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* From the Departments of Thoracic Surgery (Drs. de Oliveira and Macedo-Neto), Pulmonology (Drs. John and Menna-Barreto), Radiology (Dr. Jungblut), Pathology (Dr. Prolla), and Anesthesiology (Dr. Fortis), Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Correspondence to: Hugo G. de Oliveira, MD, PhD, Department of Thoracic Surgery, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Sala 2050 MI CEP, 90035-004 Porto Alegre, RS, Brazil; e-mail: hugo{at}oliveira.com
Abstract
Objective: Describe the results of a 1- to 24-month follow-up of individuals undergoing transbronchoscopic placement of one-way valves.
Design: Longitudinal, noncomparative study.
Setting: University hospital.
Patients: Nineteen heterogeneous emphysema patients.
Measurements and results: Pulmonary function testing, imaging examination, and videobronchoscopy were performed at 1, 3, 6, 12, and 24 months after the insertion of one-way valves. Mean age was 67.63 ± 8.71 years, mean body mass index (BMI) was 24.02 ± 2.65, and mean exposure to smoking was 65.32 ± 27.46 pack-years (± SD). Baseline BODE index (BMI, degree of airflow obstruction and dyspnea, exercise capacity as measured by the 6-min walk test [6MWT]) was 7 to 10 in 10 patients (estimated 4-year mortality, 80%) and 5 to 6 in 9 patients (estimated 4-year mortality, 40%). Sixty-four valves were inserted. There was no procedure-related mortality. Nonsustained atelectasis was observed within 48 h in 2 of 12 patients with right upper lobe occlusion. Fifty-six bronchoscopic examinations were performed in 24 months. Granulomas not requiring treatment were the main complication. Mucus clogging the valve, mainly at 1 month, was easily cleaned. Eighteen patients completed the 1- and 3-month follow-ups, 14 patients completed the 6-month follow-up, 11 patients completed the 12-month follow-up, and 5 patients completed the 24-month follow-up. Improvement was observed in the 6MWT after 1 month (p = 0.028) and in the BODE index at 3 months (p = 0.002). FEV1 or FVC improvement 
12% or 150 mL was observed, respectively, in 4 of 18 patients and 8 of 18 patients at 1 month, 4 of 18 patients and 7 of 18 patients at 3 months, and in 3 of 14 patients and 5 of 14 patients at 6 months. After 24 months, one of five patients and three of five patients, respectively, retained an FEV1 and FVC change 12% or 150 mL. Significant improvement (decrease 4%) in the St. George Respiratory Questionnaire was observed at 3 months and 6 months in three of four domains.
Conclusion: Endobronchial valves are safe, but the criteria to measure improvement and to select patients should be refined. Atelectasis should be reconsidered as primary treatment goal.
Key Words: atelectasis • bronchoscopy • pulmonary emphysema • therapeutics
Lung volume reduction surgery (LVRS) and lung transplantation are still the treatments of choice for selected patients with advanced emphysema, a major worldwide cause of morbidity and mortality.1 However, because only a restricted group of patients are suited for these complex procedures, which are also associated with high mortality,2 there has been a search for nonsurgical alternatives to improve clinical status in emphysema. In 1966, Crenshaw3 described a procedure in which air-filled, space-consuming sections of the lung were obliterated by chemical stenosis of the lobar bronchus using a bronchoscope. More recently, other investigators4567891011 have reported favorable results with a novel treatment based on the same rationale proposed by Crenshaw: deflate emphysematous sections to allow expansion of the functional lung. In the procedure currently being tested, a one-way valve is implanted in the lung to reduce gas trapping and improve ventilation. This has been dubbed bronchoscopic lung volume reduction. However, in the present article it is proposed that a more appropriate designation would be transbronchoscopic pulmonary emphysema treatment (TPET), since many patients have been observed to improve even without static volume reduction, and also because bronchoscopy is but a means to deliver treatment.512
Short-term results suggest that TPET is safe and produces significant benefits for some patients, particularly those with the most severe disease (lower vital capacity and higher respiratory rate during peak exercise).5 In addition, studies have shown a low complication rate and improvement in gas transfer6 and in the median FEV1 after 4 weeks.7 Another study11 has reported significant improvements in pulmonary function, exercise tolerance, dyspnea scores, and health-related quality of life. That same study11 also points out that admission to the ICUs is not required with TPET, even in high-risk patients.
