research Group A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema New Engl J Med 2003;348:2059-2073.[Medline]
  10. Sciurba FC, Rogers RM, Keenan RJ, et al. Improvements in pulmonary function and elastic recoil after lung-reduction surgery for diffuse emphysema N Engl J Med 1996;334:1095-1099.[Medline]



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