When considering these findings, it is important to underscore that the results published so far are based on a maximum follow-up of 1 month567 and 3 months (two studies).1011 In addition, follow-up bronchoscopic examinations have not been extensively documented. The objective of the present article is to describe the findings of a 1- to 24-month follow-up with detailed videobronchoscopic monitoring of patients with severe emphysema undergoing TPET for insertion of one-way endobronchial valves (EBVs).
Materials and Methods
This longitudinal, noncomparative study was designed for prospective selection of 20 patients with severe COPD for TPET. From January 2002 to September 2004 (33 months), 73 patients were referred to us by the COPD clinic at Hospital de Clinicas de Porto Alegre. Inclusion criteria were clinical and radiologic diagnoses of heterogeneous upper lobe emphysema, dyspnea during usual tasks in the presence of optimal clinical care, absence of other diseases that could cause dyspnea, not smoking for at least 6 months, diffusion capacity of the lung for carbon monoxide (DLCO) < 45%, residual volume (RV) > 130%, and not participating in another research project. Exclusion criteria were refusal to provide informed consent, respiratory infection requiring antibiotic treatment more than three times a year, chronic expectoration (suggestive of bronchial disease), and comorbidities associated with < 2 years of life expectancy. Twenty patients were selected. One patient died 2 weeks before TPET (pneumonia and respiratory arrest). Thus, 19 patients were treated. All patients were receiving the best possible clinical treatment and had undergone a basic rehabilitation program before entering the study. No changes were made in medication during the study period. The study protocol was approved by the hospital Research Ethics Committee (institutional review board equivalent).
Protocol
After clinical assessment by a pulmonologist, surgeon, radiologist, and anesthesiologist, patients underwent blood collection, pulmonary function testing, 6-min walk testing (6MWT), chest radiography, high-resolution CT, and scintigraphy. The 6MWT followed established guidelines,13 except that patients walked a 27-m distance and were monitored while walking using digital oximetry. Starting with the seventh patient, the 3-month version of the St. George Respiratory Questionnaire (SGRQ) validated for Brazilian Portuguese1415 was applied. The responses to the 50-item questionnaire can be aggregated into an overall score and three subdomains (symptoms, activity, and impact), and the results are expressed as a percentage (0% = best score and 100% = worst score). An alteration 4% in SGRQ results following an intervention indicates a significant change in quality of life.14 Severity of disease was determined based on PCO2 measurements (severe, > 48 mm Hg) and on a multidimensional grading system that takes into consideration the BODE index (body mass index [BMI], degree of airflow obstruction and dyspnea, and exercise capacity measured by the 6MWT).16
Procedure
Topical anesthesia was performed with 1% lidocaine. Anesthesia was achieved with continuous infusion of dexmedetomidine (1 µg/kg/min for 10 min; 0.5 to 0.7 µg/kg/h plus low doses of propofol and remifentanil for maintenance). Patients were kept on spontaneous ventilation with a fraction of inspired oxygen of 1.0. A flexible bronchoscope (model 1T30; Olympus; Tokyo, Japan) with a 2.8-mm channel was used. Images were captured using a videobronchoscope (model VB1830; Pentax; Montvale, NJ).
Airway diameter was measured (Fig 1 ) for determination of valve size. The procedure with first-generation valves was performed as described by Toma et al.17 After the adoption of transcopic (TS) valves (TS-EBVs), a guide wire was no longer required, since this valve model is introduced directly through the flexible bronchoscope channel (Fig 2 ).
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Statistical Analysis
Statistical software (version 12.0; SPSS; Chicago, IL) was used for data analysis. Continuous variables were expressed as mean ± SD. Student t test was used to compare means. Dichotomic variables were described based on their distribution, with comparison of frequency.18
Results
Between April 2002 and October 2004 (30 months), 64 valves were inserted (26 EBVs and 38 TS-EBVs) in the lungs of 19 patients (13 men, 68.42%). Treatment was reversed in one patient (all valves removed), who was excluded from the analysis. Table 1 summarizes the demographic characteristics, smoking history, comorbidities, and BODE index of these individuals. Mean age was 67.63 ± 8.71 years (range, 51 to 88 years). The mean BMI was 24.02 ± 2.65 (range, 19.14 to 28.89). Mean exposure to smoking was 65.32 ± 27.46 pack-years (range, 30 to 120 pack-years). In terms of severity of disease, five patients had PCO2 > 48 mm Hg at baseline. The baseline BODE index16 was 7 to 10 in 10 patients and 5 to 6 in 9 patients (80% estimated mortality in 4 years and 40% in 4 years, respectively).
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Complications
Pneumothorax developed in one patient 48 h after the procedure (Table 2). Three days after chest drainage, the lung had not re-expanded and the EBV inserted in B3 of the RUL was removed. The pneumothorax then resolved, and the patient was discharged on the ninth postoperative day.
Another patient presented with bronchial hypersecretion with worsening of clinical status. The EBVs inserted in B1 and B2 of the RUL were removed 12 days after the procedure. The patient was discharged on the same day. However, due to the persistence of respiratory dysfunction and bronchial hypersecretion, the EBV inserted in the B1 + 2 segment of the left upper lobe (LUL) was also removed 29 days after the procedure in an outpatient setting. Therefore, treatment was reversed in this patient.
A third patient remained hospitalized for 4 days due to bronchospasm (TS-EBV). Finally, atelectasis and pneumothorax involving the RUL developed in another patient with an EBV. This was attributed to negative pleural pressure (ex-vacuum pneumothorax). Treatment was conservative, and the patient was discharged on the fifth postoperative day.
Bronchoscopic Follow-up
From a maximum number of 74 possible bronchoscopic examinations, 56 were performed in this study (75.7%). Seven bronchoscopic examinations were not performed because of treatment reversal (one patient), death (one patient, due to a massive digestive hemorrhage caused by a peptic ulcer), and a broken leg (one patient). In the other patients, bronchoscopy was not performed for logistical reasons, and the patients were well enough to forgo the examination. Figures 3, 4
show several aspects of implanted EBVs and TS-EBVs at 1, 6, and 24 months.
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4%) in the SGRQ was observed at 3 months and 6 months in three of four domains.
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150 mL at 24 months. Discussion
The present study reports the results of a 1- to 24-month follow-up of emphysema patients submitted to TPET. Our study suggests that the treatment of severe heterogeneous emphysema predominantly affecting the upper lobes using TPET/EBV is a safe, potentially reversible procedure associated with a low complication rate and no mortality, which promoted a transient but significant improvement in quality of life as measured by the SGRQ and the multidimensional BODE index. We also provide important information concerning the behavior of one-way valves after 24 months, an aspect that has not yet been discussed in the literature.
In comparison to previous cohorts, our patients are among the oldest and most severely ill.5671011 This may account for the decreased rate of improvement with time, which could be reflecting the continuous progression of emphysema and the natural decline of pulmonary function. A similar behavior has been reported for LVRS, that is, decline after 18 months to 2 years.2 Therefore, it is possible that the positive short-term results reported by other groups will decline over time, leading to the question of whether the insertion of additional valves is warranted and at what intervals, and also to the issue of how to select the best candidates for TPET. In any case, only large randomized controlled trials will be able to address these questions.
It is still difficult to compare the results of TPET with those of LVRS. First of all, the largest TPET patient series5671011 so far have included a maximum of 20 patients; second, the rationale supporting TPET has entailed the selection of the most severely ill patients (SGRQ activity score of 86.20 in the present study), some of them too ill to undergo surgery. However, a previous study21 with 250 LVRS patients reports air leaks > 7 days as the most common complication, with 7.2% of the patients requiring reintubation and mechanical ventilation after the surgery and an in-hospital mortality of 4.8%. This contrasts with the present study, in which not even the procedure itself required mechanical ventilation, and in which the procedure-associated mortality was equal to zero. However, Ciccone et al21 conclude that, in selected patients, the benefits of LVRS appear to last for at least 5 years. Perhaps we should view LVRS and TPET as complementary procedures, each of which is the best choice for carefully selected emphysema patients.
In the present study, atelectasis developed in only 2 of our 19 patients in the first couple of days after the procedure. In both cases, atelectasis was associated with the development of pneumothoraces and was later reversed. At the end of the 4-week follow-up described by Toma et al,7 the lung had collapsed in four of eight patients. Snell et al,6 who performed occlusion of the RUL in all the patients, observed segment atelectasis in only one patient, lasting until the 1-month follow-up. Yim et al11 describe collapse of > 75% in four lobes at 1 month and 3 months. The investigators in these and other studies510 are unanimous in stating that TPET is still beneficial even in the absence of atelectasis. Hopkinson et al5 proposed that the mechanism underlying such improvement is the decrease in dynamic hyperinflation promoted by one-way EBVs, which is best reflected by exercise capacity. Thus, it could be that in addition to atelectasis, the treatment goal in TPET should be the control and prevention of dynamic hyperinflation. Our team has already collected data on the usefulness of detecting dynamic hyperinflation to select patients for TPET. Also, the findings of previous studies679101122 and the results of our series demonstrate the presence of prominent collateral ventilation in patients with severe emphysema, which could prevent atelectasis in occluded segments.23 Such a hypothesis is supported by the persistent airflow through the one-way valves observed during videobronchoscopic follow-up as late as 24 months.
The use of the BODE index to assess severity of the disease is a useful tool for emphysema patients. As stated by Celli et al,16 the grade of severity is often determined in COPD using the FEV1 alone. However, this index does not account for other systemic manifestations of COPD. Taking into consideration the hypothesis that improvement in emphysema patients treated with EBV is closely related to the control of dynamic hyperinflation and to an increase in exercise capacity, the BODE, a multidimensional index that contemplates BMI, the degree of airflow obstruction and dyspnea, and exercise capacity measured by the 6MWT, could provide important information for patient selection and become a means to define improvement in valved patients.
In our study, not all improvement was translated into statistical significance, but this could be reflecting the progression of the disease in patients with low life expectancy. On the other hand, although statistical significance was observed in the mean 6MWT after 1 month, that improvement did not meet the minimal clinically significant change of 54 m for the group as a whole.1920 As stated by Solvay et al,19 however, the cutoff point of 54 m could be smaller for more severely disabled patients. The population studied by Redelmeier et al20 to establish this minimal clinically significant change had an average 6MWT distance of 371 m, vs 264.2 ± 110.9 m in the present study. Kadikar et al24 found that walking < 300 m in 6MWT was a useful indicator of when to prioritize patients for lung transplantation. In that sense, the mean improvement we recorded after 1 month could have been truly significant for this specific population. We also observed that three of the five patients who completed the 24-month follow-up had improved FVC (> 12% and 150 mL).
On average, 3.35 valves were inserted in each of our patients. Using a higher number of valves may increase the chance of reducing lung volume; however, taking into consideration the principle of restricting the insertion of valves to nondependent segments, not more than five valves are usually necessary. Only two of our patients received five valves. In the series of 10 patients treated by Snell et al,6 4 to 11 valves were inserted per patient. Toma et al7 inserted 3.12 valves per patient, and Yim et al11 inserted on average 4.14 valves in 21 patients.
Occlusion of the RUL can be achieved with three to four valves. Among our 19 patients, RUL occlusion was achieved in 12 patients using 40 valves; in 4 patients, two valves were required to occlude B3. This occurred because in these patients B3 was too short to accommodate a valve, and so two valves had to be inserted in subsegments. Bilateral TPET was performed whenever a patient with very severe disease had reasonably preserved perfusion in any segment in both upper lobes; thus, we occluded the most affected segments bilaterally. In two patients, RUL occlusion was performed in association with LUL treatment in order to achieve the best possible results. The best strategy concerning occlusion and the optimal number of valves has yet to be defined, which may have to be done on an individual basis.
A novel aspect of the present study was the performance of 56 follow-up bronchoscopic examinations in 19 patients, in contrast with previous studies.5671011 This careful monitoring revealed, for example, that some valves were obstructed by mucus at 1 month; this was corrected with saline solution washing and aspiration. This finding was increasingly less frequent in subsequent evaluations, and in general the valves were functional after 2 years.
The main complication we observed on bronchoscopy was the presence of small granulomas around the valve, without functional compromise. No treatment was required; and with the use of TS-EBVs, the occurrence of granulomas decreased dramatically, possibly because of the shape of this valve model and the insertion technique, which causes less mucosal trauma. The performance of bronchoscopic examinations was also important to increase experience and to determine valve positioning in subsequent patients. Among 19 patients in a maximum of 24 months, only two valves were displaced, and only one of these had to be removed. It should also be noted that the valves performed well in patients in whom pneumonia developed in nonvalved segments even in the presence of mechanical ventilation.
In conclusion, the use of TPET and EBVs, especially TS valves, is safe and easily reversible. Further studies should continue to focus on the mechanisms by which TPET contributes to the improvement of emphysema patients and also on the role of earlier treatment and insertion of additional valves. Randomized controlled clinical trials are still required to determine all the benefits of TPET for this progressive disease.
Acknowledgements
We are grateful for the technical assistance provided by Brigitta Hund Prates, Ligia T. M. dos Santos, Julio Cesar S. Salvador, and Anara Maria Cabral Santos; and for the extremely useful suggestions made by Professors Patrícia Rieken Macedo Rocco (Universidade Federal do Rio de Janeiro), Eduardo Bethlem (UniRio), Wilson Leite Pedreira Junior (Universidade de São Paulo), Carlos Antonio Mascia Gottschall (Universidade Federal do Rio Grande do Sul [UFRGS]), Paulo de Tarso Roth Dalcin (UFRGS), Alvaro Furtado Porto Alegre (UFRGS) and Jose Roberto Goldim (Hospital de Clínicas de Porto Alegre). We also thank the State of Rio Grande do Sul Medical Foundation (accredited by the Brazilian Department of Science and Technology and by the Brazilian Department of Education) for the management of all financial resources.
Footnotes
Abbreviations: 6MWT = 6-min walk test; BMI = body mass index; BODE = body mass index, degree of airflow obstruction and dyspnea, exercise capacity as measured by the 6-min walk test; DLCO = diffusion capacity of the lung for carbon monoxide; EBV = endobronchial valves; LUL = left upper lobe; LVRS = lung volume reduction surgery; RUL = right upper lobe; RV = residual volume; SGRQ = St. George Respiratory Questionnaire; TPET = transbronchoscopic pulmonary emphysema treatment; TS = transcopic
This work was carried out at Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Emphasys Medical provided valves free of charge, as well as a grant to the Medical Foundation of Rio Grande do Sul, which has partially funded the salary of Drs. de Oliveira and Macedo-Neto. The company had no part in the analysis of data or in the preparation of this manuscript. At the presubmission stage, Emphasys Medical reviewed the manuscript for factual errors and to ensure that there were no patentable disclosures that they had not already had an opportunity to cover or that were considered proprietary. This review led to no changes in the manuscript.
Received for publication August 16, 2005. Accepted for publication January 14, 2006.
References
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